Lung Disease Due to the More Common Nontuberculous Mycobacteria

doi:10.1378/chest.129.6.1653

Chest

Volume 129, Issue 6, June 2006, Pages 1653-1672

https://doi.org/10.1378/chest.129.6.1653 Get rights and content

As the prevalence of tuberculosis (TB) declines in the developed world, the proportion of mycobacterial lung disease due to nontuberculous mycobacteria (NTM) is increasing. It is not clear whether there is a real increase in prevalence or whether NTM disease is being recognized more often because of the introduction of more sensitive laboratory techniques, and that more specimens are being submitted for mycobacterial staining and culture as the result of a greater understanding of the role of NTM in conditions such as cystic fibrosis, posttransplantation and other forms of iatrogenic immunosuppression, immune reconstitution inflammatory syndrome, fibronodular bronchiectasis, and hypersensitivity pneumonitis. The introduction of BACTEC liquid culture systems (BD; Franklin Lakes, NJ) and the development of nucleic acid amplification and DNA probes allow more rapid diagnosis of mycobacterial disease and the quicker differentiation of NTM from TB isolates. High-performance liquid chromatography, polymerase chain reaction, and restriction fragment length polymorphism analysis have helped to identify new NTM species. Although treatment regimens that include the newer macrolides are more effective than the earlier regimens, failure rates are still too high and relapse may occur after apparently successful therapy. Moreover, treatment regimens are difficult to adhere to because of their long duration, adverse effects, and interactions with the other medications that these patients require. The purpose of this article is to review the common presentations of NTM lung disease, the conditions associated with NTM lung disease, and the clinical features and treatment of the NTM that most commonly cause lung disease.

Section snippets

Epidemiology

With the advent of effective treatment for TB in the 1950s, mycobacterial specimens began to be routinely cultured, and it was recognized that some of the apparent cases of TB were due to NTM.²⁵ The prevalence of TB has declined in the developed world, and the proportion of mycobacterial disease due to NTM has increased. Surveys26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 have identified human disease due to NTM in most parts of the world. The paucity of reports of NTM disease from the developing

Cavitary Lung Disease

The earliest recognized pattern of NTM lung disease was cavitary disease, predominantly involving the upper lobes, similar to the pulmonary TB seen in sanitarium patients.39, 40, 56 Patients with NTM lung disease tended to be older than TB patients and were not infectious for family members or staff.³⁹ They were predominantly male, often with a history of tobacco and/or alcohol abuse, and usually had underlying lung disease.26, 57 Patients are usually symptomatic, but it is hard to distinguish

Transplantation

Infection with NTM has been reported in patients after solid-organ and hematopoietic stem-cell transplantation. Fortunately, NTM are not common in transplant recipients since drug interactions occur between the antibiotics used to treat NTM and the immunosuppressive medications.⁹⁷

Pleuropulmonary infections were the most common type in lung transplant patients, accounting for 55% of the NTM infections; and MAC (32%) was the most common NTM isolated, followed by M abscessus (26%) and

Diagnosis

Clinical suspicion and requesting that respiratory specimens be stained and cultured for mycobacteria are the first steps in the diagnosis of NTM lung disease. Whenever mycobacterial disease is considered, it is important rule out pulmonary TB. In patients without HIV infection, those with pulmonary TB are more likely to have systemic symptoms, such as fever, night sweats, and weight loss, and hemoptysis; but patients with more advanced NTM lung disease may have similar symptoms.⁴² Features

M avium

M avium is the most common cause of NTM lung disease in most parts of the world.7, 8, 9, 10, 29, 30, 31, 32, 33, 34 MAC can also cause lymphadenitis (usually in children), soft-tissue infections, and disseminated disease in immunocompromised patients, usually patients with AIDS with a CD4⁺ count < 50/μL.165, 166, 167, 168

In patients with underlying lung disease, MAC often causes cavitary disease, similar to the lung disease caused by other NTM.169, 170, 171 MAC can also cause lung disease in

Conclusion

The prevalence of NTM disease has increased because of the increased number of patients with immunosuppression. Although the reported prevalence of NTM lung disease in immunocompetent patients has increased, it is not clear whether this is a true increase or whether more sensitive laboratory techniques for the isolation and identification of NTM explain the apparent increase. Some of the apparently increased prevalence is due to greater appreciation of the role of NTM in different lung

