Approach to a patient with

fever of unknown origin

Fever is a protective response to infection and injury. An elevated temperature enhances the body’s innate defense mechanisms by making conditions lessfavorable

for infectious microorganisms to thrive.

Elevated body temperature decreases the levels of iron in the bloodstream, thus inhibiting the growth of some microorganisms.

There are some microorganisms that are heat sensitive, and do not grow well at elevated body temperature.

What is PUO

>Originally defined in 1961 by Petersdorf and Beeson

>Fever >38.3C on two occasions

>Fever for more then three weeks

>Uncertain diagnosis after one week in hospital

Fever of Unknown Origin - Definition

> 1. Fever >38.3 degree C ( 101 degree F) on at least two occasions

> 2. Illness duration of > or = 3 weeks

> 3. No known immunocompromised state

> 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase，creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST) .

The answer will be A

The commonest cause of PUO is:

a) A common disease presenting in an atypical way.

b) A rare disease presenting in atypical way.

c) A common disease presenting typically.

d) A rare disease presenting typically.

EPIDEMIOLOGY:

Infection accounts for about 20-25 % of cases of FUO in Western countries; next in frequency are neoplasms and non infectious inflammatory diseases.

Outside Western countries infection causes 43% casesof FUO.Up to 50% of these cases are due to Tuberculosis.

EPIDEMIOLOGY(GEOGRAPHY WISE)

A study on FUO patients in SKIMS, Srinagar(July 2010- Sept 2012):

n=91Infection=40 cases, (32.26% Brucellosis)Malignancy=11 cases Inflammatory disease=11 cases Miscellaneous=4 cases Undiagnosed=25 cases

Mir T, Dhobi GN, Koul AN, Saleh T. Clinical profile of classical FUO. Caspian J Intern Med 2014; 5(1):35-39.

Studies in India:

Although in India, approximately 80% of the population has close contact with domestic or wild animals owing to their residence or occupation, carrying a risk for zoonotic diseases including brucellosis, but only less than 10% of cases of FUO are attributed to brucellosis as evident from various studies from India. This could be explained by either the disease is overlooked or difficulty in correct diagnosis.

Kejariwal D et al from India observed his series of 100 cases of FUO, 53% were attributed to tuberculosis, predominantly extra pulmonary. Sharma et al. reported 50% cases of FUO caused by tuberculosis in northern India.

Kejariwal et al. and Ramamoorthy et al. estimated an incidence of 17% and 3.61% of malignancy as a case of FUO, respectively.

Ramamoorthy K and Bang M. Pyrexia of unknown origin. CME 2004; pp; 385-390. Availible at: URL: http://appiindia.org/pdf/pg-med-2004/chapter-52. Accessed Nov 18, 2013. Pdf.

Kejariwal D, Sarkar N, Chakraborti SK, Agarwal V, Roy S. Pyrexia of Unknown Origin: A Prospective Study of 100 Cases. J Postgrad Med 2001; 47: 104-7.

Sharma BK, Kumari S, Varma SC, Sagar S, Singh S. Prolonged undiagnosed fever in North India. Trop Geogr Med 1992; 44: 32-6.

Four Proposed Categories of FUO

> Based on potential etiology of FUO

> All require temperature > 38.3C

> Categorization be especially helpful in organizing an “approach” topatient evaluation

>Classic

>Nosocomial

>Immune-deficient (neutropenic)

>HIV-related

Classic Category of FUO

> Definition:

Duration > 3 weeks, evaluation of at least 3 outpatient visits or 3 days in-hospital

> Common etiologies:

Infection, malignancy, CVD

Nosocomial Category of FUO

> Definition:

Hospitalization of at least 24 hrs with no fever on admission, evaluation of at least 3 days

Common causes

This is commonly related to hospital associated factors such as,

▪ Surgery

▪ use of urinary catheter

▪ intravascular devices (i.e. "drip", pulmonary artery catheter)

▪ drugs (antibiotics induced Clostridium difficile colitis, and drug fever)

▪ immobilization (decubitus ulcers). Sinusitis in the intensive care unit is associated with nasogastric and orotracheal tubes.

