Rheumatology Advance Access published online on November 18, 2006
Rheumatology, doi:10.1093/rheumatology/kel375
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Histoplasmosis in a child with JRA on low-dose methotrexate
Division of Infectious Diseases and 1Division of Immunology and Rheumatology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
Correspondence to:
Correspondence to: A. R. French, MD, PhD, Division of Immunology and Rheumatology, Department of Pediatrics, Washington University, One Children's Place, St Louis, MO 63110, USA. E-mail: french_a{at}kids.wustl.edu
SIR, Patients receiving immunosuppressive agents are at risk for opportunistic infections (OIs), highlighted by recent reports of tuberculous and fungal infections in patients receiving anti-TNF
therapy. OIs are rare in children receiving low-dose methotrexate, despite its frequent use in the management of rheumatological conditions. We present a case of histoplasmosis in a child with polyarticular juvenile rheumatoid arthritis (JRA) receiving low-dose methotrexate.
A 7-yr-old Missouri female presented with diffuse joint complaints and morning stiffness. She had synovitis with decreased range of motion in the wrists, ankles, knees and neck; and fusiform swelling of the fingers. She was diagnosed with polyarticular JRA and given naproxen sodium 250 mg bid (13 mg/kg/day) and prednisone 10 mg qd (0.26 mg/kg/day). She improved over 2 weeks, and oral methotrexate 12.5 mg/week (11 mg/m2/week) was initiated. Over the ensuing 3 months, methotrexate was increased to 15 mg/week while prednisone was tapered to 2.5 mg every other day and subsequently discontinued.
Several days after her last dose of prednisone, she developed fever, sore throat and cough. Her primary care provider prescribed an oral antibiotic; her sore throat resolved, but fever and cough persisted. After 10 days of fever, she was admitted for evaluation. She had lost 1.5 kg over 3 weeks. Her chest was clear to auscultation. Splenomegaly was present, but there was no palpable lymphadenopathy or evidence of active joint involvement. Her haemoglobin was 10.3 g/dl (decreasing to 9.6 g/dl 3 days later), leucocyte count was 7.5 x 109/l, and platelet count was 236 x 109/l. Erythrocyte sedimentation rate was 52 mm/h. Alanine aminotransferase (ALT) was 43 U/l (normal range, 10–35). Blood culture was negative. Serological studies for Epstein-Barr virus, cytomegalovirus (CMV), Mycoplasma, Bartonella, Histoplasma and Blastomyces were negative. Gastric aspirates were negative for acid-fast bacilli (AFB). Tuberculin skin test was negative. Radiography and CT scan of the chest demonstrated mediastinal lymphadenopathy (including a 2.2 x 2.2 cm right paratracheal lymph node and a 1.2 x 2 cm pretracheal node), right hilar lymphadenopathy, and a 7 x 6 mm non-calcified nodule in the right lower lobe.
Mediastinal lymph node biopsy demonstrated necrotizing granulomas with giant cells. AFB staining was negative. Gomori methenamine silver stain revealed small round organisms morphologically consistent with Histoplasma or Cryptococcus. Urinary Histoplasma antigen at that time was 3.5 units (normal range <1 unit; MiraVista Diagnostics, Indianapolis, IN). Because the microbiological diagnosis was established, bone marrow studies were not pursued.
She received oral itraconazole (200 mg/day) for 6 weeks. Fever resolved after 15 days, although her cough persisted. Histoplasma serologies one week after discharge were positive (mycelial complement fixation titer, 1:16; yeast complement fixation titer, 1:128; reactive H band on immunodiffusion).
Histoplasmosis is the most common pulmonary and systemic mycosis in the United States and is endemic in the Ohio and Mississippi River valleys [1]. Fewer than 5% of infected people develop systemic illness; however, immunocompromised individuals are at greater risk for life-threatening, disseminated infections [1, 2]. Four prior reports have described six cases (all in adults) of disseminated histoplasmosis in patients receiving low-dose methotrexate (Table 1) [3–6].
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Symptoms of acute pulmonary histoplasmosis consist primarily of low-grade fever, chest pain and upper respiratory symptoms. Disseminated disease presents with evidence of extrapulmonary involvement including hepatosplenomegaly, lymphadenopathy, adrenal masses, CNS infection, haematological abnormalities, elevated hepatic enzymes, or isolation of Histoplasma capsulatum from extrapulmonary locations [1, 7]. In the absence of extrapulmonary cultures, symptom duration has been used to distinguish disseminated disease from self-limited infections, which generally resolve within 14 days [2]. Patients with disseminated histoplasmosis have a greater degree of antigenuria than patients with self-limited infections, though urinary antigen can be positive in
20% of patients with acute, localized (non-diffuse) pulmonary histoplasmosis [8]. Antifungal therapy is indicated for histoplasmosis in immunocompromised hosts because of the risk for progressive disease. Two reviews have summarized 36 previous reports of OIs in adult patients receiving low-dose methotrexate (2.5–25 mg/week) for rheumatoid arthritis (58%), psoriatic arthritis (14%) and psoriasis (8%) among other conditions [3, 7]. Slightly over 50% were also receiving prednisone. The most frequent OI (42%) was Pneumocystis jiroveci pneumonia. Four patients (11%) had disseminated histoplasmosis, with H. capsulatum isolated from bone marrow or liver biopsy. Other OIs included cryptococcal pneumonia (11%), Nocardia pneumonia (8%), CMV pneumonitis (6%) and disseminated herpes zoster (17%). In contrast, only two OIs are reported in pediatric patients treated with low-dose methotrexate. A 16-yr-old female with psoriatic arthritis receiving methotrexate (10 mg/week) and prednisone (3 mg/day) developed Pneumocystis pneumonia [9], and a 14-yr-old female with dermatomyositis receiving methotrexate (25 mg/week) and prednisone (150 mg/day) developed disseminated nocardiosis [10].
Evidence for disseminated disease in our patient included prolonged fever, splenomegaly, anaemia, elevated ALT and significant antigenuria (in the setting of non-diffuse pulmonary involvement). Her symptoms resolved after discontinuation of methotrexate and treatment with itraconazole. OIs are rare in children treated with low-dose methotrexate, but vigilance for OIs is warranted in these patients.
The authors have declared no conflicts of interest.
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