Fever of Unknown Origin

Dr. V. B. Kasyapa. JPG I year

Date : 29-11-2016

Definition

• Petersdorf and Beeson, 1961– ≥ 3 week duration– ≥ 38.3⁰C (101⁰F) on 2 occasions– Uncertain diagnosis despite 1 week in-patient

evaluation

Quantitative criterion Qualitative criterion

New Definition• Fever ≥ 38.3⁰C (101⁰F) on 2 occasions, at least.• Duration ≥ 3 weeks• No known immuno-compromised state.• Uncertain diagnosis after

ETIOLOGY

• Changing patterns are seen– Causes being early AMD and Steroid therapies and

newer diagnostics• West :– Infections (20 – 25 %)– Neoplasms– NIID (non infectious inflammatory diseases;

collagen, rheumatic, vasculitis and granulomatous)• India :– Infections ( 43% )– Neoplasms & NIID

• Problem with NIID :– Preceded by fever for longer periods– Diagnosis is after prolonged observation and

exclusion• Technical problem for increased FUO incidence:– Many FUO’s causes are being diagnosed earlier– So criteria is being only met by really unidentified

cases• A less aggressive approach in patient with

recurrent fever with asymptomatic in between episodes

Recurrent Fever

• Definition :– Repeated episodes of fever– Fever-free interval of at least 2-3 weeks (apparent

remission of underlying disease in this interval)• More over aetiology is found only in <50%

cases

Differentials

• It is exhaustive but

– Ex : Endocarditis, Diverticulitis, Vertebral osteomyelitis, Extra pulmonary TB

Atypical presentation of common disease is more than rare disease

Clues Potential DiagnosisRural area, contact with animals/ valvular heart diseases/ aortic aneurysms/ prosthetic valves

Q – fever

CNS, GIT and joint symptoms

PCR for Trophyrema whipplei

Fever + Signs of Endocarditis (A new or changed heart murmur, Night sweats, Persistent cough, petechiae and pedal edema) + Culture Negative

- difficult to culture bacteria (nutritionally variant)HACEK group

Hemophilus parainfluenza, H. Paraphrophilus, Aggregatibacter actinomycetom comitans, A.Aphrophilus, Cardiobacterium hominis, C. Valvarum, Eikenella corrodens, Kingella kingae

Coxiella burnettiTrophyrema whippleiBartonella species

- Marantic endocarditis (sterile thrombotic as PNS in adenocarcinoma)

- Sterile endocarditis (APLA, SLE,..)

• NIID :– Common : large vessel vasculitis, polymyalgia

rheumatica, Sarcoidsis, Familial Mediterranean fever, adult-onset Still’s

– Rare : hereditary auto inflammatory syndromes (mostly in young pts)

– Schnitzler’s syndrome : any age• FUO + Urticaria + Bone pain + Monoclonal gammopathy

• Neoplasms :– (MC) Malignant lymphoma• Fever starts even before lymphadenopathy

• Misc :– Drug fever (MC) : virtually all can cause• DRESS (Drug reaction with eosinophil and systemic

symptoms)• Ex : Allopurinol, Carbamazepine, Lamotrigene,

Phenytoin, Sulfasalazine, Furosemide, AMD (sulfonamides, minocycline, vancomycin, BL, isoniazide), CVS drugs (quinidine), ART (Nevirapine)

– Exercise induced hyperthermia :• With moderate to strenuous exercise• 30min – several hrs without increase in CRP/ESR• Sweating during temperature elevation

• Misc :– Factitious fever :

• Artificially induced by patient• (MC) with young female in health care profession.• By injecting contaminated water through IV or some other

– Fradulent fever :• Normo-thermic, by manipulating thermometer• Simultaneous measurement of different sites (ear, rectum,

mouth, etc..) can rule it out• There will be dissociation between temperature and pulse

rate.• Heart rate is known to increase by 10 beats per minute

(bpm) per degree centigrade temperature increase

Approach

Initial tests

• Always, throughout the course, look for PDC (potential diagnostic clues)

• PDC : Any localising sign, symptom and abnormal test that point towards a specific diagnosis

• There may be many PDCs, which may be misleading, but they sure narrow the area to search.

