FEVER OF UNKNOWN ORIGIN

Dr. S. Aswini Kumar. MD.

Professor of Medicine,

Medical College Hospital,

Thiruvananthapuram.

Definition:

Fever of unknown origin (FUO) was defined by Petersdorf and Beeson in

1961 as

temperatures higher than 38.3°C on several occasions, a duration of fever of more than 3 weeks, and failure to reach a diagnosis despite 1 week of

in-patient investigation.

New classification:

Durack and Street have proposed a new system for classification of

FUO:

(1)classic FUO,

(2)nosocomial FUO,

(3)neutropenic FUO, and

(4) FUO associated with HIV infection

Classic PUO:

This category corresponds closely to the earlier definition of FUO , but

the new definition is broader,

stipulating three outpatient visits or 3 days in the hospital without

elucidation of a cause or 1 week of "intelligent and invasive" ambulatory

investigation.

1. Diagnosis ?

A 50 year old man was admitted with fever of three weeks duration. On examination there was hepatosplenomegaly. Routine urine and blood examinations were normal. Widal test and Mantouex test were negative. Chest X-Ray and HIV were negative. Liver biopsy showed presence of granulomas

Granulomatous hepatitis

Systemic Sarcoidosis

Miliary tuberculosis

Lymphomas

Wegener’s

Brucellosis

Histoplasmosis

Shistosomiasis

Systemic Sarcoidosis

History• Fever, fatigue, weight loss• cough, dyspnea, polyarthritis

Examination• Ocular findings - uveitis, conjunctivitis• Skin findings - erythema nodosum

Diagnosis• Serum levels of ACE - increased• Liver Biopsy – granulomas

Liver Biopsy in FUO

Mehngini/Vim’s/True cut needle To be cultured and retained

Advantages

Disadvantages

2. Diagnosis?

A 45 year old man was admitted to the CCU with acute MI, thrombolysed and reperfused, but then went into persistent hypotension following a cardiac arrest. He developed fever on Day 5. Routine blood investigation showed a polymorpho-nuclear leucocytosis. Blood culture was diagnostic

Nosocomial FUO:

“In nosocomial FUO, a temperature of ³38.3°C develops on several

occasions in a hospitalized patient who is receiving acute care and in

whom infection was not manifest or incubating on admission.

Three days of investigation, including at least 2 days' incubation

of cultures, is the minimum requirement for this diagnosis”

Nosocomial FUO

Post Myocardial infarction syndrome

Pulmonary thromboembolism

Occult Nosocomial infection

Transfusion related viral infections

Infected intra-vascular lines

Catheter related infections

Drug related fever

Blood Culture in FUO

Method

10ml blood

Venipuncture

2-3 bottles

Aseptic

Uncontaminated

Rapid identification

Dressler’s Syndrome

History• Chest pain of pericarditis • Large/multiple infarction

Examination• Pericardial rub, pleural rub• Periarthritis shoulder and hands

Investigation• ECG changes of pericarditis• ST elevation, PR Depression

3. Diagnosis?

A 30 year old farmer working in a diary farm in Tamil Nadu was admitted to the ward with low grade fever and evening rise of temperature. On examination there was generalized lymphadenopathy and hepato-splenomegaly. Blood routine, Chest X-ray PA view & Blood Widal test were negative

Systemic bacterial infections

Brucellosis

Typhoid fever

Leptospirosis

Campylobacter infection

Meningococcemia

Lyme’s disease

Legionaire’s disease

Brucellosis

History• Travel to an endemic area• Consumption of unpasteurized milk

Examination• Hepatosplenomegaly, epididymoorchitis• Polyarthritis or septic arthritis

Investigations• IgM IgG and IgA antibodies• Isolation from blood, CSF, marrow or joint

Serological Tests

Widal Test Methodology

Salmonellosis• Somatic O and Flagellar H

• Not specific False +ve

Brucellosis

• Somatic-O only

ELISA • 2 Mercapto-ethanol added• Diiferentiates IgG and IgM

4. Diagnosis?

A 49 year old college Professor came with pain in the right loin and fever of one month duration. Loss of appetite and loss of weight were present. He was investigated for UTI. Repeated URE and urine cultures were negative. Renal angle was dull but non tender. CT scan of abdomen was diagnostic

