|Year : 2020 | Volume
| Issue : 6 | Page : 495-500
Nontuberculous mycobacteria: A report of eighteen cases from a tertiary care center in India
Nitin Gupta1, Ankit Mittal1, Vettakkara Kandy Muhammed Niyas1, Sayantan Banerjee1, Yogiraj Ray1, Parul Kodan1, Sundeep Malla2, Wasim Khot1, Farhan Fazal1, Binit Kumar Singh1, Pankaj Jorwal1, Neeraj Nischal1, Manish Soneja1, Naveet Wig1
1 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radio-Diagnosis, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||11-Aug-2020|
|Date of Acceptance||30-Sep-2019|
|Date of Web Publication||30-Oct-2020|
Dr. Manish Soneja
Department of Medicine, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: Nontuberculous mycobacteria (NTM) are ubiquitous mycobacteria present in environment and generally affect patients with either structural lung disease or immunosuppression and commonly involve lungs, lymph node, or skin. Materials and Methods: Between July 2016 and February 2019, 18 cases of NTM were diagnosed and their relevant clinical, diagnostic, and treatment details were recorded after taking informed consent. Results: We report 18 cases of NTM involving lungs (n = 11), skin and soft tissue (n = 3), joint (n = 2), genitourinary (n = 1), and central nervous system (n = 1). History of immunosuppression was present in two patients, whereas history of some form of intervention was seen in six patients. Mycobacterium fortuitum group (n = 5) was the most commonly isolated organism, followed by Mycobacterium avium complex (n = 4), Mycobacterium abscessus (n = 3), Mycobacterium kansasii (n = 2), and Mycobacterium chelonae (n = 1). In two patients, M. chelonae and M. abscessus were isolated in succession. Of these 18 patients, clinical response was present in 15 of the patients. Diagnosis and treatment of NTM in resource limited settings is extremely challenging. Conclusion: Most of the patients with NTM are misdiagnosed and are treated as tuberculosis in India, sometimes with a multidrug resistance regimen, which results in significant morbidity and mortality. We present these cases to shed some light on the epidemiology of NTM in this part of India.
Keywords: Mycobacterium abscessus, Mycobacterium avium complex, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasii
|How to cite this article:|
Gupta N, Mittal A, Niyas VK, Banerjee S, Ray Y, Kodan P, Malla S, Khot W, Fazal F, Singh BK, Jorwal P, Nischal N, Soneja M, Wig N. Nontuberculous mycobacteria: A report of eighteen cases from a tertiary care center in India. Lung India 2020;37:495-500
|How to cite this URL:|
Gupta N, Mittal A, Niyas VK, Banerjee S, Ray Y, Kodan P, Malla S, Khot W, Fazal F, Singh BK, Jorwal P, Nischal N, Soneja M, Wig N. Nontuberculous mycobacteria: A report of eighteen cases from a tertiary care center in India. Lung India [serial online] 2020 [cited 2021 Jun 19];37:495-500. Available from: https://www.lungindia.com/text.asp?2020/37/6/495/299658
| Introduction|| |
Nontuberculous mycobacteria (NTM) encompass all mycobacteria (more than 140 species), except the members of Mycobacteriumtuberculosis complex and Mycobacteriumleprae. NTM is ubiquitously present in the environment, most notably in water supplies. Their presence in tap water is attributed to their natural resistance to commonly used water disinfectants. Because of this, routine exposure to NTM, most notably in the form of airborne particles, is extremely common. Considering the rarity of clinically significant NTM infection, it is safe to assume that certain risk factors are important for an individual to get an NTM infection. Two most important risk factors that are described in published literature are structural lung disease (cystic fibrosis, chronic obstructive pulmonary tuberculosis, past history of tuberculosis, etc.) and immunosuppression (HIV, transplantation, primary immunodeficiency, etc.). Four common sites of NTM involvement are known: pulmonary, lymph node, skin, and bones/joints. Central nervous system including eye and ear involvement is considerably rare. The most common syndrome due to NTM is chronic pulmonary involvement followed by lymphadenitis. Cutaneous and bone NTM usually follow an invasive procedure and are a result of surgical site infection due to contaminated instruments. Disseminated NTM is usually described in immunosuppressed patients such as HIV/AIDS. NTM are classically classified based on the duration they take to grow on subculture on solid media into slow growers (>7 days) and rapid growers (<7 days). The most important clinically relevant slow growers include Mycobacteriumavium complex (MAC), Mycobacteriumkansasii, MycobacteriumMarinum, and MycobacteriumUlcerans, whereas the most important clinically relevant rapid growers include Mycobacteriumabscessus complex (MABC), Mycobacteriumfortuitum complex, and Mycobacteriumchelonae. There are very few reports of large series of clinical cases with follow-up from the Indian subcontinent. We report a series of eighteen cases of nontubercular mycobacteria to shed some light on the epidemiology of NTM infections in India.
