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Year : 2020  |  Volume : 152  |  Issue : 3  |  Page : 185-226

Epidemiology, diagnosis & treatment of non-tuberculous mycobacterial diseases

Department of Molecular Medicine, Jamia Hamdard Institute of Molecular Medicine, Jamia Hamdard (Deemed-to-be-University), New Delhi, India

Date of Submission03-Apr-2020
Date of Web Publication17-Oct-2020

Correspondence Address:
Dr Surendra K Sharma
Department of Molecular Medicine, Jamia Hamdard Institute of Molecular Medicine, Jamia Hamdard (Deemed-to-be-University), Hamdard Nagar, New Delhi 110 062
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmr.IJMR_902_20

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Non-tuberculous mycobacteria (NTM) are ubiquitously present in the environment, but NTM diseases occur infrequently. NTM are generally considered to be less virulent than Mycobacterium tuberculosis, however, these organisms can cause diseases in both immunocompromised and immunocompetent hosts. As compared to tuberculosis, person-to-person transmission does not occur except with M. abscessus NTM species among cystic fibrosis patients. Lung is the most commonly involved organ, and the NTM-pulmonary disease (NTM-PD) occurs frequently in patients with pre-existing lung disease. NTM may also present as localized disease involving extrapulmonary sites such as lymph nodes, skin and soft tissues and rarely bones. Disseminated NTM disease is rare and occurs in individuals with congenital or acquired immune defects such as HIV/AIDS. Rapid molecular tests are now available for confirmation of NTM diagnosis at species and subspecies level. Drug susceptibility testing (DST) is not routinely done except in non-responsive disease due to slowly growing mycobacteria ( M. avium complex, M. kansasii) or infection due to rapidly growing mycobacteria, especially M. abscessus. While the decision to treat the patients with NTM-PD is made carefully, the treatment is given for 12 months after sputum culture conversion. Additional measures include pulmonary rehabilitation and correction of malnutrition. Treatment response in NTM-PD is variable and depends on isolated NTM species and severity of the underlying PD. Surgery is reserved for patients with localized disease with good pulmonary functions. Future research should focus on the development and validation of non-culture-based rapid diagnostic tests for early diagnosis and discovery of newer drugs with greater efficacy and lesser toxicity than the available ones.

Keywords: Diagnosis - non-tuberculous mycobacteria pulmonary disease - NTM - NTM extrapulmonary disease - treatment

How to cite this article:
Sharma SK, Upadhyay V. Epidemiology, diagnosis & treatment of non-tuberculous mycobacterial diseases. Indian J Med Res 2020;152:185-226

How to cite this URL:
Sharma SK, Upadhyay V. Epidemiology, diagnosis & treatment of non-tuberculous mycobacterial diseases. Indian J Med Res [serial online] 2020 [cited 2021 Sep 18];152:185-226. Available from:

   Introduction Top

Non-tuberculous mycobacteria (NTM) are known by several names including environmental mycobacteria, atypical mycobacteria or anonymous mycobacteria, mycobacteria other than Mycobacterium tuberculosis (Mtb) (MOTT) and its close relatives, M. africanum, M. bovis, M. canetti, M. caprae, M. pinnipedii and M. leprae[1]. These organisms are ubiquitous in the environment and have been isolated from air, soil, dust, plants, natural and drinking water sources including biofilms, wild animals, milk and food products[2],[3]. NTM are characterized by a thin peptidoglycan layer surrounded by a thick outer lipid-rich coating that enables NTM attachment to rough surfaces and by offering resistance to antibiotics and disinfectants, helping NTM survival in low oxygen and carbon concentrations and in other adverse conditions[4]. Based on their growth characteristics from the subculture, NTM are divided into rapidly growing mycobacteria (RGM; <7 days) and slowly growing mycobacteria (SGM; ≥7 days)[5][Table 1]. At present, there is no evidence for the latency of NTM[6]. Taxonomy of the genus Mycobacterium includes about 200 species and 13 subspecies[7],[8],[9].
Table 1: Common non-tuberculous mycobacteria (NTM) species causing human diseases

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In high tuberculosis (TB)-burden countries, diagnosis of NTM is rarely made because of lack of awareness among healthcare providers about the NTM diseases and poor access to adequate laboratory resources including mycobacterial culture and molecular methods for identification or speciation[10]. In these resource-limited settings, there is a heavy reliance on smear microscopy for the diagnosis of TB, and the diagnosis of NTM is frequently missed and these patients are empirically treated as drug-sensitive and -resistant TB[11].

   Epidemiology Top

NTM disease burden

[Table 2] describes the distribution of various NTM species in the environment[2],[3]. [Table 3] details the major differences between NTM and Mtb[1],[2],[3],[4],[5],[6],[9],[12],[13],[14],[15],[16],[17],[18],[19],[20]. Although recent reports regarding the transmission of M. abscessus and M. massiliense have not proven person-to-person transmission, but these are highly suggestive of indirect transmission among cystic fibrosis (CF) patients[21]. Systematic reporting of NTM diagnosis is not done because the disease is not notifiable to public health authorities in several countries[10]. NTM lung infection rates, defined as individuals with NTM-positive cultures and those with defined NTM pulmonary disease (NTM-PD), increase with age[22] and differ considerably among various countries[23],[24],[25]. Many studies have suggested an increase in the prevalence rates of NTM over the last four decades[22],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36]. The data from the USA suggest that the current prevalence of NTM-positive culture ranges between 1.4 and 6.6/100,000 individuals[26], whereas UK data suggest that NTM-positive culture incidence has increased from 4/100,000 to 6.1/100,000 individuals between 2007 and 2012[35]. A study from Canada has reported a significant increase in the prevalence of NTM-PD from 29.3 cases/100,000 in 1998-2002 to 41.3/100,000 individuals tested in 2006-2010[36]. Several factors that have contributed to this increase in the incidence and prevalence are listed in [Box 1][37],[38]. Published reports on rate of NTM isolation from several countries are summarized in [Table 4][22],[29],[30],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63].
Table 2: Environmental niches of non-tuberculous mycobacteria (NTM)

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Table 3: Differences between non-tuberculous mycobacteria (NTM) and Mycobacterium tuberculosis (Mtb)

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Table 4: Global prevalence of pulmonary non-tuberculous mycobacteria (NTM) isolation and NTM disease

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Details of 13 Indian studies published between 1985 and 2019 are summarized in [Table 5][59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71]. Most of these studies have reported NTM isolation rates from laboratories without describing clinical features and treatment details. Two studies were done exclusively on extrapulmonary specimens and 11 on both pulmonary and extrapulmonary specimens. NTM isolation prevalence varied between 0.38 and 23.7 per cent. Six of these 13 studies reported NTM prevalence ≤1 per cent among TB suspects. Almost all except one study have not provided treatment outcomes. Most of the studies (11/13) were hospital based and had selection bias. A large community-based study from south India conducted at four sites in the pre-HIV era has reported NTM isolation prevalence between 4.5 and 8.6 per cent in the sputum specimens. This variable NTM prevalence can be attributed to the following factors: (i) differences in study designs, (ii) standard American Thoracic Society (ATS) (2007)[17] and British Thoracic Society (BTS) (2017)[1] guidelines criteria were not followed in most of these studies, (iii) only laboratory-related NTM culture data have been reported, and (iv) most of the studies have not provided clinical details and treatment outcomes. Of the 13 studies, only two[61],[71] followed ATS guidelines (2007)[17] and one of these reported treatment outcomes[61]. Future studies should report about extrapulmonary NTM diseases in addition to clinical details including treatment outcomes of various NTM diseases.
Table 5: Summary of Indian studies on non-tuberculous mycobacteria (NTM)

