J Infect Chemother 21 (2015) 468e472
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
Disseminated Mycobacterium gordonae and Mycobacterium mantenii infection with elevated anti-IFN-g neutralizing autoantibodies Isano Hase a, b, *, Kozo Morimoto c, Takuro Sakagami d, Yuko Kazumi e, Yoshiki Ishii b, Jakko van Ingen f a
Department of Respiratory Disease, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama-shi, Fukushima 963-8563, Japan Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose-shi, Tokyo 204-0022, Japan d Division of Respiratory Medicine and Infectious Disease, Department of Homeostatic Regulation and Development, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Niigata-shi, Niigata 951-8510, Japan e Molecular Epidemiology and Genetic Identification Division, Department of Mycobacteria References and Research, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose-shi, Tokyo 204-8533, Japan f Department of Medical Microbiology, Radboud University Medical Center, P.O. Box 9101, 6500HB Nijmegen, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 October 2014 Received in revised form 20 January 2015 Accepted 3 February 2015 Available online 12 February 2015
A case of disseminated nontuberculous mycobacteria(l) (NTM) infection in a patient with positive neutralizing anti-interferon-g (IFN-g) autoantibodies involving bone, bronchus, systemic lymph nodes, and skin is reported. The causative NTMs were two different strains: Mycobacterium gordonae, which rarely causes true disease, and Mycobacterium mantenii, which is extremely rare. Anti-mycobacterial treatment successfully ameliorated all disseminated lesions. Although the concentration of anti-IFN-g autoantibodies increased during the pre-treatment period, it gradually decreased after antimycobacterial treatment was started. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Disseminated nontuberculous mycobacterium infection Mycobacterium gordonae Mycobacterium mantenii Anti-IFN-g neutralizing autoantibodies
1. Introduction The first cases of disseminated nontuberculous mycobacterial (NTM) infection with elevated anti-interferon-g (IFN-g) neutralizing autoantibodies were reported in 2004, and similar cases have since been reported, mostly from East Asia. In most cases, the causative agents of disseminated NTM include Mycobacterium avium complex (MAC) and rapid-growing mycobacteria [1e3]. The concentration or neutralizing capacity of anti-IFN-g autoantibodies was reduced after the initiation of anti-mycobacterial agents and rituximab in a few cases [4,5]. A case of disseminated Mycobacterium gordonae and Mycobacterium mantenii in a patient with anti-IFN-g autoantibodies is described. After starting
* Corresponding author. Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 3210293, Japan. Tel.: þ81 282 87 2151; fax: þ81 282 86 5080. E-mail address: [email protected] (I. Hase).
anti-mycobacterial treatment, the autoantibody concentration decreased along with improvement of the disseminated lesions. 2. Case report A previously healthy 65-year-old man who worked in building operations presented with a 12-kg weight loss in 1 year, swollen left cervical lymph nodes, and persistent low-grade fever. He was a current smoker (60 pack-years). His temperature was 37.0 C. Multiple swollen lymph nodes, 1e2 cm in diameter, were palpable on the left side of the neck. Laboratory data showed an elevated white blood cell count (11,270/mL), erythrocyte sedimentation rate (72 mm/h), serum Creactive protein level (2.36 mg/dL), alkaline phosphatase level (381 U/L), and immunoglobulin-G level (2140 mg/dL). No anti-HIV antibody or anti-human T-cell leukemia virus antibodies were detected. The IFN-g-releasing assay was performed with the QuantiFERON®-TB Gold In-Tube test. Despite a positive purified protein derivative skin test, IFN-g release from peripheral blood
http://dx.doi.org/10.1016/j.jiac.2015.02.003 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
I. Hase et al. / J Infect Chemother 21 (2015) 468e472
mononuclear cells could not be detected in the assay, even if stimulated by mitogen. Chest computed tomography (CT) on admission showed subcarinal lymphadenopathy, a polypoid lesion in the lumen of the left main bronchus, thickening of mucosa of the left upper bronchus, and a 1-cm-diameter nodule in the right upper lobe (Fig. 1). Neither miliary lesions nor bronchiectasis was detected on chest CT. F-18 fluorodeoxyglucose (FDG)-positron emission tomography/ computed tomography (FDG-PET/CT) showed an obvious increase in FDG uptake in these lesions (Fig. 2a). FDG uptake was also slightly increased in some bones, but not significantly. Histopathological examination of the left cervical lymph nodes showed reactive lymphadenitis with massive infiltration of plasma cells (polyclonal pattern) and histiocytes. A nontuberculous mycobacterium, identified as M. gordonae by sequence analysis of the rpoB gene [6], was cultured from the lymph node samples. Bronchoscopic examination revealed almost complete occlusion of the left main bronchus lumen by multiple polypoid lesions. Successful endoscopic