Annals of the Rheumatic Diseases 1994; 53: 429-433 429 MASTERCLASS Ann Rheum Dis: first published as 10.1136/ard.53.7.429 on 1 July 1994. Downloaded from Fever of unknown origin in childhood: difficulties in diagnosis Katherine Martin, E Graham Davies, John S Axford Case report (CRP) 208 mg/I. Liver function tests were A twelve year old white boy presented to abnormal: alanine transaminase 91 IUAL another hospital with a two month history of (normal range 1-40), gamma glutamyl intermittent fever with night sweats, general transferase 134 IUAL (normal range 0-60), malaise, arthralgia and myalgia. He had bilirubin 18 micromolVL (0-17), alkaline marked cervical lymphadenopathy. Latex phosphatase 217 IU/L (30-100) and albumin agglutination for toxoplasma antibodies was 18 g/l (35-45). Renal impairment was apparent positive at a dilution of 1/128. A diagnosis of with a raised serum creatinine (224 micromol/ acquired toxoplasmosis was made and sulpha- L (60-110)). Chest radiograph showed right diazine 1 g four times a day, trimethoprim 300 middle lobe consolidation. Abdominal mg twice a day and folinic acid 15 mg ultrasound scan (USS) confirmed hepato- alternative days, were started. Over the next splenomegaly and ascites. Echocardiogram week he developed a generalised urticarial rash, showed a small pericardial effusion. peripheral oedema and profuse bloody A diagnosis of Stevens-Johnson syndrome diarrhoea and was referred to our unit. with acute renal failure and disseminated On examination he was delirious with a intravascular coagulation (DIC) was made. persistent fever of up to 42°C and he was Supportive therapy, broad spectrum anti- bleeding from his nose and mouth. He was biotics and discontinuation of sulphonamides generally oedematous with marked ascites and resulted in marked improvement. Cultures of bilateral pleural effusions. His skin was blood, cerebrospinal fluid, urine and stool grew erythematous with a petechial rash and after a no pathogenic organisms. Repeat toxoplasma few days began to desquamate. His liver was serology showed a positive dye test (125 units) palpable 5 cm below the costal margin. Full and positive latex agglutination at a dilution of blood count and film revealed a normochromic 1/128, but negative IgM by enzyme linked http://ard.bmj.com/ normocytic anaemia (haemoglobin 6-8 g/dl), immunosorbent assay and immunosorbent Academic neutrophilia with left shift (white cell count agglutination assay, indicating probable past Rheumatology Group 41 6 X 109/1 with 93% polymorphonuclear infection. Serology for Epstein-Barr virus, and Department of cells) and thrombocytopaenia (platelet count cytomegalovirus, viral hepatitis, mycoplasma, Child Health, St. was George's Hospital 66 x 109/1). The circulating lymphocyte count brucella, leptospira and legionella Medical School, was normal (1-2 X 109/1). Coagulation studies negative. Mantoux at a dilution of 1/1000 was London, United revealed evidence of disseminated intra- anergic. Anti-streptolysin 'O' titre was less than on September 29, 2021 by guest. Protected copyright. Kingdom time 16 s 200 IU/ml, anti-deoxyribonuclease B titre was K Martin vascular coagulation (prothrombin E G Davies (control 11-15 s), kaolin partial thrombo- less than 100 U/ml. Anti-nuclear antibody was J S Axford plastin time 68 s (control 34-48 s), thrombin negative. Plasma immunoglobulin levels and Correspondence to: time 18 s (control 11-15 s), plasma fibrinogen immunoglobulin G subclass levels were within Dr Katherine Martin, Department of Child Health, 1-2 g/l (normal 2-0-4-0 g/l), fibrinogen the normal range and complement studies St. George's Hospital degradation products 64 to 128 mg/l (normal were normal. Medical School, Cranmer < Terrace, London SW17 ORE, 8 mg/1)). Erythrocyte sedimentation rate Two weeks after admission the patient was United Kingdom. (ESR) was 30 mm/hour, C-reactive protein much improved but had persistent intermittent fevers and marked hepatomegaly. Liver function tests returned to normal. Repeat _ - . .I I I p I -cm abdominal USS showed a diffusely abnormal A2lOUj,s,q2lOUIWZ,I2IMAJa26I32d12i2,41S722B2a 4iUi"=2 sho4m62II liver texture. Liver biopsy showed minimal 416 .... .. focal fatty change with no signs of vasculitis. Bone marrow trephine showed hypercellularity and reactive changes only. Both were sterile on ,4 1 - . 4.-. 7ii[=20 culture. 37.0 300 The patient continued to experience daily as 37S.1 ..I l.-.-. I . fevers (fig 1) and a fine evanescent rose I 3" | . tt t / \ lfif4 * 270 coloured maculopapular rash which exhibited Koebner's phenomenon (fig 2) was noted for the first time at the peak of the fever. He 3" 1: A nI developed swelling and stiffness of the 37.0 -4-6--IJ210. 4-..\ w 0---r o proximal interphalangeal joints of the hands 3vL 2001. ., ..