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Risk factors for NTM disease

Risk factors for NTM diseases vary according to the clinical type of NTM disease[72],[73],[74]. Various risk factors for NTM-PD are described in [Box 2]A[72],[73],[74]. Pre-existent lung disease is mostly present in these patients. In the absence of obvious structural lung disease, patients may have quantitatively impaired ciliary function or may be heterozygous for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations[75],[76]. Extrapulmonary NTM disease can occur due to breaches in skin or soft tissues or due to several nosocomial factors, which are detailed in [Box 2]B[72],[73],[74]. Disseminated NTM disease generally occurs in patients having primary or acquired immunodeficiency conditions. Certain environmental and organism-related factors such as water sources and reservoirs, and NTM growth characteristics in different climatic conditions, have also been reported as risk factors [Box 2]B[72],[73],[74]. In addition, habits, hobbies and profession of an individual may also increase the risk of having NTM disease[74].

Immunopathogenesis of NTM disease

In addition to lung, the most common organ involved affected by NTM, localized and disseminated NTM infections can occur[73]. Patients with disseminated NTM infections (defined as involvement of two or more non-contiguous body organs) usually have underlying generalized immune defect such as HIV/AIDS, and 2-8 per cent of these patients may have concurrent pulmonary involvement[77]. Identification of the underlying immune defect is crucial for early diagnosis, treatment and prevention. Patients with NTM disease and underlying primary immunodeficiencies typically present in their childhood or adulthood, whereas those with acquired immunodeficiencies can present at any age [Table 6][73].
Table 6: Primary and acquired immune deficiencies associated with disseminated non-tuberculous mycobacterial (NTM) infection

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Antimycobacterial cell-mediated immunity requires a close interaction between myeloid and lymphoid cells [Figure 1][73]. Mononuclear phagocytes after engulfing mycobacteria secrete interleukin-12 (IL-12) which, in turn, stimulates T cells and NK (natural killer) cells through the IL-12 receptor (heterodimer of IL12RB1 and IL12RB2). A complex cascade is triggered by IL-12 receptors via TYK2 (tyrosine kinase) and JAK2 (Janus kinase) signals, leading to STAT-4 (signal transducer and activator of transcription) phosphorylation, homodimerization and nuclear translocation to induce interferon-gamma (IFN-γ) secretion [Figure 1]. IFN-γ binds to its receptor IFNG receptor (IFNGR) (heterodimer of IFNGR1 and IFNGR2) and leads to phosphorylation of JAK2, JAK1 and STAT1 and phosphorylated STAT1 (pSTAT1) homodimerisation. The pSTAT1 homodimer [IFN-γ activators (GAF)] binds to IFN-γ activation sequence which upregulates IFN-γ responsive gene transcription. This cascade leads to activation and differentiation of macrophages. As a result, upregulation of IL-12 and tumour necrosis factor-α (TNF-α) secretions facilitates granuloma formation. After these events, macrophages can kill intracellular mycobacteria being assisted by maturation of mycobacterial phagosome, nutrition deprivation and induction of autophagy, exposure to antimicrobial peptides and reactive oxygen species. The nuclear factor (NF) κB essential modulator-mediated pathway and oxidative burst from macrophages are also important to fight against NTM infection[73]. Genetic defects in any of these immune factors may disturb the cascade of protection against mycobacterial infection and may lead to disseminated NTM disease[73]. These immune defects have been summarized in [Table 6][73].
Figure 1: Host defence mechanisms against non-tuberculous mycobacteria (NTM). Defects leading to disseminated NTM infection are shown in red. ISG15, interferon-stimulated gene 15; IFNGR, interferon-gamma receptor; TYK, tyrosine kinase; JAK, Janus kinase; STAT, signal transducer and activator of transcription; IRF, interferon regulatory factor; GATA, transcription factor implicated in early haemopoietic, lymphatic, and vascular development; NEMO, nuclear factor kappa-light-chain-enhancer of activated B cells essential modulator; IL, interleukin; TNF, tumour necrosis factor; TLR, toll-like receptors. Source: Reproduced with permission from Ref. 73.

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   Clinical manifestations Top

The clinical manifestations of NTM disease are similar to those of TB and may pose a diagnostic challenge even to an experienced clinician. NTM disease is classified into four clinical types: (i) chronic PD, (ii) lymphadenopathy, (iii) skin and soft tissues, rarely, bones and joints, and (iv) disseminated disease[73].

Chronic pulmonary disease (PD)

The ATS and Infectious Disease Society of America (IDSA), 2007[17], and BTS, 2017[1], ATS/ERS/ESCMID/IDSA[18] have published guidelines to standardize the diagnosis and treatment of NTM diseases. While evaluating NTM suspects, the following criteria should be followed: (i) pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or high-resolution computed tomography (CT) scan that shows multifocal bronchiectasis with multiple, small nodules; (ii) positive culture results from at least two separate expectorated sputum samples [if the results from the initial sputum samples are non-diagnostic, consider repeat sputum acid-fast bacilli (AFB) smear and culture]; single-positive NTM culture from CT-directed bronchoalveolar lavage or bronchial washing specimen from the affected lung segment of NTM suspect who cannot expectorate sputum or whose sputum is consistently culture-negative; and (iii) other disorders such as TB and fungal infections must be excluded[1],[17].

Patterns of NTM-PD: Chronic PD is the most common form of NTM disease. Three patterns of pulmonary involvement have been described[17]: (i) fibro-cavitary type, which usually occurs in the upper lobe with a history of smoking in an older male patient with pre-existent lung disease such as chronic obstructive pulmonary disease (COPD), bronchiectasis and CF [Figure 2]; (ii) nodular/bronchiectatic type of pattern occurring in post-menopausal, non-smoking females, predominantly having right middle lobe and left lingular bronchiectasis with a few lung nodules. This syndrome was described after the main character in Oscar Wilde's eponymous play as 'Lady Windermere syndrome'[78], and was believed to occur from voluntary cough suppression[79], however, subsequently, this hypothesis was discarded[80]. Other features include mitral valve prolapse, scoliosis and pectus excavatum; high prevalence of gastro-oesophageal reflux disease (GERD) (26-44%)[81],[82]; increased adiponectin; decreased leptin and estrogen levels and abnormalities in fibrillin gene. Presence of all these features increases the susceptibility of these females to MAC infections[83]; and (iii) hypersensitivity pneumonitis-like NTM PD or 'hot tub lung' occurring due to exposure to aerosols from indoor hot tub. Various risk factors for NTM-PD are listed in [Box 2]A.
Figure 2. (A) Chest radiograph in a 62 yr old female with asthma, allergic bronchopulmonary aspergillosis and bronchiectasis. Mycobacterium simiae was isolated repeatedly from the sputum. (B) High-resolution computed tomography chest (axial section) showing bilateral bronchiectasis in the right middle lobe, lingula and lower lobes.