resection revealed almost the same histopathology as that of the cervical lymph nodes. Mycobacterial cultures remained negative. M. gordonae from the lymph node specimen was considered a contaminant at this stage. Unable to make a definite diagnosis, the patient's condition was monitored carefully. The patient was readmitted to the hospital 7 months later to investigate recurrent fever with appearance of leg pain and skin lesions. Follow-up PET-CT showed bilateral cervical and mediastinal lymphadenopathy, which increased in size and the number of involved nodes (Fig. 2c). A second biopsy of the left cervical lymph nodes again revealed M. gordonae in the culture, with no apparent granulomas. Multifocal osteosclerosis with destructive lesions was identified, including in the spine, and painful long bone lesions were located in the metaphyses. Biopsy of the osteolytic lesion from the left tibia revealed inflammatory granulation tissue, which proved positive for acid-fast bacilli (AFB) on direct microscopy. Culture was not performed because a neoplasm was suspected at the time. Repeated bronchoscopy showed relapse of the endobronchial polyps in the left main bronchus positive for AFB. 16S rRNA gene sequencing of endobronchial sputum cultures revealed M. mantenii. M. mantenii was also isolated from biopsy specimens of the chronic skin ulcer in front of the sternum, and M. gordonae was isolated from a subcutaneous mass near the second cervical lymph node. Mycobacterial blood cultures remained negative. Based on the isolation of M. gordonae from 3 normally sterile sites and M. mantenii from endobronchial sputum and biopsy specimens of the skin ulcer, disseminated NTM caused by M. gordonae and M. mantenii was finally diagnosed. The patient was treated with clarithromycin (800 mg/day), rifampicin (450 mg/ day), and ethambutol (500 mg/day) as both species are, by nature, clarithromycin-susceptible; treatment guidelines for
469
clarithromycin-susceptible MAC were followed [7,8]. These antimycobacterial treatments seemed effective. His increasing bone pain subsided after 5 days of treatment, fever remitted at 1 week, and almost all skin lesions disappeared at 2 months. One year after antibiotic treatment, FDG-PET showed no abnormal FDG uptake in the lesion sites (Fig. 2e and f). The patient is alive for more than 3 years without recurrence with continuous treatment. The IFN-g-releasing assay suggested the presence of anti-IFN-g neutralizing autoantibodies. The neutralizing capacity of IFN-g and the relative concentration of anti-IFN-g autoantibodies were analyzed in the patients serum by previously reported methods [9]. Anti-IFN-g autoantibodies with biological neutralizing capacity were detected in his serum. The relative concentrations of antibodies during the disease course are illustrated in Fig. 3. A higher serum anti-IFN-g autoantibody concentration was detected compared with normal control serum during the pre-treatment period. The autoantibody concentration decreased gradually with the above-mentioned treatment, though it remained above the normal level. Furthermore, the neutralizing capacity remained even after the disease activity was controlled by the treatment. 3. Discussion The present case is unique in three respects. First, the pathogens were two bacterial strains, the extremely low virulent M. gordonae and the very rare M. mantenii. Second, the concentration of antiIFN-g autoantibodies decreased after initiating anti-mycobacterial treatment without rituximab. Third, asymptomatic and extensive bone and endobronchial lesions developed with disease progression during the clinical course. Because M. gordonae is ubiquitously distributed in the environment and has extremely low virulence, diagnosis of M. gordonae infection should be made with caution [7]. In the present case, M. gordonae was isolated from 3 different specimens, including 2 from the cervical lymph nodes, and was considered pathogenic. Disseminated M. gordonae cases have been rarely reported. Four cases in patients without acquired immunodeficiency syndrome (AIDS) have been reported to have foreign bodies in place, such as ventriculoatrial and ventriculoperitoneal shunts and a prosthetic aortic valve; in three of these cases, the foreign body was considered the source of infection [10]. However, the present case lacked foreign bodies. In cases involving anti-IFN-g autoantibodies, the causative agents of disseminated NTM include slow-growing mycobacteria, such as MAC, and rapid-growing mycobacteria [1e3]. Only one case of M. gordonae has been previously reported in a case series of disseminated NTM involving anti-IFN-g autoantibodies [2]. M. mantenii, first reported in 2009, is a slowly growing and extremely rare scotochromogenic species, and, to date, only three articles have reported isolation of this species. It was formally
Fig. 1. Chest computed tomography (CT) on admission shows subcarinal lymphadenopathy, a polypoid lesion in the lumen of the left main bronchus, thickening of the mucosa of the left upper bronchus, and a 1-cm-diameter nodule in the right upper lobe.
