FEVER OF UNKNOWN

ORIGIN (FUO)
1
FEVER OF UNKNOWN ORIGIN (FUO)

▰ Reserved only for prolonged febrile illnesses without an established

etiology despite of intensive evaluation and diagnostic testing.

2
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Definitions

▰ Petersdorf and Beeson had defined FUO in 1961 as patients having:

➢ Temperatures of >38.3°C (>101°F) at least on two occasions;

duration of more than 3 weeks
➢ Failure to reach a diagnosis despite 1 week of inpatient investigation

3
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
The current definition of FUO

▰ 1. Fever ≥38.3°C (≥101°F) on at least two occasions

▰ 2. Duration of illness of ≥3 weeks

▰ 3. No known immunocompromised state

▰ 4. Diagnosis that remains uncertain after a thorough history-taking,

physical examination, and the following obligatory investigations:

4
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
The current definition of FUO (Cont..)

▰ 4. Diagnosis that remains uncertain after a thorough history-taking, physical

examination, and the following obligatory investigations:
➢ ESR and CRP (C-reactive protein) level
➢ Platelet count, leukocyte count (total and differential), and hemoglobin
➢ Electrolytes, creatinine, total protein, ferritin and protein electrophoresis
➢ Enzymes - alkaline phosphatase, alanine aminotransferase, aspartate
aminotransferase, lactate dehydrogenase, creatine kinase

5
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
The current definition of FUO (Cont..)

➢ Antinuclear antibodies, and rheumatoid factor

➢ Urine analysis
➢ Culture: blood cultures (3 negative cultures) and urine culture
➢ Radiology
➢ Tuberculin test

6
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Etiology of FUO

▰ Infections (36%) - This accounts for majority of FUO cases.

▰ Neoplasms (19%) - lymphoma, leukemia, myeloma, renal, colon & liver Ca
▰ Non-infectious Inflammatory Diseases (19%) - connective tissue
disorders like rheumatoid arthritis, SLE etc.
▰ Miscellaneous Causes (19%) – Granulomatous diseases, inherited &
metabolic diseases etc.
▰ Undiagnosed cases (7%).
7
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Infectious causes of fever of unknown origin

Bacterial causes
Localized pyogenic infections Systemic bacterial infections
➢ Appendicitis ➢ Mycobacterial infections
➢ Cholangitis ➢ Typhoid fever
➢ Cholecystitis ➢ Rickettsial infections
➢ Localized abscess ➢ Melioidosis
➢ Mesenteric lymphadenitis ➢ Listeriosis
➢ Osteomyelitis ➢ Bartonellosis
➢ Pelvic inflammatory disease ➢ Actinomycosis and Nocardiosis
➢ Sinusitis ➢ Spirochete infections:
➢ Suppurative thrombophlebitis ❖ Syphilis
➢ Intravascular infections ❖ Lyme disease
❖ Relapsing fever
❖ Leptospirosis

8
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Infectious causes of fever of unknown origin (Cont..)

Non-bacterial causes
Viral infections Parasitic infections Fungal infections
➢ Cytomegalovirus and EBV ➢ Malaria ➢ Aspergillosis
infection ➢ Amoebiasis ➢ Mucormycosis
➢ Coxsackie virus group B ➢ Leishmaniasis ➢ Blastomycosis
infection ➢ Chagas’ disease ➢ Histoplasmosis
➢ Viral hepatitis ➢ Toxoplasmosis ➢ Coccidioidomycosis
➢ HIV infection ➢ Strongyloidiasis ➢ Paracoccidioidomycosis
➢ HSV infection ➢ Echinococcosis ➢ Candidiasis
➢ Dengue ➢ Schistosomiasis ➢ Cryptococcosis
➢ West Nile virus infection ➢ Toxocariasis ➢ Pneumocystis infection
➢ Hantavirus infection ➢ Sporotrichosis
➢ Parvovirus infection

9
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis- Specimen Collection

▰ Prior to specimen collection, a complete clinical history (including details

of travel, immunization, exposure to any other patients) and physical
examination should be carried out - may be helpful in choosing the
appropriate specimen

10
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis - Microscopy

▰ Blood microscopy
▰ Stool wet mount
▰ Gram stain of pus, sputum and other specimens
▰ Ziehl-Neelsen stain for M. tuberculosis.
▰ PAS or GMS stain

11
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis - Culture

▰ Blood culture - typhoid fever, brucellosis

▰ Culture on Lowenstein Jensen medium - M. tuberculosis
▰ Culture of pus and exudate specimen from the abscesses
▰ Sabouraud dextrose agar (SDA) culture - fungal isolation
▰ Cell line culture

12
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis - Serological Tests

▰ ELISA and rapid tests for viral diseases - hepatitis B and C, HIV, CMV, EBV
infections, etc.
▰ Standard agglutination test: For brucellosis
▰ Microscopic agglutination test: For leptospirosis
▰ Cold agglutination test: For Mycoplasma
▰ Weil Felix test: For rickettsial diseases

13
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis - Serological Tests (Cont..)

