- Email: [email protected]
Bilateral pneumonia by Mycobacterium aurum in a patient receiving infliximab therapy
Letters to the Editor
167
duration of fever, i.e., three weeks or more, since it is believed that many infectious causes of fever e mostly viral diseases e are self-limited and will be subsided within three weeks. However, neither in the original definition nor in the currently-used definition of FUO, none of the word ‘‘worksup’’ or its intensity has been defined clearly. In this way, a patient who is labeled as a case of FUO in one hospital with limited access to new diagnostic tests, might have soon been found to have tuberculosis in another well-equipped hospital. This poor case definition causes numerous difficulties in running several clinical studies such as case-control studies, cohort studies and clinical trials in conduction of which a clear case definition is of paramount importance. This also causes trouble with synthesis of ‘‘evidence’’ which mainly relies on systematic reviews in heart of which is meta-analysis of data. When we do not have a clear case definition for FUO, we cannot correctly compare the results reported by different research groups. If we want to sustain our current definition of FUO without considering a well-defined battery of tests to be done prior to labeling a patient as having FUO, no matter how long these tests will take to be completed, the causes of FUO and the related discussions reported from each center have only applicability for those health care centers where use similar diagnostic tests and approaches to a feverish patient. If we do specify a list of tests to be done before labeling a patient as a case of FUO, some wellequipped centers may complete the necessary works-up within a short period of time, say one day, while some other centers for limited access or lack of access to new diagnostic techniques may need more time to do or even cannot do some of the tests. Reasonably, only those centers with access to the specified required diagnostic techniques are authorized to label a patient as having FUO. In the era of modern medicine, we are in desperate need of well-defined definitions for all medical conditions so that we can be sure when we are talking about a single entity, we really are.
References 1. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961;40:1e30. 2. Cunha BA. Fever of unknown origin: clinical overview of classic and current concepts. Infect Dis Clin North Am 2007;21(4): 867e915, vii.
Farrokh Habibzadeh* Mahboobeh Yadollahie* Shiraz NIOC Medical Education and Research Center, Shiraz, Iran *Corresponding authors. Tel.: +98 711 225 2258. E-mail address: [email protected] (F. Habibzadeh) Accepted 22 May 2008 Available online 30 June 2008 0163-4453/$34 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.05.009
Bilateral pneumonia by Mycobacterium aurum in a patient receiving infliximab therapy In a recent article of the Journal of Infection, Salvana et al.1 highlighted the risk of Mycobacterium other than tuberculosis (MOTT) infection during infliximab treatment. Reinforcing the importance of this problem, we report the case of Mycobacterium aurum pulmonary infection in a patient during infliximab therapy; this is the first evidence of solid organ infection with this organism. As a human pathogen, M. aurum has been isolated from blood cultures (but not in a solid organ) in two immunocompromised patients treated for malignancies.2,3 A 25-year-old man was diagnosed with idiopathic bilateral uveitis, without any additional evidence of other underlying rheumatic disease. On diagnosis, chest X-ray was normal and the tuberculin test was negative (induration 0 mm). A response to systemic corticosteroids (prednisone 60 mg/day) was obtained, but relapse of uveitis followed the tapering doses of steroids, even after adding cyclosporine or methotrexate to steroids. We were able to reduce the doses of prednisone progressively after adding infliximab to therapy, giving satisfactory control of the uveitis. Infliximab had been administered at three weeks and one week before his admission to the hospital. On the day of admission, the patient presented with fever (39 C) and weakness, but with no other symptoms. At this point in time, the steroid dose was 30 mg/day of deflazacort. On physical examination, cushingoid appearance and crackles on both lung fields were noted; no peripheral adenopathy was palpable. Blood test showed the following results: haemoglobin, 11.9 gr/dl; leukocyte count, 15,450/ ml (neutrophils, 94%); platelets, 262,000/ml; erythrocyte sedimentation rate 70 mm; biochemistry values were normal except for C-reactive protein (14.99 mg/dl vs. normal values of <0.5 mg/dl). Both chest radiographs and thorax CT scan showed bilateral peripheral nodular infiltrates, mainly in the middle and upper lung fields, without cavitation or enlarged lymph nodes (Fig. 1). A further tuberculin skin reaction test continued to be negative. Blood and sputum cultures were negative. A fiberoptic bronchoscopy with bronchoalveolar lavage was performed; aerobic, anaerobic, fungal and mycobacterial cultures were negative, as were direct immunofluorescence for Pneumocystis jirovecii and all appropriate serological tests. Empirical therapy with meropenem, levofloxacin and voriconazole was applied for 21 days; fever subsided after 2 days of therapy with slight improvement seen in the chest radiograph. Two weeks after finishing the therapy, the patient’s condition worsened: fever reappeared and lung infiltrates increased, with enlarged lymph nodes and cavitation in some nodules on thorax CT scan. A new bronchoscopy was performed but all samples (cultured in the same media as previously indicated) were negative. Histological analysis of transbronchial lung biopsy demonstrated the presence of noncaseating granulomas, negative for acidfast bacilli staining. A CT-guided fine-needle aspiration biopsy was performed. After 3 days of incubation of the lung biopsy at 35 C in BACTEC MGIT 960 system (Becton Dickinson, San Jose, CA, USA), acid-fast bacilli grown in modified liquid medium Middlebrook 7H9. Pigmented
168
Letters to the Editor
Figure 1
Thorax X-ray (left) and computed tomography (right) showing peripheral infiltrates.
