Nontuberculous Mycobacterial Lung Disease Research Articles

Sputum bacterial microbiota signature as a surrogate for predicting disease progression of nontuberculous mycobacterial lung disease

ObjectivesPredicting progression of nontuberculous mycobacterial lung disease (NTM-LD) remains challenging. This study evaluated whether sputum bacterial microbiome diversity can be the biomarker and provide novel insights into related phenotypes and treatment timing. MethodsWe analyzed 126 sputum microbiomes of 126 patients with newly diagnosed NTM-LD due to Mycobacterium avium complex, M. abscessus complex, and M. kansasii between May 2020 and December 2021. Patients were followed for 2 years to determine their disease progression status. We identified consistently representative genera that differentiated the progressor and nonprogressor by using six methodologies. These genera were used to construct a prediction model using random forest with 5-fold cross validation. ResultsDisease progression occurred in 49 (38.6%) patients. Compared with nonprogressors, α-diversity was lower in the progressors. Significant compositional differences existed in the β-diversity between groups (p=0.001). The prediction model for NTM-LD progression constructed using seven genera (Burkholderia, Pseudomonas, Sphingomonas, Candidatus Saccharibacteria, Phocaeicola, Pelomonas, and Phascolarctobacterium) with significantly differential abundance achieved an area under curve of 0.871. ConclusionsIdentification of the composition of sputum bacterial microbiome facilitates prediction of the course of NTM-LD, and maybe used to develop precision treatment involving modulating the respiratory microbiome composition to ameliorate NTM-LD.

Trends in Non-Tuberculous Mycobacterial Lung Disease and Treatment Outcomes in a Low-Tuberculosis Prevalence Setting: A Retrospective Analysis.

Information on the management of non-tuberculous mycobacterial (NTM) lung infection and disease is scarce. The aim of this study was to investigate the trends in NTM lung infections, and the factors associated with the initiation of treatment and treatment outcomes. A retrospective analysis was carried out on patient medical records from Haukeland University Hospital, Bergen, Norway, from 2000 to 2021. Among 154 patients with NTM lung infection, the majority (70%) were older than 65 years, and 49% had an underlying pulmonary comorbidity. The most frequently observed mycobacterial species was M. avium complex (MAC), followed by M. malmoense and M. abscessus. In total, 72 (47%) patients received antibiotic treatment. Patients with high symptom scores, aged below 65, and with MAC infection had more than three times the odds of receiving antibiotic treatment. A favourable response and culture conversion was observed in 53 of 72 (74%) patients. However, 17 (32%) of them had a relapse. Out of 82 patients who did not receive treatment, 45 (55%) had spontaneous culture conversion, and 8 (18%) of them had a relapse. No factor was identified to be significantly associated with a favourable treatment response. A favourable response to treatment was seen in 74% of patients with a high relapse rate.

Prominent transcriptomic changes in Mycobacterium intracellulare under acidic and oxidative stress.

Mycobacterium avium complex (MAC), including Mycobacterium intracellulare is a member of slow-growing mycobacteria and contributes to a substantial proportion of nontuberculous mycobacterial lung disease in humans affecting immunocompromised and elderly populations. Adaptation of pathogens in hostile environments is crucial in establishing infection and persistence within the host. However, the sophisticated cellular and molecular mechanisms of stress response in M. intracellulare still need to be fully explored. We aimed to elucidate the transcriptional response of M. intracellulare under acidic and oxidative stress conditions. At the transcriptome level, 80 genes were shown [FC] ≥ 2.0 and p < 0.05 under oxidative stress with 10mM hydrogen peroxide. Specifically, 77 genes were upregulated, while 3 genes were downregulated. In functional analysis, oxidative stress conditions activate DNA replication, nucleotide excision repair, mismatch repair, homologous recombination, and tuberculosis pathways. Additionally, our results demonstrate that DNA replication and repair system genes, such as dnaB, dinG, urvB, uvrD2, and recA, are indispensable for resistance to oxidative stress. On the contrary, 878 genes were shown [FC] ≥ 2.0 and p < 0.05 under acidic stress with pH 4.5. Among these genes, 339 were upregulated, while 539 were downregulated. Functional analysis highlighted nitrogen and sulfur metabolism pathways as the primary responses to acidic stress. Our findings provide evidence of the critical role played by nitrogen and sulfur metabolism genes in the response to acidic stress, including narGHIJ, nirBD, narU, narK3, cysND, cysC, cysH, ferredoxin 1 and 2, and formate dehydrogenase. Our results suggest the activation of several pathways potentially critical for the survival of M. intracellulare under a hostile microenvironment within the host. This study indicates the importance of stress responses in M. intracellulare infection and identifies promising therapeutic targets.