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Fig. 2. Maximum intensity projection image and axial views of F-18 fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (FDG-PET/CT). FDG-PET on admission (a) shows focal FDG uptake in the left cervical and subcarinal lymph nodes and an endobronchial polyp (arrow). At seven months after admission, cervical and mediastinal lymphadenopathy has increased in size and number (c). FDG uptake of the spine and long bone lesions such as the clavicle (b) has become obvious (d). Most long bone lesions are located in the metaphyses, with the first scan showing only slight FDG uptake (arrow head). FDG-PET one year after treatment (e,f) shows improvement of the permeative lesion and no abnormal FDG uptake. PET images in c and e have been spliced for display purposes.
described after isolation from the lymph nodes of two Dutch children with NTM lymphadenitis, from lung specimens in two elderly Dutch patients with pre-existing pulmonary disease, and from a surface water sample in Zambia [8]. In addition, a subsequent study reported isolation of M. mantenii from aquarium water samples in the Czech Republic [11]. The virulence of M. mantenii has never been clearly demonstrated. A previous report of adult-onset
immunodeficiency reported one case of M. mantenii in its supplementary appendix, although it was not stated whether the case involved anti-IFN-g autoantibodies [3]. To the best of our knowledge, this is the first reported case of disseminated M. mantenii disease known to involve anti-IFN-g autoantibodies. Low levels of anti-IFN-g autoantibodies have been found in healthy controls and in other patients with disseminated MAC
I. Hase et al. / J Infect Chemother 21 (2015) 468e472
Fig. 3. Relative concentration of anti-interferon-g autoantibodies compared with normal control serum, a higher serum anti-IFN-g autoantibody concentration is seen during the pre-treatment period. After antimycobacterial treatment, the high concentration of anti-IFN-g autoantibodies has decreased gradually, although it has remained above the normal level.
infection. Although the mechanism of antibody production and the acquisition of neutralizing capacity remain unknown, some reports have speculated on the association between the antibody and NTM infection. Two groups from the USA reported the utility of rituximab against disseminated NTM in patients with anti-IFN-g autoantibodies [4,5]. The subjects went into remission along with reduction in the concentration or neutralizing capacity of anti-IFNg autoantibodies as a consequence of rituximab administration. This suggests that the autoantibody itself is the causal agent of the immunodeficiency. Others have suggested that the infection might be the trigger for the secondary production of anti-IFN-g autoantibodies. The autoantibodies might arise through cross-reactivity between the pathogen and host cytokines [12]. In the present case, the concentration of anti-IFN-g autoantibodies increased during the pre-treatment period, and then autoantibody production decreased during treatment. This supports the idea that the autoantibodies were produced secondary to infection. This, however, does not preclude the possibility of spontaneous regression of the autoantibodies. Extensive bone and endobronchial lesions became apparent with disease progression in the present case. A previous study of 16 patients with disseminated NTM involving anti-IFN-g autoantibodies reported bone and pulmonary involvement in 9 (56.2%) and 8 (50%) patients, respectively, although a positive mycobacterial blood culture was reported in 2 (12.5%) patients [1]. Asymptomatic lesions may go unnoticed; the bone lesions in the present case showed slight FDG uptake in the early stage of the disease. Therefore, the distribution of the lesions may not always be completely identified and reported. The portal of entry of the pathogen in disseminated NTM cases involving anti-IFN-g autoantibodies is unknown. Despite the negative mycobacterial blood cultures, hematogenous dissemination was likely involved at various sites of infection in the present patient. Osteomyelitis due to NTM, especially in the vertebrae, is uncommon in patients without penetrating trauma, surgery, or the use of intravenous drugs or immunosuppressants. Endobronchial polyps due to NTM are also extremely rare. The atypical sites of disease involvement and the bone involvement are reminiscent of the disease sites seen in Mendelian Susceptibility to Mycobacterial Disease (MSMD) syndromes, caused by mutation in IFN-g or IL-12 receptors [13]. However, these atypical NTM lesions are occasionally reported in AIDS patients with immune reconstitution inflammatory syndrome (IRIS), in which pulmonary-thoracic disease
