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Non-tuberculous mycobacterial lung disease: a brief review focusing on radiological findings

Abstract

The incidence and prevalence of lung disease caused by non-tuberculous mycobacteria (NTM-LD) has increased worldwide and its diagnosis represents a complex challenge. This article aims to review the tomographic findings of NTM-LD in order to facilitate their definitive diagnosis. The search for publications on the subject was performed in PMC and Scielo using the keywords ‘non-tuberculous mycobacteria’, ‘lung disease and computed tomography (CT)’ and ‘radiological findings’. The radiological findings described by 18 articles on mycobacteriosis were reviewed. In addition, CT images of patients diagnosed with NTM-LD were considered to represent radiological findings. Eighteen publications were used whose main findings were pulmonary cavitation (88.9%), bronchiectasis (77.8%), and pulmonary nodules (55.6%). Despite the overlaps in imaging-related analysis of myocobacterioses with other pulmonary infections, such as tuberculosis, the predominant involvement of the middle lobe and lingula should raise suspicion for NTM-LD.

Keywords:
Non-tuberculous mycobacteria; Lung disease; Computed tomography; Radiological findings

INTRODUCTION

Mycobacteria are a unique genus, called Mycobacterium, which are members of the family Mycobacteriaceae and the order Actinomycetales11. Trabulsi LR, Alterthum F. Mycobacterium. Ducati RG, Leão SC, Basso LA, Santos DS, editors. Microbiologia In: 6 th ed. São Paulo: ed. Atheneu; 2015. p. 424-45.,22. Kweon O, Kim S-J, Blom J, Kim S-K, Kim B-S, Baek D-H, et al. Comparative functional pan-genome analyses to build connections between genomic dynamics and phenotypic evolution in polycyclic aromatic hydrocarbon metabolism in the genus Mycobacterium. Biomed Cent. 2015;15(21):1-23.. It is speculated that mycobacteria emerged 150 million years ago and so far over 170 different species and subspecies have been identified. These species can be organized into three groups: Mycobacterium tuberculosis complex (MTBC), M. leprae, and non-tuberculous mycobacteria (NTMs)33. Murray PR, Rosenthal KS, Pfaller MA. Mycobacterium. Microbiologia Médica In: 3 rd ed. Rio de Janeiro: ed Elsevier; 2014. p. 513-30..

NTMs, previously identified as atypical mycobacteria, are defined as a heterogeneous group of species with distinct genotypic and phenotypic characteristics than MTBC or M. leprae44. Baldwin SL, Larsen SE, Ordway D, Cassell G, Coler RN. The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases. Plos Negleted Trop Dis. 2019;13(2):1-23.,55. Tan Y, Su B, Shu W, Cai X, Kuang S, Kuang H, et al. Epidemiology of pulmonary disease due to nontuberculous mycobacteria in southern. BMC Pulm Med. 2018;18(168):1-7.. NTMs are geographically distributed heterogeneously and can be found in animal species, vegetation, biofilms and especially in water and soil44. Baldwin SL, Larsen SE, Ordway D, Cassell G, Coler RN. The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases. Plos Negleted Trop Dis. 2019;13(2):1-23.,66. Jagielski T, Minias A, van Ingen J, Rastoji N, Brzostek A, Zaczek A, et al. Methodological and clinical aspects of the molecular epidemiology of Mycobacterium tuberculosis and other mycobacteria. Clin Microbiol Rev. 2016;29(2):239-90.,77. Panagiotou M, Papaioannou AI, Kostikas K, Paraskeua M, Velentza E, Kanellopoulou M, et al. The epidemiology of pulmonary nontuberculous mycobacteria: data from a general Hospital in Athens, Greece, 2007 - 2013. Pulm Med. 2014;2014(1):1-9..

The human pathogenicity of NTMs has been of interest to the scientific community, but this has not been the case always88. Velayati AA, Farnia P, Mozafari M, Malekshahian D, Seif S, Rahideh S, et al. Molecular epidemiology of nontuberculous mycobacteria isolates from clinical and environmental sources of a metropolitan city. PLoS One. 2014;9(12):1-12.. The first description of pathogenic NTMs occurred in 1950 when around 2% of patients initially diagnosed with tuberculosis (TB) did not respond to traditional treatments and were subsequently diagnosed with mycobacterial infections that did not cause tuberculosis88. Velayati AA, Farnia P, Mozafari M, Malekshahian D, Seif S, Rahideh S, et al. Molecular epidemiology of nontuberculous mycobacteria isolates from clinical and environmental sources of a metropolitan city. PLoS One. 2014;9(12):1-12.,99. Billinger ME, Olivier KN, Viboud C, Montes de Oca R, Steiner C, Holland SM, et al. Nontuberculous mycobacteria - associated lung disease in hospitalized persons. Emerg Infect Dis. 2009;15(10):1998-2005.. Since then, other studies are being conducted to improve the understanding of the pathophysiological mechanisms involved in NTM-related diseases1010. Mirsaeidi M, Farnia P, Sadikot R, Hsued P-R, Aliberti S. Nontuberculous mycobacteria: epidemiologic, mycobacteriologic, and clinical aspects. Biomed Res Int. 2015;2015:523697..