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NTM species and NTM-PD: Because of variable virulence, it is important to identify NTM species and M. abscessus subspecies for the management of NTM-PD. It has been reported that only 25-60 per cent of patients with positive respiratory specimen fulfil clinical, radiographic and microbiological criteria of NTM-PD[84]. Patients in whom M. kansasii and M. malmoense are isolated from respiratory specimens frequently meet clinical disease criteria, as these NTM isolates are clinically highly relevant, whereas 40-60 per cent with MAC, M. abscessus and M. xenopi and <20 per cent of patients with M. chelonae and M. fortuitum meet clinical disease criteria[44],[85],[86],[87],[88],[89].

The potential to produce specific clinical type of lung disease also varies among NTM species. While M. kansasii, M. xenopi and M. malmoense commonly cause fibro-cavitary disease but rarely nodular-bronchiectatic disease[17],[44],[90],[91], MAC and M. abscessus cause both types of NTM-PDs and MAC and M. immunogenum cause hypersensitivity pneumonitis-like NTM-PD[17].

MAC is the most common NTM isolated from respiratory secretions in patients with NTM-PD. While a single strain of MAC species is repeatedly isolated in the cavitary type, several strains of MAC species may occur simultaneously or the strain may change sequentially in nodular-bronchiectatic type[92],[93]. Relapse versus new re-infection of MAC infection after treatment completion can be differentiated by MAC genotyping[94].

According to one study from the USA, while tap water was the source of M. avium infection, soil was the source of M. intracellulare infection[94]. It has been suggested that patients with M. intracellulare lung disease present at a later stage with adverse prognosis than patients with M. avium lung disease, and M. chimaera is less virulent than M. avium and M. intracellulare[95],[96]. Significant geographic variation exists in the distribution of NTM species in the USA; where M. avium complex was the most common species isolated in the South, M. abscessus/M. chelonae was proportionately higher in the West in one study[97]. MAC species also vary from region to region: while M. avium is dominantly found in South America and Europe, M. intracellulare is found in South Africa and Australia[23]. Recurrence rates in MAC-associated lung disease also differ among MAC species[95].

The second common NTM species also has a geographical variation. While M. abscessus is the second most common cause of NTM-PD in the USA[98], M. kansasii in some European countries including the UK, M. xenopi in some parts of Europe and Canada and M. malmoense in northern Europe are the second most common causes of NTM-PD[99]. M. kansasii, one of the slowly growing NTM, is most virulent[98]. About 80 per cent of NTM-PD due to RGM results from M. abscessus[100]. There are three subspecies of M. abscessus: (i) M. abscessus subsp. abscessus, which is the most common pathogen (45-65%), followed by (ii) M. abscessus subsp. massiliense (20-55%), and (iii) M. abscessus subsp. bolletii (1-18%)[101]. Patients with gastro-oesophageal disease may have NTM-PD due to RGM such as M. fortuitum[17].

Clinical features: Respiratory symptoms and signs in NTM-PD vary depending on the clinical type. In the cavitary type, these may be severe due to the pre-existent underlying lung disease and include shortness of breath, cough with expectoration and haemoptysis, whereas patients with nodular-bronchiectasis have milder respiratory symptoms without pre-existing parenchymal lung disease and nagging cough may be prominent. Constitutional symptoms such as fever, anorexia, progressive fatigue, malaise and weight loss may be present especially in cavitary type of NTM-PD[1],[17]. The clinical and radiographic presentation in M. kansasii PD is similar to Mtb and includes fever, cough with or without haemoptysis and chest pain, and chest X-ray often shows infiltrates and cavitary lesions[17],[102] [Figure 3]. Patients with hypersensitivity pneumonitis-like NTM-PD have subacute onset of respiratory symptoms involving young individuals without pre-existing lung disease and the prognosis is good[17],[103],[104].
Figure 3: Chest radiograph in a 29 yr old female patient with Mycobacterium kansasii- pulmonary disease. (A) Chest X-ray reveals a cavitary lesion in the left lung. (B) Axial section in the high-resolution computed tomography scan demonstrates a cavity in the left lung (white arrow) and tree-in-bud appearance in the right lung (white circle).

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In low TB-burden countries, single-site lymphadenitis is the most common manifestation of NTM infection in younger children[74],[105]. Solitary lymph node is usually localized to the submandibular or cervical region and rarely, can also involve other groups either singly or multiple such as axillary, inguinal region in the disseminated NTM disease in severely immunocompromised individuals[106]. The lymph node enlargement usually starts as a painless swelling and later in the advanced stage, the swelling becomes fluctuant with pus inside, which may later burst out with a sinus formation. Constitutional symptoms such as fever, weight loss and fatigue may be absent. Smear microscopy and culture may be negative because of paucibacillary nature of the disease[17]. Molecular tests may be used to establish the diagnosis. MAC is the most frequently isolated NTM species. There is an inverse relationship of TB incidence and NTM disease and in high TB-burden countries, Mtb is the most frequent cause of lymphadenitis in all ages[106].

Skin, soft tissues and bone NTM infections

Three types of clinical presentations have been described: (i) Buruli ulcer (predominantly occurring in Uganda) or Bairnsdale ulcer disease (predominantly occurring in Australia), certain regional pockets in Latin America and China: it is a severe cutaneous disease due to M. ulcerans which progresses from nodular cutaneous lesions into large painless ulcers[107]. These organisms produce a toxin, mycolactone, which produces damage to the skin[108]. Early diagnosis and treatment is essential to minimize morbidity and costs and prevent long-term disability[109]; (ii) infection due to M. marinum is also known as fish-tank granuloma (previously known as swimming pool granuloma) and the infection can be acquired from swimming pools, cleaning of fish tanks or any other fish- or water-related activity[110]. Organisms usually gain access through skin cuts or abrasions[111]. It starts as a single papulonodular, verrucous or ulcerated granulomatous lesion over the hand and forearm that progresses to form multiple skin lesions in a sporotrichoid pattern - appearance which is similar to skin lesions due to Sporothrix schenckii and rarely, the underlying bone involvement occurs[112]; and (iii) localized skin and soft-tissue infections occurring due to RGM (M. abscessus, M. fortuitum and M. chelonae) at wound or injection sites[113],[114],[115][Figure 4] and [Figure 5] and slowly growing mycobacteria in both immunocompromised and immunocompetent individuals[115],[116]. These organisms gain access through skin breaks following trauma and surgical procedures, following the use of surgical instruments without autoclaving, during cosmetic surgery, pedicure and manicure procedures in beauty salons, surgical procedures involving placement of various implants, in mesh used for hernial site repair [Figure 6], tattooing procedures following inoculation of contaminated ink containing M. haemophilum, intravenous punctures and lines, abscesses due to intramuscular injections through contaminated needles and use of tap water for skin cleaning[112],[113].
Figure 4: (A) A 35 yr old female presented with discharge from the right nipple, Mycobacterium abscessus was isolated from the pus on several occasions prior to treatment. (B) Computed tomography (CT)-chest showing enhancement of the margin of the abscess (black arrow) with intravenous contrast. Source: Reproduced with permission from Ref. 61.