Malignancies

Renal cell carcinoma

Pancreatic cancer

Cancer colon

Lymphoma

Leukemia

Hepatoma

Sarcoma

Renal Cell carcinoma

History• Fever, weight loss• Painless hematuria

Examination• Anemia, Hypertension• Abdominal mass

Investigations• USS, CT Abdomen• Nephrectomy and Histopathology

Ultra-sound scan in FUO

Look at

Organs

Liver

Spleen

Kidney

Tumors

RCC

Hepatoma

Lymphoma

Pus

Abscess

Appendicitis

PID

USS Abd in RCC

5. Diagnosis?

A 14 year old boy was admitted with high grade fever and pallor. On examination no hepatosplenomegaly, lymphadenopathy or bone tenderness were present. The blood counts were as follows: Hb 8gm%, TC 3800, P8 L86 E4 M2, ESR 20 mm in 1st hr. Platelet count 2.5 lakhs, BT 1’30” CT 3’30”

Neutropenic FUO:

Neutropenic FUO is defined as a temperature of 38.3°C on several occasions in a patient

whose neutrophil count is <500/L or is expected to fall to that level in 1–2 days.

The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigation, including at

least 2 days' incubation of cultures

Neutropenic FUO

Focal infections Systemic infectionsBacterial infections Fungal infectionsCatheter infections Perianal infections Infections due to HSV and CMV

Cyclic Neutropenia

History• Fever every 21 days• Autosomal dominant

Examination• Anemia and infections• Premature tooth loss

Investigations• Cyclic Hematopoesis in Bone marrow• Mutation in Neutrophil Elastase Gene

Bone Marrow studies

Bone marrow aspiration Yields

• Anemia, Leukemia,

Pancytopenia, Myeloma

Haemto-logical

disorders

• Septicemia, Tuberculosis, Myco. avium,

Brucellosis

Culture of marrow aspirate

6. Diagnosis?

A 55 year old woman presented with high grade remittent fever and severe pain in the right shoulder. No pallor/lymphadenopathy. Liver was palpable 8 cm below the costal margin. Soft and non tender. X ray chest and fluoroscopy showed elevated right hemi diaphragm with reduced movements

Pus somewhere

Pancreatic abscess

Pelvic inflammatory disease

Prostatic abscess

Tubo-ovarian abscess

Sub diaphragmatic abscess

Liver abscess

Dental abscess

Pancreatic Abscess

History• High grade intermittent Fever• Epigastric pain or discomfort

Examination• Epigastric tenderness • Mass if Pseudocyst Formation

Investigations• USS Scan insufficient• CT scan diagnostic

CT Scan as a tool in FUO

Pacreatic Abscess in CT Superior to USS Abd

• Kidney• Pancreas

Organo megaly

• Retroeritoneal• Lymphnodes

Mass abdomen

• Pancreatic• Pelvic

Pus somewhere

7. Diagnosis?

A 19 year old girl was diagnosed to have infective endocarditis, because she had fever, pallor and systolic murmur. Repeated blood cultures were negative and she did not improve with antibiotics given for SBE. After 4 weeks she was skin and bones and still febrile. This time CXR was diagnostic

Tuberculosis

Miliary tuberculosis

Pulmonary Tuberculosis

Tuberculous pleural effusion

Tuberculous pericarditis

Intestinal tuberculosis

TB Lymphadenitis

Renal tuberculosis

Miliary Tuberculosis

History• Low grade fever• Poor natural immunity

Examination• Ill look and emaciation• Signs of meningeal irritation

Investigations• Serial chest X-Rays • Liver biopsy - granulomas

Chest X-Ray in FUO

Diagnosis from CXR

PTB

Infilteration

Breaking down

Cavitation

Empyema

Tuberculous

Diabetes

Traumatic

Parenchymal

Miliary TB

Lung tumor

Lofflers

Encysted Empyema in CXR

8. Diagnosis?

A 25 year-old woman was admitted with a suspicion of rheumatic fever. A mid-diastolic murmur was audible to 4 out of 11 post graduate doctors in medicine who examined the case. ECG did not show RVH nor was there any straightening of the left border of heart in the chest X-ray PA view.