Non-tuberculous lung disease (NTM-LD) is the most common infection caused by NTMs, especially in immunosuppressed individuals. NTM-LD is not reportable to public health authorities and therefore it is difficult to estimate its epidemiological characteristics. Nevertheless, it is noted that the incidence and prevalence of NTM-LD has been increasing considerably in several regions of Brazil44. Baldwin SL, Larsen SE, Ordway D, Cassell G, Coler RN. The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases. Plos Negleted Trop Dis. 2019;13(2):1-23.. It is also suspected that other regions are experiencing a silent epidemic of this disease44. Baldwin SL, Larsen SE, Ordway D, Cassell G, Coler RN. The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases. Plos Negleted Trop Dis. 2019;13(2):1-23.,1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31..

Additionally, the diagnosis of NTM-LD requires compatible clinical and radiological findings, along with two or more positive sputum samples for the same NTM species or one positive bronchial wash/lavage or compatible histopathological findings with at least one positive culture1212. Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, et al. British thoracic society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). BTS Guidel. 2017;72(2):1-64.. Fungal infections or other mycobacterial infections might present similar clinical manifestations and radiological findings and so they pose an additional challenge for the correct microbiological identification and diagnosis1212. Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, et al. British thoracic society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). BTS Guidel. 2017;72(2):1-64.

13. Dall Bello AG., Severo CB., Oliveira FDM, Hallal Junior RJ, Hochhergger B, Severo LC. Histoplasmosis presenting with multiple pulmonary nodules. A case mimicking radiological features of pulmonary metastasis. Rev Inst Med trop S Paulo. 2013;55(3):209-11.
-1414. Shikanai-Yasuda MA, Mendes RP, Colombo AL, Queiroz-Telles FD, Kono ASG, Paniago AM et al.. Brazilian guidelines for the clinical management of paracoccidioidomycosis. Rev Soc Bras Med Trop. 2017;50(5):715-40.. Hence, NTM-LD represents a complex challenge for patients, health care, and health authorities around the world1212. Haworth CS, Banks J, Capstick T, Fisher AJ, Gorsuch T, Laurenson IF, et al. British thoracic society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). BTS Guidel. 2017;72(2):1-64..

This article reviewed the radiological findings described in other articles on MNT-LD to identify the major pulmonary changes presented by these patients. The results obtained could contribute in differentiating between MNT-LD and TB and can facilitate the diagnosis of MNT-LD.

METHODOLOGY

For this review, the search and selection of publications was performed on the following platforms: Pubmed Central (PMC) and Scientific Eletronic Library Online (SciELO). The search terms used were ‘non-tuberculous mycobacteria’, ‘lung disease and computed tomography’, and ‘radiological findings’.

The inclusion criteria for articles were those published in Portuguese, English or Spanish from 1999 to 2019. The reference lists of all retrieved articles were checked to identify other eligible publications. Comments, gray literature and other publications that did not meet the inclusion criteria were excluded.

The flow diagram of this review is detailed in Figure 1. In total, 18 articles were considered and all the radiological findings are summarized in Table 1. To represent tomographic findings, computed tomography (CT) images (Figure 2 and Figure 3) obtained from archives of medical assistants in the region of Goiânia, Goiás, Brazil, were used. It is important to highlight that these images were set as anonymous by the professionals in charge before being made available for this review.

FIGURE 1:
A flow diagram describing the stages of article identification, screening, eligibility and inclusion which are considered in this brief review.

TABLE 1:
Radiological findings of CT scans from patients with NTM-DP.

FIGURE 2:
(A) CT scan of an immunocompromised patient with M. asiaticum; extensive varicose bronchiectasis is observed in a severe form of the disease associated with bronchial parietal thickening (black arrow). Centrilobular opacities with attenuation in “ground-glass” are also visible (black arrow). (B) CT scan of patients with M avium-intracelulare; consolidation of the middle lobe. The associated bronchiectasis predominance of the middle lobe and lingual are noted (black arrow). Centrilobular opacities with attenuation in “ground-glass” is also evident (black arrow).

FIGURE 3:
(A) CT scan of a patient with M. fortuitum; bronchiectasis in the middle lobe is associated with micronodules in the right upper lobe. (B) CT scan of a patient with M. intracelulare; bronchiectasis and micronodules is visible in the middle lobe and lingula. (C) Cavitation with thick walls in the upper lobes and centrilobular micronodules and some with “budding tree” pattern in the left upper lobe (black arrows).

EPIDEMIOLOGY

Considering the epidemiological data of NTM-LD available in the literature, it is observed that the disease prevalence varies between regions. In general, the epidemiology of this disease accompanies the distribution characteristic of NTM species44. Baldwin SL, Larsen SE, Ordway D, Cassell G, Coler RN. The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases. Plos Negleted Trop Dis. 2019;13(2):1-23..

Based on the surveyed literature, the most frequent species are M. kansasii and the M. avium complex (MAC), which includes the subspecies M. avium, M. intracellulare, and M. chimaera. These pathogens are very common in Europe (80% of cases), North America, South Korea and are often associated with LD cases that are similar to TB66. Jagielski T, Minias A, van Ingen J, Rastoji N, Brzostek A, Zaczek A, et al. Methodological and clinical aspects of the molecular epidemiology of Mycobacterium tuberculosis and other mycobacteria. Clin Microbiol Rev. 2016;29(2):239-90.,1515. Hu C, Huang L, Cai M, Wang W, Shi X, Chen W. Characterization of non-tuberculous mycobacterial pulmonary disease in Nanjing district of China. BMC Infect Dis. 2019;19(764):1-8.

16. Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis. 2014;6(3):210-20.
-1717. Prevots DR, Shaw PA, Strickland D, Jackosn LA, Raebel MA, Blosky MA, et al. Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. Am J Respir Crit Care Med. 2010;182(7):970-6..

M. xenopi is also associated with LD and is found in Europe and in certain regions of Canada. In the Middle East, the most common clinical isolate is M. simiae, which can cause infection in various organs, especially the lung66. Jagielski T, Minias A, van Ingen J, Rastoji N, Brzostek A, Zaczek A, et al. Methodological and clinical aspects of the molecular epidemiology of Mycobacterium tuberculosis and other mycobacteria. Clin Microbiol Rev. 2016;29(2):239-90.,1515. Hu C, Huang L, Cai M, Wang W, Shi X, Chen W. Characterization of non-tuberculous mycobacterial pulmonary disease in Nanjing district of China. BMC Infect Dis. 2019;19(764):1-8.,1818. Habib S, Rajdev K, Pervaiz S, Siddiqui AH, Azam M, Chalhoub M. Pulmonary cavitary disease secondary to Mycobacterium xenopi complicated by respiratory failure case presentation. Cureus. 2018;10(10):1-6..

Recently, other NTMs have emerged as human pathogens, including M. fortuitum, M. chelonae and the M. abscessus complex (MABSC)66. Jagielski T, Minias A, van Ingen J, Rastoji N, Brzostek A, Zaczek A, et al. Methodological and clinical aspects of the molecular epidemiology of Mycobacterium tuberculosis and other mycobacteria. Clin Microbiol Rev. 2016;29(2):239-90.,1919. Hurst-Hess K, Rudra P, Ghosh P. Mycobacterium abscessus whiB7 regulates a species-specific repertoire of genes to confer extreme antibiotic resistance. Antimicrob Ag. 2017;61(11):1-11.. Genome sequencing technology has enabled the taxonomic organization of the MABSC into three subspecies: M. abscessus subsp. bolletii, M. abscessus subsp. abscessus and M. abscessus subsp. massiliense, and these are common in Asia, Oceania and South Korea1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31.,1515. Hu C, Huang L, Cai M, Wang W, Shi X, Chen W. Characterization of non-tuberculous mycobacterial pulmonary disease in Nanjing district of China. BMC Infect Dis. 2019;19(764):1-8.,2020. Steindor M, Nkmouano V, Stefanski A, Stuehler K, Ioerger TR, Bogumil D, et al. A proteomics approach for the identification of species-specific immunogenic proteins in the Mycobacterium abscessus complex. Microbes Infect. 2018;21(3-4):154-62.,2121. Jeon K, Kwon OJ, Lee NY, Kim B-J, Kook Y-H, Lee S-H, et al. Antibiotic treatment of Mycobacterium abscessus lung disease a retrospective analysis of 65 patients. Am J Respir Crit Care Med . 2009;180(9):896-902.. These emerging NTMs can cause skin, soft tissue, and central nervous system infections and can also lead to LD1919. Hurst-Hess K, Rudra P, Ghosh P. Mycobacterium abscessus whiB7 regulates a species-specific repertoire of genes to confer extreme antibiotic resistance. Antimicrob Ag. 2017;61(11):1-11.,2020. Steindor M, Nkmouano V, Stefanski A, Stuehler K, Ioerger TR, Bogumil D, et al. A proteomics approach for the identification of species-specific immunogenic proteins in the Mycobacterium abscessus complex. Microbes Infect. 2018;21(3-4):154-62.,2222. Lin C, Russel C, Soll B, Chow D, Bamrah S, Brostrom R, et al. Increasing prevalence of nontuberculous mycobacteria in respiratory specimens from US-Affiliated Pacific. Emerg Infect Dis . 2018;24(3):485-91.,2323. Carneiro MS, Nunes LS, De David SMM, Dias CF, Bartg AL, Unes G. Nontuberculous mycobacterial lung disease in a high tuberculosis incidence setting in. J Bras Pneumol. 2018;44(2):106-11.. LD caused by MABSC mainly affects patients with predisposed diseases such as cystic fibrosis2020. Steindor M, Nkmouano V, Stefanski A, Stuehler K, Ioerger TR, Bogumil D, et al. A proteomics approach for the identification of species-specific immunogenic proteins in the Mycobacterium abscessus complex. Microbes Infect. 2018;21(3-4):154-62.,2424. Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann J-L, Nick J-A, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fi brosis. Thorax. 2016;71(1):1-22..

TRANSMISSION AND CLINICAL MANIFESTATIONS

NTM-LD guidelines include the various forms of transmission of the etiological agent. For a long period of time, it was accepted that the transmission of NTMs occurred through the environment. It was later reported that some species were related to medical devices used in surgical procedures or esthetic treatments2525. Werf MJVD, Ködmön1 C, Katalinić-Janković V, Kummil T, Soini H, Richter E, et al. Inventory study of non-tuberculous mycobacteria in the European Union. BMC Infect Dis . 2014;14(62):1-9.. Recently, direct transmission of NTM species among cystic fibrosis patients has also been documented2020. Steindor M, Nkmouano V, Stefanski A, Stuehler K, Ioerger TR, Bogumil D, et al. A proteomics approach for the identification of species-specific immunogenic proteins in the Mycobacterium abscessus complex. Microbes Infect. 2018;21(3-4):154-62..