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Figure 5: (A) Clinical photograph of a 30 yr old male, showing right-sided post-injection gluteal abscess (black arrow) in a patient with NTM infection. (B) Transaxial fused[18]F-fluorodeoxyglucosepositron emission tomography-computed tomography ([18]F-FDG-PET-CT) image of the same patient, at the level of acetabulum showing FDG accumulation in the subcutaneous thickening and stranding (arrow) involving the underlying right gluteus muscle superficially in right gluteal region. Source: Reproduced with permission from Ref. 61.

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Figure 6: Clinical photograph of a 35 yr old male, showing discharging sinus (white arrow) in the abdominal wall in a patient infected with Mycobacterium abscessus following hernia repair with mesh. Source: Reproduced with permission from Ref. 61.

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Disseminated NTM disease

Disseminated NTM disease due to MAC is frequent in HIV/AIDS especially in patients with CD4+ lymphocyte count <50 cells/μl. Isolated pulmonary involvement is rare in HIV/AIDS[117]. Pulmonary involvement occurs in 2.5-8 per cent of patients with disseminated MAC[77]. The portal of entry in these patients is believed to be through bowel[118],[119],[120] and occasionally through lungs with subsequent haematogenous dissemination. MAC (predominantly M. avium) is the most common NTM species isolated in these patients[17]. These patients typically present with insidious onset of constitutional symptoms comprising fever with night sweats, weight loss, abdominal pain, diarrhoea and malaise[17]. They may have anaemia, hepatosplenomegaly and lymphadenopathy[17]. Somehow, disseminated NTM infections due to rapidly growing NTM (M. abscessus and M. fortuitum) are rare in HIV/AIDS patients[121]. Besides M. avium, less common NTM species such as M. genavense and M. simiae can also cause disseminated NTM disease in HIV/AIDS patients[17].

M. kansasii can cause pulmonary involvement in HIV/AIDS patients at higher CD4+ counts, and its isolation should always be considered a potential pathogen[17],[122]. Pulmonary involvement can also occur in other immunocompromised populations such as organ transplantation (6.5%)[123], bone marrow (2.9%)[124] and rarely liver and kidney transplantation. CF patients undergoing lung transplantation may develop life-threatening infection with M. abscessus[124]. Disseminated NTM infections can also occur in a few other rare settings [Figure 7]A, [Figure 7]B, [Figure 7]C, [Figure 7]D, [Figure 7]E, [Figure 7]F, [Figure 7]G which will require appropriate investigations. These have been listed in [Box 2]B[73]. NTM, especially M. abscessus [Figure 7] and M. fortuitum, may infect deep indwelling lines[17],[122]. Anti-tumour necrosis factor-α agents (infliximab, etanercept and adalimumab) used to treat several diseases such as rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease can predispose to both TB and NTM diseases[125]. A good response to rituximab in disseminated MAC patients with interferon-gamma autoantibodies has also been reported[126],[127].
Figure 7: The patient, a 14 yr old male, had disseminated Mycobacterium intracellulare infection; no immune defect could be detected. He was successfully treated. (A) The magnetic resonance imaging scan shows osteomyelitis of foot bone (black arrow). (B) Black arrow shows healing of cutaneous lesion by keloid formation. (C) Upper part of thigh shows another healed skin lesion (black arrow). (D and E) Hypodense lesions in the spleen (white open circles) and peri-splenic abscess (white arrows). (F) Bilateral conglomerate necrotic axillary (extreme-left and -right arrows) and right paratracheal lymph nodes (long and short arrows in the centre of CT image), calcification is also noted in the lymph nodes. (G) Iliopsoas abscess on the right side (white asterisk). Source: Reproduced with permission from Ref. 61.

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   Diagnosis Top

Criteria for the diagnosis of NTM disease

Healthcare providers should carefully assess causality association of the isolated NTM species with patient's symptoms and signs. Approximately, one-third of NTM species are potentially pathogenic for humans[128]. Some of the common pathogenic NTM species are listed in [Table 7][2],[3],[10],[129]. It is possible that an individual with a particular NTM isolate may not have an active disease or the isolate may not be clinically relevant. While evaluating NTM suspects, the following criteria should be followed: (i) pulmonary symptoms, nodular or cavitary opacities on chest radiograph or high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules; (ii) positive culture results from at least two separate expectorated sputum samples (if the results from the initial sputum samples are non-diagnostic, consider repeat sputum AFB smear and culture; single-positive NTM culture from CT-directed bronchoalveolar lavage or bronchial washing specimen from the affected lung segment of NTM suspect who cannot expectorate sputum or whose sputum is consistently culture negative); and (iii) other disorders such as TB and fungal infections must be excluded[1],[17].
Table 7: Clinically relevant non-tuberculous mycobacteria species

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Differential diagnosis

Because of similar clinical features and radiographic appearances, diseases such as TB, recurrent pulmonary aspirations, pneumonitis, bronchiectasis, histoplasmosis, aspergillosis and lung cancer should be considered in the differential diagnosis and should be appropriately ruled out. In the laboratory, the presence of Pseudomonas aeruginosa, Staphylococcus aureus, Nocardia and Aspergillus in the specimens must be carefully tested[17]. It is important to consider the differential diagnosis of Sporothrix schenckii infection in patients suspected to have skin and soft-tissue NTM disease due to M. marinum[113].

Specimen collection, transportation and processing

A proper sample collection is crucial to establish a correct laboratory diagnosis of NTM disease. In case of NTM-PD patients, during collection of sputum, environmental and personal contamination should be avoided. To differentiate NTM-PD from occasional presence of NTM in tracheobronchial tract, at least 3 sputum specimens should be tested on separate occasions[18]. Sampling from extrapulmonary specimens should be obtained directly from the lesion or organ concerned[130]. Further, instruments used for sampling should be devoid of any contamination, especially in hospital settings. Storage and transportation of specimens should be done carefully[130]. Once the specimen reaches the laboratory, the process of decontamination should be done in fully sterilized set-up. As NTM are resistant to most of the common disinfectants, careful selection of disinfectants is necessary[130]. Various precautions for sample collection, transportation and laboratory processing are listed in [Box 3][130].

