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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 4  |  Page : 104-109

Nontuberculous mycobacteria and bronchiectasis


Cystic Fibrosis and Bronchiectasis Unit, Pulmonology Service, Hospital Universitario La Paz, Instituto de Investigación IdiPaz, Paseo de la Castellana, 261, 28046 Madrid, Spain

Date of Web Publication17-Jan-2017

Correspondence Address:
Dr. Concepción Prados Sánchez
Servicio de Neumología, Hospital Universitario La Paz, Cantoblanco, Carlos III, Madrid
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2225-6482.198489

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  Abstract 

Non-tuberculous mycobacteria (NTM) are ubiquitous microorganisms in our environment. Although data are not truthful, we can say that we are experiencing an increase in the incidence-prevalence of infections by these microorganisms, especially in vulnerable population such as those with certain respiratory diseases, such as bronchiectasis (BQ). In all species NTM, the most studied is Mycobacterium avium complex, although the M abscessus is considered the most serious species in cystic fibrosis (CF) and M. xenopi in non-CF BQ. They described five clinical forms, the most frequent nodular/bronchiectasis and severe disseminated. The diagnosis of NTM lung disease in BQ is complicated, and continues to rely on three variables: clinical, radiological and microbiological. Given this difficulty, many suggest an observation period before starting a treatment, not always well tolerated and with side effects. Although morbidity and mortality is not high, they have been described risk factors that make it essential early treatment to avoid further serious complications.

Keywords: Bronchiectasis, diagnosis, nontuberculous mycobacteria, treatment, prognosis


How to cite this article:
Sánchez CP, González G, Fernández SQ, Redondo MM, Moro AM. Nontuberculous mycobacteria and bronchiectasis. Community Acquir Infect 2016;3:104-9

How to cite this URL:
Sánchez CP, González G, Fernández SQ, Redondo MM, Moro AM. Nontuberculous mycobacteria and bronchiectasis. Community Acquir Infect [serial online] 2016 [cited 2021 Dec 1];3:104-9. Available from: http://www.caijournal.com/text.asp?2016/3/4/104/198489


  Introduction Top


Nontuberculous mycobacteria (NTM) are ubiquitous agents. There are described more than 160 species, some of which may lead sometimes to pulmonary disease.[1],[2] The person-person or animal-person transmission is very rare, so it is considered that the external environment is the source of infection.[2],[3]

NTM can be divided into two groups depending on the speed of its growth: (1) Those fast growing, needing less than 7 days to complete their growth in culture (Mycobacterium abscessus) and (2) slow growth, requiring more than 7 days to complete (Mycobacterium avium complex [MAC] and Mycobacterium kansasii).[2]


  Prevalence Top


According to different jobs review, patients with bronchiectasis (BQ) have a frequency of developing disease NTM ranging from 5% to 30%.[4],[5] In general, it has shown an increased prevalence in recent years, being in the USA of 6.6/100,000 h and Wales and Northern Ireland of 2.9/100,000 h.[6],[7]

Many studies have also shown an increase in the incidence of NTM in patients with BQ.[6] According to a recent meta-analysis, the work carried out in this field so far are scarce and few patients. The conclusions reached were that published data are more credible if: The sample size is ≥100, the post-2002 publications are still retrospectives, and geographical location was Asia.[8] This is because the more recent studies are the better study skills in micronucleus test (MNT) and are thought more frequently in patients with BQ, without forgetting that the means of transmission, especially contaminated water, are more common in our days and in areas such as Asia.

When the prevalence of certain species of MNT in BQ was analyzed, it was found that the MAC lung disease was of 13-81%, Mycobacterium chelonae, Mycobacterium fortuitum, and M. abscessus of 43-81%. Interestingly, when compared with the general population, the latter was affected especially by M. kansasii and Mycobacterium xenopi, with prevalence 10%.[8]

When the prevalence of certain species of NTM in BQ was analyzed, it was found that the MAC lung disease was of 13-81%, by M. chelonae, M. fortuitum and M. abscessus of 43-81%. Interestingly, when compared with the general population, the latter was affected especially by M. kansasii and M. xenopi, with prevalence 10%.[9]


  Pathogenesis Top


The three most important factors in the pathogenesis of NTM infection are:

  • Exposure: Because they are ubiquitous, how to acquire probably be inhaled directly from the water or hot water systems[2]
  • Pulmonary pathology base: All those who have impaired mucociliary or epithelial damage system are predisposed to NTM infection
  • Defects of immunity: Since not all patients in contact with a contaminated environment develop NTM disease, a failure of immunity is postulated. Innate immunity is involved in the activation of antimicrobial activity, phagocytosis of NTM, and modulating adaptive immune response activity.[10] We found relations with the human leukocyte antigen system so that in those with certain defects of it would have a predisposition, both NTM lung disease as the worsening of it.[11],[12] In mice, it has been found that the long-term azithromycin could favor M. abscessus infection by damaging cell phagocytic capacity and also found cystic fibrosis (CF) transmembrane conductance regulator gene mutations in patients without CF BQ, which would mean an association with the transmembrane ion and water transport.[13] Other factors that compromise systemic immunity, such as diabetes mellitus, transplantation, or neoplasms, favor NTM infection.[2]



  Clinical and Radiological Features Top


There have been described five clinical forms, especially with the MAC: (1) Nodular/bronchiectasis disease (NB); (2) cavity lung disease (CLD); (3) solitary pulmonary nodule; (4) extensive disease (ED); and (5) hypersensitivity-like disease.[7]

One question that many authors make is: What is the first? BQ or pulmonary NTM infection? Which is not yet resolved. It is clear that diseases such as CF or posttuberculous infection precede BQ.[8] Although it has always been said that the cause of NTM is BQ, there is so far little evidence. Infection seems NTM cause destruction of bronchial cartilage and muscle layer, granuloma formation, and ulceration of the bronchial mucosa so that could subsequently lead to the development of BQ.[14]

Of these, NB is the most typical form and has been associated with nonsmoking women, postmenopausal, affecting the middle lobe or lingula.[4],[15],[16] Although data on the disease FC do not match, they have been associated with men aged 40-50 years and even with over 70 years.[8],[17]

In general, most authors have shown that long-term survival after suffering a form NB is good although described radiological deteriorations in following 10 years.[7],[18] It has also been shown that following the natural history of disease, 40% never worsened after 2 years of follow-up.[19]

Comparing radiological forms with different species of NTM, it was found that MAC was associated with BQ (42%) and consolidations (43%), M. chelonae/M. abscessus cavitation (37%), M. kansasii to BQ (9%), cavitation (15%), and consolidations (13%).[2] When compared the cavity forms produced by a MNT against tuberculosis, the first affecting more middle lobe and lingula, are thin-walled and >3 cm.[20]

Comparing radiological forms with different species of NTM, it was found that the MAC was associated with BQ (42%) and consolidations (43%), M. chelonae/M. abscessus cavitation (37%), M. kansasii to BQ (9%), cavitation (15%) and consolidations (13%).[2] When compared the cavity forms produced by a NTM against tuberculosis, the first affecting more middle lobe and lingula, are thin-walled and >3 cm.[20]


  Diagnosis Top


Diagnosis is complicated because there may be the possibility of contamination or simply colonization without clinical manifestation. According to the criteria of the American Thoracic Society (ATS),[4] there must be two clinical criteria: symptoms and radiological findings and one microbiological (in this case, and with the high possibility of contamination, is required more than one positive sample). In the case that exists clinical criteria, but without result in sputum, a single sample is required from bronchoscopy. It is not known today, the value of aspiration of lymph nodes (endobronchial ultrasound transbronchial needle aspiration), although they have reached the 69% diagnosis of mediastinal granulomatous disease.[21]

Although with limitations, molecular tests are being effective for the rapid identification of NTM species most frequently.[22]

A major problem is coinfection by other microorganisms, such as Pseudomonas aeruginosa (25-50%), Staphylococcus aureus (28%), Haemophilus influenzae (12%), and Stenotrophomonas maltophilia (4%); fungi can also coexist as Candida albicans (8%) or Aspergillus Fumigatus,[4] and even Nocardia species, other species of NTM or other genotypes of the same species of NTM (very typical with the MAC) that often cause relapses.[2]


  Risk Factors of Mortality Top


According to a systematic review on this topic and the heterogeneity of the studies, the data found are very different.[23] Of all NTM, MAC is the one that produces most frequently NTM lung disease.[7] It has been shown that the clinical forms more associated with mortality are ED and CLD in immunosuppressed patients such as HIV.[15] Mortality will depend on certain factors although most are medical literature data on the radiological nodular form/BQ and MAC.[16]