▪ deep-vein thrombophlebitis

▪ pulmonary embolism,

▪ transfusion reactions, acalculous cholecystitis

▪ alcohol/drug withdrawal

▪ adrenal insufficiency

▪ pancreatitis

IMMUNE DEFICIENT PUO

> Fever >38.0° C, >3 days duration, negative cultures after 48 hrs.

> Higher chance of atypical infections.

> Immunodeficiency can be seen in patients receiving chemotherapy or in hematologic malignancies.

> Fever is concommittent with neutropenia (neutrophil <500/uL) or impaired cell-mediated immunity. The lack of immune response masks a potentially dangerous course.

> Infection is the most common cause

HIV-Associated Category of FUO

> Definition:

>Duration of at least 4 weeks for outpatients and 3 days forinpatients, HIV confirmed

> Etiologies:

>Cytomegalovirus, MAC, Pneumocystis, drugs,Kaposi’s,

lymphoma

CAUSES:

Infection:Bacterial (specific and non specific ) FungalParasiticViral

Non infectious inflammatory:Systemic rheumatic and autoimmune disease VasculitisGranulomatous disease (Sarcoidosis)Auto inflammatory syndromes

Neoplasm:Hematologic malignancySolid tumorsBenign tumors

Miscellaneous:ADEMAtrial myxoma Drug fever Aortic dissectionExtrinsic allergic alveolitis Metal fume fever Pulmonary embolism Ulcerative colitisSweet syndrome Thrombosis

Thermoregulatory disorder:Brain tumor EncephalitisAnhidrotic ectodermal dysplasia

Etiologies of FUO

> Infection

>Tuberculosis: .. Disseminated

>The single most common infection in most PUO series except in children and elderly.

>Usually extrapulmonary or miliary

>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%

Etiologies of FUO

>Abscess:

>Usually located in abdomen or pelvis.

>Secondary to appendicitis or diverticulitis.

>Amoebic liver abscess is one of the common causes

>Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration.

>Splenic abscess is usually secondary tohematogenous seeding.

>Perinephric or renal abscess is usually secondary to UTI.

Etiologies of FUO

> 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

>Legionelle

} Special media

} long time

>Mycoplasm/Chlamydia }

>Fungal → usually sterile

>Peripheral signs may not be detected.

>Right-side Endocarditis → Lack murmurs → self antibiotics →

growth (-ve).

Etiologies of FUO

> Lymphoma:

>Fever is a well-recognized manifestation.

>Source of fever → production of cytokines.

>Fever is a negative prognostic factor …

> Renal Cell Carcinoma (Adult)

>20% →Fever

>Microscopic hematuria/Erythromytosis

Etiologies of FUO

> Wilms Tumor (Children)

>Peak incidence 2-3 years.

>Abdominal mass but FEVER can be a presentation.

> Solid Tumor

>Fever is rare except:

>Secondaries to the liver

>Ductal obstruction or perforation…likecholangioacarcinoma or ampulla ca.

>Lung carcinoma with obstruction and pneumonia.

Etiologies of FUO

> Still’s Disease Adult Onset

>Age 16 – 33 yrs with (-ve) RF & ANA

>Fever is high and spiking with Temp. up to 41.6oC

>Fever is either intermittent or remittent…peaks typicallyat night

>Most patient seek medical attention within 2 weeks.

>A distinctive evanescent macular or maculopapular rash is typically present during the course of the illness.

Etiologies of FUO

>Diagnosis is strictly a clinical one …RF isalmostuniformally negative.

>Other features → myalgias, arthritis may appear after weeks or months & leukocytosis (neutrophils), hepatosplenomegaly & lymphadenopathy.

>Very high serum ferritin …more than2000

Etiologies of FUO

> Temporal Arteritis:

Very serious condition if not diagnosed early

…Very difficult to establish the etiology of fever if onedoes not have the index of suspicion

Typically Caucasian but it occurs in others

>Fever and malaise may be the only manifestation.Headache is the most common.

>Raised ESR is suggestive

Etiologies of FUO

> Polymyalgia Rheumatica:

>Can cause fever, arthralgia, myalgia & ↑ ESR > 50.