scotochromogen colonies were observed on Lowensteine Jensen medium after 5 days of culture. M. aurum was identified according to biochemical tests: absence of growth at 45 C, negative nitrate reduction, positive Tween and urea hydrolysis test, positive arylsulfatase test in 14 days, and using acetate (but not galactose) as carbon source. An antimicrobial susceptibility test (disk diffusion method) showed inhibition areas 30 mm for clarithromycin, ciprofloxacin, levofloxacin, imipenem, amikacin, tetracycline, co-trimoxazole and rifampicin. Therapy with levofloxacin (500 mg/ day), rifampicin (600 mg/day) and clarithromycin (500 mg/ 12 h) was administered. Three months later, the patient was afebrile and lung infiltrates had been resolved. Because infliximab had been stopped and lower doses of steroids were administered, symptoms of uveitis worsened. A further increase of steroids was required. Antimicrobial treatment was maintained for one year, without evidence of clinical or radiological relapse of pulmonary disease. Clinical use of antibodies anti-TNF-a agents has been implicated in the reactivation of recent or remotely acquired tuberculosis infection4 as well as in an increase of MOTT infection.1,5 M. aurum was first described as a new species in 1966,6 and to date, only two cases of infection by M. aurum have been reported: both presented with central venous catheter-related bacteremia in patients with immunosuppression induced by chemotherapy to control a T-cell non-Hodgkin’s lymphoma2 and a metastatic Wilms’ tumor,3 respectively. Although our patient had never had a central venous catheter in place, and blood cultures were negative, his lungs might have been infected following haematogenous dissemination, as in the previous described cases. That would explain why cultures from bronchoalveolar lavage were negative, together with the fact that lung infiltrates were mostly peripheral. Diagnostic criteria have been developed for diagnosis of MOTT lung disease, which fit best with Mycobacterium avium complex, Mycobacterium kansasii and Mycobacerium abscessus infections (although there is not enough knowledge about most other MOTT).7 This patient met accepted criteria for diagnosis: he had clinical symptoms (fever, dyspnea), radiographic findings (nodular or cavitary opacities) and microbiology criteria (granulomatous inflammation and positive culture for MOTT). Other infectious agents were properly excluded during the microbiology study. Overall, the clinical and radiological response to antimicrobial therapy supports the
diagnosis of infection, otherwise lung infiltrates would have been worsened when immunosuppressive treatment was reduced, if they were related to underlying disease. Identification of rapidly growing pigmented mycobacteria traditionally relies on isolation of the Mycobacterium and subsequent identification by phenotypic conventional biochemical tests or whole-cell fatty acid analysis. Molecular-based methods would be the ‘‘gold-standard’’ in ambiguous cases, but no commercially available polymerase or ligase chain reaction is available for the identification of rapidly growing pigmented mycobacteria.8 In our case, the biochemical test identified the microorganism definitively. Disease-modifying agents (such as infliximab) appear to increase the frequency and severity of certain infections.9 We report the first case of M. aurum affecting a solid organ after treatment with infliximab. This is an additional organism of which clinicians should be aware. Lack of experience in the treatment of infections by atypical mycobacteria in patients with maintained steroid therapy prompted us to use antimycobacterial drugs for a prolonged period.