471
was noted in 15 of 51 (29%) patients with typically negative mycobacterial blood cultures [14]. Given its etiology, it is unexpected that the distribution of NTM lesions in anti-IFN-g autoantibody-positive patients resembles the patterns observed in AIDS patients with IRIS more closely than those of true blood culture-positive disseminated NTM disease in AIDS patients [7], in whom concomitant pulmonary disease has been identified in only 2.5% of cases [15], and bone involvement is rarely reported. In summary, a case of disseminated M. gordonae and M. mantenii disease in a patient with anti-IFN-g autoantibodies involving bone, bronchus, systemic lymph nodes, and skin was presented. This case showed that extremely low-virulent (M. gordonae) and very rare (M. mantenii) NTMs can cause disseminated NTM disease in patients with anti-IFN-g autoantibodies. The concentration of antiIFN-g autoantibodies decreased along with the improvement of disseminated lesions after anti-mycobacterial treatment was initiated, and that the clinical features of disseminated NTM disease in anti-IFN-g autoantibodies in HIV-negative patients show involvement of atypical disease sites such as bone and bronchus, as seen in AIDS patients with IRIS.
Conflict of interest None.
Acknowledgments The authors would like to thank Koichi Fujiu and Hideaki Miyamoto for patient care, Yusuke Mada and Akiyoshi Konno for surgical biopsy of lymph nodes, Fumio Kaneko for skin biopsy, and Hideo Sakuma for pathological evaluation (Southern Tohoku General Hospital). The authors would also like to thank Hiroaki Arakawa for manuscript editing (Dokkyo Medical University).
References [1] Kampitak T, Suwanpimolkul G, Browne S, Suankratay C. Anti-interferon-g autoantibody and opportunistic infections: case series and review of the literature. Infection 2011;39:65e71. [2] Chi CY, Chu CC, Liu JP, Lin CH, Ho MW, Lo WJ, et al. Anti-IFN-g autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection. Blood 2013;121:1357e66. [3] Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med 2012;367:725e34. [4] Browne SK, Zaman R, Sampaio EP, Jutivorakool K, Rosen LB, Ding L, et al. AntiCD20 (rituximab) therapy for anti-IFN-g autoantibody-associated nontuberculous mycobacterial infection. Blood 2012;119:3933e9. [5] Czaja CA, Merkel PA, Chan ED, Lenz LL, Wolf ML, Alam R, et al. Rituximab as successful adjunct treatment in a patient with disseminated nontuberculous mycobacterial infection due to acquired anti-interferon-g autoantibody. Clin Infect Dis 2014;58:e115e8. [6] Itoh S, Kazumi Y, Abe C, Takahashi M. Heterogeneity of RNA polymerase gene (rpoB) sequences of Mycobacterium gordonae clinical isolates identified with a DNA probe kit and by conventional methods. J Clin Microbiol 2003;41: 1656e63. [7] Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious disease Society of America. Am J Respir Crit Care Med 2007;175: 367e416. [8] van Ingen J, Lindeboom JA, Hartwig NG, de Zwaan R, Tortoli E, Dekhuijzen PN, et al. Mycobacterium mantenii sp. nov., a pathogenic, slowly growing, scotochromogenic species. Int J Syst Evol Microbiol 2009;59:2782e7. [9] Shima K, Sakagami T, Tanabe Y, Aoki N, Moro H, Koya T, et al. Novel assay to detect increased level of neutralizing anti-interferon gamma autoantibodies in non-tuberculous mycobacterial patients. J Infect Chemother 2014;20:52e6. [10] Weinberger M, Berg SL, Feuerstein IM, Pizzo PA, Witebsky FG. Disseminated infection with Mycobacterium gordonae: report of a case and critical review of the literature. Clin Infect Dis 1992;14:1229e39.