Building size and disinfectant type influence the detection and concentration of Mycobacterium spp. in hot water plumbing

The number of nontuberculous mycobacteria (NTM) lung disease cases is increasing in the United States (US). This respiratory disease is primarily caused by three NTM species: Mycobacterium avium, M. intracellulare, and M. abscessus. Since disease transmission could occur through water aerosolization, this study investigated these three species' occurrence (sporadic and persistent) in hot water samples collected from residences (n = 70) and office buildings (n = 30) across the US. A longitudinal survey design was used. Three quantitative Polymerase Chain Reaction (qPCR) assays were used to measure the mycobacterial species in the water samples. Additionally, the water's disinfectant residual was measured. A structure's age and square footage were evaluated to predict mycobacterial contamination. Also, the seasonal occurrence of each species was assessed by structure type. Residences had a 43 % (30/70), and office buildings had a 77 % (23/30) detection frequency of one or more Mycobacterium spp. in their hot water. The age of the structure influenced M. intracellulare detection frequency but not M. avium and M. abscessus. The structure's square footage affected M. avium and M. intracellulare detection frequency but not M. abscessus. In chlorinated water, M. intracellulare was detected 1.4× more often in office buildings' hot water than in chloraminated water. In chloraminated water, the Mycobacterium spp. were detected 2–2.5× more often in residences, while M. avium and M. abscessus were detected 1.5–2.3× more often in office buildings, compared to chlorinated water. Each Mycobacterium spp. had a different trend associated with the type of structure and disinfectant. Further research is needed to better understand NTM occurrence in the built environment to improve public health.

Effect of Lipid Composition on the Interaction of Liposomes with THP-1-Derived Macrophages.

Recently, liposomal formulations that target macrophages have been used to treat lung diseases. However, the detailed mechanism of the cellular uptake must be elucidated to identify a formulation with excellent cellular uptake efficiency to treat non-tuberculous mycobacterial lung disease. We studied the effect of lipid composition on the cellular uptake of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol (Chol) liposomes with a size of approximately 200 nm into THP-1-derived macrophages. The amount of DPPC/Chol liposomes (80/20 mol%) was greater than that of DPPC/Chol (60/40 mol%) and DPPC/Chol (67/33 mol%) liposomes. The anisotropy of 1,6-diphenyl-1,3,5-hexatriene indicated that the membrane fluidity of the DPPC/Chol (80/20 mol%) liposomes was higher than that of the other two liposomes. DPPC/Chol (80/20 mol%) and DPPC/Chol (67/33 mol%) liposomes were taken up via clathrin- and caveolae-mediated endocytosis and phagocytosis. However, proteins involved in cellular uptake through ligand-receptor interactions were adsorbed to a greater extent on DPPC/Chol (80/20 mol%) liposomes than on DPPC/Chol (67/33 mol%) liposomes. Pretreatment of cells with antibodies against the low-density lipoprotein receptor and scavenger receptor type B1 largely inhibited the uptake efficiency of DPPC/Chol (80/20 mol%) liposomes. Our results indicate that the membrane fluidity of DPPC/Chol liposomes, which is controlled by the Chol ratio, is an important factor in controlling protein adsorption and the subsequent uptake efficiency of liposomes.

Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease.