>Chronic muscle complaints → symmetrical pain and

stiffness that are typically worse at morning and affects lumbar spine and large proximal muscles.

> Other vasculitides that cause FUO:

>Polyarteritis nodosa

>Wegener’s Granulomatosis

>Mixed Cryoglobulinemia

Drug Fever

> Almost any drug can cause fever

PATHOGENESIS

> Contamination of the drug with a pyrogen or microorganism.

> Related to the pharmacologic action of the drug itself (e.g amphotericin B).

> Allergic (hypersensitivity) reaction to the drug.

> Fever out of proportion to clinical picture

> Pattern of fever variable

> Associated findings:Rigor (43%), Myalgia (25%), Rash (18%), Headache (18%)

> Leukocytosis (22%), Eosinophilia (22%), Serum sickness (fever, swelling, rash, LN enlargement), Proteinuria, Abnormal liver function test

Allopurinol Carbamazepine Cimetidine Clofibrate Erythromycin Furosemide Heparin HydralazineHydrochlorothiazide Isoniazid

Minocycline Nevirapine Nitrofurantoin Lamotrigine Penicillin Phenytoin Procainamide Quinidine Sulfasalazine Vancomycin

Agents commonly associated with drug-induced fever

Onset and duration:

> Onset: Typically occur 7 to 10 days (can be up to 21 days) after initiation

> Usually resolves within 48 hrs after discontinuation of the drug (depending on the half-life of the drug)

Endocrine causes for FUO

❑ Adrenal insuffiency

❑ Hashimotos encephalopathy

❑ Hypothalamic hypopituitarism

❑ Primary hyperparathyroidism

❑ Sub acute thyroiditis

❑ Hyperthyroidism

❑ Pheochromocytoma

EVALUATION

History

> Fever (Pattern, periodicity, how was it measured

associated symptoms such as sweating, vomiting, headaches etc.)

> Past medical and surgical history ( prosthesis in situ, cardiac illness, diabetes,

h/o transplant)

> Occupation, Travel

> Pets

> Contact with ticks, animals

> Diet (Drinking unpasteurised milk)

> History of addiction

> Sexual behaviour(any other high risk behaviour)

> Drug history

> Immunisation

Diagnostic Approach –Physical Examination

The general appearance

The skin: rash, cutaneous findings of endocarditis

Perineum and feet

Spine,bones,joints,abdomen,thyroid

Digital rectal and pelvic examination

Lymphadenopathy

Cardiac examination

Repeated examination may be needed

Altered mentation—tuberculous meningitis, cryptococcal meningitis, carcinomatousmeningitis, brucellosis, typhoid fever, sarcoid meningitis

Arthritis or arthralgia—systemic lupus erythematosus, infective endocarditis, Lymedisease, lymphogranuloma venereum, Whipple’s disease, brucellosis, inflammatorybowel disease

Animal contact—brucellosis, toxoplasmosis, cat scratch disease, psittacosis, leptospirosis, Q fever, rat bite fever

Cough—tuberculosis, Q fever, typhoid fever, sarcoidosis, Legionnaires’ disease

Conjunctival suffusion—leptospirosis, relapsing fever, Rocky Mountain spotted fever

Common signs and symptoms and associated causes of fever

Epistaxis—Wegener’s granulomatosis, relapsing fever,psittacosis

Epididymo-orchitis—tuberculosis, lymphoma, polyarteritis nodosa, brucellosis,leptospirosis, infectious mononucleosis

Hepatomegaly—lymphoma, disseminated tuberculosis, metastatic carcinoma of liver, alcoholic liver disease, hepatoma, relapsing fever, granulomatous hepatitis, Q fever, typhoid fever, malaria, visceral leishmaniasis

Lymphadenopathy—lymphoma, cat scratch disease, tuberculosis, lymphomogranuloma venereum, infectious mononucleosis, cytomegalovirus infection, toxoplasmosis, HIV infection, brucellosis, Whipple’s disease, Kikuchi’sdisease

