The International Journal of Mycobacteriology

REVIEW ARTICLE
Year
: 2021  |  Volume : 10  |  Issue : 3  |  Page : 217--227

Nontuberculous mycobacterium: An emerging pathogen: Indian perspective


Priya Rajendran1, Chandrasekaran Padmapriyadarsini2, Rajesh Mondal3,  
1 Department of Bacteriology, ICMR- National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India
2 Department of The Director, ICMR- National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India
3 Mini Unit-5, ICMR - Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India

Correspondence Address:
Chandrasekaran Padmapriyadarsini
Director, ICMR-National Institute for Researc in Tuberculosis, No. 1. Mayor Sathya Moorthy Road, Chetpet, Chennai - 600 031, Tamilnadu
India

Abstract

Nontuberculous mycobacteria (NTM), considered as mere contaminants, are off late, being reported as potential pathogens through various studies. The infections due to NTM range from pulmonary to extra pulmonary including skin and soft-tissue infections, traumatic and surgical wound infections, and catheter and implant-associated infections. Although extrapulmonary infections are extensively explored, pulmonary infections are scarcely reported due to their misdiagnosis as tuberculosis caused by M. tuberculosis (MTB). Appropriate detection methods are essential in order to facilitate the differential diagnosis of NTM from MTB infections. We aimed to collate the data available on NTM diagnosis and its epidemiology in India in this review. While diagnosis of MTB itself is more challenging in India, for appropriate treatment of NTM, special training and attention is needed for differential diagnosis of the former from latter. Currently, in India, in addition to the available techniques for identification of NTM, line probe assay (Hains life sciences) is proving to be a promising tool for the detection of NTM (common mycobacteria/additional species kit) and their antimicrobial resistance (Genotype NTM-DR VER 1.0). In future, with the price of sequencing steadily coming down, with proper monitoring, whole-genome sequencing could be the test of choice to predict the species, drug resistance, outbreaks in hospitals, and transmission dynamics.



How to cite this article:
Rajendran P, Padmapriyadarsini C, Mondal R. Nontuberculous mycobacterium: An emerging pathogen: Indian perspective.Int J Mycobacteriol 2021;10:217-227


How to cite this URL:
Rajendran P, Padmapriyadarsini C, Mondal R. Nontuberculous mycobacterium: An emerging pathogen: Indian perspective. Int J Mycobacteriol [serial online] 2021 [cited 2021 Nov 30 ];10:217-227
Available from: https://www.ijmyco.org/text.asp?2021/10/3/217/325501


Full Text



 Introduction



Nontuberculous mycobacteria (NTM) are pervasive environmental bacteria that include mycobacterial species other than Mycobacterium tuberculosis complex (MTBC) and Mycobacterium leprae.[1] They are reported to cause a varied spectrum of diseases following environmental exposure and account for 80%–90% of infections.[2] Based on their growth characteristics, NTM are classified as slow growers (growth on culture media taking more than 7 days) that include Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium scrofulaceum, Mycobacterium avium complex (MAC)-M. avium M. intracellulare, Mycobacterium chimaera, Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium simiae, Mycobacterium malmoense, Mycobacterium szulgai, Mycobacterium haemophilum and rapid growers (growth in <7 days) that includes Mycobacterium abscessus, Mycobacterium Fortuitum, and Mycobacterium chelonae. The infections due to NTM range from pulmonary[3] to extrapulmonary including skin and soft-tissue infections, traumatic and surgical wound infections, catheter, and implant-associated infections.[4] Although MAC accounts for the majority of NTM infections worldwide, there is significant regional variability of the species.[5] M. abscessus, M. kansasii, M. malmoense, M. fortuitum, M. chelonae, and M. xenopi are the other clinically significant species.[6] Based on the species of NTM involved in the disease, the treatment regimen and clinical course also vary, thereby emphasizing the need for accurate diagnosis. However, due to their similar morphological appearance as MTB in sputum smears and their similar clinical presentation,[7] misdiagnosis of NTM is common leading to their underreporting[8] misclassification and improper treatment.[3] With these given challenges, NTM have gained more attention in recent years and understanding of their biology, epidemiology, diagnosis, and management of infections caused by them has undergone considerable research globally. However, in India, NTM are still struggling to get their importance due to their misdiagnosis or incorrect diagnosis.[8] We have tried to compile the data published from year 1990 till date on epidemiology of NTM, their diagnosis, and drug susceptibility testing (DST) methods with respect to Indian perspective. We have limited the review pertaining to laboratory aspects and have not included clinical aspects. The search terms included “Pulmonary NTM,” “Extra pulmonary NTM,” and “Antimicrobial susceptibility of NTM” with “India,” in PubMed. The purpose of the review is to document the NTM reports in India to elucidate their importance and establish need for research in future studies. This is because in some studies, NTM diagnosis was by serendipity in presumptive TB population. In such cases, NTM in resource-constrained settings are very often misdiagnosed or sometimes given appropriate attention only after obtaining a history of failed anti-TB treatments.[9]