Once transmitted, NTMs can settle in any organ and can develop an asymptomatic infection or can lead to a disseminated disease that can be fatal to humans2525. Werf MJVD, Ködmön1 C, Katalinić-Janković V, Kummil T, Soini H, Richter E, et al. Inventory study of non-tuberculous mycobacteria in the European Union. BMC Infect Dis . 2014;14(62):1-9.,2626. Albrecht C, Ringshousen F, Ott S, Wagner D, Rademacher J, Schneider M, et al. Should all adult cystic fibrosis patients with repeated nontuberculous mycobacteria cultures receive specific treatment? A 10-year case - control study. Eur Respir J. 2016;47(1):1575-7.. The lung is the target organ of NTM-LD and its involvement implies different clinical manifestations that negatively impact patients' quality of life2727. Mehta M, Marras TK. Impaired health-related quality of life in pulmonary nontuberculous mycobacterial disease. Respir Med. 2011;105(11):1718-25.. It is described in the literature that NTM-LD might occur in three prototypic forms: fibrocavitary disease, nodular bronchiectasia, and hypersensitivity pneumonitis2828. Larsson LO, Polverino E, Hoefsloot W, Codecasa LR, Diel R, Jenkins SG, et al. Pulmonary disease by non-tuberculous mycobacteria - clinical management, unmet needs and future perspectives. Expert Rev Respir Med . 2017;11(12):977-89., and the radiological findings of these three forms were described in various articles as cited in Table 1.

Signs and symptoms of fibrocavitary disease have traditionally included nonspecific symptoms such as purulent sputum, dyspnea, hemoptysis, chest pain, fever, asthenia, weight loss, shortness of breath, and night sweats1010. Mirsaeidi M, Farnia P, Sadikot R, Hsued P-R, Aliberti S. Nontuberculous mycobacteria: epidemiologic, mycobacteriologic, and clinical aspects. Biomed Res Int. 2015;2015:523697.,2323. Carneiro MS, Nunes LS, De David SMM, Dias CF, Bartg AL, Unes G. Nontuberculous mycobacterial lung disease in a high tuberculosis incidence setting in. J Bras Pneumol. 2018;44(2):106-11.,2929. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. American Thoracic Society Documents an Official ATS / IDSA Statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am Thorac Soc Doc. 2007;175(4):367-416.. It is common for the patient with this manifestation to also develop underlying diseases such as TB, chronic obstructive pulmonary disease (COPD), or pneumoconiosis1010. Mirsaeidi M, Farnia P, Sadikot R, Hsued P-R, Aliberti S. Nontuberculous mycobacteria: epidemiologic, mycobacteriologic, and clinical aspects. Biomed Res Int. 2015;2015:523697.,1616. Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis. 2014;6(3):210-20.,2929. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. American Thoracic Society Documents an Official ATS / IDSA Statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am Thorac Soc Doc. 2007;175(4):367-416.,3030. Stout JE. Evaluation and management of patients with pulmonary nontuberculous mycobacterial infections. Expert Rev Anti Infect Ther. 2006;4(6):981-93.. Fibrocavitary disease is more common in males over 50 years of age and among Caucasian population and smokers2828. Larsson LO, Polverino E, Hoefsloot W, Codecasa LR, Diel R, Jenkins SG, et al. Pulmonary disease by non-tuberculous mycobacteria - clinical management, unmet needs and future perspectives. Expert Rev Respir Med . 2017;11(12):977-89.. Advanced cases might result in respiratory failure within 1 to 2 years after the onset of the disease. This predisposing condition is responsible for the highest mortality rate caused by NTM-LD2929. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. American Thoracic Society Documents an Official ATS / IDSA Statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am Thorac Soc Doc. 2007;175(4):367-416.

30. Stout JE. Evaluation and management of patients with pulmonary nontuberculous mycobacterial infections. Expert Rev Anti Infect Ther. 2006;4(6):981-93.
-3131. 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(5):575-83..

Nodular bronchiectasis has a much slower progression rate and typically has no underlying LD3232. Weiss CH, Glassroth J. Pulmonary disease caused by nontuberculous mycobacteria. Expert Rev Respir Med . 2012;6(6):597-613.. Furthermore, hypersensitivity pneumonitis is considered an inflammatory reaction caused by the inhalation of large quantities of aerosols containing NTMs2929. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. American Thoracic Society Documents an Official ATS / IDSA Statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am Thorac Soc Doc. 2007;175(4):367-416.,3333. Falkinham JO 3rd. Nontuberculous mycobacteria in the environment. Clin Chest Med. 2002;23(3):529-51.. The signs and symptoms of nodular bronchietasia and hypersensitivity pneumonitis are similar to fibrocavitary disease and in all cases, the diagnosis is made from evidences found via chest radiography or CT2828. Larsson LO, Polverino E, Hoefsloot W, Codecasa LR, Diel R, Jenkins SG, et al. Pulmonary disease by non-tuberculous mycobacteria - clinical management, unmet needs and future perspectives. Expert Rev Respir Med . 2017;11(12):977-89.,2929. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. American Thoracic Society Documents an Official ATS / IDSA Statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am Thorac Soc Doc. 2007;175(4):367-416..