Factors, such as comorbidities, weight loss, low body mass index (BMI), anemia, or elevated systemic inflammation factors, are more found in the disease CLD and CLD + NB than in the NB form.[15] The latter can present, in its evolution, development radiological worsening with BQ or cavitations, almost indistinguishable from the initial BQ disease.[24] It is also considered worse prognosis the presence of spread, recurrence or resistance, and infection with M. xenopi.[25],[26],[27]

If we focus on host factors, it is considered poor prognosis male, elderly, and high number of comorbidities.[15] To these should be added certain radiological factors in acute although treatment with rifampicin (RF) seems to be protective.[26] In the study of Hayash et al.[15] published as the CLD poor prognosis clinical forms, disseminated or unclassifiable, BMI <18.5 kg/m2 and anemia.

In short, radiological forms non-NB, being male, with advanced age, presence of comorbidities, anemia, hypoalbuminemia, BMI <18.5 kg/m2 , or erythrocyte sedimentation rate >50 mm/h are considered poor prognostic factors in disease NTM in general, while the forms CLD or CLD + NB, elevated C-reactive protein (CRP), BMI <18.5 kg/m2 are for MAC pulmonary disease.[6] Referred to radiological deterioration of patients with MAC lung disease has found several risk factors: anemia, increase in serum albumin and CRP, or have had hemoptysis.[7]

More complicated it is to find correlation between mortality and therapeutic regimens, either two or five drugs, since it seems that those who need more drugs are those that have more risk factors.[15] For MAC, therapeutic success reaches 39%, treatment failures 27%, relapse 6%, and 17% may die (4.8% at 10 years lung disease and if evolves cavitation reaches 28.1%).[7]


  Treatment Top


The evaluation of therapeutic response is based on the negative sputum culture, clinical and radiological improvement, reactivation of infection and mortality.[14]

In recent years, we have seen an evolution in the treatment employed, and from the late 1950 to 1970s, the election were isoniazid (INH), para-amino-salicylic acid and streptomycin; RF and ethambutol (EB) were used from 70 to 90, and from this date, macrolides[15] were included. Because mortality was not inconsiderable, the British Thoracic Society (BTS) conducted a clinical trial with various antibiotic regimens, observing that overall, this was about 30-40%.[28]

According to various studies, given the significant side effects of medications used for the treatment of NTM, it is recommended to keep under observation elderly, fragile and with important comorbidities patients, may in them, become a chronic and incurable process, mortalities at 5 years 2% and 10 years of 9%.[4],[15]

According to the clinical trial conducted by SBT, comparing to 2 years two therapeutic forms (RF + EB + clarithromycin vs. RF + EB + ciprofloxacin), the best results were in the regime with ciprofloxacin. Therefore, the SBT recommended to administer INH + ciprofloxacin in patients in whom treatment was <12 months.[28]

One of the main questions that we, especially when we are facing a clinically NB, is the speed of initiation of treatment. When trying to answer it, we can find different answers. Two groups were asked, one of pulmonologists and other experts in NTM, if ever actively try a new case of NTM infection. In pulmonologists respondents, 50% would try, while 37.5% would not try; however, experts answered that 79% would try and only 10% would not treat.[11] In another very recent work, faced with a similar question, <20% of American physicians and 53% of Canadians were trying NTM lung disease.[29]

As no agreements have been reached, Gochi et al.[7] found that if there are certain risk factors, treatment should start early. If these are not recorded, it would be indicated close monitoring of the patient.

In short, although it is reached NTM disease diagnosis, treatment indication is not always mandatory. Given the side effects, it should clearly assess the risk-benefit of therapy for each patient. First, you must have a clear understanding of the species of NTM and its association with morbidity and mortality. Second, it is considered appropriate to meet patient comorbidities, severity of the disease, its evolution, and tolerability of therapy. Finally, it is helpful to know whether BQ base was responsible for the worsening of the patient.[19] Many authors recognized that kept active observation, starting treatment if there was evidence of disease progression.[7]

Most recommendations for the treatment of disease rely NTM in treating MAC. Due to the discrepancies between in vivo and in vitro, only resistance to macrolides[27],[30] is analyzed, so it is recommended to avoid monotherapy with these drugs.