Laboratory diagnosis of NTM disease

[Figure 8] illustrates various steps for NTM isolation and identification in the laboratory. Initially, the specimens are simultaneously subjected to AFB (Ziehl-Neelsen or fluorochrome) staining and GeneXpert for Mtb detection. Samples that are positive on AFB staining and negative on GeneXpert are considered NTM suspects, and the culture for such specimens should be done. Most of the NTM are cultivable in Lowenstein-Jensen, Middle-brook and Dubos Broth and Agar. A novel agar-based medium, RGM medium, has been specifically developed for the isolation of rapidly growing NTM. It provides an alternative method for the recovery of NTM from respiratory specimens, particularly from CF patients, by offering a simple and rapid method for specimen processing[131]. For some NTM species, additional supplements (haemin for M. haemophilum and mycobactin J for M. paratuberculosis and M. genavense)[130] are added in the culture medium for optimal growth. Incubation temperatures of 36±2°C for SGM and 28±2°C for RGM have been recommended[18]. Appropriate adjustments in the incubation temperature (M. xenopi: 42-45°C, M. ulcerans and M. marinum: 30°C) may be done for a few NTM species[18],[130]. Some NTM species such as M. tilburgii which are not cultivable need to be tested directly from the specimen using molecular methods[132]. In patients with a high suspicion of NTM-PD but negative cultures, reassessment of decontamination procedures, use of supplemented media and molecular methods may be helpful[18]. Culture isolates of NTM-suspected specimens should be tested with Mtb-specific tests such as MPT64 antigen immunochromatographic test or GeneXpert, and if found negative, then it is likely to be NTM and thereafter its species identification should be done.
Figure 8: Diagnostic algorithm for detection of NTM disease.*According to Ref. 16, consecutive three sputum samples are obtained, positive results from at least two separate expectorated sputum samples confirms the diagnosis.While sputum collection, the patient should not rinse mouth with municipal or untreated water. Spontaneous sputum should be collected or sputum should be induced if no sputum is produced by patient.Whole genome sequencing (NGS) and multi-locus targeted gene sequencing of gene such as 16S rRNA, hsp 65, rpoB, 16S-23S rRNA internal transcribed region (ITS), gyrB, dan A, rec A and sec A. HRCT, high-resolution computed tomography; CSF, cerebrospinal fluid; ICA, immunochromatographic assay; CBNAAT, cartridge based nucleic acid amplification test; L-J, Lowenstein-Jensen media, HPLC: high-performance liquid chromatography, SGM, slowly growing mycobacteria; RGM, rapidly growing mycobacteria; DST, drug susceptibility testing; LPA, line probe assay; PNB: para-nitro benzoic acid; PCR/PRA, polymerase chain reaction/restriction endonuclease assay; MAC, Mycobacterium avium complex; MALDI-TOF MS, matrix-assisted laser desorption ionization-time of flight mass spectrometry.

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Earlier, several biochemical tests were done for NTM identification[130][Table 8]. These tests were cumbersome and time consuming and are obsolete now. High-performance liquid chromatography (HPLC)-based analysis of mycolic acid was used for NTM identification in the past. This method identifies slowly growing NTM species such as MAC and M. kansasii, but it is less specific in identifying RGM accurately[130],[133]. It also has low discriminatory power to identify closely related SGM and RGM species[130],[133]. These tests have now been replaced by molecular tests for NTM species and subspecies identification. These tests include polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, gene probes and line probe assays (LPA)[130][Table 8]. These molecular tests though identify a limited number of NTM species, but fail to differentiate genetically closely related NTM species[133].
Table 8: Laboratory methods for non-tuberculous mycobacteria (NTM) identification

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At present, DNA sequencing is the most accepted method for the identification and characterization of NTM species and subspecies[134],[135]. These techniques include targeted gene sequencing and multi-locus sequence typing (MLST) that involve analysis of conserved genes such as rpoB, hsp65, 16S rRNA and 16S-23S rRNAinternal transcribed spacer (ITS) region[134]. Targeted sequencing of single gene may identify a reasonable number of NTM species but sometimes may not distinguish species having close genetic association. MLST is preferred as multiple conserved genes are sequenced with this technique and on the basis of consensus analysis of different gene sequences, NTM species are identified more accurately[134].

Whole genome sequencing (WGS) is considered the gold standard for NTM species identification and is helpful in understanding the geographical and environmental distribution of NTM species. It is also useful to study healthcare-associated disease outbreaks and transmission[134]. WGS of NTM species can provide information on other characteristics such as virulence and resistance to various antimicrobial agents[135],[136]. However, DNA sequencing is an expensive method and requires expertise[130]. This technique is not available in the routine laboratory set-up for NTM diagnosis in resource-limited countries[130].

Matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS)-based analysis of conserved proteins is another technique available for NTM species identification[137]. MALDI-TOF-MS is considered the most rapid technique[137] which identifies around 160 NTM species[138]. However, like other techniques, MALDI-TOF-MS also fails to identify closely linked NTM species[130]. Details of various NTM identifications methods[130] are summarized in [Table 8].

Drug susceptibility testing (DST)

DST for NTM is controversial because of discrepancy between in vitro susceptibility and the treatment response[101]. DST should follow the Clinical and Laboratory Standards Institute (CLSI) guidelines[16]. CLSI recommends that phenotypic DST should be performed using broth microdilution method[18]. Both phenotypic and genotypic DST for MAC and M. kansasii are performed for initial and recurrent isolates. Acquired resistance for macrolide in MAC occurs due to point mutations in the 23S rRNA (rrl) gene and for amikacin due to mutations in 16S rRNA (rrs) gene (amikacin resistance is observed in MAC isolates cultured from sputum specimens of patients who were extensively exposed to the drug or related aminoglycosides)[18]. For MAC, DST against macrolides [clarithromycin is used as a class agent; minimum inhibitory concentration (MIC) cut-off: >32 μg/ml] and amikacin (MIC cut-off: >64 μg/ml for parenteral and >128 μg/ml for liposomal amikacin) and, for M. kansasii, DST against rifampicin (MIC >2 μg/ml) and clarithromycin are used (MIC ≥32 μg/ml)[128]. When M. kansasii is resistant against rifampicin, DST for amikacin, ciprofloxacin, doxycycline, linezolid, minocycline, moxifloxacin, rifabutin, and trimethoprim-sulfamethoxazole is recommended[18]. RGM species (and subspecies) show different drug resistance patterns[1], and DST should be selectively done for the following antibiotics: macrolides, amikacin, tobramycin, imipenem, trimethoprim-sulphamethoxazole, doxycycline, minocycline, tigecycline, cefoxitin and linezolid[1],[65]. Information on an active erm (41) gene is important in RGM (esp. in M. abscessus subspecies) as it can lead to inducible resistance to macrolides[1],[17]. In M. abscessus subsp massiliense, the erm (41) gene is nonfunctional owing to a large deletion, thus rendering the strains macrolide susceptible. The erm (41) gene is non-functional in some M.abscessus subsp. abscessus due to presence of C instead of T at the nucleotide 28 (arginine 10 instead of tryptophan 10)[18]. Constitutive resistance to macrolides can occur due to mutation in 23S rRNA gene[1]. [Table 9] describes various conditions of macrolide resistance among M. abscessus subspecies. M. chelonae is resistant to cefoxitin and sensitive to tobramycin[1].
Table 9: Interpretation of extended clarithromycin susceptibility results for Mycobacterium abscessus