Cardiac Causes of FUO

Left atrial myxoma

Sub acute bacterial endocarditis

Prosthetic valve endocarditis

Aortic dissection

Tuberculous pericardial effusion

Chronic constrictive Pericarditis

Post myocardial infarction syndrome

Left atrial myxoma

History• Low grade fever• Minimal cardiac symptoms

Examination• Mid-diastolic murmur• Dynamic nature of the murmur

Investigation• Echodemonstration of tumor• Surgical Removal and Histopathology

ECHO in FUO

Diagnosis by ECHO

• Endocarditis• Vegetations

Endocardium

• Infarction• Abscess

Myocardium

• Effusion• Pericarditis

Pericardium

Vegetation in ECHO

9. Diagnosis?

A 45 year old man , who returned from Mumbai where he was working as a taxi driver for the past twelve years. He was admitted with low grade fever and cervical lymphadenopathy. He was undergoing treatment from various hospitals for irritable bowel syndrome since last six months

HIV associated FUO:

“HIV associated FUO is defined by a temperature of 38.3C (101F) on several occasions over a period of 4 weeks for

outpatients or 3 days for hospitalized patients with HIV infection.

This diagnosis is invoked if appropriate investigation over 3 days, including 2 days’ incubation of cultures, reveals no source.”

Human Inmmuno Deficiency

HIV Infection as such

Pulmonary Tuberculosis

Pneumocystis Infection

Toxoplasmosis

Cytomegalovirus infection

M. Avium or M. Intracellulare

Non-Hodgkin’s Lymphoma

Toxoplasmosis

History• Influenza like symptoms• Muscle aches and pains

Examination• Cervical lymphnodes • Choroidoretinitis , FND

Investigations• Tachyzoites in lymph nodes or blood• IgG and IgM antibody

HIV testing in FUO

IV Generation Screening

Screening

Anti HIV IgG and IgM

Suspicion Window

P24 Antigen

Confirm

CD4 counts and HIV RNA copies

10. Diagnosis?

A 15 year old boy was admitted with history of fever of seven days duration. Clinical examination showed a generalized maculopapular rash and generalized lymphadenopathy, hepatosplenomegaly. All the routine investigations for a underlying bacterial infection were found negative

Viral Infections

Infectious Mononucleosis

Hepatitis A B C D and E

Ebstein Barr virus infection

Cytomegalovirus infection

Parvovirus infection

Dengue hemorrhagic fever

Lymphocytic chorio-meningitis

Cytomegalovirus infection

History• Fevers, chills, profound fatigue• Myalgias, jaundice and headache

Examination• Myocarditis, pleuritis, • Arthritis, and encephalitisInvestigations• CMV-specific IgM in serial samples• Virus excretion or viremia-detected by

culture

Virology in FUO

Availability limitation

Dengue Measles HAV

HBVMumps

CGU H1N1 HZV

HSV

H1N1 Serology

11. Diagnosis?

A sixty year old man was admitted with history of fever, headache and vomiting. O/E neck stiffness was present. Initial CSF study showed 50cells P60 L40. Repeat LP showed protein 45mg% and sugar 80mg%. Patient did not improve much in spite of combined regimen with antibiotics and ATT

Fungal Infections

Cryptococcal meningitis

Aspergillosis

Blastomycosis

Candidiasis

Histoplasmosis

Mucormycosis

Sporotrichosis

Cryptococcal meningitis

History• Chronic headache, neck pain• Visual loss, double vision, cranial nerve palsy

Examination• Signs of meningeal irritation• Focal cerebral signs

Investigation• India ink or fungal wet mount • Antigen detection in CSF

CSF Study in FUO

Highly informative

Bacterial• Low sugar

• Polymorphes

Tuberculous• High protein• Lymphocyes

Cryptococcal• India ink

• Fungal wet mount

Any time investigation

12. Diagnosis?

A 20 year-old college student ,while on an All India Tour on motor cycle , was involved in a road traffic accident and suffered from multiple fractures of the femur which necessitated multiple blood transfusions. He developed high grade fever with chills and rigor after one week

Parasitic Infections

Malaria

Amoebiasis

Leishmaniasis

P.carinii

Toxoplasmosis

Trichinosis

Strongiloidiasis

Malaria

History• Classical alternate day fever • Travel to endemic area

Examination• Triphasic fever with pallor• Jaundice, splenomegaly

Investigations• Peripheral smear examination• Antibody-based card tests

Peripheral Smear in FUO

Simple bed side test

Parasites• Malaria• Kala azar

Hematologic• Leukemia

• Neutropenia

Peripheral smear in Leukemia

13. Diagnosis?

A 14 year old girl was suffering from recurrent generalized seizures. She was put on Phenobarbitone and Dilantin sodium for the same. She had persistent low grade fever, but no lymph node enlargement or hepatosplenomegaly. Blood examination showed evidence of megaloblastic anemia