| Materials and Methods|| |
Between July 2016 and February 2019, 18 cases of NTM were diagnosed based on available diagnostic criteria. Clinical features, radiological features, method of microbiological diagnosis, treatment details, and outcome were recorded after taking informing consent. Microbiological diagnosis was established in our accredited laboratory in 15 of the patients. Ziehl–Neelsen (ZN) staining was done on the direct specimen followed by liquid culture on mycobacterium growth indicator tube (Becton Dickinson, Sparks, MD). This contains a liquid broth (modified Middlebrook 7H9) in conjunction with a fluorescence quenching-based oxygen sensor that detects mycobacterial growth. Line probe assay in the name of GenoType® mycobacterium common mycobacteria/additional species assay (Hain Lifescience, Nehren, Germany) was done on the positive cultures. Diagnosis of NTM was established in an outside laboratory in three patients due to logistic reasons. Two patients were diagnosed by matrix-assisted laser desorption and ionization time of flight-mass spectrophotometry (MALDITOF-MS) and one patient was diagnosed by sequencing [Table 1].
|Table 1: Demography, clinical features, diagnosis, treatment, and response of patients with nontuberculous mycobacteria|
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| Results|| |
Of the 18 cases of NTM, 11 were male. The mean age was 41 ± 17 years. The state-wise distribution was as follows: Delhi (n = 8), Bihar (n = 2), Haryana (n = 2), Uttar Pradesh (n = 2), Madhya Pradesh (n = 2), West Bengal (n = 1), and Jammu and Kashmir (n = 1). The localization of NTM was as follows: pulmonary (n = 11), skin and soft tissue (n = 3), joint (n = 2), genitourinary (n = 1), and central nervous system (n = 1). The median duration of illness at presentation was 15 months (5.25–27 months). History of immunosuppression was present in two patients (HIV-1 and idiopathic CD4 lymphocytopenia-1). Six patients had a history of surgical intervention [Table 1]. All of these patients had rapidly growing mycobacteria as the causative agent. Constitutional symptoms such as fever, loss of appetite, and loss of weight were present in 13 patients [Table 1]. All except three patients had a history of receipt of conventional four-drug antitubercular therapy (ATT) for tuberculosis. The median duration of conventional ATT received before diagnosis was 6 months (5–30 months) [Table 1].
Of the 18 patients with culture positivity, culture isolates were speciated in 17 patients. Of the 17 patients, the same mycobacteria were cultured on multiple occasions in 15 patients. The organisms isolated on culture were M.fortuitum group (n = 5), MAC (n = 4), M.abscessus (n = 3), M.kansasii (n = 2), and M.chelonae (n = 1). In two patients, two different species were detected at different times in the course of illness. Both the patients had M.chelonae and M.abscessus in succession [Table 1]. Most patients were on a total of four drugs at a time (n = 9), followed by three drugs (n = 7), five drugs (n = 2), and six drugs (n = 1). The mean number of drugs was 3.8 ± 0.9. Most commonly used drugs in the regimens included clarithromycin (n = 11), amikacin (n = 9), ethambutol (n = 9), rifampicin (n = 6), linezolid (n = 5), levofloxacin (n = 5), doxycycline (n = 4), rifabutin (n = 4), streptomycin (n = 4), imipenem (n = 3), azithromycin (n = 3), isoniazid (n = 2), moxifloxacin (n = 1), and pyrazinamide (n = 1). Of these 18 patients, two died and one was lost to follow-up. Clinical response was present in the rest of the patients [Table 1]. Those patients with clinical response were on specific therapy for an average duration of 13.7 ± 6.5 months.
