Pyrexia of unknown origin

04/11/2023 Dr.T.V.Rao MD 1

Pyrexia of Unknown OriginPUO or FUO

Dr.T.V.Rao MD

04/11/2023 Dr.T.V.Rao MD 2

What is the normal human body temperature?

A. 37.5° CB. 98.6° FC. Each human being is a unique individual, and

therefore, normal temperature cannot be defined.

04/11/2023 Dr.T.V.Rao MD 3

What is the normal human body temperature?

A. 37.6° CB. 98.6° FC Each human being is a unique individual, and

therefore, normal temperature cannot be defined.

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Normal Body Temperature

• For healthy individuals 18 to 40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F)

• Low levels occur at 6 A.M. and higher levels at 4 to 6 P.M.

• The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.

• These values define the 99th percentile for healthy individuals.

Mackowiak, et al., JAMA 1992;268:1578

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Definition• Fever > 38.3 on

several occasions• Fever lasting

more than 3 weeks

• No diagnosis despite 1 week of inpatient workup

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Terminology• Old Definition:

1. Fever higher than 38.3oC on several occasions.

2. Duration of fever – 3 weeks3. Uncertain diagnosis after one week of study

in hospital• New Definition:

– Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital. … Ambulatory as well as in hospital

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Historical Causes of FUO• Hippocrates: excess of yellow bile• Middle Ages: demonic possession

(encephalitis?)• 18th Century: Friction associated with the

flow of blood through the vascular system and from fermentation and putrefaction occurring in the blood and intestines

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Definition Expansion1. Classical PUO2. Nosocomial

PUO3. Neutropenia

PUO4. HIV-Associated5. Transplant

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Categories of FUOFeature Nosocomial Neutropenic HIV-associated Classic

Patient’s situation

Hospitalized, acute care, no infection when admitted

Neutrophil count either <500/µL or expected to reach that level in 1-2 days

Confirmed HIV-positive

All others with fevers for ≥3 weeks

Duration of illness while investigated

3 daysb 3 daysb 3 daysb (or 4 weeks as outpatient)

3 daysb or 3+ outpatient visits

Examples Septic thrombophlebitis, sinusitis, C. difficile colitis, drug fever

Perianal infection, aspergillosis, candidemia

MAIc infection, TB, non-Hodgkin’s lymphoma, drug fever

Infections, malignancy, inflammatory diseases, drug fever

aAll require temperatures of ≥38.3°C (101°F) on several occasions.bIncludes at least 2 days’ incubation of microbiology cultures.cM. avium/M. intracellulare.

Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds): Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

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Pattern of Fever

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Etiologies of PUO• Infection: Three major

causes• Abscess .. especially

occult ..• Intracellular

organisms. (salmonella mycobacterium, brucella)

• Intravascular … SBE

“True Fever”• Occurs when IL-1, IL-6, TNF-ά or other cytokines are

released from monocytes and macrophages in response to infection, tissue injury, drugs, and other inflammatory processes, increasing the body’s set point. The anterior hypothalamus maintains an inherent set point near 36ºC(98.6ºF).

• Normal circadian rhythm, which is highest(up to 2ºC, 3ºF) ~6pm and lowest at 6am. This accounts for increased volume of ER visits that peaks in the evening. Most true fevers follow this diurnal pattern.

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Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas,

etc)• Appendicitis, cholecystitis, tubo-ovarian

abscess, pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung

abscess• Septic jugular phlebitis, mycotic aneurysm,

endocarditis, intravenous catheter infection, vascular graft infection

• Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

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Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas, etc)• Appendicitis, Cholecystitis, tubo-ovarian abscess,

pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung abscess• Septic jugular phlebitis, mycotic aneurysm,



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Infectious Causes of FUO• Intraabdominal abscess (liver, splenic, psoas, etc)• Appendicitis, Cholecystitis, tubo-ovarian abscess,

pyometra• Intracranial abscess, sinusitis, dental abscess• Chronic pharyngitis, tracheobronchitis, lung abscess• Septic jugular phlebitis, mycotic aneurysm,



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Bacterial Pyrogens• Lipopolysaccharide (LPS)

endotoxinEndotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNFα.

• Staphylococcus aureus enterotoxins

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Infectious Causes of FUO

• Tuberculosis, Mycobacterium avium complex, syphilis, Q fever, Legionellosis

• Salmonellosis (including typhoid fever), Listeriosis, ehrlichiosis,

• Actinomycosis, nocardiosis, Whipple’s disease• Fungal (candidaemia, cryptococcosis, sporotrichosis,

Aspergillosis, Mucormycosis, Malassezia furfur)• Malaria, Babesiosis, toxoplasmosis, schistosomiasis,

fascioliasis, Toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasis

• Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus, parvovirus B19

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Miscellaneous Causes of FUO• Complex partial status epilepticus,

cerebrovascular accident, brain tumor, encephalitis

• Drug fever, Sweet’s syndrome, familial Mediterranean fever

• Gout, pseudo gout• Kawasaki’s syndrome, Kikuchi’s syndrome• Crohn’s disease, ulcerative colitis, sarcoidosis,

granulomatous hepatitis• Deep vein thrombosis• Atelectasis?

