Pulmonary Nontuberculous Mycobacterial Research Articles

CT informs detection and treatment options in rheumatoid arthritis complicated by pulmonary non-tuberculous mycobacterial disease from the FIRST registry

ObjectiveTo investigate the early detection of pulmonary non-tuberculous mycobacterial (PNTM) disease by CT before the initiation of molecular-targeted therapeutic drugs in patients with rheumatoid arthritis (RA) and the efficacy and...

The risk of pulmonary NTM infections and water-quality constituents among persons with cystic fibrosis in the United States, 2010-2019.

The prevalence of nontuberculous mycobacterial (NTM) pulmonary disease varies geographically in the United States. Previous studies indicate that the presence of certain water-quality constituents in source water increases NTM infection risk. To identify water-quality constituents that influence the risk of NTM pulmonary infection in persons with cystic fibrosis in the United States. We conducted a population-based case-control study using NTM incidence data collected from the Cystic Fibrosis Foundation Patient Registry during 2010-2019. We linked patient zip code to the county and associated patient county of residence with surface water data extracted from the Water Quality Portal. We used logistic regression models to estimate the odds of NTM infection as a function of water-quality constituents. We modeled two outcomes: pulmonary infection due to Mycobacterium avium complex (MAC) and Mycobacterium abscessus species. We identified 484 MAC cases, 222 M. abscessus cases and 2816 NTM-negative cystic fibrosis controls resident in 11 states. In multivariable models, we found that for every 1-standardized unit increase in the log concentration of sulfate and vanadium in surface water at the county level, the odds of infection increased by 39% and 21%, respectively, among persons with cystic fibrosis with MAC compared with cystic fibrosis-NTM-negative controls. When modeling M. abscessus as the dependent variable, every 1-standardized unit increase in the log concentration of molybdenum increased the odds of infection by 36%. These findings suggest that naturally occurring and anthropogenic water-quality constituents may influence the NTM abundance in water sources that supply municipal water systems, thereby increasing MAC and M. abscessus infection risk.

Metagenomic next-generation sequencing assistance in identifying non-tuberculous mycobacterial infections.

The advent of metagenomics next-generation sequencing (mNGS) has garnered attention as a novel method for detecting pathogenic infections, including Non-Tuberculous Mycobacterial (NTM) and tuberculosis (TB).However, the robustness and specificity of mNGS in NTM diagnostics have not been fully explored. In this retrospective study, we enrolled 27 patients with NTM genomic sequences via mNGS and conducted a comprehensive clinical evaluation. Pulmonary NTM disease was the most commonly observed presentation, with a subset of patients also presenting with extrapulmonary NTM infections.mNGS analysis identified six distinct NTM species, primarily Mycobacteriumavium complex (MAC), followed by Mycobacterium intracellulare andMycobacterium abscessus. Conventional routine culture methods encountered challenges, resulting in negative results for all available 22 samples. Among the 10 patients who underwent quantitative polymerase chain reaction (qPCR) testing, five tested positive for NTM. It is important to note that further species typing is necessary to determine the specific NTM type, as traditional pathogen detection methods serve as an initial step. In contrast, when supplemented with pathogen data, enables the identification of specific species, facilitating precise treatment decisions. In conclusion, mNGS demonstrates significant potential in aidingthe diagnosis of NTMdisease by rapidly detecting NTM pathogens and guiding treatment strategies. Its enhanced performance, faster turnaround time (TAT), and species identification capabilities make mNGS a promising tool for managing NTM infections.

Prevalence of systemic and local risk factors for pulmonary non-tuberculous mycobacterial disease in Japan: a single-institution study.

