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 CHAPTER 3 17 histiocytosis, multiple myeloma, myelodysplastic myelodysplastic myeloma, multiple histiocytosis, syndrome, mastocytosis, systemic plasmacytoma, lymphoma, myelofibrosis, in sickle cell disease crisis vaso-occlusive metastases solid tumors and - most Solid tumours non-Hodgkin’s causing most commonly Those fever. can cause PUO are and renal cell carcinomas pancreatic, breast, colon, hepatocellular, Defective lung, encephalitis, accident, tumor, cerebrovascular thermoregulatory hypothalamic dysfunction causes: Drug Brain cephalosporins, phenytoin, Carbapenems, Fever: Minocycline. erythromycin, Isoniazid, Barbiturates, carbamazepine, TREATMENT FDG PET SCAN PET FDG STUDIES The emphasis in patients of examination with avoidance and observation with PUO is on vital signs “Shotgun” empirical therapy. However, continued for empirical an indication instability or neutropenia is FDG-PET is based on the increased uptake of FDG uptake of on the increased based FDG-PET is (fluorodeoxyglucose) by activated inflammatorymalignancy. FDG- and in infection, NIID occurs which cells, imaging technique with high PET/CT is a non-invasive early therefore be performed should yield and diagnostic 40% in helpful was FDG-PET FUO. of investigation the in and FDG-PET/CT in 54% of cases. But in countries India where FDG PET scans are not readily available like more cases of PUO remains undiagnosed. ,relatively Evaluation patients primary approach to these and important most The clinical examination are thorough history taking, proper and obligatory investigations. PDCs are defined potentially localizing signs, symptoms, and abnormalities as all 2. in Table a diagnosis are given pointing toward information about History: The history should include the fever pattern (continuous ,intermittent ,remittent or history, present recurrent) and duration, previous medical sexual history, recent and recent drug use, family history, exposures environmental unusual travel, remote and animal contacts. or hobbies, and associated with travel One of the first steps should be to rule out factitious in patients without signs particularly fraudulent fever, or of inflammation in laboratory and nutritional including nonprescription drugs tests. All medications, early in the supplements, should be discontinued to exclude drug fever evaluation lymph eyes, the to attention special examination: Physical previous of ,sites spleen liver, arteries, temporal nodes, membranes. surgery, entire skin surface, and mucous PDCs, misleading or with only In patients without PDCs by an ophthalmologist may be useful in the fundoscopy early stage of the diagnostic workup. b. 10. 11. Possible diagnosis Possible Leptospirosis Tuberculosis Brucellosis Alcoholic hepatitis, HIV HCV, HBV, Metastasis Factitious fever Nosocomial infection Abscess,endocarditis. Adenovirus,herpes,tick borne Adult stills disease,SLE Lymphoma, Leptospirosis IBD, Chikungunya Cat scratch disease,EBV,CMV Vasculitis: Allergic vasculitis, Churg-Strauss Allergic vasculitis, Vasculitis: giant cell vasculitis/polymyalgia syndrome, rheumatica, granulomatosis with polyangiitis, disease, Kawasaki’s hypersensitivity vasculitis, arteritis. nodosa, Takayasu polyarteritis Granulomatous :Sarcoidosis Autoinflammatory CAPS (cryopyrin-associated Still’s disease, syndrome:familial disease, Crohn’s syndromes), periodic hemophagocytic syndrome, Mediterranean fever, Adult-onset idiopathic arthritis. juvenile Haematological malignancy- Amyloidosis, angioimmunoblastic lymphoma, Hodgkin’s leukemia, syndrome, hypereosinophilic disease, lymphomatoid granulomatosis, malignant spondylitis, antiphospholipid syndrome, antiphospholipid spondylitis, autoimmune autoimmune hemolytic anemia, hepatitis, Behçet’s gout, Felty syndrome, dermatomyositis, disease, polymyositis, disease, mixed connective-tissue cryoglobulinemia, arthritis, relapsing pseudogout, reactive rheumatoid polychondritis, rheumatic fever, lupus syndrome, systemic arthritis, Sjögren’s erythematosus. Abdominal disorders History of transfusions Psychiatric illness Recent hospitalization fresh water exposure fresh water living conditions (homeless) pets ,wild animals to areas recent travel with endemic diseases drug intravenous user multiforme,petechiae) Lymphadenopathy • • Malignancy • • Table 2: Potential Diagnostic clues 2: Potential Table Clues *Medical history • • • • • Conjunctivitis/uveitis • Hepatosplenomegaly • Polyarthralgia • *Exposure • *High risk behavior • *Physical • rash(erythema 7. 8. 9. Malignancy: a. 6. 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

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

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 receptor antagonist, anakinra, can be tried. alternative diagnosis. A response of rheumatic fever and Remission of symptoms is expected within 24–48 hours. still’s disease to aspirin and NSAIDs may be dramatic. If anakinra is ineffective after two weeks of treatment, CHAPTER 3 19

9(8): Fever Fever Medicine 2012; Am J Med Sci Am J Med Int J Med Sci Int J 1997; 76:392–400. doi: 10.7150/ijms.4591 online 2012 Oct 1. 682–689. Published of definition Revised E. Tekeli A, Azap A, Willke O, Ergönül J origin’: limitations and opportunities. of unknown ‘fever Infect 2005; 50:1–5. and Investigating P, Doherty T. GM, Trowbridge Varghese unknown origin in adults. BMJ 2010; managing pyrexia of 341:C5470. Hayakawa K, Ramasamy B, Chandrasekar PH. Fever review. an evidence-based unknown origin: of 2012; 344:307–316. JW. Meer, der van JP, Vandenbroucke, EM, Kleijn, de of unknown origin (FUO). I. A study of 167 patients with FUO, using fixed epidemiologic prospective multicenter Group. Study FUO Netherlands The criteria. entry (Baltimore) Longo Longo D, Fauci A, Kasper 19th Medicine, of Internal Principles Harrison’s origin, D (Eds), Fever of unknown 26 Hill,e-chapter McGraw edition. Bilgul Mete, Ersin Vanli, Mucahit Balkan, Yemisen, Hilal Ilker Dagtekin, Resat Inanc Ozaras, Nese Saltoglu, Ali Mert, Recep Ozturk, Fehmi Tabak 5. 6. 7. 8. 3. 4. 1961; 40:1-30. 2011; 3:329-33 Petersdorf Petersdorf RG, Beeson PB. Fever of Medicine (Baltimore) report on 100 cases. unexplained origin: Bandyopadhyay Bandyopadhyay D, Bandyopadhyay R, Paul f unknown origin in patients Etiological study of fever R, Roy D. Eastern of hospital teaching a of ward medicine to admitted India. J Global Infect Dis REFERENCES PROGNOSIS 1. The overall prognosis of cause of In patients in whom no underlying disease. FUO is determined FUO by can the be established, and prognosis mortality is is low. Up generally to 75% good of although this may take of fever, spontaneous remission patients experience or corticosteroids with NSAIDs a long time. Treatment further. even increases this proportion 2. a beneficial effect should not expected be and be stopped. should the drug and vigilance equanimity, compassion, Patience, intellectual exibility are indispensable attributes for the with PUO. in dealing successfully clinician