Tuberculosis Dr.Sh.Sali “ Labafinejad Hospital” 2013 In the name of God Dr. Sh. Sali.

TuberculosisTuberculosis

Dr.Sh.Sali

“Labafinejad Hospital”

2013

In the name of GodIn the name of God

Dr. Sh. SaliDr. Sh. Sali

TuberculosisTuberculosis

• One of the oldest diseases.• A major cause of death world.• Usually affects lungs.• One-third of cases other organs.• Curable: property treat.• Mortality: 50-60% untreated.


OverviewOverview• Etiology agent

• Epidemiology

• From exposure to infection

• From infection to diseases

• Natural History of Diseases


Etiology of agent


Tuberculosis spp.Tuberculosis spp.

• Rod-shaped, non spore forming, thin aerobic bacterium,0.3x3µm.

• Non decolorized by acid alcohol(AFB)• ( Nocardia, Rhodococcus, Leigionella,

Isospora,Cryptosporidium)• Actinomycetales Mycobacteriaceae

M.Tubercolosis complex (M.Bovis,M.Africanum,M.Microti,M.Pinnipedii,M.Canettii.)


EpidemiologyEpidemiology

• WHO,2005:5,000,000 new cases were reported.(>90% from developing countries: Asia, Africa and middle East) insufficient case detection, incomplete notification~60% of estimated cases.

• 1.6 million deaths.• During 1980-1990 increased TB reporter

from industry countries:immigration,HIV, social problems , dismantling.

• After peaking in 2001,incidence has recently stabilized.


From Exposure to InfectionFrom Exposure to Infection• Droplet Nuclei by: Coughing(3000),Sneezing or

speaking.

• Skin and Placenta(no epidemiological significant)

• Determinants of transmission: Intimacy and duration of contact, degree of infectiousness of the case and shared environment.

• Close contact: a-smear+(cavitary,Laryngial)10 5-7 AFB/ml

b- smear-culture+

c- culture- smear- :Essential noninfectious

d- HIV+ less infectious than without HIV

In high prevalence setting up to 20 contacts may be infected each smear+ before index case is

found.


From Infection to diseaseFrom Infection to diseaseDepends largely on endogenous factors: Innate immunigical and nonimmunigical defenses and level of function of CMI.1-Primary Tubercolosis: Up to 4y and among IC.

May be severe, not generally with high level transmissibility , majority develop TB within the 1 and 2y.

dormant bacilli may persist for Ys before reactivation, up to 10% develop active TB in their lifetime(much higher in HIV),reinfection is common in area with rates of TB transmission.


From Infection to diseaseFrom Infection to diseaseRisk diseases after infection: Age: adolescence and early childhood. Sex:in 25-34 F>M, after that opposite.

“Risk factors for active TB among persons infected TB Bacili” Factor Relative risk/Odds

(old infection)

Recent infection (<1 year 12.9

Fibrotic lesions (spontaneously healed) 2-20

Comorbidity

HIV infection 21->30

Silicosis 30

Chronic renal failure/hemodialysis 10-25

Diabetes 2-4

Intravenous drug use 10-30

Immunosuppressive treatment 10

Gastrostomy 2-5

Jejunoileal bypass 30-60

Posttransplantation period (renal, Cardiac) 20-70

Tobacco smoking Malnutrition and severe underweight

2-32


Natural History of DiseaseNatural History of Disease

-Before advent of chemotherapy•Sputum smear+:5 year mortality was 65%

~60% spontaneous remission -With effective, timely and proper chemotherapy•Very high chance of being cured.•Reducing mortality rates.•May also result chronic infectious with drug-resistsnt Bacilli.