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[11] Slany M, Jezek P, Fiserova V, Bodnarova M, Stork J, Havelkova M, et al. Mycobacterium marinum infections in humans and tracing of its possible environmental sources. Can J Microbiol 2012;58:39e44. [12] Kampmann B, Hemingway C, Stephens A, Davidson R, Goodsall A, Anderson S, et al. Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma. J Clin Invest 2005;115:2480e8. [13] Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT, Baretto R, et al. Clinical features of dominant and recessive interferon-g receptor 1 deficiencies. Lancet 2004;364:2113e21.
[14] Phillips P, Bonner S, Gataric N, Bai T, Wilcox P, Hogg R, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005;41: 1483e97. [15] Kalayjian RC, Toossi Z, Tomashefski Jr JF, Carey JT, Ross JA, Tomford JW, et al. Pulmonary disease due to infection by Mycobacterium avium complex in patients with AIDS. Clin Infect Dis 1995;20:1186e94.
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
Disseminated Mycobacterium gordonae and Mycobacterium mantenii infection with elevated anti-IFN-g neutralizing autoantibodies Isano Hase a, b, *, Kozo Morimoto c, Takuro Sakagami d, Yuko Kazumi e, Yoshiki Ishii b, Jakko van Ingen f a
Department of Respiratory Disease, Southern Tohoku General Hospital, 7-115 Yatsuyamada, Koriyama-shi, Fukushima 963-8563, Japan Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose-shi, Tokyo 204-0022, Japan d Division of Respiratory Medicine and Infectious Disease, Department of Homeostatic Regulation and Development, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Niigata-shi, Niigata 951-8510, Japan e Molecular Epidemiology and Genetic Identification Division, Department of Mycobacteria References and Research, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, 3-1-24 Matsuyama, Kiyose-shi, Tokyo 204-8533, Japan f Department of Medical Microbiology, Radboud University Medical Center, P.O. Box 9101, 6500HB Nijmegen, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 October 2014 Received in revised form 20 January 2015 Accepted 3 February 2015 Available online 12 February 2015
A case of disseminated nontuberculous mycobacteria(l) (NTM) infection in a patient with positive neutralizing anti-interferon-g (IFN-g) autoantibodies involving bone, bronchus, systemic lymph nodes, and skin is reported. The causative NTMs were two different strains: Mycobacterium gordonae, which rarely causes true disease, and Mycobacterium mantenii, which is extremely rare. Anti-mycobacterial treatment successfully ameliorated all disseminated lesions. Although the concentration of anti-IFN-g autoantibodies increased during the pre-treatment period, it gradually decreased after antimycobacterial treatment was started. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Disseminated nontuberculous mycobacterium infection Mycobacterium gordonae Mycobacterium mantenii Anti-IFN-g neutralizing autoantibodies
1. Introduction The first cases of disseminated nontuberculous mycobacterial (NTM) infection with elevated anti-interferon-g (IFN-g) neutralizing autoantibodies were reported in 2004, and similar cases have since been reported, mostly from East Asia. In most cases, the causative agents of disseminated NTM include Mycobacterium avium complex (MAC) and rapid-growing mycobacteria [1e3]. The concentration or neutralizing capacity of anti-IFN-g autoantibodies was reduced after the initiation of anti-mycobacterial agents and rituximab in a few cases [4,5]. A case of disseminated Mycobacterium gordonae and Mycobacterium mantenii in a patient with anti-IFN-g autoantibodies is described. After starting
* Corresponding author. Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 3210293, Japan. Tel.: þ81 282 87 2151; fax: þ81 282 86 5080. E-mail address: [email protected] (I. Hase).