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This study investigates the impact of nontuberculous mycobacterial lung disease (NTM-LD) on mortality and mechanical ventilation use in critically ill patients.
We enrolled patients with NTM-LD or tuberculosis (TB) in intensive care units (ICU) and analysed their association with 30-day mortality and with mechanical ventilator-free survival (VFS) at 30 days after ICU admission.
A total of 5996 ICU-admitted patients were included, of which 541 (9.0 %) had TB and 173 (2.9 %) had NTM-LD. The overall 30-day mortality was 22.2 %. The patients with NTM-LD had an adjusted hazard ratio (aHR) of 1.49 (95 % CI, 1.06–2.05), and TB patients had an aHR of 2.33 (95 % CI, 1.68–3.24), compared to ICU patients with negative sputum mycobacterial culture by multivariable Cox proportional hazard (PH) regression. The aHR of age<65 years, obesity, idiopathic pulmonary fibrosis, end-stage kidney disease, active cancer and autoimmune disease and diagnosis of respiratory failure were also significantly positively associated with ICU 30-day mortality. In multivariable Cox PH regression for VFS at 30 days in patients requiring invasive mechanical ventilation, NTM-LD was negatively associated with VFS (aHR 0.71, 95 % CI: 0.56–0.92, p = 0.009), while TB showed no significant association. The diagnosis of respiratory failure itself predicted unfavourable outcome for 30-day mortality and a negative impact on VFS at 30 days.
NTM-LD and TB were not uncommon in ICU and both were correlated with increasing 30-day mortality in ICU patients. NTM-LD was associated with a poorer outcome in terms of VFS at 30 days.
Histologic Clues to Infection as an Etiology to Lung Disease
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Solitary pulmonary nodules caused by Mycobacterium avium complex
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The prevalence of Mycobacterium avium complex (MAC) pulmonary disease (PD) is increasing significantly in Japan. Among the patterns of MAC-PD, a solitary pulmonary nodule (SPN) is less common and often resembles lung cancer. The aim of this study was to identify the clinical features of MAC-SPN.
SPNs culture-positive for MAC (definite cases) and culture-negative SPNs showing nucleic acid amplification test (NAAT)-positive status (probable cases) that presented between January 2007 and December 2017 were enrolled. The patients' clinical, laboratory, radiological, and microbiological findings and outcomes were investigated.
This study included 28 patients (median age, 66 years; 16 men, 12 women). All patients were asymptomatic when the disease was detected. Median SPN size was 23.5 mm. Twenty-six patients underwent video-assisted thoracoscopic surgery, while the others underwent percutaneous needle biopsy for diagnosis. Granulomatous inflammation was confirmed in all cases. Microbiologically, the 28 cases were divided into 17 in the definite group and 11 in the probable group. In both groups, M. avium was predominant. There were no significant differences in clinical and radiological findings and follow-up periods between the 2 groups. After diagnosis, 6 patients received medical treatment, while the others did not. The median follow-up period was 42 months, and no recurrence was observed in both groups.
MAC should be considered in the differential diagnosis of SPNs in asymptomatic patients. To overcome the difficulties in diagnosing MAC-SPN, this study underscores the importance of diagnostic interventions and identification of MAC by culture and/or NAAT in biopsied specimens.
Mono- and poly-functional T cells in nontuberculous mycobacteria lung disease patients: Implications in analyzing risk of disease progression
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The diagnosis and progression of nontuberculous mycobacteria lung disease (NTN-LD) are important for clinical judgement but cannot easily be predicted. The immunological response of mono- and poly-functional T cells, a representative of host reactivity to NTM, could be a surrogate biomarker for disease and progression prediction.
Mycobacterium avium complex (MAC) and M. abscessus (MAB) induced lung disease (LD) have become a clinical concern. Predicting clinical disease relevance and progression is important, but suitable biomarkers are lacking. The host immune response of mono- and poly-functional T cells might aid in clinical judgement.
We enrolled 140 participants, including 42 MAC-LD, 25 MAB-LD, 31 MAC airway colonization (MAC-Co), 15 MAB-Co patients, and 27 healthy controls. Their blood mono- and poly-functional T cells were measured and analyzed after in-vitro stimulation.
Patients with MAC-LD generally had lower total IFN-γ+, total TNF-α+ and triple-positive T cells but higher mono-IL-2+ expression than the controls and MAC-Co group. The MAB-LD group had lower total IL-2 and triple positive cells than the controls and colonization group. Multivariate analysis revealed that body mass index (BMI), mono-IL2+ CD4+ and triple positive-CD8+ cells (PMA stimulation) significantly predicted MAC-LD from the controls. By contrast, male gender and triple positive-CD4+ cells predicted MAC-LD from colonization. On the other hand, the triple positive-CD4+ cells (PMA stimulation) alone or together with the mock/MAB ratio of IL-2+/TNF-α+ CD4 cells could predict MAB-LD in the MAB-Co group or the controls. Among MAC/MAB-LD patients without anti-mycobacterial treatment, MAC-specific mono-IFN-γ+ CD4+ cells and PMA-induced triple positive-CD4+ cells were correlated with progression, with an area under the ROC curve of 0.875.
The patients with MAC/MAB-LD had attenuated poly-functional T cells. The triple-positive CD4+ cells could be useful in diagnosing disease from colonization. MAC-specific mono-IFN-γ+ CD4+ cells and triple positive-CD4+ might predict radiographic progression, which could be useful in making treatment decisions.
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Chest