Objective: To identify the prevalence of risk factors for pulmonary non-tuberculous mycobacterial (NTM) disease in a Japanese population. Patients and Methods: We reviewed 337 consecutive Japanese patients (210 women) with pulmonary NTM disease, including 225 patients with Mycobacterium avium complex (MAC) disease (95.8%) at our hospital during 2006-2017. We calculated the prevalence of risk factors reported in Western countries among mycobacterial species. Results: Pulmonary MAC disease cases comprised 78.2% of pulmonary NTM patients in their 40s, increasing to 100% at age ≥80 years. Body mass index (BMI) was <18.5 in approximately 40% of patients, which was significantly higher than the prevalence of underweight in the Japanese population. The percentage of male heavy smokers (Brinkman index ≥600) was 58.2% of pulmonary NTM disease and was high for all mycobacterial species. In pulmonary MAC disease, systemic factors were observed in the order of malignant tumors (other than lung cancer), diabetes, rheumatoid arthritis, and tuberculosis. Local factors were observed in the order of bronchiectasis, chronic obstructive pulmonary disease, lung cancer, and bronchial asthma. Conclusion: The risk factors reported in Western countries were relatively highly prevalent among Japanese pulmonary NTM disease patients. This observation may help elucidate disease onset mechanisms.

Pharmacokinetics and Adverse Effects of Clofazimine in the Treatment of Pulmonary Non-Tuberculous Mycobacterial Infection.

Clofazimine (CFZ) is used to treat pulmonary non-tuberculous mycobacterial (NTM) infection; however, its pharmacokinetics remain unexplored in patients with pulmonary NTM, and the relationship between CFZ serum concentration and adverse effects has not been investigated. The objectives of this study were to characterize the pharmacokinetics of CFZ in pulmonary NTM disease treatment and to investigate the relationship between the steady-state CFZ serum concentration and adverse effects. A prospective observational study was conducted on 45 patients with pulmonary NTM treated with CFZ (UMIN000041053). A maximum of five serum samples per patient were taken at the CFZ trough, and serum concentration was measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The pharmacokinetics of CFZ were analyzed using a nonlinear mixed effect model. The relationships among steady-state CFZ serum concentration and adverse effects, pigmentation, and heart rate-corrected QT (QTc) interval were investigated. Twenty-six patients had M. avium or M. intracellulare infection and nineteen had M. abscessus infection. The primary CFZ dosage was 50 mg/day. The estimated apparent CFZ clearance, apparent volume of distribution, and half-life were 2.4 L/h, 2,960 L, and 36 days, respectively. The combined use of rifampicin and CFZ significantly reduced CFZ exposure by 22%. Although there was no relationship between CFZ serum concentration and pigmentation intensity, the QTc interval was significantly correlated with CFZ serum concentration. The estimation of accurate pharmacokinetics for CFZ required approximately 5 months of monitoring. The relationship between the serum concentration and specific adverse effects of CFZ confirmed that CFZ serum concentration was not associated with pigmentation but did affect the QTc interval.

Clinical Aspects of Pulmonary Nontuberculous Mycobacteriosis

Nontuberculous mycobacterial (NTM) infections are an emerging problem. Common organisms include Mycobacterium avium, M. intracellulare, and M. kansasii, along with the M. avium intracellulare complex (MAC), which includes both M. avium and M. intracellulare. Typically, NTM infections affect the lungs and subsequently demonstrate a chronic course. Therefore, persistent respiratory symptoms generally indicate of the presence of pulmonary NTM diseases, and chest radiography, along with a sputum examination, are essential for its diagnosis. Because NTM are ubiquitous environmental organisms, a positive culture from a minimum of two separate expectorated sputum samples are required to make a diagnosis. The repertoire of effective drugs for treatment is considerably limited, indicating the need for long-term management with multiple drugs. Establishing a treatment regimen with high therapeutic efficacy and safety is an important issue for the future.