Pathogenesis and immunityPathogenesis and immunity

Infection and macrophage invasion

Droplet nuclei: majority of bacilli are

trapped in UEW,a fraction(10%) reach the

alveoli---Macrophage bacilli by

nonactivated alveolar phagocyte


Virulence of tubercle bacilliVirulence of tubercle bacilli

• Several genes: KatG, rpoV(Virulence) erp(contribute to virulence)

Bejing/W(outbreak,mortality,MDR)

• Innate resistance to infection

Genetic factors:NRAMP1 maps chromosome 2q HLA,IFN-Gama, TGF-B, vitD receptor,IL-1


• The host responseGranoloma formation

• The host responseGranoloma formation

• The macrophage activated response• The delated-type hypersensitivity reaction• Role of macrophage and monocyte,

lymphocyte.• Skin test reactivity(DTH):in person without

symptom(TST),CD4+TL,Protective immunity, active tuberculosis, reinfection.


Clinical manifestationClinical manifestation1-Pulmonary Tuberculosis1-Pulmonary Tuberculosis

A-primary diseaseA-primary disease• Soon after the initial infection-middle and lower

lung zones, peripheral, hilar or paratracheal L.Adenopathy, spontaneously heals,small cacified nodule(Ghon Lesion).

• Progress rapidly(HIV,IC),PE(2/3)• Progressive primary tubercolosis(necrosis,cavitation),

Child(Hilar-mediastinal LN, obstruction, emphysema,bronchiectasis,metastase and granulomatous lesions,miliary(HIV-IC).

• Soon after the initial infection-middle and lower lung zones, peripheral, hilar or paratracheal L.Adenopathy, spontaneously heals,small cacified nodule(Ghon Lesion).

• Progress rapidly(HIV,IC),PE(2/3)• Progressive primary tubercolosis(necrosis,cavitation),

Child(Hilar-mediastinal LN, obstruction, emphysema,bronchiectasis,metastase and granulomatous lesions,miliary(HIV-IC).


Clinical manifestationClinical manifestationB-Post primary disease (Adult type, Reactivation, Secondry)B-Post primary disease (Adult type, Reactivation, Secondry)

Usually, Apical and posterior segments of upper lobes(higher mean O2)frequently, superior segments of lower lobes, from small infiltrates to extensive cavitary disease(satellite lesions), pneumonia: a-classical ”galloping consumption” of the past. B-progressively debilitating course(consumption)

some lesion fibrotic and calcify(infectious)

Usually, Apical and posterior segments of upper lobes(higher mean O2)frequently, superior segments of lower lobes, from small infiltrates to extensive cavitary disease(satellite lesions), pneumonia: a-classical ”galloping consumption” of the past. B-progressively debilitating course(consumption)

some lesion fibrotic and calcify(infectious)


Sign and symptom in PPDSign and symptom in PPD

• Early:nonspecific and insidious (F, N.Sweat, W.Loss, Anorexia, G.Malaise, Weakness)

• Cough:nonproductive, productive, blood streaking,massive hemoptysis(blood vessel in cavity”Rasmussen’s aneurysm” or from aspergilloma formation), sometimes:pleurotic chest pain, rarely:ARDS.

• PH.ex: many patients no abnormality, sometimes• Rales during inspiration, especially after coughing


Sign and symptom in PPDSign and symptom in PPD

Amphoric breath sound: CavityFever: Low G, intermittent, up to 80%.In some cases: pallor and finger clubbing.Heamatologic finding: mild anemia, leucocytosis.

SIADH: hyponatremia has been reported.


Center for Food Security and Public Health, Iowa State University, 2008

Clinical manifestationClinical manifestation

2-Extrapulmonary Tuberculosis2-Extrapulmonary Tuberculosis

In order of frequency: LN, Pleura, Genitourinary, Bones and joints, Meninges,

Peritoneum and Pericardium. More

commonly today than the past(HIV).

In order of frequency: LN, Pleura, Genitourinary, Bones and joints, Meninges,

Peritoneum and Pericardium. More

commonly today than the past(HIV).


Lymph Node tuberculosisLymph Node tuberculosis

>40% EXP.TB, frequent among HIV: past,M.bovis, today, M.tuberculosis.Painless swelling, most commonly at posterior cervical and supraclavicular(scrofula).Usually discrete and nontender, may be inflamed and have a fistulous tract draining caseou material.>40%+pulmonary disease.

Diagnosis: FNA>50% AFB+ ,70-80% culture+, granumatous Lesion(no HIV)

DD: Infectious, Neoplastic, Rarely(Kikuchi,Kimura’s, Castleman’s diseases).

