Fever and Inflammatory Syndromes of Unknown

FEVER AND INFLAMMATORY SYNDROMES OF UNKNOWN ORIGIN Steven Vanderschueren General Internal Medicine UZ Leuven TACKLING FEVER AND INFLAMMATION OF UNKNOWN ORIGIN The do’s & don’ts NOT EVERY FLYING OBJECT IS AN UFO

NOT EVERY UNIDENTIFIED FEVER IS A FUO Fever of unknown origin (FUO): 1961 definition 1. Illness >3 wks 2. Temperatures >38.3°C, repeatedly documented. 3. No diagnosis after 1 week in-hospital investigation

RT Petersdorf 1926-2006

PB Beeson 1908-2006

Petersdorf RT, Beeson PB. Fever of unexplained origin: Report on 100 cases. Medicine 1961;40:1-30. Classic FUO: definition

Petersdorf & Beeson Contemporary 1. Illness >3 wks. 1. Illness >3 wks. 2. Temp. >38.3°C. 2. Temp. >38.3°C, or lower but with CRP >30 mg/L. 3. No diagnosis after 1 week 3. No diagnosis after an initial in hospital diagnostic evaluation. 4. Exclusion of nosocomial fevers, HIV infection, and severe immunocompromise. 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

D Knockaert J Int med 2003;253:263

Broadest differential diagnosis in IM

“FUO defies simplification. Reported causes exceed 200, and fall into diverse sub-speciality categories. There are no algorithms and few clues that reliably suggest or exclude particular diagnoses. The clinician must rely on very careful evaluation and detailed knowledge of a wide variety of diseases.”

Arnow, Flaherty. Lancet 1997; 350: 575-580. Retroperitoneal hematoma? CAPS? Granulomatosis Behçet’s disease? CMV infection? Trichinellosis? with polyangiitis? Castleman’s disease? Psittacosis? Familial mediterranean fever? Leukemia? Drug fever? Polyarteritis nodosa? Renal cell carcinoma? Bartonellosis? Non-Hodgkin lymfoma? Spondylodiscitis? Endocarditis? Brucellosis? Antiphosholipid syndrome? Trypanosomiasis? Melioidosis? Mycotic aneurysm?

Adult-onset Still disease? Bartonellosis? Sjögren syndrome? Cholesterol embolism? Weber-Christian disease? Multiple myeloma? Giant cell arteritis? Schnitzler syndrome? Subacute thyroiditis? Malakoplakia? Hypereosinophilic syndrome? Whipple’s disease? Kikuchi’s disease? Mevalonate kinase deficiency? Pulmonary embolism? Addison’s disease? Colon carcinoma? Angioimmunoblastic lymphadenopathy? TRAPS? Disscecting aneurysm? Sarcoïdosis? Erlichiosis? Leishmaniasis? Dressler syndrome? Mixed connective tissue disease? Factitious fever? Crohn’s disease? Melioidosis? Should not forget to inform my wife that I will be late… Vogt-Koyanagi-Harada syndrome? Should have chosen surgery…

Infection

Inflammation

Tumor THINK CATEGORICAL: REMEMBER THE BIG 3 … 1. Infections 2. 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 unnecessary drugs

2. Factitious fever: document the fever

3. Habitual hyperthermia: compose a temperature chart THINK ‘INFLAMMATORY’, NOT ‘INFECTIOUS’ • Fever is not a sign of amoxicillin clavulanic acid deficiency Rare diseases are rare

“Most patients with FUO are not suffering from unusual diseases; instead they exhibit atypical manifestations of common illnesses.”

Petersdorf RT, Beeson PB. Fever of unexplained origin: Report on 100 cases. Medicine 1961;40:1-30. Frequent diseases are frequent 14 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 OR ARE MISLEADING… ‘WHOLE BODY INFLAMMATION TRACER SCINTIGRAPHY’

FDG-PET scintigraphy: FDG-PET scintigraphy: Giant cell arteritis Foreign body (osteosynthetic) infection Beware of selective testing

• Indicated in case of individual suspicion, to confirm the diagnosis (biopsy!, culture!); not as a routine (‘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 in 50+ Evolution of the diagnostic spectrum: are we losing our diagnostic skills?

Mourad et al. Arch Int Med 2003;163:545 Why does the diagnostic yield decrease? • Probably, ↑ selection of enigmatic cases that persist for > 3 weeks and defy the baseline diagnostic evaluation • Avoidance of premature closure & intellectual integrity • Up to 50% of autoimmune rheumatic disease cannot be readily diagnosed with a specific disorder within the 1st year Goldblatt et al. Autoimmune rheumatic diseases. 1. Clinical aspects of autoimmune rheumatic diseases. Lancet 2013;382:797-808, Therapeutic trials in classic FUO

- Therapeutic trails are rarely diagnostically rewarding and tend to obscure rather than to illuminate. - 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 because the attending physicians overlook, disregard or reject an obvious clue. No malice is implied by this observation; it simply means that clinicians, being human instruments, are far from perfect. In order to mitigate the frequency and magnitude of these human errors, clinicians have to work that much harder. This means going over the patient again and again, repeating the history and physical examination, reviewing the chart, discussing the problem with colleagues in order to glean new ideas, and spending time in quiet contemplation of the clinical enigma. The approach to the patient with FUO is not to bring on yet another barrage of tests, some of which might be painful and all of which probably are expensive, nor to douse the patient with antimicrobials or to subject him to exploratory surgery, in the absence of clinical clues and only as a last resort. There is no substitute for observing the patient, talking to him and thinking about him.” 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 the William Osler, 1849-1919 greatest, is fever”

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

• “Extreme specialization is bad for medicine and

perhaps worse for the patient”. JAMA 1896;26:999-1004 CID 1196;23:1139-49, REMEMBER OSLER -2

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

• “Fever in its varied forms is still with us… but it is of equal importance to know that the way has been opened, and that the united efforts of many workers in many lands are day by day disarming the great enemy of the race.” REMEMBER OSLER -2 FUO • “Syphilis simulates every other disease. It is the only disease necessary to know. One then becomes an expert dermatologist, an expert laryngologist… an expert internist, an expert diagnostician”

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 a source for humility on the part of the diagnostician, but may at the same time serve as an impetus for continued 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.”