▰ Paul-Bunnell test: For infectious mononucleosis

▰ Widal test: For typhoid fever
▰ Microimmunofluorescence test for chlamydial infections
▰ Rheumatoid arthritis (RA) factor: For rheumatoid arthritis

14
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis - Molecular Tests

▰ PCR can be carried out to amplify the specific genes

15
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis - Other Tests

▰ Complete blood count: Increased neutrophil count indicates pyogenic

infections

▰ Raised ESR (erythrocyte sedimentation rate)

▰ Histopathological examinations of the biopsies obtained from tumors

may suggest the underlying etiology

16
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Laboratory Diagnosis - Other Tests (Cont..)

▰ Imaging methods: Chest X-ray (for diagnosis of tuberculosis) and CT or

MRI scan to identify the malignant tumors and their extension

▰ ECG and echocardiography: Rheumatic fever and IE

17
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Questions:

18
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
CLINICAL CASE OF
FUO
19
Clinical Case of FUO

▰ A 45-year-old female presents with a persistent fever for the past 5

weeks. The fever is typically low-grade but occasionally spikes to 39°C
(102.2°F). She reports night sweats, fatigue, and a weight loss of 7 kg
over the last two months. She has no significant past medical history
and no recent travel. She works as a school teacher and has not been
in contact with anyone known to have tuberculosis.

20
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO

▰ History and Physical ExaminationHistory: The patient denies cough,

hemoptysis, or respiratory symptoms. She has no history of chronic
illnesses, immunosuppression, or recent infections. She lives with her
husband and two children; no one at home has been sick recently.

21
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO

▰ Physical Examination: On examination, she appears pale and fatigued.

Vital signs show a temperature of 38.2°C (100.8°F), a pulse of 90 beats
per minute, blood pressure of 110/70 mmHg, and respiratory rate of 18
breaths per minute. There are no significant findings on lung, heart, or
abdominal examination. Mild cervical lymphadenopathy is noted.

22
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO
▰ Initial Laboratory Investigations
▰ Complete Blood Count (CBC): Hemoglobin 10.5 g/dL, WBC count 9,000/µL,
▰ Platelets 300,000/µL.
▰ Erythrocyte Sedimentation Rate (ESR): Elevated at 70 mm/hr.
▰ C-Reactive Protein (CRP): Elevated at 40 mg/L.
▰ Liver Function Tests: Normal.
▰ Renal Function Tests: Normal.Blood Cultures: No growth after 48 hours.Urine
Analysis: Normal.
23
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO
▰ Initial ImagingChest X-Ray: Unremarkable, no signs of active pulmonary TB or
other abnormalities
▰ Extended Laboratory TestsTuberculin Skin Test (TST): Induration of 15 mm at
48 hours, indicating exposure to Mycobacterium tuberculosis.
▰ Interferon-Gamma Release Assay (IGRA): Positive, supporting latent TB
infection.
▰ HIV Test: Negative.
▰ Blood Cultures for Mycobacteria: Negative.
24
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO

▰ Advanced ImagingComputed Tomography (CT) Scan of the Chest and

Abdomen: Multiple small nodules in the lungs and enlarged para-aortic
lymph nodes.

▰ CT-guided Fine-Needle Aspiration (FNA) of Enlarged Lymph Nodes:

Granulomatous inflammation with caseous necrosis, suggestive of TB.

25
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO

▰ Microbiological TestsSputum Culture (induced sputum): Negative for

Mycobacterium tuberculosis.

▰ Lymph Node Biopsy: Positive for acid-fast bacilli on Ziehl-Neelsen staining.

26
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO

▰ Diagnosis

▰ Based on the clinical presentation, positive TST and IGRA, radiological

findings, and histopathological evidence of granulomatous
inflammation with acid-fast bacilli, the patient is diagnosed with
extrapulmonary tuberculosis (lymph node TB) causing FUO.

27
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers
Clinical Case of FUO

28
Essentials of Medical Microbiology, 4/e by Apurba S Sastry © Jaypee Brothers Medical Publishers