RADIOLOGICAL DIAGNOSIS

Current diagnostic criteria of NTM-LD were established in 2007 by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA). Since then, diagnosis is based on clinical evidence, microbiological identification, and radiological findings44. Baldwin SL, Larsen SE, Ordway D, Cassell G, Coler RN. The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases. Plos Negleted Trop Dis. 2019;13(2):1-23.,3434. Jarand J, Levin A, Zhang L, Huitt G, Mitchell JD, Daley CL. Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease. Clinical Infectious Disease. 2011;52(1):565-71.. Various studies describing the tomographic appearance of NTM-LD have been performed over time and these are listed in Table 1.

This review noted that 77.8% of the articles on NTM-LD published between 1999 and 2019 described bronchiectasis among their CT findings (Table 2). Bronchiectasis is characterized by permanent and abnormal dilation of the bronchi triggered after persistent bacterial airway infection3535. King PT. The Role of the immune response in the pathogenesis of bronchiectasis. Biomed Res Int . 2018;2018:6802637.. Figure 2A and Figure 2B show representative images of CT scans showing bronchiectasis in an anonymous patient who was diagnosed with NTM-LD according to the ATS and IDSA criteria.

A study by Fujita et al. (1999) suggests that discrete nodule bronchiectasis is an important radiological finding of MAC infection and colonization3636. Fujita J, Ohtsuki Y, Suemitsu I, Shigeto E, Yamadori I, Obayashi Y, et al. Pathological and radiological changes in resected lung specimens in Mycobacterium avium intracellulare complex disease. Eur Respir J . 1999;13(3):535-40.. Another study conducted with the Korean population revealed that bronchiectasis was associated with lung colonization by M. kansasii in LD patients3737. Park HK, Koh W-J, Shim TS, Kwon J. Clinical characteristics and treatment outcomes of Mycobacterium kansasii lung disease in Korea. Yonsei Med J. 2010; 51(4):552-6.. Baghaei et al. (2012) also associated bronchiectasis with LD caused by M. simiae among the Iranian population3838. Baghaei P, Tabarsi P, Farnia P, Marjani M, Sheikholeslami F-M, Chitsaz M, et al. Pulmonary disease caused by Mycobacterium simiae in Iran ’ s national referral center for tuberculosis. J Infect Dev Ctries. 2012;6(1):23-8..

Another study by Bonnet et al. (2017) showed that approximately two-thirds of patients with NTM-LD also had fibrocavitary disease with bronchiectasis (60%) and cavitation (40%)3939. Bonnet M, San KC, Pho Y, Sok C, Dousset J-P, Brant W, et al. Nontuberculous mycobacteria infections at a provincial Reference Hospital, Cambodia. Emerg Infect Dis . 2017;23(7):1139-47.. Bronchiectasis is also among the most predominantly identified radiological observations in CT scans of patients with NTM infection as described in a study conducted by Cowman and Loebinger (2018)4040. Cowman SA, Loebinger MR. Diagnosis of nontuberculous mycobacteria lung disease. Semin Respir Crit Care Med. 2018;39(03):343-50..

Ueyama et al. (2016) also reported that bronchiectasis was observed via CT images among 96% of adult patients with NTM-LD evaluated in their study4141. Ueyama M, Asakura T, Morimoto K, Namkoong H, Matsuda S, Osawa T, et al. Pneumothorax associated with nontuberculous mycobacteria. Medicine. 2016;95(29):1-9.. In the study by Hirama, Brode and Marras (2018), it was identified that 42.6% of the patients with LD by M. xenopi also presented nodular bronchiectasis based on CT scans4242. Hirama T, Brode SK, Marras TK. Radiologic types of Mycobacterium xenopi pulmonary disease: different patients with similar short-term outcomes. Eur J Clin Microbiol Infect Dis. 2019;38(2):373-81.. Interestingly, in this retrospective study, patients with nodular bronchiectasis were predominantly female. These patients had characteristics which were suggestive of milder disease and were treated less frequently. In addition, these patients received fewer anti-mycobacterial drugs during treatment. Taken together, these results were not sufficient to determine a specific radiological pattern for LD by M. xenopi4242. Hirama T, Brode SK, Marras TK. Radiologic types of Mycobacterium xenopi pulmonary disease: different patients with similar short-term outcomes. Eur J Clin Microbiol Infect Dis. 2019;38(2):373-81..

In Brazil, a study on clinical aspects of patients with LD by MABSC identified the presence of nodular bronchiectasis in individuals diagnosed with NTM infection but were not undergoing any treatment. However, these results are not sufficient to determine a radiological standard for NTM-LD findings4343. Monteiro JTC, Lima KVB, Barreto AR, Furlaneto IP, Gonçalves GM, da Costa ARF, et al. Clinical aspects in patients with pulmonary infection caused by mycobacteria of the Mycobacterium abscessus complex, in the Brazilian Amazon. J Bras Pneumol . 2018;44(2):93-8..