Association between the Use of Inhaled Corticosteroids and Pulmonary Nontuberculous Mycobacterial Infection: A Systematic Review

The incidence of nontuberculous mycobacterial (NTM) pulmonary disease has increased in recent years. It seems that patients with structural lung diseases treated with inhaled corticosteroids (ICS) are at risk of pulmonary NTM infection. This systematic review investigated the articles focused on the association between the use of ICS and pulmonary NTM infection. The current study assessed four categories, namely the association between the use of ICS therapy and NTM infections, bacterial factors involved in the incidence of NTM infection in patients undergoing ICS therapy, the relationship between dosage and long-term use of ICS therapy in the incidence of NTM infection, and main risk factors of the incidence of NTM infection in patients undergoing ICS therapy. Based on the obtained results of the present study, there was an association between the use of ICS therapy and NTM infections. It seems that ICS increases the risk of NTM infection by 1.8 to 8 times. Accordingly, 40-90% of patients with NTM had a history of ICS usage. Mycobacterium avium complex was the most common bacterial factor in NTM patients undergoing ICS therapy. The relationship between a higher dosage of ICS therapy and an increased risk of NTM was confirmed in the majority of the studies. Age, gender, smoking history, and underlying diseases are the main risk factors for the incidence of NTM in patients receiving ICS therapy.

Safety and Efficacy of Nontuberculous Mycobacteria Treatment among Elderly Patients.

Background and objectives: Incidence rates of pulmonary nontuberculous mycobacterial (NTM) disease have been increasing, especially in the elderly population. Given the limited evidence regarding the safety and efficacy of NTM treatment, this study aimed to evaluate the same among elderly patients. Material and methods: Patients diagnosed with NTM disease at a tertiary hospital from January 2007 to December 2017 were enrolled and data were then retrospectively collected. Data of elderly patients who received antimycobacterial treatment were then analyzed. Results: A total of 161 patients satisfied the diagnostic criteria for NTM disease. There were 40 elderly patients who received treatments. Of the patients, 60% received the guideline oriented standard regimens. Single drug regimens were administered to 22.5% of patients. Only 55.0% of the patients were able to continue any treatment. Treatment-related discontinuation was observed in 44.4% of discontinued or changed patients. There were no significant differences in the characteristics of patients with or without adverse events. Patients who were able to continue the treatment for >12 months had a lower proportion of activities of daily living (ADL) disability (nine in 18, 50.0% vs. three in 22, 13.6%, p = 0.018) and heart disease (six in 18, 33.3% vs. 1/22, 4.6%, p = 0.033). Sputum culture conversion was achieved in 28 out of 40 (70.0%) elderly patients treated, and those who achieved sputum culture conversion had more standard regimens prescribed than those who failed sputum culture conversion (21 in 28, 75% vs. 3 in 12, 25%; p = 0.005). Conclusion: Age may not be an obstacle for receiving the benefits of the treatment of NTM disease with a precise evaluation of patient’s comorbidities. Furthermore, elderly patients without heart disease and ADL disability may have better rate of continuing the NTM treatment. The current study suggested that selecting standard regimens to treat pulmonary NTM is important for elderly patients.

Costs Associated with Nontuberculous Mycobacteria Infection, Ontario, Canada, 2001–2012

To determine incidence-based healthcare costs attributable to nontuberculous mycobacterial (NTM) pulmonary disease (PD) and NTM pulmonary isolation (PI), from the healthcare payer perspective, we conducted a population-based matched cohort study in Ontario, Canada. We established cohorts of patients with incident NTM-PD and NTM-PI during 2001–2012 by using individually linked laboratory data and health administrative data, matched to unexposed persons from the general population. To estimate attributable costs for acute and long-term illness, we used a phase-of-care approach. Costs were stratified by age, sex, and healthcare resource, and reported in 2018 Canadian dollars (CAD) and US dollars (USD), standardized to 10 days. Costs were highest during the before-death phase (NTM-PD CAD $1,352 [USD $1,044]; NTM-PI CAD $731 [USD $565]). The cumulative mean attributable 1-year costs were CAD $14,953 (USD $11,541) for NTM-PD and CAD $8,729 (USD $6,737) for NTM-PI. Costs for patients with NTM-PD and NTM-PI were higher than those for unexposed persons.