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Bacterial Pyrogens• Staphylococcus aureus toxic shock

syndrome toxin (TSST)Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-gamma in large amounts

• Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNFα but also IL1 and IL-6

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CAUSES CLASSIC PUO

• INFECTIVE 20-30%• CANCER 10-20%• AUTOIMMUNE 15-20%• MISC 15-25%• UNDIAGNOSED 5-10%

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Classic FUO

•Infection•Malignancy•Collagen vascular diseases

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Infectious Causes of FUO

• Chronic pharyngitis, tracheobronchitis, lung abscess

• Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection


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GeographyMalaria Saudi (malaria area)/Africa/India

Brucella Saudi/Gulf Area

Kala-Azar Yemen/Jazan/Sudan/India

Leprosy Yemen/Najran…

Typhoid India/Pakistan/Egypt/Indonesia

Histoplasmosis USA … (West Coast)

N.B.: Ease of Travel → Infection → All parts of the world.

Tuberculosis

All over the world.Liver Abscess

AIDS

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Pathophysiology• Meningitis and sepsis are serious etiologies

of fever in infants and young children. • Neonates' immature immune systems place

them at greater risk of systemic infection. Hematogenous spread of infection is most common in this age group or in patients who are immunocompromised. For these same reasons, infants who have a focal bacterial infection have a greater risk of developing sepsis.

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Bacterial Pyrogens• Lipopolysaccharide (LPS) endotoxin

Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNFα.

• Staphylococcus aureus enterotoxins• Staphylococcus aureus toxic shock syndrome toxin

(TSST)Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-gamma in large amounts

• Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNFα but also IL1 and IL-6

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What are common Causes• The following are among the most common bacterial etiologies of serious bacterial

infection in this age group:

• Streptococcus pneumoniae

• Group B streptococci

• Neisseria meningitidis

• Haemophilus influenzae type b

• Listeria monocytogenes

• Escherichia coli

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Consequences of Fever can be confusing

• Approximately 2.5-3% of highly febrile children younger than 3 years develop occult bacteremia, which typically is caused by S pneumoniae. Viral infections are common in the young child as well; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever.

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History Taking• Family History:

– Scrutinized for possible infectious or hereditary disorders• Tuberculosis• FMF

• Past Medical Condition:Lymphoma → may recurRheumatic Fever → may recurStill’s Disease → may recurBehcet’s Disease → may recur

• Exposure to sexual partner … Acute HIV• Illicit drug abuse (IV) … infective endocarditis,

Hepatitis … HIV

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Physical Examination….. Looking for the KEY physical sign …. Diagnostic yield60% in children (50%repeated)

• Document the Fever:– Significant and persistent for more than ONE occasion.

• Analyzing the Pattern:– Neither specific Nor sensitive enough to be considered diagnostic …

EXCEPT

Tertian & Quarter Pattern → MalariaPel-Ebstein Pattern → Lymphoma/

TuberculosisPulse-Temp Dissociation → Typhoid/

Brucellosis

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Infections

• Tuberculosis (especially extrapulmonary)Abdominal abscessesPelvic abscessesDental abscessesEndocarditisOsteomyelitis

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Infections• Sinusitis

CytomegalovirusEpstein-Barr virusHuman immunodeficiency virusLyme diseaseProstatitisSinusitis

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Etiologies of PUO• Infection

– Tuberculosis: .. Disseminated• The single most common infection in most PUO series

except in children and elderly.• Usually extrapulmonary or military, or• Occurs in the lungs and significant pre-existing lung

disease.• Pulmonary TB in AIDS is often subtle (normal chest x-

rays → 15 – 30%).• PPD is (+ve) < 50% of TB with PUO.• Diagnosis often requires Bx of LN/Liver/Bone marrow.• Sputum smear (+) only 25%

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Etiologies of PUO– Abscess:

• Usually located in abdomen or pelvis.• Secondary to appendicitis or diverticulitis.• Pyogenic liver abscess usually follow biliary tract

dis./abd. Suppuration.• Amoebic liver abscess is similar to pyogenic →

amoebic serology is positive > 95% of cases.• Splenic abscess is usually secondary to

hematogenous seeding.• Perinephric or renal abscess is usually secondary to

UTI.

