Legionella pneumonia after infliximab in a patient with Rheumatoid Arthritis

Abstracts

The antagonists of tumour necrosis factor (anti-TNF) have been successfully used in several chronic inflammatory diseases such as Rheumatoid Arthritis (RA), but some studies have observed the development of infections by intracellular pathogens in patients using anti-TNF. We report a case of a female patient with previous diagnosis of RA for 16 years that used several disease-modifying anti-rheumatic drugs (DMARDs) that resulted in treatment failure, and then was treated with infliximab. After fifteen days of the second dose, the patient developed ventilatory-dependent chest pain, dry cough and dyspnea. She was hospitalized, and the diagnosis of pneumonia by Legionella pneumophila was confirmed by the presence of Legionella antigen in an urine test. TNF is an inflammatory cytokine that also acts inhibiting the bacterial growth of intracellular pathogens, and its inhibition seems to increase susceptibility to these infections in some patients.

Legionella pneumophila; Tumour necrosis factor alpha; Rheumatoid arthritis; Infliximab

Os antagonistas do fator de necrose tumoral (anti-TNF) têm sido utilizados com sucesso em várias doenças inflamatórias crônicas, como artrite reumatoide (AR), mas alguns estudos observaram a ocorrência de infecções por patógenos intracelulares em pacientes medicados com anti-TNF. Relatamos um caso de paciente mulher com diagnóstico prévio de AR durante 16 anos e que estava sendo medicada com várias drogas antirreumáticas modificadoras de doença (DARMDs), tendo como resultado o insucesso terapêutico, sendo em seguida tratada com infliximab. Depois de transcorridos 15 dias da segunda dose, a paciente foi acome- tida por dor torácica ventilatório-dependente, tosse seca e dispneia. Foi hospitalizada, e o diagnóstico de pneumonia por Legionella pneumophila foi confirmado pela presença do antí- geno de Legionella na urina. TNF é uma citocina inflamatória que também promove inibição do crescimento bacteriano de patógenos intracelulares, e sua inibição parece aumentar a sensibilidade a essas infecções em alguns pacientes.

Legionella pneumophila; Fator alpha de necrose por tumor; Artrite reumatoide; Infliximabe

Introduction

Antagonists of tumor necrosis factor (anti-TNF) have shown significant changes in the course of a number of chronic inflammatory diseases, such as Crohn's disease, ankylosing spondylitis and RA.¹

The tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine with multiple targets and interactions, but it has a well-established role in the pathogenesis of rheumatoid inflammation.

Besides this proinflammatory function in RA, TNFα also acts as a cellular defence mechanism against infections. Studies have observed that anti-TNF therapy may be related to increased risk of infections by intracellular pathogens, including Mycobacterium tuberculosis, Legionella pneumophila, Listeria monocytogenes, Aspergillus fumigatus, Histoplasma capsulatum and Pneumocystis jiroveci.

The evidence supporting this association between anti-TNF and increased risk of infections include case reports, epidemiological studies and experiments with animal models.²

We report a case of Legionella pneumonia in a patient with RA during the use of anti-TNF and discuss the main factors possibly involved in the genesis of this type of infection.

Case report

Female patient, 50 years-old, with a history of erosive RA and rheumatoid factor-positivity for 16 years. The patient made use of several disease-modifying antirheumatic drugs (DMARDs), including hydroxychloroquine, sulfasalazine, methotrexate (MTX), leflunomide, and combination therapy with MTX and 25 mg/week SC, and leflunomide 20 mg/day. After treatment failure and gastrointestinal intolerance to MTX, the patient began treatment with infliximab.

Based on that, we opted to introduce infliximab associated with leflunomide. On that occasion, the chest X-ray was normal, and PPD = 10 mm; isoniazid 300 mg/day was introduced as prevention against reactivation of latent tuberculosis.

fifteen days after the second dose of infliximab, the patient developed fever, dry cough, ventilatory-dependent chest pain, and dyspnea. She was admitted at the hospital presenting hypoxemia and alveolar consolidations in the left hemithorax (fig. 1A). The bronchoalveolar lavage fluid was negative for acid-fast bacilli and fungi, as well as for HIV. A diagnosis of legionellosis was confirmed by a positive search for L. pneumophila antigen in urine.

Figure 1
A. Chest radiograph showing extensive consolidation into the left hemithorax. B. Chest radiograph aftertreatment with a macrolide and a quinolone (azithromycin and levofloxacin).

The patient experienced improvement after four weeks of combined use of a macrolide and a quinolone (fig. 1B), remaining persistent activity (DAS28 > 5.1) despite the combination of methotrexate and leflunomide used as therapeutic option. One year after the resolution of the infection, the patient restarted infliximab, and since then, has maintained clinical remission (DAS-28 < 2.6) without further infectious complications.

Discussion

Anti-TNF drugs act, in general, by blocking TNF-α. The use of these drugs has provided excellent results. Its effects range from symptomatic improvement in patients resistant to treatment with DMARDs to the interruption of progression of joint damage in RA.³

TNF is a cytokine with an important role in the defence against intracellular microorganisms. It is produced by monocytes and macrophages, stimulates nitric oxide production and induces differentiation of macrophages in epithelioid macrophages, which are necessary for the formation of granulomas. Macrophages and monocytes are also useful in the recognition and destruction of any macrophages, and monocytes are also useful in the recognition and destruction of any intracellular pathogen able or unable of forming granulomas. In addition, TNF is essential for maintaining the integrity ofthe granuloma.⁴ Granuloma formation is essential to counterinfections and, thus, to prevent their spread. This becomes particularly important in infections with Mycobacterium tuberculosis.

