Tuberculosis in a nine-year-old girl treated with infliximab for systemic juvenile idiopathic arthritis
W. Armbrust1,2,
S. S. M. Kamphuis1,
T. W. F. Wolfs1,
T. J. W. Fiselier3,
P. G. Nikkels1,
W. Kuis1 and
N. M. Wulffraat1
1University Hospital for Children and Youth, Het Wilhelmina Kinderziekenhuis, Utrecht, 2University Hospital Groningen, The Beatrix Kinderkliniek, Groningen and 3University Medical Centre Nijmegen, Nijmegen, The Netherlands
Correspondence to: N. M. Wulffraat, Department of Immunology, University Hospital for Children and Youth, Het Wilhelmina Kinder Ziekenhuis, PO Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: n.wulffraat{at}wkz.azu.nl
SIR, A 5-yr-old girl presented in 1998 with typical features of systemic juvenile idiopathic arthritis (s-JIA). Remission was difficult to accomplish despite the use of steroids and indomethacin. Because of a polyarticular course and multiple relapses of fever, high-dose methotrexate (MTX), cyclosporin and recurrent methyl prednisone pulses were administered. In 2000 she developed severe, persistent lymphopenia and decreased in vitro cellular responses to mitogens, antigens and purified protein derivate (PPD). This was probably caused by the prolonged use of immunosupressive medication. Because of persistent disease activity and steroid dependency, etanercept (0.4 mg/kg twice a week) was added in 2001 to the MTX and prednisone. Cyclosporin was stopped. Increasing the dose to 0.8 mg/kg twice a week did not have any effect on the arthritis. Etanercept was stopped and high-dose infliximab (20 mg/kg/month) was added in January 2002 [1]. Fever changed from a spiking pattern to a more continuous pattern and arthritis persisted. Infliximab was stopped. Recurrent extensive microbiological screening did not reveal pathogenic micro-organisms. Bronchoalveolar lavage was negative for pathogens, including Mycobacterium tuberculosis. Given the resistant nature of her s-JIA, the girl was evaluated for possible autologous stem-cell transplantation. During this evaluation she developed a cystic subcutaneous swelling at the left wrist which had no clear connection to the joint. MRI showed a cystic process without signs of osteomyelitis. The fluid of the cyst was aspirated. PCR was positive for M. tuberculosis. Culture was negative. Cultures and PCR of cerebrospinal fluid, fasting stomach contents, bone marrow aspirate and blood for M. tuberculosis remained negative. Because she had an extrapulmonary lesion in the presence of a chronic immunodeficient state, tuberculostatic therapy with ethambutol, isoniazid, pyrazinamide and rifampicin was started. One month later a central venous line was removed. Within an hour after general anaesthesia she developed acute respiratory insufficiency and cardiac arrest. After resuscitation, high-pressure ventilatory support was needed. Saturation remained low (65%), with high central venous pressure. Under the suspicion of a pulmonary embolism, anticoagulation therapy was started. A few hours later she died due to respiratory and circulatory failure. On autopsy no pulmonary embolism could be diagnosed. Macroscopically, the lungs showed a fine granular aspect on the cut surface. Microscopy revealed a massive lipid pneumonia with fulminant alveolar damage and an infiltrate of neutrophils and macrophages (Fig. 1). Hardly any normal lung tissue was seen. A chronic (opportunistic) infection on the basis of these findings was strongly suspected. Auramin and Ziehl-Neelsen preparations were negative, however, as were PCR tests for M. tuberculosis on the lung tissue and pleural fluid. Therefore, the diagnosis of pulmonary tuberculosis could not be confirmed. Culture of the catheter tip was positive for Escherichia coli. Cultures for specific mycobacterial species, atypical pathogens and opportunistic agents were also negative. Bacterial cultures showed E. coli and Enterobacter species.

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FIG. 1. Microscopy of lung tissue. Magnification x400; haematoxylin and eosin staining. The normal microscopic appearance, with alveoli and thin septi, is completely absent. A, dense alveolar infiltration with neutrophils; B, enlarged interstitial space filled with neutrophils and macrophages, with signs of regeneration. Alveolar lining cells (arrow) are damaged
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Etanercept and infliximab are immune-modulating agents that block anti-TNF-
. Etanercept was found to be effective in children with a polyarticular course of JIA, where conventional therapy had failed [2, 3]. In children, anti-TNF-
therapy is used less often than in adults. Few side-effects of etanercept have been described other than increased susceptibility to airway infections [4]. Although one case has been reported of a child developing osteoarticular tuberculosis shortly after commencing treatment with etanercept [5], an increased incidence of tuberculosis has not been proven during etanercept treatment, in contrast to infliximab [2]. An overview identified 70 cases of tuberculosis after treatment with infliximab of approximately 147 000 adults for rheumatoid arthritis or Crohn's disease [4]. Among these 70 cases, a high incidence of extrapulmonary and disseminated disease was found (56% and 24%). Apart from tuberculosis, other opportunistic infections (Pneumocystis jeroveci pneumonia, listeriosis, histoplasmosis, aspergillosis and candidiasis) have been described in patients on anti-TNF-
therapy [4]. In mouse models, TNF-
induced and maintained latency of tuberculosis infection. Blocking TNF-
results in failure to form granulomas [6]. The difference in the incidence of tuberculosis in patients treated with infliximab vs etanercept may be explained by the mechanism by which both agents neutralise TNF-
[7], but also suggests a more complicated mechanism than simply the effect of TNF-
neutralization. It is estimated that approximately 10% of individuals who acquire tuberculosis infection and are not given pre-emptive therapy will develop active tuberculosis [8]. Criteria for risk assessment for latent tuberculosis have been described [9]. When one or more criteria are positive, one should carefully monitor the development of active tuberculosis while on treatment with infliximab, or pre-emptive tuberculostatic therapy should be considered. The diagnosis of tuberculosis in immune-compromised patients on anti-TNF-
therapy is difficult, and in the absence of granulomas due to anti-TNF-
therapy, radiological screening and histopathology are mostly inconclusive. Skin testing is often negative due to impaired cellular immunity. It is advisable to perform PCR on tissue [8]. The reliability of PCR vs culture is sometimes difficult to assess. The specificity of PCR for TB is at least 9598% when cultures are positive and 95% when there is a negative culture. In the USA, 90% of adult tuberculosis cases were confirmed by culture. In contrast, only 28% of the children with tuberculosis had positive cultures, and here PCR appears to be more reliable [8].
We present the first case of extrapulmonary tuberculosis in a child with severe s-JIA treated with infliximab who also developed a fatal (opportunistic) pulmonary infection. The diagnosis of tuberculosis is difficult to make in an immunocompromised host. One must be alert to alarming symptoms indicating possible tuberculosis, even in children without risk factors. While a patient is on immunosuppressive therapy, one must look out for opportunistic infections and the possibility of an atypical presentation.
The authors have declared no conflicts of interest.
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Accepted 13 October 2003