>40% EXP.TB, frequent among HIV: past,M.bovis, today, M.tuberculosis.Painless swelling, most commonly at posterior cervical and supraclavicular(scrofula).Usually discrete and nontender, may be inflamed and have a fistulous tract draining caseou material.>40%+pulmonary disease.

Diagnosis: FNA>50% AFB+ ,70-80% culture+, granumatous Lesion(no HIV)

DD: Infectious, Neoplastic, Rarely(Kikuchi,Kimura’s, Castleman’s diseases).


Pleural TuberculosisPleural Tuberculosis

• ~20% EXP.TB, common in primary, many cases of pleurisy accompanying postprimary diseases: actual penetration by tubercle bacilli into the pleural space(small or large).

• Dullness, absence of breath sounds. 1/3 cases paranchymal lesion, thorocentesis: straw-colored,at times hemorrhagic; it is

• Exudate, Pr>50% of serum(4-6 gr/dl), normal to low Glucose, PH~ 7.3, WBC~500-6000/µL:early N↑, typical mononuclear↑, AFB only 10-20%, Culture+ 25-75%(postprimary cases),

• ADA, useful(screening Test)

• ~20% EXP.TB, common in primary, many cases of pleurisy accompanying postprimary diseases: actual penetration by tubercle bacilli into the pleural space(small or large).

• Dullness, absence of breath sounds. 1/3 cases paranchymal lesion, thorocentesis: straw-colored,at times hemorrhagic; it is

• Exudate, Pr>50% of serum(4-6 gr/dl), normal to low Glucose, PH~ 7.3, WBC~500-6000/µL:early N↑, typical mononuclear↑, AFB only 10-20%, Culture+ 25-75%(postprimary cases),

• ADA, useful(screening Test)



• Pleural Biopsy: reveals granulomas, culture+ up to 80%, Lymphocyte↑, smear and culture is often +.

• Responds well to chemotherapy,glucocortioid is doubtful.



Empyema: less common complication of pulmonary TB.

Rupture of a cavity, spllige of a large number of

organism, maybe bronchopleural fistula(air fluid

level). Smear and culture often+.

Chemotherapy + surgical dranage, may fibrosis and

restrictive lung diseases(decortication).

Empyema: less common complication of pulmonary TB.

Rupture of a cavity, spllige of a large number of

organism, maybe bronchopleural fistula(air fluid

level). Smear and culture often+.

Chemotherapy + surgical dranage, may fibrosis and

restrictive lung diseases(decortication).


Upper AirwaysUpper Airways

• Larynx, Pharynx and epiglottis.

• Symptoms: hoarseness, dysphonia, dysphagia with chronic productive cough.

• May be seen on laryngoscopy.

• Smear often+, biopsy to establish the diagnosis.

• DD: carcinoma of pharynx(painless)

• Larynx, Pharynx and epiglottis.

• Symptoms: hoarseness, dysphonia, dysphagia with chronic productive cough.

• May be seen on laryngoscopy.

• Smear often+, biopsy to establish the diagnosis.

• DD: carcinoma of pharynx(painless)


Genitourinary TuberculosisGenitourinary Tuberculosis

• ~15%, up to 1/3 pulmonary disease.• Frequency, dysuria, nocturia, hematuria,

flank or abdominal pain.• U/A abnormal 90%: pyuria and

hematuria(C-, acidic urine).• IVP, CT or MRI: deformity, obstruction,

calcifications and ureteral strictures and hydronrphrosis.


Genitourinary TuberculosisGenitourinary Tuberculosis

F>m: fallopian tubes and endometrium, may infertility, pelvic pain and menstrual abnormalities. Dig: D&C and biopsy,culture.

Male: Epididymis(tender mass), fistula tract orchitis and prostatitis, half of cases UTI.Well response to chemotherapy.


Skeletal tuberculosisSkeletal tuberculosis

• ~10% Exp.TB.• 40% spine:Pott’s disease, 2-3, child:upper

thorasic-adult;lower thorasic and upper lumbar, 13% hip, 10% knees.Body, intervertebral disk, collapse, kyphosis(gibbus), paravertebral cold abcess(psoas abscess).

