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Pyrexia of Unknown Origin - Physician’S Challenge CHAPTER Pyrexia of Unknown Origin - Physician’s Challenge 3 Asha N Shah PUO(FUO) should be reserved for prolonged febrile cause of fever is often found before three weeks of illness illnesses without an established etiology despite intensive and therefore only more difficult to diagnose cases meet evaluation and diagnostic testing. FUO remains a the definition of FUO as given in Table 1. challenging diagnostic problem with all the physicians. The etiologies of the PUO have changed over time With the development of better diagnostic techniques, the because of shifting disease patterns and new diagnostic techniques. In general, infection accounts for about Table 1: Definition of PUO 20–25% of cases of PUO in Western countries; next in 0 frequency are neoplasms and noninfectious inflammatory Original (1961, • Temperature >101 F(38.3 C) on diseases (NIIDs). In tropical and subtropical areas(INDIA), petersdorf and several separate occasions infections are a much more common cause of PUO), while Beteson) • Fever lasting for more than 3 the proportions of cases due to NIIDs and neoplasms weeks are similar. Up to 50% of cases caused by infections in • Evaluation of at least one week in patients with PUO outside Western nations are due to hospital tuberculosis, which is a less common cause in the United Revised (1991) • Temperature of >1010F on several States and Western Europe. separate occasions CAUSES • Fever lasting more than 3 weeks More than 200 causes of PUO have been described in • Evaluation of at least 3 outpatient literature. The causes for PUO are extensive, but it is visits or 3 days in inpatient care important to remember that PUO is far more often caused New • Temperature >1010F documented by an atypical presentation of a rather common disease clinically on several separate than by a very rare disease. occasions 1. Bacterial: Tuberculosis, typhoid fever and other • Duration of illness >3weeks salmonelloses, Abdominal abscess, appendicitis, cholangitis, cholecystitis, endocarditis, epidural • Non immunocompromised (neutropaenia>1 week ,known abscess, infected vascular catheter, infected joint HIV, Hypogammaglobulinaemia prosthesis, infected vascular prosthesis, infectious or use of steroids >10mg *2weeks arthritis, intracranial abscess, liver abscess, in 3 months prior to fever lung abscess, mastoiditis, osteomyelitis, pelvic inflammatory disease, prostatitis, pyelonephritis, • Appropriate initial diagnostic urinary tract infection. work up does not reveal the etiology of the fever(erythrocyte 2. Unusual infections: Actinomycosis, atypical sedimentation rate or C-reactive mycobacterial infection, brucellosis, Campylobacter protein, hemoglobin, platelet infection, Chlamydia pneumonia infection, chronic count, leukocyte count and meningococcemia, gonococcemia, legionellosis, differentiation, electrolytes, leptospirosis, Lyme disease, rickettsiosis, syphilis, creatinine, total protein, tick-borne relapsing fever (Borrelia duttonii), protein electrophoresis, Whipple’s disease (Tropheryma whipplei), alkaline phosphatase, aspartate yersiniosis. aminotransferase, alanine aminotransferase, lactate 3. Parasitic: Malaria, Amebiasis, babesiosis, dehydrogenase, creatine echinococcosis, malaria, schistosomiasis, kinase, antinuclear antibodies, strongyloidiasis, toxoplasmosis, trypanosomiasis. rheumatoid factor, microscopic 4. Viral: Dengue, coxsackie virus infection, urinalysis, ferritin, three cytomegalovirus infection, Epstein-Barr virus blood cultures, urine culture, infection, hepatitis (A, B, C, D, E), herpes simplex, chest X-ray, abdominal ultrasonography and tuberculin HIV infection, parvovirus infection. skin test. 5. Non infectious autoimmune diseases: Ankylosing Table 2: Potential Diagnostic clues histiocytosis, multiple myeloma, myelodysplastic 17 syndrome, myelofibrosis, non-Hodgkin’s Clues Possible diagnosis lymphoma, plasmacytoma, systemic mastocytosis, *Exposure vaso-occlusive crisis in sickle cell disease • fresh water exposure Leptospirosis b. Solid tumours - most solid tumors and metastases • living conditions Tuberculosis can cause fever. Those most commonly causing (homeless) Brucellosis PUO are breast, colon, hepatocellular, lung, • pets ,wild animals pancreatic, and renal cell carcinomas • recent travel to areas 10. Defective thermoregulatory causes: Brain with endemic diseases tumor, cerebrovascular accident, encephalitis, hypothalamic dysfunction *Medical history CHAPTER 3 • Abdominal disorders Alcoholic hepatitis, 11. Drug Fever: Barbiturates, carbamazepine, phenytoin, Carbapenems, cephalosporins, • History of transfusions HBV, HCV, HIV erythromycin, Isoniazid, Minocycline. • Malignancy Metastasis • Psychiatric illness Factitious fever STUDIES Evaluation • Recent