Tuberculosis (TB) drug discovery and development has undergone nothing short of a revolution over the past 20 years. Successful public-private partnerships and sustained funding have delivered a much-improved understanding of mycobacterial disease biology and pharmacology and a healthy pipeline that can tolerate inevitable attrition. Preclinical and clinical development has evolved from decade-old concepts to adaptive designs that permit rapid evaluation of regimens that might greatly shorten treatment duration over the next decade. But the past 20 years also saw the rise of a fatal and difficult-to-cure lung disease caused by nontuberculous mycobacteria (NTM), for which the drug development pipeline is nearly empty. Here, we discuss the similarities and differences between TB and NTM lung diseases, compare the preclinical and clinical advances, and identify major knowledge gaps and areas of cross-fertilization. We argue that applying paradigms and networks that have proved successful for TB, from basic research to clinical trials, will help to populate the pipeline and accelerate curative regimen development for NTM disease.

A narrative review of the controversy on the risk of mycobacterial infections with immune checkpoint inhibitor use: does Goldilocks have the answer?

Immune checkpoint inhibitors (ICIs) have revolutionized oncologic treatment. Whether ICIs increase susceptibility to or provide protection against mycobacterial infections remains controversial. The objective of this narrative review is to summarize the literature on the link between ICI use and mycobacterial infections-tuberculosis and non-tuberculous mycobacterial (NTM) infections-and to critically discuss evidence linking ICIs with mycobacterial infections, the possible confounders, and, if indeed the ICIs predispose to such infections, the potential mechanisms of how this may occur. We conducted a literature search on PubMed for relevant articles published from 2011 to current time [2024] utilizing specific keywords of "immune checkpoint inhibitors", "programmed cell death protein-1", "PD-1", "programmed death-ligand 1", "PD-L1", "cytotoxic T-lymphocyte-associated protein-4", or "CTLA-4" with that of "non-tuberculous mycobacterial lung disease", "tuberculosis", or "mycobacteria". The bibliographies of identified papers were perused for additional relevant articles. Ex vivo studies using human cells indicate that ICIs would be salubrious for the host against mycobacteria. Yet, many case reports associate ICI use with mycobacterial infections, mostly tuberculosis. Potential confounders include immunosuppression from the cancer, concomitant use of immunosuppressive drugs, lung injury and distortion from chemotherapeutics or radiation, and reporting bias. Mice with genetic disruption of the programmed cell death protein-1 (PD-1) gene are paradoxically more susceptible to Mycobacterium tuberculosis (M. tuberculosis). In contrast, mice administered neutralizing antibody to T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) or knocked out for TIM3 gene have greater capacity to control an M. tuberculosis infection. We posit that hosts with greater baseline immunodeficiency are more likely to derive benefit from ICIs against mycobacterial infections than those with more intact immunity, where ICIs are more likely to be detrimental. Studies are needed to test the hypothesis that ICIs may either protect or predispose to mycobacterial infections, depending on the baseline host immune status. Prospective studies are required of patients on ICIs that control for potential confounders as anecdotal case reports are insufficient to provide a causal link. Murine studies with ICIs are also required to corroborate or refute studies of mice with genetic disruption of an immune checkpoint.

Prevalence of pulmonary artery dilation in non-cystic fibrosis bronchiectasis: a computed tomography analysis from a cohort of the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry.

Although pulmonary artery (PA) dilation is independently associated with significant morbidity and mortality in patients with pulmonary diseases irrespective of diagnosed pulmonary hypertension, its relationship with nontuberculous mycobacteria (NTM) is unknown. The Bronchiectasis and NTM Research Registry is a multicenter registry created to foster research in non-cystic fibrosis (CF) bronchiectasis and NTM lung disease. The majority of patients with non-CF bronchiectasis at Oregon Health & Science University have NTM infections. To determine the prevalence of PA dilation in these patients and its association with supplemental oxygen use, severity of bronchiectasis, tobacco use, and NTM in the sputum culture, we evaluated the chest computed tomography (CT) scans from 321 patients in a cross-sectional analysis. We measured the severity of bronchiectasis by applying modified Reiff criteria and measured the diameters of the PA and aorta (Ao), with PA dilation defined as a PA:Ao ratio >0.9. In our cohort, the mean age was 67.3 years and 83.2% were female. The mean modified Reiff score was 7.1, indicating moderate disease severity. Forty-two patients (13.1%) were found to have PA dilation. PA dilation was positively associated with the use of supplemental oxygen (P<0.001), but there was no association between PA dilation and NTM infection.

