PPDS DEPARTEMEN PULMONOLOGI DAN ILMU KEDOKTERAN RESPIRASI FKUI – RS PERSAHABATAN JUNI 2011

HARRISON’S PRACTICES ASSOCIATED WITH PULMONOLGY

DOWNLOAD BY ISMAEL AND ARRANGED BY EFRIADI

Harrison's Practice

1. Tuberculosis

Definition

Caused by the Mycobacterium tuberculosis complex Usually affects the lungs, but affects other organs in one-third of cases Primary tuberculosis (TB)

o Acute clinical illness directly following infection Latent TB

o Evidence of exposure without active disease

o Possible persistence of dormant bacilli for years o Noninfectious

o Risk of secondary TB Secondary TB

o Also known as adult-type TB or reactivation TB o Reactivation of previously acquired infection

o Caused by previously dormant bacilli o Often infectious

Epidemiology

Incidence of active TB o 8.8 million new cases worldwide in 2005

95% of cases occur in developing countries. Asia (4.9 million)

Africa (2.6 million) Middle East (0.6 million)

Latin America (0.4 million) o 1.6 million deaths in 2005

98% in developing countries o Number of cases is decreasing in industrialized countries.

In U.S. (2005): 14,097 cases (4.8 cases per 100,000 persons)

Lowest rate recorded since reporting began in 1953 ~50% occur in foreign-born patients.

Prior increase in incidence attributed to HIV/AIDS and multidrug resistance. Secondary (reactivation) TB

o 10% of persons infected in youth eventually develop active TB. Reactivation risk is highest (5%) in the first 2 years after primary infection.

5% over remaining lifetime after 2 years o 10% risk of reactivation per year in HIV-infected patients

o Natural history One-third of untreated patients die of severe pulmonary TB within a few weeks or

months after reactivation. May remit spontaneously Potential for progressively debilitating course ("consumption")

Risk Factors

Acquisition: exogenous factors o Close contact with infected person

Poverty

Homelessness Drug abuse

Incarceration Residence in nursing home or other long term–care facility

o Exposure to endemic area Primary TB

o Age: common among children ≤ 4 years of age Secondary (reactivation) TB: endogenous factors

o Recent infection (< 2 years) o HIV infection

No CD4+ count protects fully against associated risk.

Risk is highest at low CD4+ counts. o Immunosuppressive treatment

Glucocorticoids Immunomodulating drugs

Tumor necrosis factor α blockers (e.g., infliximab) Chemotherapy

o Jejunoileal bypass o Post-transplantation period (renal, cardiac)

o Chronic renal failure/hemodialysis o Silicosis o Fibrotic lesions on chest radiography (spontaneously healed) o Diabetes o Intravenous drug use

o Gastrectomy o Malnutrition/severe underweight

o Head/neck carcinoma o Lymphomas/leukemias

o Recent immigration (< 5 years) from high-prevalence area o Age

Incidence highest in late adolescence and early adulthood Risk increased in elderly persons

Etiology

Mycobacteria that cause TB o Most common/important agent: M. tuberculosis

o Other species (e.g., M. bovis): cause small percentage of cases in developing countries M. tuberculosis complex

o Rod-shaped, nonspore-forming, thin aerobic bacterium o Once stained, cannot be decolorized by acid alcohol; hence classified as acid-fast bacilli (AFB) o Can survive for several hours in respiratory droplets outside host

Transmission o Aerosolized respiratory droplets emitted by infected person during coughing, sneezing,

speaking Poor ventilation increases intensity of contact and transmission rate.

o Most effective transmission occurs from patients whose sputum contains AFB visible by

microscopy. Patients with culture-negative pulmonary TB and extrapulmonary TB are essentially

noninfectious. Natural disease progression

o Primary Inhaled bacilli transported by alveolar macrophages to regional lymph nodes

Disseminate to many organs/tissues T cells (mainly CD4+) induce protection by releasing lymphokines that cause

macrophage activation. Skin-test conversion in 6–8 weeks

o Latent

Viable bacilli lie dormant in macrophages. Positive skin test with no evidence of active infection

o Secondary (reactivation) Activated latent infection related to failure of immune system to keep disease in check

Associated Conditions

HIV infection occurs frequently in conjunction with TB. o See Tuberculosis Associated with HIV/AIDS for details.

Symptoms & Signs

Pulmonary TB

Primary

o Usually self-limited o Can produce an acute pneumonia with systemic symptoms, but often is not clinically apparent

o Can progress to advanced disease in young or immunocompromised patients Hematogenous spread can cause miliary or meningitic TB.

o Pleural effusion (found in up to two-thirds of cases) o Young children may develop hilar or mediastinal lymphadenopathy.

Enlarged lymph nodes compress bronchi, causing obstruction and subsequent segmental or lobar collapse.

Partial obstruction may cause obstructive emphysema and bronchiectasis. Secondary (reactivation)

o Symptoms/signs are often nonspecific and insidious. o Fever

Often low-grade and intermittent In up to 80% of cases

o Night sweats o Weight loss, anorexia, wasting o General malaise o Weakness

o Cough eventually develops in most cases. Initially unproductive Later accompanied by purulent sputum production Frequent blood streaking of sputum

Massive hemoptysis may ensue.

o Pleuritic chest pain o Extensive disease may produce dyspnea and adult respiratory distress syndrome.

o On examination, often no abnormalities Sometimes, rales in involved areas during inspiration

Occasionally, rhonchi due to partial bronchial obstruction and classic amphoric breath sounds (in areas with large cavities)

Extrapulmonary TB

All organ systems may be affected. Extrapulmonary sites most commonly involved, in descending order of frequency

o Lymph nodes (>40% of cases in the U.S. in series of studies) o Pleura (~20% of extrapulmonary cases in the U.S.) o Upper airways o Genitourinary tract (15% of extrapulmonary cases in the U.S.) o Bones/joints (~10% of extrapulmonary cases in the U.S.) o Meninges (~5% of extrapulmonary cases in the U.S.) o GI tract/peritoneum (3.5% of extrapulmonary cases in the U.S.) o Pericardium

Lymph node TB (tuberculous lymphadenitis)

o Scrofula: painless swelling of lymph nodes, usually at posterior cervical and supraclavicular sites May be inflamed and have a fistulous tract draining caseous material Systemic symptoms usually limited to HIV-infected patients Concomitant lung disease is seen in > 40% of cases.

Pleural TB o May or may not cause symptoms

Fever Pleuritic chest pain Dyspnea

Dullness to percussion/absence of breath sounds TB of upper airways (larynx, pharynx, and/or epiglottis)

o Hoarseness o Dysphonia

o Dysphagia o Chronic productive cough

Genitourinary tract TB o Urinary frequency

o Dysuria

o Hematuria o Nocturia

o Flank or abdominal pain o Patients may be asymptomatic and disease discovered only when severe renal lesions develop.

o In women, may cause: Infertility

Pelvic pain Menstrual abnormalities

o In men, epididymis disease causes a slightly tender mass that may drain externally through a fistulous tract; orchitis and prostatitis may also develop.

o In half of genital TB cases, urinary tract disease is also present.

Skeletal TB o Weight-bearing joints are affected most commonly.

Spine in 40% of cases Hips in 13%

Knees in 10% o Spinal TB (Pott’s disease, tuberculous spondylitis) often involves ≥ 2 adjacent vertebral bodies.

Back pain Neurologic signs of spinal cord compression, including paraplegia

Upper thoracic spine most common site of spinal TB in children Lower thoracic and upper lumbar vertebrae usually affected in adults

Kyphosis (from vertebral body collapse) in advanced disease

o Joints Hip: pain, limping

Knee: pain, swelling; sometimes follows trauma Tuberculous meningitis

o Typically evolves over 1–2 weeks but may present acutely o Headache

o Mental changes (confusion/lethargy) o Neck rigidity

o Low-grade fever o Malaise o Anorexia o Irritability o Paresis of cranial nerves, particularly ocular nerves (frequent) o Involvement of cerebral arteries may produce focal ischemia. o Coma, with hydrocephalus and intracranial hypertension

Tuberculoma: uncommon o Seizures and focal signs

GI TB o Bowel disease

Abdominal pain (at times similar to appendicitis) Swelling Diarrhea Obstruction Hematochezia Palpable abdominal mass Fever Weight loss

Anorexia Night sweats

With intestinal-wall involvement, ulcerations/fistulae simulating Crohn’s disease Anal fistulae: rectal TB

o Tuberculous peritonitis Nonspecific abdominal pain

Fever Ascites

Pericardial TB (tuberculous pericarditis) o Onset may be subacute. o Acute presentation

Dyspnea Fever

Dull retrosternal pain Friction rub

o Effusion eventually develops in many cases. o Cardiovascular symptoms/signs of cardiac tamponade may ultimately appear.

Less common sites o Eyes

Chorioretinitis Uveitis

Panophthalmitis

Phlyctenular conjunctivitis (painful) o Tuberculous otitis

Hearing loss Otorrhea

Tympanic membrane perforation o Nasopharyngeal

Simulates Wegener’s granulomatosis o Cutaneous

Abscesses/chronic ulcers Scrofuloderma Lupus vulgaris Miliary lesions Erythema nodosum

o Adrenal Signs of adrenal insufficiency Previously, the primary cause of adrenal insufficiency worldwide

Miliary (disseminated) TB

Clinical manifestations are nonspecific, depending on the predominant site of involvement.

Majority of cases o Fever

o Night sweats o Anorexia

o Weakness o Weight loss

o Cough/other respiratory symptoms

o Hepatomegaly o Splenomegaly

o Lymphadenopathy o Eye examination may reveal choroidal tubercles (pathognomonic in up to 30% of cases).

o Meningismus (< 10% of cases) Rare presentation in elderly persons (cryptic miliary TB)

o Mild intermittent fever o Anemia o Ultimately, meningeal involvement (precedes death)

Acute septicemic form (nonreactive miliary TB): very rare, rapidly fatal

Differential Diagnosis

Very broad differential diagnosis, depending on TB syndrome; includes cancer, other infections, inflammatory illnesses

Pulmonary TB (primary or secondary) o Community-acquired pneumonia o Cancer o Fungal infections o Wegener’s granulomatosis o Inflammatory illness (e.g., sarcoidosis) o Nontuberculous mycobacterial disease

Limited abnormalities on chest radiography Sputum positive for AFB

M. avium complex M. kansasii

Factors favoring nontuberculous mycobacterial disease Absence of risk factors

Negative purified protein derivative (PPD) skin test Underlying chronic obstructive pulmonary disease and bronchiectasis

Lymph node TB

o Variety of infectious conditions o Neoplastic diseases (e.g., lymphomas, metastatic carcinomas)

o Rare disorders Kikuchi disease (necrotizing histiocytic lymphadenitis)

Kimura’s disease Castleman’s disease

Tubercular meningitis o Bacterial meningitis

Diagnostic Approach

General principles

TB diagnosis supported by: o Epidemiology (e.g., history of close contact with infectious patient) o Abnormal radiograph (e.g., upper-lobe infiltrate on chest radiography) o Positive tuberculin skin test (TST) o Positive sputum smear

Smear may be negative if organism burden is low. Positive result of polymerase chain reaction or culture may take up to 6 weeks.

o Clinical and radiographic response to treatment Adenosine deaminase (ADA)

o Determination of ADA levels in pleural fluid may be useful in the diagnosis of pleural tuberculosis.

o Utility of this test in the diagnosis of other forms of extrapulmonary tuberculosis (e.g., pericardial, peritoneal, and meningeal) is less clear.

By site

Pulmonary TB o Sputum specimens for AFB smear and culture o For patients unable to produce sputum

Sputum induction by ultrasonic nebulization of hypertonic saline Children often do not expectorate sputum; specimens from early-morning gastric lavage

may yield positive cultures.

Bronchoscopic sampling with bronchoalveolar lavage Lymph node TB

o Diagnosis established by fine-needle aspiration or surgical biopsy AFB seen in up to 50% of cases Cultures positive in 70–80% of cases Histologic examination shows granulomatous lesions (less commonly in HIV-infected

patients). Pleural TB

o Chest radiography reveals an effusion and, in < 30% of cases, a parenchymal lesion. o Thoracentesis is required to ascertain the nature of effusion.

Fluid is straw-colored and at times hemorrhagic. It is an exudate.

Protein concentration >50% of that in serum (usually ~4–6 g/dL) Normal to low glucose concentration

pH of ~7.3 (occasionally < 7.2) Detectable white blood cells (usually 500–6000/μL)

Neutrophils may predominate early, while mononuclear cells are typical later. Mesothelial cells are generally rare or absent.

o AFB are seen on direct smear in only 10–25% of cases. o Cultures may be positive for M. tuberculosis in 25–75% of cases.

Positive cultures are more common among postprimary cases. o Determination of the pleural concentration of ADA is a useful screening test.

Tuberculosis is virtually excluded if the value is very low.

o Needle biopsy of pleura is often required for diagnosis. Reveals granulomas and/or yields positive culture (up to 80% of cas es)

TB of upper airways o Ulcerations may be seen on laryngoscopy.

o Acid-fast smear of sputum is often positive, but biopsy may be necessary for diagnosis. Genitourinary TB

o Urinalysis Abnormal in 90% of cases (pyuria, hematuria)

Culture-negative pyuria in acidic urine suggests TB.

o Intravenous pyelography, abdominal CT, or MRI may aid in diagnosis. Suggestive findings: deformities and obstructions, calcifications and ureteral strictures

o Culture of 3 morning urine specimens yields a definitive diagnosis in nearly 90% of cases. o In female patients, diagnosis of genital TB requires biopsy or culture of specimens obtained by

dilatation and curettage. Skeletal TB

o CT or MRI reveals a characteristic lesion in the spine. In the upper spine, the paravertebral abscess may track to the chest wall as a mass. In the lower spine, the abscess may reach the inguinal ligaments or present as a psoas

abscess. o Aspiration of the abscess or bone biopsy confirms the diagnosis.

Cultures usually positive Histologic findings highly typical

o TB of joints (hip or knee) Diagnosis requires examination of synovial fluid.

Thick in appearance High protein concentration

Variable cell count Synovial fluid culture is positive in a high percentage of cases.

Synovial biopsy and tissue culture may be necessary to establish the diagnosis. Meningeal TB

o Lumbar puncture: cornerstone of diagnosis

Cerebrospinal fluid (CSF) leukocyte count Up to 1000/μL

Usually lymphocyte predominance; neutrophil predominance in early stage High CSF protein concentration (100–800 mg/dL)

Low CSF glucose concentration AFB on direct smear of CSF in up to one-third of cases

Repeated punctures increase the yield. CSF culture (gold standard) is diagnostic in up to 80% of cases.

Polymerase chain reaction (PCR) has a sensitivity of up to 80%, but rates of false-positivity reach 10%.

ADA concentration may be a sensitive test but has low specificity. CT or MRI may show hydrocephalus and abnormal enhancement of basal cisterns or

ependyma. CNS tuberculoma

o CT or MRI reveals contrast-enhanced ring lesions. o Biopsy necessary to establish diagnosis

GI TB

o Diagnosis can be established by histologic examination and culture of specimens obtained intraoperatively.

o Tuberculous peritonitis Paracentesis reveals exudative fluid with:

High protein content Leukocytosis (usually lymphocytic; occasional neutrophil predominance)

Low yield of direct smear and culture: improves with high-volume sample Peritoneal biopsy (with a specimen best obtained by laparoscopy) is often needed to

establish the diagnosis. Pericardial TB

o Diagnose by pericardiocentesis, with or without biopsy. Pericardial fluid studies: exudative, hemorrhagic, mononuclear predominance

Direct smear examination is very rarely positive. Culture reveals M. tuberculosis in up to two-thirds of cases.

Pericardial biopsy: higher yield High levels of adenosine deaminase and interferon γ may suggest TB.

Miliary TB

Chest radiography o Often reveals miliary reticulonodular pattern (more easily seen on underpenetrated film)

o No abnormality evident early or among HIV-infected patients o Other findings

Large infiltrates Interstitial infiltrates (especially in HIV-infected patients) Pleural effusion

Nonspecific hematologic abnormalities may be seen. o Anemia with leukopenia o Neutrophilic leukocytosis/leukemoid reactions o Polycythemia o Disseminated intravascular coagulation

o Elevated alkaline phosphatase levels and other liver function test values TST may be negative in up to half of cases (reactivity may be restored during chemotherapy); sputum

smear is negative in 80% of cases. Invasive diagnostic procedures are often indicated.

o Specimens of involved sites are obtained. o Bronchoalveolar lavage and transbronchial biopsy are performed. o Granulomas are evident in liver or bone-marrow biopsy specimens from many patients.

Laboratory Tests

Nonspecific laboratory tests o Mild anemia o Leukocytosis o Hyponatremia (syndrome of inappropriate antidiuretic hormone secretion) o Elevated alkaline phosphatase and other liver biochemical values

Cytokine-release assays o Recommended for latent TB screening o Whole-blood cytokine assay o Limitation: unknown ability to predict development of active TB

Acid-fast smear/microscopy

o Presumptive diagnosis commonly based on detection of AFB by microscopic examination of specimen with special stains

o Rapid and inexpensive o Relatively low sensitivity (40–60%) in confirmed cases of pulmonary tuberculosis o For suspected pulmonary TB

3 sputum specimens, preferably collected early in the morning, for AFB smear and mycobacteriology culture

o AFB microscopy on urine or gastric lavage fluid Limited value; can yield false-positive results

Mycobacterial culture o Slow growth (>7 days); may require 4–8 weeks

o Faster with use of liquid media Speciation of isolates by methods faster than culture

o Nucleic acid probes Permit diagnosis in several hours

High specificity and sensitivity approaching that of culture Most useful for the rapid confirmation of TB in AFB-positive specimens Also have utility for diagnosis of AFB-negative pulmonary and extrapulmonary

tuberculosis o High-pressure liquid chromatography of mycolic acids

Bacteriologic confirmation in 2–3 weeks Drug susceptibility testing

o Test for susceptibility to: Isoniazid (INH)

Rifampin (RIF) Ethambutol (EMB)

o Expanded susceptibility testing mandatory when: Resistance is found

Patient does not respond to initial therapy Patient has a relapse after completion of treatment

o May be conducted:

With the clinical specimen With mycobacterial cultures

On solid or liquid medium Results are most rapid with direct testing on liquid medium; the average

reporting time is 3 weeks. With indirect testing on solid medium, results may take > 8 weeks.

o Molecular methods for rapid identification of genetic mutations known to be associated with resistance to rifampin and isoniazid

PCR to detect mutations in the rpoB gene associated with resistance to RIF Not marketed in the U.S.

Imaging

Chest radiography o Primary TB: lung lesions

Often localized to middle and lower lung zones A lesion forming after infection, usually peripheral, may not be detectable.

A lesion usually heals spontaneously; it may later be evident as a small calcified nodule (Ghon lesion).

o Secondary (reactivation) TB "Classic" picture: upper-lobe disease with infiltrates and cavities Localized to:

Apical and posterior segments of upper lobes Superior segments of lower lobes

Virtually any radiographic pattern may be seen. Normal

Solitary pulmonary nodule Diffuse alveolar infiltrates in patients with adult respiratory distress syndrome

Pleural effusion, lymphadenopathy The extent of lung parenchymal involvement varies greatly, from small infiltrates to

extensive cavitary disease. o Immunosuppressed patients may have "atypical" findings on chest radiography—e.g., lower-

zone infiltrates without cavity formation.

CT o May be useful in interpreting questionable findings on plain chest radiography o May be helpful in diagnosing some forms of extrapulmonary tuberculosis (e.g., Pott’s disease)

MRI o Useful in the diagnosis of intracranial tuberculosis

See Diagnostic Approach for other imaging studies.

Diagnostic Procedures

TST with tuberculin PPD o Inject 5 tuberculin units of polysorbate-stabilized PPD intradermally into the volar surface of

the forearm (Mantoux method). o Read at 48–72 hours as transverse diameter in millimeters of induration.

Diameter of erythema is not relevant in interpreting the test result. Induration >15 mm is required for diagnosis in persons at low or no risk. Induration of 10–14 mm is the diagnostic criterion for health care workers, IV drug

users, recent immigrants from endemic regions, and individuals living in long term–care institutions.

Induration of 5–9 mm is the diagnostic criterion for immunosuppressed patients, persons with highly suspicious chest x-rays, and patients recently in contact with

someone with active TB. o PPD reactivity may wane with time but can be recalled by a second skin test administered ≥ 1

week after the first (booster). o Most widely used in screening for latent M. tuberculosis infection (LTBI)

o Limited value in the diagnosis of active TB

Relatively low sensitivity and specificity Inability to discriminate between latent infection and active disease

o False-negative reactions are common in immunosuppressed patients and in those with overwhelming TB.

o False-positive reactions may be caused by infections with nontuberculous mycobacteria and by bacille Calmette-Guérin (BCG) vaccination.

o See Treatment Approach for test result interpretation. IFN-γ release assays (IGRAs)

o In vitro assays that measure T cell release of IFN-γ in response to stimulation with the highly tuberculosis-specific antigens ESAT-6 and CFP-10

o Recently, 2 IGRAs have become commercially available. QuantiFERON-TB Gold (Cellestis Ltd., Carnegie, Australia) is a whole-blood enzyme-

linked immunosorbent assay (ELISA) for measurement of IFN-γ. T-SPOT.TB (Oxford Immunotec, Oxford, UK) is an enzyme-linked immunospot (ELISpot)

assay.

o IGRAs are more specific than the TST. o IGRAs appear to be at least as sensitive as the TST for active tuberculosis (used as a surrogate

for LTBI). o Other potential advantages of IGRAs include:

Logistical convenience Need for fewer patient visits to complete testing Avoidance of unreliable and somewhat subjective measurements such as skin

induration

Ability to perform serial testing without inducing the boosting phenomenon (a spurious TST conversion due to boosting of reactivity on subsequent TSTs among BCG-vaccinated persons and those infected with other mycobacteria)

o IGRAs are likely to replace the TST for LTBI diagnosis in low-incidence, high-income settings where cross-reactivity due to BCG might adversely affect the interpretation and utility of the

TST. o Further studies are underway to assess the performance of these tests in contact investigations

and in persons with suspected tuberculosis disease, health care workers, HIV-infected individuals, persons with iatrogenic immunosuppression, and children.

Invasive sampling of respiratory tract o If 3 sputum samples are smear negative or if radiographic abnormalities are consistent with

other diagnoses (e.g., bronchogenic carcinoma), consider performing: Fiberoptic bronchoscopy with bronchial brushings or transbronchial biopsy of lesion

Bronchoalveolar lavage of lung segment containing abnormality For extrapulmonary disease, see Diagnostic Approach.

o Testing of specimens from involved sites (e.g., CSF for tuberculous meningitis, pleural fluid and

biopsy samples for pleural disease) o In addition, biopsy and culture of bone marrow and liver tissue

Good diagnostic yield in disseminated (miliary) tuberculosis Particularly in HIV-infected patients, who also have a high frequency of positive

blood cultures

Treatment Approach

Treatment goals

To interrupt transmission o Initial/bactericidal phase

To cure o Continuation/sterilizing phase

Treatment principles

Multiple drugs: to prevent emergence of resistance

Long duration: to prevent recurrence

Strategic approaches

If TB is strongly suspected (e.g., AFB-positive smear, positive PPD test result, and strong clinical evidence) and concern about drug resistance is low

o Start with a 4-drug regimen. o Adjust the regimen once cultures and sensitivity results are available.

Direct observation of treatment (DOT) o Facilitates treatment completion o Believed to lessen chance of relapse and acquired drug resistance, although not all studies have

confirmed a benefit of DOT over self-administered therapy o Supervisory personnel usually available through TB control programs of local public health

departments Provision of fixed-drug-combination products to prevent resistance

o Isoniazid/rifampin o INH/RIF/pyrazinamide (PZA)

Alternative regimens for drug intolerance or adverse reactions

Treatment regimens

Frequency of dosing o Daily throughout the course, or o Intermittently

3 times weekly throughout the course or Twice weekly after an initial phase of daily therapy (This option is not recommended by

the World Health Organization.) Intermittent administration is especially useful with DOT.

Many drug interactions Extrapulmonary disease at certain sites (bones/joints, CNS), pregnancy, drug resistance, drug

intolerance, or other factors may necessitate a longer treatment course. o The patient’s age may have implications for duration.

Special considerations

Patients with chronic renal failure o Should not receive aminoglycosides o Should receive ethambutol only if serum levels can be monitored

o Dosages of INH and PZA should be reduced in severe renal failure unless the patient is undergoing hemodialysis.

Patients with hepatic disease o Severe disease may be treated with ethambutol and streptomycin and possibly another drug

[e.g., a fluoroquinolone (FQ)]. If INH and RIF are required, administer under close supervision.

o Avoid PZA in liver failure. o Patients should be given no more than 1 month’s supply of drug at each visit.

o Silicotuberculosis necessitates the extension of therapy by at least 2 months. HIV-infected patients

o Because recommendations are frequently updated, consultation of the U.S. Centers for Disease Control and Prevention (CDC) Web site is advised (www.cdc.gov/tb/TB_HIV_Drugs/default.htm).

o Should avoid RIF while taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors

o Rifamycins induce the cytochrome p450 (CYP3A4) system and decrease the concentration of HIV medications.

RIF is the most potent inducer. Rifabutin is the least potent inducer.

o Rifabutin is recommended except with saquinavir and delavirdine. o Ritonavir inhibits CYP3A4 and may cause toxic levels of rifamycins, including rifabutin.

Pericardial TB o A course of glucocorticoid treatment (e.g., prednisone, 20–60 mg/d for up to 6 weeks) is useful

in managing acute disease and decreasing mortality but does not inhibit progression to chronic constrictive pericarditis.

Meningitis

o Dexamethasone is recommended for all patients. o Dose: 12 mg/d for children > 25 kg and adults o Treat for 3 weeks and then taper over 3 weeks. o Limited data

In children, the American Academy of Pediatrics recommends 9–12 months of treatment for:

o Bone/joint TB o Tuberculous meningitis

o Miliary TB Medical consultation on difficult-to-manage cases is provided by the CDC Regional Training and

Medical Consultation Centers (www.cdc.gov/tb/rtmcc.htm).

Treatment challenges

Long treatment period required/poor compliance o Patient-related factors

Lack of belief that illness is significant and/or that treatment will be beneficial Concomitant medical conditions (notably substance abuse) Lack of social support Poverty, joblessness, homelessness

o Provider-related factors to promote compliance Education/encouragement of patients Convenient clinic hours Provision of incentives (meals, bus tokens)

Specific Treatments

First-line agents for susceptible organisms

See Monitoring for adverse effects.

Isoniazid o Daily dose: 5 mg/kg; maximum, 300 mg

o 3-times-weekly dose: 15 mg/kg; maximum, 900 mg o To prevent INH-related neuropathy, pyridoxine (10–25 mg/d) should be added for persons at

high risk for vitamin B6 deficiency.

Alcoholics Malnourished persons

Pregnant and lactating women Patients with chronic renal failure

Diabetic patients Patients with HIV infection or AIDS

o Persons who rapidly acetylate (inactivate) INH are particularly prone to INH-induced hepatitis. Elevations of aminotransferases occur in 10–20% of patients, but these patients only

rarely have to stop taking the drug. They should be monitored closely during therapy because ~1.5% of patients

develop clinical hepatitis, and death from hepatic failure has been reported (see Monitoring).

The risk of hepatitis increases when INH is given in combination with RIF.

Rifampin o Daily dose: 10 mg/kg; maximum, 600 mg

o 3-times-weekly dose: 10 mg/kg; maximum, 600 mg Pyrazinamide

o Daily dose: 20–25 mg/kg; maximum, 2 g o 3-times-weekly dose: 30–40 mg/kg; maximum, 3 g

Ethambutol

o Daily dose: 15–20 mg/kg o 3-times-weekly dose: 25–30 mg/kg

Dosages for children are similar, but some authorities recommend: o Higher doses of INH (10–15 mg/kg daily; 20–30 mg/kg intermittent)

o Higher doses of RIF (10–20 mg/kg)

Second-line agents

Generally used only for treatment of TB resistant to first-line drugs or in cases of intolerance/toxicity Especially important to consult an expert in treatment of TB before prescribing second-line agents

o Injectable Streptomycin

Other aminoglycosides: kanamycin, amikacin Capreomycin Monthly audiography Weekly measurement of serum blood urea nitrogen and creatinine once steady state is

reached o Oral

Fluoroquinolone (third-generation agents are preferred) Levofloxacin

Moxifloxacin Ethionamide

Side effect: GI irritation Monitor liver function monthly.

Cycloserine Psychosis Peripheral neuropathy Some authorities recommend monitoring serum drug levels (goal, 20–35 mg/L).

Para-aminosalicylic acid

Side effect: GI irritation

Treatment duration and approaches

Disease acquisition in area with INH resistance rate < 4% o New smear- or culture-positive cases

Initial phase: INH/RIF/PZA/EMB for 2 months Continuation phase: INH/RIF for 4 months

If culture-positive at 2 months and/or cavitary disease, INH/RIF for 7 months o New culture-negative cases

Initial phase: INH/RIF/PZA/EMB for 2 months Continuation phase: INH/RIF for 2 months

If HIV-positive: INH/RIF for 4 months o Pregnancy or intolerance to PZA

Initial phase: INH/RIF/EMB for 2 months

Continuation phase: INH/RIF for 7 months Treatment not a contraindication to breastfeeding

Regimens for resistance (Tailor per drug susceptibility tests in consultation with experts at specialized treatment centers.)

o Resistance (or intolerance) to INH

RIF/PZA/EMB for 6 months, with or without fluoroquinolone o Resistance (or intolerance) to RIF: INH/PZA/EMB/FQ for 9–18 months

o Resistance to INH and RIF PZA/EMB/fluoroquinolone plus streptomycin or another injectable agent, with or

without another alternative agent, for 18–24 months Amikacin, kanamycin, or capreomycin can be used instead of streptomycin.

Should be discontinued after 2–6 months, depending on tolerance/response o Resistance to all first-line drugs

1 injectable agent, plus 3 of the following 4 agents Ethionamide

Cycloserine

Fluoroquinolone Para-aminosalicylic acid

Total duration: 24 months

Monitoring

Treatment response

Pulmonary TB o Examine sputum monthly until at least 2 consecutive cultures are negative. o By the end of 3 months, virtually all patients should be culture-negative. o AFB smear conversion may follow culture conversion. o If sputum cultures remain positive for > 3 months, treatment failure and drug resistance should

be suspected. o A sputum specimen should be collected by the end of treatment to document cure. o If mycobacterial cultures are not practical, monitoring by AFB smear examination should be

undertaken at 2, 5, and 6 months. Smears positive after 5 months indicate treatment failure.

o Serial chest radiography is not recommended for monitoring response to treatment. Extrapulmonary TB

o Culture not feasible o Response must be assessed clinically and radiographically.

Chest radiography may be performed at the end of treatment to use for comparative purposes if the patient develops symptoms of recurrent TB months or years later.

Baseline monitoring

At baseline

o Liver function tests (aminotransferases, bilirubin, alkaline phosphatase) o Serum creatinine o Platelet count

o Visual acuity and red-green color discrimination testing (before EMB treatment) o HIV testing

o Hepatitis B and C serologies in at-risk patients Follow-up testing in cases of:

o Abnormal baseline laboratory values or visual disturbance o HIV infection o Liver disease, including alcohol abuse

o Suspected drug reaction o Pregnancy or early postpartum period

Drug toxicity

Hepatitis

o Common with INH, RIF, PZA Educate patients about signs/symptoms (e.g., dark urine, loss of appetite).

Instruct patients to discontinue treatment and see health care provider. In adults, perform baseline assessment of liver function (e.g., measurement of serum

levels of hepatic aminotransferases and serum bilirubin). Monitor monthly, with repeated measurements of aminotransferases, during initial

phase of treatment of: Older patients Patients with concomitant diseases Patients with history of hepatic disease Patients using alcohol daily

Up to 20% of patients have increases in aspartate aminotransferase level (up to 3 times the upper limit of normal) unaccompanied by symptoms.

Of no consequence

In patients with symptomatic hepatitis or marked (5- to 6-fold) elevations in aspartate aminotransferase level

Stop treatment. Reintroduce drugs 1 at a time after liver function returns to normal.

Hypersensitivity reactions o Require discontinuation of all drugs

When applicable, rechallenge with 1 drug at a time. PZA: hyperuricemia/arthralgia

o Treatment: administration of acetylsalicylic acid

o Should be stopped if patient develops gouty arthritis RIF: autoimmune thrombocytopenia

o Treatment: permanent discontinuation EMB: optic neuritis

o Causes diminished visual acuity and red-green color alteration o Treatment: permanent discontinuation

Pruritus and GI upset o Generally managed without interruption of therapy

Treatment failure

Sputum cultures positive after 3 months or AFB smears positive after 5 months o Current isolate must be tested for susceptibility to first- and second-line agents. o Changes in regimen can be postponed pending results. o If the clinical condition is deteriorating, an earlier change in regimen is indicated.

Add at least 2 and preferably 3 drugs that have never been used and to which bacilli are likely to be susceptible.

Patient may continue to take INH and RIF along with new agents. Relapse

o Low concern about resistance to drugs used for initial treatment (DOT, no significant likelihood

of reinfection with drug-resistant strain) While awaiting results of susceptibility testing, restart all 4 first-line drugs plus

streptomycin. o Concern about resistance to drugs used for initial treatment (suboptimal adherence, risk of

subsequent reinfection with drug-resistant strain) While awaiting results of susceptibility testing, restart 4 first-line drugs plus at least 2

additional agents (e.g., a fluoroquinolone and an aminoglycoside) to which the organism is thought most likely to be susceptible.

Complications

Pulmonary TB o Tuberculous empyema

Result of: Rupture of a cavity, with delivery of many organisms into the pleural space, or

Bronchopleural fistula from a pulmonary lesion Chest radiography may show pyopneumothorax with an air–fluid level.

May result in severe pleural fibrosis and restrictive lung disease Removal of the thickened visceral pleura (decortication) is occasionally necessary

to improve lung function.

Genitourinary TB o Severe ureteral strictures may lead to hydronephrosis and renal damage.

Bone/joint TB o If disease goes unrecognized, joints may be destroyed.

o A catastrophic complication of Pott’s disease (TB of the spine) is paraplegia, usually due to an abscess or a lesion compressing the spinal cord.

Paraparesis due to a large abscess is a medical emergency and requires abscess drainage.

Meningitis o If unrecognized, uniformly fatal

o Neurologic sequelae are documented in 25% of treated cases, in most of which the diagnosis has been delayed.

o Patients given adjunctive glucocorticoids may experience faster resolution of CSF abnormalities and elevated CSF pressure.

Adjunctive dexamethasone (0.4 mg/kg per day given IV and tapering by 0.1 mg/kg per

week until the fourth week, when 0.1 mg/kg per day is administered; followed by 4 mg/d given by mouth and tapering by 1 mg per week until the fourth week, when 1

mg/d is administered) Significantly enhanced the chances of survival among persons >14 years of age

Did not reduce the frequency of neurologic sequelae Pericardial TB

o Without treatment, usually fatal o Even with treatment, complications may develop.

Chronic constrictive pericarditis with thickening of the pericardium, fibrosis, and sometimes calcification, which may be visible on chest radiography

Pregnancy o Congenital TB (rare) results from transplacental spread of tubercle bacilli to the fetus or from

ingestion of contaminated amniotic fluid.

o Affects Liver

Spleen Lymph nodes

Various other organs In young children, hematogenous dissemination may result in fatal miliary TB or tuberculous

meningitis.

Prognosis

When properly treated, TB caused by drug-susceptible strains is curable in virtually all cases. If untreated, disease may be fatal within 5 years in 50–65% of cases. Tuberculous meningitis

o If unrecognized, uniformly fatal o Neurologic sequelae documented in 25% of treated cases, usually when diagnosis is delayed

o Adjunctive glucocorticoid treatment leads to significantly faster resolution of CSF abnormalities/elevated CSF pressure.

Enhances survival Tuberculous pericarditis

o Fatality rates as high as 40% in some series

Nonreactive miliary TB o If pancytopenia, rapidly fatal

Miliary TB o If unrecognized, fatal

o With proper treatment, curable

Prevention

Rapid diagnosis of infectious cases and administration of appropriate treatment until cure Respiratory isolation of persons with suspected pulmonary TB until proved noninfectious Periodic screening of personnel who may come into contact with infected patients

Contact investigation

BCG vaccination

Range in efficacy; in trials, 0–80% effective Local tissue response 2–3 weeks after vaccination, with scar formation and healing within 3 months

o Size of TST reactions does not predict degree of protection. Side effects (1–10% of persons)

o Ulceration at vaccination site o Regional lymphadenitis o Disseminated BCG infection and death in 1–10 cases per 10 million doses administered; almost

exclusively in impaired immunity o Induces TST reactivity that tends to wane over time

Recommended for routine use at birth in countries with high TB prevalence The Centers for Disease Control and Prevention recommends that HIV-infected adults and children not

receive BCG vaccine.