CapitalBio Mycobacterium real-time polymerase chain reaction detection test: Rapid diagnosis of Mycobacterium tuberculosis and nontuberculous mycobacterial infection

ObjectivesTo evaluate the accuracy of the CapitalBio Mycobacterium real-time polymerase chain reaction (RT-PCR) detection test for pulmonary Mycobacterium tuberculosis (MTB) and nontuberculous mycobacterial (NTM) infection. MethodsThis study analyzed 2,460 samples from patients with suspected pulmonary mycobacterial infection collected between 01 June 2018 and 31 July 2019. It aimed to determine the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of the CapitalBio Mycobacterium detection test for MTB and NTM infections, and to evaluate its diagnostic accuracy compared with mycobacterial culture. ResultsThe sensitivity, specificity, PPV, NPV, and AUC of the CapitalBio Mycobacterium detection test for MTB was 83.0%, 79.9%, 80.8%, 82.2%, and 0.81, respectively. This was similar to the diagnostic accuracy of Xpert MTB/RIF for MTB and was significantly higher than that of smear. For pulmonary NTM infection, the sensitivity, specificity, PPV, NPV, and AUC of the test was 82.0%, 99.6%, 94.1%, 98.5%, and 0.91, respectively. The diagnostic accuracy of the CapitalBio Mycobacterium detection test was also significantly higher than that of smear for NTM. ConclusionsThe CapitalBio Mycobacterium detection test had good diagnostic accuracy for MTB and NTM infections. This is of great significance for the differential diagnosis of early pulmonary mycobacterial infection.

Epidemiology and Risk Factors Associated with NTM Pulmonary and Extrapulmonary Infections in a High Tuberculosis Endemic Region

AbstractIntroduction: Non-tuberculous mycobacteria, although identified as pathogenic to humans long time ago, are emerging as the new threat in the past two decades. Even in tuberculosis endemic country such as India, they are being isolated from the clinical specimens more often than previously. This change in trend is of concern, because they are often misdiagnosed as Mycobacterium tuberculosis or even as drug-resistant tuberculosis. Objectives: A prospective, observational study was planned to identify the frequency and risk factors associated with pulmonary and extrapulmonary non-tuberculous mycobacterial (NTM) infections. Agreement between two commercially available molecular systems, namely GenoType Mycobacteria CM assay and matrix-assisted laser desorption/ionisation time of flight mass spectrometry (MALDI TOF MS) used in the identification of mycobacterial species is also analysed. Materials and Methods: NTM isolated from pulmonary and extrapulmonary clinical specimens over a period of 1½ year was included in the study. Patient demographics were collected, and the risk factors associated with NTM infections were analyzed. NTM grown on culture was speciated using GenoType Mycobacteria CM assay (HAIN Life Sciences, Germany) and MALDI TOF MS (bioMerieux, France). Drug-susceptibility tests were done for rapid-growing NTM using E-test (bioMerieux, France). Results: Eight hundred and fifty-four mycobacteria were isolated from 5009 specimens processed during the study period. Out of the mycobacteria grown, 74 (8.7%) were NTM and 780 (91.3%) were Mycobacterium tuberculosis complex. The NTM isolated from pulmonary specimens were 46 (62.16%) and from extrapulmonary sources were 28 (37.84%). The most common species isolated from pulmonary specimens was Mycobacterium intracellulare and from extrapulmonary specimens was Mycobacterium abscessus. Concordance between the two commercial assays used for the identification was 96.49%. The most common risk factor associated with pulmonary NTM was previous lung pathology, while with extrapulmonary NTM infection was previous surgical intervention. Drug-susceptibility tests for rapid growers showed amikacin and clarithromycin as the most active drugs in vitro. Conclusions: NTM plays a significant role in causing pulmonary and extrapulmonary infections even in our part of the country with high endemicity of tuberculosis. NTM has emerged as important pathogens even in the immunocompetent patients. There is a need for rapid diagnosis and susceptibility testing of NTM to aid physicians administer timely and appropriate treatment to the patients.