• CT, MRI, aspiration of abcess or bone biopsy.chemotherapy, may surgery.


Meningitis and TuberculomaMeningitis and Tuberculoma• ~50% of EXP.TB(CNS in USA). often young

children, more than half pulmonary, over 1-2w, paresis of cranial nerves(ocular).

• LP: WBC>1000/µL, Lymphocytes↑, Pr=100-800µg/dL, low glucose, smear+:up to 1/3, culture+ up to 80%, PCR= up to 80% sensitivity but false+ 10%, ADA: low specificity.

• Treat: chemotherapy+ dexa.

• Tuberculoma (seizure and focal signs).


Gastrointestinal TuberculosisGastrointestinal Tuberculosis• Up to 3.5% EXP.TB. • mechanism: swallowing of sputum,

hematogenous, milk from cows.• Terminal illeum and the cecum.• Fever, W.Loss, anorexia, night sweats,

may be fistula(DD: crohn’s), Anal.• Most cases surgery, histology, culture.• Peritonitis: ruptured of LN and

intraabdominal organs or hematogenous, exudative, low culture+, Biopsy.


Pericardial TubercolosisPericardial Tubercolosis

• Primary focus, reactivation of a latent focus, rupture of an adjacent subcarinal LN, elderly, HIV+, tamponad.

• Mortality 40%- subacute, effusion, pericardiocentesis unther echo, thickness, exudative, mononuclear↑, Hemorrhagic, culture+2/3, Biopsy, ADA and IFNgama.

• Without treatment fatal, constrictive pericarditis(calcified), prednisone: 20-60 mg/d up to 6 w.


Miliary or disseminated TBMiliary or disseminated TB

• Hematogenous: Child: primary infection Adult: recent infection or reactivation.Yellowish granulomas, 1-2mm, millet seeds.

Clinical manifestation: nonspecific, Fever, night sweat, anorexia, weakness, W.Loss, sometimes cough, abdominal pain.

PH.ex: hepatomegaly, splenomegaly, LN.



• Pathogonomonic of miliary TB:chroidal tubercle, up to 30%

• Meningismus<30%• Chest x-ray: underpenetrated film,

miliary pattern, large or interstitial infiltrate(HIV) and PE.Smear-80%, anemia, leukopenia, lymphopenia, leukemoid reaction and polycytemia.



• DIC, LFT↑, TST may be-50%, BAL,Biopsy(transbronchial, liver, BM)

• Rare: a- cryptic miliary tuberculosis

chronic, mild intermittent fever anemia, meningitis and death. b- nonreactive miliary tuberculosis massive hematogenous, pancytopenia, rapidly fatal.


Less common EXP formsLess common EXP forms

• Chorioretinitis, Uveitis, Panophthalmitis, painful conjunctivitis, Otitis, Cutaneous, Adrenal. • Congenital: Transplacental spread of bacilli or ingestion of contaminated amniotic fluid.

liver, spleen, LN…


HIV-Associated TuberculosisHIV-Associated Tuberculosis

TST+= 3-13% annual risk of developing active TB. At any stage of HIV: - Early,pulmonary, upper-lobe, cavitation without significant LN. - Late, diffuse interstitial, no cavitation, intrathoracic LN, smear+:lesExp.TB is common(40-60%): lymphatic, disseminated, pleural and pericardial.


Diagnosis of TBDiagnosis of TB

• Key is a high index of suspicion!

• Respiratory symptoms: x-ray: a-Typical: upper lobe infiltration

with cavitation.

b- Atypical: IC, lower-zone infiltration without cavity formation.


AFB MicroscopyAFB Microscopy

• Rapid, inexpensive, low sensitivity in pulmonary(40-60%).

3 sputum, early in the morning. for culture not be put in formaldehyde.

• Traditional method for staining: Kinyoun or Ziel-Neelson.(Light microscopy)

• Modern method: auramin-rhodamine(Fluorescence

microscopy)


Mycobacterial cultureMycobacterial culture

• Definitive diagnosis: isolation and identification of DNA.