It should be noted that some of the studies cited here were performed in patients with cystic fibrosis who had a predisposition to changes such as bronchiectasis4444. Redondo M, Keyt H, Dhar R, Chalmers JD. Global impact of bronchiectasis and cystic fibrosis. Breathe. 2016;12(3):222-35.. Hence, it is not possible to state whether the onset of bronchiectasis favors lung colonization by NTMs or vice versa4545. Bonaiti G, Pesci A, Marruchella A, Lapadula G, Gori A, Aliberti S. Nontuberculous mycobacteria in noncystic fibrosis bronchiectasis. Biomed Res Int . 2015;2015:197950.,4646. Koh W-J, Kwon OJ, Kyung SL. Nontuberculous mycobacterial pulmonary diseases in immunocompetent patients. Korean J Radiol. 2002;3(3):145-57..

This characterization of bronchial alterations as an important radiological finding of NTM-LD is relevant for the diagnosis and also for the patient recovery. A study by Cowman et al. (2018) suggested that bronchiectasis interfered with the duration of the disease and was associated with severe lung disease prognosis4747. Cowman SA, Jacob J, Obaidee S, Floto RA, Wilson R, Haworth CS, et al. Latent class analysis to define radiological subgroups in pulmonary nontuberculous mycobacterial disease. BMC Pul. 2018;18(1):1-8..

Another obstacle for the radiological diagnosis of NTM-LD was highlighted by Bonnet et al. (2017) where the authors showed that CT scans from TB patients also feature post-inflammatory bronchiectasis3939. Bonnet M, San KC, Pho Y, Sok C, Dousset J-P, Brant W, et al. Nontuberculous mycobacteria infections at a provincial Reference Hospital, Cambodia. Emerg Infect Dis . 2017;23(7):1139-47.. According to Kwak et al. (2016), NTM-LD and pulmonary TB bronchiectasis are difficult to distinguish and, therefore, it is necessary to observe other radiological characteristics4848. Kwak N, Lee C-H, Lee H-J, Kang YA, Lee JH, Han SK, et al. Non-tuberculous mycobacterial lung disease: diagnosis based on computed tomography of the chest. Eur Soc Radiol. 2016;26(12):4449-56., such as, cavities and distribution of pulmonary changes in CT images. Compared with pulmonary TB, NTM-LD tends to form cavities less frequently5656. Kendall BA, Varley CD, Choi D, Cassidy M, Hedberg K, Ware MA, et al. Distinguishing tuberculosis from nontuberculous mycobacteria lung disease, Oregon, USA. Emerg Infect Dis . 2011;17(3):506-9. and involves more of the middle and/or lower lung regions and bilateral lungs more frequently5757. Kow W-J, Yu C-M, Su GY, Chung MP, Kim H, Kwon OJ, et al. Pulmonary TB and NTM lung disease: comparison of characteristics in patients with AFB smear-positive sputum. The International Journal of Tuberculosis and Lung Disease. 2006;10(9):1001-7..

This review found that 55.6% and 88.9% of the articles indicate presence of pulmonary nodules and presence of cavitation on CT images of patients with NTM-LD, respectively (Table 2). Figure 3C represents CT images of patients with NTM-LD who presented cavitation and pulmonary nodules based on radiological findings.

Pulmonary nodules were also identified in 98% of adult patients with NTM-LD evaluated in the study by Ueyama et al. (2016). Interestingly, in that study, other findings were also reported, including cavitation ( in 77% of patients)4141. Ueyama M, Asakura T, Morimoto K, Namkoong H, Matsuda S, Osawa T, et al. Pneumothorax associated with nontuberculous mycobacteria. Medicine. 2016;95(29):1-9..

Studies by Shitrit et al. (2008) and Matveychuck et al. (2012) conducted among Israeli population revealed numerous upper lobe cavitations in patients with M. kansasii infection4949. Shitrit D, Peled N, Bishara J, Priess R, Pitlik S, Samra Z, et al. Clinical and radiological features of Mycobacterium kansasii infection and Mycobacterium simiae infection. Respir Med . 2008;102(11):1598-603.,5858. Matveychuck A, Fuks L, Priess R, Hahim I, Shitrit D. Clinical and radiological features of Mycobacterium kansasii and other NTM infections. Respiratory Medicine. 2012;106(1):1472-7.. In a subsequent study, the prevalence of thin-walled cavities in upper lobes of patients with infections caused by NTMs was also observed. In these cases, some pleural abnormalities around the cavities were observed1616. Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis. 2014;6(3):210-20..

In the study by Shitrit et al. (2008), pleural abnormalities and lymphadenopathy were also identified. However, in this study, these abnormalities were only associated with the presence of pulmonary infiltrates located in the middle and upper lobes among patients with infections caused by M. simiae4949. Shitrit D, Peled N, Bishara J, Priess R, Pitlik S, Samra Z, et al. Clinical and radiological features of Mycobacterium kansasii infection and Mycobacterium simiae infection. Respir Med . 2008;102(11):1598-603.. On the other hand, it has been reported that MTBC is also capable of promoting cavitation formation. Thus, it was concluded that cavitations are nonspecific alterations of NTM-LD and might reflect infections caused by several pathogens commonly found in diseases that compromise airway functions44. Baldwin SL, Larsen SE, Ordway D, Cassell G, Coler RN. The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases. Plos Negleted Trop Dis. 2019;13(2):1-23.,2424. Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann J-L, Nick J-A, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fi brosis. Thorax. 2016;71(1):1-22..