Treatment of persons with latent TB who are at high risk for active disease

Whom to treat is based on: o TST result in mm o Probability that a TST reaction represents true infection o Likelihood that the person, if infected, will develop TB

Current guidelines recommend ignoring BCG administration history.

o ≥5 mm Close contacts of patients with TB

Give prophylaxis for 2–3 months after contact ends; if TST retesting remains negative, discontinue prophylaxis.

Give HIV-infected contacts a full course of treatment regardless of TST results. HIV-infected persons or immunosuppressive therapy recipients Previously untreated patients with chest radiography evidence of healed TB

o ≥10 mm Recently infected persons (within past 2 years) Recent immigrants (< 5 years) from endemic area Persons with high-risk medical conditions (See Risk Factors.) Consider treatment for persons from TB-endemic countries, even with a history of BCG

vaccination. o ≥15 mm

Low-risk persons; decision to treat based on individual risk/benefit considerations Except for employment purposes where longitudinal screening is anticipated, TST is not

indicated for these low-risk persons. o Some TST-negative individuals are also candidates for treatment.

Infants and children who have come into contact with infectious cases should be treated.

Should have a repeat skin test 2 or 3 months after contact ends Those whose test results remain negative should discontinue treatment.

HIV-infected persons who have been exposed to an infectious tuberculosis patient

should receive treatment regardless of the TST result. Treatment regimens

o Isoniazid, 5 mg/kg/d (up to 300 mg/d) Duration: 6–12 months; optimal, 9–10 months

Consider a 6-month course for HIV-negative adults with normal chest radiographs when financial considerations are important.

When supervised treatment is desirable/feasible, INH may be given at a dose of 15 mg/kg (up to 900 mg) twice weekly.

Contraindicated in active liver disease

o Rifampin Alternative regimen for adults

600 mg PO daily for 4 months Consider if an INH-resistant strain is likely.

ICD-9-CM

011.9_ Pulmonary tuberculosis, unspecified, (bacteriology/histology specified by fifth digit) Tuberculosis

011.90 Pulmonary tuberculosis, unspecified, unspecified (bacteriology/histology) Tuberculosis

See Also

Approach to Weight Loss Bronchoscopy Infection Control Infections in Bone Marrow and Hematopoietic Stem Cell Transplant Recipients Infections in Cancer Patients: Overview Infections in Solid Organ Transplant Recipients Nontuberculous Mycobacterial Infections Tuberculosis Associated with HIV/AIDS

Internet Sites

Professionals o Division of Tuberculosis Elimination

U.S. Centers for Disease Control and Prevention o Stop TB Department

World Health Organization Patients

o Tuberculosis MedlinePlus

General Bibliography

Benator D et al: Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 360:528, 2002 [PMID:12241657]

Blumberg HM et al: American Thoracic Society/Centers for Disease Control and Preve ntion/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 167:603, 2003 [PMID:12588714]

Burman WJ, Jones BE: Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 164:7, 2001 [PMID:11435232]

Cegielski JP et al: The global tuberculosis situation. Progress and problems in the 20th century, prospects for the 21st century. Infect Dis Clin North Am 16:1, 2002 [PMID:11917808]

Centers for Disease Control and Prevention: Control of tuberculosis in the United States: Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR 54:RR1, 2005

Centers for Disease Control and Prevention (CDC), American Thoracic Society: Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and

pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. MMWR Morb Mortal Wkly Rep 52:735, 2003 [PMID:12904741]

Centers for Disease Control and Prevention (CDC): Trends in tuberculosis --United States, 2004. MMWR Morb Mortal Wkly Rep 54:245, 2005 [PMID:15772584]

Centers for Disease Control and Prevention (CDC): Tuberculosis associated with blocking agents against tumor necrosis factor-alpha--California, 2002-2003. MMWR Morb Mortal Wkly Rep 53:683, 2004 [PMID:15295313]

Hopewell PC et al: International standards for tuberculosis care. Lancet Infect Dis 6:710, 2006 [PMID:17067920]

Menzies D, Pai M, Comstock G: Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 146:340, 2007

[PMID:17339619] Pai M, Kalantri S, Dheda K: New tools and emerging technologies for the diagnosis of tuberculosis: part

I. Latent tuberculosis. Expert Rev Mol Diagn 6:413, 2006 [PMID:16706743] Raviglione MC, Smith IM: XDR tuberculosis--implications for global public health. N Engl J Med

356:656, 2007 [PMID:17301295] Raviglione MC, Uplekar M: WHO’s new Stop TB Strategy. Lancet 367:952, 2006

Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint

Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention

(CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 161:S221, 2000

[PMID:10764341] Thwaites GE et al: Dexamethasone for the treatment of tuberculous meningitis in adolescents and

adults. N Engl J Med 351:1741, 2004 [PMID:15496623] Volmink J, Garner P: Directly observed therapy for treating tuberculosis. Cochrane Database Syst Rev

, 2007 [PMID:17943789] World Health Organization: Guidelines for the programmatic management of drug-resistant

tuberculosis. Geneva, WHO, 2006 World Health Organization: Treatment of tuberculosis. Guidelines for national programmes. Geneva,

World Health Organization, 2003 This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 158, Tuberculosis

by MC Raviglione and RJ O’Brien.

PEARLS

Reactivation pulmonary TB classically causes fevers, sweats, weight loss, hemoptysis, and an upper-lobe infiltrate on chest imaging.

o Atypical syndromes of pulmonary reactivation disease and protean features of disease in other

organ systems may make diagnosis challenging. In areas of high TB prevalence, BCG vaccine may help prevent infection; in all regions, recognition and

treatment of latent TB effectively decrease the risk of reactivation disease. o Respiratory isolation of active cases is important in preventing further spread.

Successful therapy for active TB requires treatment with multiple active drugs.

o Active TB should be considered and ruled out before single-drug treatment of latent TB is started.

o Avoid empirical fluoroquinolone monotherapy for respiratory infection if TB is a consideration. Patients with active TB should be evaluated for HIV infection.

Refer all active TB cases to the local health department for contact tracing and treatment.

Tub

Harrison's Practice

2. Tuberculosis Associated with HIV/AIDS

Definition

Tuberculosis (TB) is a disease caused by bacteria belonging to the Mycobacterium tuberculosis complex.

o Infection of the lung is most common.

o In up to 10–25% of cases, other organs may be involved. o See Tuberculosis for a general discussion.

HIV infection and AIDS

o This human retroviral infection causes profound immunodeficiency with susceptibility to opportunistic infections.

o See HIV, AIDS for a general discussion. TB in HIV/AIDS

o TB is the most common opportunistic infection among HIV-infected patients and the most common cause of death in coinfected patients worldwide.

o The clinical presentation depends on the degree of immunosuppression. o HIV is the risk factor most strongly associated with progression from M. tuberculosis infection

to active TB.

Epidemiology

Prevalence o ~11% of TB cases worldwide occur in patients with HIV infection. o In certain areas of sub-Saharan Africa, the rate of HIV infection among TB patients is 60–80%.

o Worldwide, ~one-third of all AIDS-related deaths are associated with TB. o In the U.S., ~5% of patients with AIDS have active TB.

Incidence o HIV-infected patients with latent TB infection have a 3–13% annual risk of developing active TB.

Age o Active TB is most common among patients 25–44 years of age.

Race

o In the U.S., the TB burden is greatest among racial and ethnic minorities, including African Americans, Hispanics, and Asians.

Geography o Worldwide, TB infection occurs in one-third of the global population, with higher rates in the

developing world. o In the U.S., TB rates are disproportionately high among foreign-born racial/ethnic minorities

and HIV-infected individuals.

Risk Factors

Risk of developing TB is greatly increased among HIV-infected persons.

o Risk that latent infection will proceed to active disease is highly related to the degree of immunosuppression.

Depends on CD4+ T cell count

Yet risk is increased even in the early stages of HIV infection. o HIV infection increases the risk of developing active TB by a factor of 100. o Patients with HIV are at higher risk of TB reactivation, primary progressive disease, and

reinfection. o TB is associated with a significant increase in HIV replication.

See also Tuberculosis: Risk Factors.

Etiology

The Mycobacterium tuberculosis complex includes: o M. tuberculosis

Most common and most important causative agent for TB o M. bovis

Cause of a small percentage of cases in developing countries o M. africanum

Isolated from cases in West, Central, and East Africa

o M. microti The "vole" bacillus, less virulent and rarely encountered

o M. canettii Very rare isolate in African cases

M. tuberculosis o Acid-fast bacilli (AFB)

o Transmitted by aerosolized droplet nuclei o See Tuberculosis: Etiology for determinants of transmission and natural history of TB infection.

Pathogenesis in HIV-infected patients

o CD4+ lymphocytes are crucial to host defense. o Defects of CD4+ T cells explain the inability of HIV-infected individuals to contain mycobacterial

proliferation. o TB can present during any stage of HIV infection.

o Patients with HIV are at higher risk for reactivation, primary progressive disease, and reinfection.

o Antiretroviral therapy significantly reduces the risk of TB in HIV-infected patients.

Associated Conditions

Although HIV infection is the main risk factor for development of TB, coinfected individuals wi th the

following additional comorbidities are at even higher risk: o Diabetes

o End-stage renal disease o Pneumoconiosis

o Gastric bypass o Malignancy/chemotherapy

o Immunosuppressive therapy See also Tuberculosis: Risk Factors.

Symptoms & Signs

TB presentation varies with the stage of HIV infection, as indicated by the CD4+ T cell count. o See HIV, AIDS for details on CD4+ T cell counts.

Patients with CD4+ T cell counts > 200 cells/µL o More apt to present with more typical presentations of active TB, such as apical-posterior

pulmonary disease or cavitary disease Patients with lower CD4+ T cell counts

o Disseminated disease is more common.

60–80% of patients have pulmonary disease. 30–40% of patients have extrapulmonary disease.

Up to 10% of patients with sputum cultures growing M. tuberculosis may have no visible radiographic abnormalities on chest x-ray.

o Extrapulmonary infection can involve any site and can occur even in the absence of overt pulmonary disease.

Pleura, pericardium Meninges, central nervous system (CNS)

Gastrointestinal tract Lymph nodes (particularly cervical)

Viscera

See Tuberculosis: Symptoms & Signs: Extrapulmonary TB for details. In severely immunocompromised patients (CD4+ T cell counts < 50 cells/µL), TB can present as a severe

systemic disease. o Rapid progression and mortality in patients with delays in diagnosis

o Mycobacterial cultures from blood can be positive in ~50% of patients.

Differential Diagnosis

Differential diagnosis of TB is extremely broad in HIV-infected patients.

o Depends on: Site of infection

CD4+ T cell count Encompasses many other opportunistic infections, including:

o Fungal infections (e.g., histoplasmosis, coccidioidomycosis, cryptococcosis) o Bacterial infections (e.g., salmonellosis, nocardiosis, brucellosis, bartonellosis)

o Viral infections o Other mycobacterial infections (e.g., disseminated Mycobacterium avium-intracellulare

infection) o See HIV, AIDS for details.

Also includes malignancy o Lymphoma o Castleman’s disease o Other malignancies related to human herpesvirus 8

Diagnostic Approach

Diagnosis is based on a combination of history, physical findings, and appropriate diagnostic tests, depending on the site of infection.

o Culture of M. tuberculosis from an involved site provides a definitive diagnosis. Difficulties in diagnosis of TB in HIV-infected patients

o Many HIV-related pulmonary conditions can mimic tuberculosis.

o Sputum smears in the setting of more advanced immunosuppression are more often negative. o Radiographic findings may be atypical.

Negative results on tuberculin skin test (TST) or quantitative interferon test does not rule out a diagnosis of TB.

Delay in timely diagnosis and treatment in this population is associated with increased mortality rates.

Laboratory Tests

Sputum samples for AFB smear and culture o Samples should be obtained from patients with pulmonary symptoms, pleural abnormalities,

cervical adenopathy, or abnormalities on chest x-rays. o Sputum smears are negative in a substantial fraction of cases of pulmonary TB in HIV-infected

patients. Therefore, submission of specimens for culture is imperative.

o Drug susceptibility testing should be done on all culture-positive specimens. Mycobacterial blood cultures

o Positive in a significant proportion of patients Positive especially often in those with advanced immunosuppression

Nucleic acid amplification tests have been less formally evaluated in this population. o Therefore, results must be interpreted with caution (variable sensitivity).

Other markers, such as adenosine deaminase (ADA), are less sensitive and specific than in patients not infected with HIV.

See Tuberculosis: Laboratory Tests for details on mycobacterial microbiologic testing and other TB-related laboratory findings.

Imaging

Chest x-ray o HIV-infected patients with TB may have "atypical" findings on chest radiography.

o Findings include: Lower-zone infiltrates without cavity formation

Diffuse or lower-lobe bilateral reticulonodular infiltrates consistent with miliary spread Pleural effusions

Hilar and/or mediastinal adenopathy Interstitial infiltrates

o No radiographic abnormality may be evident in HIV-infected patients. Occurs in ~10% of HIV-infected patients with culture-positive pulmonary TB

CT or MRI

o Useful as an adjunct in diagnosis of various TB manifestations (depending on site—e.g., spinal TB)

o Brain imaging may show hydrocephalus and abnormal enhancement of basal cisterns or ependyma in tubercular meningitis.

Mass lesions are more common among HIV-infected patients with TB meningitis. o May demonstrate visceral lesions and intraabdominal adenopathy in abdominal TB

Diagnostic Procedures

Invasive diagnostic procedures often are indicated for patients with suspected TB, given the difficulties in establishing the diagnosis as well as the possibility of concomitant processes (multiple infections).

o Type of procedure depends on the sites involved. Miliary TB

o Bronchoalveolar lavage and transbronchial biopsy may confirm the diagnosis. o Bone marrow and liver biopsies for histopathology and culture

Good diagnostic yield in miliary TB, particularly in HIV-infected patients Presence of granulomas varies with the stage of HIV infection.

Genital TB

o Diagnosis requires biopsy or culture of specimens obtained by dilatation and curettage. Spinal TB

o Bone biopsy or aspiration of adjacent paraspinal or psoas abscesses (if present) o Cultures usually are positive, and histologic findings highly typical.

Peritoneal TB o Paracentesis can be performed.

Reveals exudative fluid with: High protein content

Leukocytosis (usually lymphocytic) o Yield of direct smear and culture is variable.

o Culture of a large volume of ascitic fluid can increase yield.

o Peritoneal biopsy often is needed to establish the diagnosis. Pleural TB

o Thoracentesis can be performed, but pleural biopsy has the highest yield. o Fluid is straw-colored and sometimes hemorrhagic.

o Fluid is an exudate with: Protein concentration >50% of that in serum (usually ~4–6 g/dL)

Normal to low glucose concentration pH of ~7.3 (occasionally < 7.2)

Detectable white blood cells (usually 500–6000/μL) Neutrophils may predominate early, while mononuclear cells are typical later. Mesothelial cells are generally rare or absent.

o Needle biopsy of the pleura often required Reveals granulomas and/or yields a positive culture in up to 80% of cases

Lymph node TB o Established by fine-needle aspiration or surgical biopsy o AFB seen in up to 50% of cases o Cultures positive in 70–80% of cases

o Granulomas variably seen on histologic examination Tubercular meningitis

o Lumbar puncture: cornerstone of diagnosis o Cerebrospinal fluid (CSF) findings can include:

High leukocyte count Lymphocytic predominance is the usual finding, yet early in infection there may

be a neutrophilic predominance. On occasion, few cells may be present.

Elevated protein content Low glucose concentration

However, any of the above parameters can be within the normal range. AFB on direct smear of CSF in up to one-third of cases

Repeated punctures increase the yield. CSF culture (gold standard) is diagnostic in up to 80% of cases.

o Adenosine deaminase is less sensitive and specific in this population than in persons without HIV infection.

Pericardial TB o Pericardiocentesis is often performed. o Pericardial fluid must be submitted for biochemical, cytologic, and microbiologic study. o Pericardial fluid studies: exudative, hemorrhagic, mononuclear predominance

Direct smear examination is very rarely positive.

Culture: reveals M. tuberculosis in up to two-thirds of cases Pericardial biopsy: higher yield (if submitted for both culture and histopathology)

Treatment Approach

Standard treatment regimens for pulmonary TB are equally efficacious in HIV-positive and -negative patients.

o Treatment is most effective in programs that involve directly observed therapy (DOT). o Multiple drugs and DOT are used to:

Provide effective therapy Prevent acquisition of drug resistance during treatment

Allow cure with a relatively short course of treatment (6–12 months) o Although drug interactions make rifamycin use challenging in this patient population, rifamycins

are an important component of the treatment regimen. Patients with HIV-TB coinfection should receive a regimen including a rifamycin for the

full course of TB treatment unless the isolate is resistant to the rifamycins or the patient has a severe adverse reaction that is clearly due to the rifamycins.

o See Tuberculosis: Treatment Approach for details. Important considerations in HIV-infected patients

o Optimal treatment duration is uncertain, especially in extrapulmonary disease.

o Risk of acquired rifamycin resistance is higher at lower CD4+ T cell counts and with intermittent regimens given < 3 times per week.

o Use of potent antiretroviral therapy may cause overlapping drug toxicity profiles, drug -drug interactions, and immune reconstitution inflammatory syndrome (IRIS) (paradoxical reactions;

see below).

Specific Treatments

Special considerations in HIV disease

Treatment of TB in HIV-infected patients often must be initiated before the diagnosis is confirmed. o Treatment delay may prove fatal to these patients. o With advancing immunosuppression come higher rates of extrapulmonary and disseminated

TB. o Diagnostic challenges include:

Higher rates of smear-negative TB Atypical radiographic findings

Treatment for TB should always take precedence over antiretroviral therapy.

o Decisions should be made in conjunction with an experienced specialist in this field. o Timing of antiretroviral therapy is a complex decision that depends on the stage of

immunosuppression and the form of tuberculosis. Drug interactions between antiretroviral therapy and rifamycins

o Because recommendations are frequently updated, consultation of the U.S. Centers for Disease Control and Prevention website is advised (www.cdc.gov/tb/TB_HIV_Drugs/default.htm).

o Rifampin is a potent inducer of enzymes of the cytochrome P450 system. Lowers serum levels of many HIV protease inhibitors and some nonnucleoside reverse-

transcriptase inhibitors Also interacts with CCR-5 receptor antagonists and integrase inhibitors

o Rifabutin is subject to fewer drug interactions than rifampin and can be used in its place.

However, some antiretroviral agents cause increased rifabutin levels associated with higher toxicity.

Therefore, dose adjustments for rifabutin and/or the antiretroviral drugs may be necessary.

Adverse drug effects may be especially pronounced in HIV-infected patients. o May include serious or even fatal skin reactions to thiacetazone in up to 28% of patients.

Thus this agent is no longer recommended by the World Health Organization. o Higher rates of GI and neuropathy-related side effects

Increased frequency of paradoxical reactions known as IRIS o Defined as exacerbations in symptoms, signs, and laboratory or radiographic manifestations of

TB

o Associated with administration of antiretroviral regimens but can occur even without concomitant antiretroviral therapy

o More common among patients with advanced immunosuppression and extrapulmonary tuberculosis

o Thought to occur in the setting of improving immune function o In coinfected patients, should be a diagnosis of exclusion

Before concluding that the clinical presentation is due to a paradoxical reaction, ensure that there is not:

Progressive disease due to treatment failure or drug resistance A concomitant HIV-associated infection or complication

o Risk factors for paradoxical reactions/immune reconstitution are: Low CD4+ T cell counts Extrapulmonary disease

o Mild paradoxical reactions can be managed with symptom-based treatment. o Glucocorticoids may be of use in more severe reactions.

There are several ongoing clinical trials to determine the best strategy for optimal timing of antiretroviral therapy in conjunction with treatment of active TB in patients with HIV.[1]

Antituberculous therapy

If a patient is already receiving antiretroviral therapy or will soon need such therapy, decisions about antitubercular and antiretroviral drugs must be carefully reviewed because of the potential for

significant drug interactions. Likelihood of drug-resistant TB must be weighed before an empiric drug combination is selected.

o If there is concern about drug resistance, expert advice should be obtained. Standard regimen for drug-susceptible TB (if no contraindications)

o Isoniazid (INH), rifampin (RIF) or rifabutin, pyrazinamide (PZA), and ethambutol (EMB) are given

for 2 months, followed by o INH and RIF (or rifabutin) for 4 months when the disease is caused by organisms known or

presumed to be susceptible to first-line anti-TB drugs. When the organism is known to be susceptible to INH, RIF, and PZA, EMB can be discontinued.

Schedule

o The CDC recommends daily DOT during the first 2 months and thrice-weekly DOT during the continuation phase.

o Rifamycins in the continuation phase for < 3-times-per-week regimens are no longer recommended because of an increased risk of resistance, especially in patients wi th lower CD4+ T cell counts.

See Tuberculosis: Specific Treatments for specific doses. Prolonged therapy

o Courses of up to 9 months are recommended when: Clinical response to therapy is delayed (i.e., the patient remains symptomatic at or after

2 months of therapy). Bacteriologic response is delayed (i.e., culture results remain positive at or after 2

months of therapy). Cavitary disease is detected by chest radiography.

o TB at certain sites (e.g., bone, meninges) may be treated with longer courses (e.g., 12 months). Drug resistance and treatment failure

o Requires treatment by an experienced specialist or in close consultation with a specialized

treatment center

Monitoring

See Tuberculosis: Monitoring.

Coinfected patients require at least monthly clinical and laboratory monitoring during treatment for tuberculosis.

Complications

Disseminated infection is more likely in HIV-positive patients. Delays in diagnosis and treatment are associated with higher complication and mortality rates.

Delays in treatment may lead to progression to disseminated disease in coinfected patients. See Tuberculosis: Complications for details.

Prognosis

Drug-susceptible TB is a curable disease in HIV-infected patients. Patients with HIV infection and TB are at 2–4 times greater risk of death than HIV-positive patients

without TB. o Independent of CD4+ T cell count

Among HIV-coinfected patients, delays in TB diagnosis and treatment are strongly associated with a fatal outcome, as are lower CD4+ T cell counts and extrapulmonary disease (especially TB involving the CNS).

TB reinfection occurs more commonly in HIV-infected patients and accounts for up to 60–75% of new TB episodes in areas with intense TB transmission.

o Reinfection with drug-resistant strains has been well documented in these populations. Multidrug-resistant TB in HIV-coinfected patients carries a poor prognosis with excessive mortality

(>80% in most series).

Prevention

Respiratory isolation and a negative-pressure room o For all patients in whom a diagnosis of pulmonary TB is being considered or has been

established o Critical for limiting nosocomial and community spread of infection

BCG (bacille Calmette-Guérin) vaccine

o Given safety and efficacy concerns about this live attenuated vaccine in HIV-infected patients, the World Health Organization advises against its use in this population.

Exception: infants of HIV-infected mothers living in areas with endemic TB Treatment of latent tuberculosis infection to prevent active disease (formerly called preventive

chemotherapy or chemoprophylaxis) o Clinical trials have shown that isoniazid reduces rates of TB among TST-positive persons with

HIV infection. o Diagnosis of latent TB

All patients with HIV infection should undergo TST. Anergy testing is not of value in HIV infection.

HIV-infected individuals who have a skin test reaction of > 5 mm or who are

close household contacts of persons with active TB should receive treatment. Isoniazid: 5 mg/kg PO qd (up to 300 mg/d) for 9 months

The role of the quantitative interferon gamma release assay (QFT) is unclear. In 1 study, overall concordance between QFT and TST in HIV infection was high,

but agreement among subjects with positive tests by either modality was low. o HIV-infected persons who have been exposed to an infectious TB patient should receive

treatment regardless of the TST or QFT result.

ICD-9-CM

011.9_ Pulmonary tuberculosis, unspecified, (bacteriology/histology specified by fifth digit)

Tuberculosis associated with HIV/AIDS 011.90 Pulmonary tuberculosis, unspecified, unspecified (bacteriology/histology) Tuberculosis

associated with HIV/AIDS

See Also

HIV, AIDS Nontuberculous Mycobacterial Infections Tuberculosis

Internet Sites

Professionals o TB Guidelines in HIV/AIDS

U.S. Centers for Disease Control and Prevention Patients

o Tuberculosis MedlinePlus

o Tuberculosis: The Connection between TB and HIV U.S. Centers for Disease Control and Prevention

References

1. Blanc FX et al: Treatment strategies for HIV-infected patients with tuberculosis: ongoing and planned clinical trials. J Infect Dis 196 Suppl 1:S46, 2007 [PMID:17624825]

General Bibliography

Benator D et al: Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical

trial. Lancet 360:528, 2002 [PMID:12241657] Benson CA et al: Treating opportunistic infections among HIV-exposed and infected children:

recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep 53:1, 2004 [PMID:15841069]

Blumberg HM et al: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 167:603, 2003 [PMID:12588714]

Burman WJ, Jones BE: Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 164:7, 2001 [PMID:11435232]

Centers for Disease Control and Prevention: Control of tuberculosis in the United States: Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of

America. MMWR 54:RR1, 2005 Corbett EL et al: The growing burden of tuberculosis: global trends and interactions with the HIV

epidemic. Arch Intern Med 163:1009, 2003 [PMID:12742798] de Jong BC et al: Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med

55:283, 2004 [PMID:14746522] Fujiwara PI, Clevenbergh P, Dlodlo RA: Management of adults living with HIV/AIDS in low-income, high-

burden settings, with special reference to persons with tuberculosis. Int J Tuberc Lung Dis 9:946, 2005

[PMID:16158886] Havlir DV, Barnes PF: Tuberculosis in patients with human immunodeficiency virus infection. N Engl J

Med 340:367, 1999 [PMID:9929528] Luetkemeyer AF et al: Comparison of an Interferon-{gamma} Release Assay to Tuberculin Skin Testing

in HIV-Infected Individuals. Am J Respir Crit Care Med Jan 11, 2007 [PMID:17218620] Murray JF: Pulmonary complications of HIV-1 infection among adults living in Sub-Saharan Africa. Int J

Tuberc Lung Dis 9:826, 2005 [PMID:16104626] Nahid P et al: Treatment Outcomes of Patients with HIV and Tuberculosis. Am J Respir Crit Care Med

Feb 8, 2007 [PMID:17290042] Onyebujoh PC, Ribeiro I, Whalen CC: Treatment Options for HIV-Associated Tuberculosis. J Infect Dis

196 Suppl 1:S35, 2007 [PMID:17726832] Onyebujoh P et al: Treatment of tuberculosis: present status and future prospects. Bull World Health

Organ 83:857, 2005 [PMID:16302043] Reid A et al: Towards universal access to HIV prevention, treatment, care, and support: the role of

tuberculosis/HIV collaboration. Lancet Infect Dis 6:483, 2006 [PMID:16870527]

Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint

Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America.

(IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 161:S221, 2000 [PMID:10764341]

This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 158, Tuberculosis, by MC Raviglione and RJ O’Brien.

PEARLS

TB is the most common cause of death among HIV-infected patients worldwide. HIV infection increases the risk of TB reactivation, primary progressive disease, and reinfection. TB is independently associated with a 2- to 4-fold increase in the risk of death in HIV-infected patients,

regardless of CD4+ T cell count. Clinical presentation depends heavily on the degree of immunosuppression.

o At CD4+ counts > 200/µL, more typical presentations of TB are noted, including upper-lobe cavitary disease.

o As counts decline, rates of smear-negative, extrapulmonary, and disseminated disease rise.

Harrison's Practice

3. Pneumothorax

Definition

Presence of gas in the pleural space o Spontaneous pneumothorax: occurs without antecedent trauma to the thorax o Primary spontaneous pneumothorax: occurs in the absence of apparent underlying lung disease

o Secondary spontaneous pneumothorax: occurs in the presence of underlying lung disease o Traumatic pneumothorax: results from penetrating or nonpenetrating chest injuries

o Tension pneumothorax: pneumothorax in which the pressure in the pleural space is positive

throughout the respiratory cycle

Epidemiology

Age o Usually occurs in persons 20–40 years of age

Sex o More common in men

Primary spontaneous pneumothorax

o Typically occurs in tall, thin boys and men 10–30 years of age o Age-adjusted incidence

7.4–18 cases per 100,000 persons per year among men 1.2–6 cases per 100,000 persons per year among women

Secondary spontaneous pneumothorax o Age

Peak incidence at 60–65 years of age o Incidence

6.3 cases per 100,000 persons per year among men 2.0 cases per 100,000 persons per year among women

26 per 100,000 patients with chronic obstructive pulmonary disease per year

Risk Factors

Interstitial and obstructive lung diseases predispose to pneumothorax. Primary spontaneous pneumothorax occurs almost exclusively in smokers.

o Suggests they have subclinical lung disease

o Smoking increases likelihood 22-fold in men and 8-fold in women.[1] Incidence is directly related to amount smoked.

Etiology

Primary spontaneous pneumothorax o Usually due to rupture of apical pleural blebs

Secondary spontaneous pneumothorax o Usually due to chronic obstructive pulmonary disease

o Reported with virtually all lung diseases

o May occur in association with connective-tissue disease, sarcoma, lung cancer, and thoracic endometriosis

Traumatic pneumothorax o Penetrating or blunt trauma to the chest causes air to enter the pleural space.

Directly through the chest wall

Penetration of the visceral pleura Alveolar rupture due to sudden compression of the chest

o Iatrogenic pneumothorax An increasingly common cause

Transthoracic needle aspiration Thoracentesis

Insertion of central intravenous catheters Tension pneumothorax

o Usually occurs during mechanical ventilation or resuscitative efforts o The positive intra-pressure may be life threatening.

Ventilation is severely compromised.

The positive pressure is transmitted to the mediastinum, resulting in decreased venous return to the heart and reduced cardiac output.

Symptoms & Signs

All types of pneumothorax o Chest pain

Abrupt onset

Sharp

Pleuritic Located on side of pneumothorax

o Dyspnea o Tachycardia

o Hypoxia o Hypotension

o Decreased breath sounds on side of pneumothorax Tension pneumothorax

o Difficulty in ventilation during resuscitation o High peak inspiratory pressures during mechanical ventilation

o Enlarged hemithorax with no breath sounds and shift of the mediastinum to the contralateral side

Differential Diagnosis

Pulmonary embolism Myocardial infarction

Congestive heart failure Worsening of underlying lung disease

Anxiety

Diagnostic Approach

Retain a high index of suspicion based on patient’s history, particularly in those with lung disease, and symptoms.

Confirm diagnosis with chest radiography.

Laboratory Tests

Not indicated

Imaging

Posterior–anterior chest radiography o Thin, visceral pleural line (< 1 mm in width) that is displaced from the chest wall confirms

pneumothorax. o Giant bulla may appear to be a pneumothorax on radiography.

The line runs parallel to the chest wall in pneumothorax.

Bullous lesions that abut the chest wall have a concave appearance. Chest CT should be performed if the diagnosis is not clear.

Diagnostic Procedures

Tension pneumothorax o Insert a large-bore needle into the pleural space through the second anterior intercostal space.

o If a large amount of gas escapes from the needle after insertion, the diagnosis is confirmed.

Treatment Approach

Be prepared to manage as a life-threatening medical emergency. Determine if it is necessary to remove air from pleural space.

Prevent recurrence.

Specific Treatments

Primary spontaneous pneumothorax

Observation

o May be appropriate if pneumothorax involves < 15% of hemithorax o Reabsorption of air by the pleura occurs at a rate of 2% per day in patients breathing room air.

Supplemental oxygen accelerates reabsorption 4-fold. Simple aspiration

o Successful in 70% of patients with moderate-sized primary spontaneous pneumothorax o Likely to fail if patient is > 50 years of age or if > 2.5 L of air is aspirated

Tube thoracostomy (chest tube) o Success rate of 90% for treatment of a first pneumothorax

o Rate decreases to 50% for treatment of a first recurrence and 15% for treatment of a second recurrence.

o Large air leaks and pleural effusions that clog the tube contribute to failure. If the lung does not expand or if patient has a recurrence, thoracoscopy (in most centers this is video-

assisted thoracoscopy, or VATS) with stapling of blebs and pleural abrasion is indicated. Treatment algorithm[2]

o Administer oxygen. o Determine size of pneumothorax and stability of patient.

Small with stable patient: observation Large with stable patient: aspiration or small bore chest tube Any size with unstable patient: aspiration or small bore chest tube

o If chest tube: Connect to water seal ± suction. No air leak: Remove chest tube (± clamp tube before removal).

Air leak present: Monitor 4 days. If not resolved, proceed to surgical intervention.

Secondary spontaneous pneumothorax

Tube thoracostomy and instillation of a sclerosing agent, such as doxycycline or tetracycline

Suction may be added in patients with persistent air leaks or if lungs fail to re-expand after drainage. Thoracoscopy (VATS) with bleb resection and pleural abrasion for:

o Persistent air leak o Unexpanded lung after 3 days of tube thoracostomy o Recurrent pneumothorax

Pleurodesis is effective in preventing recurrent spontaneous pneumothorax.[1] o There is no evidence examining when pleurodesis should be administered. o General consensus: after second or third spontaneous pneumothorax

Treatment algorithm[2] o Administer oxygen. o Determine size of pneumothorax and stability of patient.

Small with stable patient

Chest tube with aspiration Observation in selected cases; hospitalize

Large with stable patient Chest tube

Any size with unstable patient Chest tube

o If chest tube: Connect to water seal ± suction. No air leak: Remove chest tube (± clamp tube before removal). Air leak present: Monitor 5 days.

If not resolved, proceed to surgical intervention.

Traumatic pneumothorax

Tube thoracostomy, unless very small Hemopneumothorax

o One chest tube should be placed in the superior part of the hemithorax to evacuate the air. o Another chest tube should be placed in the inferior part of the hemithorax to remove the

blood. Iatrogenic pneumothorax

o Treatment differs according to the degree of distress and size of pneumothorax. Observation with supplemental oxygen Aspiration Tube thoracostomy

Tension pneumothorax

Tube thoracostomy Must be treated as a medical emergency

o If the tension in the pleural space is not relieved, patient is likely to die from inadequate cardiac output or marked hypoxemia.

The large-bore needle inserted to confirm diagnosis should be left in place until a thoracostomy tube can be inserted.

Monitoring

Serial chest radiography o Frequency is guided by direction and rate of change in the clinical status.

After hospital discharge o Follow-up care and chest radiography within 7–10 days

Complications

Hemothorax Cardiovascular compromise secondary to tension pneumothorax

Bronchopleural fistula Complications of chest tube drainage

o Pain o Pleural infection

o Hemorrhage o Hypotension o Pulmonary edema due to lung re-expansion

Recurrence (See Prognosis.)

Prognosis

Life threatening in patients with lung disease because of the lack of pulmonary reserve. Primary spontaneous pneumothorax

o Death is rare. o United Kingdom mortality[1]

1.26 per million per year in men

0.62 per million per year in women o Published recurrence rates vary.

Retrospective case control study of U.S. military personnel: total recurrence rate of 35%[3]

Denmark cohort study: 23% suffered a recurrence in 5 years, most in the first year.[4] o Thoracoscopy (VATS) or thoracotomy with pleural abrasion is almost 100% successful in

preventing recurrence.

Prevention

No specific prevention known

Smoking cessation may reduce risk.

ICD-9-CM

512._ Pneumothorax, (specific type specified by fourth digit) 512.8 Other spontaneous pneumothorax

See Also

Chest Pain Chronic Obstructive Lung Disease

Internet Sites

Professionals

o Clinical Guidelines for Pneumothorax National Guideline Clearinghouse

o Treatment Options for Pneumothorax American College of Emergency Physicians

Patients o Pneumothorax

MedlinePlus

References

1. Wakai A: Spontaneous pneumothorax. Clin Evid , 2006 [PMID:16973077] 2. Baumann MH: Management of spontaneous pneumothorax. Clin Chest Med 27:369, 2006

[PMID:16716824] 3. Voge VM, Anthracite R: Spontaneous pneumothorax in the USAF aircrew population: a retrospective

study. Aviat Space Environ Med 57:939, 1986 [PMID:3778392] 4. Lippert HL et al: Independent risk factors for cumulative recurrence rate after first spontaneous

pneumothorax. Eur Respir J 4:324, 1991 [PMID:1864347]

General Bibliography

Light RW: Pleural Diseases, 4th ed. Philadelphia, Lippincott Williams&Wilkins, 2001 McCool FD, Rochester DF: The lungs and chest wall diseases, in Textbook of Respiratory Medicine, JF

Murray, JA Nabel (eds). Philadelphia, Saunders, 2000, pp 2357–2376

Sahn SA, Heffner JE: Spontaneous pneumothorax. N Engl J Med 342:868, 2000 [PMID:10727592] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 257, Disorders of

the Pleura and Mediastinum by RW Light.

Harrison's Practice

4. Pleural Effusion

Definition

Pleural space: the potential space between the lung and chest wall that normally contains a very thin layer of fluid

Pleural effusion: an excess quantity of fluid in the pleural space o Normally, there is only between 10 and 25 mL of fluid between the visceral and parietal pleurae. o In disease states, up to 3 L of pleural fluid can accumulate.