Renal angle tenderness—perinephric abscess, chronic pyelonephritis

Splenomegaly—leukaemia, lymphoma, tuberculosis, brucellosis, sub acute bacterial endocarditis, cytomegalovirus infection, Epstein-Barr virus mononucleosis, rheumatoid arthritis, sarcoidosis, psittacosis, relapsing fever, alcoholic liver disease, typhoid fever, Kikuchi’sdisease

Subconjunctival hemorrhage—infective endocarditis, trichinosis, leptospirosis

Uveitis—tuberculosis, sarcoidosis, adult Still’s disease, systemiclupus

erythematosus, Behcet’sdisease

Points to be remembered during evaluation of a patient with FUO :

➢ Previous case reports and history given by the patient should be reviewed properly.

➢ Initial errors of omission may cause unnecessary investigations.

➢ Even when initial evaluation was thorough, patients often remember new details when questioning is repeated.

➢ Conversely clinicians should not ignore previous test results and should not repeat tests without considering how likely results are to be different.

Clues to the diagnosis of factitious fever

Diagnostic Approach –Laboratory Investigations

> CBC, ESR,CRP

> Routine chemistry including LFT,LDH,CPK

> Renal function test

> Urinalysis and microscopy

> Stool for ova, cyst, parasite

> Blood culture (including fungal culture)

> Study of fluid from joint aspiration, pleural fluid,

Ascitic fluid, CSF, gastric aspirate

❖Typhoid Serology

❖HIV, Hepatitis, Dengue serology

❖CXR, sputum test

❖Tuberculin test, interferon gamma assay

❖USG abdomen

❖MP/MPDA, Microfilaria

❖Test for CMV, EBV, Q fever

❖ANA, ANCA, Rheumatoid factor

> Abdominal CT> Useful to look for abdominal lymphoma and abscess

> Diagnostic yield in case series 19%

> Clinical follow-up showed that only 1/32 patients with normal scans had an intra-abdominal causefor FUO

>Chest CTInvaluable in identification of

small nodules, hilar or

mediastinal adenopathy.

Liver Biopsy:

>Diagnostic yield 14%-17% regardless of whether abnormal physical exam or liver enzymes exist

>Complications in FUO from biopsy only 0.32% at most

>Recommended

Temporal artery biopsy:

❖ Large studies comprised of elderly with FUO lacking❖ Arteritis cause of FUO ~16% of patients❖ Safe, recommended in elderly with FUO

> Other tissue diagnosis: Bone marrow, skin, pleura, lymph nodes, intestine.

> (biopsy specimens should be evaluated by histopathologic examination & cultured for bacteria, fungi, viruses, mycobacteria or sent for PCR)

Splenic aspiration: visceral leishmaniasis

Bone marrow biopsy has a diagnostic yield up to 15%, most often revealing hematologic malignancy, myelodysplasia, or tuberculosis, and also identifying brucellosis, typhoid fever or visceral leishmaniasis.

Muscle biopsy and skin biopsy from rashes may confirm vasculitis.

Laparoscopy & abdominal exploration

Other investigations:

Lumbar puncture

Bone Tc-scan (osteomyelitis)

UGIE

Pulmonary angiogram

Ophthalmoscopy

Echocardiography

Recent studies have highlighted the usefulness of early use of FDG-PET([18F] fluoro-2-deoxy-D-glucose positron emission tomography), whichmay be useful in helping to pinpoint a source of fever.

Fluoro-2-deoxy-D-glucose is preferentially taken up by cells such astumor and inflammatory cells, in which glucose metabolism is high.

The diagnostic yield may be increased further by simultaneously using FDG-PET with conventional computed tomography (CT). Several small retrospective studies have shown sensitivities from 56% to100%, specificities from 75% to 81%, and negative predictive values of 100%, when a combination of CT and FDG-PET scanning is used.