| Discussion|| |
Most reports from India are laboratory data of culture isolates [Table 2].,,,,,,,,,, Because NTM are commonly known to colonize or contaminate nonsterile specimens, mere isolation does not establish disease and these reports although informative may not be the true representation of the epidemiology of NTM in India. Diagnosis of NTM infection, therefore, requires relevant clinical background. On the other hand, because the clinical features and radiological findings are often so nonspecific, microbiological diagnosis becomes mandatory to make a diagnosis of NTM.
Pulmonary involvement is the most common NTM syndrome known worldwide. There are two major forms of pulmonary NTM: fibrocavitary and nodular bronchiectasis. Of the 11 patients with pulmonary NTM in our series, eight patients had cavitary disease (bilateral – 3 and unilateral – 5), whereas the rest three had nodular/bronchiectatic pattern. All but one patient with pulmonary NTM in our series had a prior history of ATT intake due to presumed pulmonary tuberculosis. MAC is the most common etiology of pulmonary NTM and is also responsible for lymphadenitis and disseminated infection in patients with HIV. Mycobacterium avium complex includes M. avium, Mycobacterium intracellulare and several other species closely related to M. intracellulare like Mycobacterium chimaera, Mycobacterium indicus pranii, M. Marseillense, etc. It is interesting to note that M.chimaera is reported to be less virulent than M.avium and M.intracellulare.M.kansasii is the second most common cause of lung disease worldwide and is usually believed to be a true pathogen in most cases.
Rapid growers such as MABC (M.abscessus subsp. abscessus, M.abscessus subsp. Bolletii,andM.abscessus subsp. massiliense), M.fortuitum group (including Mycobacteriumsenegalense, Mycobacteriumsepticum, and Mycobacteriumbrisbanense), and M.chelonae are important causes of pulmonary infection and surgical site infection. Rapid growers are commonly health care associated (prosthetic devices, postinjection abscesses, cosmetic, and laparoscopic procedures) because of their ubiquitous presence in water and ability to form biofilms.,, History of procedure, prosthetic device, intramuscular injection, or road traffic accident was present in six of our patients.
The first step in the microbiological diagnosis of NTM is visualization of acid-fast bacilli in ZN stain. Subtle differences have been described to differentiate between M.tuberculosis and NTM on ZN stain, but conclusive diagnosis of NTM cannot be established on microscopy alone. Classically, the standard of diagnosis for NTM has been culture followed by biochemical identification, but due to the cumbersome nature of tests, most laboratories have moved on to molecular identification following culture. The most common molecular methods for speciation of NTM are 16SrRNA sequencing, line probe assay, and MALDITOF-MS.,
Recommended treatment for MAC is a three-drug macrolide-based regimen with an aim to achieve at least 12 months of negative cultures in cases of pulmonary NTM. M.kansasii is usually responsive to treatment and requires a combination of rifampicin, isoniazid, and ethambutol. For rapid growers, combination therapy is recommended for a total of at least 4–6 months. Intravenous drugs should be a part of the initial combination until there is clinical improvement after which oral combination therapy can be used. The treatment of NTM is usually guided by the ATS/IDSA guidelines and the British thoracic guidelines, but the adherence to these guidelines is often difficult., Except for liposomal inhaled amikacin, which is not available in India, there are no other Food and Drug Administration-approved drugs for NTM. Treatment of NTM is largely based on small observational studies and expert opinion. Furthermore, the speciation of NTM is often not available at the first go. More often than not, the diagnosis of NTM is usually based on the negativity of immunochromatography test that detects antigens specific for M.tuberculosis complex. The speciation if available is often delayed that results in administration of empiric treatment regimens. Furthermore, drug susceptibility of NTM is not available in most centers and it is difficult to predict response without susceptibility. This results in use of more drugs than recommended in absence of early response because of fear of nonsusceptibility. For this reason, most of our patients were on three to four drugs at a time. Microbiological cure is often very difficult to achieve, and therefore, duration of treatment in most cases has to be decided on a case-to-case basis. The average duration in our series was more than a year. The treatment outcome in NTM depends on the underlying host factors, organ involved, and the disease severity. In our series, history of immunosuppression was present in only two patients. The time of initiation and choice of treatment regimens also have considerable bearing on the outcomes. Favorable outcome of NTM infections varies with the definitions of cure used in different studies. In a systematic review, proportion of sputum culture conversion was around 61% for MAC (on triple drug regimen), 41% for M.abscessus, and 80% for M.kansasii., A favorable clinical outcome in terms of resolution of clinical symptoms was reported in 15 of 18 patients. In patients with pulmonary NTM, eight out of eleven patients showed culture conversion.