Empyema: a grossly purulent effusion

Epidemiology

Incidence o Not known precisely o Small population-based studies have shown 320 cases per 100,000 persons.

Mechanism

Under normal circumstances o Each lung produces 250 mL of pleural fluid daily. o Fluid enters the pleural space from the capillaries in the parietal pleura and is removed via the

lymphatics in the parietal pleura. o Fluid can also enter the pleural space from the interstitial spaces of the lung via visceral pleura or from

the peritoneal cavity via small openings in the diaphragm. o The lymphatics have the capacity to absorb 20 times more fluid than is normally formed.

Pleural effusion may develop when there is: o Excess pleural fluid formation o Decreased fluid removal by the lymphatics

Effusions with normal pleura are ultrafiltrates of plasma (transudates). o Leading causes of transudative pleural effusions in the U.S.

Left ventricular failure Pulmonary embolism Cirrhosis

Effusions due to pleural disease resemble plasma (exudates). o Leading causes of exudative effusions

Bacterial pneumonia Cancer Viral infection Pulmonary embolism

Symptoms & Signs

Symptoms o Dyspnea and tachypnea are common, although sometimes even moderate-sized effusions are

asymptomatic. o Chest pain, typically pleuritic (exacerbated by deep breathing and coughing), and cough can be

associated with pleural effusions and pleural inflammation (pleuritis). o Fever may be present, especially if effusion is infectious or autoimmune.

o In patients with significant disease of the lungs (e.g., pneumonia, lung cancer), it can be difficult to determine the extent to which the symptoms are due to the disease vs the effusion.

Signs

o Tracheal shift can be seen with large effusions. o Shift away from the side of the effusion o On physical examination

Decreased breath sounds over the effusion Dullness to percussion over the effusion Crackles may be heard above the effusion because of atelectasis.

Differential Diagnosis

In the U.S., the most commonly diagnosed causes of pleural effusion are: o Congestive heart failure o Parapneumonic effusion o Malignancy o Tuberculosis o Hepatic cirrhosis o Collagen vascular diseases o Pulmonary embolism o Renal disease

Effusions are typically divided into transudates and exudates based on protein and lactate dehydrogenase (LDH) levels (see Diagnostic Approach and Laboratory Tests).

Transudative pleural effusions

Congestive heart failure o Most common cause o Increased quantities of fluid in the lung interstitial spaces exit across the visceral pleura, overwhelming

the capacity of the lymphatics in the parietal pleura to remove fluid. o Effusions may be bilateral or unilateral; if unilateral, right side is more commonly involved.

Cirrhosis o Pleural effusions secondary to hepatic hydrothorax occur in approximately 5% of patients with cirrhosis

and ascites. o Caused by direct movement of peritoneal fluid through small holes in the diaphragm into the pleural

space. o The effusion is usually right-sided and may be large enough to produce severe dyspnea.

Pulmonary thromboembolism o Commonly overlooked as a cause of pleural effusion o Pleural fluid is usually exudative but can be transudative.

Nephrotic syndrome Peritoneal dialysis Superior vena cava obstruction Myxedema

Exudative pleural effusions

Infectious diseases

The most common cause of exudative effusions o Bacterial infections

Parapneumonic effusion is associated with bacterial pneumonia, lung abscess, or bronchiectasis. Common, and should be considered whenever a patient with a bacterial pneumonia is initially

evaluated Patients present with acute fever, chest pain, sputum production, and leukocytosis. Patients with anaerobic infections present with a subacute illness with weight loss, brisk

leukocytosis, mild anemia, and a predisposition to aspiration. o Tuberculosis

Patients present with fever, weight loss, dyspnea, and/or pleuritic chest pain. Relatively uncommon in the U.S.

o Fungal infections o Viral infections

Probably responsible for a sizable percentage of undiagnosed exudative pleural effusions Often resolve spontaneously with no long-term residua

o Parasitic infections

Neoplastic diseases

Metastatic disease to pleura o Common in lung carcinoma, breast carcinoma, and lymphoma

Most patients report dyspnea, frequently out of proportion to the size of the effusion. Glucose level may be reduced if the tumor burden in the pleural space is high. Mesothelioma

o Patients present with chest pain and shortness of breath.

Pulmonary emboli

Effusion is usually an exudate but may be a transudate.

GI disease

Esophageal perforation o pH of pleural fluid < 6.0

Pancreatic disease o Pleural fluid amylase level is elevated.

Intraabdominal abscess o Patient is febrile, has predominantly polymorphonuclear cells in the pleural fluid, and has no pulmonary

parenchymal abnormalities. Diaphragmatic hernia After abdominal surgery Endoscopic variceal sclerotherapy After liver transplantation

Collagen vascular diseases

Rheumatoid pleuritis Systemic lupus erythematosus Drug-induced lupus Immunoblastic lymphadenopathy Sjögren’s syndrome Wegener’s granulomatosis Churg–Strauss syndrome

After coronary artery bypass surgery

Effusions occurring within the first weeks are typically left-sided and bloody, with large numbers of eosinophils, and respond to 1 or 2 therapeutic thoracenteses.

Effusions occurring after the first few weeks are typically left-sided and clear yellow, with predominantly small lymphocytes, and tend to recur.

Other diagnoses

Asbestos exposure: diagnosis of exclusion Sarcoidosis Uremia Meigs’ syndrome (ascites and pleural effusion associated with pelvic tumors *e.g., ovarian fibroma+) Yellow nail syndrome (lymphedema of the legs and nail discoloration) Drug-induced pleural disease: Fluid is usually eosinophilic.

o Nitrofurantoin o Dantrolene o Methysergide o Bromocriptine o Procarbazine o Amiodarone

Trapped lung Radiation therapy Post–cardiac injury syndrome Hemothorax Iatrogenic injury Ovarian hyperstimulation syndrome: ascites and pleural effusion Pericardial disease Chylothorax

o Occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space o Patients present with dyspnea.

Other medical manipulations that induce pleural effusions o Abdominal surgery o Endoscopic variceal sclerotherapy o Radiation therapy o Liver or lung transplantation o Intravascular insertion of central lines

Diagnostic Approach

Diagnostic algorithm

Small effusions in an obvious nonthreatening clinical setting generally do not need to be tapped. A diagnostic (as opposed to therapeutic) thoracentesis may be required anytime the diagnosis is in doubt,

particularly in a seriously ill patient (fever, pleuritic chest pain, etc.). o Success rate is highest when the fluid is free-flowing and layering on lateral decubitus films.

If there is evidence of loculation, the yield of a diagnostic thoracentesis is low. Measure pleural fluid protein and LDH.

o If any of the following criteria are met, pleural fluid is considered an exudate. Ratio of pleural fluid protein to serum protein level > 0.5 Ratio of pleural fluid LDH to serum LDH level > 0.6 Pleural fluid LDH level > two-thirds the upper normal serum limit

o The above criteria misidentify approximately 25% of transudates as exudates. If ≥ 1 of the exudative criteria are met and the patient is clinically thought to have a condition

producing a transudative effusion, check serum-to-effusion albumin gradient. Gradient > 1.2 g/dL (12 g/L) is most likely a transudative pleural effusion.

If a transudate, evaluation is complete; treat underlying causes (congestive heart failure, cirrhosis, nephrosis). If an exudate, measure pH, amylase, and glucose.

o If amylase level is elevated, consider: Esophageal rupture (pH is < 6.0) Pancreatic pleural effusion Cancer

o If glucose level is < 60 mg/dL, consider: Cancer Bacterial infections Rheumatoid pleuritis

If no diagnosis is found, consider pulmonary embolism (spiral CT or lung scan). If no pulmonary embolus is found, test fluid for tuberculosis (PPD, stain and culture). If no tuberculosis is found and symptoms are improving, observe patient. If symptoms are not improving, consider:

o Thoracoscopy o Open pleural biopsy

Laboratory Tests

Initial studies should include pleural fluid LDH and protein measurement. o If infection is suspected, glucose, pH (sent in a gray-top tube), cytology, differential cell count, and Gram

and tuberculosis staining with culture should also be obtained. o Check simultaneous serum LDH, protein, and glucose levels.

Cell count differential is useful in exudative effusions. o > 50% lymphocytes suggests malignancy or tuberculosis. o > 50% polymorphonuclear leukocytes suggests a parapneumonic process. o > 10% eosinophils can be seen with air (pneumothorax) or blood (hemothorax) in the pleural space,

benign asbestosis, as well as some malignancies, fungal and parasitic infections, and certain drug-induced effusions.

Many eosinophilic effusions are idiopathic and resolve spontaneously. If tuberculous effusion is suspected, check adenosine deaminase level.

o Elevated levels, particularly > 70 U/L, are highly suggestive of tuberculosis. o Elevated levels can also be seen in empyema, malignancy, and rheumatoid disease. o Other helpful measures include:

Interferon γ level > 140 pg/mL Positive polymerase chain reaction for tuberculous DNA

A pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) >1500 pg/mL is virtually diagnostic of an effusion secondary to congestive heart failure.

In chylothorax, biochemical analysis reveals a triglyceride level > 1.2 mmol/L (110 mg/dL).

Imaging

Chest radiography o Parapneumonic effusion

Presence of free pleural fluid can be demonstrated with a lateral decubitus radiograph. o Mesothelioma

Pleural effusion, generalized pleural thickening, and a shrunken hemithorax o Chylothorax

Large pleural effusion is present.

Chest CT o Preferably done with intravenous contrast

Can identify pulmonary embolism as the cause Exudative effusions tend to show pleural enhancement, although this should not be used solely

to guide management. o Chylothorax

Assess the mediastinum for lymph nodes. o Mesothelioma

May see irregular or nodular pleural thickening, discrete tumor masses, mediastinal and hilar adenopathy

Pulmonary arteriography o Alternative to diagnose pulmonary embolism as the cause

Ultrasonography o Presence of free pleural fluid can be demonstrated and used to guide thoracentesis.

Lymphangiography o Patients with chylothorax and no obvious trauma, to assess the mediastinum for lymph nodes

Diagnostic Procedures

Diagnostic thoracentesis o Empyema

Thoracentesis reveals purulent/frank pus. o Chylothorax

Thoracentesis reveals milky fluid. o Hemothorax

If pleural fluid is bloody, a hematocrit should be obtained on the pleural fluid. If the hematocrit is > 50% that of the peripheral blood, the patient has a hemothorax.

Therapeutic thoracentesis o Consider if the patient is dyspneic and/or hypoxic. o Perform paracentesis first if hepatohydrothorax is present. o Do not remove more than 1.5 L in 24 hours.

May cause re-expansion pulmonary edema Diagnostic thoracoscopy

o Effusion secondary to cancer If initial cytologic examination is negative, thoracoscopy is the best next procedure if cancer is

strongly suspected. o Mesothelioma

Open pleural biopsy (or thoracoscopy) usually necessary to establish the diagnosis Pleural biopsy

o Closed needle biopsy can disclose malignancy or granulomas of tuberculosis.

Treatment Approach

Treat underlying cause of effusion. Therapeutic thoracentesis

o For symptomatic relief, especially with hypoxia o For patients with large effusions, particularly with lung compression

Tube thoracoscopy for recurrent effusion

Specific Treatments

Effusion due to heart failure

Best treated with diuretics o If the effusion persists despite diuretic therapy, diagnostic thoracentesis should be performed.

Hepatic hydrothorax

If medical management does not control hepatic failure, ascites, and the pleural effusion, consider liver transplantation.

o If the patient is not a candidate for transplantation, the best alternative is insertion of a transjugular intrahepatic portal systemic shunt.

Parapneumonic effusion

If free fluid separates the lung from the chest wall by > 10 mm on chest radiography, therapeutic thoracentesis should be performed.

Factors indicating the likely need for a procedure more invasive than a thoracentesis (in increasing order of importance)

o Loculated pleural fluid o Pleural fluid pH < 7.20 o Pleural fluid glucose level < 3.3 mmol/L (< 60 mg/dL or < 50% serum glucose) o Positive Gram staining or culture of the pleural fluid o Presence of gross pus in the pleural space (empyema)

If the fluid recurs after the initial therapeutic thoracentesis, repeat thoracentesis. If the fluid recurs a second time, tube thoracostomy should be performed if any of the above prognostic factors

are present. If the fluid cannot be completely removed with therapeutic thoracentesis, consider:

o Inserting a chest tube and instilling a thrombolytic agent (streptokinase, 250,000 U) or o Performing thoracoscopy with the breakdown of adhesions o Decortication should be considered when the above are ineffective.

Frank empyema almost always requires chest tube drainage plus parenteral antibiotics. o When there is extensive loculation present, these patients often do not respond to fibrinolysis and

require decortication to free the trapped lung(s).

Effusion secondary to cancer

Presence of an effusion indicates disseminated disease. o Many cancers associated with pleural effusion are not curable with chemotherapy.

If patient’s lifestyle is compromised by dyspnea, and if the dyspnea is relieved with a therapeutic thoracentesis, then consider:

o Tube thoracostomy with instillation of a sclerosing agent, such as doxycycline, 500 mg or o Insertion of a small indwelling catheter

Effusion secondary to pulmonary embolization

Treatment is the same as for any patient with pulmonary emboli (anticoagulation, fibrinolytic therapy). o If the pleural effusion increases in size after anticoagulation, the patient probably has:

Recurrent emboli or Hemothorax or Pleural infection

Tuberculous pleuritis

Treatment of pleural and pulmonary tuberculosis in adults is identical.

Effusion secondary to viral infection

These effusions resolve spontaneously with no long-term residua.

Chylothorax

Treatment of choice for most chylothoraces is insertion of a chest tube plus the administration of octreotide. If these modalities fail, a pleuroperitoneal shunt should be placed unless the patient has chylous ascites. Patients with chylothorax should not undergo prolonged tube thoracostomy with chest tube drainage.

o Will lead to malnutrition and immunologic incompetence

Hemothorax

Most patients should be treated with tube thoracostomy, which allows continuous quantification of bleeding. If the bleeding emanates from a laceration of the pleura

o Apposition of the 2 pleural surfaces is likely to stop the bleeding. If pleural hemorrhage > 200 mL/h

o Consider thoracoscopy or thoracotomy.

Monitoring

Watch for reaccumulation of fluid. Perform upright chest radiography after all thoracenteses to rule out an iatrogenic pneumothorax. Consider retapping an effusion if a patient’s clinical condition deteriorates.

Complications

Untreated exudative effusion will lead to fibrosis and trapped lung with residual decrease in pulmonary functional status.

Untreated empyema can lead to severe morbidity and death. Multiple thoracenteses can lead to drainage of protein stores and malnutrition.

Prognosis

Most transudative pleural effusions will resolve if they are small. Mortality is mainly attributed to complicated, exudative effusions that are not evacuated.

Prevention

Pleurodesis has been used to prevent reaccumulation of effusions, especially those that are malignant.

ICD-9-CM

511.9 Unspecified pleural effusion

See Also

Acute Heart Failure Chronic Heart Failure

Cirrhosis and its Complications

Drug-Induced Lung Diseases Nephrotic Syndrome Pulmonary Thromboembolism Systemic Lupus Erythematosus Sjögren’s Syndrome Tuberculosis Wegener’s Granulomatosis

Internet Sites

Professionals o Homepage

American College of Chest Physicians Patients

o Pleural effusion MedlinePlus

General Bibliography

Heffner JE et al: Management of parapneumonic effusions. An analysis of physician practice patterns. Arch Surg 130:433, 1995 [PMID:7710346]

Light RW: Clinical practice. Pleural effusion. N Engl J Med 346:1971, 2002 [PMID:12075059] Light RW: Pleural Diseases, 5th ed. Philadelphia, Lippincott Williams & Wilkins, 2006 Porcel JM: The use of probrain natriuretic peptide in pleural fluid for the diagnosis of pleural effusions resulting

from heart failure. Curr Opin Pulm Med 11:329, 2005 [PMID:15928501] Rahman NM, Davies RJ, Gleeson FV: Investigating suspected malignant pleural effusion. BMJ 334:206, 2007

[PMID:17255615] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 257, Disorders of the

Pleura and Mediastinum by RW Light.

Harrison's Practice

5. Asthma

Definition

A chronic inflammatory disease of airways, characterized by increased responsiveness of the tracheobronchial tree to various stimuli

o Bronchospasm, once thought to be the primary event in asthma, is now recognized as a secondary phenomenon caused by the underlying inflammatory process.

Manifested physiologically by widespread narrowing of the air passages, and clinically by paroxysms of dyspnea, cough, chest tightness and wheezing

Episodic disease, with acute exacerbations interspersed with symptom-free periods o Most attacks are short-lived, lasting minutes to hours, and can be managed relatively easily. o Less often, patients develop persistent disease necessitating aggressive therapy. o Status asthmaticus is the most severe form of asthma.

Severe obstruction persists for days or weeks Can be life threatening

Epidemiology

Prevalence o Increasing in many parts of the world, but it is unclear whether this is due to an actual increase in

incidence or to overall population growth o Worldwide: 300 million people o Affluent countries:

Adults: 10–12% Children: 15%

o Developing countries: lower prevalence but may be rising due to increased urbanization Incidence in the U.S.

o 10–11 million persons had acute attacks in 1998. o 13.9 million outpatient visits o 2 million requests for urgent care o 423,000 hospitalizations o Total cost: >$6 billion

Ethnic distribution o More prevalent in minorities and inner-city African-American and Hispanic populations

Age o All ages affected, but more prevalent in early life

Peak age: 3 years o ~50% of cases develop before 10 years of age. o Another one-third of cases occur before 40 years of age.

Sex o 2:1 male-to-female ratio in childhood o Sex ratio equalizes by 30 years of age.

Risk Factors

First-degree relative with a history of asthma Personal or family history of atopy History of multiple respiratory infections during childhood Obesity[1]

Other risk factors that may be implicated o Lower maternal age o Prematurity o Low birth weight o Inactivity o Acetaminophen consumption

Breast feeding during infancy appears to reduce risk of childhood asthma.

Etiology

Airway hyperresponsiveness to both specific and nonspecific stimuli is the hallmark of asthma. o Etiology is unknown, but genetic susceptibility and airway inflammation are believed to play

fundamental roles. o Cells thought to be important in the inflammatory response include mast cells, eosinophils,

lymphocytes, and airway epithelial cells. Allergic (extrinsic) asthma

o Associated with a personal and/or family history of allergic diseases, such as rhinitis, urticaria, or eczema o Immunoglobulin E (IgE) mediated o Precipitants

Dust mites (often found in pillows, mattresses, carpets and drapes) Cockroaches Animal dander, especially cats Seasonal pollens

Idiosyncratic (intrinsic) asthma o No defined immunologic mechanism o Precipitants

Upper respiratory infections Exercise Gastroesophageal reflux (rarely causes asthma symptoms) Exposure to cold air Tobacco smoke Pollutants: ozone, nitrogen dioxide, sulfur dioxide Sulfites in food Emotional stress Pharmacologic agents Aspirin NSAIDs Tartrazine dyes β-Adrenergic antagonists Dietary factors (controversial) Diets low in antioxidants (vitamin A, vitamin C, magnesium, selenium, omega-3 polyunsaturated

fats) Diets high in sodium, omega-6 polyunsaturated fats

Occupational asthma can be both allergic and nonallergic, with hundreds of precipitants having been identified.

Associated Conditions

Allergic conditions, such as rhinitis, urticaria, and eczema Gastroesophageal reflux

Symptoms & Signs

Classic symptom triad o Wheezing o Dyspnea o Cough

Typical acute attack o Often occurs at night

With occupational asthma, attacks may occur at work or after work. o Patients experience a sense of constriction in the chest, often with a nonproductive cough. o Respiration becomes audibly harsh. o Wheezing is first noted during expiration and then with inspiration as well. o Expiration becomes prolonged. o If attack is severe or prolonged, there may be loss of adventitial breath sounds.

Wheezing becomes very high pitched. o In extreme situations, mucus plugging and impending suffocation are signaled by:

Lessening or disappearance of wheezing Cough may become extremely ineffective.

o Accessory muscles become visibly active, and a paradoxical pulse often develops. These 2 signs are very valuable in indicating the severity of the obstruction.

o The end of an episode is frequently marked by a cough that produces thick, stringy mucus. Less typically, the patient may have intermittent episodes of nonproductive cough or exertional dyspnea.

o Patients tend to have normal breath sounds but may wheeze after repeated forced exhal ations. Patients with allergic asthma

o Exposure to antigen typically produces an immediate response. o Airway obstruction develops in minutes and then resolves. o 30–50% of patients have a second wave of bronchoconstriction, a "late reaction," 6–10 hours later. o In a minority, only a late reaction occurs.

Patients with idiosyncratic asthma o Bronchospasm typically follows an upper respiratory infection.

Other physical findings o Respiratory rate

Increases with severity o Heart rate

Increases with severity Relative bradycardia may develop with impending respiratory failure

o Use of accessory respiratory muscles Increases with severity Paradoxical thoracoabdominal movement with impending respiratory failure

o Pulsus paradoxus (normally < 10 mmHg) 10–25 mmHg in moderate episode >25 mmHg in severe episode

o Ear, nose, and throat examination Nasal polyps in patients with allergic asthma, cystic fibrosis, aspirin sensitivity

o Skin Eczema and atopic dermatitis in allergic patients

Differential Diagnosis

Recurrent pulmonary emboli o Can be very difficult to distinguish from asthma o Lung scans may not be diagnostic because of the ventilation–perfusion abnormalities characteristic of

asthma. o Chest CT is now preferred at many centers for the diagnosis of a pulmonary embolism. o Rarely, pulmonary angiography may be necessary.

Upper airway obstruction by tumor or laryngeal edema o Typically presents with stridor, and harsh respiratory sounds can be localized to the trachea. o Diffuse wheezing throughout both lung fields is usually absent. o Indirect laryngoscopy or bronchoscopy may be required.

Glottic dysfunction o Narrowing glottis during inspiration and expiration produces episodic attacks of severe airway

obstruction. o Unlike asthma, arterial oxygen tension is well preserved. o Alveolar–arterial gradient for oxygen narrows during the episode but widens in lower airway

obstruction. o Normal findings of glottic examination during symptoms exclude the diagnosis; normal findings during

asymptomatic periods do not. Endobronchial disease (e.g., foreign-body aspiration, neoplasm, or bronchial stenosis)

o Indicated by persistent wheezing localized to 1 area of the chest, in association with paroxysms of coughing

Carcinoid tumors o Usually associated with stridor o Recurrent episodes of bronchospasm can occur.

Chronic bronchitis or emphysema o No true symptom-free periods, history of chronic cough and sputum production as a background to

acute attacks of wheezing Eosinophilic pneumonia, various chemical pneumonias, and exposures to insecticides and cholinergic drugs Acute left ventricular failure

o Moist basilar rales, gallop rhythms, blood-tinged sputum, and other signs of heart failure Systemic vasculitis with pulmonary involvement Vocal cord dysfunction

Diagnostic Approach

In any patient presenting with dyspnea, the first step must be to ascertain the severity of the compromise even before a specific diagnosis is made.

o This can be accomplished quickly by: Observation of the patient’s difficulty breathing (general appearance, ability to speak between

breaths, use of accessory muscles, etc.) Obtaining vital signs, including pulsus paradoxus and oxygen saturation (which may be falsely

elevated in a patient with tachypnea) Diagnosis of asthma is made by history and physical examination, with confirmation by pulmonary function

tests. History

o Course of previous attacks (e.g., need for hospitalization, steroid treatment) Previous intensive care unit admission or intubation: marker of severe disease and high-risk

patient o Response to medications o If occupational exposure is suspected

Ask about workplace and work history in detail. Specific contaminants? Availability and use of protective devices? Ventilation (dose of environmental agent influenced by intensity and physiology—ventilation

rate and depth) Do coworkers have similar complaints? Ask about every job; short-term exposures may be significant.

Physical examination o Presence of wheezing, especially expiratory

Absence of wheezing may signify poor airflow and impending respiratory failure. o Assessment of severity of airflow obstruction

Increased respiratory rate, tachycardia, use of accessory muscles for breathing, and an elevated pulsus paradoxus are all helpful indicators of severity.

Pulmonary function tests (see Diagnostic Procedures) o Show initial airflow obstruction and reversibility with bronchodilator inhalation

The most useful measures are peak flow and forced expiratory volume in 1 second (FEV 1) evaluated as a percent of predicted normal values.

These can be obtained quickly and easily at the bedside. o Bronchoprovocation test may be required if wheezing or airflow obstruction is not initially

demonstrated.

Laboratory Tests

Complete blood count may show eosinophilia. Serum IgE level

o Elevated in allergic asthma o Normal in idiosyncratic asthma o Marked elevations may suggest allergic bronchopulmonary aspergillosis.

Sputum examination o Eosinophilia o Curschmann’s spirals (casts of small airways) o Charcot–Leyden crystals o Presence of large numbers of neutrophils suggests bronchial infection.

Arterial blood gas o Rarely required o May show hypoxemia during a severe attack o Hypocarbia and respiratory alkalosis may also be present. o Normal or elevated arterial partial pressure of carbon dioxide suggests severe respiratory muscle fatigue

or airways obstruction and impending respiratory failure. o Metabolic acidosis is another indicator of impending respiratory collapse. o Arterial blood gas abnormalities are helpful when present, but are insensitive indicators of severe

disease. Electrocardiogram

o May show reversible changes of right axis deviation, P pulmonale, right bundle branch block, or right ventricular hypertrophy with repolarization abnormalities

Imaging

Chest radiography o Not always necessary o Important when complicating infection or pneumothorax is a consideration o May show hyperinflation or patchy infiltrates due to atelectasis behind plugged airways

Diagnostic Procedures

Pulmonary function tests o Support the clinical diagnosis by demonstrating reversible airway obstruction. o Reversibility is defined as a ≥ 15% increase in FEV1 after 2 puffs of a β-adrenergic agonist. o Helpful in judging severity of airway obstruction and for following response to treatment o More reliable than clinical examination or patient’s subjective symptoms o Findings in asthma

Forced vital capacity (FVC); FEV1; maximum, mid-, and peak expiratory flow rate; and FEV1/FVC ratio are all decreased.

Residual volume and total lung capacity are increased. Diffusing capacity of the lung for carbon dioxide is usually normal or slightly increased. An FEV1 of < 25% predicted or < 0.75 L after administration of a bronchodilator indicates severe

disease. Bronchoprovocation test

o May be required when spirometry results are normal and no wheezing is present o Heightened airway responsiveness is found when the patient is challenged with:

Histamine Methacholine Isocapnic hyperventilation of cold air

Skin tests o Positive wheal-and-flare reactions can be demonstrated to various allergens in patients with allergic

asthma. Findings do not necessarily correlate with the intrapulmonary events.

o A significant number of asthmatic patients have negative allergic histories and do not react to skin tests with specific allergens.

Classification

Asthma is quantified by severity. o As severity will vary over time, so will the patient’s classification.

The purpose of classification is to enable the clinician to optimize therapy as quickly as possible. The 4 major classes are:

o Mild, intermittent Symptoms occur 2 or fewer times per week. Asymptomatic between attacks Exacerbations are brief (hours to at most days) and of varying intensity. Nocturnal symptoms are rare, less than twice a month. The FEV1 is greater than 80% predicted during episodes.

o Mild, persistent Symptoms occur more than 2 times a week but less than once a day. Exacerbations may affect normal activity. Nocturnal symptoms occur more than twice a month. FEV1 is greater than 80% predicted during episodes.

o Moderate, persistent Symptoms occur daily. Exacerbations occur more than twice a week and may last days. Exacerbations affect normal activity. Nocturnal symptoms occur more than twice a month. FEV1 is between 60% and 80% during episodes.

o Severe, persistent Symptoms are continual. Physical activity is limited. Exacerbations are frequent. Nocturnal symptoms are frequent. FEV1 is always abnormal and less than 60% predicted during episodes.

Treatment Approach

Emergencies

Identify life-threatening airway obstruction. o Presence of a paradoxical pulse, use of accessory muscles, and marked hyperinflation of the thorax

signify severe airways obstruction. o Failure of these signs to remit promptly after aggressive therapy mandates frequent monitoring of:

Arterial blood gases Peak expiratory flow rate (PEFR) or FEV1

If at presentation the PEFR or FEV1 is ≤ 20% of that predicted and does not double after 1 hour of intensive therapy

o Patient is likely to require intensive treatment, including systemic glucocorticoids and inpatient treatment.

o If the clinical signs of a paradoxical pulse and accessory muscle use are diminishing and/or the PEFR is increasing

No need to change medications or doses Patient needs to be followed closely.

o If the PEFR decreases by > 20% of its previous value or if the magnitude of the pulsus paradoxicus is increasing

Serial measures of arterial blood gases are required. Reconsider the therapeutic methods being used.

o If the patient has hypocarbia, continue the current approach. If the arterial partial pressure of carbon dioxide is within the normal range or is elevated

Patient should be monitored in an intensive care setting. Therapy should be intensified to reverse or arrest the patient’s respiratory failure.

Failure of PEFR to improve to ≥ 70% of baseline with emergency treatment suggests need for hospitalization, with the final decision made on the basis of individual factors (e.g., symptoms, history).

Chronic stable asthma

Goals

General: a stable, asymptomatic state with the best pulmonary function possible using the least medication Specific

o Minimal or absent chronic symptoms or exacerbations o No limitation on activities o No absences from school or work o Maintenance of normal or near-normal pulmonary functions o Minimal use of short-acting β2-agonists (less than once daily, < 1 canister/month) o Minimal or absent adverse effects from medications

A primary step is educating patients. o Patients should monitor PEFR regularly at home and at work. o Asthma triggers should be avoided.

Assess severity of the illness and monitor with objective measures of lung function. o Disappearance of subjective symptoms or wheezing in an acute attack should not be used as the end

point for therapy. Plan for both long-term management and treatment of exacerbations.

Stepwise pharmacologic approach of the National Asthma Education and Prevention Program

Step 1: mild, intermittent o No daily medication needed o Short acting inhaled β2-agonist or glucocorticoid used as needed during exacerbations only

Step 2: mild, persistent

o Low-dose inhaled glucocorticoids taken daily in lowest dose necessary to control symptoms o Short acting β2-agonists used as needed for exacerbations o Alternative treatments (listed alphabetically): cromolyn, leukotriene modifier, nedocromil, or sustained-

release theophylline (serum concentration target of 5–15 μg/mL) Step 3: moderate, persistent

o Low- to medium-dose inhaled glucocorticoids often combined with long-acting inhaled β2-agonists (salmeterol, albuterol sustained-release tablets) are used daily.

o Alternative treatment: leukotriene modifier or theophylline instead of β2-agonists o Short acting β2-agonsts are again used for exacerbations.

Step 4: severe, persistent o Moderate to high-dose inhaled glucocorticoids and long-acting inhaled β2-agonists are used daily and o If needed, glucocorticoid tablets or syrup long term (generally not exceeding 60 mg/d)

Make repeated attempts to reduce systemic glucocorticoids and maintain control with high-dose inhaled glucocorticoids.

o Short acting β2-agonists are again used for exacerbations. Failure to respond quickly may necessitate hospitalization.

Quick relief for all patients

Short-acting bronchodilator: 2–4 puffs inhaled β2-agonists (e.g., albuterol, terbutaline, pirbuterol) as needed for symptoms

Intensity of treatment will depend on the severity of exacerbation. o Up to 3 treatments at 20-minute intervals or a single nebulizer treatment as needed o A course of systemic glucocorticoids may be needed.

Use of short-acting β2-agonists > 2 times a week in intermittent asthma (daily, or increasing use in persistent asthma) may indicate need to initiate or increase long-term control.

Patients with coexisting conditions

Examples: heart disease, pregnancy Treatment does not differ materially from that outlined above. Inhaled β2-selective and anti-inflammatory agents are the mainstay. Use the lowest doses of adrenergics that produce the desired effects.

Occupational asthma

Therapy follows usual guidelines.

Specific Treatments

Emergencies

Aerosolized β2-agonists are the primary therapy for acute episodes. o 3 doses given every 20 minutes by handheld nebulizer, then a single dose every 2 hours until the attack

subsides o Some studies suggest that continuous nebulized β2-agonists may be more effective than intermittent

treatment, especially in severe acute exacerbations. o Treatment with albuterol administered by jet nebulizer, metered-dose inhaler (MDI), or dry powder

inhaler (DPI) all provide equal resolution in acute situations when doses are matched. o Optimum cumulative dose of albuterol is 5–10 mg.

Systemic glucocorticoids o Prednisone (1 mg/kg PO once daily) or Solu-Medrol (125 mg IV every 6 hours)

o No difference between oral and intravenous administration in moderate exacerbations o Intravenous therapy is preferred in severe exacerbations.

Theophylline may speed resolution after the first hour in 5–10% of patients. Magnesium (as magnesium sulfate)

o A smooth muscle–cell relaxant; may also reduce inflammatory bronchoconstriction through actions on mast cells

o Several small randomized, controlled trials support use of magnesium (2 g IV) in acute severe asthma exacerbations.

o Especially useful if the response to inhaled β2-agonist in appropriate dose is inadequate

Adrenergic stimulants

Dilate the airways, decrease release of mediators, and improve mucociliary transport Short-acting β-adrenergic agonists

o The resorcinols (e.g., fenoterol) and saligenins (e.g., albuterol) are highly selective for the respiratory tract and devoid of significant cardiac effects except at high doses.

o Are active by all routes of administration o May last 4–6 hours o Major side effect is tremor. o Inhalation is the preferred route of administration.

Allows maximal bronchodilation with fewer side effects o In treating episodes of severe asthma, intravenous administration offers no advantage over the inhaled

route. o Safety

Association between asthma mortality and the amount of short-acting β-adrenergic agonists used

Increased use of rescue short-acting β-adrenergic agonists reflects poor asthma control, which is a risk factor for asthma death.

Methylxanthines

Used rarely in acute situations, infrequently in chronic cases Serum monitoring is important (target serum concentration of 5–15 μg/mL at steady state). Theophylline and its various salts are medium-potency bronchodilators with questionable anti-inflammatory

properties. o Liquids, sustained-release tablets, and capsules o Starting dose for adults: 10 mg/kg daily

Dose required to achieve desired level varies widely from patient to patient owing to differences in drug metabolism.

o Clearance decreases with age, congestive heart failure, liver disease, pneumonia, viral infection and vaccination, high-carbohydrate diet, and concurrent use of erythromycin and other macrolide antibiotics; quinolone antibiotics; and troleandomycin, allopurinol, cimetidine, and propranolol, zileuton, zafirlukast.

o Clearance increases with use of cigarettes, marijuana, phenobarbital, phenytoin, or any other drug capable of inducing hepatic microsomal enzymes; high-protein, low-carbohydrate diet; barbecued meat; and childhood.

Adjust dose on the basis of the clinical response, with the aid of serum theophylline measurements. Single-dose administration in the evening

o Reduces nocturnal symptoms o Helps keep patients symptom-free during the day

For maintenance therapy, usually given once or twice daily Minimal evidence for additional benefit when used with optimal doses of β-adrenergic stimulants

May decrease inflammation, but as with the long-acting β2-agonists, the effect is not large and clinical impact is undefined.

Side effects: nervousness, nausea, vomiting, anorexia, and headache o At plasma levels > 30 μg/mL, there is a risk of seizures and cardiac arrhythmias.

Anticholinergics

Drugs such as ipratropium bromide o Free of major side effects o Of particular benefit for patients with coexistent heart disease, in whom the use of methylxanthines and

β-adrenergic stimulants is undesirable Major disadvantages

o Slow to act (60–90 minutes may be required before peak bronchodilation achieved) o Of only modest potency

Long-term controller medications

Inhaled glucocorticoids

Drugs of choice in the long-term control of asthma o The combination of an inhaled steroid and a long-acting β-agonist (see below) seems particularly

efficacious in patients with mild to moderate disease. Controls inflammation, facilitates long-term prevention of symptoms, reduces need for glucocorticoids taken as

a tablet or syrup, minimizes acute exacerbations, and prevents hospitalizations No fixed dose works for all patients. There is no convincing reason to prefer one inhaled steroid to another. Inhaled steroids can take ≥ 1 week to produce improvements.

o In rapidly deteriorating situations, prescribe oral preparations and initiate inhaled drugs as the dose of the former is reduced.

o In less emergent circumstances, increase the quantity of inhaled drug up to 2–2.5 times the recommended starting doses.

Side effects increase in proportion to the dose-time product. o Thrush and dysphonia o Increased systemic absorption that accompanies larger doses of inhaled steroids can cause adrenal

suppression, cataract formation, decreased growth in children, interference with bone metabolism, and purpura.

