FEVER AND INFLAMMATORYSYNDROMES OF UNKNOWN

ORIGINSteven Vanderschueren

General Internal MedicineUZ Leuven

TACKLING FEVER ANDINFLAMMATION OFUNKNOWN ORIGIN

The do’s & don’ts

NOT EVERY FLYING OBJECT IS ANUFO

NOT EVERY UNIDENTIFIEDFEVER IS A FUO

Fever of unknown origin (FUO): 1961 definition

1. Illness >3 wks2. Temperatures >38.3°C, repeatedly documented.

3. No diagnosis after 1 week in-hospitalinvestigation

Petersdorf RT, Beeson PB. Fever of unexplained origin: Report on 100 cases.

Medicine 1961;40:1-30.

RT Petersdorf 1926-2006

PB Beeson 1908-2006

Classic FUO: definition

Petersdorf & Beeson

1. Illness >3 wks.

2. Temp. >38.3°C.

3. No diagnosis after 1 weekin hospital

Contemporary1. Illness >3 wks.2. Temp. >38.3°C, or lower but

with CRP >30 mg/L.3. No diagnosis after an initial

diagnostic evaluation.4. Exclusion of nosocomial

fevers, HIV infection, andsevere immunocompromise.

D Knockaert J Int med 2003;253:263

Minimum diagnostic evaluation to qualify as FUO • Comprehensive history (including travel history, sexual risk behavior, contact with animals , etc.)

• Metculous physical examination (including temporal arteries, rectal examination, etc.)

• Blood tests (CBC including differential, ESR or CRP, electrolytes, renal and hepatic tests, CK and LDH)

• Microscopic urinalysis

• Cultures of blood, urine other normally sterile compartments if indicated, e.g. joints, pleura, cerebrospinal fluid

• Chest radiograph

• Abdominal (including pelvic) ultrasonography

• Antinuclear and antineutrophilic cytoplasmic antibodies, rheumatoid factor

• Tuberculin skin test

• Serological tests directed by local epidemiological data

• Further evaluation directed by abnormalities detected by above test; e.g.

- HIV testing in case of suspicious exposure

- CMV-IgM and EBV serology in case of abnormal differential WBC count

- Abdominal or chest helical CT scan

- Echocardiography in case of cardiac murmur

“FUO defies simplification. Reportedcauses exceed 200, and fall into diversesub-speciality categories. There are noalgorithms and few clues that reliablysuggest or exclude particular diagnoses.The clinician must rely on very carefulevaluation and detailed knowledge of awide variety of diseases.”

Broadest differential diagnosis in IM

Arnow, Flaherty. Lancet 1997; 350: 575-580.

Leukemia?

Endocarditis?

Adult-onset Still disease?

Polyarteritis nodosa? Non-Hodgkin lymfoma?

Schnitzler syndrome?

Sjögren syndrome?

Pulmonary embolism?

Sarcoïdosis?

Crohn’s disease?

Subacute thyroiditis?

Psittacosis?

Erlichiosis?

Whipple’s disease?

Leishmaniasis?

CMV infection?

Angioimmunoblastic lymphadenopathy?

Mycotic aneurysm?

Malakoplakia?

Behçet’s disease?

Addison’s disease?

Vogt-Koyanagi-Harada syndrome?

Dressler syndrome?

Granulomatosis with polyangiitis?

Disscecting aneurysm?

Giant cell arteritis?

CAPS?

TRAPS?

Familial mediterranean fever?

Antiphosholipid syndrome?

Kikuchi’s disease?

Cholesterol embolism?

Brucellosis?

Bartonellosis?

Melioidosis?

Hypereosinophilic syndrome?

Mixed connective tissue disease?

Trypanosomiasis?

Drug fever?

Factitious fever?

Weber-Christian disease?

Renal cell carcinoma?

Bartonellosis?

Retroperitoneal hematoma?

Mevalonate kinase deficiency?

Should not forget to inform my wife that I will be late…Should have chosen surgery…

Colon carcinoma?

Multiple myeloma?

Spondylodiscitis?

Melioidosis?

Castleman’s disease?Trichinellosis?

Infection

Inflammation

Tumor

THINK CATEGORICAL:REMEMBER THE BIG 3 …

1. Infections2. Non-infectious inflammatory disorders

– Rheumatic inflammatory diseases– Vasculitides– Granulomatous disorders

3. Malignancies

4. Miscellaneous disorders (e.g., hematoma, VTE,endocrinopathies, hereditary fever syndromes, the little 3)

5. No diagnosis

… AND THE LITTLE 3

1. Drug fever

2. Factitious fever

3. Habitual hyperthermia

… AND THE LITTLE 3

1. Drug fever: stop all unnecessarydrugs

2. Factitious fever: document the fever

3. Habitual hyperthermia: compose atemperature chart

THINK ‘INFLAMMATORY’,NOT ‘INFECTIOUS’

• Fever is not a sign of amoxicillinclavulanic acid deficiency

Rare diseases are rare

“Most patients with FUO are notsuffering from unusual diseases;instead they exhibit atypicalmanifestations of common illnesses.”

Petersdorf RT, Beeson PB. Fever of unexplained origin: Report on 100 cases.

Medicine 1961;40:1-30.

Frequent diseases are frequent14 disorders ~ 2/3 of diagnoses

– Infections: • Endocarditis• Tuberculosis• Abdominal abcesses• EBV/CMV infections

– Malignancies: • Lymphoma• Leukemia

– Non-infectious inflammatory disorders• Adult-onset Still disease• Systemic lupus erythematosus• Polymyalgia rheumatica – giant cell arteriitis• Sarcoidosis• Crohn’s disease

– Miscellaneous• Habitual hyperthermia• Drug fever• Subacute thyroiditis

Vanderschueren S. et al. From prolonged febrile illness to Fever of Unknown Origin:The challenge continues. Arch Intern Med 2003;163:1033.