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   Treatment of NTM disease Top

Principles of treatment

Several guidelines have been published for the management of NTM diseases[1],[17],[18],[19],[139]. While ATS/ IDSA deals with both pulmonary and extrapulmonary NTM diseases, the US Cystic Fibrosis Foundation and European Cystic Fibrosis Society (ECFS) guidelines, 2016[139], include consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF, and the BTS guidelines (2017)[1] and ATS/ERS/ESCMID/IDSA guideline (2020)[18] deal with NTM-PDs. The treating physician should be well versed with the prevalence of various NTM species in the geographical area of his/her practice[1],[17]. Despite repeated isolation of NTM, laboratory contamination and colonization in the host must be ruled out. As MAC is the most common cause of NTM-PD worldwide, causality association of repeated NTM isolation in the respiratory specimens should be carefully established after reviewing clinical and radiographic features[1],[17]. Subsequently, the underlying predisposing structural lung disease should be identified and its severity should be evaluated. NTM-PD should be stratified into mild to moderate (non-severe) and severe NTM-PD [Box 4] on the basis of patient's systemic signs and symptoms, chest radiographic appearances and microbiologic features (acid-fast smear status, bacillary load, mycobacterial culture, NTM species and subspecies characterization)[1]. The conventional microbiological outcomes are smear status, culture conversion and relapse[1],[140],[141][Box 5].

The decision to start treatment should be made carefully as patients due to MAC remain stable without antibiotic treatment[1],[17]. Early identification of certain clinical, radiographic and microbiological features that are associated with NTM-related progressive PD, is required. These include presence of severe symptoms, low body mass index (BMI) and poor nutritional status (esp. low albumin), lung cavitation, extensive disease, presence of comorbidity, elevated inflammatory markers, and positive AFB smears and isolation of more virulent NTM species[18],[94],[142],[143]. Recent ATS/ERS/ESCMID/IDSA guideline (2020)[18] suggests initiation of treatment rather than watchful waiting, especially in the context of positive AFB sputum smears and/or cavitary lung disease. Whereas, a watchful waiting is preferred in patients with mild signs and symptoms of disease, higher chances of drug intolerance and adverse drug reactions and NTM species less responsive to treatment (e.g.,M. abscessus). In such cases, treatment should be initiated after counselling the patient about potential adverse effects of antimicrobial therapy, the uncertainties surrounding the benefits of antimicrobial therapy, and the possibility for recurrence including reinfection (specifically in nodular-bronchiectatic disease setting). It is also recommended that treatment regimens should be designed by experts in the management of complicated NTM infections[18].

NTM-PD is generally treated with a drug regimen, consisting of 3-4 antibiotics, administered either daily or thrice weekly depending on the severity of disease, patient's tolerance of drugs and occurrence of side effects, and the therapy is continued for at least 12 months following sputum conversion[17],[18]. [Table 10] summarizes the treatment durations of pulmonary and extrapulmonary NTM diseases[144] due to different species.
Table 10: Durations of treatment for different non-tuberculous mycobacteria (NTM) diseases

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A significant proportion of patients with NTM-PD discontinues the prescribed treatment because of lengthy duration and occurrence of side effects[145]. The treatment regimens vary depending on the isolation of NTM species, clinical phenotypes and drug susceptibility profiles, leading to varying therapeutic responses. The variable treatment responses are related to several factors such as NTM species (M. avium vs. M. abscessus) and subspecies (M. abscessus subsp. massiliense vs. M. abscessus subsp. abscessus), disease phenotype [fibrocavitary vs. nodular bronchiectatic (NB)] and the treatment regimen (drug treatment regimen with macrolide vs. without macrolide)[146],[147],[148].

NTM-PD due to MAC is treated with a drug regimen comprising rifampicin (or rifabutin in HIV-positive individuals to avoid drug-drug interactions[19]), ethambutol and macrolide (azithromycin or clarithromycin; some patients tolerate azithromycin better)[1],[17]. There is an

in vitro synergy of antimycobacterial action between rifampicin and ethambutol as the latter destabilizes mycobacterial cell wall and facilitates rifampicin entry into the Mycobacteria to its target site, the RNA polymerase[149],[150]. These two drugs also prevent development of macrolide resistance[151]. Neither isoniazid nor moxifloxacin is much active against MAC; clofazimine and amikacin are good alternatives. The BTS guidelines (2017)[1] and ATS/ERS/ESCMID/IDSA guideline (2020)[18] recommend intermittent three times-weekly treatment for non-cavitary (non-severe) MAC-PD due to potential benefits, better treatment adherence and comparable efficacy[1],[152]. As per guidelines, intravenous or nebulized amikacin can be added as the fourth drug for the initial three months in patients with severe or macrolide-resistant MAC-PD[1] [Table 11]. The pooled treatment success rates in MAC-PD in the five systematic reviews ranged from 32 to 65 per cent, and 12 to 16 per cent of the enrolled patients had not completed treatment[153],[154],[155],[156],[157].
Table 11: Suggested antibiotic regimens for adults with Mycobacterium avium complex (MAC)-pulmonary disease

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Miwa et al[158] in a preliminary open-label study compared three-drug regimen (clarithromycin, ethambutol and rifampicin) with two-drug regimen (clarithromycin and ethambutol) and demonstrated the rate of sputum culture conversion at 40.6 per cent with three-drug regimen versus 55 per cent with two-drug regimen, suggesting that two-drug regimen was not inferior to three-drug regimen. Further, the incidence of adverse events leading to treatment discontinuation was higher with the three-drug regimen (37.2 vs. 26.6%)[158].

Koh et al[159] evaluated 481 treatment-naïve patients with MAC lung disease who underwent antibiotic treatment for ≥12 months between January 2002 and December 2013. Nearly 58 per cent had non-cavitary NB disease, 17 per cent had cavitary NB disease and 25 per cent had fibrocavitary disease. The treatment outcomes and redevelopment of NTM lung disease after treatment completion differed by the clinical phenotype of MAC lung disease. Cavitary disease was independently associated with unfavourable outcomes. The NB form was an independent risk factor for the redevelopment of NTM lung disease. Of the

29 per cent of favourable outcomes, redevelopment of NTM lung disease occurred with the same MAC species in 55 per cent patients. In patients with recurrent MAC lung disease due to the same species, genotyping revealed that 74 per cent of cases were attributable to reinfection and 26 per cent to relapse[159].

Addition of once-daily administration of amikacin liposome inhalation suspension (ALIS) (supplied in single-use vials delivering 590 mg amikacin to the nebulizer), also known as 'Arikayce' to standard guideline-based therapy (GBT) in adults with refractory MAC lung disease (with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least six months of stable therapy considered to be macrolide-based multidrug treatment), has been reported[141]. Addition of ALIS to GBT for the treatment of refractory MAC lung disease achieved significantly greater culture conversion by six month than GBT alone. Respiratory adverse events (primarily dysphonia, cough and dyspnoea) were reported more (87.4%) in patients receiving ALIS+GBT than those receiving GBT alone (50%)[141]. Patients with limited and refractory MAC-PD should be considered for lung resection[134].