Specific agents o Beclomethasone: 42 μg/puff

Low dose: 4–12 puffs Medium dose: 10–12 puffs High dose: >20 puffs

o Budesonide: 200 μg/dose Low dose: 1–2 inhalations Medium dose: 2–3 inhalations High dose: >3 inhalations

o Flunisolide: 250 μg/dose Low dose: 2–4 puffs Medium dose: 4–8 puffs High dose: >8 puffs

o Fluticasone MDI: 44, 110, 220 μg/puff

Low dose: 2–6 puffs (44 μg) or 2 puffs (110 μg)

Medium dose: 2–6 puffs (110 μg) High dose: >6 puffs (110 μg)

Daily permissible intake: 50, 100, 250 μg/puff Low dose: 2–6 inhalations (50 μg) Medium dose: 3–6 inhalations (100 μg) High dose: >6 inhalations (100 μg)

o Triamcinolone: 100 μg/puff Low dose: 4–10 puffs Medium dose: 10–20 puffs High dose: >20 puffs

Systemic glucocorticoids

The most potent and most effective anti-inflammatory medications available Most beneficial

o In acute illness, when severe airway obstruction is not resolving or is worsening despite intense optimal bronchodilator therapy

o In chronic disease, when there has been failure of a previously optimal regimen and frequent recurrences of symptoms of increasing severity

Prevent relapse after acute exacerbations when given for a 5- to 10-day "burst" at 40–60 mg/d PO o Tapering the dose is not necessary.

When continued steroid therapy is needed: o Institute an alternate-day schedule to minimize side effects

Particularly important in children because continuous glucocorticoid administration interrupts growth

Specific agents o Methylprednisolone

Adults: 7.5–60 mg/d PO in a single dose in the morning or every other day as needed for control o Prednisolone

Adults: Short-course "burst" to achieve control: 40–60 mg/d PO as a single dose or 2 divided doses for 3–10 days

o Prednisone Adults: 40-60 mg/d PO

Long-acting β-adrenergic agonists

Provide sustained effects for 9–12 hours Often used together with inhaled glucocorticoids Particularly helpful for such conditions as nocturnal and exercise-induced asthma Salmeterol

o MDI: 21 μg/puff; adult dose, 2 puffs every 12 hours o DPI: 50 μg/blister; adult dose, 1 blister every 12 hours

Formoterol o DPI: 12 μg/single-use capsule; adult dose, 1 capsule every 12 hours

Long-acting inhaled β2-agonists should not be used for symptom relief or for exacerbations. o Relatively slow onset of action (~30 minutes)

Long half-life means that administration of extra doses can cause cumulative side effects. Safety

o Slight excess in mortality associated with the use of long-acting β-adrenergic agonists is related to the lack of use of concomitant inhaled corticosteroids (ICS), as the long-acting β-adrenergic agonist therapy does not deal with the underlying inflammation

Always use an ICS when long-acting β-adrenergic agonists are given.

Combined medications

Glucocorticosteroid/β2-agonist o Adds convenience and effectiveness in the care of chronic asthma o Tends to work best in patients with milder disease o Fluticasone/salmeterol

DPI: 250 μg/50 μg Adult dose: 1 inhalation bid; dose depends on severity of asthma

o Budesonide/formoterol MDI: 80 µg/4.5 µg; 160 μg/4.5 μg Adult dose: 2 inhalations bid; dose depends on severity of asthma

Mast cell–stabilizing agents

Block the acute obstructive effects of exposure to antigen, industrial chemicals, exercise, or cold air Prevent release of chemical mediators of anaphylaxis Most effective in atopic patients with seasonal disease or perennial airway stimulation Need not be used continuously; protection can be obtained by taking the drug 15–20 minutes before contact

with a precipitant. Specific agents

o Cromolyn MDI: 1 mg/puff; adult dose: 2–4 puffs tid or qid

A therapeutic trial of 2 puffs 4 times daily for 4–6 weeks is frequently necessary before the beneficial effects are seen.

Nebulizer: 20 mg/ampule; adult dose: 1 ampule tid or qid o Nedocromil

MDI: 1.75 mg/puff; adult dose: 2–4 puffs bid to qid

Leukotriene modifiers

Not uniformly effective in all patients with asthma (< 50% responders) o If no improvement is seen after 1 month, treatment can be discontinued.

Leukotriene blockers have been associated with uncovering of Churg–Strauss syndrome. Specific agents

o Zileuton The only 5-lipoxygenase synthesis inhibitor available in the U.S.

Reduces asthma morbidity, provides protection against exercise-induced asthma, diminishes nocturnal symptoms

Limited effectiveness against allergens Hepatic enzyme levels can be elevated after its use; there are significant interactions

with other drugs metabolized in the liver. 300- or 600-mg tablet Adults: 2400 mg/d (tablets given qid)

o Montelukast Leukotriene D4 receptor antagonist Longer acting than zileuton; has same therapeutic profile 4- or 5-mg chewable tablet, 10-mg tablet Adults: 10 mg at bedtime

o Zafirlukast Leukotriene D4 receptor antagonist Longer acting than zileuton; has same therapeutic profile 10- or 20-mg tablet

Adults: 40 mg/d, as 20-mg tablet bid

Anti IgE

A blocking antibody that neutralizes circulating IgE without binding to cell-bound IgE; it thus inhibits IgE-mediated reactions.

Reduces the number of exacerbations in patients with severe asthma and may improve asthma control Very expensive Suitable only for highly selected patients who are not controlled on maximal doses of inhaler therapy and have a

circulating IgE within a specified range o Omalizumab

Give 3–4 month trial of therapy to show objective benefit. Subcutaneous injection every 2–4 weeks No significant side effects

Miscellaneous agents

Opiates, sedatives, and tranquilizers should be absolutely avoided in the acutely ill patient with asthma. Expectorants and mucolytic agents do not add significantly to treatment. Little evidence that intravenous fluids hasten recovery in acute asthma Desensitization or immunotherapy has limited scientific support and minimal clinical effectiveness.

Monitoring

Once control is reached and sustained for several weeks, a step-down reduction in therapy should be undertaken.

o Goal is to find the minimum amount of medication required to keep the patient well. o Begin with dose reduction of glucocorticosteroid.

Medication adjustments should be based on objective changes in lung function (PEFR at home and/or the FEV 1 in the office) as well as on symptoms.

o Review treatment every 1–2 months. When a patient’s asthma is destabilizing, frequent assessments are required.

o Important to gain control as quickly as possible, then step down to the least medication necessary. o Before increasing treatment, review the patient’s inhaler technique, adherence to therapeutic

recommendations, and environment control. In patients taking theophylline, monitor serum levels.

o Goal: 5–15 μg/mL at steady state o Risk of toxicity, including cardiac arrhythmias and seizure at levels > 20 μg/mL

In patients requiring oral corticosteroid treatment for maintenance o Monitor bone density. o Institute preventive treatment if bone density is low.

Calcium and vitamin D Bisphosphonates Estrogen (postmenopausal women)

Complications

Patients who smoke or have other comorbid stimuli may develop irreversible changes in lung function. Spontaneous pneumothorax and/or pneumomediastinum occur rarely. Status asthmaticus Respiratory failure

Prognosis

Mortality o The most recent figures for the U.S. indicate < 6000 deaths per year among ~10 million patie nts at risk. o Death rates appear to be increasing in inner-city areas where there is limited availability of health care. o Only 0.09–0.25% of admissions to hospital are at risk of an untoward event. o Major risk factors for asthma deaths

Poorly controlled disease with frequent use of bronchodilator inhalers Lack of corticosteroid therapy Previous admission to the hospital with near-fatal asthma

Particularly good prognosis for those whose disease is mild and develops in childhood o The proportion of children who still have asthma 7–10 years after the initial diagnosis varies from 26–

78% (average, 46%). o Only 6–19% continue to have severe disease.

Cigarette smoking and asthma o More severe disease o More frequent hospitalizations o Faster decline in lung function o Higher risk of death from asthma

Even when untreated, persons with asthma do not continuously move from mild to severe disease with time. o Clinical course is characterized by exacerbations and remissions. o Some studies suggest:

Spontaneous remissions occur in approximately 20% of those who develop the disease as adults.

~40% can be expected to experience improvement, with less frequent and severe attacks, as they grow older.

Prevention

There is no known primary prevention for asthma. In patients with known disease

o Asthma triggers, including tobacco smoke and other precipitants (see Etiology), should be avoided or controlled.

o Plans should be made for both long-term management and treatment of exacerbations. o Regular follow-up care is mandatory.

ICD-9-CM

493.__ Asthma, (type of asthma specified with fourth digit, degree of severity specified with fifth digit) 493.90 Asthma, unspecified (type of asthma), unspecified (degree of severity)

See Also

Allergic Rhinitis Anaphylaxis Chronic Obstructive Lung Disease Pulmonary Function Tests

Internet Sites

Professionals

o Information for professionals American Academy of Allergy Asthma & Immunology

o Clinical Trials ClinicalTrials.gov

Patients o Asthma

MedlinePlus o Homepage

Asthma and Allergy Foundation of America

References

1. Beuther DA, Sutherland ER: Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 175:661, 2007 [PMID:17234901]

General Bibliography

Arshad SH: Primary prevention of asthma and allergy. J Allergy Clin Immunol 116:3, 2005 [PMID:15990764] Cabana MD, Le TT: Challenges in asthma patient education. J Allergy Clin Immunol 115:1225, 2005

[PMID:15940138] Currie GP et al: Recent developments in asthma management. BMJ 330:585, 2005 [PMID:15761000] Dolovich MB et al: Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American

College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest 127:335, 2005 [PMID:15654001]

Hall JB: Concise review: Contemporary management of status asthmaticus. New York: McGraw-Hill, www.harrisonsonline.com

Heaney LG, Robinson DS: Severe asthma treatment: need for characterising patients. Lancet 365:974, 2005 Mar 12-18 [PMID:15767000]

Szczeklik A, Stevenson DD: Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 111:913, 2003 [PMID:12743549]

Tarlo SM, Liss GM: Occupational asthma: an approach to diagnosis and management. CMAJ 168:867, 2003 [PMID:12668547]

Togias A: Rhinitis and asthma: evidence for respiratory system integration. J Allergy Clin Immunol 111:1171, 2003 [PMID:12789212]

This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 248, Asthma by PJ Barnes.

Harrison's Practice

6. Chronic Obstructive Lung Disease

Definition

A disease state characterized by airflow limitation that is not fully reversible Conditions include:

o Emphysema: anatomically defined condition characterized by destruction and enlargement of

the lung alveoli o Chronic bronchitis: clinically defined condition with chronic cough and phlegm

o Small-airways disease: condition in which small bronchioles are narrowed

Epidemiology

Fourth leading cause of death in the U.S. Affects > 16 million persons in the U.S. Global Initiative for Chronic Obstructive Lung Disease (GOLD) estimates suggest that chronic

obstructive lung disease (COLD) will increase from the sixth to the third most common cause of death worldwide by 2020.

>70% of COLD-related health care expenditures go to emergency department visits and hospital care

(>$10 billion annually in the U.S.). Sex

o Higher prevalence in men, probably secondary to smoking o Prevalence of COLD among women is increasing as the gender gap in smoking rates has

diminished. Age

o Higher prevalence with increasing age Dose–response relationship between cigarette smoking intensity and decreased

pulmonary function

Risk Factors

Smoking (See Figure 1.) o Cigarette smoking is a major risk factor. o Cigar and pipe smoking

Evidence less compelling; likely related to lower dose of inhaled tobacco by-products o Passive (secondhand) smoking

Associated with reductions in pulmonary function Its status as a risk factor for COLD remains uncertain.

Airway hyperresponsiveness Respiratory infections

o Risk factor for exacerbations of COLD

o The association of adult and childhood respiratory infections with development and progression of COLD remains unproved.

Occupational exposures to dust and fumes (e.g., cadmium) o Likely risk factors

o Magnitude of these effects appears substantially less important than the effect of cigarette smoking.

Ambient air pollution o Prolonged exposure to smoke produced by biomass combustion—a common mode of cooking

in some countries—appears to be a significant risk factor for COLD among women in those

countries. o The relationship of other forms of air pollution to COLD remains unproved.

Second-hand smoking exposure o While it has been associated with reductions in pulmonary function, the importance of this risk

factor in the development of the severe pulmonary function reductions in COLD remains uncertain.

Genetic factors o α1 antitrypsin (α1AT) deficiency: Many variants of the protease inhibitor (PI or SERPINA1) locus

that encodes α1AT have been described. M allele: normal levels

S allele: slightly reduced levels

Z allele: markedly reduced levels Individuals with 2 Z alleles or 1 Z and 1 null allele have the most common form of severe

α1AT deficiency. Lowest levels of α1AT are associated with incidence of COLD.

α1AT deficiency interacts with cigarette smoking to increase risk. o Genetic factors probably contribute to the level of pulmonary function achieved during growth

and to the rate of decline in response to smoking and other environmental factors.

Etiology

COLD

o Causal relationship between cigarette smoking and development of COLD has been proved. However, the response to cigarette smoking varies considerably among individuals.

COLD exacerbation o Bacterial infections

Streptococcus pneumoniae Haemophilus influenzae

Moraxella catarrhalis Mycoplasma pneumoniae or Chlamydia pneumoniae (5–10% of exacerbations)

o Viral infections (one-third) o No specific precipitant identified (20–35%)

Associated Conditions

Lung cancer Asthma

Symptoms & Signs

3 most common o Cough

o Sputum production o Exertional dyspnea

Additional signs and symptoms o Dyspnea at rest o Prolonged expiratory phase and/or expiratory wheezing on lung examination o Decreased breath sounds

o Barrel chest o Large lung volumes and poor diaphragmatic excurs ion, as assessed by percussion

o Use of accessory muscles of respiration o Pursed lip breathing (predominantly emphysema)

o Characteristic "tripod" sitting position to facilitate the actions of the sternocleidomastoid, scalene, and intercostal muscles

o Cyanosis, visible in lips and nail beds o Traditional clinical designation

"Pink puffers" are patients with predominant emphysema: thin, noncyanotic at rest, and have prominent use of accessory muscles

"Blue bloaters" are patients with predominant bronchitis: heavy and cyanotic

Most patients have elements of both bronchitis and emphysema, and the physical examination does not reliably differentiate the 2 entities.

o Advanced disease accompanied by systemic wasting Significant weight loss

Bitemporal wasting Diffuse loss of subcutaneous adipose tissue

Paradoxical respiration: inward movement of the rib cage with inspiration (Hoover’s sign)

o Cor pulmonale Signs of overt right heart failure Relatively infrequent since the advent of supplemental oxygen therapy

Differential Diagnosis

Differential diagnosis o Congestive heart failure o Asthma

o Bronchiectasis

o Obliterative bronchiolitis o Pneumonia

o Tuberculosis o Atelectasis

o Pneumothorax o Pulmonary embolism

Considerations o COLD is present only if chronic airflow obstruction occurs.

Chronic bronchitis without chronic airflow obstruction is not COLD. o Asthma

Reduced forced expiratory volume in 1 second (FEV1) in COLD seldom shows large responses (>30%) to inhaled bronchodilators, although improvements up to 15% are common.

Patients with asthma can also develop chronic (not fully reversible) airflow obstruction. o Problems other than COLD should be suspected when hypoxemia is difficult to correct with

modest levels of supplemental oxygen. o Lung cancer

Clubbing of the digits is not a sign of COLD.

In patients with COLD, development of lung cancer is the most likely explanation for newly developed clubbing.

Diagnostic Approach

Initial assessment o History and physical examination (See Signs & Symptoms.) o Pulmonary function testing to assess airflow obstruction o Radiographic studies

Recent guidelines have suggested testing for α1AT deficiency in all subjects with COLD and chronic airflow obstruction.

Assessment of exacerbation o History

Fever Change in quantity and character of sputum

Ill contacts Associated symptoms

Frequency and severity of prior exacerbations o Physical examination

Tachycardia

Tachypnea Chest examination

Focal findings Air movement

Symmetry Presence or absence of wheezing

Paradoxical movement of abdominal wall Use of accessory muscles

Perioral or peripheral cyanosis Mental status

o Radiographic studies Chest radiography focal findings (pneumonia, atelectasis)

o Arterial blood gases Hypoxemia (see below) Hypercapnia (see below)

o Hospitalization recommended for: Respiratory acidosis and hypercarbia

Significant hypoxemia Severe underlying disease

Living situation not conducive to careful observation and delivery of prescribed treatment

Laboratory Tests

Arterial blood gases and oximetry o Although not sensitive, they may demonstrate resting or exertional hypoxemia. o Blood gases provide additional information about alveolar ventilation and acid–base status by

measuring arterial PCO2 and pH. Change in pH with PCO2 is 0.08 units/10 mmHg acutely and 0.03 units/10 mmHg in the

chronic state. Arterial pH allows classification of ventilatory failure, defined as PCO2 > 45 mmHg, into

an acute or chronic condition. Elevated hematocrit suggests chronic hypoxemia.

Testing for α1AT deficiency o Serum level of α1AT is a reasonable initial test.

o For patients with low α1AT levels, definitive diagnosis requires PI type determination. Isoelectric focusing of serum reflects the genotype at the PI locus for the common

alleles and many of the rare PI alleles. Molecular genotyping can be performed for the common PI alleles (M, S, and Z) only.

Sputum Gram stain and culture (for COLD exacerbation)

Imaging

Chest radiography o Emphysema: obvious bullae, paucity of parenchymal markings, or hyperlucency o Increased lung volumes and flattening of the diaphragm suggest hyperinflation.

Chest CT o Definitive test for establishing the absence or presence of emphysema

o Does little to influence therapy except in those individuals considering surgical therapy for their

disease

Diagnostic Procedures

Pulmonary function tests/spirometry o Chronically reduced ratio of FEV1 to forced vital capacity (FVC)

In contrast to asthma, the reduced FEV1 in COLD seldom shows large responses (>30%) to inhaled bronchodilators, although improvements up to 15% are common.

o Reduction in forced expiratory flow rates o Increases in residual volume o Increases in ratio of residual volume to total lung capacity

o Increased total lung capacity (late in the disease) o Diffusion capacity may be decreased in patients with emphysema.

Electrocardiography may demonstrate right ventricular hypertrophy.

Classification

GOLD stage

o 0 Severity: at risk Symptoms: chronic cough, sputum production Spirometry: normal

o I Severity: mild

Symptoms: with or without chronic cough or sputum production Spirometry: FEV1:FVC < 0.7 and FEV1 ≥ 80% predicted

o IIA Severity: moderate Symptoms: with or without chronic cough or sputum production

Spirometry: FEV1:FVC < 0.7 and FEV1 50–80% predicted o III

Severity: severe Symptoms: with or without chronic cough or sputum production

Spirometry: FEV1:FVC < 0.7 and FEV1 30–50% predicted o IV

Severity: very severe Symptoms: with or without chronic cough or sputum production

Spirometry: FEV1:FVC < 0.7 and FEV1 < 30% predicted or FEV1 < 50% predicted with respiratory failure or signs of right heart failure

Classification based on pathologic type

o Centriacinar emphysema Type most frequently associated with cigarette smoking

Most prominent in upper lobes and superior segment of the lower lobes of the lungs o Panacinar emphysema

Usually observed in patients with α1AT deficiency Most prominent in lower lobes

Treatment Approach

General o Institute therapy after assessment of symptoms, potential risks, costs, and benefits.

o Only 3 interventions have been demonstrated to influence the natural history. Smoking cessation

Oxygen therapy in chronically hypoxemic patients Lung volume reduction surgery in selected patients with emphysema

o All other current therapies are directed at improving symptoms and decreasing frequency and severity of exacerbations.

o There is suggestive, but not definitive, evidence that the use of inhaled glucocorticoids may alter mortality (but not lung function).

o Therapeutic response should determine continuation of treatment. Pharmacotherapy

o Bronchodilators Used to treat symptoms The inhaled route is preferred.

Side effects are less than with parenteral delivery. o Anticholinergic agents

Trial of inhaled anticholinergics is recommended in symptomatic patients. Side effects are minor.

Improve symptoms and produce acute improvement in FEV Do not influence rate of decline in lung function

o β-agonists Provide symptomatic benefit Long-acting inhaled β-agonists have benefits similar to anticholinergics.

Addition of a β-agonist to inhaled anticholinergic therapy provides incremental benefit. Side effects include tremor and tachycardia.

o Inhaled glucocorticoids May reduce frequency of exacerbations by 25–30% May slow decline in quality of life

Recent meta-analysis showed no effect on mortality. No evidence of a beneficial effect for the regular use of inhaled glucocorticoids on the

rate of decline of lung function, as assessed by FEV1 Consider a trial in patients with frequent exacerbations (≥2 per year) and those who

demonstrate a significant amount of acute reversibility in response to inhaled bronchodilators.

Risks include increased rates of oropharyngeal candidiasis and loss of bone density. o Oral corticosteroids

Long-term use of oral glucocorticoids is not recommended. Side effects include osteoporosis, weight gain, cataracts, glucose intolerance, and

increased risk of infection.

Exacerbation o Assess the severity of both the acute and chronic components of the patient’s illness.

o Attempt to identify and treat the precipitant of the exacerbation.

Specific Treatments

Stable-phase COLD, pharmacotherapy

Oxygen o Supplemental O2 is the only pharmacologic therapy demonstrated to decrease mortality. o In resting hypoxemia (resting O2 saturation < 88% or < 90% with signs of pulmonary

hypertension or right heart failure), the use of O2 has been demonstrated to significantly affect mortality.

o Supplemental O2 is commonly prescribed for patients with exertional hypoxemia or nocturnal hypoxemia.

Rationale for supplemental O2 in these settings is physiologically sound, but benefits are not well substantiated.

Anticholinergic agents

o Ipratropium bromide (short-acting anticholinergic) (Atrovent) Inhaled: 30-min onset of action; 4-h duration

Atrovent: metered-dose inhaler (or in nebulized solution); 18 μg per inhalation; 1–2 inhalations qid

o Tiotropium (long-acting anticholinergic) (Spiriva) Spiriva: powder via handihaler; 18 μg per inhalation; 1 inhalation qd Improves symptoms and reduces exacerbations

β-agonists o Salmetrol (Serevent):

Powder via diskus; 50-μg inhalation every 12 h o Formoterol (Foradil):

Powder via aerolizer; 12-μg inhalation every 12 h o Albuterol (short-acting) (Proventil HFA, Ventolin HFA, Ventolin, Proventil)

Metered-dose inhaler (or in nebulizer solution); 180-μg inhalation every 4–6 h as needed

Combined β-agonist/anticholinergic: o Albuterol/ipratropium

Metered-dose inhaler (or in nebulized solution); 120 mcg/21 μg per inhalation 1–2 inhalations qid

Inhaled glucocorticoids

o Beclomethasone (QVAR) Metered-dose inhaler; 40–80 μg/spray; 40–160 μg bid

o Budesonide (Pulmicort) Powder via Turbuhaler; 200 μg/spray; 200 μg inhaled bid

o Fluticasone (Flovent) Metered-dose inhaler; 44, 110 or 220 μg/spray; 88–440 μg inhaled bid

o Triamcinolone (Azmacort) Metered-dose inhaler via built-in spacer; 100 μg/spray; 100–400 μg inhaled bid

Other agents o Theophylline

Produces modest improvements in expiratory flow rates and vital capacity and a slight

improvement in arterial oxygen and carbon dioxide levels in moderate to severe COLD Dose: various dosages and preparations; typical dose 300–600 mg/d, adjusted based on

levels o N-acetyl cysteine

Used for its mucolytic and antioxidant properties A prospective trial failed to find any benefit with respect to decline in lung function or

prevention of exacerbations. o Intravenous α1AT augmentation therapy for patients with severe α1AT deficiency

A randomized, controlled trial of α1AT augmentation therapy has never proved efficacious in reducing decline of pulmonary function.

o Antibiotics Long-term suppressive or "rotating" antibiotics are not beneficial.

Stable-phase COLD, nonpharmacologic therapies

Smoking cessation o All patients with COLD should be strongly urged to quit and educated about the benefit of

cessation and risks of continuation.

o Combining pharmacotherapy with traditional supportive approaches enhances considerably the chances of successful smoking cessation.

Bupropion Varenicline

Nicotine replacement (gum, transdermal, inhaler, nasal spray, lozenge) The U.S. Surgeon General recommendation is for all smokers considering quitting to be

offered pharmacotherapy in the absence of any contraindication. General medical care

o Annual influenza vaccine

o Polyvalent pneumococcal vaccine is recommended, although proof of efficacy in patients with COLD is not definitive.

Pulmonary rehabilitation o Improves health-related quality of life, dyspnea, and exercise capacity

o Rates of hospitalization are reduced over 6–12 months. Lung volume reduction surgery

o Offers both a mortality benefit and a symptomatic benefit in certain patients with emphysema Patients with upper lobe–predominant emphysema and a low postrehabilitation

exercise capacity are most likely to benefit. o Contraindications

Significant pleural disease

A pulmonary artery systolic pressure > 45 mm Hg Extreme deconditioning

Congestive heart failure Other severe comorbid conditions

FEV1 < 20% of predicted and diffusely distributed emphysema on CT or diffusing capacity for CO < 20% of predicted (due to increased mortality)

Lung transplantation o COLD is the leading indication.

o Candidates ≤65 years

Severe disability despite maximal medical therapy

No comorbid conditions, such as liver, renal, or cardiac disease Anatomic distribution of emphysema and presence of pulmonary hypertension are not

contraindications. o Unresolved issues include whether single- or double-lung transplantation is preferred.

Exacerbations of COLD

Bronchodilators o Inhaled β-agonist, often with addition of an anticholinergic agent

o Frequency of administration depends on severity of disease. o Initial treatment with nebulized therapy is common; it is often easier to administer in older

patients or those in respiratory distress. o Conversion to metered-dose inhalers is effective and allows an easier transition to outpatient

care. o Methylxanthines (e.g., theophylline) can be added to this regimen, although proof of efficacy is

lacking; serum levels should be monitored to minimize toxicity. Antibiotics

o Choice should be based on local patterns of antibiotic susceptibility of pathogens and the

patient’s clinical condition. Glucocorticoids

o Have been demonstrated to reduce the length of hospital stay, hasten recovery, and reduce the chance of subsequent exacerbation or relapse for up to 6 months

o GOLD guidelines recommend 30–40 mg of oral prednisolone or its equivalent for 10–14 days. o Two weeks of glucocorticoid therapy produces benefit indistinguishable from 8 weeks of

therapy. o For mild to moderate exacerbations, no difference between intravenous and oral

corticosteroids[1]

o Side effects: hyperglycemia, particularly with preexisting diagnosis of diabetes Oxygen

o Supplemental O2 should be supplied to keep arterial saturation ≥ 90%. Mechanical ventilatory support

o Noninvasive positive pressure ventilation in patients with respiratory failure (PaCO2> 45 mmHg) Significantly reduces:

Mortality Need for intubation Complications of therapy Length of hospital stay

Contraindications

Cardiovascular instability Impaired mental status or inability to cooperate

Copious secretions or inability to clear secretions Craniofacial abnormalities or trauma precluding effective fitting of mask

Extreme obesity o Invasive (conventional) mechanical ventilation via endotracheal tube

Indications Severe respiratory distress despite initial therapy

Life-threatening hypoxemia Severe hypercapnia and/or acidosis

Markedly impaired mental status

Respiratory arrest Hemodynamic instability

Other complications Goal: correct the aforementioned conditions

For patients ≥ 65 years of age admitted to the intensive care unit for treatment, mortality doubles over the next year to 60%, regardless of whether mechanical

ventilation was required.

Monitoring

Symptom assessment

Pulse oximetry Serial pulmonary function tests

Complications

Cor pulmonale o Right ventricular hypertrophy and failure induced by hypoxia

Spontaneous pneumothorax occurs in a small proportion of emphysematous patients.

Prognosis

The degree of airflow obstruction is an important prognostic factor in COLD and is the basis for the GOLD disease classification.

o Patients who continue to smoke cigarettes experience a yearly decrease in FEV1 of 80–100 mL. o Even for patients who quit smoking, the FEV1 decreases by 30 mL per year.

More recently it has been shown that a multifactorial index incorporating airflow obstruction, exercise

performance, dyspnea, and body mass index is a better predictor of mortality than pulmonary function alone.

Median survival for severe disease (FEV1 < 1 L) is 4 years. COLD exacerbations

o The mortality of patients requiring mechanical ventilatory support is 17–30% for that particular hospitalization.

o For patients age >65 admitted to the intensive care unit for treatment, the mortality doubles over the next year to 60%, regardless of whether mechanical ventilation was required.

Prevention

Smoking prevention or cessation Prevention of exacerbations

o Long-term suppressive antibiotics are not beneficial. o Inhalation glucocorticoids should be considered in patients with frequent exacerbations or in

patients with an asthmatic component. Vaccination against influenza and pneumococcal infection

ICD-9-CM

496.00 Chronic airway obstruction, not elsewhere classified (includes COPD, unspecified)

See Also

Approach to Weight Loss Asthma Cor Pulmonale Cough

Dyspnea Lung Cancer, General

Pulmonary Arterial Hypertension, Secondary Pulmonary Function Tests

Respiratory Failure

Internet Sites

Professionals

o Homepage Global Initiative for Chronic Obstructive Lung Disease

o Standards for the Diagnosis and Management of Patients with COPD American Thoracic Society and European Respiratory Society

Patients o Tobacco Cessation

U.S. Surgeon General o COPD

Medline Plus

References

1. de Jong YP et al: Oral or Intravenous Prednisolone in the Treatment of COPD Exacerbations: a randomized controlled, double blind study. Chest Jul 23, 2007 [PMID:17646228]

General Bibliography

Celli BR et al: The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 350:1005, 2004 [PMID:14999112]

Fiore MC et al: Treating Tobacco Use and Dependence, Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service, June, 2000

Hersh CP et al: Chronic obstructive pulmonary disease, in Respiratory Genetics, EK Silverman et al, eds.

London, Hodder-Arnold, 2005 Pauwels RA et al: Global strategy for the diagnosis, management, and prevention of chronic

obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 163:1256, 2001 [PMID:11316667]

Rabe KF et al: Update in chronic obstructive pulmonary disease 2006. Am J Respir Crit Care Med 175:1222, 2007 [PMID:17545457]

Rennard SI: Treatment of stable chronic obstructive pulmonary disease. Lancet 364:791, 2004 Aug 28-Sep 3 [PMID:15337408]

Sin DD et al: Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 290:2301, 2003 [PMID:14600189]

Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American

Thoracic Society. Am J Respir Crit Care Med 152:S77, 1995 [PMID:7582322] Wilt TJ et al: Management of stable chronic obstructive pulmonary disease: a systematic review for a

clinical practice guideline. Ann Intern Med 147:639, 2007 [PMID:17975187] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 254, Chronic

Obstructive Pulmonary Disease by JJ Reilly Jr., EK Silverman, and SD Shapiro.

PEARLS

Dyspnea with arm work, especially above the shoulder, is particularly common and severe in COLD.

Harrison's Practice

7. Sepsis and Septic Shock

Definition

Bacteremia: presence of bacteria in blood Septicemia: presence of any pathogenic microorganism or its toxins in blood Sepsis: clinical condition of proven or suspected infection plus evidence of a systemic inflammatory

response

Systemic inflammatory response syndrome (SIRS) is defined by the presence of at least 2 of the

following: o Fever (oral temperature > 38°C) or hypothermia (< 36°C)

o Tachypnea (>24 breaths/min) o Tachycardia (>90 beats/min)

o Leukocytosis (>12,000/μL), leukopenia (< 4,000/μL), or > 10% bands o The etiology of SIRS may be infectious or noninfectious.

Severe sepsis (similar to "sepsis syndrome") o SIRS plus ≥ 1 sign of organ dysfunction

Cardiovascular: arterial systolic blood pressure ≤ 90 mmHg or mean arterial pressure ≤ 70 mmHg that responds to administration of intravenous fluid

Renal: urine output < 0.5 mL/kg per hour for 1 hour, despite adequate fluid resuscitation

Respiratory: ratio of arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FIO2) ≤ 250 or, if the lung is the only dysfunctional organ, ≤ 200

Hematologic: platelet count < 80,000/μL or 50% decrease in platelet count from highest value recorded over previous 3 days

Unexplained metabolic acidosis: a pH ≤ 7.30 or a base deficit ≥ 5.0 mEq/L and a plasma lactate level > 1.5 times the upper limit of normal for the reporting laboratory

Adequate fluid resuscitation: pulmonary artery wedge pressure ≥ 12 mmHg or central venous pressure ≥ 8 mmHg

Septic shock o Sepsis with hypotension (arterial blood pressure < 90 mmHg systolic or 40 mmHg less than

patient’s normal blood pressure) for at least 1 hour despite adequate fluid resuscitation) or o Need for vasopressors to maintain systolic blood pressure ≥ 90 mmHg or mean arterial pressure

≥ 70 mmHg Refractory septic shock

o Septic shock that: Lasts for >1 hour and Does not respond to fluid or pressor administration

Multiple-organ dysfunction syndrome o Dysfunction of > 1 organ

o Intervention required to maintain homeostasis

Harrison's Practice

8. Pulmonary Thromboembolism

Definition

A condition in which venous thrombi dislodge from their site of formation and embolize to the pulmonary arterial circulation

Clinical syndromes o Massive pulmonary thromboembolism (PE)

Systemic arterial hypotension and anatomically widespread thromboembolism o Moderate to large PE

Right ventricular (RV) hypokinesis, but normal systemic arterial pressure o Small to moderate PE

Normal right-heart function and normal systemic arterial pressure

Epidemiology

PE o Incidence

69 cases per 100,000 persons annually o Age

More common with advancing age o Sex

More common in women than in men; ratio, 1.3:1 Venous thromboembolism (VTE): encompasses deep venous thrombosis (DVT) and PE

o VTE-related deaths in the U.S. are estimated at 300,000 annually. 7% diagnosed with VTE and treated 34% sudden fatal PE 59% as undetected PE

o Symptomatic VTE events Approximately two-thirds are hospital acquired. One-third are community acquired. Residents of nursing facilities are especially vulnerable.

o Estimated hospitalized patients at risk for VTE in the U.S. 13.4 million patients annually

5.8 million surgical patients at moderate–high risk 7.6 million medical patients with comorbidities such as heart failure, cancer, and stroke

Risk Factors

Acquired risk factors o Long-haul air travel o Obesity o Cigarette smoking o Oral contraceptive use o Pregnancy o Postmenopausal hormone replacement o Surgery o Trauma o Antiphospholipid antibody syndrome o Cancer

Greater risk of fatal PE[1] o Systemic arterial hypertension o Chronic obstructive pulmonary disease

Genetic risk factors o Factor V Leiden o Prothrombin gene mutation o Antithrombin III deficiency o Protein C deficiency o Protein S deficiency o Homocysteinemia o Family or personal history of VTE

Iatrogenic (upper-extremity DVT) o Long-term indwelling central venous catheters o Permanent pacemakers o Internal cardiac defibrillators

Other risk factors[1] o Varicose veins o Oral corticosteroids o Inflammatory bowel disease

PE (not DVT specific) risk factors[1] o Ischemic heart disease o Heart failure o Cerebrovascular disease

Greater risk of fatal PE

Etiology

Caused by dislodgement of venous thrombi traveling to pulmonary arterial circulation o About half of patients with pelvic vein thrombosis or proximal leg DVT have PE. o Isolated calf vein thrombi pose a lower risk of PE. o Upper-extremity DVTs are becoming a more common problem with increased use of:

Long-term indwelling central venous catheters for hyperalimentation and chemotherapy Frequent insertion of permanent pacemakers and internal cardiac defibrillators

Thrombi occur due to: o Blood vessel wall injury o Blood stasis/venous stasis o Hypercoagulability

Associated Conditions

Deep venous thrombosis

Symptoms & Signs

Dyspnea (most frequent symptom) Tachycardia (most frequent sign) Chest pain

o In massive PE, pain may resemble pain of myocardial infarction. o Pleuritic pain in PE patients with pleural involvement

Tachypnea Low-grade fever Neck vein distention

Accentuated pulmonic component of the second heart sound Massive PE is often indicated by:

o Dyspnea o Syncope o Hypotension o Cyanosis

Small PE located distally near the pleura is often indicated by: o Pleuritic pain o Cough o Hemoptysis o Pulmonary infarction

Young and previously healthy persons (even those with an anatomically large PE): o May appear anxious o Have dyspnea on moderate exertion o Lack classic signs

In older patients experiencing vague chest discomfort: o PE may not be apparent unless signs of right-heart failure are present

Edema Congestive hepatomegaly Systemic venous distention

Differential Diagnosis

Acute coronary syndrome, including unstable angina and acute myocardial infarction Pneumonia, bronchitis, exacerbation of asthma or chronic obstructive pulmonary disease Congestive heart failure Pericarditis Pleurisy, including "viral syndrome"; costochondritis; other musculoskeletal discomfort Rib fracture, pneumothorax Primary pulmonary hypertension Anxiety Nonthrombotic PE

o Fat embolism from: Blunt trauma Long-bone fracture

o Tumor embolism o Bone marrow embolism o Air embolism o Amniotic fluid embolism o Cement and bony fragment emboli can occur after total hip or knee replacement. o Embolism in intravenous drug users

Hair Talc Cotton

Diagnostic Approach

Diagnostic strategy for PE o Initial task is to decide whether the clinical likelihood of PE is high (see below). o Outpatient or emergency department setting

Non-high-clinical likelihood: Check D-dimer level on enzyme-linked immunosorbent assay (ELISA).