Role of FDG-PET:

A high NPV has previously been reported for FDG-PET/CT in the diagnosis of large vesselvasculitis, with a sensitivity ranging between 77% and 92% and specificity ranging between 89% and 100%. 18F-FDG-PET/CT offers a useful contribution to the diagnostic work-up of large vessel vasculitis.

http://dx.doi.org/10.1016/j.ijid.2013.10.009

Nuclear scintigraphy, for example with 67Ga-citrate and111In labelled leukocytes, is a much cheaper and more widely available imaging technique that may perform a similar role in localizing pathology, though it is more time consuming and less sensitive and specific than FDG-PET. However, the probability of reaching a diagnosis was observed in 71% with a sensitivity of 75% and specificity 83%. Leukocyte scintigraphy may be helpful in diagnosing inflammatory and infectious conditions and rarely of use in neoplasm.

Nuclear study:

History is crucial. Will help to narrow down possible list of diseases.

Exposure: Duration, exact location, urban/rural, type of accommodation

Timing: Consider incubation period and onset of symptoms. 66% of dengue presents within one week of return. 34% of hepA presents within 6 weeksFood history is important Sexual history is important Vaccine history

FOR TRAVELLERS

Evaluation

> Thick and Thin smears for malaria

> Blood count

> Renal profile

> Liver profile: hepatitis

> Coagulation screen

> CXR if respiratory symptoms

Treatment:55

> 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 specificdiagnosis.

> Side effect of the drugs can be misleading.

In general, empirical therapy has little or no role in cases of fever of unknown origin (FUO).Treatment should be directed toward the underlying cause, as needed, once a diagnosis is made.

Empirical therapeutic trials with antibiotics, glucocorticoids, or antituberculous agents should be avoided in FUO except when a patient's condition is rapidly deteriorating after the aforementioned diagnostic tests have failed to provide a definite diagnosis.

Empirical antibiotic therapy: Hemodynamic instability or neutropenia Good indication

Anti tuberculous therapy: If the skin test is positiveGranulomatous disease with anergyMiliary tuberculosis

If the fever does not respond after 6 weeks Another diagnosis

❑ Colchicine is highly effective in preventing attacks of familial Mediterranean fever. With colchicine treatment most patients show remarkable improvements in the frequency and severity of subsequent febrile episodes within weeks to months.

❑ The response of adult onset Still’s disease to NSAIDS is dramatic in somecases.

❑ The effects of glucocorticoids on giant cell arteritis and polymyalgia rheumatica are equally impressive.

❑ The ability of glucocorticoids to mask symptoms while permitting the spreadof infection dictates that their use should be avoided unless infectious diseases have been ruled out and inflammatory disease is probable and is likely to be debilitating or threatening.

Anakinra:Interleukin (IL)1 is a key cytokine in local and systemic inflammation and the febrile response.The availability of specific IL-1-targeting agents has revealed a pathologic role of IL-1 mediated inflammation in a growing list of diseases.

Anakinra, a recombinant form of the naturally occurring I L-1 receptor antagonist ( lL-1Ra), blocks the activity of both IL-1α and IL-1ß.

Anakinra is extremely effective in the treatment of many autoinflammatorysyndromes, such as

familial Mediterranean fever，cryopyrin-associated periodic syndrome，tumor necrosis factor receptor-associated periodic syndrome，hyper- lgD syndrome.

PROGNOSIS:

✓ FUO-related mortality rates have continuously declined over recent decades.

✓ The majority of fevers are caused by treatable diseases.

✓ Studies have also shown that malignancy accounts for most FUO-related deaths.

✓ Non Hodgkin's lymphoma carries a disproportionately highdeath toll.

✓ In nonmalignant FUO, fatality rates are very low.✓ The good outcome in patients without a diagnosis confirms

that potentially lethal occult diseases are very unusual.

✓ Empirical therapy with antibiotics, antituberculous agents, or glucocorticoids is rarely required in stable patients.

✓ In less affluent regions, infectious diseases are still a major problem.

CONCLUSION:

>FUO is often a diagnostic dilemma.

>Infections comprise ~30% of cases.

>Diagnostic approach should occur in a step-wise fashion

>Patients that remain undiagnosed generally have a good prognosis.

18F-FDG-PET/CT has an incremental diagnostic value in the diagnosis and management of FUO. In the future, 18F-FDG-PET/CT may well be included in the initial diagnostic work-up for the investigation of the etiology of FUO.