 Pulmonary Infection



Pulmonary NTM infections are often misdiagnosed as tuberculosis in countries like India that have high prevalence of latter disease. Although fever is less common in NTM infections, the chest X-ray images among the infected individuals, mimic the nodular lesions and infiltrations seen as in MTB infection.[10] Detection of MAC, Mycobacterium abscessus complex (MABC), M. kansasii, M. malmoense, M. xenopi, and M. szulgai from pulmonary specimens are indicated as potential pathogens, whereas less virulent species, such as Mycobacterium gordonae, Mycobacterium terrae, and M. fortuitum complex, are usually reported as contaminants instead of citing them as disease-causing agents.[11] While this is the distribution scenario worldwide, other species are also reported from various parts of India but in fewer numbers. The summary of NTM distribution in India is listed out in [Table 1]. In spite of the efforts taken by diagnostic laboratories in differentiating NTM and MTB, the possibility of missing out the NTM infection is still high.[10] Due to this, the patients are started on antituberculosis treatment; they respond in the initial stages but soon stop responding. Such patients are considered as drug failures or cases of multidrug-resistant tuberculosis (MDRTB) and are started on MDRTB regimen. In recent years, this is becoming an issue of serious concern as NTM can develop antimicrobial resistance which would make the treatment difficult. Hence, appropriate differential diagnosis of MTB and NTM is essential. The normal trend in distribution of NTM species in pulmonary infections includes M. kansasii, MAC, M. fortuitum, and M. abscessus as described in [Table 1].{Table 1}

 Case Reports



In addition, there are also few case reports of NTM species causing pulmonary disease as a follow-up of postoperative complication such as nosocomial infection or disseminated disease. For example, in the year 2001, M. fortuitum chelonae complex causing pulmonary infection postallogeneic bone marrow transplantation was reported from Mumbai.[22] A decade later in 2013, Mycobacterium massiliense was reported for the first time in a 60-year-old female suffering from MDR-TB who later developed an invasive infection of the respiratory tract with this NTM species.[23] In the year 2014, M. abscessus was reported in bronchoalveolar lavage (BAL) culture obtained from a 2-year child admitted with pulmonary complication at Chennai hospital.[24] Mycobacterium lentiflavum, a rare entity of human disease, was reported in the year 2017 from BAL of a 15-year-old boy in Punjab who was initially diagnosed with cervical lymphadenitis.[25] A 9-year-old immunocompetent girl presenting with M. aviumintracellulare empyema was reported from Mumbai in the year 2018 indicating the need for routine diagnosis of pleural fluid for Mycobacteria other than MTB in pleural effusion cases.[26] In 2021, from Chennai, a case series of four patients with a history of TB treatment was reported with M. abscessus pulmonary infections.[27] The case reports documented so far on pulmonary involvement of NTM indicate the need for monitoring them as a part of routine diagnostic algorithm.