anti-mycobacterial treatment, the autoantibody concentration decreased along with improvement of the disseminated lesions. 2. Case report A previously healthy 65-year-old man who worked in building operations presented with a 12-kg weight loss in 1 year, swollen left cervical lymph nodes, and persistent low-grade fever. He was a current smoker (60 pack-years). His temperature was 37.0 C. Multiple swollen lymph nodes, 1e2 cm in diameter, were palpable on the left side of the neck. Laboratory data showed an elevated white blood cell count (11,270/mL), erythrocyte sedimentation rate (72 mm/h), serum Creactive protein level (2.36 mg/dL), alkaline phosphatase level (381 U/L), and immunoglobulin-G level (2140 mg/dL). No anti-HIV antibody or anti-human T-cell leukemia virus antibodies were detected. The IFN-g-releasing assay was performed with the QuantiFERON®-TB Gold In-Tube test. Despite a positive purified protein derivative skin test, IFN-g release from peripheral blood
http://dx.doi.org/10.1016/j.jiac.2015.02.003 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
I. Hase et al. / J Infect Chemother 21 (2015) 468e472
mononuclear cells could not be detected in the assay, even if stimulated by mitogen. Chest computed tomography (CT) on admission showed subcarinal lymphadenopathy, a polypoid lesion in the lumen of the left main bronchus, thickening of mucosa of the left upper bronchus, and a 1-cm-diameter nodule in the right upper lobe (Fig. 1). Neither miliary lesions nor bronchiectasis was detected on chest CT. F-18 fluorodeoxyglucose (FDG)-positron emission tomography/ computed tomography (FDG-PET/CT) showed an obvious increase in FDG uptake in these lesions (Fig. 2a). FDG uptake was also slightly increased in some bones, but not significantly. Histopathological examination of the left cervical lymph nodes showed reactive lymphadenitis with massive infiltration of plasma cells (polyclonal pattern) and histiocytes. A nontuberculous mycobacterium, identified as M. gordonae by sequence analysis of the rpoB gene [6], was cultured from the lymph node samples. Bronchoscopic examination revealed almost complete occlusion of the left main bronchus lumen by multiple polypoid lesions. Successful endoscopic resection revealed almost the same histopathology as that of the cervical lymph nodes. Mycobacterial cultures remained negative. M. gordonae from the lymph node specimen was considered a contaminant at this stage. Unable to make a definite diagnosis, the patient's condition was monitored carefully. The patient was readmitted to the hospital 7 months later to investigate recurrent fever with appearance of leg pain and skin lesions. Follow-up PET-CT showed bilateral cervical and mediastinal lymphadenopathy, which increased in size and the number of involved nodes (Fig. 2c). A second biopsy of the left cervical lymph nodes again revealed M. gordonae in the culture, with no apparent granulomas. Multifocal osteosclerosis with destructive lesions was identified, including in the spine, and painful long bone lesions were located in the metaphyses. Biopsy of the osteolytic lesion from the left tibia revealed inflammatory granulation tissue, which proved positive for acid-fast bacilli (AFB) on direct microscopy. Culture was not performed because a neoplasm was suspected at the time. Repeated bronchoscopy showed relapse of the endobronchial polyps in the left main bronchus positive for AFB. 16S rRNA gene sequencing of endobronchial sputum cultures revealed M. mantenii. M. mantenii was also isolated from biopsy specimens of the chronic skin ulcer in front of the sternum, and M. gordonae was isolated from a subcutaneous mass near the second cervical lymph node. Mycobacterial blood cultures remained negative. Based on the isolation of M. gordonae from 3 normally sterile sites and M. mantenii from endobronchial sputum and biopsy specimens of the skin ulcer, disseminated NTM caused by M. gordonae and M. mantenii was finally diagnosed. The patient was treated with clarithromycin (800 mg/day), rifampicin (450 mg/ day), and ethambutol (500 mg/day) as both species are, by nature, clarithromycin-susceptible; treatment guidelines for
469