Identification of a Rothia mucilaginosa Strain in a Clinical Specimen Based on PCR-Sequencing with Mycobacterium hsp65 Primers

Introduction: Tuberculosis (TB) is one of the top 10 causes of death worldwide. Xpert Mycobacterium tuberculosis (MTB)/Rifampicin (RIF) has been recommended by World Health Organisation (WHO) to diagnose TB, while hsp65-Polymerase Chain Reaction (PCR) has been used for mycobacteria identification. Aim: To report a false positive result (Rothia mucilaginosa) using hsp65-PCR for detection of mycobacteria in a clinical specimen. Materials and Methods: A sputum sample from a 58-year-old, male, suspected-TB patient was studied by Xpert MTB/RIF and hsp65-PCR. The amplified hsp65-PCR product was sequenced and analysed using bioinformatics for bacterial identification and primer specificity. Results: Xpert MTB/RIF showed a negative result, while hsp65-PCR was positive, suggested the presence of Pulmonary Non-Tuberculous Mycobacterial (PNTM) Infection. The analysis of the sequencing result of the amplified hsp65-PCR fragment showed 98% similarity to Rothia mucilaginosa, a member of the normal flora of the human oropharynx and upper respiratory tract, which may cause pneumonia. Further analysis showed that the mycobacteria hsp65 primers used have high percentage of similarity with Rothia mucilaginosa gene sequence, resulting in non-specific detection. Conclusion: This study showed the possibility of false positive results in clinical specimens using PCR-hsp65 primers considered specific for mycobacteria, therefore, this test should be used in clinical samples with caution and it is suggested the need of its further re-optimisation.

Patients with Idiopathic Pulmonary Nontuberculous Mycobacterial Disease Have Normal Th1/Th2 Cytokine Responses but Diminished Th17 Cytokine and Enhanced Granulocyte-Macrophage Colony-Stimulating Factor Production.

Although disseminated nontuberculous mycobacterial infection is attributed to defects in the interleukin (IL)-12/interferon-γ circuit, the immunophenotype of idiopathic pulmonary nontuberculous mycobacterial (PNTM) disease is not well defined. We phenotyped Th1, Th2, Th17, and Treg cytokines and colony-stimulating factor production from patients with idiopathic PNTM disease. Data were compared with healthy donors, cystic fibrosis (CF), and primary ciliary dyskinesia (PCD) patients with PNTM disease. Both supernatant cytokine production and intracellular cytokines expressed by various leukocyte subpopulations following mitogen and antigen stimulation were assayed by electrochemiluminescence-based multiplex immunoassay and flow cytometry, respectively. Regardless of antigen or mitogen stimulation, neither intracellular nor extracellular Th1, Th2, and Treg cytokine levels differed between patients and controls. Th17 cells and IL-17A levels were lower in idiopathic PNTM patients, whereas monocyte granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in response to NTM stimulation was higher compared with healthy donors. Besides, distinct cytokine responses following stimulation by Mycobacterium abscessus and Mycobacterium avium were observed consistently within each group. The IL-12/IFN-γ circuit appeared intact in patients with idiopathic PNTM disease. However, idiopathic PNTM patients had reduced Th17 response and higher mycobacteria-induced monocyte GM-CSF expression.

‘Lady Windermere's counterpart? Pulmonary nontuberculous mycobacteria in men with bronchiectasis

Pulmonary nontuberculous mycobacterial (NTM) disease occurs frequently in older women, and phenotypes of men with NTM disease are largely undescribed. We conducted a case–control study of 34 men with non-cystic fibrosis pulmonary NTM disease (cases), and three male and female control groups with or without NTM disease. Cases were median 71 years of age (range 30–94) and mostly non-Hispanic white (85.3%). These men had similarly low BMI as their female NTM patient counterparts, which was lower than both healthy men (p < 0.001) and bronchiectatic men without NTM (p = 0.06). Kyphoscoliosis was also more common in cases than healthy men (p= 0.007) or bronchiectatic men without NTM (p = 0.02). Our study was the first study to our knowledge to examine demographic features and phenotypes of men with NTM disease. Larger studies are needed to ascertain whether these phenotypes are characteristic of men with NTM disease.

