Pulmonary Mycobacterium szulgai Infection and Treatment in a Patient Receiving Anti-Tumor Necrosis Factor Therapy

Jakko van Ingen; Martin Boeree; Matthijs Janssen; Erik Ullmann; Wiel de Lange; Petra de Haas; Richard Dekhuijzen and Dick van Soolingen

Disclosures

Nat Clin Pract Rheumatol. 2007;3(7):414-419. 

In This Article

Summary and Case

Summary

Background: A 54-year-old man with a 22-year history of rheumatoid arthritis and an 8-year history of chronic obstructive pulmonary disease presented with dyspnea on exertion, nonproductive cough and fatigue of 1 month's duration. His medication at presentation consisted of etanercept, azathioprine, naproxen and inhaled fluticasone and salbutamol.
Investigations: At presentation, the patient underwent physical examination, chest X-ray and high-resolution CT, blood tests, and bronchoalveolar lavage fluid analysis including auramine stains and gene sequence analysis of cultured Mycobacterium szulgai. The patient underwent minithoracotomy after 6 months, and bronchoalveolar lavage fluid analysis, culture and chest X-ray after 18 months. Further chest imaging and culture of sputum samples were performed another year later.
Diagnosis: Pulmonary M. szulgai infection.
Management: Triple drug therapy with rifampicin, ethambutol hydrochloride and clarithromycin. Anti-tumor necrosis factor treatment was continued.

The Case

A 54-year-old man presented to the respiratory department of a regional hospital with dyspnea on exertion, nonproductive cough and fatigue, which he had experienced for 1 month. The patient had a 22-year history of rheumatoid-factor positive, severe, nodular, erosive rheumatoid arthritis (RA; Steinbrocker class III) and an 8-year history of chronic obstructive pulmonary disease (COPD; Global Initiative for Chronic Obstructive Lung Disease stage I). The patient's RA had been treated with subcutaneous etanercept 25 mg twice weekly for 24 months, azathioprine 50 mg twice daily for 8 months and naproxen 500 mg twice daily for over 10 years. Previous treatment with subcutaneous methotrexate 30 mg once weekly had not been successful. The patient's COPD had been treated for 3 years with inhaled fluticasone propionate 500 µg twice daily and salbutamol 100 µg 1-6 times daily, as needed.

Physical examination of the chest revealed decreased breath sounds but no wheezes, crackles or prolonged expiration. A chest X-ray (Figure 1A) and high-resolution CT at presentation showed generalized emphysema, an infiltrate in the lingula, apical bullae, cavities with fibrosis in the right upper lobe, and diffuse peribronchial alveolar consolidations. Chest X-rays, which had been performed before initiation of etanercept treatment, had not shown these abnormalities. Bronchoalveolar lavage fluid analysis at presentation revealed acute, nonspecific inflammation with an elevated cell count, lymphocytosis and an elevated CD4/CD8 T-lymphocyte ratio. Blood tests showed that the CD4/CD8 T-lymphocyte ratio was normal in the serum. Three auramine stains of the bronchoalveolar lavage fluid were negative; one of three corresponding cultures yielded Mycobacterium szulgai, a nontuberculous mycobacterium. No other micro-organisms were cultured. At this time, the M. szulgai was considered to be a contaminant in the culture, and a firm diagnosis of nontuberculous mycobacterial infection could not be made according to the American Thoracic Society 1997 criteria (see "Sidebar: Summary of the American Thoracic Society Diagnostic Criteria for Nontuberculous Mycobacterial Infection").[1] A minithoracotomy was performed 6 months later for histological diagnosis, which revealed panacinar emphysema, bronchiolitis and low-intensity granulomatous pneumonitis with epithelioid cell granuloma. The differential diagnosis now included sarcoidosis, tuberculosis, fungal infection, M. szulgai infection, and occupational pulmonary disease such as asbestosis, berylliosis and silicosis. At this stage, the patient's stable pulmonary and rheumatologic condition did not warrant a therapy change.

Figure 1.

The patient's chest X-rays. (A) At initial presentation. The image shows patchy consolidations in both lungs. (B) 2 years after initial presentation and 1 year prior to antimycobacterial therapy. The image shows progression of the patchy consolidations to fibrotic, cavitary lesions in the upper lobes. (C) 3 years after initial presentation and at the start of antimycobacterial treatment. The image shows progression of the fibrotic and cavitary lesions in both upper lobes. (D) After antimycobacterial treatment. The image shows that the fibrotic, cavitary lesions in the upper lobes are slightly decreased in size.