| Conclusion|| |
India is highly endemic for tuberculosis, but the epidemiology of NTM in India is not well defined. Most of the patients with NTM are misdiagnosed and are treated as tuberculosis, sometimes with a multidrug resistance regimen, which results in significant morbidity and mortality. Diagnosis and treatment of NTM in resource-limited settings is extremely challenging. There is an urgent need for increased suspicion, better diagnostic facilities that provide drug-susceptibility testing, and newer evidence-informed treatment guidelines.
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| References|| |
Porvaznik I, Solovič I, Mokrý J. Non-tuberculous mycobacteria: Classification, diagnostics, and therapy. Adv Exp Med Biol 2017;944:19-25.
Fernandes HMZ, Conceição EC, Gomes KM, da Silva MG, Dias RCS, Duarte RS. Recovery of Non-tuberculous Mycobacteria from Water is Influenced by Phenotypic Characteristics and Decontamination Methods. Curr Microbiol 2019 May 20. doi:10.1007/s00284-019-01704-w. [Epub ahead of print] Review. PubMed PMID: 31111226.
Honda JR, Knight V, Chan ED. Pathogenesis and risk factors for Nontuberculous mycobacterial lung disease. Clin Chest Med 2015;36:1-1.
Griffith DE, Aksamit T, Brown-Elliott 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;175:367-416.
Singh AK, Maurya AK, Umrao J, Kant S, Kushwaha RA, Nag VL, et al.
Role of genoType(®) mycobacterium common mycobacteria/Additional species assay for rapid differentiation between Mycobacterium tuberculosis
complex and different species of Non-tuberculous mycobacteria. J Lab Physicians 2013;5:83-9.
] [Full text]
Umrao J, Singh D, Zia A, Saxena S, Sarsaiya S, Singh S, et al.
Prevalence and species spectrum of both pulmonary and extrapulmonary Nontuberculous Mycobacteria isolates at a tertiary care center. Int J Mycobacteriol 2016;5:288-93. [Full text]
Desikan P, Tiwari K, Panwalkar N, Khaliq S, Chourey M, Varathe R, et al.
Public health relevance ofNon-tuberculous Mycobacteria among AFB positive sputa. Germs 2017;7:10-8.
Jesudason MV, Gladstone P. Non Tuberculous Mycobacteria isolated from clinical specimens at a tertiary care hospital in South India. Indian J Med Microbiol 2005;23:172-5.
] [Full text]
Jain S, Sankar MM, Sharma N, Singh S, Chugh TD. High prevalence of Non-tuberculous mycobacterialdisease among non-HIV infected individuals in a TB endemic country – Experience from a tertiary center in Delhi, India. Pathog Glob Health 2014;108:118-22.
B S, Gogia A, Kakar A, Byotra SP. 781. Non-Tuberculous mycobacterium: Often a Missed Entity. Open Forum Infect Dis 2018;5 Suppl 1:S280.