hospitalization Nosocomial infection The most important and primary approach to these patients *High risk behavior are thorough history taking, proper clinical examination • intravenous drug Abscess,endocarditis. and obligatory investigations. PDCs are defined as all user localizing signs, symptoms, and abnormalities potentially *Physical pointing toward a diagnosis are given in Table 2. • rash(erythema Adenovirus,herpes,tick History: The history should include information about multiforme,petechiae) borne the fever pattern (continuous ,intermittent ,remittent or • Conjunctivitis/uveitis Adult stills disease,SLE recurrent) and duration, previous medical history, present and recent drug use, family history, sexual history, recent • Hepatosplenomegaly Lymphoma, Leptospirosis and remote travel, unusual environmental exposures • Polyarthralgia IBD, Chikungunya associated with travel or hobbies, and animal contacts. • Lymphadenopathy Cat scratch One of the first steps should be to rule out factitious or disease,EBV,CMV fraudulent fever, particularly in patients without signs of inflammation in laboratory tests. All medications, spondylitis, antiphospholipid syndrome, including nonprescription drugs and nutritional autoimmune hemolytic anemia, autoimmune supplements, should be discontinued early in the hepatitis, Behçet’s disease, cryoglobulinemia, evaluation to exclude drug fever dermatomyositis, Felty syndrome, gout, mixed connective-tissue disease, polymyositis, Physical examination: special attention to the eyes, lymph pseudogout, reactive arthritis, relapsing nodes, temporal arteries, liver, spleen ,sites of previous polychondritis, rheumatic fever, rheumatoid surgery, entire skin surface, and mucous membranes. arthritis, Sjögren’s syndrome, systemic lupus In patients without PDCs or with only misleading PDCs, erythematosus. fundoscopy by an ophthalmologist may be useful in the 6. Vasculitis: Allergic vasculitis, Churg-Strauss early stage of the diagnostic workup. syndrome, giant cell vasculitis/polymyalgia rheumatica, granulomatosis with polyangiitis, FDG PET SCAN hypersensitivity vasculitis, Kawasaki’s disease, FDG-PET is based on the increased uptake of FDG polyarteritis nodosa, Takayasu arteritis. (fluorodeoxyglucose) by activated inflammatory cells, which occurs in infection, NIID and malignancy. FDG- 7. Granulomatous :Sarcoidosis PET/CT is a non-invasive imaging technique with high 8. Autoinflammatory syndrome: Adult-onset diagnostic yield and should therefore be performed early Still’s disease, CAPS (cryopyrin-associated in the investigation of FUO. FDG-PET was helpful in 40% periodic syndromes), Crohn’s disease, familial and FDG-PET/CT in 54% of cases. But in countries like Mediterranean fever, hemophagocytic syndrome, India where FDG PET scans are not readily available juvenile idiopathic arthritis. ,relatively more cases of PUO remains undiagnosed. 9. Malignancy: TREATMENT a. Haematological malignancy- Amyloidosis, The emphasis in patients with PUO is on continued angioimmunoblastic lymphoma, Hodgkin’s observation and examination with avoidance of disease, hypereosinophilic syndrome, leukemia, “Shotgun” empirical therapy. However, vital signs lymphomatoid granulomatosis, malignant instability or neutropenia is an indication for empirical 18 Approach to patients of pyrexia of prolonged duration Pa�ents with temperature >1010F on several occasions Comprehensive history and physical examina�on looking for diagnos�c clues yes Clues found? Order appropriate tests No INFECTION Perform minimum diagnos�c work up Complete blood count,chest radiography,urinalysis,urine culture ESR,CRP,electrolyte panel,liver enzymes LDH,crea�nine kinase,Blood cultures,ANA,RF, serological tes�ng(EBV,CMV,HIV) PPD test, interferon gamma assay(TB),abdominal and pelvic USG or CT imaging No yes Diagnosis evident ? Complete appropriate evalua�on and treatment Meets the defini�on of fever of unknown origin Addi�onal diagnos�c work up Measure ferri�n level Cryoglobulins An� neutrophilic cytoplasmic an�bodies Serum protein electrophoresis Complement studies Thyroid tes�ng At last, �ssue biopsy(lymph node ,liver temporal artery, bone marrow) or 18 FDG PET scan therapy with fluoroquinolone plus piperacillin. If Effects of glucocorticoids on temporal arteritis and Mantoux test is strongly positive and granulomatous polymyalgia rheumatica and granulomatous hepatitis are disease is suggested (and sarcoid seems unlikely) then a equally dramatic. Steroids are not to be given early in the therapeutic trial for tuberculosis should be undertaken course as they may mask various PDCs of the diseases. In with treatment continued for up to 6 weeks. A failure patients with a suspected autoinflammatory disorder the of the fever to respond over this period suggests other interleukin-1
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