In Vitro Evaluation of Drug-Drug Interaction Potential of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor.

Epetraborole (EBO) is a boron-containing inhibitor of bacterial leucyl-tRNA synthetase, with potent activity against nontuberculous mycobacteria (NTM) and Gram-negative bacteria, including Burkholderia pseudomallei. EBO is being developed for the treatment of NTM lung disease and melioidosis, administered in combination with other therapeutic agents in both diseases. Therefore, EBO and its major circulating metabolite M3 were evaluated in comprehensive drug-drug interaction (DDI) in vitro studies. The CYP inhibitory and substrate potential of EBO and M3 were assessed using hepatic microsomes. Stably transfected cells that expressed individual efflux or uptake transporters were used to determine whether EBO or M3 were substrates or inhibitors for these receptors. Stability studies indicated that EBO is a poor substrate for major CYP enzymes. Neither EBO nor M3 was a potent reversible or time-dependent inhibitor of major CYP enzymes. EBO was not an inducer of CYP1A2 mRNA, while it was a weak inducer of CYP2B6 and CYP3A4. EBO was a substrate only for OCT2. At clinically relevant concentrations, neither EBO nor M3 inhibited major human efflux or uptake transporters. Based on these data, at clinically relevant concentrations of EBO and M3, there is a low risk of victim or perpetrator DDI.

The impact of nontuberculous mycobacterial lung disease in critically ill patients: Significance for survival and ventilator use

BackgroundThis study investigates the impact of nontuberculous mycobacterial lung disease (NTM-LD) on mortality and mechanical ventilation use in critically ill patients. MethodsWe 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. ResultsA 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. ConclusionsNTM-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.

Multiparameter immunoprofiling for the diagnosis and differentiation of progressive versus nonprogressive nontuberculous mycobacterial lung disease-A pilot study.

Clinical prediction of nontuberculous mycobacteria lung disease (NTM-LD) progression remains challenging. We aimed to evaluate antigen-specific immunoprofiling utilizing flow cytometry (FC) of activation-induced markers (AIM) and IFN-γ enzyme-linked immune absorbent spot assay (ELISpot) accurately identifies patients with NTM-LD, and differentiate those with progressive from nonprogressive NTM-LD. A Prospective, single-center, and laboratory technician-blinded pilot study was conducted to evaluate the FC and ELISpot based immunoprofiling in patients with NTM-LD (n = 18) and controls (n = 22). Among 18 NTM-LD patients, 10 NTM-LD patients were classified into nonprogressive, and 8 as progressive NTM-LD based on clinical and radiological features. Peripheral blood mononuclear cells were collected from patients with NTM-LD and control subjects with negative QuantiFERON results. After stimulation with purified protein derivative (PPD), mycobacteria-specific peptide pools (MTB300, RD1-peptides), and control antigens, we performed IFN-γ ELISpot and FC AIM assays to access their diagnostic accuracies by receiver operating curve (ROC) analysis across study groups. Patients with NTM-LD had significantly higher percentage of CD4+/CD8+ T-cells co-expressing CD25+CD134+ in response to PPD stimulation, differentiating between NTM-LD and controls. Among patients with NTM-LD, there was a significant difference in CD25+CD134+ co-expression in MTB300-stimulated CD8+ T-cells (p <0.05; AUC-ROC = 0.831; Sensitivity = 75% [95% CI: 34.9-96.8]; Specificity = 90% [95% CI: 55.5-99.7]) between progressors and nonprogressors. Significant differences in the ratios of antigen-specific IFN-γ ELISpot responses were also seen for RD1-nil/PPD-nil and RD1-nil/anti-CD3-nil between patients with nonprogressive vs. progressive NTM-LD. Our results suggest that multiparameter immunoprofiling can accurately identify patients with NTM-LD and may identify patients at risk of disease progression. A larger longitudinal study is needed to further evaluate this novel immunoprofiling approach.