Development and exacerbation of pulmonary nontuberculous mycobacterial infection in patients with systemic autoimmune rheumatic diseases

Objectives: To examine the development and exacerbation of pulmonary nontuberculous mycobacterial (NTM) infection in patients with systemic autoimmune rheumatic diseases (SARD).Methods: We conducted a case–control study. Seventeen of 7013 patients with SARD fulfilling the criteria for pulmonary NTM infection were enrolled in the NTM group. The control group was matched for age, sex, and SARD at a ratio of 2:1.Results: Eight patients with rheumatoid arthritis, four with systemic vasculitis, three with Sjögren’s syndrome, and one each with dermatomyositis and systemic lupus erythematosus were included in the NTM group. Mycobacterium avium was detected in 12 (71%) patients, M. chelonae in 2, and M. intracellulare, M. abscessus, and M. kansasii in 1 patient each. Preexisting lung disease was more common in the NTM group than in the control group (88% versus 38%, p = .0009), particularly bronchiectasis (65% versus 29%, p = .033). The body mass index and serum albumin level were significantly lower in the NTM group than in the control group. Six patients (35%) experienced NTM exacerbation during observation. Clinical immune status at the time of NTM diagnosis, as indicated by the peripheral blood leukocyte/lymphocyte count and serum immunoglobulin G level, was unremarkable and comparable between patients with and without exacerbation, as were the treatments for SARD.Conclusions: In patients with SARD, pulmonary NTM infection may develop and exacerbate without clinically apparent immunosuppression.

BCG Vaccination Induces M. avium and M. abscessus Cross-Protective Immunity.

Pulmonary non-tuberculous mycobacterial (NTM) infections particularly caused by Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are becoming major health problems in the U.S. New therapies or vaccines which will help prevent the disease, shorten treatment duration and/or increase treatment success rates are urgently needed. This study was conducted with the objective of testing the hypothesis that Bacillus Calmette Guerin (BCG), a vaccine used for prevention of serious forms of tuberculosis (TB) in children and adolescents in tuberculosis hyperendemic countries, induces cross-protective T cell immunity against Mycobacterium avium (MAV) and MAB. Human TB and NTM cross-protective T cells were quantified using flow cytometric assays. The ability of BCG expanded T cells to inhibit the intracellular growth of MAV and MAB was assessed in co-cultures with infected autologous macrophages. In both BCG-vaccinated and M. tuberculosis (Mtb)-infected mice, NTM cross-reactive immunity was measured using IFN-γ ELISPOT assays. Our results demonstrate the following key findings: (i) peripheral blood mononuclear cells from TB skin test-positive individuals contain MAV and MAB cross-reactive T cells, (ii) both BCG vaccination and Mtb infection of mice induce MAV and MAB cross-reactive splenic cells, (iii) BCG-expanded T cells inhibit intracellular MAV and MAB, (iv) CD4, CD8, and γδ T cells play important roles in inhibition of intracellular MAV and MAB and (v) BCG vaccination of healthy volunteers induces TB and NTM cross-reactive T cells. In conclusion, BCG-vaccination induces NTM cross-reactive immunity, and has the potential for use as a vaccine or immunotherapy to prevent and/or treat pulmonary NTM disease.

Prevalence and risk factors of pulmonary nontuberculous mycobacterial infections in the Zhejiang Province of China.