Normal: Stop workup; negative quantitative D-dimer latex immunoassay result and a low pretest probability of thromboembolism together are sufficient to exclude acute PE.[2]

Elevated: See "Imaging" for patients with high likelihood. o Inpatient or high likelihood: Use imaging.

Chest CT with contrast, if renal function is normal and no contrast allergy Lung scan, if renal insufficiency or renal contrast allergy

o Imaging nondiagnostic: Check lower-extremity ultrasonography. Positive for DVT: Treat accordingly. Normal or nondiagnostic: Check transesophageal echocardiography or MR or pulmonary

angiography. Assessment of clinical likelihood

o High clinical likelihood of PE if the point score exceeds 4. Signs and symptoms of DVT: 3 Alternative diagnosis less likely than PE: 3 Heart rate >100/min: 1.5 Immobilization >3 days; surgery within 4 weeks: 1.5 Prior PE or DVT: 1.5 Hemoptysis: 1 Cancer: 1

o Non-high likelihood if score ≤ 4

Laboratory Tests

Plasma D-dimer ELISA o Elevated level (>500 ng/mL) in > 95% of patients with PE sensitive, but nonspecific for PE

Levels increase in patients with myocardial infarction, sepsis, or almost any systemic illness. Therefore, test has no useful role for people who are already hospitalized.

o Can be used to help exclude PE: negative predictive value of up to 99.6% Arterial blood gases lack diagnostic utility for PE. Cardiac biomarkers

o Serum troponin levels increase in RV microinfarction. o Myocardial stretch often results in elevation of brain natriuretic peptide (BNP) or NT-pro-brain

natriuretic peptide. o Elevated cardiac biomarkers predict an increase in major complications and mortality from PE.

Imaging

Chest radiography

Normal or near-normal result in a dyspneic patient occurs in PE. Well-established abnormalities

o Focal oligemia (Westermark’s sign) o Peripheral wedge-shaped density above the diaphragm (Hampton’s hump) o Enlarged right descending pulmonary artery (Palla’s sign)

Venous ultrasonography

Confirmed DVT is usually an adequate surrogate for PE. Loss of vein compressibility is the primary criterion for DVT. Half of patients with PE have no imaging evidence of DVT, probably because the clot has already embolized to

the lung or is in the pelvic veins.

Workup for PE should continue if there is high clinical suspicion, despite a normal result on ultrasonography.

Chest CT

CT with intravenous contrast is superseding lung scanning as the principal diagnostic imaging test for PE (see Figure 1).

Can effectively diagnose large, central PE Can detect peripherally located thrombi in sixth-order branches In patients without PE, lung parenchymal images may establish alternative diagnoses not apparent on chest

radiography.

Lung scanning

Second-line diagnostic test for PE o Mostly used for patients who cannot tolerate intravenous contrast

Perfusion scan defect indicates absent or decreased blood flow, possibly due to PE. Ventilation scans, obtained with radiolabeled-inhaled gases such as xenon or krypton, improve the specificity of

the perfusion scan. o Abnormal ventilation scans indicate an abnormal nonventilated lung, providing possible explanations for

perfusion defects other than acute PE. o High probability of PE is defined as ≥ 2 segmental perfusion defects in the presence of normal

ventilation. Diagnosis of PE is very unlikely in patients with normal and near-normal scans but is ~90% certain in patients

with high-probability scans. o Most patients have nondiagnostic scans, and fewer than half of patients with angiographically

confirmed PE have a high-probability scan. o As many as 40% of patients with high clinical suspicion for PE and low-probability scans have PE

confirmed by angiography.

MRI

Results are similar compared with first-generation chest CT. MRI also assesses RV function. MR pulmonary angiography detects large proximal PE but is not reliable for smaller segmental and

subsegmental PE. Promising as single test for both diagnosis of PE and assessment of hemodynamic effect

Echocardiography

>50% of patients with PE have normal echocardiograms. Helps with rapid triage of extremely ill patients (can usually reliably differentiate among illnesses that have

radically different treatment) o Acute myocardial infarction o Pericardial tamponade o Dissection of the aorta o PE complicated by right-heart failure

Transthoracic echocardiography o Rarely images thrombus directly o McConnell’s sign (best known indirect sign of PE on transthoracic echo)

RV free-wall hypokinesis with normal RV apical motion, appears to be specific for PE. Transesophageal echocardiography

o Should be considered when CT scanning facilities are not available or when a patient has renal failure or severe contrast allergy that precludes administration of contrast despite premedication with high-dose corticosteroids

o Can directly visualize large proximal PE Detection of RV dysfunction due to PE helps to stratify risk, delineate prognosis, and plan optimal management.

Pulmonary angiography

Selective pulmonary angiography is the most specific examination available for definitively diagnosing PE. o Detects emboli as small as 1–2 mm

Definitive diagnosis of PE depends on visualization of intraluminal filling defect in > 1 projection. Secondary signs of PE

o Abrupt occlusion ("cut-off") of vessels o Segmental oligemia or avascularity o Prolonged arterial phase with slow filling o Tortuous, tapering peripheral vessels

Chest CT with contrast (see above) has virtually replaced invasive pulmonary angiography as a diagnostic test. Invasive catheter-based diagnostic testing is reserved for:

o Patients with technically unsatisfactory chest CTs o Patients in whom an interventional procedure such as catheter-directed thrombolysis or embolectomy

is planned

Contrast phlebography

Replaced by venous ultrasonography Costly, uncomfortable, and occasionally results in contrast allergy or contrast-induced phlebitis

Diagnostic Procedures

Electrocardiography o Classic abnormalities

Sinus tachycardia New-onset atrial fibrillation or flutter S1Q3T3 sign: S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III

o QRS axis is often > 90°. o T-wave inversion in leads V1 to V4: reflects RV strain

Treatment Approach

General guidelines

Primary therapy o Treatment options

Clot dissolution with thrombolysis or Removal of PE by embolectomy

o Primary therapy is reserved for patients at high risk of an adverse clinical outcome. Hemodynamic instability RV dysfunction

Detection of RV hypokinesis on echocardiography is the most widely used approach to risk stratification.

Meta-analysis of 2 trials demonstrated no benefit of thrombolysis vs. anticoagulation in these patients when normotensive.[3]

Elevation of troponin level due to RV microinfarction Secondary prevention of recurrent PE

o Anticoagulation with heparin and warfarin o Placement of an inferior vena caval (IVC) filter

Inpatient vs. outpatient treatment o Some uncomplicated, hemodynamically stable patients may be treated with low-molecular-weight

heparin (LMWH) as outpatients. o Both prognostic scores and biomarkers, specifically BNP and troponin, have been used to try to identify

low-risk patients who may be candidates for outpatient therapy. o While outpatient treatment is a recognized therapy for DVT, no randomized, controlled trials have

addressed this strategy for treating PE. Duration of treatment

o Provoked PE: 3–6 months of anticoagulation o Idiopathic: indefinite

VTE that occurs during long-haul air travel is considered unprovoked.

Modified American College of Chest Physicians consensus guidelines[4]

Initial treatment o Subcutaneous LMWH , intravenous unfractionated heparin (UFH), or subcutaneous fondaparinux for at

least 5 days and until the international normalized ratio (INR) is ≥ 2.0 for at least 24 hours LMWH preferred in nonmassive PE UFH preferred for:

Massive PE Concern for adequate SC absorption Thrombolytic therapy being considered or planned

o Initiate oral anticoagulation on first treatment day along with heparin or fondaparinux. Fibrinolytics

o Not recommended for most patients o Recommended for:

Hemodynamically unstable patients unless major contraindication present due to bleeding risk Selected high-risk patients who are not hypotensive and have a low risk of bleeding

IVC filter placement o Recommended if anticoagulation is contraindicated due to bleeding risk o These patients should subsequently receive a conventional course of anticoagulation if their bleeding

risk resolves. Embolectomy recommended in selected patients who have failed routine therapy if appropriate expertise is

available. Duration of oral anticoagulation

o Transient (reversible) risk factor: 3 months o Unprovoked PE: at least 3 months, then evaluate risks and benefits of long-term therapy

Long-term therapy recommended if first unprovoked VTE is PE and for second unprovoked VTE if no risk factors for bleeding are present

o Target INR is 2.5 (range 2.0–3.0) for all treatment durations. Same initial and long-term anticoagulation treatment is recommended for patients who are unexpectedly found

to have an asymptomatic PE.

Specific Treatments

Primary therapy

Fibrinolysis

o Recombinant tissue plasminogen activator, 100 mg, as a continuous peripheral IV infusion over 2 hours o Patients appear to respond to fibrinolysis for up to 14 days after the PE has occurred. o Complications

Major bleeding 10% 1–2% risk of intracranial hemorrhage

o Contraindications Intracranial disease Recent surgery Trauma

Embolectomy o Open surgical o Catheter-based o Avoids risk of intracranial hemorrhage associated with fibrinolysis in patients with massive PE

Pulmonary thromboendarterectomy o Patients with chronic pulmonary hypertension due to prior PE with severe pulmonary symptoms may

benefit. o Mortality rate at experienced centers is ~5%.

Adjunctive therapy

Pain relief (especially with NSAIDs) Supplemental oxygenation Psychological support Dobutamine and dopamine

o May be effective in the treatment of RV failure and cardiogenic shock Volume loading

o Should be undertaken cautiously to avoid further reductions in left ventricular forward output

Secondary prevention

Heparin

Heparin prevents additional thrombus formation and permits endogenous fibrinolytic mechanisms to lyse clot that has already formed.

o After 5–7 days of heparin, residual thrombus begins to stabilize in the endothelium of the vein or pulmonary artery.

o Does not directly dissolve thrombus that already exists. UFH

o IV bolus, 5000–10,000 U, then continuous infusion of 1000–1500 U/h o Activated partial thromboplastin time (aPTT) at least twice the control value should provide a

therapeutic level. o Nomograms based on a patient’s weight may assist in adjusting the dose.

Weight based: initial bolus of 80 U/kg, then initial infusion rate of 18 U/kg hourly LMWH

o Enoxaparin Preferred dose: 1 mg/kg SC twice daily Alternate dose: 1.5 mg/kg daily

o Tinzaparin 175 units/kg once daily with normal renal function o Greater bioavailability, more predictable dose response, few complications, and longer half-life than

UFH o No laboratory monitoring or dose adjustment is needed unless the patient is markedly obese or has

renal dysfunction.

o Overall 29% reduction in mortality and major bleeding rates compared with UFH o Weight-adjusted doses must be adjusted downward in renal insufficiency because the kidneys excrete

LMWH. Complications

o Hemorrhage If life-threatening or intracranial hemorrhage, administer protamine sulfate 1–1.5 mg IV per 100

U heparin Maximum, 50 mg/dose; rate, 5 mg/min Monitor aPTT

o Osteopenia Less frequent with LMWH

o Heparin-induced thrombocytopenia o Thrombosis due to heparin-induced thrombocytopenia

Manage with a direct thrombin inhibitor. Argatroban for patients with renal insufficiency

Dosage: 2 μg/kg per minute IV; maximum, 10 μg/kg per minute IV Adjust dose on the basis of aPTT.

Hirudin or lepirudin for patients with hepatic failure Hirudin dosage: initial bolus 0.4 mg/kg, maximum, 44-mg bolus; continuous infusion

0.15 mg/kg per hour Lepirudin dosage: IV 0.4 mg/kg (up to 110 kg body weight, max bolus 44 mg) slowly

(e.g., over 15–20 sec) as a bolus followed by 0.15 mg/kg (up to 110 kg of body weight, max 16.5 mg/h) as a continuous IV infusion

Adjust dose on the basis of aPTT. Bivalirudin in the setting of percutaneous coronary intervention

o Elevations in aminotransferase levels

Fondaparinux

Anti-Xa pentasaccharide Approved by the U.S. Food and Drug Administration to treat DVT and PE Administration: once-daily subcutaneous injection Dosing

o Patients weighing < 50 kg receive 5 mg o Patients weighing 50–100 kg receive 7.5 mg o Patients weighing >100 kg receive 10 mg o Dose must be adjusted downward for patients with renal dysfunction because the drug is excreted by

the kidneys. No laboratory monitoring is required. Risk of thrombocytopenia close to zero. No specific antidote, but recombinant factor VIIa is recommended in the case of major bleeding. Research is ongoing for 2 oral direct Xa inhibitors.

o Apixaban o Rivaroxaban

Warfarin

Full effect of warfarin often requires 5 days. o Overlapping with heparin for 5 days counteracts early procoagulant effect of unopposed warfarin.

Dose o Usual starting dose is 5–10 mg/d. o Most common maintenance doses

Average-sized adult: 5 mg/d

Obese or large young patients who are otherwise healthy: 7.5 or 10 mg/d Malnourished patients or after prolonged courses of antibiotics: 2.5 mg/d

o Prothrombin time is standardized with the INR to assess anticoagulant effect. o Target INR is usually 2.5, with a range of 2.0–3.0.

Complications o Hemorrhage

Cryoprecipitate or fresh-frozen plasma (usually 2 U) to achieve immediate hemostasis Recombinant factor VIIa for life-threatening bleeding in the setting of excessive warfarin Vitamin K for less serious bleeding or an excessively high INR

o Skin necrosis (rare) o Alopecia

Contraindications o Pregnancy

IVC filters

Indicated when active bleeding precludes anticoagulation Complications

o Caval thrombosis with marked bilateral leg swelling o Filter may fail, permitting passage of small to medium-sized clots or o Large thrombi to embolize to the pulmonary arteries via collateral veins o By providing a nidus for clot formation, filters double the DVT rate in the 2 years after placement.

If clinically safe, patients receiving filters should also receive concomitant anticoagulation.

Monitoring

Heparin therapy o An aPTT at least twice the control value should provide therapeutic level. o Monitor platelet counts to possible complications of thrombocytopenia and development of heparin-

induced thrombocytopenia. Warfarin therapy

o Prothrombin time is standardized with the INR to assess anticoagulant effect. o Target INR is usually 2.5, with a range of 2.0–3.0. o INR is monitored daily after second or third dose until in therapeutic range for 2 consecutive days.

Then 2–3 times weekly for first 1–2 weeks Then weekly for first 4 weeks If stable, once every 4 weeks

o More frequent monitoring is required if dosage is adjusted. Chronic thromboembolic pulmonary hypertension

o It used to be considered a rare complication (about 1 of 500) of acute PE. However, it appears to be a more common development, occurring in ~4% of patients who

develop acute PE. o Patients with PE should be followed to ensure that if they have initial pulmonary hypertension, it abates

over time (usually 6 weeks). All patients receiving anticoagulation therapy should be monitored for bleeding complications.

Complications

Hypoxemia Right-heart failure Hypotension Lung hemorrhage

Chronic thromboembolic pulmonary hypertension

Prognosis

Progressive RV failure is the usual cause of death from PE. o RV dysfunction on baseline echocardiography of patients with PE who presented with a systolic blood

pressure >90 mmHg was associated with a doubling of the 3-month mortality rate. Combination of RV dysfunction plus elevated biomarkers such as troponin portends an especially ominous

prognosis. Elevated cardiac biomarkers predict an increase in major complications and mortality from PE. Successful thrombolytic therapy rapidly reverses RV failure and leads to a lower rate of death and recurrent PE.

Prevention

Mechanical and pharmacologic measures often succeed in preventing PE. o Minidose UFH: 5000 U SC tid o LMWH

Enoxaparin: 40 mg SC qd Dalteparin: 2500 or 5000 U SC qd

o Graduated compression stockings (GCS): 10–18 mmHg o Intermittent pneumatic compression devices (IPC)

Prophylaxis based on risk group o High-risk general surgery

Minidose UFH + GCS or LMWH + GCS

o Thoracic surgery Minidose UFH + IPC

o Cancer surgery, including gynecologic cancer surgery (consider 4 weeks of prophylaxis) LMWH

o Total hip replacement, total knee replacement, hip fracture surgery (treat for 4–6 weeks) LMWH or Fondaparinux, 2.5 mg SC qd or Warfarin (target INR, 2.5) (except for total knee replacement)

o Neurosurgery GCS + IPC

o Neurosurgery for brain tumor Minidose UFH + IPC + predischarge venous ultrasonography or LMWH + IPC + predischarge venous ultrasonography

o Benign gynecologic surgery Minidose UFH + GCS

o Medically ill patients Minidose UFH or LMWH Meta-analysis suggests that LMWH is more effective at preventing DVT.[5]

No difference in risk of bleeding or thrombocytopenia seen o Anticoagulation contraindicated

GCS + IPC o Long-haul air travel

Consider LMWH for very-high-risk patients.

IVC filters o Acute proximal DVT with contraindication to anticoagulation is the only universally agreed upon

indication for placement. o Other commonly used indications

Patients at high risk for a poor outcome should another PE occur while on anticoagulation therapy

Progression of DVT despite full anticoagulation Recurrent VTE despite full anticoagulation Prevention of recurrent PE in patients with right heart failure who are not candidates for

fibrinolysis Primary prophylaxis in extremely high-risk patients

Trauma patients at increased risk for bleeding and prolonged immobilization Patients undergoing bariatric surgery with history of VTE

o Retrievable filters Indications for placement

Transient bleeding risk Treatable cause of hemorrhage Temporary high risk of PE

These filters can be retrieved up to several months following insertion, unless thrombus forms and is trapped within the filter.

o Alternatives to IVC filter placement in anticoagulation failures Increase the intensity of anticoagulation Switch to a different anticoagulant

ICD-9-CM

415.11 Iatrogenic pulmonary embolism and infarction 415.19 Other pulmonary embolism and infarction (includes pulmonary embolism/thromboembolism, not

otherwise specified)

See Also

Cor Pulmonale Deep Venous Thrombosis Fibrinolytic Therapy Pulmonary Arterial Hypertension, Secondary

Internet Sites

Professionals o Antithrombotic and Thrombolytic Therapy Guidelines

American College of Chest Physicians o Pulmonary Embolism

ClinicalTrials.gov Patients

o Pulmonary Embolism MedlinePlus

o Pulmonary Embolism National Heart, Lung, and Blood Institute

References

1. Huerta C et al: Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 167:935, 2007 [PMID:17502535]

2. Froehling DA et al: Evaluation of a quantitative D-dimer latex immunoassay for acute pulmonary embolism diagnosed by computed tomographic angiography. Mayo Clin Proc 82:556, 2007 [PMID:17493420]

3. Worster A et al: Thrombolytic Therapy for Submassive Pulmonary Embolism? Ann Emerg Med Apr 19, 2007 [PMID:17449142]

4. Kearon C et al: Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:454S, 2008 [PMID:18574272]

5. Wein L et al: Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med 167:1476, 2007 [PMID:17646601]

General Bibliography

Agnelli G, Becattini C: Acute pulmonary embolism. N Engl J Med 363:266, 2010 [PMID:20592294] Aklog L et al: Acute pulmonary embolectomy: a contemporary approach. Circulation 105:1416, 2002

[PMID:11914247] Blondon M, Bounameaux H, Righini M: Treatment strategies for acute pulmonary embolism. Expert Opin

Pharmacother 10:1159, 2009 [PMID:19405790] Goldhaber SZ: Risk factors for venous thromboembolism. J Am Coll Cardiol 56:1, 2010 [PMID:20620709] Goldhaber SZ: Pulmonary Embolism, in Braunwald’s Heart Disease, 8th ed, P Libby et al (eds). Philadelphia:

Elsevier, 2008 Hill J, Treasure T: Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary

embolism) in inpatients having surgery: summary of NICE guidance. BMJ 334:1053, 2007 [PMID:17510154] Ingber S, Geerts WH: Vena caval filters: current knowledge, uncertainties and practical approaches. Curr Opin

Hematol 16:402, 2009 [PMID:19550322] Konstantinides S et al: Heparin plus alteplase compared with heparin alone in patients with submassive

pulmonary embolism. N Engl J Med 347:1143, 2002 [PMID:12374874] Osinbowale O, Ali L, Chi YW: Venous thromboembolism: a clinical review. Postgrad Med 122:54, 2010

[PMID:20203456] Ridker PM et al: Long-term, low-intensity warfarin therapy for the prevention of recurrent venous

thromboembolism. N Engl J Med 348:1425, 2003 [PMID:12601075] Segal JB et al: Management of venous thromboembolism: a systematic review for a practice guideline. Ann

Intern Med 146:211, 2007 [PMID:17261856] Spyropoulos AC: Emerging strategies in the prevention of venous thromboembolism in hospitalized medical

patients. Chest 128:958, 2005 [PMID:16100192] Tschoe M et al: Retrievable vena cava filters: a clinical review. J Hosp Med 4:441, 2009 [PMID:19753574] van Belle A et al: Effectiveness of managing suspected pulmonary embolism using an algorithm combining

clinical probability, D-dimer testing, and computed tomography. JAMA 295:172, 2006 [PMID:16403929] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 256 Deep Venous

Thrombosis and Pulmonary Thromboembolism by SZ Goldhaber.

Harrison's Practice

9. Pulmonary Edema

Definition

Accumulation of fluid in the interstitium and alveoli of the lungs o Classified as cardiogenic or noncardiogenic

Cardiogenic pulmonary edema

o Due to increased pulmonary capillary pressure, as in severe left ventricular (LV) failure and mitral valve disease

Mild: engorgement of pulmonary vasculature

Moderate: extravasation into interstitial space due to changes in oncotic pressure Severe: alveolar filling

Noncardiogenic pulmonary edema o Increased alveolar–capillary membrane permeability (acute respiratory distress syndrome

[ARDS]) o Decreased plasma oncotic pressure

o Increased negativity of pulmonary interstitial pressure o Lymphatic insufficiency or obstruction

o Other, unknown mechanisms

Epidemiology

Incidence in the U.S. o Heart failure

~0.5 million new cases annually

5–10% of patients reach stage D, in which pulmonary edema is common. o ARDS

Estimated to be 10 per 100,000 persons annually o High-altitude pulmonary edema

1–2% of persons who ascend above 3000 m (9800 ft) at usual ascent rates May be as high as 10% in people who ascend rapidly to 4500 m (14,800 ft)

Risk Factors

Vary by cause

Etiology

Cardiogenic

Basic pathophysiology: A rise in pulmonary venous and pulmonary capillary pressures pushes fluid into the pulmonary alveoli and interstitium.

Causes o Acute myocardial infarction (MI)/ischemia

LV failure

Ventricular septal rupture

Papillary muscle/chordal rupture causing severe mitral regurgitation o Refractory sustained tachyarrhythmias o Acute fulminant myocarditis o Advanced, dilated cardiomyopathy o Hypertrophic cardiomyopathy with severe outflow obstruction

o Aortic dissection with aortic regurgitation o Severe valvular heart disease

Critical aortic or mitral stenosis Acute severe aortic or mitral regurgitation

o Toxic–metabolic Beta blocker or calcium-channel blocker overdose

Noncardiogenic

Altered alveolar–capillary membrane permeability (ARDS) o Infectious pneumonia: bacterial, viral, parasitic o Sepsis/systemic inflammatory response syndrome o Inhaled toxins (e.g., phosgene, ozone, chlorine, Teflon fumes, nitrogen dioxide, smoke) o Circulating foreign substances (e.g., snake venom, bacterial endotoxins) o Aspiration of acidic gastric contents o Acute radiation pneumonitis o Endogenous vasoactive substances (e.g., histamine, kinins) o Disseminated intravascular coagulation o Immunologic: hypersensitivity pneumonitis, drugs (nitrofurantoin), leukoagglutinins o Shock lung in association with nonthoracic trauma

o Acute hemorrhagic pancreatitis Decreased plasma oncotic pressure

o Hypoalbuminemia Increased negativity of interstitial pressure

o Re-expansion pulmonary edema: rapid removal of pneumothorax with large applied negative pressures (unilateral)

o Large negative pleural pressures due to acute airway obstruction with increased end-expiratory volumes (asthma)

Lymphatic insufficiency

o After lung transplantation o Lymphangitic carcinomatosis

o Fibrosing lymphangitis (e.g., silicosis) Unknown or incompletely understood

o High-altitude pulmonary edema Occurrence depends on altitude, rate of ascent, and individual susceptibility.

High intravascular pressures in the lungs appears to lead to stress failures of the pulmonary microvascular endothelium and leakage of fluid into the extravascular space.

Susceptible individuals have abnormally accentuated pulmonary vascular responses to

hypoxia. Acclimatized high-altitude natives can develop the syndrome upon return to high

altitude after a relatively brief sojourn at a lower altitude. More common in persons < 25 years of age

o Neurogenic pulmonary edema

Patients with central nervous system disorders and without apparent preexisting LV dysfunction

o Narcotic overdose The most frequent cause is use of parenteral heroin. Also associated with parenteral and oral overdoses of legitimate preparations of

morphine, methadone, and dextropropoxyphene o Eclampsia

o Cardioversion o Anesthesia

o Cardiopulmonary bypass o Transfusion-related acute lung injury

Symptoms & Signs

Acute pulmonary edema usually presents with: o Rapid onset or aggravation of dyspnea at rest

o Tachypnea o Tachycardia

o Extreme anxiety o Signs of severe hypoxemia

o Hypertension Due to endogenous release of catecholamines

o Rales o Wheezing

Due to airway compression from peribronchial cuffing

o Frothy and blood-tinged sputum More commonly associated with cardiogenic cause

o Evidence of heart failure S3 gallop

Jugular venous distention Unilateral pulmonary edema after rapid evacuation of large pneumothorax

o Findings may be apparent only by radiography. o Occasionally, dyspnea with physical findings localized to edematous lung

Lymphatic blockade secondary to fibrotic and inflammatory diseases or lymphangitic carcinomatosis o Both clinical and radiographic manifestations are dominated by the underlying disease process.

Differential Diagnosis

Other common causes of acute-onset dyspnea o Pulmonary embolism

o Pneumonia Community acquired

Hospital acquired o Aspiration

Pneumonia Pneumonitis

Foreign body

o Pneumothorax o Mucous plug

o Exacerbation of chronic obstructive pulmonary disease o Asthma exacerbation

Diagnostic Approach

Following history and physical examination, it may be difficult to distinguish cardiogenic and noncardiogenic causes.

o In patients with coexisting chronic lung disease, the clinical diagnosis of pulmonary edema may not be clearcut, and the additional steps listed below will also be helpful.

The following steps have been proposed to differentiate between cardiogenic and noncardiogenic pulmonary edema.[1]

o Perform: History and physical Laboratory examination including cardiac enzymes and B-type natriuretic peptide (BNP)

measurement Chest radiography

o If diagnosis remains uncertain, echocardiography is indicated. o Pulmonary artery catheterization may be necessary when:

Cause remains uncertain Disease is refractory to therapy

Disease is accompanied by hypotension

Laboratory Tests

Arterial blood gas analysis o Early in the clinical course, arterial partial pressures of both oxygen and carbon dioxide are

reduced.

o Later, with progressive respiratory failure, hypercapnia develops with progressive acidemia. Serum cardiac biomarkers

o If MI is suspected o See Acute ST Elevation Myocardial Infarction for details.

BNP measurement o Level < 100 pg/mL: heart failure unlikely, negative predictive value 90% o Most patients with symptomatic heart failure have a BNP >400 pg/mL. o 100–400 pg/mL: indiscriminate zone; clinical judgment and additional testing required o Elevated levels may be seen in critically ill patients and those with renal failure.

Proposed cutoff for diagnosis of heart failure in patients with renal disease is >200 pg/mL.

o May be falsely low in patients with flash pulmonary edema, acute papillary muscle rupture, and obesity (body mass index >30 kg/m2)

Imaging

Chest radiography o Sometimes difficult to differentiate cardiogenic from noncardiogenic pulmonary edema o A cardiogenic cause is favored with:

Cardiomegaly

Kerley B lines and loss of distinct vascular margins Cephalization: engorgement of vasculature to the apices

In full-blown clinical pulmonary edema, may show diffuse haziness of lung fields with greater density in more proximal hilar regions, "butterfly" appearance

Pleural effusion o A noncardiogenic cause is favored with:

Cardiomegaly absent

Alveolar edema Lack of cephalization

Pleural effusion less common Echocardiography with color flow Doppler

o May identify systolic and diastolic ventricular dysfunction and valvular lesions suggestive of cardiogenic causes

Diagnostic Procedures

Electrocardiography o ST elevation and evolving Q waves

Usually diagnostic of acute MI Should prompt immediate institution of MI protocols and coronary artery reperfusion

therapy (See Acute ST Elevation Myocardial Infarction.) Pulmonary artery catheterization

o Indicated when: Cause (i.e., cardiogenic vs noncardiogenic) remains uncertain

Pulmonary capillary wedge pressure < 18 mmHg is consistent with a noncardiogenic cause.

Pulmonary capillary wedge pressure >20 mmHg favors a cardiogenic cause.

Pulmonary edema refractory to therapy or accompanied by hypotension o Helps to differentiate high-pressure (cardiogenic) and normal-pressure (noncardiogenic) causes

Treatment Approach

Emergency management o Oxygen/intubation as needed o Intravenous furosemide, 0.5–1.0 mg/kg o Intravenous morphine, 2–4 mg o Sublingual nitroglycerin

Noninvasive positive-pressure ventilation (NIPPV) can:

o Rest respiratory muscles o Improve oxygenation and cardiac function

o Reduce need for intubation Mechanical ventilation can relieve the work of breathing more completely than NIPPV can, but is

associated with more complications. Acute cardiogenic pulmonary edema

o Patients often have identifiable cause of acute LV failure, such as: Arrhythmia

Myocardial ischemia MI

Myocardial decompensation

o Often can be rapidly treated, with improvement in gas exchange o Unless having an acute MI, can sometimes be supported with NIPPV

o Further therapeutic considerations Intra-aortic balloon pump (IABP) Reperfusion/revascularization

Noncardiogenic edema o Usually resolves much less quickly

o Most patients require mechanical ventilation. o NIPPV usually not adequate, as underlying process not readily reversible

o See Acute Respiratory Distress Syndrome for therapeutic details of that condition. Conditions that frequently complicate pulmonary edema must be corrected.

o Infection o Acidemia

o Anemia o Renal failure

Specific Treatments

Support of oxygenation and ventilation

Work of breathing and oxygen requirements are increased in pulmonary edema, which may impose significant physiologic stress on the heart.

Oxygen therapy o Essential to ensure adequate oxygen delivery to tissues

Positive-pressure ventilation o Should be initiated in patients with inadequate oxygenation or ventilation despite supplemental

oxygen o NIPPV

Continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPap) An early trial suggested an increased risk of MI associated with CPAP compared with

BiPap, but this has not been confirmed in subsequent trials. CPAP, but not BiPap, has been shown to reduce mortality.

o Mechanical ventilation Positive end-expiratory pressure can have multiple beneficial effects.

Decreases both preload and afterload, thereby improving cardiac function Redistributes lung water from intra-alveolar to extra-alveolar space, where it

does not interfere as much with gas exchange Increases lung volume to avoid atelectasis

Reduction of preload

Loop diuretics

o Effective in most forms of pulmonary edema Even in presence of hypoalbuminemia, hyponatremia, or hypochloremia

o Furosemide, 0.3–1.0 mg/kg IV < 0.5 mg/kg for new-onset acute pulmonary edema without hypervolemia

1 mg/kg for acute or chronic volume overload, renal insufficiency, long-term diuretic use, hypervolemia, or after failure of lower dose

o Recommended as combination therapy with nitrates[2]

Nitrates o Sublingual nitroglycerin (0.4 mg × 3 every 5 minutes)

First-line therapy for acute cardiogenic pulmonary edema If pulmonary edema persists and in absence of hypotension, may be followed by

intravenous nitroglycerin, commencing at 5–10 μg/min and titrating up to 100 µg/min if necessary and systolic blood pressure > 100 mmHg

o Intravenous nitroprusside (0.1–5 μg/kg per min)

Potent and predominantly arterial vasodilator Useful for patients with pulmonary edema and hypertension and for cautious afterload

and preload reduction if systolic blood pressure > 100 mmHg Requires close monitoring and titration, including use of arterial catheter for continuous

blood pressure measurement in intensive care unit Limited use owing to cyanide toxicity

Morphine o Given in 2- to 4-mg intravenous boluses

o Transient venodilator that reduces preload while relieving dyspnea and anxiety o In patients with pulmonary edema and systemic hypertension, can diminish:

Stress

Catecholamine levels Tachycardia

Ventricular afterload Angiotensin-converting enzyme inhibitors

o Reduce both afterload and preload o Recommended in hypertensive patients

o Reduce short- and long-term mortality in acute MI with heart failure Other preload-reducing agents

o Intravenous recombinant BNP (nesiritide) Potent vasodilator with diuretic properties Use reserved for refractory patients presenting with acute dyspnea at rest Starting dose is a 2-μg/kg IV bolus, followed by 0.01-μg/kg per min infusion. Should be used in conjunction with a diuretic Monitor serum creatinine.

Physical methods o Patients without hypotension should be maintained in a sitting position with legs dangling along

the side of the bed to reduce venous return and preload.

Inotropic and inodilator drugs

Consider in poorly responsive cardiogenic pulmonary edema. Sympathomimetic amines dopamine and dobutamine

o Potent inotropic agents o Dobutamine causes vasodilation.

o Dopamine causes vasoconstriction. Bipyridine phosphodiesterase-3 inhibitors (inodilators)

o Stimulate myocardial contractility while promoting peripheral and pulmonary vasodila tion

o Indicated in patients with cardiogenic pulmonary edema and severe LV dysfunction and elevated left heart filling pressures[3]

o Milrinone: 50 μg/kg, followed by 0.25–0.75 μg/kg per min Digoxin: 0.75 μg IV loading dose, followed by 0.125–0.25 μg daily maintenance dose

o Once a mainstay of treatment because of positive inotropic action

o May be especially useful for control of ventricular rate in patients with rapid atrial fibrillation or flutter and LV dysfunction

Does not have negative inotropic effects of other drugs that inhibit atrioventricular nodal conduction

IABP

May help to relieve cardiogenic pulmonary edema Indicated as stabilizing measure when acute severe mitral regurgitation or ventricular septal rupture

causes refractory pulmonary edema o Especially in preparation for surgical repair

IABP or LV-assist devices o Useful as bridging therapy to cardiac transplantation in patients with refractory pulmonary

edema secondary to myocarditis or cardiomyopathy

Treatment of arrhythmias

Relief of pulmonary congestion will slow sinus rate or ventricular response in atrial fibrillation.

Primary tachyarrhythmia may require cardioversion. Patients with reduced LV function and without atrial contraction or with lack of synchronized

atrioventricular contraction o Consider placement of an atrioventricular sequential pacemaker.

Treatment of acute coronary syndrome

See Acute ST Elevation Myocardial Infarction for details.

Treatment of ARDS

See Acute Respiratory Distress Syndrome for details.

Unusual types of edema

Re-expansion pulmonary edema

o Develops after removal of air or fluid that has been in pleural space for some time o Patients may develop hypotension or oliguria resulting from rapid fluid shifts into lung.

o Diuretics and preload reduction are contraindicated. o Intravascular volume repletion is often needed while supporting oxygenation and gas exchange.

High-altitude pulmonary edema o Oxygen and bed rest

o Descent o Inhaled nitric oxide, if feasible

o Nifedipine may also be effective. o See High-Altitude Illness.

Pulmonary edema resulting from upper-airway obstruction o Recognition of the obstructing cause is key. o Treatment is to relieve or bypass obstruction.

Monitoring

Patients with pulmonary edema need to be in a closely monitored setting, such as telemetry or an intensive care unit, where immediate attention can be given.

Monitor oxygenation. o Continuous pulse oximetry is recommended.

Monitor urine output.

o A Foley catheter is recommended for accurate measurement. Monitor electrolytes.

Monitor BNP. o BNP has a short half-life, and successful therapy is accompanied by a declining BNP.

Complications

Iatrogenic cardiogenic shock o Vasodilators lower blood pressure, and, particularly when used in combination, their use may

lead to: Hypotension

Coronary artery hypoperfusion Shock

o In general, patients with a hypertensive response to pulmonary edema tolerate and are benefited by these medications.

o In normotensive patients, low doses of single agents should be instituted sequentially, as needed.