Utilizing Deep Learning and Computed Tomography to Determine Pulmonary Nodule Activity in Patients With Nontuberculous Mycobacterial-Lung Disease.

To develop and evaluate a deep convolutional neural network (DCNN) model for the classification of acute and chronic lung nodules from nontuberculous mycobacterial-lung disease (NTM-LD) on computed tomography (CT). We collected a data set of 650 nodules (316 acute and 334 chronic) from the CT scans of 110 patients with NTM-LD. The data set was divided into training, validation, and test sets in a ratio of 4:1:1. Bounding boxes were used to crop the 2D CT images down to the area of interest. A DCNN model was built using 11 convolutional layers and trained on these images. The performance of the model was evaluated on the hold-out test set and compared with that of 3 radiologists who independently reviewed the images. The DCNN model achieved an area under the receiver operating characteristic curve of 0.806 for differentiating acute and chronic NTM-LD nodules, corresponding to sensitivity, specificity, and accuracy of 76%, 68%, and 72%, respectively. The performance of the model was comparable to that of the 3 radiologists, who had area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy of 0.693 to 0.771, 61% to 82%, 59% to 73%, and 60% to 73%, respectively. This study demonstrated the feasibility of using a DCNN model for the classification of the activity of NTM-LD nodules on chest CT. The model performance was comparable to that of radiologists. This approach can potentially and efficiently improve the diagnosis and management of NTM-LD.

Incremental mortality associated with nontuberculous mycobacterial lung disease among US Medicare beneficiaries with chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with nontuberculous mycobacterial lung disease (NTMLD). Both conditions are associated with increased morbidity and mortality, but data are lacking on the additional burden associated with NTMLD among patients with COPD. Thus, the goal of this study was to assess the incremental mortality risk associated with NTMLD among older adults with COPD.MethodsA retrospective cohort study was conducted using the US Medicare claims database (2010–2017). Patients with preexisting COPD and NTMLD (cases) were matched 1:3 by age and sex with patients with COPD without NTMLD (control patients). Patients were followed up until death or data cutoff (December 31, 2017). Incremental risk of mortality was evaluated by comparing the proportions of death, annualized mortality rate, and mortality hazard rate between cases and control patients using both univariate and multivariate analyses adjusting for age, sex, comorbidities, and COPD severity.ResultsA total of 4,926 cases were matched with 14,778 control patients. In univariate analyses, a higher proportion of cases (vs. control patients) died (41.5% vs. 26.7%; P < 0.0001), unadjusted annual mortality rates were higher among cases (158.5 vs. 86.0 deaths/1000 person-years; P < 0.0001), and time to death was shorter for cases. This increased mortality risk was also reflected in subsequent multivariate analyses. Patients with COPD and NTMLD were more likely to die (odds ratio [95% CI], 1.39 [1.27–1.51]), had higher mortality rates (rate ratio [95% CI], 1.36 [1.28–1.45]), and had higher hazard of death (hazard ratio [95% CI], 1.37 [1.28–1.46]) than control patients.ConclusionsThe substantial incremental mortality burden associated with NTMLD in patients with COPD highlights the importance of developing interventions targeting this high-risk group and may indicate an unmet need for timely and appropriate management of NTMLD.

Building a model for the differential diagnosis of non-tuberculous mycobacterial lung disease and pulmonary tuberculosis: A case-control study based on immunological and radiological features