Risk factors and prevalence of pulmonary nontuberculous mycobacterial (NTM) diseases were retrospectively evaluated in 1208 suspected pulmonary TB patients seeking care at the Affiliated Hospital of Hangzhou Normal University between July 2018 and December 2018. Further analysis of 390 culture-positive cases demonstrated that 358 (358/390, 91.8%) were infected with Mycobacterium tuberculosis (MTB), 24 (24/390, 6.2%) with NTM and eight (8/390, 2.0%) with both MTB and NTM. M. intracellulare was the most prevalent NTM isolated (16/24, 66.7%), followed by M. abscessus (3/24), M. kansasii (2/24), M. avium (1/24), M. szulgai (1/24) and M. fortuitum (1/24). The difference between NTM and TB case rates for the ⩾65-year-old age group significantly exceeded the difference for the reference group (patients aged 25-44 years) (OR (95% CI): 4.63 (1.03-20.90)). Pulmonary NTM diseases incidence positively correlated with prior TB history (OR (95% CI): 12.92 (3.24-31.82)). Moreover, pulmonary NTM patients were significantly more likely to exhibit underlying bronchiectasis than pulmonary TB patients (OR (95% CI): 18.89 (7.54-47.88)). In conclusion, approximately one-tenth of culture-positive suspected pulmonary TB patients are infected with NTM (most frequently M. intracellulare) in Zhejiang Province, China. The elderly and those with bronchiectasis or a history of TB are at the greatest risk of contracting pulmonary NTM disease.

MmpL3 as a Target for the Treatment of Drug-Resistant Nontuberculous Mycobacterial Infections.

Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species account for 70–95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12–18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against M. abscessus in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in Mycobacterium tuberculosis and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against M. tuberculosis compared to NTM.

Epidemiology of nontuberculous mycobacterial infections in the U.S. Veterans Health Administration.

ObjectiveWe identified patients with non-tuberculous mycobacterial (NTM) disease in the US Veterans Health Administration (VHA), examined the distribution of diseases by NTM species, and explored the association between NTM disease and the frequency of clinic visits and mortality.MethodsWe combined mycobacterial isolate (from natural language processing) with ICD-9-CM diagnoses from VHA data between 2008 and 2012 and then applied modified ATS/IDSA guidelines for NTM diagnosis. We performed validation against a reference standard of chart review. Incidence rates were calculated. Two nested case-control studies (matched by age and location) were used to measure the association between NTM disease and each of 1) the frequency of outpatient clinic visits and 2) mortality, both adjusted by chronic obstructive pulmonary disease (COPD), other structural lung diseases, and immunomodulatory factors.ResultsNTM cases were identified with a sensitivity of 94%, a specificity of >99%. The incidence of NTM was 12.6/100k patient-years. COPD was present in 68% of pulmonary NTM. NTM incidence was highest in the southeastern US. Extra-pulmonary NTM rates increased during the study period. The incidence rate ratio of clinic visits in the first year after diagnosis was 1.3 [95%CI 1.34–1.35]. NTM patients had a hazard ratio of mortality of 1.4 [95%CI 1.1–1.9] in the 6 months after NTM identification compared to controls and 1.99 [95%CI 1.8–2.3] thereafter.ConclusionsIn VHA, pulmonary NTM disease is commonly associated with COPD, with the highest rates in the southeastern US. After adjustment, NTM patients had more clinic visits and greater mortality compared to matched patients.

Epidemiology of Nontuberculous Mycobacteriosis.

Annual prevalence estimates for pulmonary nontuberculous mycobacterial (PNTM) disease in the contiguous United States range from 1.4 to 13.9 per 100,000 persons, while one study found an annual prevalence of up to 44 per 100,000 persons in Hawaii. PNTM prevalence varies by region, sex, and race/ethnicity, with higher prevalence among women and persons of Asian ancestry, as well as in the Southern United States and Hawaii. Studies consistently indicate that PNTM prevalence is increasing, with estimates ranging from 2.5 to 8% per year. Most PNTM disease is associated with Mycobacterium avium complex (MAC), although the proportion of disease attributed to MAC varies by region. Host factors identified as influencing disease risk include structural lung disease, immunomodulatory medication, as well as variants in connective tissue, mucociliary clearance, and immune genes. Environmental variables including measures of atmospheric moisture and concentrations of certain soil factors have also been shown to correlate with higher PNTM prevalence. Prevalence of extrapulmonary NTM disease is lower, stable, and associated with different risk factors, including primary immune deficiencies or HIV infection.