References 1. Salvana EM, Cooper GS, Salata RA. Mycobacterium other than tuberculosis (MOTT) infection: an emerging disease in infliximab-treated patients. J Infect 2007;55:484e7. 2. Esteban J, Ferna ´ndez-Roblas R, Roma ´n A, Molleja A, Jime ´nez MS, Soriano F. Catheter-related bacteremia due to Mycobacterium aurum in an immunocompromised host. Clin Infect Dis 1998;26:496e7. 3. Koranyi KI, Ranalli MA. Mycobacterium aurum bacteremia in an immunocompromised child. Pediatr Infect Dis J 2003;22:1108e9. 4. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003;3:148e55. 5. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261e5. 6. Tsukamura M, Tuskamura S. Mycobacterium aurum, a new species. Igaku To Seibutsugaku 1966;72:270e3. 7. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367e416.
Letters to the Editor
169
8. Woo PC, Tsoi HW, Leung KW, Lum PN, Leung AS, Ma CH, et al. Identification of Mycobacterium neoaurum isolated from a neutropenic patient with catheter-related bacteremia by 16S rRNA sequencing. J Clin Microbiol 2000;38:3515e7. 9. Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-a antagonists. Medicine 2005;84:291e302.
Enrique Gonza ´lez-Moya Department of Pulmonary Diseases, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
Andre ´s Martı´n-Aspas* Francisca Guerrero-Sa ´nchez Department of Internal Medicine, ‘‘Puerta del Mar’’ University Hospital, Av. Ana de Viya 21, 11009 Ca´diz, Spain *Corresponding author. Tel.: þ34 956 002388; fax: þ34 956 004618. E-mail address: [email protected] (A. Martı´n-Aspas)
Jose ´ Antonio Giro ´n Gonza ´lez Department of Internal Medicine, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
Pedro Garcı´a-Martos Department of Microbiology, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
0163-4453/$34 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.04.010
Fermı´n Medina-Varo Department of Rheumatology, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
Accepted 28 April 2008 Available online 13 June 2008
167
duration of fever, i.e., three weeks or more, since it is believed that many infectious causes of fever e mostly viral diseases e are self-limited and will be subsided within three weeks. However, neither in the original definition nor in the currently-used definition of FUO, none of the word ‘‘worksup’’ or its intensity has been defined clearly. In this way, a patient who is labeled as a case of FUO in one hospital with limited access to new diagnostic tests, might have soon been found to have tuberculosis in another well-equipped hospital. This poor case definition causes numerous difficulties in running several clinical studies such as case-control studies, cohort studies and clinical trials in conduction of which a clear case definition is of paramount importance. This also causes trouble with synthesis of ‘‘evidence’’ which mainly relies on systematic reviews in heart of which is meta-analysis of data. When we do not have a clear case definition for FUO, we cannot correctly compare the results reported by different research groups. If we want to sustain our current definition of FUO without considering a well-defined battery of tests to be done prior to labeling a patient as having FUO, no matter how long these tests will take to be completed, the causes of FUO and the related discussions reported from each center have only applicability for those health care centers where use similar diagnostic tests and approaches to a feverish patient. If we do specify a list of tests to be done before labeling a patient as a case of FUO, some wellequipped centers may complete the necessary works-up within a short period of time, say one day, while some other centers for limited access or lack of access to new diagnostic techniques may need more time to do or even cannot do some of the tests. Reasonably, only those centers with access to the specified required diagnostic techniques are authorized to label a patient as having FUO. In the era of modern medicine, we are in desperate need of well-defined definitions for all medical conditions so that we can be sure when we are talking about a single entity, we really are.
References 1. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961;40:1e30. 2. Cunha BA. Fever of unknown origin: clinical overview of classic and current concepts. Infect Dis Clin North Am 2007;21(4): 867e915, vii.