Drug fever/Non-infectious causes

Gout

Hematoma

Haemolysis

Cirrhosis of liver

Pulmonary emboli

Subacute thyroiditis

Tissue infarction

Gout

History• Acute mono-articular pain• Meta-tarso-phalangeal joint

Examination• Joints warm, red, and tender• Chronic synovitis/tophi

Investigations• Synovial fluid cell counts up to 60,000/L• Needle-shaped MSU crystals

Biochemical Tests in FUO

Blood Chemistry Tests to be ordered

LFT

Bilirubin

OT PT

ALP

PT INR

RFT

Urea

CrUric AcidCr Cl

CFT

ECG

CPK

Trop T

Trop I

14. Diagnosis?

A 30 year old police man came with recurrent episodes of abdominal pain and abdominal distension, loss of weight and loss of appetite. He had fistulectomy on 2 occasions. He was weighing only 32kg. Pallor +. Abdomen was soft. No hepato-splenomegaly.Colonoscopy was diagnostic

Inflammatory Bowel Diseases

Crohn’s disease

Ulcerative colitis

Intestinal tuberculosis

Cholangitis

Cholecystitis

Mesenteric adenitis

Osteomyelitis

Crohn’s disease

History• Rt lower quadrant pain & diarrhoea• Weight loss and fever of low grade

Examination• Mass right lower quadrant• Bowel obstruction or Stricture

Investigations• Cobblestoning from ulcerations• Radiographic “string sign

Tissue Biopsy in FUO

Biopsy specimens

L Nodes Pleural Thyroid

Liver Kidney Skin

Prostate Intestine Marrow

Advantages & limitations

15. Diagnosis?

A 75 year-old man came with fever and headache of 4 months duration. He had generalized body aches and pains.He was admitted to ophthalmic hospital one week before for complaints of sudden loss of vision in one eye. Routine investigations were negative except for a high ESR

Connective tissue disorders

Temporal arteritis

Adult Still’s disease

Systemic lupus erythematosus

Rheumatoid arthritis

Poly-arteritis nodosa

Mixed connective tissue disease

Relapsing polychondritis

Temporal arteritis

History• Individuals >50 years• Headaches and polyarthralgias

Examination• Tortuous and thickened temporal artery• Anterior Ischemic Optic Neuropathy

Investigation• High ESR, Normochromic Anemia• Temporal artery biopsy

Collagen Work up in FUO

ANA Profile

Rheumatological tests

• RA F Anti CCP in RF• Anti-Ro Anti-La in Sjogren’s

ANA Profile

• Anti dsDNA, Anti Smith-SLE• Anti U1 RNP in SLE MCTD

Direct Immunoflourescence

16. Diagnosis?

A 45 year old lady came with generalized weakness, loss of weight and frequent loose stools. She always felt hot in her body and sweated excessively. Fine abnormal movements were present in the fingers. She had a fast heart rate which was out of proportion to her body temperature

Metabolic/endocrine disorders

Hyperthyroidism

Central causes

Cerebrovascular accidents

Encephalitis

Brain tumor

Hypothalamic dysfunction

Pheochromocytoma

Hyperthyroidism

History• Tremor, palpitations• Anxious and fidgety nature

Examination• Proptosis, Lid lag, Thyroid bruit• Tachycardia or AF

Investigations• Ultrasound scan of thyroid• Thyroid Function Tests

Endocrine Tests in FUO

Array of tests

FBS

PPBS

T3

T4TSH

GH LHFSH

VMA

Cover the system

17. Diagnosis?

A 19 year-old nursing student attending the OPD complained that she had high grade fever on several occasions in a day for past four weeks. She was unable to attend the ward examinations during this period because of the persistent fever. In between the fevers she was apparently healthy

Miscellaneous Disorders

Factitious fever

Habitual hyperthermia

Afebrile FUO (<38.3oC)

Exaggerated circadian rhythm

Hysterical Fever

Maliganant Hyperthermia

Neuroleptic Malignant Syndrome

Habitual hyperthermiaHistory –

. Young female

. Years of illness

Examination

. Long continued low grade fever

. Otherwise physically well

Investigation

. Each physicians approach may be different

. Prolonged fruitless investigations

Conclusions

Sit with the patient and spend more time to take history

Take history from the patient and not the bystanders

Make a thorough and complete physicalexamination

Make sure you examine the fundus of the eye

Do appropriate investigations, but not total screening

Order relevant investigations without hesitation

Thank You for the patient listening