 Extrapulmonary Infection



In contrast to prospective studies on the prevalence of NTM in pulmonary infections, their contribution toward extrapulmonary infections in India is documented mostly as retrospective studies [Table 2]. This could be because there was inadequate knowledge on whether an NTM isolate was to be considered as contaminant or of clinical significance. Furthermore, there was poor communication between clinicians and the laboratory due to the absence of standard tailored regimen for treatment. With the increase in the awareness on NTM, their prevalence pattern is being revisited in extrapulmonary sites of infection. Moreover, in recent years, there are numerous case reports documenting the evidence regarding involvement of NTM in extrapulmonary infection [Table 3]. Involvement of skin or soft tissue is the most common manifestation seen in NTM-infected individuals whose wounds may get exposed to soil, water, or medical devices contaminated with environmental mycobacteria after traumatic injury, surgery, or cosmetic procedures. Frequently encountered species in skin infections worldwide include MABC, M. chelonae, and M. fortuitum[83] and Indian data reported so far is consistent with these findings. Other common extrapulmonary NTM infections include disseminated disease, lymphadenitis, and bone or joint infections. The most commonly identified species in bone and joint infections are M. intracellulare, M. abscessus, M. fortuitum, and M. marinum and similar panel of species have been reported from other parts of the world. Disseminated infections occur as a complication of surgery and are more common in immunocompromised patients, while in immunocompetent, it is usually localized. Although rare, involvement of NTM (M. chelonae and M. abscessus) in ocular infection (keratitis and endophthalmitis) has been documented in various studies.[84] In addition, rare species such as M. manitobense also has been reported in a patient with postoperative endophthalmitis.[39] NTM diagnosis in extrapulmonary infection usually requires blood or tissue samples and detection is by microscopy, culture, or molecular methods. Management of extrapulmonary NTM infection is a tedious process since it requires an extended therapy and surgical interventions and in spite of that the outcome is poor in many cases. Continuous monitoring is essential in order to facilitate early diagnosis and appropriate treatment in such cases.{Table 2}{Table 3}

Diagnosis

Since NTM are environmentally ubiquitous, their diagnosis in respiratory specimens is complicated and needs to be done with utmost care to rule out contaminants. An official statement by American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) in 2007[2] and British Thoracic Society[85] in 2017 was made on diagnosis, treatment, and prevention of pulmonary NTM disease. According to its guidelines, clinical, radiological, and microbiological evidence is mandatory for appropriate diagnosis of NTM and following criteria need to be taken into account for laboratory diagnosis of pulmonary infections.

Positive culture for NTM from at least two sputum specimensPositive culture from at least one bronchial washExpert consultation to be sought in case of frequent NTM encountersWhen the diagnostic criteria of a patient are not met but are suspected of NTM pulmonary disease, he/she should be followed up until the diagnosis is well establishedTherapy should be initiated not merely on the basis of detection of NTM and the pathogenic evidence of isolate but after weighing the potential risks and benefits of treatment for the patient.

In immunocompromised patients, a combined diagnostic criterion (radiologic, clinical, and bacteriologic) is still applicable provided that other possible pulmonary pathogens are excluded.[2] In case of extrapulmonary infections, the clinical specimens collected from the site of infection (skin, bone, and other body fluids) are subjected to routine NTM diagnosis after appropriate processing.[86] While diagnosis of MTB itself is challenging, NTM diagnosis needs special training and attention to differentiate the latter from former for appropriate diagnosis and treatment. Although a standard diagnostic algorithm has been recommended recently, research studies that tried to standardize techniques for the diagnosis of NTM are listed below to demonstrate the changing trend in techniques for the identification of NTM and to emphasize the need for future research.

 Phenotypic Tests



Culture methods

A decontamination procedure was standardized in the year 2004 by Parashar et al. from JALMA, Agra for isolation of environmental mycobacteria. Treatment of soil and water samples with 3% sodium dodecyl sulfate, 4% NaOH, and 2% cetrimide was found to be effective for complete decontamination of other microbes and facilitated isolation of environmental mycobacteria.[87] With the range of contaminants present in different types of settings, this study elucidated the importance of developing an in-house method of decontamination procedures depending on the setting and sample. In the same year, Narang et al. demonstrated the use of Paraffin Slide Culture method for the detection of NTM from stool and sputum of AIDS patients. This kit-based method (Infectech Identikit™) was proved to be useful in baiting out NTM from the specimen and the principle behind the kit is based on NTM's ability to grow on paraffin slide while MTB do not. The authors claim that in situ staining and biochemical tests were also possible with NTM culture grown by this method along with genetic characterization.[88] However, there is no evidence in India of further validation studies based on this culture method. Currently recommended culture method involves the use of specific growth inhibitors such as nitro-alpha-acetyl amino-beta-hydroxypropiophenone or Para nitro benzoic acid that allow the growth of NTM and inhibit the MTBC, thereby facilitating the differential diagnosis as well.[89]