Original ResearchLung Disease Due to the More Common Nontuberculous Mycobacteria

Section snippets

Epidemiology

Cavitary Lung Disease

Transplantation

Diagnosis

M avium

Conclusion

Clin Lab Med

Clin Chest Med

Clin Chest Med

Am J Med Sci

Cytokine Growth Factor Rev

Lancet Infect Dis

Chest

Respir Med

J Infect Chemother

Respir Med

Chest

Tuberc Lung Dis

Tuberc Lung Dis

Chest

Chest

Chest

Clin Chest Med

Chest

Mayo Clin Proc

Chest

Respir Med

J Pediatr

Infect Dis Clin North Am

Chest

PCR based method to differentiate the subspecies of theMycobacterium tuberculosiscomplex on the basis of genomic deletions

J Clin Microbiol

Epidemiology of infection by nontuberculous mycobacteria

Clin Microbiol Rev

Health impacts of environmental mycobacteria

Clin Microbiol Rev

Incidence and clinical significance of non-tuberculous mycobacteria isolated from clinical specimens during a 2-y nationwide survey

Scand J Infect Dis

National atypical mycobacteria survey, 2000

Commun Dis Intel

Non-tuberculous mycobacteria: patterns of isolation: a multi-country retrospective survey

Int J Tuberc Lung Dis

American Thoracic Society. Diagnosis and treatment of disease caused by nontuberculous mycobacteria

Am J Respir Crit Care Med

Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunist mycobacterial infections: Joint Tuberculosis Committee guidelines 1999

Thorax

A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection

N Engl J Med

Interferon-γ-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection

N Engl J Med

Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection

J Clin Invest

Immune deficiency presenting as mycobacterial infection

Clin Rev Immunol

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

Nat Genet

Immunotherapy of mycobacterial infections

Semin Respir Infect

Expression of IL-18 byMycobacterium avium-infected human monocytes: association withM aviumvirulence

Clin Exp Immunol

IL-12 promotes drug-induced clearance ofMycobacterium aviuminfection in mice

J Immunol

Abnormal regulation of interferon-γ, interleukin-12, and tumor necrosis factor-α in human interferon-γ receptor 1 deficiency

J Infect Dis

Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation

Science

Nontuberculous mycobacteria and associated diseases

Am Rev Respir Dis

Chronic pulmonary disease due to atypical mycobacterial infections

Am Rev Respir Dis

Investigation by seroagglutination of strains of the Mycobacterium intracellulare M scrofulaceum group from house dusts and sputum in southeastern Queensland

Am Rev Respir Dis

A study of mycobacterial species isolated from patients with chronic respiratory disease

Am Rev Respir Dis

Epidemiologic aspects of nontuberculous mycobacterial disease and of tuberculosis in British Columbia

Am Rev Respir Dis

Water as a source of potentially pathogenic mycobacteria

Original Research
Lung Disease Due to the More Common Nontuberculous Mycobacteria