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Home , Childhood arthritis, Fever of unknown origin

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 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 , general transferase 134 IUAL (normal range 0-60), , arthralgia and . He had bilirubin 18 micromolVL (0-17), alkaline marked cervical . Latex phosphatase 217 IU/L (30-100) and albumin agglutination for toxoplasma 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 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 , 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 Group 41 6 X 109/1 with 93% polymorphonuclear . Serology for Epstein-Barr virus, and Department of cells) and thrombocytopaenia (platelet count , viral , 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 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 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 . 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 (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

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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, . http://ard.bmj.com/

Table 1 Causes ofFUO Discussion Differential diagnosis offever of unknown Post-infectious inflammatory disease, for example, 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 erythematosus the diagnosis of S-JCA. The child's initial presentation was with fever of unknown origin Kawasaki's disease inflammatory bowel disease (FUO) which has been defined as "the 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 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 * cytomegalovirus* * hepatitis A, B* human immunodeficiency virus* Endocarditits Bacterial, for example * Occult (for example, hepatic, pelvic) * * *may also cause arthritis legionellosis cat scratch fever Rickettsial disease (for example, ) Chlamydial diseases (for example, ) Spirochaete infections (for example, *, ) Parasitic infections (for example, , toxoplasmosis) Fungal infections (for example, ) 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 ' 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, , 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 either the detection of pyogenic infections, tuberculosis and lym- IgM or a rise in IgG titre. phomal and several authors2 5 have found that the pattern of fever was not useful in differentiating the cause of FUO. Systemic onset juvenile chronic arthritis. A rash occurs in up to 94% of children with Diagnostic criteria and epidemiology S-JCA9 13-14 but may not be present or Diagnostic criteria for systemic onset juvenile characteristic on initial evaluation. Typically it chronic arthritis have recently been suggested.6 is erythematous, fine and mascular. It is The criteria for the diagnosis of 'definite' evanescent, usually appearing at the height of S-JCA are arthritis, characteristic rash and the fever and it is therefore essential to re- quotidian fever lasting for more than two examine the child when febrile. The weeks. A 'probable' diagnosis of S-JCA can be commonest sites are the trunk and limbs23 but made if there is typical rash and fever, the face and neck are affected in more than organomegaly and/or lymphadenopathy and/or 50% of cases and the rash may also occur on serositis in the absence of arthritis. the palms and soles. Occasionally, the rash may

Juvenile chronic arthritis (JCA) has an be confined to the axillae and might therefore http://ard.bmj.com/ annual incidence of approximately one in five be missed unless specifically searched for. The to ten thousand children.7 8 Four to thirty per rash is rarely pruritic, but Koebner's cent of these present with systemic onset phenomenon is common at sites of friction disease.7'- S-JCA may occur at any age from clothing and may sometimes be throughout childhood. The reported sex inci- demonstrated by rubbing the skin. dence varies showing an excess of males in Children with S-JCA may develop oligo- or

some senes - 1113-14 and an excess of females poly-arthritis. The commonest sites of arthritis on September 29, 2021 by guest. Protected copyright. in others.'5"-7 in S-JCA are the wrists, knees, ankles, elbows, The diagnosis of S-JCA was delayed in this hips, metacarpo-phalangeal joints and proxi- case because the clinical picture was obscured mal inter-phalageal joints.'2 17 Involvement of by the development of a persistent high fever, the temporo-mandibular joints also occurs desquamating erythematous rash, mucositis, frequently and involvement of the cervical encephalopathy, renal failure and DIC. This spine is present at onset of disease in about a was attributed to an acute hypersensitivity quarter of patients.'2 Although arthralgia and reaction to sulphadiazine. Intolerance to myalgia are frequent but non-specific suphonamides appears to occur with increased symptoms at the onset of S-JCA, arthritis may frequency in patients with S-JCA. Sustained be transient or absent at presentation. In high fever and rash were reported in three of Schaller and Wedgwood's series'4 29 of 32 four patients with S-JCA treated with sulpha- patients with S-JCA had overt arthritis during salazine.'8 In one case there were associated the first six months of disease but Calabro liver function abnormalities. Two children out describes 18 of 40 children with systemic onset of five with S-JCA were withdrawn from a disease in whom arthritis was initially absent.9 second study of suphasalazine'9 because of These children were originally diagnosed as severe side effects (fever, rash and leucopaenia having FUO, the diagnosis of S-JCA being in one and nausea, vomiting, and made after the development of arthritis four abnormal liver function tests in the other). months to nine years (mean 2-2 years, median DIC has also been described in S-JCA both as 8-5 months) after the onset of fever. a direct manifestation of disease activity in association with renal and hepatic damage,2021 in association with presumed infection22 and in (B) OTHER FEATURES association with non-steroidal anti-inflam- Reticuloendothelial hyperplasia, most fre- matory drug and intramuscular gold quently lymphadenopathy, occurs in approxi- therapy.2' mately 80-90% of children with active 432 Martin, Davies, Axford