clarithromycin-susceptible MAC were followed [7,8]. These antimycobacterial treatments seemed effective. His increasing bone pain subsided after 5 days of treatment, fever remitted at 1 week, and almost all skin lesions disappeared at 2 months. One year after antibiotic treatment, FDG-PET showed no abnormal FDG uptake in the lesion sites (Fig. 2e and f). The patient is alive for more than 3 years without recurrence with continuous treatment. The IFN-g-releasing assay suggested the presence of anti-IFN-g neutralizing autoantibodies. The neutralizing capacity of IFN-g and the relative concentration of anti-IFN-g autoantibodies were analyzed in the patients serum by previously reported methods [9]. Anti-IFN-g autoantibodies with biological neutralizing capacity were detected in his serum. The relative concentrations of antibodies during the disease course are illustrated in Fig. 3. A higher serum anti-IFN-g autoantibody concentration was detected compared with normal control serum during the pre-treatment period. The autoantibody concentration decreased gradually with the above-mentioned treatment, though it remained above the normal level. Furthermore, the neutralizing capacity remained even after the disease activity was controlled by the treatment. 3. Discussion The present case is unique in three respects. First, the pathogens were two bacterial strains, the extremely low virulent M. gordonae and the very rare M. mantenii. Second, the concentration of antiIFN-g autoantibodies decreased after initiating anti-mycobacterial treatment without rituximab. Third, asymptomatic and extensive bone and endobronchial lesions developed with disease progression during the clinical course. Because M. gordonae is ubiquitously distributed in the environment and has extremely low virulence, diagnosis of M. gordonae infection should be made with caution [7]. In the present case, M. gordonae was isolated from 3 different specimens, including 2 from the cervical lymph nodes, and was considered pathogenic. Disseminated M. gordonae cases have been rarely reported. Four cases in patients without acquired immunodeficiency syndrome (AIDS) have been reported to have foreign bodies in place, such as ventriculoatrial and ventriculoperitoneal shunts and a prosthetic aortic valve; in three of these cases, the foreign body was considered the source of infection [10]. However, the present case lacked foreign bodies. In cases involving anti-IFN-g autoantibodies, the causative agents of disseminated NTM include slow-growing mycobacteria, such as MAC, and rapid-growing mycobacteria [1e3]. Only one case of M. gordonae has been previously reported in a case series of disseminated NTM involving anti-IFN-g autoantibodies [2]. M. mantenii, first reported in 2009, is a slowly growing and extremely rare scotochromogenic species, and, to date, only three articles have reported isolation of this species. It was formally
Fig. 1. Chest computed tomography (CT) on admission shows subcarinal lymphadenopathy, a polypoid lesion in the lumen of the left main bronchus, thickening of the mucosa of the left upper bronchus, and a 1-cm-diameter nodule in the right upper lobe.
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I. Hase et al. / J Infect Chemother 21 (2015) 468e472
Fig. 2. Maximum intensity projection image and axial views of F-18 fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (FDG-PET/CT). FDG-PET on admission (a) shows focal FDG uptake in the left cervical and subcarinal lymph nodes and an endobronchial polyp (arrow). At seven months after admission, cervical and mediastinal lymphadenopathy has increased in size and number (c). FDG uptake of the spine and long bone lesions such as the clavicle (b) has become obvious (d). Most long bone lesions are located in the metaphyses, with the first scan showing only slight FDG uptake (arrow head). FDG-PET one year after treatment (e,f) shows improvement of the permeative lesion and no abnormal FDG uptake. PET images in c and e have been spliced for display purposes.
described after isolation from the lymph nodes of two Dutch children with NTM lymphadenitis, from lung specimens in two elderly Dutch patients with pre-existing pulmonary disease, and from a surface water sample in Zambia [8]. In addition, a subsequent study reported isolation of M. mantenii from aquarium water samples in the Czech Republic [11]. The virulence of M. mantenii has never been clearly demonstrated. A previous report of adult-onset
immunodeficiency reported one case of M. mantenii in its supplementary appendix, although it was not stated whether the case involved anti-IFN-g autoantibodies [3]. To the best of our knowledge, this is the first reported case of disseminated M. mantenii disease known to involve anti-IFN-g autoantibodies. Low levels of anti-IFN-g autoantibodies have been found in healthy controls and in other patients with disseminated MAC
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Fig. 3. Relative concentration of anti-interferon-g autoantibodies compared with normal control serum, a higher serum anti-IFN-g autoantibody concentration is seen during the pre-treatment period. After antimycobacterial treatment, the high concentration of anti-IFN-g autoantibodies has decreased gradually, although it has remained above the normal level.