• History :– Thorough, complete and repeated..– Regarding pattern, duration, previous history, drug

history, family history, sexual history, country of origin, travel, environmental exposure and animal contacts, etc…

• Examination :– Thorough and repeated..– Do not avoid; eyes, lymphnodes, temporal

arteries, liver, spleen, sites of previous surgery, entire skin and mucous membranes

– Stop all the drugs before diagnostic tests (imp; AMDs and Corticosteroids/CS)

– Abdominal USG, CXR-PA are must.– Don’t do biochemical tests that lead to definitive

diagnosis in the absence of PDCs– Inform the lab of the intent to test for unusual

organisms– Performing more than three blood cultures and

more than one urine culture, in the absence of PDC, is useless.

– Repeating cultures are useful only when previously cultured samples were collected during AMD/CS therapy or within one week of their discontinuation.

– Microbiological serology shouldn’t be included in the diagnostic workup without PDCs.

– Diagnostic yield of 2D ECHO, Upper GI endoscopy, Sinuses radiography, Bronchoscopy is Very low in the absence of PDCs.

– History & Physical examination should therefore be repeated regularly.

– If fever persists beyond 72 hrs after discontinuation of a drug, it is unlikely that the drug is causative.

– Investigation of Cryoglobulins can be done (relatively low cost & vague symptoms)

– Allow blood samples for longer periods to ensure the growth of fastidious organisms.

– Any FUO with headache CSF examination• r/o HSV, cryptococcus neoformans, M.TB• TB meningitis - ↓ glucose <45 mg% ↑ protein 100 – 500 mg% cell count 100 – 500 mg%

– TST may be negative – miliary TB, malnutrition, immunosuppression

TST sensitivity = Interferon γ release sensitivity– In miliary TB do liver biopsy for AFB, culture,

PCR (highest diagnostic yield)

• Recurrent fever :– Look for the clues to recurrent syndromes

– All tests should be done/ repeated during symptomatic phase

– If recurrent fever > 2 years• Not probably infection/ malignancy

• Scintigraphy :– A non invasive technique to allow delineation of foci

in all parts of the body on the basis of functional changes in tissues

– Ga67 citrate/ In111/ 99mTc (MC)– It is not useful in early phase – due to lack of

substantial pathological changes– It is different to delineate between – active/ healing/

cured/ surgery remains

Scintigraphy

• PET Scan (Positron Emission Tomography) :

– FDG (Fluorodeoxyglucose) accumulates in tissues with high

rate of glycolysis

– Malignant cells/ activated leucocytes

– Brain, heart, bowel, kidney and bladder intake is normal

– In fever BM may show increase uptake

• d/t cytokine activation up regulating glucose transporters

– Higher resolution, greater sensitivity in chronic low grade

infection

– Higher accuracy in central skeleton

– Vascular intake increase in Vasculitis– Difficult b/w • inflammation/ • infection/ • malignancy

– Use : targeted biopsy – Always stop CS (↓ pathological uptake in LN &

vasculitis)– Dis adv : • availability, • expense (may be cost effective in early stages to reduce

hospital stay)

Late tests

• Lymphadenopathy LN biopsy• Skin lesions skin biopsy• Pulmonary wedge excision, excised tonsil

histology and peritoneal biopsy were useful in some cases

• Screening chest CT (has 80% specific but doesn’t add much to FDG PET CT)

• Screening abdominal CT (only 65% specific)

• BM aspiration only with PDCs ( bcz FDG PET is highly sensitive for lymphoma, carcinoma or osteomyelitis)

• Liver biopsy more complicated, do with PDCs, Abnormal LFT is not an indication

• Temporal artery biopsy Gaint-cell arteritis is (MC) in elderly.– As it is not possible to see in PET (d/t its size)– Preferred in all FUO with headache in ≥ 55 years.

• Other late stage diagnostics are more expensive and more discomfort to patient, so look for PDCs

• Diagnostic delay often from a failure to recognize PDC in the available information

• If patient is stable in b/w episodes– Wait for newer PDCs to appear

• If patient is unstable – Do further work up

Final word in Diagnosis

Treatment

• Avoid empirical therapy unless rapidly deteriorating

• AMD, ATT irrevocably diminish the ability to culture fastidious bacteria/ mycobacteria

• AMD use only if Neutropenia/ hemo-dynamically unstable

• ATT TST positive/ granulomatous disease with anergy or sarcoidosis is unlikely/ suspicious of miliary TB

• If fever doesn’t respond to 6 week empirical ATT go for other diagnosis

• Colchicine :– Can prevent attacks of FMF– But not effective once attack starts– So, response to this is not reliable– ↓ frequency & severity of further attacks over weeks of

treatment is suggestive• Early CS :– Masks symptoms– Sometimes we fail to diagnose life threatening