SUTTON’S LAW “Go where the money is!”

$$$$

‘do not carry out a battery of “routine”

examinations in a conventional sequence’

Willie Sutton °1901- +1980

SUTTON’S LAW

IF CLUES ARE ABSENT ORARE MISLEADING…

‘WHOLE BODY INFLAMMATIONTRACER SCINTIGRAPHY’

FDG-PET scintigraphy:Giant cell arteritis

FDG-PET scintigraphy:Foreign body (osteosynthetic)

infection

Beware of selective testing• Indicated in case of individual suspicion, to

confirm the diagnosis (biopsy!, culture!); not as aroutine (‘fishing expedition’)– Endoscopic techniques (e.g., GI, bronchoscopy)– Selective radiographs (e.g., of teeth, sinuses, sacroiliac joints)– Contrast studies (e.g., GI, arteriography) – Invasive studies (mediastinoscopy, thoracoscopy, laparoscopy)– Blind punctures (bone marrow, liver, lumbar puncture)

• Consider less invasive techniques (e.g., EBUS,echoendoscopy)

• Exception to the rule: temporal artery biopsy in50+

Mourad et al. Arch Int Med2003;163:545

Evolution of the diagnostic spectrum:are we losing our diagnostic skills?

Why does the diagnostic yielddecrease?

• Probably, ↑ selection of enigmatic cases thatpersist for > 3 weeks and defy the baselinediagnostic evaluation

• Avoidance of premature closure &intellectual integrity

• Up to 50% of autoimmune rheumatic diseasecannot be readily diagnosed with a specificdisorder within the 1st year Goldblatt et al. Autoimmune rheumatic diseases. 1. Clinical aspects ofautoimmune rheumatic diseases. Lancet 2013;382:797-808,

Therapeutic trials in classic FUO

- Therapeutic trails are rarely diagnosticallyrewarding and tend to obscure rather than toilluminate.

- Symptomatic: NSAID- Therapeutic trail to be considered in case of

deterioration:* Antibiotics:

- Broad spectrum antibiotics: stop if no defervescence after 3 days.- Consider tetracyclines (or macrolides)

* Antituberculous therapy: strongly consider in case of

clinical deterioration.* Corticosteroids:

• Do not start too early• Consider adding antituberculous therapy.

Current prognosis of FUO• 436 patients with FUO, 2000-2010• Mortality (attributed to febrile dissease) in 30

(6.9%)– One-year mortality in 26 (6.0%)– Malignancy: cause of FUO in 48 (11%), but of

mortality in 18 (60% of fatalities)• Undiagnosed category: favorable prognosis - ‘time

is the internist’s best friend’• In comparison: Petersdorf: 32/100 patients died (17 of the

19 patients with malignancies)

Acta Clinica Belgica 2014(69):12-16

Some lessons from the past – standing on the schoulders of

giants

“… many patients are placed in the FUO category becausethe attending physicians overlook, disregard or rejectan obvious clue. No malice is implied by this observation;it simply means that clinicians, being humaninstruments, are far from perfect.

In order to mitigate the frequency and magnitude ofthese human errors, clinicians have to work that muchharder. This means going over the patient again andagain, repeating the history and physical examination,reviewing the chart, discussing the problem withcolleagues in order to glean new ideas, and spendingtime in quiet contemplation of the clinical enigma.

The approach to the patient with FUO is not to bring onyet another barrage of tests, some of which might bepainful and all of which probably are expensive, nor todouse the patient with antimicrobials or to subject himto exploratory surgery, in the absence of clinical cluesand only as a last resort. There is no substitute forobserving the patient, talking to him and thinking abouthim.”

Larson EB et al. Medicine 1982; 61:269-292.

‘a general specialist’‘a specialized generalist’

REMEMBER OSLER - 1

• “Humanity has but three great enemies: fever, famine and war; of these by far thegreatest, is fever”

• “There are, in truth, no specialities in medicine,since to know fully many of the most importantdiseases a man must be familiar with theirmanifestations in many organs”

• “Extreme specialization is bad for medicine andperhaps worse for the patient”. JAMA 1896;26:999-1004

CID 1196;23:1139-49,

William Osler, 1849-1919

REMEMBER OSLER -2

• “Syphilis simulates every other disease. It is theonly disease necessary to know. One then becomesan expert dermatologist, an expert laryngologist…an expert internist, an expert diagnostician”

• “Fever in its varied forms is still with us… but it isof equal importance to know that the way has beenopened, and that the united efforts of manyworkers in many lands are day by day disarmingthe great enemy of the race.”

REMEMBER OSLER -2

• “Syphilis simulates every other disease. It is theonly disease necessary to know. One then becomesan expert dermatologist, an expert laryngologist…an expert internist, an expert diagnostician”

• “Fever in its varied forms is still with us… but it isof equal importance to know that the way has beenopened, and that the united efforts of manyworkers in many lands are day by day disarmingthe great enemy of the race.”

FUO

REMEMBER OSLER -3

There is no substitute for observing the patient,talking to him and thinking about him.”

Daniël Knockaert

CONCLUSION• FUO remains a challenge

‘Some fevers remain of unknown origin and represent asource for humility on the part of the diagnostician,but may at the same time serve as an impetus forcontinued research.’

• Remember– To think in categories (big 3, little 3)– To think inflammatory, rather than infectious– Frequent diseases (‘in disguise’) are most frequent– Go where the money is (sometimes PET will tell); culture, biopsy

(‘tissue is the issue’).– Be humble, be honest, be patient, avoid premature closure– “There is no substitute for observing the patient, talking to him

and thinking about him.”