This review identified other radiological findings such as pleural effusion and mediastinal lymphadenopathy, which were observed in a study by Bakula et al. (2018). Other findings of this study were consolidation (50%), ground-glass opacities (33.3%), other pleural diseases (22.2%), pleural lymphadenopathy (27.8%), atelectasis (22.2%), “budding tree” pattern (22.2%), fibrotic alteration / volume loss / pulmonary architecture distortion (38.9%), hydropneumotorax / pneumothorax (11.1%), and bronchiolitis (5.6%). All the findings are summarized in Table 2.

TABLE 2:
Frequency of studies that report radiological findings among NMT infections as described in the articles included in this review.

Gommans et al. (2014) pointed out that the variability observed among radiological findings of infections caused by NTMs is common and is dependent on the species causing infection. Furthermore, it is suggested that the presence of consolidation on CT images of patients diagnosed with NTM infection is an important predictor of mortality5050. Gommans EPAT, Even P, Linssen CFM, van Dessel H, van Haren E, de Vries GJ, et al. Risk factors for mortality in patients with pulmonary infections with non-tuberculous mycobacteria: A retrospective cohort study. Respir Med . 2015; 109(1):137-45.. On the other hand, Hwang et al. (2017) suggested that the presence of fibrocavitary alterations and advanced age are negative prognostic factors for survival of patients with LD by MAC5151. Hwang JA, Kim S, Jo K-W, Shim TS. Natural history of Mycobacterium avium complex lung disease in untreated patients with stable course. Eur Respir. 2017;49(3):1600537..

These fibrocavitary changes were associated with 39.4% of the cases of LD due to M. xenopi based on a study by Hirama et al. (2019)4242. Hirama T, Brode SK, Marras TK. Radiologic types of Mycobacterium xenopi pulmonary disease: different patients with similar short-term outcomes. Eur J Clin Microbiol Infect Dis. 2019;38(2):373-81.. Cowman and Loebinger (2018) had previously identified these fibrocavitary changes in CT scans of patients with NTM infections4040. Cowman SA, Loebinger MR. Diagnosis of nontuberculous mycobacteria lung disease. Semin Respir Crit Care Med. 2018;39(03):343-50.. In the same study, consolidation was suggested as a common radiological finding4040. Cowman SA, Loebinger MR. Diagnosis of nontuberculous mycobacteria lung disease. Semin Respir Crit Care Med. 2018;39(03):343-50..

Additionally, studies by Kobashi et al. (2013) and Ueyama et al. (2016) revealed that pneumothorax has been recognized in the lungs of certain patients diagnosed with NTM infections4141. Ueyama M, Asakura T, Morimoto K, Namkoong H, Matsuda S, Osawa T, et al. Pneumothorax associated with nontuberculous mycobacteria. Medicine. 2016;95(29):1-9.,5252. Kobashi Y, Mouri K, Obase Y, Kato S, Oka M. Clinical analysis of patients with pulmonary nontuberculous mycobacterial disease complicated by pneumothorax. Inter Med. 2013;52(22):2511-15.. Yoon et al. (2016) also suggested that the presence of pneumothorax in CT scans is indicative of the spread of MAC infection but the meaning of this association is not clear5959. Yoon HJ, Chung MJ, Lee KS, Kim JS, Park HY, Koh W-J. Broncho-Pleural Fistula with Hydropneumothorax at CT: Diagnostic Implications inMycobacterium aviumComplex Lung Disease with Pleural Involvement. Korean J Radiol . 2016;17(2):295-301..

The loss of lung mass volume is also a characteristic that is frequently identified among the radiological findings of patients with lung diseases. De Marca et al. (2019) suggested that there is a relationship between mass and lung functions, however, this relationship is not yet fully elucidated5353. De Marca PGC, Goldenberg T, Mello FCQ, Carvalho ARS, Guimarães ARM, Mogami R, et al. Pulmonary densitovolumetry using computed tomography in patients with nontuberculous mycobacteria: correlation with pulmonary function tests. Pulmonary Medicine. 2019;2019(5942783):1-9..

Although all the findings described above are not specific towards a definitive NTM-LD diagnosis, it is described in the literature that the disease form with nodular infiltrates and bronchiectasis frequently affects the middle lobe and lingula regions3737. Park HK, Koh W-J, Shim TS, Kwon J. Clinical characteristics and treatment outcomes of Mycobacterium kansasii lung disease in Korea. Yonsei Med J. 2010; 51(4):552-6.,4141. Ueyama M, Asakura T, Morimoto K, Namkoong H, Matsuda S, Osawa T, et al. Pneumothorax associated with nontuberculous mycobacteria. Medicine. 2016;95(29):1-9.. Representative images of these alterations are shown in Figures 3A and Figure 3B.