Infections / malignant lymphoma– Use only these are largely excluded cases

• NSAIDs :– Supportive– Dramatic response may be seen in Adult onset Still’s

• ANAKINRA : last ditch– Recombinant IL – 1 Receptor antagonist– Blocks IL - 1α, IL - 1β– Use : Anti inflammatory syndromes (FMF,

cryopyrin/TNF associated periodic sydrome, Hyper IgD syndrome, Schnitzler’s syndrome)

– Monotherapy improves symptoms without CS side effects in most of the chronic inflammatory conditions

Prognosis

• Most FUO related deaths occur with

– Malignant FUOs (non hodgekins)

• Non malignant FUO related deaths

– Very rare

• These good outcomes in patients without diagnosis

indicates

– RARE DISEASES ARE ALWAYS RARE

New classification

• By Durack & Street, 1991

1. Classic FUO

2. Nosocomial FUO

3. Neutropenic FUO

4. HIV associated FUO

Nosocomial FUO

• Fever > 38.3⁰C ( >101⁰F ) on several occasions

• In a hospitalised patient

• Receiving acute care

• Not manifesting an infection on admission

• With no diagnosis after 3 days of investigations

• Including 2 days incubation of cultures

• (MC) Infections

• Non infectious : Drug fever, DVT, Acalculous cholecystitis,

Pancreatitis, Pulmonary embolism

• Repeated Blood & fluid cultures

• IV lines, Catheters frequent change

• Empirical AMD after ≥3 blood samples for cultures only if

Hypotension/ARDS/MODS

• Therapy depends on underlying comorbidities, surgical & medical

procedures underwent and duration

• Within 10 days of surgery mostly surgery related

Clinical Pulmonary Infection Score (CPIS)

Neutropenic FUO

• Fever > 38.3⁰C ( >101⁰F ) on several occasions

• In a neutropenic ( ANC < 500/cumm or fall to

this level is expected in 1-2 days )

• No diagnosis after 3 days of investigations

• Including 2 days of incubation of cultures

Neutropenic FUO

• (MC) Infections

– Fungal ( candida, aspergillus)

– Viral ( CMV, HSV )

• Examine – fundus, skin, peri rectal area and PNS

• Risk factors duration, rapidity, disrupted barriers,

associated neoplasia, comorbidities, IV lines and

MAB therapy

Neutropenic FUO

• If fungal suspected,

– Serum galactmannan

– Serum beta D glucan

– HRCT

• CMV is mainly seen in,

– BM transplant and chemo induced leukopenia patients

– Prolonged fever, mononucleosis syndrome, organ

involvement (hepatitis, colitis)

Treatment • Pseudomonas, Gram Negative (GUT bacteria

translocation) cover

• Cultures

• Carbapenams & III/IV gen Cephalosporins

– for ESBL gram negative; like E coli, Klebsiella,

pseudomonas;

– gram positive; like S. aureus, coagulase negative staph

HIV associate FUO

• Fever > 38.3⁰C ( >101⁰F ) on several occasions

• In a HIV patient

• No diagnosis after investigations for

– >4 weeks in OPD

– 3 days in IP

HIV associated FUO

• (MC) Infections,

– Opportunistic (TB)

– Disseminated cryptococcus

– Pneumocystis pneumonia

– Community Acquired pneumonia

– Liver abscess

• CD4 count good predictor

• In INDIA MAC is not common ( may be d/t M.TB conferring

immunity)

During HAART

• Initial 6 months,

– Immune reconstitution inflammatory syndrome (IRIS)

– Drug fever

– ART associated opportunistic infections (d/t initial very

low CD4 counts)

• After 6 months,

– Causes are like classical FUO

CD4 count Possible Infections

Greater than 500 cells/mm3 As normal people

500 cells/mm3 to 200 cells/mm3 Oral Thrush, Kaposi sarcoma (HHV 8)

200 cells/mm3 to 100 cells/mm3 PCP, Histoplasmosis,Coccidioidomycosis,Progressive Multifocal Leucencephalopathy (PML - JC virus)

100 cells/mm3 to 50 cells/mm3 Cryptococcosis,Toxoplasma,Cryptosporidiosis,CMV

Less than 50 Cells/mm3 MAC

THANK YOU