At a routine follow-up visit 18 months later, bronchoalveolar lavage fluid analysis again yielded one positive culture for M. szulgai. Radiological progression of disease was noted, with progression of cavitary and fibrotic lesions, traction-bronchiectasis and resolution of patchy consolidations (Figures 1B and 2A). A tentative diagnosis of stage IV sarcoidosis was made on the basis of results from chest X-rays and histology, and because the diagnostic criteria for nontuberculous mycobacterium according to the American Thoracic Society had not been met (see "Sidebar: Summary of the American Thoracic Society Diagnostic Criteria for Nontuberculous Mycobacterial Infection").[1] Etanercept treatment was terminated, and treatment with adalimumab 40 mg every 2 weeks was started with the intention of treating both RA and the potential sarcoidosis.

Figure 2.

The patient's CT images. (A) 2 years after initial presentation and 1 year prior to antimycobacterial therapy. The image shows fibrotic and cavitary lesions. (B) 3 years after initial presentation and at the start of antimycobacterial therapy. The image shows that the fibrotic and cavitary lesions have worsened since the previous year. The smaller image in the bottom right-hand corner shows the anatomical position of the section displayed. (C) 4 years after initial presentation and 1 year after antimycobacterial treatment. The image shows that the fibrotic and cavitary lesions have partially regressed. The smaller image in the bottom right-hand corner shows the anatomical position of the section displayed.

Another year later, the patient returned with a mild cough, malaise and night sweats. Chest imaging (Figures 1C and 2B) revealed thickening of cavity walls, reappearance of consolidations, a nodular pattern in the right middle lobe, and ground glass appearance. Three sputum samples were positive for acid-fast bacilli on microscopy, and corresponding cultures yielded M. szulgai. At this time, the patient met the American Thoracic Society diagnostic criteria for nontuberculous mycobacterium infection (see "Sidebar: Summary of the American Thoracic Society Diagnostic Criteria for Nontuberculous Mycobacterial Infection").[1] Treatment was started with rifampicin 600 mg once daily, ethambutol hydrochloride 1400 mg (20 mg/kg) once daily and clarithromycin 500 mg twice daily for a duration of 18 months. Adalimumab therapy was continued during the antimycobacterial treatment. The patient's cough and dyspnea diminished within the first month after initiation of antimycobacterial treatment, constitutional symptoms resolved after 4 months, and radiological abnormalities had improved after 1 year of therapy (Figures 1D and 2C).

The patient's erythrocyte sedimentation rate and serum C-reactive protein concentration were repeatedly measured during the course of the patient's disease and after antimycobacterial treatment was initiated (Figure 3). Genotyping of all the patient's M. szulgai isolates with random amplified polymorphic DNA analysis as previously described,[2] using OPA18 and IS986 FP as primers, was performed at the Dutch national tuberculosis reference laboratory after the patient's symptoms resolved. The results of the genotyping showed that all the M. szulgai isolates were of a similar, distinct genotype (Figure 4).

Figure 3.

Microbiological and serological parameters during the course of the patient's disease. This figure shows the culture results and the ESR and CRP levels, which rise after the first Mycobacterium szulgai culture, with CRP levels rising more pronouncedly after adalimumab treatment is started. Both ESR and CRP levels regress to their normal range during combined antimycobacterial and anti-TNF treatment. This figure indicates that the patient had chronic infection, which deteriorated during adalimumab therapy, but which was successfully treated without cessation of adalimumab therapy. Abbreviations: AFB, acid-fast bacilli (visible on direct microscopy); CRP, C-reactive protein; Cult, culture results for M. szulgai; ESR, erythrocyte sedimentation rate.

Figure 4.

A photograph of genotyping results of the patient's Mycobacterium szulgai isolates. The genotyping was performed using random amplified polymorphic DNA analysis with OPA18 and IS986 FP as primers. Lanes A-D show the genotyping for pulmonary samples from four patients in the same geographical region as the case patient. Lanes E-G show the genotyping for the case patient's pulmonary samples: 3 years after initial presentation and at the start of antimycobacterial therapy (E); 2 years after initial presentation and 1 year prior to the start of antimycobacterial therapy (F); and at initial presentation (G, extra band in IS986 FP). This figure shows that in the case patient, the same strain of M. szulgai was isolated on all three occasions. Pulmonary M. szulgai isolates from the four other patients within the same geographical region and the same period were unrelated to those obtained from the case patient.

Mycobacterial smears and cultures were negative after 1 year of antimycobacterial treatment and remained negative on subsequent tests. This patient is still treated with adalimumab and his RA remains stable.

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