Patients with clarithromycin-resistant MAC-PD should be treated with rifampicin, ethambutol and isoniazid or a quinolone and intravenous amikacin or nebulized amikacin (if intravenous amikacin is not tolerated or impractical to administer or is contraindicated) for initial three months[1][Table 11]. The treatment of macrolide-resistant (MR) MAC-PD is challenging because of poor sputum culture conversion rates (15-36%) and high mortality rates at two year (9-15%) and five-year (47%)[160],[161]. A recent systematic review and meta-analysis of nine studies reported poor treatment outcomes in MR-MAC-PD with overall 21 per cent sputum culture conversion rate and 10 per cent one-year all-cause mortality with no difference between NB and FC types of MR-MAC-PD[162]. Despite the combination of multiple antibiotics including ALIS and surgical resection, the treatment outcomes of MR-MAC-PD remained poor.

Patients with NTM-PD due to rifampicin-sensitive M. kansasii are treated with a treatment regimen similar to pulmonary TB[1],[17] comprising rifampicin, ethambutol and isoniazid along with pyridoxine for a fixed duration of 12 months instead of 12 months beyond culture conversion[18]. Even one-time isolation of M. kansasii from patient's sputum sample is considered pathogenic and should be treated immediately[18][Table 12]. Because MICs (minimum inhibitory concentrations) of isoniazid are higher as compared to Mtb, therefore, macrolide (clarithromycin or azithromycin) is preferred over isoniazid for the treatment of M. kansasii[163]. Pyrazinamide is not recommended for M. kansasii pulmonary disease as the organismisnaturally resistant to pyrazinamide (a prodrug) due to reduced pyrazinamidase activity preventing conversion of the drug into pyrazinoic acid which is an active bactericidal compound[164]. Cure rates for rifampicin-sensitive M. kansasii have been >98 per cent[17]. [Table 12] describes treatment regimens for rifampicin-sensitive and rifampicin-resistant M. kansasii[1].
Table 12: Suggested antibiotic regimen for adults with Mycobacterium kansasii-pulmonary disease

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[Table 13] details the treatment of PD due to M. xenopi. While four-drug regimen (rifampicin, ethambutol, macrolide and moxifloxacin) is used to treat non-severe disease, intravenous amikacin or nebulized amikacin is added to the regimen as a fifth drug for severe disease[1]. In a retrospective matched cohort study comparing M. xenopi PD to MAC-PD, 24-month mortality was higher in M. xenopi-PD with comorbidities, especially COPD. Rifampicin was less frequently used in M. xenopi[165].
Table 13:Suggested antibiotic regimens for adults with Mycobacterium xenopi-pulmonary disease

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Treatment response of macrolide-containing regimen in patients with M. malmoense NTM-PD is better than that of MAC or M. xenopi[90]. [Table 14] provides the details of drug regimen. Treatment for other slowly growing NTM can be extrapolated from common NTM species. Isolation of M. simiae is rarely associated with true infection. Limited success is seen in M. simiae infection with rifampicin- and ethambutol-based drug regimen[166], and a combination of amikacin and clofazimine may be used to construct a drug regimen to treat the infection[167].
Table 14: Suggested antibiotic-regimens for adults with Mycobacterium malmoense-pulmonary disease

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The treatment details of PD due to M. abscessus are provided in [Table 15], and antibiotic combination is administered according to the DST profile. In patients with M. abscessus, pulmonary disease is caused by strains with inducible and mutational macrolide resistance, a macrolide-based regimen is recommended if the drug is used as an immunomodulator (macrolide is not considered as active drug in multidrug regimen)[18]. A precise identification of subspecies along with information on erm (41) gene is important in M. abscessus infection[1] because of a variable treatment response. The treatment outcomes among the three subspecies of M. abscessus differ due to erm (41) gene and inducible and constitutive resistance to macrolides[1] [Table 16]. About 15 per cent of M. abscessus strains have a T to C mutation at position 28 in erm (41) gene, making them macrolide susceptible[168].
Table 15: Suggested antibiotic regimens for adults with Mycobacterium abscessus-pulmonary disease

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Table 16: Drugs used in non-tuberculous mycobacteria (NTM) disease, monitoring and adverse drug reactions

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A systematic review and meta-analysis of the studies on the effect of chemotherapy on pulmonary M. abscessus with macrolide-containing regimens reported adverse microbiological outcomes with frequent recurrences according to the subspecies[169]. A good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Macrolide-containing regimens achieved SSCC in only 34 per cent (77/233) patients with new M. abscessus subsp. abscessus vs. 54 per cent (117/141) in those with M. abscessus subsp. massiliense. In refractory disease, SSCC was achieved in 20 per cent of patients, which was not significantly different across subspecies. The proportion of patients with good outcomes (SSCC rate without relapse) was 23 per cent (52/223) with M. abscessus subsp. abscessus versus 84 per cent (118/141) with M. abscessus subsp. massiliense disease. The pooled sputum culture conversion rate was 20 per cent (95% confidence interval, 7-36%), which on follow up after stopping therapy for

12 months was not significantly different across the mycobacterial species. Overall, disease recurrence in M. abscessus subsp. abscessus-infected patients was 40 per cent versus seven per cent in M. abscessus subsp. massiliense-infected patients. The odds ratio of recurrence in M. abscessus subsp. abscessus-infected versus M. abscessus subsp. massiliense-infected patients was 6.2[169].

In patients with lung infection due to M. fortuitum, the underlying GERD should be carefully evaluated and treated[17],[170]. Surgical excision is the treatment of choice for younger children with cervicofacial lymphadenitis due to NTM[105],[171]. Treatment of the skin disease due to M. marinum depends on the extent of lesions, hence drug regimen comprising rifampicin and ethambutol or ethambutol and clarithromycin is administered for a single small lesion, whereas triple-drug regimen of rifampicin, ethambutol and a macrolide is used for severe disease[172],[173],[174]. Adjunctive surgical debridement is recommended for the underlying bone and joint involvement. Eight-week drug regimens of rifampicin with either clarithromycin or quinolone are administered for the treatment of M. ulcerans skin disease[175],[176]. Disseminated skin and subcutaneous abscesses caused by RGM can be treated with two-drug regimen based on DST results for four months[17] in addition to surgical debridement[177],[178]. For M. fortuitum infection, drug regimen may include a combination of co-trimoxazole, tobramycin, imipenem, doxycycline and fluoroquinolones[17]; M. chelonae infection is treated with two-drug combinations of tobramycin, linezolid, macrolides and imipenem[17],[177],[178]. M. abscessus infections may be treated with a combination of the following antibiotics: amikacin, linezolid, cefoxitin, macrolides and imipenem based on DST results[17],[18]. The utility of macrolides depends on erm (41) gene functional status [Table 4].