 Immunological Assays



Use of KatG protein as marker for ELISA-based diagnostic test in MAC-infected patients was demonstrated by Gupta et al. from Chandigarh in 2010.[90] The rapid discrimination of MTBC and NTM in clinical isolates from extra-pulmonary tuberculosis was carried out by an immunochromatographic test (ICT) based on mouse monoclonal anti-MPT64 and was evaluated in the year 2011.[91] The study showed that the ICT could be performed using the culture isolates and was simple and less time consuming. Simultaneously, its cost-effectiveness was also demonstrated by Shenoy and Mukhopadhyay from Karnataka in the year 2014.[92] The utility of fluorescence in situ hybridization assay in differentiating MTBC and NTM in resource-limited setup was demonstrated in their study by Baliga et al. from Karnataka in the year 2018. The results obtained showed the limit of detection of MTB in spiked sputum sample to be 2.2 × 104 CFU/ml and the assay could be completed in 2 h.[93]

 Genotypic Tests



Polymerase chain reaction

In the year 1997, considerable number of MAC isolates reported to have discrepant results by AccuProbe test, polymerase chain reaction (PCR) restriction enzyme analysis (PRA) or 16S rRNA sequencing were characterized by DT6-DT1 PCR. Among 84 strains (a mixture of clinical and environmental isolates from Caribbean Isles, Europe, and the Indian subcontinent) identified as members of MAC, 19 discrepant isolates could be further characterized and identified by DT1 PCR.[94] A single step multiplex PCR from three different DNA target amplifications was developed in the year 2003 by Bhattacharya et al. from Kolkata to differentiate MTB and NTM. The developed protocol was tested on the retrospective specimens (411) collected from suspected cases of tuberculosis and mycobacterioses during 1996–2001. The multiplex PCR was positive for 379 cases compared with 280 cases by standard techniques, thereby endorsing its utility in NTM detection.[95] A novel PCR method was developed in the same year with a set of primers targeting the gene encoding for early secreted antigen-6 (ESAT 6) by Singh et al. from New Delhi to differentiate MTBC from NTM. The ESAT 6 gene is absent in most of the NTM and is conserved only in MTBC, M. kansasii and M. marinum. From the total of 145 isolates (detected by16srRNA PCR) the novel PCR could detect 122 (84.2%) MTBC and 23 (15.8%) NTM isolates and was further confirmed by 16srRNA species-specific sequencing.[96] For differential diagnosis, a triplex PCR was developed by Gopinath Singh in 2009 that could detect and differentiate MTB, M. avium, and other mycobacterial isolates in a single reaction tube.[97] Similarly, a species-specific accuprobe test was developed in 2011 by Verma et al. in Delhi to differentiate MTBC and NTM and compared to conventional tests, it showed increased sensitivity and specificity.[98] In the year 2017, two targets Rv1458c and hsp65 were used in a duplex PCR assay to demonstrate their use as a diagnostic marker for differential identification of MTBC and NTM.[99]

Polymerase chain reaction – Restriction fragment length polymorphism

In the year 2007, Aravindhan et al. from Chennai developed a PCR-restriction fragment length polymorphism assay that targets mycobacterial groES gene to differentiate M. avium and M. intracellulare and the assay proved as a complement to HPLC in the differentiation of MAC isolates.[100] In 2013, Varma-Basil et al. from New Delhi developed a novel PCR restriction analysis with hsp65 gene as target to identify Mycobacterium spp. and further digestion with restriction enzymes NruI and BamHI was used to differentiate between MTBC and NTM.[101] Similar to this study, in 2015, Verma et al. from New Delhi developed a PCR targeting the same gene followed by restriction analysis using different enzymes (BstEII and HaeIII) and applied it to 109 clinical isolates. The results obtained were comparable with the results of biochemical tests for all 109 NTMs and 107 of them could be identified up to species level.[102]