L. pneumophila is a facultative intracellular bacterium that preferably invades and infects macrophages and monocytes. Studies in animal models have shown that the infection of macrophages by L. pneumophila induces the production of proinflammatory cytokines, such as TNF and IL-1, and that the addition of recombinant TNF to macrophages infected with L. pneumophila results in a significant resistance of these cells to bacterial growth.⁵ The mechanism by which TNF reduces the bacterial replication has not been fully clarified; some suggest that the cytokine acts synergistically with interferon-gamma synthesized by T lymphocytes in the inhibition of bacterial growth, aided by increased concentrations of nitric oxide and by the depletion of intracellular iron induced by TNF activity.⁶

In addition to these aforementioned mechanisms, TNF also appears to act mediating the induction of glutathione, a powerful antioxidant. In this way, TNF would minimize the effects of L. pneumophila- and hyperoxia-induced lung injury.⁷

After the introduction of anti-TNF in clinical practice, the appearance of opportunistic infections and infections by intracellular bacteria was observed. In vitro studies have concluded that cultured macrophages treated with TNF showed resistance to infection by L. pneumophila, but also noted that this resistance decreased after administration of anti-TNF in these cultures. In addition, animal models infected with L. pneumophila treated with anti-TNF exhibited persistent pneumonia, with greater numbers of infected macrophages and bacteria versus controls untreated with anti-TNF.⁸

Epidemiological studies suggesting an increased risk of opportunistic infections in general in patients treated with anti-TNF were published.^9,10 Case reports and case series in the literature called the attention of physicians to the development of L. pneumophila infection in patients treated with anti-TNF. Tubach et al. estimated that the relative risk of infection by L. pneumophila in patients treated with anti-TNF is about 16.5 times greater than in the general population in France.¹¹

Most reports of L. pneumophila infection are associated with infliximab. The same pattern is confirmed when we refer to M. tuberculosis infection. Data from the Food and Drug Administration (FDA) show that the incidence of this infection may be 8 to 9 times greater in patients treated with infliximab versus etanercept.

The anti-TNF drugs mentioned have different mechanisms of action, which may partly explain the difference in the incidence of infections. Infliximab, by being a monoclonal antibody, forms more stable and irreversible bonds with the TNF bound to cell membrane. Etanercept, which behaves like a soluble TNF receptor, forms complexes less cytokine-avid.¹²

Therefore, physicians should be alert to the diagnosis of this disease in patients treated with anti-TNF. Despite the well established effectiveness and safety of these drugs, potentially serious side effects should be monitored.

REFERÊNCIAS

• ¹
  Ruiz AA, Pijoan JI, Ansuategui E, Urkaregi A, Calabozo M, Quintana A. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and meta analysis of efficacyand safety. BMC Musculoskelet Disord. 2008;9:52.
• ²
  Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-alpha antagonists. Medicine (Baltimore). 2005;84:291-302.
• ³
  Kolarz B, Targon'ska-Stepniak B, Darmochwal- Kolarz D, Majdan M. Autoimmune aspects of treatment with TNF-alpha inhibitors. PostepyHig Med Dosw. 2007;61:478-84.
• ⁴
  Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55.
• ⁵
  McHugh SL, Newton CA, Yamamoto Y, Klein TW, Friedman H. Tumor necrosis factor induces resistance of macrophagesto Legionella pneumophila infection. Proc Soc Exp Biol Med. 2000;224:191-6.
• ⁶
  Gobbi FL, Benucci M, Angela Del Rosso MD. Pneumonitis Caused by Legionella pneumoniae in a Patient With Rheumatoid Arthritis Treated With Anti-TNF-Therapy (Infliximab). J Clin Rheumatol. 2005;11:119-20.
• ⁷
  Nara C, Tateda K, Matsumoto T, Ohara A, Miyazaki S, Standiford TJ. Legionella-induced acute lung injury in the setting of hyperoxia: protective role of tumour necrosis factor-alpha. J Med Microbiol. 2004;53:727-33.
• ⁸
  Wondergem M, Voskuyl AE, Agtmael MA. A case oflegionellosis during treatment with TNFa antagonist. Scand J Infect Dis. 2004;36:310-20.
• ⁹
  Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA. 2006;295:2275-85.
• ¹⁰
  Freitas DS, Machado N, Andrigueti FV, Reis Neto ET, Pinheiro MM. Hanseníase virchowiana associada ao uso de inibidor dofator de necrose tumoral a: relato de caso. Rev Bras Reumatol. 2010;50:333-9.
• ¹¹
  Tubach F, Ravaud P, Salmon-Céron D, Petitpain N, Brocq O, Grados F. Emergence of Legionella pneumophila pneumoniain patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis. 2006;43:95-100.
• ¹²
  Dinarello CA. Differences between anti-tumor necrosis factor-a monoclonal antibodies and soluble TNF receptorsin host defense impairment. Rheumatology. 2005;32:40-7.

Publication Dates

• Publication in this collection
  Sep-Oct 2014

History

• Received
  18 June 2012
• Accepted
  15 Apr 2013