Farrokh Habibzadeh* Mahboobeh Yadollahie* Shiraz NIOC Medical Education and Research Center, Shiraz, Iran *Corresponding authors. Tel.: +98 711 225 2258. E-mail address: [email protected] (F. Habibzadeh) Accepted 22 May 2008 Available online 30 June 2008 0163-4453/$34 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.05.009
Bilateral pneumonia by Mycobacterium aurum in a patient receiving infliximab therapy In a recent article of the Journal of Infection, Salvana et al.1 highlighted the risk of Mycobacterium other than tuberculosis (MOTT) infection during infliximab treatment. Reinforcing the importance of this problem, we report the case of Mycobacterium aurum pulmonary infection in a patient during infliximab therapy; this is the first evidence of solid organ infection with this organism. As a human pathogen, M. aurum has been isolated from blood cultures (but not in a solid organ) in two immunocompromised patients treated for malignancies.2,3 A 25-year-old man was diagnosed with idiopathic bilateral uveitis, without any additional evidence of other underlying rheumatic disease. On diagnosis, chest X-ray was normal and the tuberculin test was negative (induration 0 mm). A response to systemic corticosteroids (prednisone 60 mg/day) was obtained, but relapse of uveitis followed the tapering doses of steroids, even after adding cyclosporine or methotrexate to steroids. We were able to reduce the doses of prednisone progressively after adding infliximab to therapy, giving satisfactory control of the uveitis. Infliximab had been administered at three weeks and one week before his admission to the hospital. On the day of admission, the patient presented with fever (39 C) and weakness, but with no other symptoms. At this point in time, the steroid dose was 30 mg/day of deflazacort. On physical examination, cushingoid appearance and crackles on both lung fields were noted; no peripheral adenopathy was palpable. Blood test showed the following results: haemoglobin, 11.9 gr/dl; leukocyte count, 15,450/ ml (neutrophils, 94%); platelets, 262,000/ml; erythrocyte sedimentation rate 70 mm; biochemistry values were normal except for C-reactive protein (14.99 mg/dl vs. normal values of <0.5 mg/dl). Both chest radiographs and thorax CT scan showed bilateral peripheral nodular infiltrates, mainly in the middle and upper lung fields, without cavitation or enlarged lymph nodes (Fig. 1). A further tuberculin skin reaction test continued to be negative. Blood and sputum cultures were negative. A fiberoptic bronchoscopy with bronchoalveolar lavage was performed; aerobic, anaerobic, fungal and mycobacterial cultures were negative, as were direct immunofluorescence for Pneumocystis jirovecii and all appropriate serological tests. Empirical therapy with meropenem, levofloxacin and voriconazole was applied for 21 days; fever subsided after 2 days of therapy with slight improvement seen in the chest radiograph. Two weeks after finishing the therapy, the patient’s condition worsened: fever reappeared and lung infiltrates increased, with enlarged lymph nodes and cavitation in some nodules on thorax CT scan. A new bronchoscopy was performed but all samples (cultured in the same media as previously indicated) were negative. Histological analysis of transbronchial lung biopsy demonstrated the presence of noncaseating granulomas, negative for acidfast bacilli staining. A CT-guided fine-needle aspiration biopsy was performed. After 3 days of incubation of the lung biopsy at 35 C in BACTEC MGIT 960 system (Becton Dickinson, San Jose, CA, USA), acid-fast bacilli grown in modified liquid medium Middlebrook 7H9. Pigmented
168
Letters to the Editor
Figure 1
Thorax X-ray (left) and computed tomography (right) showing peripheral infiltrates.