THERAPY

The objective of treatment against NTM-LD is to improve the patient's quality of life by monitoring signs and symptoms. Treatment against NTM infection is long and lasts for 18 to 24 months. The patient is considered cured when he/she is negative for sputum culture for 12 consecutive months5454. Kwak N, Dalcolmo MP, Daly CL, Eather G, Gayoso R, Hasegawa N, et al. Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis. Eur Respir J . 2019;2019(March):1-48.. Treatment is a complex decision that involves measuring the benefits and the risk of drug toxicity1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31..

The choice of drug, in general, is directed towards the elimination of the disease-causing NTM species. Microbial susceptibility testing is recommended prior to initiation of treatment. Traditionally, treatment of NTM-LD by MAC consists of the combined use of macrolides (claritormycin or azithromycin), rifampicin and ethambutol1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31.. Certain cases of resistance against macrolides and amikacin have already been reported and this resistant or refractory form can be treated alternatively with moxifloxacin, aminoglycosides and clofazimine1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31.,5555. Luo J, Yu X, Jiang G, Fu Y, Huo F, Ma Y, et al. In vitro activity of clofazimine against nontuberculous Mycobacteria Isolated in Beijin, China. Antimicrob Agents Chemother. 2018;62(7):1-9..

M. kansassi is sensitive to anti-TB drugs and is treated with rifampicin, isoniazid, rifabutin, ethambutol, fluoroquinolones, and amikacin1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31.. The pulmonary infection caused by MABSC is progressively slow and its treatment is based on the combined use of intravenous amikacin with cefoxitin or imipenem and an oral macrolide2121. Jeon K, Kwon OJ, Lee NY, Kim B-J, Kook Y-H, Lee S-H, et al. Antibiotic treatment of Mycobacterium abscessus lung disease a retrospective analysis of 65 patients. Am J Respir Crit Care Med . 2009;180(9):896-902.,2929. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, et al. American Thoracic Society Documents an Official ATS / IDSA Statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am Thorac Soc Doc. 2007;175(4):367-416.,5454. Kwak N, Dalcolmo MP, Daly CL, Eather G, Gayoso R, Hasegawa N, et al. Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis. Eur Respir J . 2019;2019(March):1-48.. Information on the effectiveness of this treatment is limited and there is evidence that MABSC is resistant to various antibiotics2121. Jeon K, Kwon OJ, Lee NY, Kim B-J, Kook Y-H, Lee S-H, et al. Antibiotic treatment of Mycobacterium abscessus lung disease a retrospective analysis of 65 patients. Am J Respir Crit Care Med . 2009;180(9):896-902.,5454. Kwak N, Dalcolmo MP, Daly CL, Eather G, Gayoso R, Hasegawa N, et al. Mycobacterium abscessus pulmonary disease: individual patient data meta-analysis. Eur Respir J . 2019;2019(March):1-48..

Despite these treatment options, it should be noted that the patient is subjected to side effects, reactions and drug interactions. In the case of macrolides, gastrointestinal discomfort is commonly observed. Use of rifampicin, imipenem and tigecycline might cause hepatotoxicity and rifampicin might alter the metabolism of other medicines such as contraceptives. The use of aminoglycosides, in turn, might cause renal toxicity and hearing impairment1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31.. The use of linezoline and ethambutol might cause peripheral neuropathy and ethambutol could also lead to decreased visual acuity1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31..

In general, it is suggested that treatment should begin within hospital units1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31.. In cases where response to chemotherapy is not efficient, surgical resection should be considered and must be conducted by a multidisciplinary technical team1111. Chalmers JD, Aksamit T, Carvalho ACC, Rendon A, Franco I. Non-tuberculous mycobacterial pulmonary infections. J Pulmonol. 2018;24(2):120-31.,2121. Jeon K, Kwon OJ, Lee NY, Kim B-J, Kook Y-H, Lee S-H, et al. Antibiotic treatment of Mycobacterium abscessus lung disease a retrospective analysis of 65 patients. Am J Respir Crit Care Med . 2009;180(9):896-902..

CONCLUSIONS

The increased incidence associated with the complexity of diagnosis makes NTM-LD a public health concern. Correct and rapid diagnosis is critical for the proper and effective choice of treatment. Currently, diagnostic criteria include clinical evidence, microbiological identification, and radiological findings. NTM-LD symptoms are similar to other pulmonary infections. Microbiological identification is not always possible. Based on the radiological alterations observed in NTM-LD, bronchiectasis, cavitations and pulmonary nodules are predominantly found. Although these alterations overlap with other lung diseases, when they are predominantly found in the middle lobe and lingula, mycobacteriosis should be suspected.

ACKNOWLEDGMENTS AND FINANCIAL SUPPORT

This work was supported by the Brazilian National Council for Scientific and Technological Development (CNPq) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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Publication Dates

  • Publication in this collection
    11 Sept 2020
  • Date of issue
    2020

History

  • Received
    07 May 2020
  • Accepted
    29 June 2020
Sociedade Brasileira de Medicina Tropical - SBMT Sociedade Brasileira de Medicina Tropical - SBMT, Núcleo de Medicina Tropical – UnB, Sala 43C – 70904-970, E-mails: rsbmt@uftm.edu.br | artes.rsbmt@gmail.com | sbmt@sbmt.org.br , WhatsApp: SBMT (61) 9.9192-6496, WhatsApp: RSBMT (34) 9.9996-5807 - Brasília - DF - Brazil
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