BackgroundAlthough the incidence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing annually, it is easily misdiagnosed as pulmonary tuberculosis (PTB). This study aimed to screen and identify the immunological and radiological characteristics that differentiate NTM-PD from PTB and to construct a discriminatory diagnostic model for NTM-PD, providing new tools for its differential diagnosis. MethodsHospitalised patients diagnosed with NTM-PD or PTB between January 2019 and June 2023 were included in the study. Immunological and radiological characteristics were compared between the two groups. Based on the selected differential features, a logistic regression algorithm was used to construct a discriminatory diagnostic model for NTM-PD, and its diagnostic performance was preliminarily analysed. ResultsPatients with NTM-PD were significantly older than those with PTB and the tuberculosis-specific interferon-gamma release assay (TB-IGRA) positivity rate was significantly lower in the NTM-PD group. Moreover, the absolute counts of total T lymphocytes, CD4+ T lymphocytes, CD8+ T lymphocytes, NK cells, and B lymphocytes were significantly lower in patients with NTM-PD and PTB than in healthy controls. Additionally, patients with NTM-PD had a significantly lower absolute count of B lymphocytes than the PTB group. Radiological analysis revealed significant differences between patients with NTM-PD and PTB in terms of cavity wall thickness, bronchial dilation, lung consolidation, pulmonary nodule size, pulmonary emphysema, lung bullae, lymph node calcification, pleural effusion, mediastinal and hilar lymphadenopathy, and the tree-in-bud sign. Bronchial dilation was identified as the predominant risk factor of NTM-PD, whereas TB-IGRA positivity, lymph node calcification, pleural effusion, and mediastinal and hilar lymphadenopathies were protective factors. Based on this, we constructed a discriminatory diagnostic model for NTM-PD. Its receiver operating characteristic curve demonstrated good diagnostic performance, with an area under the curve of 0.938. At the maximum Youden index of 0.746, the sensitivity and specificity were 0.835 and 0.911, respectively. ConclusionsPatients with NTM-PD and PTB exhibited impaired humoral and cellular immune functions as well as significant differences in radiological features. The constructed NTM-PD diagnostic model demonstrated good diagnostic performance. This study provides a new tool for the differential diagnosis of NTM-PD.

Complete genome assembly of Hawai'i environmental nontuberculous mycobacteria reveals unexpected co-isolation with methylobacteria.

Nontuberculous mycobacteria (NTM) are ubiquitous environmental opportunistic pathogens that can cause chronic lung disease. Within the United States, Hawai'i has the highest incidence of NTM lung disease, though the precise reasons are yet to be fully elucidated. One possibility is the high prevalence of NTM in the Hawai'i environment acting as a potential reservoir for opportunistic NTM infections. Through our previous initiatives to collect and characterize NTM in Hawai'i, community scientists of Hawai'i have collected thousands of environmental samples for sequencing. Here, these community scientists were invited for the first time into a high school lab in O'ahu for a genomic sequencing workshop, where participants sequenced four of the collected isolate genomic samples using the Oxford Nanopore Technologies MinION sequencer. Participants generated high quality long read data that when combined with short read Illumina data yielded complete bacterial genomic assemblies suitable for in-depth analysis. The gene annotation analysis identified a suite of genes that might help NTM thrive in the Hawai'i environment. Further, we found evidence of co-occurring methylobacteria, revealed from the sequencing data, suggesting that in some cases methylobacteria and NTM may coexist in the same niche, challenging previously accepted paradigms. The sequencing efforts presented here generated novel insights regarding the potential survival strategies and microbial interactions of NTM in the geographic hot spot of Hawai'i. We highlight the contributions of community scientists and present an activity that can be reimplemented as a workshop or classroom activity by other research groups to engage their local communities.

Blocking ADP-ribosylation expands the anti-mycobacterial spectrum of rifamycins.

The clinical utility of rifamycins against non-tuberculous mycobacterial (NTM) disease is limited by intrinsic drug resistance achieved by ADP-ribosyltransferase Arr. By blocking the site of ribosylation, we recently optimized a series of analogs with substantially improved potency against Mycobacterium abscessus. Here, we show that a representative member of this series is significantly more potent than rifabutin against major NTM pathogens expressing Arr, providing a powerful medicinal chemistry approach to expand the antimycobacterial spectrum of rifamycins. IMPORTANCE Lung disease caused by a range of different species of non-tuberculous mycobacteria (NTM) is difficult to cure. The rifamycins are very active against Mycobacterium tuberculosis, which causes tuberculosis (TB), but inactive against many NTM species. Previously, we showed that the natural resistance of the NTM Mycobacterium abscessus to rifamycins is due to enzymatic inactivation of the drug by the bacterium. We generated chemically modified versions of rifamycins that prevent inactivation by the bacterium and thus become highly active against M. abscessus. Here, we show that such a chemically modified rifamycin is also highly active against several additional NTM species that harbor the rifamycin inactivating enzyme found in M. abscessus, including M. chelonae, M. fortuitum, and M. simiae. This finding expands the potential therapeutic utility of our novel rifamycins to include several currently difficult-to-cure NTM lung disease pathogens beyond M. abscessus.