Respiratory failure Cardiac arrest

End-organ dysfunction

Prognosis

Prognosis depends on the underlying cause. Acute ST-segment elevation MI complicated by pulmonary edema

o Associated with in-hospital mortality rates of 20–40%

ARDS o Mortality estimates: 40–65%

Prevention

Compliance with medications related to underlying disease Low-salt diet

High-altitude pulmonary edema (See High-Altitude Illness.) o Acclimatization and slow ascent o Medications

Calcium-channel blockers Long-acting inhaled β2-adrenergic agonists

Tadalafil Dexamethasone

ICD-9-CM

514 Pulmonary congestion and hypostasis (includes pulmonary edema, not otherwise specified)

518.4 Acute edema of lung, unspecified (includes acute pulmonary edema, not otherwise specified)

See Also

Acute ST Elevation Myocardial Infarction Acute Heart Failure Acute Respiratory Distress Syndrome

Aortic Dissection Aortic Stenosis Chronic Heart Failure High-Altitude Illness Mitral Stenosis Ventricular Tachycardia

Internet Sites

Professionals o Homepage

National Heart, Lung, and Blood Institute Patients

o Pulmonary edema Mayo Clinic

o ARDS U.S. National Heart, Lung, and Blood Institute

References

1. Ware LB, Matthay MA: Clinical practice. Acute pulmonary edema. N Engl J Med 353:2788, 2005 [PMID:16382065]

2. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Acute Heart Failure Syndromes et al: Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med 49:627, 2007 [PMID:17408803]

3. Heart Failure Society Of America : Evaluation and management of patients with acute decompensated heart failure. J Card Fail 12:e86, 2006 [PMID:16500576]

General Bibliography

Cruden NL, Newby DE, Webb DJ: Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 347:1282, 2002 [PMID:12393831]

Imray C et al: Acute mountain sickness: pathophysiology, prevention, and treatment. Prog Cardiovasc Dis 52:467, 2010 May-Jun [PMID:20417340]

Masip J et al: Non-invasive pressure support ventilation versus conventional oxygen therapy in acute

cardiogenic pulmonary oedema: a randomised trial. Lancet 356:2126, 2000 Dec 23-30 [PMID:11191538]

Rimoldi SF et al: Flash pulmonary edema. Prog Cardiovasc Dis 52:249, 2009 Nov-Dec [PMID:19917337]

Scherrer U et al: New insights in the pathogenesis of high-altitude pulmonary edema. Prog Cardiovasc Dis 52:485, 2010 May-Jun [PMID:20417341]

Schoene RB: Illnesses at high altitude. Chest 134:402, 2008 [PMID:18682459]

Terlink JR: Diagnosis and management of acute heart failure, in Libby P et al (eds): Braunwald’s Heart Disease, 8th ed. Philadelphia: Saunders, 2008.

Weng CL et al: Meta-analysis: Noninvasive ventilation in acute cardiogenic pulmonary edema. Ann Intern Med 152:590, 2010 [PMID:20439577]

West JB, American College of Physicians, American Physiological Society: The phys iologic basis of high-

altitude diseases. Ann Intern Med 141:789, 2004 [PMID:15545679] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 33, Dyspnea and

Pulmonary Edema by RM Schwartzstein, and chapter 266, Cardiogenic Shock and Pulmonary Edema by JS Hochman and DH Ingbar.

Harrison's Practice

10. Lung Cancer, General

Definition

Malignant neoplasms arising from respiratory epithelium (bronchi, bronchioles, and alveoli) o Four major cell types make up 88% of all primary lung neoplasms.

Squamous-cell or epidermoid carcinoma

Small-cell (also called oat-cell) carcinoma Adenocarcinoma (including bronchoalveolar)

Large-cell (also called large-cell anaplastic) carcinoma

o Remainder include: Undifferentiated carcinomas

Carcinoids Bronchial gland tumors (including adenoid cystic carcinomas and mucoepidermoid

tumors) Rarer tumor types

o In the past 25 years, for unknown reasons, adenocarcinoma has replaced squamous -cell carcinoma as the most frequent histologic subtype.

This topic covers the general presentation and staging of lung cancer; for treatment details, see: o Non–small Cell Lung Cancer o Small Cell Lung Cancer

Epidemiology

Incidence/prevalence

~ 1 million new cases each year worldwide o Rose dramatically with the increased use of tobacco products, and continues to rise

215,020 new cases in the U.S. in 2008 o 114,690 males

o 100,330 females

See below for age-adjusted incidence for different histologic types. Leading cause of cancer death in both men and women

o 161,840 deaths in 2008 90,810 in men

Mortality rate from lung cancer has declined since 1991 due to decreased smoking prevalence.

71,030 in women

Mortality rate increased dramatically as societal acceptance of smoking among women led to increased smoking prevalence.

Current statistics suggest mortality rate is plateauing among women. o 29% of all cancer deaths

31% in men 26% in women

o 85% of persons die within 5 years of diagnosis.

o Overall mortality rates decreased nearly 4% between 1990 and 1995.

Demographic characteristics

Age o Incidence peaks between 55 and 65 years of age.

Sex o ~55% of cases are in men. o In recent years:

Incidence in men has decreased. Incidence in women has leveled off.

Frequency and age-adjusted incidence

Per 100,000 U.S. population, for different histologic types o Adenocarcinoma (and all subtypes)

Frequency: 32% Age-adjusted rate: 17%

o Squamous-cell (epidermoid) carcinoma Frequency: 29% Age-adjusted rate: 15%

o Small-cell carcinoma Frequency: 18%

Age-adjusted rate: 9% o Large-cell carcinoma

Frequency: 9% Age-adjusted rate: 5%

o Bronchoalveolar carcinoma Frequency: 3%

Age-adjusted rate: 1.4% o Carcinoid

Frequency: 1% Age-adjusted rate: 0.5%

o Mucoepidermoid carcinoma Frequency: 0.1% Age-adjusted rate: < 0.1%

o Adenoid cystic carcinoma Frequency: < 0.1%

Age-adjusted rate: < 0.1% o Sarcoma and other soft-tissue tumors

Frequency: 0.1% Age-adjusted rate: 0.1%

o All others and unspecified carcinomas Frequency: 11% Age-adjusted rate: 6%

o Total Age-adjusted rate: 52%

Risk Factors

Cigarette smoking o 85% of patients with lung cancer of all histologic types are current or former cigarette smokers. o Relative risk of lung cancer

Increases about 13-fold with active smoking Increases about 1.5-fold with long-term passive exposure to cigarette smoke

o Lung cancer death rate Related to total amount (often expressed in "cigarette pack-years") of cigarettes

smoked Risk increases 60- to 70-fold for a man smoking 2 packs a day for 20 years compared

with a nonsmoker o Smoking cessation

Risk decreases at least over first 10 years, but may never return to that of a nonsmoker. Asbestos exposure

o Risk of lung cancer increases synergistically with both smoking and asbestos exposure. Radon exposure

Arsenic exposure

History of radiation therapy to the chest Chronic obstructive pulmonary disease

o Also smoking-related o Further increases risk

Women o Higher relative risk per given exposure than men (~1.5-fold higher)

Likely due to higher susceptibility to tobacco carcinogens o Women with lung cancer are more likely than men to have never smoked.

Positive family history of lung cancer o Several features suggest potential for familial association

People with inherited mutations in RB (patients with retinoblastomas living to adulthood) and p53 (Li-Fraumeni syndrome) genes may develop lung cancer.

First-degree relatives of lung cancer probands Have a 2- to 3-fold excess risk of lung cancer or other cancers, many of which are

not smoking related An as yet unidentified gene in chromosome region 6q23 was found to segregate in

families at high risk of developing lung cancer of all histologic types.

Certain polymorphisms of the P450 enzyme system (which metabolizes carcinogens) or chromosome fragility (mutagen sensitivity) genotypes are associated with the development of lung cancer.

Etiology

Most lung cancers are caused by carcinogens and tumor promoters ingested via cigarette smoking.

Lung cancer cells acquire a number of genetic lesions, including activation of dominant oncogenes and inactivation of tumor suppressor or recessive oncogenes.

o Dominant oncogenes Point mutations in the coding regions of the ras family of oncogenes (particularly in the

K-ras gene in adenocarcinoma of the lung) Mutations in the tyrosine kinase domain of the EGFR found in adenocarcinomas from

nonsmokers (~10% in the U.S. with rates >50% in nonsmoking East Asian patients) Occasional mutations in BRAF and PIK3CA or activation of the PIK3CA/AKT/mTor

pathway

Amplification, rearrangement, and/or loss of transcriptional control of myc family oncogenes (c-, N-, and L-myc; changes in c-myc are found in non-small cell lung cancers, while changes in all myc family members are found in small cell lung cancer)

Overexpression of bcl-2 and other antiapoptotic proteins Overexpression of other EGFR family members such as Her-2/neu and ERBB3

Overexpression of EGFR protein or amplification of the EGFR gene has been found in as many as 70% of non-small cell lung cancers.

Activated expression of the telomerase gene in >90% of lung cancers o Recessive oncogenes (tumor suppressor genes)

Genes involved in lung cancer pathogenesis include p53, RB, RASSF1A, SEMA3B, SEMA3F, FUS1, p16, LKB1, RARβ, and FHIT.

Several tumor-suppressor genes on chromosome 3p appear to be involved in nearly all lung cancers.

Allelic loss for this region occurs very early in lung cancer pathogenesis, including in histologically normal smoking-damaged lung epithelium.

Allele loss occurs at chromosome regions:

1p, 1q, 3p12-13, 3p14 (FHIT gene) 3p21 (RASSF1A gene)

3p21-22 (gene for β-catenin) 3p24-25 (RARβ gene)

4p, 4q, 5q, 8p, 9p (p16/CDKN2, p15,p14ARF gene cluster) 11p13, 11p15, 13q14 (retinoblastoma, rb, gene)

16q 17p13 (p53 gene)

The large number of genetic and epigenetic lesions shows that lung cancer, like other common epithelial cancers, is a multistep process that is likely to involve both carcinogens and tumor promoters.

Associated Conditions

Chronic obstructive pulmonary disease Other smoking-related cancers

o Head and neck

o Esophagus o Bladder

o Kidney o Pancreas o Stomach o Cervix

Cardiovascular disease and stroke

Increased mortality from influenza and pneumonia Smoking accelerates complications of diabetes.

Symptoms & Signs

5–15% of patients with lung cancer are identified while they are asymptomatic. o Most often from routine chest x-ray

o Less commonly from other imaging studies (e.g., CT scanning, MRI)

Overall

Most patients present with some sign or symptom caused by: o Local tumor growth

o Invasion or obstruction of adjacent structures o Growth in regional nodes through lymphatic spread o Growth in distant metastatic sites after hematogenous dissemination o Remote effects of tumor products (paraneoplastic syndromes)

Central or endobronchial growth of primary tumor

May cause: o Cough (present in 45–75%) o Hemoptysis (27–57%)

o Wheeze and stridor o Dyspnea

o Postobstructive pneumonitis (fever and productive cough) Squamous cell and small cell cancers present most often as central masses with endobronchial growth.

Peripheral growth of primary tumor

May cause:

o Pain from pleural or chest wall involvement o Cough o Dyspnea on a restrictive basis o Symptoms of lung abscess resulting from tumor cavitation

Adenocarcinomas and large cell cancers most often present as peripheral nodules or masses, frequently with pleural involvement.

Regional spread of tumor in thorax

By contiguous growth or by metastasis to regional lymph nodes

May cause: o Tracheal obstruction

o Esophageal compression with dysphagia o Recurrent laryngeal nerve paralysis with hoarseness

o Phrenic nerve paralysis with elevation of hemidiaphragm and dyspnea o Sympathetic nerve paralysis with Horner’s syndrome (enophthalmos, ptosis, miosis, and

ipsilateral loss of sweating)

Malignant pleural effusion

Dyspnea

Pancoast’s (or superior sulcus tumor) syndrome

Results from local extension of tumor growing in apex of lung with involvement of eighth cervical and first and second thoracic nerves

Shoulder pain o Characteristically radiates in ulnar distribution of arm

Often radiologic destruction of first and second ribs Often coexists with Horner’s syndrome

Other problems of regional spread

Superior vena cava syndrome from vascular obstruction Pericardial and cardiac extension with resultant tamponade, arrhythmia, or cardiac failure Lymphatic obstruction with resultant pleural effusion Lymphangitic spread through lungs with hypoxemia and dyspnea

Paraneoplastic syndromes

Most commonly seen with small cell cancers due to tumor secretion of ectopic hormone o Corticotropin secretion leads to Cushing’s syndrome.

o Hyponatremia can result from excess secretion of antidiuretic hormone or atrial natriuretic factor.

Systemic symptoms may accompany all types of lung cancer. o Anorexia o Cachexia o Weight loss (30% of patients) o Fever

o Suppressed immunity

Skeletal–connective tissue syndromes

Clubbing (30% of cases) o Usually non-small cell lung carcinomas

Hypertrophic pulmonary osteoarthropathy (1–10% of cases) o Usually adenocarcinomas

o Periostitis and clubbing causing pain, tenderness, and swelling over affected bones.

Neurologic–myopathic syndromes (1% of patients)

Small cell lung cancer

o Myasthenic Eaton–Lambert syndrome (proximal muscle weakness) o Optic neuritis

All lung cancer types o Peripheral neuropathies o Subacute cerebellar degeneration o Cortical degeneration o Polymyositis

Coagulation, thrombotic, or other hematologic manifestations

1–8% of patients

Migratory venous thrombophlebitis (Trousseau’s syndrome)

Nonbacterial thrombotic (marantic) endocarditis with arterial emboli Disseminated intravascular coagulopathy with hemorrhage

Cutaneous manifestations

Uncommon (1%) Dermatomyositis Acanthosis nigricans Leser–Trelat sign (new pruritic seborrheic keratoses and skin tags)

Renal manifestations

Nephrotic syndrome or glomerulonephritis (≤1%)

Differential Diagnosis

Except in cases where the initial presentation is systemic (e.g., weakness, weight loss, a particular paraneoplastic syndrome, etc.), the differential primarily involves distinguishing lung cancer from other pulmonary lesions.

o Lymphoma o Metastatic disease from another primary cancer o Thymoma o Teratoma o Neurogenic tumor o Bacterial pneumonia

o Lung abscess o Tuberculosis o Fungal infection o Bronchogenic cyst o Sarcoidosis o Castleman’s disease o Vascular aneurysm

Diagnostic Approach

Establishing the diagnosis

Diagnosis is suggested by history, physical examination, and imaging studies.

o See Solitary Pulmonary Nodule for details of that presentation.

Once signs, symptoms, or screening studies suggest lung cancer, a tissue diagnosis must be established.

Sputum cytology is most likely to be diagnostic with centrally located tumors.

Tumor tissue can be obtained by: o Bronchial or transbronchial biopsy during fiberoptic bronchoscopy

o Node biopsy during mediastinoscopy o Operative specimen at the time of definitive surgical resection

o Percutaneous biopsy of an enlarged lymph node, soft-tissue mass, lytic bone lesion, bone marrow, or pleural lesion

o Fine-needle aspiration biopsy of thoracic or extrathoracic tumor masses by using CT guidance o Adequate cell block obtained from a malignant pleural effusion

In most cases, a pathologist should be able to: o Make a definite diagnosis of epithelial cancer

o Distinguish small cell from non-small cell lung cancer

Pretreatment staging

Determine location of tumor (anatomic staging).

Assess patient’s ability to withstand various antitumor treatments (physiologic staging).

Evaluation includes:

o Complete history and physical examination Determination of performance status and weight loss

o Complete blood count with platelet determination o Measurement of serum electrolytes, glucose, calcium, and phosphorus; renal and liver function

tests; alkaline phosphatase; albumin o Electrocardiography

o Skin test for tuberculosis o Chest radiography

o CT of chest and abdomen o CT of brain and radionuclide scan of bone if any finding suggests presence of tumor metastasis

in these organs o Fiberoptic bronchoscopy with washings, brushings, and biopsy of suspicious lesions unless

medically contraindicated or would not alter therapy (e.g., patients with very late stage disease)

o Radiography of suspicious bony lesions detected by scan or symptom o Barium-swallow radiographic examination if esophageal symptoms exist

o Pulmonary function studies and arterial blood gas measurements If signs or symptoms of respiratory insufficiency present

o Biopsy of accessible lesions suspicious for cancer if histologic diagnosis not yet made or if treatment or staging decisions would be based on whether or not lesion contained cancer

Additional pretreatment staging procedures are based on the whether lung cancer is small cell or non-small cell.

Laboratory Tests

No laboratory tests are specific for diagnosing lung cancer. Laboratory tests obtained as part of staging procedure

o Complete blood count

o Electrolyte levels o Glucose level

o Calcium level o Phosphorus level o Albumin level

o Alkaline phosphatase level o Renal function tests o Liver function tests o Coagulation tests

Imaging

Diagnostic imaging

Chest radiography and CT o Used to evaluate tumor size and nodal involvement

o Old radiographs are useful for comparison. o Squamous cell and small cell cancers

Usually present as central masses with endobronchial growth o Adenocarcinomas and large-cell cancers

Tend to present as peripheral nodules or masses, frequently with pleural involvement o Squamous-cell and large-cell cancers

Cavitate in ~10–20% of case o Bronchoalveolar carcinoma (form of adenocarcinoma arising from peripheral airways)

Single mass Diffuse, multinodular lesion Fluffy infiltrate

Pretreatment staging imaging

Chest radiography CT of chest and abdomen

o Non–small cell lung cancer, used for: Preoperative staging to detect mediastinal nodes and pleural extension and occult

abdominal disease (e.g., liver, adrenal) Planning curative radiation therapy

o Small cell lung cancer, used for: Planning chest radiation therapy Assessment of response to chemotherapy and radiation therapy

CT of brain o For suspected tumor metastases

Radionuclide bone scan o For suspected tumor metastases

Spinal CT or MRI o If signs or symptoms of spinal cord compression

Barium swallow o For esophageal symptoms

Positron emission tomography (PET) o Sensitive in detecting both intrathoracic and metastatic disease

o Useful in assessing mediastinum and solitary pulmonary nodules o Standardized uptake value > 2.5 highly suspicious for cancer o False-negative results can be seen in:

Diabetes (high serum glucose level dilutes the PET tracer) Slow-growing tumors, such as bronchoalveolar carcinoma

Concurrent infection, such as tuberculosis Lesions < 1 cm

Diagnostic Procedures

Histologic examination of tumor tissue via: o Fiberoptic bronchoscopy

Bronchial or transbronchial biopsy provides information on: Tumor size and location Degree of bronchial obstruction (i.e., assess resectability) Recurrence

o Mediastinoscopy Lymph node biopsy

o Definitive surgical resection Operative specimen

o Percutaneous biopsy

Enlarged lymph node Soft-tissue mass

Lytic bone lesion Bone marrow

Pleural lesion o Fine-needle aspiration with CT guidance

Thoracic or extrathoracic tumor masses o Thoracentesis or video-assisted thoracoscopy (VATS) for evaluation of malignant pleural

effusion

Staging procedures o Fiberoptic bronchoscopy

o Pulmonary function tests and arterial blood gas measurement For patients with signs and symptoms of respiratory insufficiency

If surgical resection is planned o Cardiopulmonary exercise testing

If performance status or pulmonary function tests are borderline If surgical resection is planned

Lumbar puncture o Examination of cerebral spinal fluid cytology in suspected leptomeningitis

Classification

Staging is dependent on type of lung cancer. o Non-small cell lung cancer: tumor, node, metastasis (TNM) international staging system

See Non-small Cell Lung Cancer. o Small cell lung cancer: simple 2-stage system

See Small Cell Lung Cancer.

Treatment Approach

Major treatment decisions are made on the basis of tumor classification.

Small cell carcinomas

o At presentation, usually have spread such that surgery is unlikely to be curative o Managed primarily by chemotherapy combined with radiotherapy for limited-stage disease o Managed primarily by chemotherapy for advanced-stage disease

Non-small cell cancers o Those localized at presentation may be cured with either surgery or radiotherapy.

o These tumors do not respond to chemotherapy as well as small cell carcinomas. o Adjuvant chemotherapy does improve survival in patients with stage I and II disease who have

undergone surgery. o For stage III disease, compared with radiation therapy alone, the addition of chemotherapy

does confer a small but significant survival benefit. The subset of patients with superior sulcus tumors have a 20% 5-year survival rate with

radiation therapy, surgery, or a combination of the two. o For stage IV disease, radiation therapy and other modalities (e.g., laser therapy, cryotherapy)

can provide significant symptomatic relief from local complications. Chemotherapy increases survival only 10–20 weeks and is generally given only to

patients who have been able to maintain a fairly active lifestyle.

Specific Treatments

Specific treatment

Dependent on the type of lung cancer and the stage of the cancer

o See specific topics for details. Small Cell Lung Cancer

Non-small Cell Lung Cancer

All patients

Radiation therapy for:

o Brain metastases o Spinal cord compression

o Weight-bearing lytic bony lesions o Symptomatic local lesions (nerve paralyses, obstructed airway, hemoptysis, intrathoracic large

venous obstruction, in non–small-cell lung cancer and in small-cell cancer not responding to

chemotherapy) Appropriate diagnosis and treatment of other medical problems and supportive care during

chemotherapy Encouragement to stop smoking

o Patients who stop fare better than those who continue. Entrance into clinical trial, if eligible

Monitoring

Monitor for progression/complications of disease. Monitor for recurrence.

Monitor for response/complications of treatment.

Complications

Metastases

May occur in every organ system Extrathoracic metastatic disease is found at autopsy in:

o >50% with squamous cell carcinoma o 80% with adenocarcinoma and large cell carcinoma o >95% with small cell cancer

Common clinical problems related to metastatic lung cancer include: o Brain metastases with neurologic deficits o Bone metastases with pain and pathologic fractures o Bone marrow invasion with cytopenias or leukoerythroblastosis o Liver metastases causing liver dysfunction, biliary obstruction, and pain o Lymph node metastases in supraclavicular region and occasionally in axilla and groin o Spinal cord compression syndromes from epidural or bone metastases

o Adrenal metastases are common but rarely cause adrenal insufficiency.

Paraneoplastic syndromes

Systemic symptoms o Anorexia

o Cachexia o Weight loss (30% of patients)

o Fever

o Suppressed immunity Endocrine syndromes (12% of patients)

o Small cell carcinoma Hyponatremia with syndrome of inappropriate secretion of antidiuretic hormone or

atrial natriuretic factor Ectopic secretion of adrenocorticotropic hormone (ACTH): commonly results in

additional electrolyte disturbances, especially hypokalemia, less often in changes in body habitus that occur in Cushing’s syndrome from pituitary adenoma

o Squamous cell cancers Hypercalcemia and hypophosphatemia may result from tumor production of

parathyroid hormone (PTH) or, more often, PTH-related peptide.

Skeletal–connective tissue syndromes

Clubbing (30% of patients) o Usually non-small cell carcinomas

Hypertrophic pulmonary osteoarthropathy (1–10% patients) o Usually adenocarcinomas o Periostitis and clubbing causing pain, tenderness, and swelling over affected bones o Positive bone scan

Neurologic–myopathic syndromes

1% of patients

Small cell cancer

o Myasthenic Eaton–Lambert syndrome o Optic neuritis

All lung cancer types o Peripheral neuropathies o Subacute cerebellar degeneration

o Cortical degeneration o Polymyositis

Coagulation, thrombotic, or other hematologic manifestations

1–8% of patients

Migratory venous thrombophlebitis (Trousseau’s syndrome) Nonbacterial thrombotic (marantic) endocarditis with arterial emboli

Disseminated intravascular coagulopathy with hemorrhage Anemia, granulocytosis, and leukoerythroblastosis Thrombotic disease is usually a poor prognostic sign.

Renal manifestations

Uncommon (≤1%) Nephrotic syndrome or glomerulonephritis

Prognosis

Overall 5-year survival rate: 15% o Has nearly doubled in past 30 years o Improvement due to advances in combined-technique treatment with surgery, radiotherapy,

and chemotherapy Overall 5-year survival rate for localized disease (20% of patients at time of diagnosis)

o Men: 30% o Women: 50%

Overall 5-year survival rate for advanced disease: 5% 5-year survival rate for different histologic types

o Data for all stages, all races, and both sexes are from SEER data on 87,128 carcinomas, 1978–

1986. Adenocarcinoma (and all subtypes): 17%

Squamous cell (epidermoid) carcinoma: 15% Small cell carcinoma: 5%

Large cell carcinoma: 11% Bronchoalveolar carcinoma: 42%

Carcinoid: 83% Mucoepidermoid carcinoma: 39%

Adenoid cystic carcinoma: 48%

Sarcoma and other soft-tissue tumors: 30% All others and unspecified carcinomas: not available

Prevention

Preventive measures

o Deterring children from taking up smoking and helping young adults stop smoking are likely to be the most effective lung cancer prevention measures.

o Smoking cessation programs Successful in 5–20% of volunteers

o Aids to smoking cessation (successful in only 20–25% of persons at 1 year)

Counseling Behavioral therapy

Nicotine replacement (gum, patch, sublingual spray, inhaler) Antidepressants (bupropion

Varenicline o Chemoprevention

Experimental approach to reduce lung cancer risk At least 2 putative chemoprevention agents, vitamin E and β-carotene, actually increase

risk in heavy smokers. At present, no benefit proved for chemoprevention intervention

Screening measures

o Sputum cytology and chest radiography To screen asymptomatic persons at high risk (men > 45 years who smoke ≥ 40 cigarettes

per day) Has not improved survival rate

Women have not been studied. o Low-dose, noncontrast, thin-slice, helical, or spiral CT of the lung

A large, randomized trial of CT screening for lung cancer (National Lung Cancer Screening Trial) involving ~55,000 individuals has completed accrual and will provide

definitive data in the next several years on whether screening reduces lung cancer mortality.

An international study of annual CT screening of over 31,00 patients at high risk for lung cancer did detect a population of patients with stage I curable lesions and demonstrated a survival benefit.

A smaller study (~3000 high risk patients) also increased lung cancer detection but did not find any survival benefit.

Until the results from the National Lung Cancer Screening Trial become available, routine CT screening for lung cancer cannot be recommended for any risk group.

For those patients who want to be screened, physicians need to discuss the possible benefits and risks of such screening, including:

Risk of false-positive scans that could result in multiple follow-up CTs Possible biopsies for a malignancy that may not be life threatening

ICD-9-CM

162.9 Malignant neoplasm of bronchus and lung, unspecified Lung Cancer, General 197.0 Secondary malignant neoplasm of lung Lung Cancer, General

231.2 Carcinoma in situ of bronchus and lung Lung Cancer, General

See Also

Adrenal Insufficiency in the Cancer Patient

Approach to the Patient with Cancer Bronchoscopy

Intestinal Obstruction in the Cancer Patient Late Consequences of Cancer and Its Treatment Metastatic Cancer of Unknown Primary Non–small Cell Lung Cancer Small Cell Lung Cancer

Solitary Pulmonary Nodule Tumors Metastatic to Bone

Tumors Metastatic to Liver Tumors Metastatic to the Central Nervous System

Internet Sites

Professionals o Lung Cancer (PDQ): Prevention

National Cancer Institute o Lung Cancer (PDQ): Screening

National Cancer Institute Patients

o Lung Cancer U.S. National Cancer Institute

o Lung Cancer MedlinePlus

o Facts About Lung Cancer American Lung Association

o Lung Cancer

American Cancer Society

General Bibliography

Bach PB et al: Computed tomography screening and lung cancer outcomes. JAMA 297:953, 2007 [PMID:17341709]

Black C et al: Population screening for lung cancer using computed tomography, is there evidence of clinical effectiveness? A systematic review of the literature. Thorax 62:131, 2007 [PMID:17287305]

Eberhardt W, Pöttgen C, Stuschke M: Chemoradiation paradigm for the treatment of lung cancer. Nat Clin Pract Oncol 3:188, 2006 [PMID:16596143]

Fu JB et al: Lung cancer in women: analysis of the national Surveillance, Epidemiology, and End Results

database. Chest 127:768, 2005 [PMID:15764756] International Early Lung Cancer Action Program Investigators et al: Survival of patients with stage I lung

cancer detected on CT screening. N Engl J Med 355:1763, 2006 [PMID:17065637] Jackman DM, Johnson BE: Small-cell lung cancer. Lancet 366:1385, 2005 Oct 15-21 [PMID:16226617]

Laskin JJ, Sandler AB: State of the art in therapy for non-small cell lung cancer. Cancer Invest 23:427, 2005 [PMID:16193643]

Mountain CF, Dresler CM: Regional lymph node classification for lung cancer staging. Chest 111:1718, 1997 [PMID:9187199]

Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:1710, 1997 [PMID:9187198]

Spira A, Ettinger DS: Multidisciplinary management of lung cancer. N Engl J Med 350:379, 2004

[PMID:14736930]

Stinnett S, Williams L, Johnson DH: Role of chemotherapy for palliation in the lung cancer patient. J Support Oncol 5:19, 2007 [PMID:17265782]

Sun S et al: Of molecules and cancer stem cells: Novel therapeutic strategies for lung cancer. J Clin Invest 117, 2007

Tyczynski JE, Bray F, Parkin DM: Lung cancer in Europe in 2000: epidemiology, prevention, and early

detection. Lancet Oncol 4:45, 2003 [PMID:12517539] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 85, Neoplasms of

the Lung by JD Minna and JH Schiller.

PEARLS

The Mayo Lung Project showed an increased rate of detection of early tumors in the group screened with frequent chest radiography and sputum cytology compared with control patients not being screened; yet the number of advanced cancers was not reduced, and mortality was not influenced by intensive screening.

o These results suggest overdiagnosis: the detection of some indolent cancers that did not need

to be detected or treated. o The notion that some lung cancers do not require treatment is a revolutionary one and requires

efforts to identify molecular features associated with indolent behavior. Lung cancer risk is increased in people occupationally exposed to diesel exhaust, but no increased risk

has been found in those exposed to welding fumes, conventional gasoline engines, or oil refining. Pancoast’s (superior sulcus) tumors can cause Horner’s syndrome (miosis, ptosis, and anhydrosis) and

shoulder pain from brachial plexus invasion. Hoarseness in lung cancer can be caused by either recurrent laryngeal nerve invasion, which produces

unilateral cord paralysis, or by a paraneoplastic neurologic syndrome, which produces bilateral cord

paralysis.

Harrison's Practice

11. Lung Abscesses and Empyema

Definition

Lung abscess o A localized area of suppuration within lung tissue that leads to parenchymal destruction

Empyema

o Purulent bacterial or fungal infection in the pleural space

Epidemiology

Incidence o Lung abscesses are uncommon, with an incidence of 4–5 cases per 10,000 hospital admissions.

o 40% of pneumonias are associated with a parapneumonic effusion. There are no reliable data on incidence of empyema occurring within parapneumonic

effusions. Incidence is assumed to be low, because the large majority of parapneumonic

effusions are small and resolve readily with appropriate therapy.

Risk Factors

Lung abscess o Risk factors include conditions associated with impaired cough reflex and/or aspiration, such as:

Alcoholism Anesthesia Drug abuse Epilepsy Stroke

o Other risk factors include:

Dental caries Bronchiectasis

Bronchial carcinoma Pulmonary infarction

Empyema o Immunocompromise

o Diabetes o Pneumonectomy and compromised stump

o Trauma and extensive pulmonary contusion o Bronchopleural fistula

Etiology

Lung abscess o Most aspiration-associated lung abscesses are due to a combination of aerobic and anaerobic

bacteria. Average of 6 or 7 bacterial species identified in an individual case

o Anaerobic bacteria include: Bacteroides fragilis group Bacteroides gracilis Prevotella intermedia Prevotella denticola

Prevotella melaninogenicus Prevotella oralis

Fusobacterium nucleatum Peptostreptococcus micros

Peptostreptococcus anaerobius Peptostreptococcus magnus

Actinomyces o Aerobic pathogens include:

Streptococcus milleri (most common) Staphylococcus aureus

Streptococcus pneumoniae

Rarely, S. pneumoniae alone (usually capsular type 3) can cause a lung abscess. Haemophilus influenzae

Pseudomonas aeruginosa Escherichia coli

Klebsiella pneumoniae o In HIV-infected patients, lung abscesses can be due to:

Pneumocystis jiroveci(rare) Rhodococcus equi

Cryptococcus neoformans Nocardia spp. Bacteria noted above

Empyema o Almost always associated with parapneumonic effusions

Caused by the same organisms that cause the adjacent pneumonia o Etiology can involve nearly all organisms, including bacteria (gram-positive or gram-negative

and anaerobic), mycobacteria, and fungi. o Animal studies have revealed that infection with a mixed bacterial flora containing aerobes and

anaerobes is more likely than infection with a single organism. o Streptococci, staphylococci, and Enterobacteriaceae species are common. o Anaerobic bacteria have been cultured from 36–76% of empyemas. o Incidence of K. pneumoniae empyema is higher among diabetic patients. o Tuberculous pleural disease

May occur without obvious concurrent pulmona ry parenchymal disease

Associated Conditions

Empyemas are almost always associated with pneumonias. o See Community-Acquired Pneumonia.

Lemierre’s syndrome is a retropharyngeal cellulitis with associated septic phlebitis of the internal jugular vein and emboli to the lung that can lead to infarction and abscess formation.

o Fusobacterium necrophorum is the usual pathogen.

Symptoms & Signs

Lung abscess o Weight loss o Malaise o Night sweats o Fever

o Productive cough o Patients with anaerobic lung abscess have foul-smelling, often foul-tasting sputum.

o Clubbing of the fingers occurs in ~10% of patients, usually in those who have had symptoms for > 3 weeks.

o Spontaneous drainage occurs via bronchial communication and is accompanied by the production of copious amounts of purulent sputum.

Empyema o Signs and symptoms of pneumonia (See Community-Acquired Pneumonia.)

o Pleuritic chest pain and chest-wall tenderness o Persistent fever despite administration of appropriate antibiotics

Differential Diagnosis

Lung abscess o Cavitating carcinoma

o Wegener’s granulomatosis o Rheumatoid nodules

o Pulmonary infarcts o Tuberculosis

o Fungal infections

Empyema o Pleural fluids that are not infected, whether transudative or exudative, need to be

differentiated from empyema. o Pleural effusion secondary to rheumatoid arthritis can easily be confused with empyema.

Like empyema effusions, rheumatoid arthritis effusions can have: Low glucose levels

Low pH Unlike empyema, rheumatoid arthritis effusions are sterile.

o Cancer, tuberculosis, and lupus pleuritis can also yield acidotic and sterile fluid.

Diagnostic Approach

Lung abscess o Diagnosis is suggested by history, physical examination, and chest radiographic findings. o Percutaneous catheter drainage can be both diagnostic and therapeutic.

Empyema o Signs and symptoms as well as radiologic findings may suggest empyema.

o Diagnosis is confirmed by detection of infection in the pleural space by means of thoracentesis.

Laboratory Tests

Lung abscess o Gram’s staining and culture should be performed on aspirated fluid. o Quantitative cultures of bronchoscopy samples can be helpful.

o Anaerobic organisms may be difficult to isolate, but anaerobic cultures should be done. Empyema

o Pleural fluid Diagnostic

Organisms on Gram staining and/or culture

Anaerobic cultures should be done. Suggestive

pH < 7.20 Glucose level < 60 mg/dL

Blood cultures should be performed and may yield a causative organism. o Not likely to yield anaerobic organisms

Leukocyte count is usually elevated in these conditions but can be normal.

Imaging

Lung abscess o Chest radiography

Classically reveals 1 or 2 thick-walled cavities in dependent areas of the lung

Particularly the upper lobes and posterior segments of the lower lobes An air-fluid level is often present.

o Chest CT (See Figure 1.) Provides a more accurate representation of the cavity and is helpful in defining abscess

size and location Useful in evaluating for additional cavities and pleural disease

o Cavitary lesions in nondependent regions like the right middle lobe or anterior segments of the

upper lobes should raise the possibility of other etiologies, including malignancy. Empyema

o Chest radiography Lateral decubitus films will identify free-flowing fluid.

An irregular border or nonlayering effusion suggests loculation. o CT with intravenous contrast should be performed for optimal management.

May reveal loculations Thickened parietal pleural with enhancement suggests empyema.

o Ultrasonography Used to help guide thoracentesis for small, free-flowing effusions

Diagnostic Procedures

Lung abscess o Ultrasonography- or CT-guided transthoracic needle aspiration

Aspirate sent for: Bacterial and fungal stains

Culture Cytologic examination

o Bronchoscopy The role of fiberoptic bronchoscopy with bronchoalveolar lavage or protected-specimen

brush for diagnosis or drainage of lung abscess is controversial.

The relatively low yield, especially with anaerobic lung abscess, should be balanced against the risk of rupture of the abscess cavity with spillage into the airways.

Perhaps most useful to rule out airway obstruction, mycobacterial infection, or malignancy

Empyema o Perform diagnostic thoracentesis for:

Parapneumonic effusions > 10 mm on lateral decubitus chest radiography

Persistent effusion, fever, or elevated leukocyte count in the face of appropriate antibiotic treatment for pneumonia

o If the effusion is loculated, thoracentesis may not yield the diagnosis. Pockets of infection are indistinguishable from pockets of inflammatory collections.

A large-bore thoracostomy tube or radiologically directed small-bore tubes should be put in place.

Multiple tubes may be needed if the effusion is multiloculated.

Treatment Approach

Antibiotic therapy should be directed at the organisms isolated and should be continued until the abscess has resolved radiographically.

Prolonged treatment is required for lung abscess and empyema (usually 6–8 weeks, depending on

clinical response). For an empyema, complete drainage of the infected fluid is essential.

