Department of Internal Medicine and INSERM Unit 644, 1 Department of Pneumology, Centre Hospitalier Universitaire de Rouen-Boisguillaume and 2 Department of Cytology, Centre Hospitalier Universitaire de Rouen, Rouen, France
Correspondence to: I. Marie, Department of Internal Medicine, Centre Hospitalier Universitaire de Rouen-Boisguillaume, 76031 Rouen Cedex, France. E-mail: isabelle.marie{at}chu-rouen.fr
SIR, Polymyositis (PM) and dermatomyositis (DM) are systemic inflammatory disorders affecting skeletal muscles and other organs. PM and DM are considered to be associated with high morbidity and mortality rates, particularly related to infectious complications, which have been described in up to 26% of patients [1]. Recently, opportunistic infections have been reported in 1221% of PM/DM patients. Many factors have been implicated in this apparently increased frequency of infections in PM/DM, especially immunosuppressive drugs [1, 2]. We report a case of fatal Mycobacterium peregrinum pneumonia in a patient with refractory PM, which occurred shortly after institution of anti-tumour necrosis factor (anti-TNF-
) therapy.
A 68-yr-old man had PM that had evolved since December 2001. Therapy with prednisone was initiated at a dose of 1 mg/kg daily. As both clinical and biochemical status continued to deteriorate gradually, subsequent treatments were started: methotrexate, azathioprine, cyclophosphamide and cyclosporin (cumulative doses of 1080 mg, 31 500 mg, 3 g and 36 000 mg, respectively), which proved ineffective. Intravenous immunoglobulins (1 g/kg/day for 2 days monthly) for 24 months resulted in partial improvement of PM. In January 2004, the patient was admitted for generalized muscle weakness. Muscle power, gauged for eight proximal muscles by a modification of the UK Medical Research Council grading system, was 59/88 points [1]. Serum creatine kinase level was 15 000 IU/l. Pulmonary function tests showed decreased vital capacity (64% of predicted values); lung computed tomography (CT) scan was normal. Other investigations, including abdominal CT scan, gastroscopy, colonoscopy and bronchoscopy, to exclude underlying malignancy, were normal. As PM was refractory to immunosuppressive therapy, the patient was given anti-TNF-, as mentioned previously [3]: infliximab (5 mg/kg) at weeks 0, 2 and 6, in addition to prednisone (20 mg daily). Before initiation of infliximab, gastric aspiration product cultures for mycobacteria were performed, which proved negative.
One month after the third infliximab infusion, the patient presented with a 3-week history of fatigue, non-productive cough and progressive dyspnoea. On admission, he was febrile (38°7C) and his general condition was poor. Physical examination revealed Velcro crackles bilaterally. Laboratory findings were as follows: erythrocyte sedimentation rate 90 mm/h, C-reactive protein 142 mg/l, haemoglobin 10.2 g/dl, white blood cell count 9.5 x 109/l (lymphocytes 9%, CD4 cell count 0.09 x 109/l), and creatine phosphokinase 12 697 IU/l. Chest radiograph revealed diffuse bilateral lung infiltrates. Blood cultures, bacterial (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella) and viral (cytomegalovirus, influenza viruses) serologies were negative. Bronchoscopy was normal; analysis of bronchoalveolar lavage fluid (BAL) was negative for Gram and GomoriGrocott staining and bacterial and fungal cultures. The patient was treated with ceftriaxone (2 g daily) and ciprofloxacin (500 mg/12 h) for 2 days; however, pulmonary clinical manifestations continued to deteriorate. Further microbiological studies (ZiehlNeelsen stain) yielded acid-fast bacilli in sputum, gastric aspiration products and BAL. The patient received combined therapy with rifampin, isoniazid, ethambutol and pirazinamide; despite the use of mechanical ventilation, he died of respiratory failure within 9 days. Cultures of BAL and three samples of sputum and gastric aspiration products grew Mycobacterium peregrinum within 15 days.
Infections are potential complications of anti-TNF- therapy [49]. In patients with rheumatoid arthritis being treated with anti-TNF-
agents, Kroesen et al. [5] have found an elevated incidence of severe infections (0.181 per anti-TNF-
therapy vs 0.008 in the 2 yr preceding anti-TNF-
therapy). In a series of patients receiving anti-TNF-
therapy, Wallis et al. [7] found the incidence rate of opportunistic infections to be as high as 313/100 000 patients; tuberculosis was the most common infection, occurring in 179/100 000 patients. Opportunistic infections due to other pathogenic microorganisms have also been observed in association with anti-TNF-
therapy; e.g. Pneumocystis carinii, Histoplasma, Aspergillus, Candida, Nocardia, Cryptococcus and non-tuberculous mycobacteria [49].
We report, to the best of our knowledge, the first case of Mycobacterium peregrinum pneumonia in a patient with refractory PM. Mycobacterium peregrinum is a non-tuberculous mycobacterium, which may cause disseminated infections in patients with connective tissue disorders. In our patient, several factors favoured Mycobacterium peregrinum pneumonia onset: (i) ventilatory insufficiency due to striated muscle weakness; and (ii) immunodeficiency secondary to denutrition, steroids and (mainly) infliximab. Mycobacterium peregrinum pneumonia, indeed, occurred shortly after institution of infliximab; our findings confirm previous data demonstrating that 75% of opportunistic infections occurred within 90 days after anti-TNF- therapy initiation [49].
Moreover, in a series of 156 PM/DM patients, we have shown a high prevalence of opportunistic infections (12%) due to, for example, fungi (56% of cases) and mycobacteria (22% of cases; Mycobacterium avium-intracellulare, xenopi, marinum and tuberculosis) [10]. Factors predisposing to opportunistic infection onset were thoracic myopathy, oesophageal motor dysfunction and lymphopenia [10]. Interestingly, the present case report therefore highlights that it is questionable to initiate anti-TNF- therapy in refractory PM/DM patients presenting with predisposing factors, placing them at risk of opportunistic infections. Our data strongly encourage searching for factors predictive of opportunistic infections in PM/DM patients before anti-TNF-
therapy is begun; these patients should undergo investigations (CD4 blood cell count, lung and oesophageal tests) and be monitored closely for onset of opportunistic infection. To date, prophylaxis against Mycobacterium tuberculosis infection is recommended for patients with a past history of tuberculosis who are undergoing anti-TNF-
therapy [49]; as shown by the variety of pathogenic agents responsible for opportunistic infections in PM/DM [10], it seems difficult to initiate primary prophylaxis in patients exhibiting risk factors for opportunistic infections before initiation of anti-TNF-
agents.
The authors have declared no conflicts of interest.
References
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