Line probe assay (LPA)

In the year 2013, a commercial kit for line probe assay (LPA), the GenoType® mycobacterium common mycobacteria/additional species (CM/AS) assay (Hain Life science, Nehren Germany) that facilitates the identification and differentiation of NTM species was evaluated by Singh et al. The study was conducted in Lucknow on a sample size of 1080 (variety of pulmonary and extrapulmonary source) and identified sixty NTM from 219 culture-positive isolates. The identification of NTM by the kit was found to be rapid and accurate compared with different genotypic and phenotypic tests.[103] A cross-sectional study conducted in Bangalore in the year 2018 employed the available NTM identification tests on culture isolates obtained from RNTCP accredited laboratories. Deeming the cost-effectiveness and operational feasibility, this study recommended that differentiation of MTBC from NTM can be done by biochemical test and speciation can be done by HPLC with further confirmation by LPA CM/AS kit.[8] LPA assays have a sensitivity and specificity of 90% and 89% and 98% and 99%, respectively, for detection of rifampin and isoniazid resistance. For now in India, as per PMDT guidelines, the LPA CM/AS kit is suggested for molecular identification and speciation of NTM species since HPLC has its own limitations like failing to identify newer species.

 Treatment and Drug Susceptibility Testing



Initially, the drug susceptibility testing of NTM is based on the recommendations given in the guidelines jointly issued by the ATS and IDSA in 2007.[2] The testing and treatment of NTM infection varies depending on the species particularly between the rapid growers and slow growers. The method of treatment could be by surgery or drug therapy or can be combined based on the site of infection and species involved. Due to the prolonged duration of treatment (continued treatment for 12 months after the sputum is negative), adverse toxic effects have been documented implicating the need for careful monitoring.[3] Recently, ATS, IDSA, European Respiratory Society (ERS), and European Society of Clinical microbiology and Infectious Diseases (ESCMID) jointly developed a guideline to update the treatment recommendations for NTM pulmonary disease in adults. This guideline proposes to help health-care professionals in treating the disease caused by the most common NTM pathogens comprising M. kansasii, M. xenopi, and MAC complex among the slow growers and M. abscessus among rapid growers.[104]

The drugs used against slow-growing NTM species include rifampicin, macrolides, ethambutol, and amikacin, while for rapid growers, the drugs used are macrolides, aminoglycosides, fluoroquinolones, oxazolidinones, tigecycline, carbapenems, and cephalosporins. However, the drug susceptibility testing (DST) of NTM against these antibiotics is not very clear since the in vitro and in vivo testing do not correlate well,[2] and this could be due to technical difficulties in laboratories and insufficient clinical validation for the tests. With the impact created by NTM in recent years, their DST has also gained importance. The reports in India that attempted different approaches for DST are described below.

 Kirby Bauer Method of Testing



In the year 2010, Gayathri et al. from Chennai looked into the susceptibility pattern of around 148 rapid growers (77 strains of M. abscessus, 66 strains of M. fortuitum, M. farcinogenes, M. fortuitum III biovariant complex, M. immunogenum, M. smegmatis, and M. chelonae [one each]) to fluoroquinolones, macrolides, cephalosporins, and amikacin using kirby–Bauer method following Clinical and Laboratory Standard Institute (CLSI) guidelines. The susceptibility pattern was demonstrated to be 98% to amikacin (146), 91% to gatifloxacin (138), 87% to moxifloxacin (132), 76% to ciprofloxacin (122), and 74% to norfloxacin (116). Majority of the RGM isolates were resistant to cefaperazone, ceftazidime, and cephotaxime, and all the M. abscessus were resistant to tobramycin. The study demonstrated that, for treatment of infection by RGM, amikacin can be the preferred drug and alternatively fluoroquinolones can also be used.[105] However, Kirby–Bauer method is currently not in use and is not recommended by CLSI.