Krishnappa R, Samarasam I. Atypical mycobacterial infection in post laparoscopy surgical wounds: Our observations and review of literature. Int Sur J 2017;4:2943-6.
Maurya AK, Nag VL, Kant S, Kushwaha RA, Kumar M, Singh AK, et al.
Prevalence of Nontuberculous mycobacteria among extrapulmonary tuberculosis cases in tertiary care centers in Northern India. Biomed Res Int 2015;2015:465403.
Shah AK, Gambhir RP, Hazra N, Katoch R. Non Tuberculous mycobacteria in surgical wounds- a rising cause of concern? Indian J Surg 2010;72:206-10.
Sharma P, Singh D, Sharma K, Verma S, Mahajan S, Kanga A, et al.
Are we neglecting Nontuberculous mycobacteria just as laboratory contaminants? Time to reevaluate things. J Pathog 2018;2018:8907629.
Garima K, Varma-Basil M, Pathak R, Kumar S, Narang A, Rawat KS, et al.
Are we overlooking infections owing to Non-tuberculous mycobacteria during routine conventional laboratory investigations? Int J Mycobacteriol 2012;1:207-11. [Full text]
Gundavda MK, Patil HG, Agashe VM, Soman R, Rodriques C, Deshpande RB, et al.
Nontuberculous mycobacterial infection of the musculoskeletal system in immunocompetent hosts. Indian J Orthop 2017;51:205-12.
] [Full text]
Wassilew N, Hoffmann H, Andrejak C, Lange C. Pulmonary disease caused by non-Tuberculous mycobacteria. Respiration 2016;91:386-402.
Daley CL. Mycobacterium avium
Complex Disease. Microbiol Spectr. 2017;5(2).
Bakuła Z, Kościuch J, Safianowska A, Proboszcz M, Bielecki J, van Ingen J, et al.
Clinical, radiological and molecular features of Mycobacterium kansasii
pulmonary disease. Respir Med 2018;139:91-100.
Nathavitharana RR, Strnad L, Lederer PA, Shah M, Hurtado RM. Top questions in the diagnosis and treatment of pulmonary M. Abscessus
disease. Open Forum Infect Dis 2019;6:ofz221.
Ghosh R, Das S, De A, Kela H, Saha ML, Maiti PK. Port-site infections by Nontuberculous Mycobacterium
: A retrospective clinico-microbiological study. Int J Mycobacteriol 2017;6:34-7.
] [Full text]
Kannaiyan K, Ragunathan L, Sakthivel S, Sasidar AR, Muralidaran, Venkatachalam GK, et al.
Surgical site infections due to rapidly growing Mycobacteria in Puducherry, India. J Clin Diagn Res 2015;9:DC05-8.
Alcaide F, Amlerová J, Bou G, Ceyssens PJ, Coll P, Corcoran D, et al.
How to: Identify Non-tuberculous Mycobacterium
species using MALDI-TOF mass spectrometry. Clin Microbiol Infect 2018;24:599-603.
Haworth CS, Floto RA. Introducing the new BTS guideline: Management of Non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thora 2017;72:969-70.
Griffith DE, Eagle G, Thomson R, Aksamit TR, Hasegawa N, Morimoto K, et al.
Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium
complex (CONVERT). A prospective, open-label, randomized study. Am J Respir Crit Care Med 2018;198:1559-69.
Diel R, Ringshausen F, Richter E, Welker L, Schmitz J, Nienhaus A. Microbiological and clinical outcomes of treating Non-mycobacterium avium
complex Nontuberculous mycobacterial pulmonary disease: A systematic review and meta-analysis. Chest 2017;152:120-42.
Diel R, Nienhaus A, Ringshausen FC, Richter E, Welte T, Rabe KF, et al.
Microbiologic outcome of interventions against Mycobacterium avium
complex pulmonary disease: A systematic review. Chest 2018;153:888-921.
[Table 1], [Table 2]