• 4-8w, new method: 2-3w

Nucleic Acid AmplificationNucleic Acid Amplification

Several test, hours, confirmation of AFB+ sometimes AFB-

Several test, hours, confirmation of AFB+ sometimes AFB-


Additional diagnostic proceduresAdditional diagnostic procedures

• Ultrasonic nebulization of hypertonic saline.

• Bronchoscopy

• BAL

• Gastric lavage, early in the morning


Serologic and diagnostic testesSerologic and diagnostic testes

• In developing countries.

• ADA level in pleural fluid is useful in pericardial, peritoneal, and meningeal is less clear


Diagnostic of latent M.T infectionDiagnostic of latent M.T infection

TST: 1891,Robert Koch, Old tuberculin.

1932, Seibert and Munday, PPD. 1941, seibert and Glenn, PPD-S Skin testing with tuberculin-PPD for latent. Low sensitivity and specificy. F- in IC and overwhelming TB. F+ in nontuberculous M. and BCG reaction.


IFN-gamma release assay(IGRAS)IFN-gamma release assay(IGRAS)

• In vitro assay, measure T cell release of it in response to stimulation with highly TB-specific Ag.

• More specific than TST

• Less cross reactivity due to BCG and

nontuberculosis M.B


TreatmentTreatment

Aims:

1- interrupt tuberculosis transmission. 2- prevent morbidity and death.1940:StreptomycinPAS1970:Rifampin1950:Pyrazinamid


TreatmentTreatment

• First line agents: Isoniazid,Rifampin, Pyrazinamid, Ethmbutol Oral, peak serum:2-4h, complete elimination:24h.

• Second line agents: Streptomycin, Kanamycin

Amikacin, Capreomycin oral: Ethionamid, Cycloserine PAS,Fluroquinolon (3th.Generation:Levofloxacin,Gatifloxacin, Moxifloxacin)


RegimensRegimens

Standard short course: a-Initial or bactericidal phase(2m. I, R,P,E) b- continuation or sterilizing phase (4m. I,R) Daily, intermittent(3w),initial(D)+2weekly

•HIV-,noncavitary:-Culture- 2m.: R+I once weekly(DOT)-Culture+ 2m.:continuation 9m.-Smear- p.TB:Total 4m.


RegimensRegimens

To prevent neuropathy: Pyridoxine (vitB6)

10-25mg/d for HR groups: alcoholic, malnourished, pregnant and lactating women and CRF, diabetes and HIV.Completion of treatment: Total number doses taken than by the duration of treatment.

Lack of adherence: Patient: Lack of belief to significant illness, beneficial effect of treatment, medical condition, social(joblessness and homelessness). Provider: education and encouragement of patients, clinic hours, meal and travel vouchers.


Regimens(strategic approaches)Regimens(strategic approaches)

• Direct observation of treatment(DOT)

• Fix drug combination(FDC):I/R, I/R/P,

I/R/P/E, May be bioavailability of R has been substandard.


Monitoring treatment response and drug toxicity


• Bacteriologic evaluation Pulmonary: monthly sputum culture>80% Neg.

third m. virtually all patient Neg. some patients: AFB smear conversion may lag:

extensive cavitary disease large number organisms Not achieve sputum culture conversion by: 2m =extended treat 3m < treat failure Smear: 2,5 and 6m.: smear+ after 5m.= treatment failure culture: end of treat




• EXP.TB: Clinically and radiographically

radiographic changes lag behind bacteriologic response and are not highly sensitive.

During treatment: The most common adverse reaction is hepatitis.(dark urine, loss of appetite).Adult: baseline of LFT, monitored closely(monthly): Older, hepatic dis.(HCV), alcohol daily.




• Up to 20% small increase in AST<3 ULN

without symptom. Symptomatic hepatitis or 5-6↑ULN stopped, after LFT

normal, drugs reintroduced one at a time.

Hypersensitivity reaction: usually require the discontinuation.