Recent recommendations for treating disseminated MAC disease in HIV/AIDS patients are provided in [Box 6][19]. Non-steroidal anti-inflammatory drugs (NSAIDS) may be used in HIV patients experiencing moderate-to-severe symptoms of immune reconstitution inflammatory syndrome (IRIS), and short-term course of corticosteroids for 4-8 wk can be used if symptoms persist.

Inhaled antibiotics for NTM-PD

Similar to TB treatment, drug treatment regimens comprising 3-4 drugs are used for treating NTM-PD for longer periods with high discontinuation rates (9-39%) due to significant side effects[145],[154],[179],[180]. Use of inhaled drugs has demonstrated successful treatment outcomes in bronchial asthma, COPD and Pseudomonas aeruginosa infections in CF patients while achieving higher drug concentrations at the disease site without developing significant systemic side effects at the same time[155]. Similar approach can be considered in NTM-PD to deliver higher drug concentrations to the infected lungs with minimal extrapulmonary exposure to avoid adverse events. Inhaled amikacin along with other oral drugs is already used in patients with severe NTM-PD[1],[180],[181],[182]. Development of inhaled clofazimine suspension for administration via nebulizer device in NTM-PD treatment is in progress[180]. In addition, studies using inhaled recombinant granulocyte-macrophage colony-stimulating factor and exogenous nitric oxide gas are in progress to evaluate their antibacterial effect on M. abscessus[183].

Non-pharmacologic treatment of pulmonary NTM disease

In addition to pharmacological therapy, other non-pharmacological measures can be tried for treating the underlying lung disease[184] These include techniques for mucus clearance such as nebulization using hypertonic saline, aerobic exercises, chest physiotherapy, postural drainage, use of oscillating positive expiratory pressure devices and high-frequency chest wall oscillation. Intake of balanced diet containing adequate calories and proteins to maintain ideal body weight is essential in the management of NTM diseases[185]. Following recovery, patients should avoid exposure to minimize re-infection from environmental sources such as hot tubs, use of tap water in humidifiers and continuous positive airway pressure units, use of specialized filtration systems in household plumbing and exposure to soil and dust.

Surgical intervention

Surgery may be considered in carefully selected individuals with NTM-PD. These patients should have localized structural lung disease and good pulmonary functions without having impaired gas exchange[1],[17],[162]. The role of a pulmonary and/or infectious disease specialist, a respiratory therapist and a nutrition expert is crucial for a successful surgical outcome[186]. A review of retrospective anatomic lung resection for NTM-PD in 236 consecutive patients revealed minimal mortality and morbidity and reported that 80 per cent of patients had MAC-PD and had received DST-guided antibiotic treatment prior to surgery[187]. Data from the annual survey between 2008 and 2012 by the Japanese Association for Thoracic Surgery (JATS) have demonstrated a steady increase in the number of NTM surgeries[188]. In patients with extrapulmonary NTM disease, surgical intervention may be required through aggressive debridement or removal of implanted material[189]. Surgical excision is the treatment of choice in patients with solitary peripheral lymph node involvement due to NTM, especially in children[105],[106],[189].

Monitoring of drug toxicities

Drugs used for the treatment of NTM diseases are associated with several adverse events especially in elderly individuals and HIV/AIDS patients with multisystem involvement. During follow up, patients should be carefully monitored for side effects[1],[144],[190]. [Table 15] provides the details of adverse events and laboratory monitoring.

   Prevention Top

[Box 6] provides details of various preventive measures to reduce NTM disease in different settings, especially those due to contamination of disinfectants, ice, wounds, injection sites, catheters, endoscopes, etc., can be prevented by proper sterilization[2],[3]. Avoiding the use of tap water is considered a key step to prevent NTM infections in the hospital settings. Further, patients undergoing cardiac surgery and transplants should receive extra attention[10]. Besides different drug regimens, certain non-pharmacological options are available which can help in improving the quality of life in patients with NTM-PD. Chest physiotherapy can be helpful in improving lung functions and mucociliary clearance, especially in cavitary disease, CF and bronchiectasis. Breathing exercises including aerobic activity such as yoga are generally believed to be helpful in pulmonary rehabilitation[160]. Besides drug therapy, exposure to NTM, especially from household plumbing and water sources, should be avoided. NTM transmission can be prevented by increasing water temperature to ≥54°C (130°F) and changing shower heads regularly[10]. Patients with GERD should be advised to avoid foods that may trigger it and avoid vulnerable body positions that may cause repeated aspirations.

Patients should be advised to pay special attention to maintain adequate calorie intake and body mass index especially if surgical intervention is contemplated. Monitoring of pre-albumin level can serve as a useful marker of nutrition[184]. In some individuals along with antibiotic regimen, probiotic therapy can be helpful.

[Box 7] details recommendations for preventing disseminated MAC disease[19] and includes indications for initiating, discontinuing and restarting primary prophylaxis. Disseminated MAC disease must be carefully ruled out before starting drugs for primary prophylaxis. While azithromycin (1200 mg PO once weekly) or clarithromycin (500 mg PO twice daily) are preferred drugs, rifabutin (300 mg PO daily) is an alternative drug for primary prophylaxis provided that the active TB has been ruled out.

   Future prospects Top

Future studies should be directed to understand the role of risk factors for developing NTM-PD so that the benefit of screening can be offered to high risk individuals for early diagnosis and treatment. As growing evidence has established human-to-human transmission of M. abscessus among CF patients, further research should be done to study mechanisms contributing to patient-to-patient transmission of other NTM species to prevent further spread. Newer non-culture-based methods should be developed for early identification and speciation of NTM from respiratory specimens as the present methods rely heavily on mycobacterial culture for identification and further characterization of NTM species, causing significant delay in treatment. Future research should focus on understanding the role of DST in predicting treatment outcomes in NTM as currently the role of DST is controversial and limited only to a few situations in the management of NTM. Studies should also focus on understanding the pathogenic potential of various NTM species and subspecies to facilitate decision-making in treatment as there are significant knowledge gaps at present. Efforts should be made to follow progression of inflammatory lung disease systematically and to study treatment outcomes after timely intervention to develop and validate newer drugs and besides conventional routes of drug administration, potential use of drugs through inhalation route should be explored. Less toxic and more effective drug treatment regimens administered for short periods should be developed for the treatment of NTM-PD especially due to M. abscessus as these NTM species respond poorly to treatment with frequent relapses occurring after stopping the treatment.

Financial support & sponsorship: The first author (SKS) is sponsored by JC Bose Fellowship of the Science & Engineering Research Board (SERB No. SB/S2/ JCB-04/2013) of the Ministry of Science & Technology, Government of India. The second author (VU) is a Junior Research Fellow in the Department of Molecular Medicine at Jamia Hamdard University, Delhi, supported by

Dr SK Sharma through SERB JC Bose Fellowship.

Conflicts of Interest: None.

   References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15], [Table 16]

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