infection. Although the mechanism of antibody production and the acquisition of neutralizing capacity remain unknown, some reports have speculated on the association between the antibody and NTM infection. Two groups from the USA reported the utility of rituximab against disseminated NTM in patients with anti-IFN-g autoantibodies [4,5]. The subjects went into remission along with reduction in the concentration or neutralizing capacity of anti-IFNg autoantibodies as a consequence of rituximab administration. This suggests that the autoantibody itself is the causal agent of the immunodeficiency. Others have suggested that the infection might be the trigger for the secondary production of anti-IFN-g autoantibodies. The autoantibodies might arise through cross-reactivity between the pathogen and host cytokines [12]. In the present case, the concentration of anti-IFN-g autoantibodies increased during the pre-treatment period, and then autoantibody production decreased during treatment. This supports the idea that the autoantibodies were produced secondary to infection. This, however, does not preclude the possibility of spontaneous regression of the autoantibodies. Extensive bone and endobronchial lesions became apparent with disease progression in the present case. A previous study of 16 patients with disseminated NTM involving anti-IFN-g autoantibodies reported bone and pulmonary involvement in 9 (56.2%) and 8 (50%) patients, respectively, although a positive mycobacterial blood culture was reported in 2 (12.5%) patients [1]. Asymptomatic lesions may go unnoticed; the bone lesions in the present case showed slight FDG uptake in the early stage of the disease. Therefore, the distribution of the lesions may not always be completely identified and reported. The portal of entry of the pathogen in disseminated NTM cases involving anti-IFN-g autoantibodies is unknown. Despite the negative mycobacterial blood cultures, hematogenous dissemination was likely involved at various sites of infection in the present patient. Osteomyelitis due to NTM, especially in the vertebrae, is uncommon in patients without penetrating trauma, surgery, or the use of intravenous drugs or immunosuppressants. Endobronchial polyps due to NTM are also extremely rare. The atypical sites of disease involvement and the bone involvement are reminiscent of the disease sites seen in Mendelian Susceptibility to Mycobacterial Disease (MSMD) syndromes, caused by mutation in IFN-g or IL-12 receptors [13]. However, these atypical NTM lesions are occasionally reported in AIDS patients with immune reconstitution inflammatory syndrome (IRIS), in which pulmonary-thoracic disease
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was noted in 15 of 51 (29%) patients with typically negative mycobacterial blood cultures [14]. Given its etiology, it is unexpected that the distribution of NTM lesions in anti-IFN-g autoantibody-positive patients resembles the patterns observed in AIDS patients with IRIS more closely than those of true blood culture-positive disseminated NTM disease in AIDS patients [7], in whom concomitant pulmonary disease has been identified in only 2.5% of cases [15], and bone involvement is rarely reported. In summary, a case of disseminated M. gordonae and M. mantenii disease in a patient with anti-IFN-g autoantibodies involving bone, bronchus, systemic lymph nodes, and skin was presented. This case showed that extremely low-virulent (M. gordonae) and very rare (M. mantenii) NTMs can cause disseminated NTM disease in patients with anti-IFN-g autoantibodies. The concentration of antiIFN-g autoantibodies decreased along with the improvement of disseminated lesions after anti-mycobacterial treatment was initiated, and that the clinical features of disseminated NTM disease in anti-IFN-g autoantibodies in HIV-negative patients show involvement of atypical disease sites such as bone and bronchus, as seen in AIDS patients with IRIS.
Conflict of interest None.
Acknowledgments The authors would like to thank Koichi Fujiu and Hideaki Miyamoto for patient care, Yusuke Mada and Akiyoshi Konno for surgical biopsy of lymph nodes, Fumio Kaneko for skin biopsy, and Hideo Sakuma for pathological evaluation (Southern Tohoku General Hospital). The authors would also like to thank Hiroaki Arakawa for manuscript editing (Dokkyo Medical University).
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