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Etiologies of PUO– Bacterial Endocarditis

• Culture remains negative in 5% of patient.• Culture negative is likely with the following organisms:

– Coxiella burnetii → no growth.– HACEK group → incubate blood 7 – 21 days– Brucella } Special media/ – Legionelle } long time– Mycoplasm/Chlamydia }– Fungal → usually sterile

• Peripheral signs may not be detected.• Right-side Endocarditis → Lack murmurs → self

antibiotics → growth (-ve).

04/11/2023 Dr.T.V.Rao MD 38

Etiologies of PUO• Infection

– Tuberculosis: .. Disseminated• The single most common infection in most PUO series

except in children and elderly.• Usually extra pulmonary or military, or• Occurs in the lungs and significant pre-existing lung

disease.• Pulmonary TB in AIDS is often subtle (normal chest x-

rays → 15 – 30%).• PPD is (+ve) < 50% of TB with PUO.• Diagnosis often requires Bx of LN/Liver/Bone marrow.• Sputum smear (+) only 25%

GeographyMalaria Saudi (malaria area)/Africa/India

Brucella Saudi/Gulf Area

Kala-Azar Yemen/Jazan/Sudan/India

Leprosy Yemen/Najran…

Typhoid India/Pakistan/Egypt/Indonesia

Histoplasmosis USA … (West Coast)

N.B.: Ease of Travel → Infection → All parts of the world.

Tuberculosis

All over the world.Liver Abscess

AIDS

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HIV associated PUO• HIV alone• TB,M avium/intracelulare• Toxoplasmosis• CMV ,PCP ,Salmonella• Cryptococcus, Histoplasmosis• Non Hodgkins Lymphoma• Drug induced

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Malignancies• Chronic leukemia

LymphomaMetastatic cancersRenal cell carcinomaColon carcinomaHepatomaMyelodysplastic syndromesPancreatic carcinomaSarcomas

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Autoimmune Conditions with Fever

• Adult Still's diseasePolymyalgia rheumaticTemporal arteritisRheumatoid arthritisRheumatoid feverInflammatory bowel diseaseReiter's syndromeSystemic lupus erythematousVasculitides

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Miscellaneous• Drug-induced fever

Complications from cirrhosisFactitious feverHepatitis (alcoholic, granulomatous, or lupoid)Deep venous thrombosisSarcoidosis

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Diagnosis

• A cost-effective individualized approach is essential in the evaluation of these patients to prevent performing inappropriate tests.

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Minimal Initial Diagnostic Workup For FUO

• Comprehensive history• Physical examination• CBC + differential• Blood film reviewed by hematopathologist• Routine blood chemistry• UA and microscopy• Blood (x 3) and urine cultures• Antinuclear antibodies, rheumatoid factor• HIV antibody• CMV IgM antibodies; heterophile antibody test (if c/w mono-like

syndrome)• Q-fever serology (if risk factors)• Chest radiography• Hepatitis serology (if abnormal LFTs)

Mourad, et al. Arch Intern Med. 2003;163:545

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Diagnostic TestingBlind application leads to excessive falsetests …• Complete Blood Count

– Anemia if present → suggest a serious underlying disease– Leukocytosis with bands → occult bacterial infection– Lymphocytosis & atypical Lymphocyte → Infectious

mononucleosis– Leucopenia and Lymphopenia → advanced HIV– Leukoerythroblastic Anemia → Disseminated TB– Thrombocytopenia → Malaria/Leukemia– Peripheral Blood → Malaria

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Diagnostic Testing• Urinalysis, Urine Culture, U/E, LFT• ESR

– If elevated → significant inflammatory process

– Greatest use in establishing a serious underlying disease, esp. if v. high → ESR > 100 mm/h …Tuberculosis … m myeloma … temporal arteritis

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Diagnostic Testing– 58% → malignancy → Lymphoma/myeloma– 25%

• Infection – Endocarditis• Giant cell arteritis

– ↑ High ESR → lacks specificity:• Drug Reaction }• Thrombophlebitis } may cause very high ESR• Nephrotic Syndrome }

– Normal ESR → significant inflammatory process is absent with exception.