-. s aI and effusions in the left knee and right ankle joints. A diagnosis of systemic onset juvenile Figure I Temperature chart. chronic arthritis (S-JCA) was made and the 430 Martin, Davies, Axford a* Ann Rheum Dis: first published as 10.1136/ard.53.7.429 on 1 July 1994. Downloaded from / Figure 2 Appearance ofrash. patient was treated with diclofenac sodium 50 CRP = 189 mg/l, ferritin 5148 microg/l). As mg three times a day. Slit lamp examination of the patient remained systemically unwell and the eyes was normal. Two weeks later there was in view of the rapidly falling haemoglobin, no improvement in systemic symptoms prednisolone 40 mg/day was added with although the arthritis had largely resolved. The resultant slow improvement. After resolution haemoglobin had fallen to 6&4 g/dl ofdisease activity steroids were weaned and the necessitating transfusion. Acute phase patient currently remains well and off all reactants remained raised (ESR = 1 5 mm/hr, medication. http://ard.bmj.com/ Table 1 Causes ofFUO Discussion Infections Differential diagnosis offever of unknown Post-infectious inflammatory disease, for example, rheumatic fever origin in childhood Non infectious inflammatory diseases This case illustrates well some of the pitfalls in For example S-JCA on September 29, 2021 by guest. Protected copyright. systemic lupus erythematosus the diagnosis of S-JCA. The child's initial polyarteritis nodosa presentation was with fever of unknown origin Kawasaki's disease inflammatory bowel disease (FUO) which has been defined as "the sarcoidosis presence of fever for eight or more days in a familial mediterranean fever Malignancies child in whom a careful and thorough history For example leukaemia and physical examination and preliminary lymphoma neuroblastoma laboratory data fail to reveal the probable cause Wilm's tumour of fever".' The differential diagnosis of FUO is Miscellaneous For example factitious fever wide and includes infectious diseases (systemic drug fever and localised), autoimmune rheumatic diabetes insipidus The hypothalamic dysfunction diseases, and neoplasia (table 1). ectodermal dysplasia commonest cause in childhood is infectious familial dysautonomia disease (22-55%)2 5 (see table 2). Table 2 Infections presenting as FUO Systemic Localised Viral, for example infectious mononucleosis* Urinary tract infection cytomegalovirus* Osteomyelitis* hepatitis A, B* Sinusitis human immunodeficiency virus* Endocarditits Bacterial, for example tuberculosis* Occult abscesses (for example, hepatic, pelvic) salmonellosis* brucellosis* *may also cause arthritis legionellosis cat scratch fever Rickettsial disease (for example, Q fever) Chlamydial diseases (for example, psittacosis) Spirochaete infections (for example, Lyme disease*, leptospirosis) Parasitic infections (for example, malaria, toxoplasmosis) Fungal infections (for example, histoplasmosis) Fever of unknown origin in childhood: difficulties in diagnosis 431 Retrospective analyses of admissions in the As the acute hypersensitivity reaction United States of America with FUO show that resolved the clinical picture returned to that at a diagnosis of 'juvenile rheumatoid arthritis' presentation with intermittent spiking fevers, Ann Rheum Dis: first published as 10.1136/ard.53.7.429 on 1 July 1994. Downloaded from was made in three to thirteen per cent of although marked hepatomegaly persisted. In cases.2-5 Other autoimmune rheumatic addition to the high spiking quotidian fever (fig diseases (systemic lupus erythematosus, 1), the appearance of the characteristic rash Henoch-Schonlein purpura, polyarteritis (fig 2) and arthritis led to the diagnosis ofJCA. nodosa, undefined vasculitis) account for up to Our patient demonstrates the need for a further 5% of cases. Autoimmune rheumatic thorough and repeated examination which diseases were commoner in the older age group other authors have stressed.4 13 (JCA was diagnosed in seven of 48 cases of FUO aged six years or older).2 An infectious aetiology was initially Clinical features ofsystemic onset considered in the above case. Marked cervical juvenile chronic arthritis lymphadenopathy together with a positive latex (A) TYPICAL FEATURES agglutination test for toxoplasma misled the Daily or twice daily temperature elevations to referring clinicians into a diagnosis of acquired 39°C or above with rapid return to baseline are toxoplasmosis. Latex agglutination for characteristic of S-JCA and often accompanied toxoplasma measures IgG and detectable titres by sweating, chills, myalgia and arthralgia. of IgG usually persist for life after acute Typically the fever spike occurs in the evening. infection. Serological diagnosis of acute However, intermittent fevers are also seen in toxoplasmosis requires