scotochromogen colonies were observed on Lowensteine Jensen medium after 5 days of culture. M. aurum was identified according to biochemical tests: absence of growth at 45 C, negative nitrate reduction, positive Tween and urea hydrolysis test, positive arylsulfatase test in 14 days, and using acetate (but not galactose) as carbon source. An antimicrobial susceptibility test (disk diffusion method) showed inhibition areas 30 mm for clarithromycin, ciprofloxacin, levofloxacin, imipenem, amikacin, tetracycline, co-trimoxazole and rifampicin. Therapy with levofloxacin (500 mg/ day), rifampicin (600 mg/day) and clarithromycin (500 mg/ 12 h) was administered. Three months later, the patient was afebrile and lung infiltrates had been resolved. Because infliximab had been stopped and lower doses of steroids were administered, symptoms of uveitis worsened. A further increase of steroids was required. Antimicrobial treatment was maintained for one year, without evidence of clinical or radiological relapse of pulmonary disease. Clinical use of antibodies anti-TNF-a agents has been implicated in the reactivation of recent or remotely acquired tuberculosis infection4 as well as in an increase of MOTT infection.1,5 M. aurum was first described as a new species in 1966,6 and to date, only two cases of infection by M. aurum have been reported: both presented with central venous catheter-related bacteremia in patients with immunosuppression induced by chemotherapy to control a T-cell non-Hodgkin’s lymphoma2 and a metastatic Wilms’ tumor,3 respectively. Although our patient had never had a central venous catheter in place, and blood cultures were negative, his lungs might have been infected following haematogenous dissemination, as in the previous described cases. That would explain why cultures from bronchoalveolar lavage were negative, together with the fact that lung infiltrates were mostly peripheral. Diagnostic criteria have been developed for diagnosis of MOTT lung disease, which fit best with Mycobacterium avium complex, Mycobacterium kansasii and Mycobacerium abscessus infections (although there is not enough knowledge about most other MOTT).7 This patient met accepted criteria for diagnosis: he had clinical symptoms (fever, dyspnea), radiographic findings (nodular or cavitary opacities) and microbiology criteria (granulomatous inflammation and positive culture for MOTT). Other infectious agents were properly excluded during the microbiology study. Overall, the clinical and radiological response to antimicrobial therapy supports the
diagnosis of infection, otherwise lung infiltrates would have been worsened when immunosuppressive treatment was reduced, if they were related to underlying disease. Identification of rapidly growing pigmented mycobacteria traditionally relies on isolation of the Mycobacterium and subsequent identification by phenotypic conventional biochemical tests or whole-cell fatty acid analysis. Molecular-based methods would be the ‘‘gold-standard’’ in ambiguous cases, but no commercially available polymerase or ligase chain reaction is available for the identification of rapidly growing pigmented mycobacteria.8 In our case, the biochemical test identified the microorganism definitively. Disease-modifying agents (such as infliximab) appear to increase the frequency and severity of certain infections.9 We report the first case of M. aurum affecting a solid organ after treatment with infliximab. This is an additional organism of which clinicians should be aware. Lack of experience in the treatment of infections by atypical mycobacteria in patients with maintained steroid therapy prompted us to use antimycobacterial drugs for a prolonged period.
References 1. Salvana EM, Cooper GS, Salata RA. Mycobacterium other than tuberculosis (MOTT) infection: an emerging disease in infliximab-treated patients. J Infect 2007;55:484e7. 2. Esteban J, Ferna ´ndez-Roblas R, Roma ´n A, Molleja A, Jime ´nez MS, Soriano F. Catheter-related bacteremia due to Mycobacterium aurum in an immunocompromised host. Clin Infect Dis 1998;26:496e7. 3. Koranyi KI, Ranalli MA. Mycobacterium aurum bacteremia in an immunocompromised child. Pediatr Infect Dis J 2003;22:1108e9. 4. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003;3:148e55. 5. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261e5. 6. Tsukamura M, Tuskamura S. Mycobacterium aurum, a new species. Igaku To Seibutsugaku 1966;72:270e3. 7. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367e416.
Letters to the Editor
169
8. Woo PC, Tsoi HW, Leung KW, Lum PN, Leung AS, Ma CH, et al. Identification of Mycobacterium neoaurum isolated from a neutropenic patient with catheter-related bacteremia by 16S rRNA sequencing. J Clin Microbiol 2000;38:3515e7. 9. Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-a antagonists. Medicine 2005;84:291e302.
Enrique Gonza ´lez-Moya Department of Pulmonary Diseases, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
Andre ´s Martı´n-Aspas* Francisca Guerrero-Sa ´nchez Department of Internal Medicine, ‘‘Puerta del Mar’’ University Hospital, Av. Ana de Viya 21, 11009 Ca´diz, Spain *Corresponding author. Tel.: þ34 956 002388; fax: þ34 956 004618. E-mail address: [email protected] (A. Martı´n-Aspas)
Jose ´ Antonio Giro ´n Gonza ´lez Department of Internal Medicine, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
Pedro Garcı´a-Martos Department of Microbiology, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
0163-4453/$34 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.04.010
Fermı´n Medina-Varo Department of Rheumatology, ‘‘Puerta del Mar’’ University Hospital, Ca´diz, Spain
Accepted 28 April 2008 Available online 13 June 2008