 Minimum Inhibitory Concentration Method of Testing



A study from Delhi conducted in the year 2007 reported the drug resistance profile of 49 MAC isolates to nine drugs by minimum inhibitory concentration (MIC) method. The sensitivity rate was demonstrated to be 28.6% to rifampicin, 22.85% to ethambutol, and isoniazid each and 36.7% to streptomycin, documenting a higher level of resistance to first-line drugs. In contrast by the same method with the second-line drug panel, more than 40% of isolates were sensitive to roxithromycin (42.86%), amikacin (46.94%), and ciprofloxacin (48.98%) by the MIC method.[106] These results were compared with the results of drug susceptibility assays in agar using recommended dilutions of drugs (single concentration). Taking Heifets ranges of the MICs as the reference point, this study confirmed the suitability of broth microdilution method (MIC) for DST of NTM. In the year 2010, MIC by E-test for the antibiotics, amikacin, tobramycin, ciprofloxacin, gatifloxacin, azithromycin, and clarithromycin against 15 rapid growers (13 M. chelonae complex and 2 M. fortuitum complex) isolated from keratitis patients was determined by Reddy et al. in Hyderabad.[107] As control starin, S. aureus ATCC 29213 was tested for every E-test performed, and the quality control was deemed to be acceptable if obtained results were within CLSI recommended range. Based on the results obtained; the group suggested that the topical amikacin in combination with oral azithromycin or clarithromycin could be a treatment choice for keratitis caused by rapid growers.

 Microtitre Plate Based Method of Minimum Inhibitory Concentration



In 2004, susceptibility test results of MAC isolates to clarithromycin done by Microplate alamar blue assay (MABA) was compared with that of BACTEC method by Vanitha and Paramasivan from Chennai. On the whole agreement between both the assays was 86% among the clinical isolates (51) and clarithromycin mutants of MAC tested, indicating the need for improvement of technical expertise in MABA.[108] A study from Agra in 2007 demonstrated that Resazurin microtitre assay (REMA) is a robust and cost-effective method for DST of mycobacteria against ethambutol and is more accurate compared to agar method.[109] Another recent study in 2021 documented the noninferiority of REMA compared to standard microbroth dilution method recommended by CLSI.[110]

Overall, in a diagnostic algorithm of NTM, most of the mycobacterial experts and CLSI recommend the identification of the organism to species level or to subspecies level[111] before DST. After their identification, the most frequently encountered NTM species are subjected to DST by the broth dilution method as per ATS and CLSI guidelines, and this is crucial for making appropriate treatment options.[112] Molecular methods of drug susceptibility testing are rapidly evolving in recent years. Genotype NTM-DR VER 1.0 is the recent LPA-based product from Hains that detects drug resistance of NTM against macrolides and amino glycosides, and it needs exploratory research in India. In upcoming years, prediction of resistance pattern and detection of NTM by whole-genome sequencing (WGS) can also be a practical method of choice since it is now becoming more accessible to clinical laboratories.[113] This could be justified by a study in 2019 where, of the 200 confirmed MTB-culture isolates subjected to WGS, 39 of them were found be mixed with NTM isolates, thereby indicating coinfection.[114] This recent study elucidated the significance of simultaneous diagnosis of NTM and MTB and the use of WGS for accurate diagnosis. The recent advances made in WGS have the potential of making commendable improvement in characterization of the microorganisms, and exploration of unexpected outbreaks. The use of WGS in the diagnosis of MTB and NTM with their drug resistance will make it an alternative diagnostic test in near future for rapid results.

 Conclusion and Way Forward



With the increasing reports on the rising incidence of NTM in recent years, there is a need for extensive research on different platforms. A differential diagnostic test is essential to discriminate the contaminants and pathogenic NTM for treatment options and in case of mixed infection to distinguish TB. A well-formulated diagnostic algorithm that includes radiological, clinical, and laboratory diagnosis of NTM is the need of the hour. As the price per sequencing is steadily coming down, WGS could be the test of choice to predict the species, drug resistance, outbreak in hospitals, and transmission dynamics. However, a standard protocol for the sequence analysis along with clinical correlation needs to be tailored and monitored.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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