In NB ways, you get to recommend a flashing three times a week therapy. In severe cases, a more aggressive therapy is needed. Dual therapy is recommended only in mild cases of NB or intolerant to treatment [Table 1]. As in CF, it is advisable to culture before starting treatment with macrolides and stop if MNT[4],[31] is isolated.
Table 1: American Thoracic Society Recommendations


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With treatment negativization is achieved in 86% of cases, with little-zero resistance. Have been reported up to 48% of recurrences after treatment correctly performed, of which 75% were reinfected by a new genotype of MNT and 25% was a recovery from the previous genotype, increasing this possibility when it occurs before age 10 months after completion of treatment. Factors that may lead to a reactivation-reinfection are low BMI, FC disease, emphysema base coexistence of allergic bronchopulmonary aspergillosis, previous resistance to macrolides, and consolidations.[18],[32]

Therefore, emphasis is placed on close monitoring of patients during and after treatment. It has been postulated that PET could help diagnose the therapeutic efficacy and possible relapse although much remains to recommend its use.[33]


  Reflections Top


CF takes years ahead against other BQ, looking for similarities and differences between them. American and European societies CF have attempted to adapt the recommendations of the ATS for the treatment of NTM.[34] I think it might be advisable to carry out another adaptation for non-CF BQ; the high prevalence is reaching NTM lung disease in them [Table 2].
Table 2: NTM lung disease care and bronchiectasis recommendatios


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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Marras TK, Prevots DR, Jamieson FB, Winthrop KL; Pulmonary MAC Outcomes Group. Opinions differ by expertise in Mycobacterium avium complex disease. Ann Am Thorac Soc 2014;11:17-22.  Back to cited text no. 11
    
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Bienvenu T, Sermet-Gaudelus I, Burgel PR, Hubert D, Crestani B, Bassinet L, et al. Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2010;181:1078-84.  Back to cited text no. 13
    
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Fujita J, Ohtsuki Y, Shigeto E, Suemitsu I, Yamadori I, Bandoh S, et al. Pathological findings of bronchiectases caused by Mycobacterium avium intracellulare complex. Respir Med 2003;97:933-8.  Back to cited text no. 14
    
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Hayashi M, Takayanagi N, Kanauchi T, Miyahara Y, Yanagisawa T, Sugita Y. Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2012;185:575-83.  Back to cited text no. 15
    
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Ahn CH, Lowell JR, Onstad GD, Shuford EH, Hurst GA. A demographic study of disease due to Mycobacterium kansasii or M intracellulare-avium in Texas. Chest 1979;75:120-5.  Back to cited text no. 17
    
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Yeung MW, Khoo E, Brode SK, Jamieson FB, Kamiya H, Kwong JC, et al. Health-related quality of life, comorbidities and mortality in pulmonary nontuberculous mycobacterial infections: A systematic review. Respirology 2016;21:1015-25.  Back to cited text no. 23
    
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Andréjak C, Lescure FX, Pukenyte E, Douadi Y, Yazdanpanah Y, Laurans G, et al. Mycobacterium xenopi pulmonary infections: A multicentric retrospective study of 136 cases in North-East France. Thorax 2009;64:291-6.  Back to cited text no. 26
    
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28.
Jenkins PA, Campbell IA, Banks J, Gelder CM, Prescott RJ, Smith AP. Clarithromycin vs. ciprofloxacin as adjuncts to rifampicin and ethambutolin treating opportunist mycobacterial lung disease and assessmentof Mycobacterium vaccae immunotherapy. Thorax 2008;63:627-34.  Back to cited text no. 28
    
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30.
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Griffith DE, Aksamit TR. Bronchiectasis and nontuberculous mycobacterial disease. Clin Chest Med 2012;33:283-95.  Back to cited text no. 31
    
32.
Zoumot Z, Boutou AK, Gill SS, van Zeller M, Hansell DM, Wells AU, et al. Mycobacterium avium complex infection in non-cystic fibrosis bronchiectasis. Respirology 2014;19:714-22.  Back to cited text no. 32
    
33.
Drijkoningen J, van der Pol H, de Vries M. PET scanning used for monitoring treatment response in Mycobacterium avium complex infection mimicking malignancy. Clin Nucl Med 2009;34:818-20.  Back to cited text no. 33
    
34.
Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax 2016;71 Suppl 1:i1-22.  Back to cited text no. 34
    



 
 
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Introduction
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