PYZ: hyperuricemia and arthralgia(A.S.A), gouty=stop!R: autoimmune thrombocytopenia(not important)E: optic neuritis(permanent discontinuation)


Treatment failureTreatment failure

• Culture+ after 3m. , Smear+ after 5m:

susceptibility test to first and second line, change postponed.

if deteriorating: 2 or 3 new drugs add.

relapse: less likely drug resistant from treatment failure. Acquired resistant is uncommon.


Drug resistant TBDrug resistant TB

• A: There is no cross resistant.• B: Monotherapy.• C: Failure health provider.• D: Patient properly.- Primary: not previously drug.(INH)- Acquired: treat with an inappropriate regimen.(MDR: Resistant to: I and R)


Drug resistant TBDrug resistant TB

• MDR: Fluroqouinolone, E, P, S for 18-24m. At least 9m After sputum culture conversion.

• Resistant to all of the first-line agents: 4 second line drugs including one injectable.

24m. Recommended. XDR: Resistant to at least flurouquinolones and one or

more of the injectable drugs.Poor prognosis, in specialized centers,locolized:lobectomy.


HIV associated TBHIV associated TB

• An increased frequency of paradoxical reaction.• Drug interaction(R) with antiretroviral.• Immune reconstitution inflammatory syndrome (IRIS) Exacerbation in symptom, sign and lab or radiologic TB.

• Advanced Immunosupersion and EXP.TB: mild: symptom base

treatment. severe reaction: corton

Rifabutin (adjustment)

CD4<100/µl: are prone to treatment failure and relapse with R-

resistance.

Recommended daily or thrice-w for entire course.


Special clinical situationSpecial clinical situation

• Children with bone and joint TB, meningitis or miliary TB: 9-12m.

• Mild to moderate renal failure: I,R,P and E only if serum levels can be monitored.

• Severe renal failure: I and P reduced, except hemodialysis.


Special clinical situationSpecial clinical situation

• Severe hepatic disease: E, S and possibly another drug(fluoroquinolone)

if required, I and R may be administered

under close supervision be avoided.

• Pregnant women : I+R+E for 2m. I+R 7m.

• Breast feeding: drugs in small quantities in breast milk.


PreventionPrevention

• BCG vaccination: vary in efficacy(80% to nil) in children: protection from meningitis and milliary TB. safe, rarely serious complications. local tissue response begins 2-3w, scar formation and healing within 3m. side effect: ulceration, regional L.adenitis(1-10%).

~1case per million osteomyelitis. ~ 1-10case per 10m. Dose: disseminated BCG infection and death.


PreventionPrevention

• BCG vaccination induces TST reactivity which wane with time.

• The presence or size of TST after vaccination does not predict the degree of protection.

• BCG vaccine recommended: At birth in countries with high prevalence.

WHO: asymptomatic HIV children residing in tuberculosis-endemic areas.


Latent tuberculosis infectionLatent tuberculosis infection

• Formely called: preventive chemotherapy or chemoprophylaxis.

• Optimal duration of treatment is 9-1om.• In the absence of reinfection, protective effect

is lifelong.• 5 unit PPD, Intradermal, forearm(Mantoux).• Read 48-72h, induration, in mm, transverse.



• >5mm: close contact, HIV, Immunosuppress, untreated persons whose healed TB in chest x-ray.

• >10mm: most other at risk.• >15mm: very low risk of developing.• TST negative candidates for treatment: infant and children who contact with infectious case,

have e repeat TST 2-3months after contact. HIV-infected who exposed to an infectious TB should receive treatment regardless of the TST result.



• INH: 5mg/kg(up to 300mg)/d for 9 m.

15mg/kg twice w when supervised.• Rif: 4m. For adult.• R+I: 3m.in UK for adult and children.• Active liver disease: no INH, R monthly

assessment of LFT.• Twice weekly: supervised when active TB

treatment in family.


Thank you

“for your attention”

Center for Food Security and Public Health, Iowa State University, 2008

Tuberculosis Dr.Sh.Sali “ Labafinejad Hospital” 2013 In the name of God Dr. Sh. Sali.

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Transcript of Tuberculosis Dr.Sh.Sali “ Labafinejad Hospital” 2013 In the name of God Dr. Sh. Sali.