S-JCA,9 11 14 but is also common in other the consideration of alternative diagnoses such causes of FUO.2 Lymphadenopathy may as malignancies or systemic lupus erythe- occasionally be so prominent as to suggest a matosus. Mildly raised transaminases are Ann Rheum Dis: first published as 10.1136/ard.53.7.429 on 1 July 1994. Downloaded from lymphoma."3 Hepatomegaly (occurring in one common35 and hypoalbuminaemia may be third of cases) is less common than spleno- marked. The erythrocyte sedimentation megaly (found in approximately 75% of rate9 12-13 33 and C-reactive protein36 are often cases),9 although massive hepatomegaly has considerably raised and hypergamma- been reported.24 globulinaemia" is common. Serum ferritin levels Serositis is common in S-JCA. Pericardial are characteristically extremely high during effusions are detectable in more than 80% of active phases of S-JCA.37 Fassbender et al38 patients during active disease25 although reported a decreased proportion of concanavalin symptomatic is much less frequent. A reactive alpha,-acid glycoprotein (AGP) Constrictive pericarditis and cardiac tam- variants in patients with S-JCA compared with ponade are extremely rare.26 Pleural effusions healthy controls and patients with acute are less common than pericardial effusions and bacterial infections. Children with S-JCA have usually small. Subclinical myocarditis is an increased prevalence of agalactosyl oligo- reported to occur in up to 10% ofchildren with saccharides associated with immunoglobulin G S-JCA25 although clinically significant compared with healthy controls.39 The myocardial involvement is rare. Myocarditis prevalence of agalactosyl-IgG is not increased, may present with chest or heart failure but however, in patients with infectious diseases.40 tachycardia out of proportion to the degree of The investigation of glycosylation of immune pyrexia or anaemia may be the only clinical molecules may prove useful in discriminating sign. Differentiation from viral myocarditis between acute infection and active JCA. may be difficult. Both pericarditis and Malignancy is the cause of 2-13% of cases of myocarditis have been reported as the FUO in children in the USA,2 is sometimes presenting manifestations of S-JCA.27 associated with arthralgia or arthritis and has Differentiation of S-JCA from acute rheu- been misdiagnosed as S-JCA.1A2 The pattern matic fever may cause problems especially in of fever is usually remittent4' (that is, the the presence of S-JCA associated carditis. temperature fluctuates but does not return to Although functional cardiac murmurs are normal), in contrast to JCA and bone or joint common, valvular disease is extremely rare in pain may be more pronounced than in S-JCA.43 JCA. Rheumatic fever is rare in children under Careful examination of full blood count and the age of five years and the fever pattern in film for any abnormalities is therefore essential. rheumatic fever is typically more sustained and Severe anaemia, leucopaenia, thrombo- lower grade than that of S-JCA.28 Associated cytopaenia or abnormal white blood cell arthritis is typically migratory, asymetric and appearance on the blood film are indications for

painful. There may be evidence of a previous bone marrow examination. In addition to its http://ard.bmj.com/ group A P-haemolytic streptococcal infection, role of diagnosis of haematological although the ASOT may be moderately and malignancies, bone marrow examination may chronically elevated in approximately one third rarely be of use in the diagnosis of infection.44 of children with JCA.29 30 A predominance of plasma cells has been Abdominal pain is occasionally a prominent reported in the bone marrow of patients with feature of S-JCA and may increase the diffi- JCA but also occurs in patients with FUO.45

culties in distinguishing S-JCA from inflam- Bone marrow examination may not always be on September 29, 2021 by guest. Protected copyright. matory bowel disease (which may also cause diagnostic of a leukaemia at presentation and FUO and arthritis). Abdominal pain or may need to be repeated.43 46 distension may occasionally be so severe as to suggest an acute abdomen.9 Pneumonitis has rarely been reported in S-JCA, but is usually Radiographic features mild and transient.3' Cerebral manifestations Careful examination ofradiographs may reveal (marked irritability, drowsiness, seizures and lesions characteristic of leukaemia (osteo- meningismus) have been reported in 25% of paenia, lytic lesions, metaphyseal rarefaction one series of children with S-JCA,'3 but these and periosteal lesions).47 Chest radiographs are rare in other series except in relation to may reveal asymptomatic pleuritis14 or an complicating factors such as metabolic increased cardiac shadow indicating possible derangements or salicylate toxicity. Iridocyclitis pericarditis or myocarditis. Scanning pro- should be sought in all patients with JCA but cedures such as abdominal and pelvic USS, is uncommon in systemic onset disease.'5-16 32 abdominal computed tomography, radio- isotope bone scanning, indium and gallium scanning may be helpful to exclude alternative Laboratory investigations diagnoses but rarely lead to an unsuspected Laboratory investigations are frequently unhelp- diagnosis in cases of FUO.3 Rheumatoid ful in the diagnosis of S-JCA. Autoimmune arthritis has been reported to be a cause offalse serology is characteristically negative. '13 Severe positive indium-labelled polymorphonuclear anaemia (commonly hypochromic and leucocyte scans.48 microcytic)33 and thrombocytosis'2 are usual in S-JCA but non-specific. Neutrophilia is often pronounced9 "-" but may also be a false pointer Summary to bacterial infection. Leucopaenia34 and We have described a child with systemic onset thrombocytopaenia are rare and should lead to juvenile chronic arthritis who presented Fever of unknown origin in childhood: difficulties in diagnosis 433

recurrent relapses in systemic juvenile rheumatoid initially with fever of unknown origin. Treat- arthritis. Ann Rheum Dis 1992; 51: 347-9. ment of a presumed infection led to a severe 21 Silverman E D, Miller J J, Bernstein B, Shafai T. Consumption coagulopathy associated with systemic Ann Rheum Dis: first published as 10.1136/ard.53.7.429 on 1 July 1994. Downloaded from allergic response with Stevens-Johnson juvenile rheumatoid arthritis. JfPediatr 1983; 103: 872-6. syndrome, renal failure and DIC. This reaction 22 De Vere-Tyndall A, Macauley D, Ansell B M. Disseminated intravascular coagulation complicating systemic juvenile obscured the features of the underlying disease chronic arthritis ("Still's disease"). Clin Rheumatol 1983; and delayed the diagnosis. 2: 415-8. 23 Calabro J J, Marchesano J M. Rash associated with juvenile rheumatoid arthritis. JfPediatr 1968; 72: 611-9. 24 SchallerJ, Beckwith B, Wedgwood R J. Hepatic involvement Key points in juvenile rheumatoid arthritis. 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