Specific Treatments

Lung abscess

Empirical antibiotic treatment should be started until definitive organisms are isolated. Options for empirical treatment and for treatment in cases where the level of clinical suspicion is high

but microbiologic studies are unrevealing include: o Clindamycin (600 mg IV every 8 hours, then 300 mg PO qid after clinical improvement)

o Ampicillin/sulbactam (3 g IV every 6 hours), then amoxicillin/clavulanate (875 mg PO bid) o Ceftriaxone (1 g IV every 24 hours) plus metronidazole (500 mg PO tid), then

amoxicillin/clavulanate (875 mg PO bid) o Penicillin (3 million U IV every 4 hours) plus metronidazole (500 mg PO tid); then:

Amoxicillin (500 mg PO qid) plus metronidazole (500 mg PO tid) OR Amoxicillin/clavulanate (875 mg PO bid)

Antibiotic therapy should be continued until the abscess has resolved radiographically (usually for 6–8 weeks).

Medical management is unsuccessful in ~10% of cases. When medical management fails or the lung abscess is large, percutaneous drainage or lobectomy

should be considered. Indications for surgery include:

o Refractory hemoptysis o Inadequate response to medical therapy

o Need for a tissue diagnosis when there is concern for a noninfectious etiology

Empyema

Antibiotic therapy should be continued until empyema has resolved (usually for 4–8 weeks). o For specific therapies, see:

Community-Acquired Pneumonia Hospital-Acquired Pneumonia

Empyema should be drained via closed thoracostomy or thoracoscopy (video-assisted thoracic surgery, VATS).

o VATS may be preferred for multiloculated empyema.

o Open surgical drainage with or without decortication may be necessary in some cases. Intrapleural fibrinolytic therapy

o Technique involves instilling fibrinolytic agents (urokinase) directly into the pleural space via chest tube in hope of breaking up loculations.

Studies generally show no clear benefit in terms of either mortality or need for surgery. Current recommendations are for use only when VATS is not available or for patients

who are not surgical candidates.[1]

Monitoring

Perform follow-up radiography after 6 weeks of therapy for both abscess and empyema. o CT is generally preferred because of superior sensitivity in the detection of persistent infection. o Plain chest radiography may be sufficient in uncomplicated cases.

Complications

Lung abscess o Rupture into the pleural space, with resultant empyema o Bronchopleural fistula

Empyema o Loculation o Pleural fibrosis

Prognosis

Lung abscess o ~90% of abscesses are cured with medical management alone. o Remaining cases may require additional interventions, such as surgery. o Prognosis is worse with:

Large abscess size (diameter > 6 cm) Right lower-lobe location Other serious coexisting diseases (e.g., lung cancer) Infection by P. aeruginosa, S. aureus, K. pneumoniae

Empyema o With appropriate therapy, the prognosis is generally good. o For empyema complicating collagen vascular disorders, cancer, surgery, trauma, or

immunodeficiency, the prognosis is influenced by the underlying condition.

Prevention

For especially susceptible patients, risk can be reduced by aspiration precautions, including:

o Positioning of head of bed at > 30 degrees o Good dental hygiene

There is no specific way to prevent empyema.

ICD-9-CM

510.0 Empyema with fistula 510.9 Empyema without mention of fistula 513.0 Abscess of lung

See Also

Community-Acquired Pneumonia Hospital-Acquired Pneumonia

Internet Sites

Professionals o Homepage

National Heart, Lung, and Blood Institute Patients

o Empyema MedlinePlus: Medical Encyclopedia

o Aspiration pneumonia MedlinePlus

References

1. Light RW: Parapneumonic effusions and empyema. Proc Am Thorac Soc 3:75, 2006 [PMID:16493154]

General Bibliography

Chen KY et al: A 10-year experience with bacteriology of acute thoracic empyema: emphasis on

Klebsiella pneumoniae in patients with diabetes mellitus. Chest 117:1685, 2000 [PMID:10858403] Chung G, Goetz MB: Anaerobic Infections of the Lung. Curr Infect Dis Rep 2:238, 2000

[PMID:11095862] Colice GL et al: Medical and surgical treatment of parapneumonic effusions : an evidence-based

guideline. Chest 118:1158, 2000 [PMID:11035692] File TM: Community-acquired pneumonia. Lancet 36:1991, 2003

Hirshberg B et al: Factors predicting mortality of patients with lung abscess. Chest 115:746, 1999 [PMID:10084487]

Mansharamani NG, Koziel H: Chronic lung sepsis: lung abscess, bronchiectasis, and empyema. Curr Opin Pulm Med 9:181, 2003 [PMID:12682562]

Mansharamani N et al: Lung abscess in adults: clinical comparison of immunocompromised to non-immunocompromised patients. Respir Med 96:178, 2002 [PMID:11905552]

This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 251, Pneumonia

by LA Mandell and R Wunderink.

PEARLS

Despite excellent activity against anaerobic flora, metronidazole alone is inadequate therapy fo r anaerobic lung abscess.

A poor response of lung abscess to antibiotic therapy should prompt consideration of noninfectious etiologies for cavitary lung lesions, such as vasculitis and neoplasm.

Pulmonary tuberculosis should be considered in all patients with cavitary lung lesions. o The probability of this diagnosis is increased by:

Current or past residence in an area with high rates of tuberculosis

HIV infection A history of a positive tuberculosis skin test

Harrison's Practice

12. Interstitial Lung Disease

Definition

Interstitial lung diseases (ILDs) represent > 200 separate diseases of known and unknown causes. All involve the parenchyma of the lung: the alveoli, alveolar epithelium, capillary endothelium, and the spaces

between these structures, as well as the perivascular and lymphatic tissues. These disorders are classified together because of similar clinical, roentgenographic, physiologic, or pathologic

manifestations. They are often associated with considerable morbidity and mortality. See also Interstitial Lung Disease Associated with Collagen Vascular Disorders.

Epidemiology

Incidence of ILD o 26–31 cases per 100,000 persons per year

Prevalence of ILD o 80.9 per 100,000 men o 67.2 per 100,000 women o Recent work with CT scanning indicates that the prevalence may be significantly higher than the rates

cited above. Estimated relative frequency of ILDs

o Idiopathic interstitial pneumonias: 40% Idiopathic pulmonary fibrosis (IPF): 55% Nonspecific interstitial pneumonia: 25% Respiratory bronchiolitis—ILD and desquamative interstitial pneumonia: 15% Cryptogenic organizing pneumonia: 3% Acute interstitial pneumonia: < 1%

o Occupational and environmental: 26% o Sarcoidosis: 10% o Connective tissue diseases: 9% o Drug and radiation: 1% o Pulmonary hemorrhage syndromes: < 1% o Other: 13%

Age o Most patients with sarcoidosis, ILDs associated with connective tissue disease (CTD),

lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis (PLCH), and inherited forms of ILD (familial IPF, Gaucher’s disease, or Hermansky–Pudlak syndrome) present between 20 and 40 years of age.

o Most patients with IPF are > 50 years of age. Sex

o Lymphangioleiomyomatosis and pulmonary involvement in tuberous sclerosis occur exclusively in premenopausal women.

o ILD in Hermansky–Pudlak syndrome (an inherited form of oculocutaneous albinism) and in the CTDs is more common in women.

An exception is ILD in rheumatoid arthritis, which is more common in men. o Because of occupational exposures, pneumoconioses occur more frequently in men.

Risk Factors

Family history of ILD Smoking Occupational or environmental exposures

o Inorganic dust o Organic dust o Various fumes or gases

Existing CTD Exposure to parasites through travel HIV infection

Etiology

General

ILDs are nonmalignant disorders and are not caused by identified infectious agents. The precise pathways leading from injury to fibrosis are unknown. Each ILD may have an acute phase and a chronic phase. Among ILDs of known cause, the largest group comprises occupational and environmental exposures. ILD is classified into 2 groups on the basis of the major underlying histopathology.

o Predominantly inflammation and fibrosis o Predominantly granulomatous reaction in interstitial or vascular areas

Each group can be further subdivided according to whether the cause is known or unknown.

Alveolitis, interstitial inflammation, and fibrosis

Known cause

Asbestos Fumes, gases Drugs: antibiotics, amiodarone, gold, and chemotherapeutic agents Radiation Aspiration pneumonia Residual of adult respiratory distress syndrome

Unknown cause

Idiopathic interstitial pneumonias o IPF, also known as usual interstitial pneumonia (UIP) o Desquamative interstitial pneumonia (DIP) o Respiratory bronchiolitis-associated ILD o Acute interstitial pneumonia (AIP), also known as diffuse alveolar damage o Cryptogenic organizing pneumonia (COP) (bronchiolitis obliterans with organizing pneumonia [BOOP]) o Nonspecific interstitial pneumonia (NSIP)

CTDs o Systemic lupus erythematosus (SLE) o Rheumatoid arthritis o Ankylosing spondylitis o Systemic sclerosis o Sjögren’s syndrome o Polymyositis and dermatomyositis

Pulmonary hemorrhage syndromes o Goodpasture’s syndrome

o Idiopathic pulmonary hemosiderosis o Isolated pulmonary capillaritis

Pulmonary alveolar proteinosis Lymphocytic infiltrative disorders

o Lymphocytic interstitial pneumonitis associated with CTD Eosinophilic pneumonias Lymphangioleiomyomatosis Amyloidosis Inherited diseases

o Tuberous sclerosis o Neurofibromatosis o Niemann–Pick disease o Gaucher disease o Hermansky–Pudlak syndrome

GI or liver diseases o Crohn’s disease o Primary biliary cirrhosis o Chronic active hepatitis o Ulcerative colitis

Graft-versus-host disease Bone marrow transplantation Solid-organ transplantation

Granulomatous reaction

Known cause o Hypersensitivity pneumonitis (organic dusts) o Inorganic dusts

Beryllium Silica

Unknown cause o Sarcoidosis o Langerhans cell granulomatosis (eosinophilic granuloma of the lung) o Granulomatous vasculitides

Wegener’s granulomatosis Allergic granulomatosis of Churg-Strauss

o Bronchocentric granulomatosis o Lymphomatoid granulomatosis

Associated Conditions

Allergy Pneumonia Infection

o Parasitic o HIV o Tuberculosis o Echinococcosis o Histoplasmosis o Coccidioidomycosis o Nocardiosis

CTDs o SLE

o Rheumatoid arthritis o Ankylosing spondylitis o Systemic sclerosis o Sjögren’s syndrome o Polymyositis and dermatomyositis

GI and liver diseases o Crohn’s disease o Primary biliary cirrhosis o Chronic active hepatitis o Ulcerative colitis

Vasculitis Graft-versus-host disease Amyloidosis Emphysema Pneumothorax Chylous pleural effusion Lymphoma Sarcoidosis

Symptoms & Signs

Symptoms o Progressive exertional dyspnea: common, and most characteristic o Nonproductive cough o Hemoptysis o Wheezing o Chest pain o Sudden worsening of dyspnea, especially if associated with acute chest pain, may indicate spontaneous

pneumothorax. o Fatigue o Weight loss

Signs o Tachypnea o Bibasilar end-inspiratory dry crackles

Common in ILD associated with inflammation, but less likely in the granulomatous lung diseases o Scattered late inspiratory high-pitched rhonchi (inspiratory squeaks) in patients with bronchiolitis o Advanced disease

Signs and symptoms of pulmonary hypertension and cor pulmonale Cyanosis of the digits Clubbing of the digits

Extrapulmonary signs and symptoms may accompany specific diagnoses. o Erythema nodosum, rash, uveitis, and conjunctivitis (e.g., in sarcoidosis and Behçet’s syndrome) o Salivary gland enlargement (e.g., with Sjögren’s syndrome and sarcoidosis) o Adenopathy and hepatosplenomegaly (e.g., with amyloidosis and sarcoidosis o Arthritis (e.g., connective tissue diseases, sarcoidosis, Behçet’s syndrome, ankylosing spondylitis) o Weakness (e.g., polymyositis) o Neurologic findings (e.g., sarcoidosis)

Differential Diagnosis

IPF/UIP

The most common form of idiopathic interstitial pneumonia Most patients with IPF are > 50 years. Biopsy is essential to confirm diagnosis; surgical biopsy is usually required.

DIP

Rare but distinct clinical and pathologic entity found exclusively in cigarette smokers Peak incidence in fourth and fifth decades Biopsy confirms the diagnosis.

AIP (Hamman–Rich syndrome)

Rare, fulminant form of lung injury Diagnosis requires idiopathic syndrome of adult respiratory distress syndrome and lung biopsy confirmation of

diffuse alveolar damage. Most patients are > 40 years of age. Onset is usually abrupt in previously healthy persons with a prodromal illness, generally lasting 7–14 days before

presentation.

NSIP

Subgroup of the idiopathic interstitial pneumonias that can be distinguished clinically and pathologically from UIP, DIP, AIP, and BOOP

Presentation similar to IPF but usually at a younger age, often associated with a febrile illness

ILD associated with CTDs

Progressive systemic sclerosis o Clinical evidence of ILD is present in ~50% of patients. o Pathologic evidence in 75%

Rheumatoid arthritis o ILD more common in men o In up to 20% of cases

SLE o Chronic progressive ILD is uncommon.

Polymyositis and dermatomyositis o 10% of cases o Clinical features similar to those of IPF o Occurs more commonly in a subgroup of patients with an anti–Jo-1 antibody

Sjögren’s syndrome o Lung biopsy frequently required to establish precise pulmonary diagnosis

Drug-induced ILD

Many classes of drugs may induce diffuse ILD. Onset may be abrupt and fulminant or insidious, extending over weeks to months. Detailed medication history is needed, including over-the-counter medications, oily nose drops, or petroleum

products (mineral oil). o Drug may have been taken for several years before a reaction develops (e.g., amiodarone). o Lung disease may occur weeks to years after drug has been discontinued (e.g., carmustine).

Extent and severity of disease are usually dose related.

COP (idiopathic BOOP)

Onset is usually in the fifth and sixth decades. May present like a flulike illness

Eosinophilic pneumonia

Eosinophilic pulmonary infiltrates and, commonly, peripheral blood eosinophilia

Pulmonary alveolar proteinosis

Not strictly an ILD, but resembles and is therefore considered with these conditions Characterized by the accumulation of lipoproteinaceous material in the distal air spaces Little or no lung inflammation, and preservation of the underlying lung architecture Typical age at presentation is 30–50 years; men predominate. Clinical presentation is usually insidious and manifested by progressive exertional dyspnea, fatigue, weight loss,

and low-grade fever. Nonproductive cough is common, but with occasional expectoration of "chunky" gelatinous material.

Pulmonary lymphangioleiomyomatosis

Rare condition in premenopausal women; suspect in young women with emphysema, recurrent pneumothorax, or chylous pleural effusion

White persons are affected much more commonly than members of other racial groups. Often misdiagnosed as asthma or chronic obstructive pulmonary disease Hemoptysis may be life threatening. Spontaneous pneumothorax occurs in 50% of patients.

Syndromes of ILD with DAH

Clinical onset is often abrupt, with cough, fever, and dyspnea. Severe respiratory distress requiring ventilatory support may be evident at initial presentation. Although hemoptysis is expected, it can be absent at the time of presentation in one-third of cases. Evaluation of lung or renal tissue by immunofluorescent techniques indicates:

o Absence of immune complexes (pauci-immune) in Wegener’s granulomatosis, microscopic polyangiitis, pauci-immune glomerulonephritis, and isolated pulmonary capillaritis

o Granular pattern is found in the CTDs, particularly SLE o Characteristic linear deposition is found in Goodpasture’s syndrome. o Granular deposition of immunoglobulin A–containing immune complexes is present in Henoch–

Schönlein purpura.

Inherited disorders associated with ILD

Tuberous sclerosis, neurofibromatosis, Niemann–Pick disease, Gaucher’s disease, Hermansky–Pudlak syndrome

ILD with a granulomatous response in lung tissue or vascular structures

Hypersensitivity pneumonitis: caused by inhalation of organic dusts Inhalation of inorganic dusts Sarcoidosis PLCH

o Rare, smoking-related, diffuse lung disease that primarily affects men 20–40 years of age o Clinical presentation varies from asymptomatic to a rapidly progressive condition. o Pneumothorax occurs in about 25% of patients.

Granulomatous vasculitides o Characterized by pulmonary angiitis with associated granuloma formation o Lungs are almost always involved, although any organ system may be affected. o Conditions associated with systemic vasculitis

Wegener’s granulomatosis Allergic angiitis and granulomatosis (Churg–Strauss)

o Conditions generally limited to the lung Necrotizing sarcoid granulomatosis Benign lymphocytic angiitis and granulomatosis

Lymphocytic infiltrative disorders

Disorders either are benign or can behave as low-grade lymphomas. Angioimmunoblastic lymphadenopathy with dysproteinemia

o Rare lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever, hepatosplenomegaly, and hemolytic anemia, with ILD in some cases

Lymphocytic interstitial pneumonitis o Rare form of ILD occurs in adults, some with autoimmune disease or dysproteinemia o Has been reported in patients with Sjögren’s syndrome and HIV o Lymphomatoid granulomatosis o Angiocentric malignant (T-cell) lymphoma characterized by a polymorphic lymphoid infiltrate, angiitis,

and granulomatosis o Pulmonary, skin, and central nervous system are most frequently involved.

Bronchocentric granulomatosis

Descriptive histologic term for an uncommon and nonspecific pathologic response to a variety of airway injuries Approximately half of patients have chronic asthma, with severe wheezing and peripheral blood eosinophilia.

Diagnostic Approach

Clinical diagnosis is possible for many forms of ILD, especially if occupational and environmental histories are aggressively pursued.

History

Acute presentation (days to weeks) is unusual, but can be seen with: o Allergy (drugs, fungi, helminths) o Acute idiopathic interstitial pneumonia o Eosinophilic pneumonia o Hypersensitivity pneumonitis

Subacute presentation (weeks to months) may occur in all ILDs, especially in: o Sarcoidosis o Drug-induced ILDs o Alveolar hemorrhage syndromes o COP o Acute immunologic pneumonia that complicates SLE or polymyositis

Chronic presentation (months to years) o Most ILDs present in this way, especially:

IPF Sarcoidosis PLCH (Langerhans cell granulomatosis, eosinophilic granuloma, or histiocytosis X) Pneumoconioses CTD

Episodic presentations are unusual and include: o Eosinophilic pneumonia o Hypersensitivity pneumonitis o COP o Vasculitides o Pulmonary hemorrhage o Churg–Strauss syndrome

Demographic factors

Age (see Epidemiology) Sex (see Epidemiology)

Family history

Familial association with autosomal dominant pattern o Tuberous sclerosis o Neurofibromatosis

Autosomal recessive pattern o Niemann-Pick disease o Gaucher disease o Hermansky–Pudlak syndrome

Familial clustering o Sarcoidosis

Familial lung fibrosis associated with mutations in surfactant protein C gene o NSIP o DIP o UIP

Smoking history

Patients with the following ILDs are almost always current or former smokers. o PLCH o DIP o Goodpasture’s syndrome o Respiratory bronchiolitis o Pulmonary alveolar proteinosis

Two-thirds to 75% of patients with IPF have a history of smoking.

Occupational and environmental history

Chronologic listing of lifelong employment, including specific duties and known exposures In hypersensitivity pneumonitis, respiratory symptoms, fever, chills, and abnormal findings on chest radiography

are often temporally related to a hobby or the workplace. o Pigeon breeder’s disease o Farmer’s lung

Symptoms may diminish or disappear after leaving the site of exposure for several days and reappear on return.

Other important history

Travel history o Parasitic infections may cause pulmonary eosinophilia.

Risk factors for HIV infection; associated conditions include: o BOOP o AIP o Lymphocytic interstitial pneumonitis o Diffuse alveolar hemorrhage (DAH)

Studies to consider

Laboratory testing when appropriate Chest radiography Chest CT Pulmonary function tests Cardiopulmonary exercise testing Fiberoptic bronchoscopy and bronchoalveolar lavage Lung biopsy is often needed to confirm diagnosis.

Laboratory Tests

Blood analysis o With a few exceptions, notably connective tissue diseases, laboratory testing is not diagnostically

specific for any particular condition. o The following are most helpful:

Elevated circulating immune-complex titers, serum immunoglobulin levels, and erythrocyte sedimentation rate in IPF

Markedly elevated serum levels of lung surfactant proteins A and D in pulmonary alveolar proteinosis

Elevated leukocyte count in DAH Decreased hematocrit in DAH Elevated serum angiotensin-converting enzyme level in sarcoidosis Serum precipitins confirm exposure if hypersensitivity pneumonitis is suspected, although they

are not diagnostic. Antineutrophil cytoplasmic or anti–basement membrane antibodies if vasculitis is suspected Antinuclear antibodies, anti-immunoglobulin antibodies (rheumatoid factors), and circulating

immune complexes are identified in some patients, even in the absence of a defined CTD. An elevated lactate dehydrogenase level is a nonspecific finding common to ILDs. Anti-basement cytoplasmic antibody is elevated in Goodpasture’s syndrome.

Urinalysis o Abnormalities may be seen with connective tissue disease, vasculitides, and drug-induced disease.

Imaging

Chest radiography

Nonspecific in most cases o ~ 20% of patients with ILD have normal chest radiographs. o Findings correlate poorly with the clinical or histopathologic stage of the disease.

Bibasilar reticular pattern is most common. Other findings that may be seen:

o Nodular or mixed pattern of alveolar filling and increased reticular markings o Nodular opacities with a predilection for the upper lung zones

Sarcoidosis PLCH Chronic hypersensitivity pneumonitis Silicosis Berylliosis Rheumatoid arthritis (necrobiotic nodular form) Ankylosing spondylitis

o Diffuse alveolar opacities may cause the following conditions to be confused with atypical pneumonias. ILD secondary to allergy (drugs, fungi, helminths) Acute idiopathic interstitial pneumonia Eosinophilic pneumonia Hypersensitivity pneumonitis

o Extensive parenchymal lung disease on chest radiography without significant dyspnea Sarcoidosis Silicosis PLCH Hypersensitivity pneumonitis Lipoid pneumonia Lymphangitis carcinomatosis, especially early in the course of the illness

o DIP: diffuse, hazy opacities o AIP: diffuse, bilateral, air-space opacification o ILD associated with polymyositis and dermatomyositis: diffuse reticular or nodular opacities with a

predilection for the lung bases o COP: bilateral, patchy, or diffuse alveolar opacities in the presence of normal lung volume o Pulmonary alveolar proteinosis: Bilateral symmetric alveolar opacities located centrally in mid and lower

lung zones result in a "bat-wing" distribution. o ILD with DAH: nonspecific, new patchy or diffuse alveolar opacities o PLCH: poorly defined or stellate nodules (2–10 mm in diameter), reticular or nodular opacities, bizarre-

shaped upper-zone cysts, preservation of lung volume, sparing of the costophrenic angles o Bronchocentric granulomatosis: irregularly shaped, unilateral and solitary nodular or mass lesions with

poorly defined margins and upper-lobe predominance

High-resolution CT

Superior to plain chest radiography for early detection and confirmation Better assessment of extent and distribution of disease Especially useful in the investigation of patients with normal chest radiographs Coexisting disease (e.g., mediastinal adenopathy, carcinoma, or emphysema) is often best recognized on high-

resolution CT. Useful for determining the most appropriate area for biopsy May be sufficiently characteristic to preclude the need for lung biopsy in:

o IPF (See Figure 1.) o Sarcoidosis o Hypersensitivity pneumonitis o Asbestosis o Lymphangitic carcinoma o PLCH

IPF: patchy, predominantly basilar, subpleural reticular opacities, often associated with traction bronchiectasis and honeycombing

DIP: diffuse hazy opacities AIP: bilateral, patchy, symmetric areas of ground-glass attenuation

NSIP: bilateral, subpleural ground-glass opacities, often associated with lower-lobe volume loss and possibly patchy areas of airs–pace consolidation and reticular abnormalities (See Figure 2.)

COP: areas of air–space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening and dilation

Pulmonary alveolar proteinosis: ground-glass opacification, thickened intralobular structures, interlobular septa Lymphangioleiomyomatosis: thin-walled cysts surrounded by normal lung without zonal predominance PLCH: Nodules and thin-walled cysts are virtually diagnostic.

Diagnostic Procedures

Tissue and cellular examination o Lung biopsy is the most effective method for confirming diagnosis and assessing disease activity. o Fiberoptic bronchoscopy with multiple transbronchial lung biopsies (4–8 biopsy samples) is often the

initial procedure of choice. o If a specific diagnosis is not made by transbronchial biopsy, surgical lung biopsy by video-assisted

thoracic surgery or open thoracotomy is indicated. o Relative contraindications to lung biopsy

Serious cardiovascular disease, honeycombing, and other radiographic evidence of diffuse end-stage disease

Severe pulmonary dysfunction Other major operative risks, especially in elderly persons

Pulmonary function testing o Abnormalities are seen in most patients.

Spirometry and lung volumes

Important in assessing extent of pulmonary involvement Most common is a restrictive defect with:

o Reduced total lung capacity o Reduced functional residual capacity o Reduced residual volume o Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) are reduced secondary to

decreased total lung capacity. o FEV1/FVC ratio is usually normal or increased.

Diffusing capacity o Reduction in the diffusing capacity of the lung for carbon monoxide (DLCO) is a common but nonspecific

finding in most ILDs. o Severity of DLCO reduction does not correlate with disease stage.

Arterial blood gas o Resting arterial blood gas may be normal or reveal hypoxemia and respiratory alkalosis. o Carbon dioxide retention is rare and is usually a manifestation of end-stage disease.

Pulmonary function studies have proven to have prognostic value in patients with idiopathic interstitial pneumonias, particularly IPF or NSIP.

Cardiopulmonary exercise testing o Because severe exercise-induced hypoxemia may go undetected, perform exercise testing with

measurement of arterial blood gases. o Serial assessment of resting and exercise gas exchange is excellent for following disease activity and

response to treatment (especially in IPF).

Fiberoptic bronchoscopy and bronchoalveolar lavage o In selected patients, cellular analysis of bronchoalveolar lavage fluid may be useful in narrowing the

differential diagnostic possibilities among various types of ILD. o See Bronchoscopy for details.

Electrocardiography o Usually normal o In pulmonary hypertension, electrocardiography demonstrates right-axis deviation, right ventricular

hypertrophy, or right atrial enlargement or hypertrophy.

Echocardiography o In pulmonary hypertension: right ventricular dilatation and/or hypertrophy

Treatment Approach

ILD is often associated with considerable morbidity and mortality. There is little consensus regarding the best management of most patients. Goals of treatment

o Early identification o Permanent removal of the offending agent, when known o Aggressive suppression of acute and chronic inflammatory process to reduce further lung damage

Smoking cessation Hypoxemia (partial pressure of arterial oxygen [PaO2] < 55 mmHg) at rest and/or with exercise should be

managed by supplemental oxygen. If cor pulmonale develops, diuretic therapy and phlebotomy may occasionally be required. Lung transplantation may be considered in certain patients.

Specific Treatments

Glucocorticoids

Mainstay of therapy for suppression of active alveolitis Success rate is low; no direct evidence that steroids improve survival or quality of life in many ILDs for which

they are commonly used Recommended for symptomatic ILD patients with:

o Idiopathic interstitial pneumonias o Eosinophilic pneumonias o COP o CTDs o Sarcoidosis o Acute inorganic dust exposures o Acute radiation pneumonitis o DAH o Drug-induced ILD o DIP o Acute and chronic stages of organic dust disease

Optimal dose and proper length of therapy with glucocorticoids in the treatment of most ILDs are not known. o Starting dose: prednisone, 0.5–1 mg/kg in a once-daily oral dose (based on the patient’s lean body

weight) o Dose is continued for 4–12 weeks, at which time the patient is reevaluated. o If patient is stable or improved, dose is tapered to 0.25–0.5 mg/kg and maintained for an additional 4–

12 weeks, depending on course.

o Rapid tapering or a shortened course of glucocorticoid treatment can result in recurrence. o If the patient’s condition continues to decline while on glucocorticoids, a second agent (see below) is

often added and the prednisone dose is lowered to or maintained at 0.25 mg/kg per day. Mainstay of therapy for DAH associated with systemic vasculitis, CTD, Goodpasture’s syndrome, and isolated

pulmonary capillaritis o IV methylprednisolone, 0.5–2.0 g daily in divided doses for up to 5 days o Followed by a gradual tapering o Maintenance on an oral preparation o Prompt initiation of therapy is important, particularly in the face of renal insufficiency, since early

initiation of therapy has the best chance of preserving renal function.

Cytotoxic agents: cyclophosphamide and azathioprine

Used with variable success in IPF, vasculitis, and other ILDs Dosage: 1–2 mg/kg lean body weight per day, with or without glucocorticoids Objective response usually requires at least 8–12 weeks. If the above drugs fail or are not tolerated, other agents may be tried: methotrexate, colchicine, penicillamine,

and cyclosporine.

Antifibrotic agents (for IPF)

Colchicine Pirfenidone Interferon γ1b No evidence that any of these treatments improves survival or quality of life

Supplemental oxygen

When PaO2 < 55 mmHg at rest and/or with exercise To prevent or delay the onset of pulmonary hypertension and cor pulmonale

Lung transplantation

See Lung Transplantation for details. May be considered in patients who experience progressive deterioration despite optimal medical management

and who meet established criteria of chronic and irreversible ILD IPF: indications

o Vital capacity or total lung capacity < 60–70% of predicted normal value o DLCO < 50–60% of predicted normal value o Pulmonary arterial hypertension o Hypoxemia (PaO2 < 60 mmHg or arterial oxygen saturation < 90%) at rest or with activity (on room air) o Progressive disease in spite of drug therapy

Other

Pulmonary alveolar proteinosis: whole-lung lavage o Provides relief of dyspnea or progressive hypoxemia o May provide long-term benefit

Pulmonary lymphangioleiomyomatosis o Hormonal therapy has been tried but without proven efficacy.

Progesterone, 10 mg/d Luteinizing hormone–releasing hormone analogues

Oophorectomy is no longer recommended, and estrogen-containing drugs should be discontinued.

Goodpasture’s syndrome o Plasmapheresis as adjunctive treatment

Hypersensitivity pneumonitis o Avoidance of the antigen causing the allergic alveolitis

Monitoring

Cardiopulmonary exercise testing o Excellent for following disease activity and response to treatment (especially in IPF) o Serial assessment of resting and exercise gas exchange o Increasingly, the 6-minute walk test is used to obtain a global evaluation of submaximal exercise

capacity in patients with ILD. The walk distance and level of oxygen desaturation tend to correlate with the patient’s baseline

lung function.

Complications

Progressive respiratory impairment Pulmonary embolism Cor pulmonale Infection Pneumothorax Drug-related complications Death

Prognosis

IPF o Poor response to therapy and poor prognosis o The clinical course is variable, with a 5-year survival rate of 20–40% after diagnosis. o Patients with acute exacerbations (an accelerated phase of rapid clinical decline) of IPF have a poor

prognosis. Acute exacerbations are defined by:

Worsening of dyspnea within a few days to 4 weeks Newly developing diffuse radiographic opacities Worsening hypoxemia Absence of infectious pneumonia, heart failure, and sepsis

Rate of these acute exacerbations ranges from 10–57%. DIP

o DIP is associated with better response to smoking cessation and systemic glucocorticoids than the more common IPF.

o 10-year survival rate: ~70% AIP

o Mortality rate is high (>60%), with most patients dying within 6 months of presentation. o Recurrences have been reported. o Those who recover often have substantial improvements in lung function.

NSIP o The majority have a good prognosis, showing improvement after treatment with glucocorticoids, often

used in combination with azathioprine. ILD associated with progressive systemic sclerosis

o Pulmonary vascular disease, alone or in association with pulmonary fibrosis, pleuritis, or recurrent aspiration pneumonitis, is strikingly resistant to current modes of therapy.

COP o Glucocorticoid therapy induces clinical recovery in two-thirds of patients. o A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.

Pulmonary lymphangioleiomyomatosis o Progression is common, with a median survival of 8–10 years from diagnosis.

PLCH o Discontinuance of smoking results in clinical improvement in one-third of patients. o Most patients have persistent or progressive disease. o Death due to respiratory failure occurs in ~10%.

Prevention

Smoking cessation

ICD-9-CM

136.3 Pneumocystosis (includes acute interstitial lung disease) 515 Postinflammatory pulmonary fibrosis (includes chronic interstitial lung disease)

See Also

Asthma Berylliosis Bronchoscopy Chronic Obstructive Lung Disease Community-Acquired Pneumonia Desquamative Interstitial Pneumonia Drug-Induced Lung Diseases Histoplasmosis Hospital-Acquired Pneumonia Hypersensitivity Pneumonitis Interstitial Lung Disease Associated with Collagen Vascular Disorders Lung Transplantation Pulmonary Function Tests Pulmonary Arterial Hypertension, Secondary Sarcoidosis Tuberculosis

Internet Sites

Professionals o Clinical Trials, Interstitial Lung Disease

ClinicalTrials.gov o Homepage

National Heart, Lung, and Blood Institute Patients

o Diffuse interstitial lung disease MedlinePlus

General Bibliography

American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161:646, 2000 [PMID:10673212]

Gal AA, Staton GW: Current concepts in the classification of interstitial lung disease. Am J Clin Pathol 123 Suppl:S67, 2005 [PMID:16100869]

Khalil N, O’Connor R: Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment. CMAJ 171:163, 2004

King TE: Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med 172:268, 2005 [PMID:15879420]

Lynch DA et al: Idiopathic interstitial pneumonias: CT features. Radiology 236:10, 2005 [PMID:15987960] Martinez FJ: Idiopathic interstitial pneumonias: usual interstitial pneumonia versus nonspecific interstitial

pneumonia. Proc Am Thorac Soc 3:81, 2006 [PMID:16493155] Sullivan EJ: Lymphangioleiomyomatosis: a review. Chest 114:1689, 1998 [PMID:9872207] Swigris JJ et al: Idiopathic pulmonary fibrosis: challenges and opportunities for the clinician and investigator.

Chest 127:275, 2005 [PMID:15653995] Vassallo R et al: Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med

346:484, 2002 [PMID:11844849] Walter N, Collard HR, King TE: Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am

Thorac Soc 3:330, 2006 [PMID:16738197] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 255, Interstitial Lung

Diseases by TE King Jr.

PEARLS

Cough and dyspnea are the most important symptoms of IPF, and clubbing of the digits is a common physical finding.

Lymphangioleiomyomatosis is the most common interstitial lung disease in premenopausal women. o Oral or intramuscular medroxyprogesterone is an effective therapy.

Harrison's Practice

13. Hypoventilation

Definition

Alveolar hypoventilation exists when arterial partial pressure of carbon dioxide (PaCO 2) increases above the upper limit of normal (i.e., 43 mmHg).

o Note that this definition relies on the Paco2 and not the Pao2.

o In clinically important hypoventilation syndromes, PaCO2 exceeds 50 mmHg. Hypoventilation disorders can be acute or chronic.

o Acute disorders

Usually life-threatening emergencies Discussed in Acute Respiratory Distress Syndrome

o Chronic hypoventilation syndromes (focus of this topic) are characterized by: Impaired respiratory drive

Defective respiratory neuromuscular system Impaired ventilatory apparatus

Chronic disorders include: o Primary alveolar hypoventilation (PAH): disorder of unknown cause characterized by chronic

hypercapnia and hypoxemia in the absence of identifiable neuromuscular disease or mechanical ventilatory impairment

o Obesity hypoventilation syndrome (OHS): BMI > 30kg/m2 plus chronic hypercapnia while awake and the presence of sleep-disordered breathing

o Congenital central hypoventilation syndrome: disorder of ventilatory control due to mutation in PHOX2B gene

Epidemiology

Prevalence o Varies depending on the underlying cause of hypoventilation

o PAH is relatively rare. o Prevalence of OHS likely increasing with global epidemic of obesity

Up to 20% of patients with obstructive sleep apnea may have OHS.

Age o Overall prevalence of hypoventilation increases with age.

o PAH occurs more commonly in early adulthood. Sex

o Occurs more frequently in men than in women

Mechanism

The physiologic hallmark of all alveolar hypoventilation syndromes is:

o Increase in alveolar PCO2 and therefore in arterial PCO2 o Respiratory acidosis

o Compensatory increase in plasma bicarbonate concentration and a decrease in chloride concentration

o Increase in alveolar PCO2 produces an obligatory decrease in alveolar partial pressure of oxygen (PO2), resulting in hypoxemia.

Alveolar hypoventilation is due to a defect in ≥ 1 respiratory systems. o Metabolic respiratory control system

Control of respiratory drive is perturbed by disorders of brainstem neurons or

chemoreceptors (central or peripheral). o Respiratory neuromuscular system

Control of respiratory muscles is impaired because of disorders of spinal or peripheral nerves or the respiratory muscles themselves.

o Ventilatory apparatus Ventilation is impaired because of mechanical changes to the chest wall, airways, or

lungs. o See Differential Diagnosis for a list of disorders corresponding to these defective mechanisms.

Symptoms & Signs

General

Cyanosis secondary to severe hypoxemia Impairment of sleep due to nocturnal hypercapnia

o Morning fatigue, daytime somnolence, mental confusion, and intellectual impairment Other clinical features associated with hypoventilation syndromes are related to the specific underlying

disease.