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Diagnostic Testing• CRP-closely associated with inflammatory

process– Not invariable components of the febrile response.– Usually does not go up with viral infection.* ESR & CRP is elevated in:

1. Bacterial Infection2. Neoplasm3. Immunological-mediated inflammatory states4. Tissue infarction

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Diagnostic Testing• Acute Phase Proteins

Proteins Increased Proteins Decreased

Fibrinogen Albumin

Ferritin Transferrin

Plasminogen Alpha-

Fetoprotein

Protein S

Cerruloplasmin

New England J Med. 1999, 340.448-454

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Diagnostic Testing• Blood Testing

– Anti-nuclear Antibodies– Rheumatoid Factor– CMV Antibody … IgM– Heterophile Antibody Test in children and young

adult– Tuberculin Skin Test … 5 unit ID– Thyroid Function Test– HIV Screening

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Diagnostic Testing• Imaging Studies: … to localize abnormalities

for definite tests or treatment– Chest x-ray:

• Military shadows → disseminated tuberculosis• Atelectasis } 1. Liver

↑ Hemi diaphragm } Abscess 2. SpleenPleural Effusion } 3. Pancreatic

4. Subphrenic• Mediastinal mass → Lymphoma/Tuberculosis/ Sarcoid• If CXR is (N) → Repeat on weekly basis

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Diagnostic Testing– CT-Scan → CT scan chest

• Mediastinal mass → Tuberculosis/Lymphoma/ Sarcoidosis

• Dorsal Spine → Spondylitis and disc space disease

• CT-Scan Abdomen → very effective to visualize– All types of abscesses– Retroperitoneal tumor, lymph node or hematoma

– MRI: spleen, lymph node and the brain

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Diagnostic Testing• Serology Test

– Brucella Titer– CMV & EBV antibody test– HIV testing (Elisa screening)– ANF

• Radio nuclear Scanning– Bone TC-scan → osteomyelitis (skeletal)– Gallium scan → occult inflammation– Indium labeled WBC-scan → occult abscesses

04/11/2023 Dr.T.V.Rao MD 55

Diagnostic Testing– Hepatomegaly or Abnormal LFT

• Hepatic Granuloma– Non-caseating: Tuberculosis/Sarcoidosis & Brucellosis– Caseating: Tuberculosis

– Bone Marrow• Granuloma ± Tubercle Bacilli → Tuberculosis• Aplastic Cells → Leukemia• Leishmania Bodies → Kala-Azar• Atypical Cells → Lymphoma• Atypical Plasma Cells → M. myeloma

– Temporal Artery → Giant Cell Arteritis– Pleural or Pericardial → Extrapulmonary Tuberculosis

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Investigation • Blood culture before the

antibiotics• Culturing of Urine• Sputum culture• Stool examination for Bacterial

and Parasitic infection.

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Etiologies of PUO– Abscess:

• Usually located in abdomen or pelvis.• Secondary to appendicitis or diverticulitis.• Pyogenic liver abscess usually follow biliary tract

dis./abd. Suppuration.• Amoebic liver abscess is similar to pyogenic →

amoebic serology is positive > 95% of cases.• Splenic abscess is usually secondary to

haematogenous seeding.• Perinephric or renal abscess is usually secondary to

UTI.

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Tuberculosis• Sputum

examination for AFB

• Culturing for AFB• Monteux test

Tuberculin test• X ray of the chest

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Diagnosis• More invasive testing, such as LP or biopsy

of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation.

• When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful.

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Etiologies of PUO• Factitious Fever

Febrile PUOIn one study … 9% of cases of PUO– False fever: thermometer manipulation using external heat

or substitute thermometer. Men use this way … physician are rare for this disorder. Increasing somewhat in elderly … 115 … 116 …

– Genuine fever (self induced) Administration of pyrogenic substances (bacterial

suspensions) Generally young women with connection to health care …

often NURSES.

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Pyrexia of Unknown Origin

The majority of disease remaining after aninitial NEGATIVE work-up are:

1. Neoplasm2. Seronegative Collagen Vascular Disease3. Increasing Tuberculosis4. Increasing Drug Addition5. Elderly with Endocarditis6. HIV with or without infection or malignancy7. Implanted prosthetic devices8. Travel … New Exposure

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Therapeutic Trials• Limitation and risk of empirical therapeutic

trials:– Rarely specific– Underlying disease may remit spontaneously false

impression of success.– Disease may respond partially and this may lead to

delay in specific diagnosis.– Side effect of the drugs can be misleading.

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Therapeutic Trials• What is the best

therapy for PUO patient?– To hold therapeutic trials

in the early stage… except in:

• Patient who is very sick to wait.

• All tests have failed to uncover the etiology.

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Prognosis• Prognosis is determined primarily by

the underlying disease.• Outcome is worst for neoplasms.• FUO patients who remain undiagnosed

after extensive evaluation generally have a favorable outcome and the fever usually resolves after 4-5 weeks.

Larson et al. Medicine 1982;61:269

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Summary• FUO is often a diagnostic dilemma• Infections comprise ~30% of cases• Bone marrow biopsies are of low

diagnostic yield• Diagnostic approach should occur in a

step-wise fashion based on the H&P• Patient’s that remain undiagnosed generally

have a good prognosis

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Pyrexia of unknown origin

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