PAH

Characterized by chronic hypercapnia and hypoxemia in the absence of identifiable neuromuscular

disease or mechanical ventilatory impairment Typically develops insidiously

o Patients typically develop lethargy, fatigue, daytime somnolence, disturbed sleep, and morning headaches.

o Dyspnea is uncommon. o Often first comes to attention when severe respiratory depression follows administration of

standard doses of sedatives or anesthetics

Eventually cyanosis, polycythemia, pulmonary hypertension, and congestive heart failure occur.

Respiratory neuromuscular disorders

Hypoventilation usually develops gradually over months to years. o Generally does not develop unless there is significant weakness of the diaphragm

Distinguishing features of bilateral diaphragmatic weakness include orthopnea and paradoxical movement of the abdomen in the supine posture.

o May come to attention when a relatively trivial increase in mechanical ventilatory load (e.g., viral bronchitis with airways obstruction) produces severe respiratory failure

Involvement of respiratory nerves or muscles o An early feature of such diseases as:

Postpolio syndrome: a form of chronic respiratory insufficiency that develops 20–30 years after recovery from poliomyelitis

Myopathy associated with adult acid maltase deficiency

Idiopathic diaphragmatic paralysis o A later feature of disorders, such as:

Motor neuron disease Myasthenia gravis Muscular dystrophy

OHS

Morbid obesity can lead to reduced functional residual capacity (i.e., end-expiratory lung volume), particularly in the recumbent posture.

o May be accompanied by:

Mild to moderate degree of airflow obstruction Decrease in central respiratory drive

Obstructive sleep apnea o Can present with dyspnea, lower extremity edema, low oxygen saturation while awake

Differential Diagnosis

Impaired respiratory drive (metabolic respiratory control system) o Peripheral and central chemoreceptors

Carotid body dysfunction, trauma Prolonged hypoxia

Metabolic alkalosis o Brainstem respiratory neurons

Bulbar poliomyelitis, encephalitis Brainstem infarction, hemorrhage, trauma Brainstem demyelination, degeneration Long-term drug administration (e.g., opiates, barbiturates, benzodiazepines) Hypothyroidism

Defective respiratory neuromuscular system o Spinal cord and peripheral nerves

High cervical trauma Poliomyelitis

Motor neuron disease (See Amyotrophic Lateral Sclerosis.) Peripheral neuropathy

o Respiratory muscles Myasthenia gravis Muscular dystrophy Chronic myopathy

Impaired ventilatory apparatus o Chest wall

Kyphoscoliosis Fibrothorax

Thoracoplasty Ankylosing spondylitis

o Airways and lungs Laryngeal and tracheal stenosis

Obstructive sleep apnea Cystic fibrosis

Chronic obstructive pulmonary disease

Diagnostic Approach

Diagnosis of hypoventilation is based on: o History and physical examination o Arterial blood gas analysis that shows elevated PaCO2 (>43 mmHg)

Localizing chronic hypoventilation may require additional diagnostic tests, such as: o Pulmonary function tests with:

Mouth pressure generated after 0.1 second of inspiration against an occluded airway Maximum inspiratory or expiratory pressure that can be generated against an occluded

airway (PImax and PEmax) o Sleep studies o Diaphragmatic electromyography (EMG) o Alveolar–arterial PO2 difference

See Figure 1 for details.

Metabolic control system impairment o Central respiratory drive is impaired in response to chemical stimuli (carbon dioxide or

hypoxia). o Diaphragmatic EMG activity, mouth pressure, and minute volume of ventilation are reduced.

o Hypoventilation during sleep is aggravated. o Tests of voluntary respiratory control, muscle strength, lung mechanics, and gas exchange are

normal. Respiratory neuromuscular system impairment

o All tests dependent on muscular activity (voluntary or in response to metabolic stimuli) are

abnormal. o Lung resistance, lung compliance, and gas exchange are normal.

Ventilatory apparatus impairments o Gas exchange is usually impaired.

o Because resistance and compliance are also impaired, all tests dependent on ventilation (whether voluntary or in response to chemical stimuli) are abnormal.

o Tests of muscle activity or strength that do not involve airflow (i.e., mouth pressure, diaphragmatic EMG) are normal.

Primary alveolar hypoventilation o Key diagnostic finding is chronic respiratory acidosis in the absence of respiratory muscle

weakness or impaired ventilatory mechanics. o Must be distinguished from other central hypoventilation syndromes that are secondary to

underlying neurologic disease of the brainstem or chemoreceptors Requires a careful neurologic investigation for evidence of brainstem or autonomic

disturbances

Unrecognized respiratory neuromuscular disorders o Often misdiagnosed as primary alveolar hypoventilation, particularly those that produce

diaphragmatic weakness o Can usually be suspected on clinical grounds and confirmed by the finding of reduced voluntary

hyperventilation, as well as PImax and PEmax o Hypercapnia may not be demonstrable in a single arterial blood sample, but the presence of an

elevated plasma bicarbonate level should draw attention to the underlying chronic disturbance.

Laboratory Tests

Arterial blood gas o PaCO2> 43 mmHg by definition (more typically > 50 mmHg) o PaO2 is often reduced. o pH: normal or slightly reduced in compensated respiratory acidosis; more reduced in the setting

of acute decompensation

Serum chemistry o Compensatory increase in the serum bicarbonate concentration secondary to respiratory

acidosis o Serum bicarb may be useful screening test for OHS in obese patients.[1]

o Hypercalcemia and hyperkalemia may also be present. Complete blood count

o May have elevated hematocrit due to chronic hypoxemia Thyroid function studies

o Because hypothyroidism may exacerbate hypoventilation, thyroid tests may be indicated in patients with a suspected central cause of hypoventilation.

Imaging

Chest radiography o Findings on chest radiography that may help determine the cause of hypoventilation

syndromes include: Hyperinflation of lung volumes and diaphragm flattening: usually seen in severe

obstructive airway disease Diaphragm elevation: seen in pneumothorax, diaphragm paralysis, or atelectasis

Evidence of bony thoracic abnormalities, such as kyphoscoliosis

o Pulmonary hypertension Findings suggestive of pulmonary artery enlargement

Cardiomegaly secondary to right ventricular enlargement Chest CT

o May be useful in detection of suspected chest or skeletal cause Brain CT

o If a central cause of hypoventilation is suspected, particularly brainstem lesions in the pons and medulla

o Specific causes that may be diagnosed include: Stroke

Central nervous system tumor or trauma Brain MRI

o If a central cause of hypoventilation is suspected and the initial brain CT is negative or inconclusive

Fluoroscopy

o Fluoroscopic sniff test: The diaphragm is visualized with fluoroscopy as the patient quickly inspires.

o Paradoxical elevation of the diaphragm is seen with inspiration in patients with unilateral diaphragmatic paralysis.

Echocardiography and Doppler flow study o May demonstrate pulmonary hypertension and right ventricular enlargement

Diagnostic Procedures

EMG o Response to transcutaneous phrenic nerve stimulation recorded from an esophageal electrode o Used to diagnose neuromuscular disorders and defects in the metabolic respiratory control

system o May reveal a neuropathic or myopathic pattern, depending on the etiology

Pulmonary function tests o Useful to diagnose obstructive lung disease and assessment of its severity

o Measurement of maximal inspiratory and expiratory pressures may be useful in screening for respiratory muscle weakness.

Measurement of transdiaphragmatic pressure o Useful in documenting respiratory muscle and diaphragm weakness

Polysomnography o PaCO2 tends to increase progressively during the night, particularly during REM sleep, in

patients with a defect in respiratory control or neuromuscular function. o Periods of apnea not accompanied by respiratory effort may also be seen.

Treatment Approach

Management is based on the underlying disorder. Therapies include:

o Correction of metabolic alkalosis, if present o Weight loss

o Supplemental oxygen o Respiratory stimulants

o Diaphragmatic pacing

o Mechanical ventilation o Some patients with thoracic deformities, such as kyphoscoliosis, may be candidates for

corrective thoracic surgical procedures.

Specific Treatments

Supplemental oxygen

Effective in attenuating hypoxemia, polycythemia, and pulmonary hypertension o However, can aggravate carbon dioxide retention and associated neurologic symptoms

Must be prescribed judiciously and the results monitored carefully o Aim to keep PaO2 between 60 and 65 mmHg.

Respiratory stimulants

May be of benefit in some patients with central causes of hypoventilation and OHS Medroxyprogesterone

o Agent most commonly used

o Dosage: 10–20 mg PO tid Other agents

o Theophylline: stimulates central drive and increases strength of diaphragm contraction o Acetazolamide: causes excretion of bicarbonate leading to metabolic acidosis, which stimulates

ventilation

Mechanical ventilatory assistance

Eventually required in most patients with chronic hypoventilation related to impairment of respiratory drive or neuromuscular disease

Ventilatory assistance only during sleep o Usually managed by positive-pressure ventilation through a nose mask o Produces dramatic improvement in clinical features and daytime arterial blood gases o Evidence of efficacy and benefit strongest in patients with motor neuron disease and weaker

for other causes of hypoventilation.[2] Continuous ventilation

o When hypoventilation is severe, treatment may be required on a 24-hour basis. o Managed by:

Intermittent negative-pressure ventilation in a cuirass or Intermittent positive-pressure ventilation delivered through a tracheostomy or nose

mask

Diaphragmatic pacing

Delivered by electrophrenic stimulation Effective in patients with reduced respiratory drive but intact respiratory lower motor neurons, phrenic

nerves, and respiratory muscles Contraindicated in patients with defects in the respiratory nerves and muscles

o Except for high cervical spinal cord lesions in which the phrenic lower motor neurons and

nerves are intact

Treatment of specific diseases

Primary alveolar hypoventilation o Supplemental oxygen o Respiratory stimulant o Avoidance of sedative medication which may induce acute respiratory failure o As condition progresses, most patients require additional treatment with:

Diaphragmatic pacing or Mechanical ventilation Administration of such treatment only during sleep is sufficient in most patients.

Neuromuscular disorder o Treatment of underlying condition, if possible o Mechanical ventilatory assistance at night (often through nasal mask) or the entire day

(typically through tracheostomy) o Diaphragmatic pacing may be an alternative for patients with high cervical spinal cord lesions.

Obesity hypoventilation syndrome o Weight loss, including consideration of bariatric surgery o Smoking cessation

o Respiratory stimulants o Nocturnal mask ventilation, if required

o See Obesity for more details. See also:

o Chronic Obstructive Lung Disease

o Sleep Apnea

Monitoring

Monitor for progression of disease, response to therapy, and complications. If hypoventilation is severe and leads to respiratory failure, admission to an intensive care unit may be

required.

Complications

Pulmonary hypertension

Cor pulmonale

Polycythemia Patients with OHS[1]

o Compared with patients with simple sleep apnea: Lower quality of life

Increased health care expenses Greater risk of pulmonary hypertension

o Greater mortality than obese patients without OHS

Prognosis

Prognosis of patients with hypoventilation syndromes is variable. o Depends on the underlying cause of hypoventilation and the severity of the underlying illness

PAH is usually progressive over months to years and ultimately fatal.

Prevention

Smoking cessation Weight loss in obese patients

ICD-9-CM

786.09 Other dyspnea and respiratory abnormalities (includes hypoventilation)

See Also

Chronic Obstructive Lung Disease Obesity

Pulmonary Arterial Hypertension, Secondary Pulmonary Function Tests Sleep Apnea

Internet Sites

Professionals o Central Hypoventilation Syndrome, Congenital

National Organization for Rare Disorders

o Hypoventilation ClinicalTrials.gov

Patients o Obesity hypoventilation syndrome (OHS)

MedlinePlus Medical Encyclopedia

o Primary alveolar hypoventilation MedlinePlus Medical Encyclopedia

References

1. Mokhlesi B, Tulaimat A: Recent advances in obesity hypoventilation syndrome. Chest 132:1322, 2007 [PMID:17934118]

2. Annane D et al: Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders. Cochrane Database Syst Rev , 2007 [PMID:17943762]

General Bibliography

Casey KR, Cantillo KO, Brown LK: Sleep-related hypoventilation/hypoxemic syndromes. Chest 131:1936, 2007 [PMID:17565028]

O'donnell CP et al: Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 159:1477, 1999 [PMID:10228114]

Olson AL, Zwillich C: The obesity hypoventilation syndrome. Am J Med 118:948, 2005 [PMID:16164877]

Phillipson EA, Slutsky AS: Hypoventilation and hyperventilation syndromes, in Textbook of Respiratory Medicine, 3d ed, JF Murray, JA Nadel (eds). Philadelphia, Saunders, 2000, pp 2139–2152

Phipps PR et al: Association of serum leptin with hypoventilation in human obesity. Thorax 57:75, 2002 [PMID:11809994]

Tankersley CG et al: Genetic control of differential baseline breathing pattern. J Appl Physiol 82:874, 1997 [PMID:9074977]

This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 258, Disorders of Ventilation by EA Phillipson.

PEARLS

Charles Dickens provided the classic description of the syndrome of hypoventilation associated with extreme obesity in his novel The Pickwick Papers; hence, it is termed Pickwickian syndrome.

o The overweight boy, Joe, exhibited daytime somnolence and cyanosis. o Syndrome also includes muscular twitching, secondary polycythemia, and right ventricular

hypertrophy and failure.

Harrison's Practice

14. Acute Respiratory Distress Syndrome

Definition

A clinical syndrome of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary infiltrates

leading to respiratory failure. Acute lung injury (ALI) is a less severe disorder but has the potential to evolve into acute respiratory

distress syndrome (ARDS).

Epidemiology

Incidence

o ARDS: estimated to be 60 per 100,000 persons annually o ALI: estimated to be 80 per 100,000 annually

Prevalence o Approximately 10% of patients admitted to the intensive care unit have acute respiratory

failure. ~20% of these patients meet criteria for ALI or ARDS.

Risk Factors

Advanced age Chronic alcohol abuse

Metabolic acidosis Critical illness

Trauma patients o Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥ 16 carries 2.5-fold

increased risk of ARDS. o APACHE II score > 20 carries > 3-fold increased risk of ARDS compared with score ≤ 9.

Pre-B-cell colony-enhancing factor (PBEF) T-1001G variant allele and related haplotype are associated with increased odds of developing ARDS among at-risk patients.[1]

PBEF C-1543T variant allele and related haplotype are associated with decreased odds of ARDS among

patients with septic shock. [1]

Etiology

Caused by diffuse lung injury from many underlying medical and surgical disorders o >80% of cases are caused by:

Sepsis Bacterial pneumonia Trauma Multiple transfusions Gastric acid aspiration

Drug overdose Mechanism of action

o Direct lung injury Pneumonia

Aspiration of gastric contents Pulmonary contusion

Near-drowning Toxic inhalation injury

o Indirect lung injury Sepsis Severe trauma

Multiple transfusions Drug overdose

Multiple bone fractures Flail chest

Head trauma Burns

Pancreatitis After cardiopulmonary bypass

Symptoms & Signs

Although usually present within 12–36 hours after the initial insult, symptoms can be delayed by 5–7 days.

o Dyspnea o Tachypnea

o Respiratory failure Additional symptoms and signs are related to the underlying etiology of ARDS.

Differential Diagnosis

Most common o Cardiogenic pulmonary edema

o Diffuse pneumonia o Alveolar hemorrhage

Less frequent o Acute interstitial lung diseases (e.g., acute interstitial pneumonitis)

o Acute immunologic injury (e.g., hypersensitivity pneumonitis) o Toxin injury (e.g., radiation pneumonitis) o Neurogenic pulmonary edema

Diagnostic Approach

Diagnostic criteria o ARDS

Oxygenation: ratio of arterial partial pressure of oxygen (PaO2) to inspiratory oxygen fraction (FiO2) < 200 mmHg

Onset: acute Chest radiography: bilateral alveolar or interstitial infiltrates

Left atrial hypertension: pulmonary capillary wedge pressure ≤ 18 mmHg or no clinical evidence of increased left atrial pressure

o ALI is a similar syndrome, with PaO2/FiO2 ratio < 200–300 mmHg. Early features are nonspecific, so alternative diagnoses must be considered.

Laboratory Tests

Arterial blood gas analysis o Initially shows hypoxemia

Brain natriuretic factor (BNP) [2] o In patients with hypoxic respiratory failure

Very low BNP levels suggest a diagnosis of ARDS/ALI.

Very high BNP levels suggest cardiogenic pulmonary edema. o BNP appears useful in:

Excluding cardiogenic pulmonary edema Identifying patients with a high probability of ARDS

o Larger studies are necessary to validate these findings. Additional testing is dictated by clinical presentation.

Imaging

Chest radiography (see Figure 1) o During the exudative phase, shows diffuse interstitial and alveolar infiltrates

Can be difficult to distinguish from left ventricular failure Chest CT (see Figure 2)

o During the exudative phase, dependent alveolar edema and atelectasis predominate.

Diagnostic Procedures

Pulmonary capillary wedge pressure ≤ 18 mmHg if Swan–Ganz catheter in use

Treatment Approach

General principles o General critical care management o New ventilator strategies to decrease tidal volume (Vt) while maintaining adequate

oxygenation General care requires:

o Treatment of underlying cause of lung injury o Minimizing procedures and their complications o Avoidance of preventable complications, such as venous thromboembolism and GI

hemorrhage, with appropriate prophylactic regimens o Recognition and treatment of nosocomial infections o Adequate nutritional support

Initial management

o Initiate volume/pressure limited ventilation o Oxygenate o Minimize acidosis o Diuresis

Specific Treatments

Mechanical ventilatory support

Overdistention of normal lung with positive pressure can produce or exacerbate lung injury, causing or worsening ARDS.

o New ventilator strategies aim to limit alveolar distention while still ensuring adequate tissue oxygenation.

o Current practice is to use low Vt combined with positive end-expiratory pressure (PEEP) at levels to achieve adequate oxygenation with the lowest FiO2.

o Other techniques that may improve oxygenation while limiting alveolar distention

Extending the time of inspiration on the ventilator Placing patient in the prone position

Stepwise approach to mechanical ventilation in ARDS (see Figure 3 ) o Calculate predicted body weight in kg.

Men: 50 + 5.42[height (cm) – 60] Women: 45.5 + 5.42[height (cm) – 60]

o Ventilator mode Volume cycle, assist control

o Vt Initial Vt: 8 mL/kg of predicted body weight

Reduce to 6 mL/kg over 2–4 hours if ventilation is adequate.

Goal inspiratory plateau pressures are < 30 cmH2O; reduce Vt to as low as 4 mL/kg as needed (and permitted by ventilation) to achieve this goal.

o Oxygenation PaO2 goal of 55–80 mmHg, or pulse oximetry oxygen saturation 88–95%

Use the minimal amount of PEEP to keep FiO2 ≤ 0.6 mmHg and meet PaO2 goal. o Respiratory rate and acidosis management

Goal arterial pH: 7.30–7.40 pH < 7.30: Increase respiratory rate to 35 breaths/min.

pH < 7.30 and respiratory rate of 35 breaths/min: Consider starting intravenous bicarbonate (or equivalent buffer).

Ancillary therapies

If stepwise mechanical ventilation approach fails and the patient has persistent hypoxemic respiratory failure, consider [3]:

o Neuromuscular blocking agents o Recruitment maneuvers o High PEEP

o Prone positioning Patients with ARDS should receive intravenous fluids only sufficient to achieve an adequate cardiac

output, tissue oxygen delivery, and organ function, as assessed by urine output, acid–base status, and arterial pressure.

o Goal: MAP ≥ 65mmHg, avoid hypoperfusion Glucocorticoids

o Routine use of glucocorticoids or other pharmacologic therapies in ARDS, except as needed to treat the underlying cause, is not recommended.

o Recent randomized, double-blind, placebo-controlled trial[4] with methylprednisolone infusion

demonstrated reductions in: Duration of mechanical ventilation

Duration of intensive care unit (ICU) stay ICU mortality

o The ARDS Network is currently conducting a large-scale study of glucocorticoids in the late phase of ARDS.

Use of nitric oxide is not currently recommended. o Meta-analysis[5]showed nitric oxide is associated with:

Limited improvement in oxygenation in patients with ALI or ARDS No mortality benefit Possible harm (renal dysfunction)

Lung replacement therapy with extracorporeal membrane oxygenation provides clear survival benefit in neonatal respiratory distress syndrome.

o No proven survival benefit in adults with ARDS

Evidence-based recommendations for ARDS therapies

A: recommended therapy based on strong clinical evidence from randomized clinical trials B: recommended therapy based on supportive but limited clinical data

C: indeterminate evidence; recommended only as alternative therapy D: not recommended based on clinical evidence against efficacy of therapy Mechanical ventilation

o Low Vt: A o High PEEP or "open-lung:" C o Prone position: C o High-frequency ventilation: D o Extracorporeal membrane oxygenation: D

Minimization of left atrial filling pressure: B Glucocorticoids: C Surfactant replacement, inhaled nitric oxide, and other anti-inflammatory therapy (e.g., ketoconazole,

prostaglandin E1, NSAIDs): D

Monitoring

Regular monitoring of oxygenation, fluid balance, and acid–base status

Complications

Emphysema-like changes, with large bullae Progressive vascular occlusion and pulmonary hypertension Pneumothorax

Pulmonary fibrosis Depression and post-traumatic stress disorder Complications of long-term intensive care Renal failure, especially in patients with sepsis Nosocomial infections

Prognosis

Natural history o Exudative phase

Duration typically ~7 days

Marked by dyspnea, tachypnea, and severe hypoxemia o Proliferative phase

Days 7–21

Most patients recover rapidly and are liberated from mechanical ventilation during this phase.

o Fibrotic phase Day 21 onward Although the majority of patients recover within 3–4 weeks of the initial insult, some

experience progressive fibrosis. Necessitating prolonged ventilatory support predisposing to complications of

long-term intensive care This phase may be a reaction to now-abandoned ventilator strategies that employed

large Vt and high lung inflation pressures. Mortality

o Mortality estimates: 40–65% Most deaths are due to nonpulmonary causes.

Sepsis and nonpulmonary organ failure account for > 80% of deaths. o Mortality has decreased with improvements in general care and use of low-Vt ventilation.

o Patients > 75 years have a substantially increased mortality rate (~60%) compared to those < 45

years (~20%). o Patients > 60 years with ARDS and sepsis have a 3-fold higher mortality rate compared with

those < 60 years. o Preexisting organ dysfunction from chronic liver disease, cirrhosis, chronic alcohol abuse,

chronic immunosuppression, sepsis, chronic renal disease, any nonpulmonary organ failure, and increased APACHE II scores have also been linked to increased mortality rates from ARDS.

o Patients with ARDS from direct lung injury (including pneumonia, pulmonary contusion, and aspiration) have nearly twice the mortality rate of those with indirect causes of lung injury.

Surgical and trauma patients with ARDS, especially those without direct lung injury, have a better survival rate than do other patients with ARDS.

o Mortality cannot be predicted from: Extent of hypoxemia Level of PEEP used in mechanical ventilation Respiratory compliance Extent of alveolar infiltrates on chest radiography Lung injury score

o Early (within 24 hours of presentation) elevation in dead space may predict increased mortality

from ARDS. Recovery

o Of patients who survive, most recover nearly normal lung function. Despite prolonged respiratory failure and dependence on mechanical ventilation for

survival o Maximum lung function is usually recovered within 6 months. o One year after endotracheal extubation:

More than one-third of survivors have normal spirometry values and diffusion capacity Most remaining patients have only mild abnormalities in pulmonary function.

o Recovery of lung function is inversely related to the extent of lung injury in early ARDS.

o Factors associated with worse recovery of pulmonary function Low static respiratory compliance

High levels of required PEEP Longer durations of mechanical ventilation

High lung injury scores

Prevention

In patients at high risk for ARDS o Careful fluid management o Aspiration precautions (e.g., elevate head of bed)

ICD-9-CM

518.5 Pulmonary insufficiency following trauma and surgery (includes adult respiratory distress syndrome)

518.82 Other pulmonary insufficiency, not elsewhere classified (includes adult respiratory distress syndrome, not elsewhere classified)

769 Respiratory Distress Syndrome (in the perinatal period)

See Also

Approach to Nosocomial Infections

Internet Sites

Professionals o Acute Respiratory Distress Syndrome

ClinicalTrials.gov o Homepage

American College of Chest Physicians Patients

o ARDS (acute respiratory distress syndrome) MedlinePlus

o Acute respiratory distress syndrome MayoClinic.com

References

1. Bajwa EK et al: Pre-B-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome. Crit Care Med 35:1290, 2007 [PMID:17414088]

2. Karmpaliotis D et al: Diagnostic and prognostic utility of brain natriuretic Peptide in subjects admitted to the ICU with hypoxic respiratory failure due to noncardiogenic and cardiogenic pulmonary edema.

Chest 131:964, 2007 [PMID:17426196] 3. Girard TD, Bernard GR: Mechanical ventilation in ARDS: a state-of-the-art review. Chest 131:921, 2007

[PMID:17356115] 4. Meduri GU et al: Methylprednisolone infusion in early severe ARDS: results of a randomized controlled

trial. Chest 131:954, 2007 [PMID:17426195]

5. Adhikari NK et al: Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 334:, 2007 [PMID:17383982]

General Bibliography

Bersten AD et al: Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 165:443, 2002 [PMID:11850334]

Chan KP, Stewart TE: Clinical use of high-frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome. Crit Care Med 33:S170, 2005 [PMID:15753724]

Fan E, Needham DM, Stewart TE: Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA 294:2889, 2005 [PMID:16352797]

Herridge MS et al: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J

Med 348:683, 2003 [PMID:12594312] Piantadosi CA, Schwartz DA: The acute respiratory distress syndrome. Ann Intern Med 141:460, 2004

[PMID:15381520] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury

and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 342:1301, 2000 [PMID:10793162]

Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342:1334, 2000 [PMID:10793167]

This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 262 Acute Respiratory Distress Syndrome by BD Levy and SD Shapiro.

Harrison's Practice

15. Cor Pulmonale

Definition

Dilation and hypertrophy of the right ventricle (RV) in response to diseases of the pulmonary vasculature and/or lung parenchyma

Sometimes leads to RV failure with elevation of transmural RV end-diastolic pressure

Often referred to as pulmonary heart disease Historically, definition has excluded congenital heart disease and those diseases in which the right

heart fails secondary to dysfunction of the left side of the heart.

Epidemiology

Prevalence o In the U.S.: 5–10% of adult heart diseases o Chronic obstructive pulmonary disease (COPD) and chronic bronchitis are responsible for

approximately 50% percent of the cases in North America. Sex

o More common in men than in women

Risk Factors

Smoking Predisposition for venous thrombosis Residence at high altitude

Etiology

Develops in response to acute or chronic changes in the pulmonary vasculature and/or the lung parenchyma that are sufficient to cause pulmonary hypertension

o The common pathophysiologic mechanism in each case is pulmonary hypertension that is

sufficient to lead to RV dilation, with or without the development of concomitant RV hypertrophy.

o The most common mechanisms that lead to pulmonary hypertension include vasoconstriction, activation of the clotting cascade, and obliteration of pulmonary arterial vessels.

Etiology of acute cor pulmonale o Massive or multiple pulmonary emboli

Etiology of chronic cor pulmonale o Diseases leading to hypoxic vasoconstriction

Chronic bronchitis COPD

Cystic fibrosis Chronic hypoventilation

Obesity Neuromuscular disease

Chest wall dysfunction Living at high altitude

o Diseases that cause occlusion of the pulmonary vascular bed Recurrent pulmonary thromboembolism Primary pulmonary hypertension Venocclusive disease Collagen vascular disease

Drug-induced lung disease o Diseases that lead to parenchymal disease

Chronic bronchitis COPD

Bronchiectasis Cystic fibrosis

Pneumoconiosis Sarcoidosis

Idiopathic pulmonary fibrosis

Associated Conditions

Obstructive sleep apnea o Sleep-disordered breathing, once thought to be a major mechanism for cor pulmonale, is rarely

the sole cause of pulmonary hypertension and RV failure.

o The combination of COPD and associated daytime hypoxemia is required to cause sustained pulmonary hypertension in obstructive sleep apnea.

Symptoms & Signs

Acute cor pulmonale o Sudden onset of severe dyspnea and cardiovascular collapse

Occurs in the setting of massive pulmonary embolism o Pallor

o Sweating o Hypotension

o Rapid pulse of small amplitude o Neck vein distention o Pulsatile distended, tender liver o Systolic murmur of tricuspid regurgitation along the left sternal border o Presystolic (S4) gallop

Chronic cor pulmonale o Dyspnea: characteristic feature

o Tachypnea: characteristic feature o Nonproductive cough

o Anterior chest pain o Hepatomegaly

o Lower extremity edema o Cyanosis due to arterial hypoxemia and low cardiac output

o RV heave: palpable along the left sternal border or in the epigastrium o High-pitched pulmonary ejection click may be audible to the left of the upper sternum.

o Fixed, narrow splitting of the second heart sound (S2)

o Right ventricular protodiastolic gallop (S3) increasing during inspiration o Systolic murmur of tricuspid regurgitation augmented by inspiration

o Diastolic murmur of pulmonary regurgitation o Prominent "a" and "v" waves in the jugular venous pulse

The onset of RV failure is reflected in: o Increase of venous pressure o Development of larger "v" waves in jugular venous pulse with increasing tricuspid regurgitation

o Positive hepatojugular reflux o Gallop rhythm with third and fourth heart sounds (S3 and S4)

Differential Diagnosis

RV myocardial infarction Left-sided heart failure Congenital heart disease with left-to-right shunting Constrictive pericarditis

Diagnostic Approach

Evaluate the patient for left ventricular systolic and diastolic dysfunction. o Most common cause of right heart failure is not pulmonary parenchymal or vascular disease,

but left heart failure. This is not referred to as cor pulmonale. History and physical examination, to determine etiology of cor pulmonale Appropriate laboratory and imaging based on the above

o Chest radiography and CT to evaluate pulmonary disease o Brain natriuretic peptide (BNP) o Pulmonary function studies

Laboratory Tests

Acute cor pulmonale o Arterial blood gas

Reduced partial pressure of arterial oxygen (PaO2) due to ventilation–perfusion mismatch

Low partial pressure of carbon dioxide (PaCO2) due to hyperventilation Chronic cor pulmonale

o Complete blood count Elevated hematocrit

o Arterial blood gas Reduced PaO2

Elevated PaCO2 due to impaired ventilation BNP and N-terminal BNP levels are:

o Elevated in patients with cor pulmonale secondary to RV stretch o May be dramatically elevated in acute pulmonary embolism

Imaging

Radiologic examination

o Pulmonary trunk and hilar vessels enlarged o Enlarged descending right pulmonary artery

Spiral CT of the chest

o Useful in diagnosing acute thromboembolic disease Ventilation-perfusion lung scan

o Remains reliable in most centers for establishing the diagnosis of chronic thromboembolic disease

High-resolution CT scan of the chest

o Most accurate means of diagnosing emphysema and interstitial lung disease Systemic venography to show deep venous thrombosis

Echocardiography o Measurement of the thickness of the RV wall, diameter of RV cavity, RV ejection fraction and

anatomy of the pulmonary and tricuspid valves o Interventricular septum may be displaced to the left and may move paradoxically during cardiac

cycle. o Doppler echocardiography, to estimate pulmonary artery and RV systolic pressure

MRI o Useful for assessing RV structure and function (RV mass, wall thickness, cavity volume, and

ejection fraction)

o Particularly useful in patients who are difficult to image with 2-D echocardiography because of severe lung disease

Diagnostic Procedures

Electrocardiography o P pulmonale: tall, peaked P waves o Right-axis deviation

o RV hypertrophy

o Supraventricular tachyarrhythmias are common. Pulmonary function may confirm underlying lung disease.

Cardiac catheterization o Right-heart catheterization is useful for confirming the diagnosis of pulmonary hypertension

and for excluding elevated left-heart pressures (measured as the pulmonary capillary wedge pressures) as a cause for right heart failure.

o Allows precise measurement of pulmonary vascular pressures o Allows calculation of pulmonary vascular resistance

o Shows responses of pulmonary vasculature to oxygen and vasodilators o Sometimes helpful to exclude congenital and left heart diseases

o Allows pulmonary angiography to confirm the nature of the pulmonary vascular obstruction Lung biopsy

o Rarely useful in demonstrating vasculitis in some types of pulmonary vascular disease, such as collagen vascular diseases, rheumatoid arthritis, and Wegener’s granulomatosis

Treatment Approach

Acute cor pulmonale o Treatment of pulmonary embolism

o Cautious expansion of blood volume to maintain cardiac output o Inhalation of 100% oxygen

Chronic cor pulmonale

o Treat the underlying disorder.

Specific Treatments

Acute cor pulmonale

Treatment of massive pulmonary embolus or multiple pulmonary emboli (See Pulmonary Thromboembolism for detailed treatment information.)

o Primary therapy Clot dissolution with thrombolysis or Removal of pulmonary embolus by embolectomy

o Secondary prevention Anticoagulation with heparin and warfarin and/or

Placement of an inferior vena cava filter

Chronic cor pulmonale

Treat the underlying disorder.

General principles of treatment o Decrease work of breathing.

Noninvasive mechanical ventilation Bronchodilation Steroids

o Treat any underlying infection. o Provide adequate oxygenation (oxygen saturation ≥90–92%).

o Transfuse packed red blood cells, if patient is anemic. o Phlebotomy, if the hematocrit exceeds 65%

o Diuretics Effective in the treatment of RV failure

Use judiciously: Chronic diuretic use may lead to contraction alkalosis and worsening hypercapnia.

o Digoxin Uncertain benefit

May lead to arrhythmias in the setting of tissue hypoxia and acidosis If administered, give at low doses and monitor carefully.

Treat RV failure.

Agents undergoing evaluation to reduce pulmonary hypertension o Infusion of prostacyclin

o Oral endothelin antagonists o Inhalation of nitric oxide

Monitoring

Acute cor pulmonale o Monitoring in the intensive care unit

Chronic cor pulmonale o Periodic outpatient follow-up with assessment of pulmonary function and right heart failure

o Pulmonary rehabilitation

Complications

Hypoxia Peripheral edema Hepatic congestion/ascites

Syncope Death

Prognosis

Once patients with chronic pulmonary or pulmonary vascular disease develop cor pulmonale, their prognosis worsens.

Acute cor pulmonale o In the U.S.: 50,000 deaths annually from pulmonary thromboembolism

Probably half of persons die within the first hour from acute right heart failure due to massive or multiple emboli

Chronic cor pulmonale o 5-year mortality rate: 10–50%

Improved with supplemental oxygen o Prognosis is poor for patients with respiratory disease, which reflects the seriousness of the

underlying pulmonary disease. COPD with cor pulmonale

3-year mortality rate: 60%

Prevention

Preventive measures are aimed at the underlying cause of cor pulmonale. o Warfarin therapy (secondary prevention of thromboembolism) o Surgical pulmonary thromboendarterectomy for patients with cor pulmonale, pulmonary

hypertension from prior pulmonary emboli o Surgical correction of congenital heart disease o Cessation of intravenous drug use o Cessation of smoking o Weight reduction o Treatment of sleep apnea

Continuous positive airway pressure

Tracheostomy Dental appliances

Surgical interventions

ICD-9-CM

416.0 Primary pulmonary hypertension (Includes acute cor pulmonale) 416.9 Chronic pulmonary heart disease, unspecified (includes chronic cor pulmonale)

See Also

Dyspnea Pulmonary Function Tests

Pulmonary Arterial Hypertension, Primary Pulmonary Arterial Hypertension, Secondary Pulmonary Thromboembolism

Internet Sites

Professionals o Homepage

American Heart Association Patients

o Cor pulmonale MedlinePlus

General Bibliography

Ferretti GR et al: Severity assessment of acute pulmonary embolism: role of CT angiography. Semin Roentgenol 40:25, 2005 [PMID:15732558]

Han MK et al: Pulmonary diseases and the heart. Circulation 116:2992, 2007 [PMID:18086941] Kessler R et al: "Natural history" of pulmonary hypertension in a series of 131 patients with chronic

obstructive lung disease. Am J Respir Crit Care Med 164:219, 2001 [PMID:11463591] Penaloza D, Arias-Stella J: The heart and pulmonary circulation at high altitudes: healthy highlanders

and chronic mountain sickness. Circulation 115:1132, 2007 [PMID:17339571] Pengo V et al: Incidence of chronic thromboembolic pulmonary hypertension after pulmonary

embolism. N Engl J Med 350:2257, 2004 [PMID:15163775] Rapaport E: Cor pulmonale, in Textbooks of Respiratory Medicine, JF Murray, JA Nadel (eds).

Philadelphia, Saunders, 2000 Rich S, McLaughlin VV: Pulmonary hypertension, in Braunwald’s Heart Disease, 8th ed, P Libby et al

(eds). Philadelphia, Saunders, 2008 Vieillard-Baron A et al: Acute cor pulmonale in massive pulmonary embolism: incidence,

echocardiographic pattern, clinical implications and recovery rate. Intensive Care Med 27:1481, 2001 [PMID:11685341]

Weitzenblum E: Chronic cor pulmonale. Heart 89:225, 2003 [PMID:12527688] This topic is based on Harrison’s Principles of Internal Medicine, 17th edition, chapter 227, Heart Failure

and Cor Pulmonale by DL Mann.