Non-tuberculous mycobacteria lung disease due to Mycobacterium chimaera in a 67-year-old man treated with immune checkpoint inhibitors for lung adenocarcinoma: infection due to dysregulated immunity?

Immune checkpoint inhibitors (ICIs) are drugs growingly employed in cancer immunotherapy which have significantly improved the prognosis of several tumours. ICIs act by restoring the “exhausted” immune system and increasing the number of T cells active against pathogens losing tolerogenic signalling, which has been linked to an increased risk of infectious events. We present the case of a 67-year-old man with locally advanced lung adenocarcinoma treated with the anti-PD-L1 durvalumab. Three months after immunotherapy started, an apparent radiological progression was found with elements suggesting a parenchymal superinfection associated with weight loss, asthenia, and sputum emission. A bronchoalveolar lavage resulted positive for Mycobacterium chimaera, and treatment with amikacin iv (for eight weeks) and daily azithromycin, ethambutol, and rifampicin was started. Thirteen months after treatment started, the patient is alive with a stable lung condition. The case highlights the risk of non-tuberculous mycobacteria lung disease (NTM-LD) in patients receiving ICIs treatment. We hypothesise that durvalumab induced an exaggerated immune response toward the mycobacteria, leading to immunopathology and overt clinical manifestations. Clinicians should be aware of this possibility in patients receiving ICIs developing new signs/symptoms related to the respiratory tract, especially in countries with a high prevalence of NTM-LD.

Dipeptidyl peptidase IV inhibitors and the risk of mycobacterial pulmonary infections in type 2 diabetes mellitus

BackgroundType 2 diabetes mellitus (DM) is a risk factor for mycobacterial pulmonary infections (MPI), including tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD). Dipeptidyl peptidase IV inhibitor (DPP4i), a common DM medication, has an immune-modulation effect that raises concerns about developing MPI. However, there is scarce research on the topic. MethodsThis retrospective study was conducted in a tertiary-referral center in Taiwan from 2009 to 2016. Patients with type 2 DM who were receiving any DM medication were enrolled. TB and NTM-LD were defined by microbiological criteria. We analyzed the risk of MPI in DPP4i users using Cox proportional hazard regression with adjusted inverse probability of treatment weighting. ResultsA total of 9963 patients were included. Among them, 3931 were classified as DPP4i users, and 6032 patients were DPP4i nonusers. DPP4i users had no increase in incidences of MPI (604 vs. 768 per 100,000 person-years, p = 0.776), NTM-LD (174 vs. 255 per 100,000 person-years, p = 0.228), and TB (542 vs. 449 per 100,000 person-years, p = 0.663) relative to those of DPP4i nonusers. After adjustment, the adjusted hazard ratios for MPI (aHR: 1.07, 95% CI: 0.79–1.45), TB (aHR: 1.15, 95% CI: 0.81–1.64) and NTM-LD (aHR: 0.85, 95% CI: 0.49–1.47) were not significantly increased relative to those of nonusers. The subgroup analysis also showed that DPP4i use did not increase the risk of MPI in different DM severities and comorbidities. ConclusionsAccording to our large cohort study, DPP4i use is safe for patients with type 2 DM and might not increase the risk of MPI.

Trends from the Last Decade with Nontuberculous Mycobacteria Lung Disease (NTM-LD): Clinicians' Perspectives in Regional Center of Pulmonology in Bydgoszcz, Poland.

Nontuberculous mycobacteria (NTM) are the cause of chronic lung disease called NTM lung disease (NTM-LD). There are about 180 known species of NTM. Nowadays the number of NTM-LD is increasing. To evaluate the clinical significance of NTM isolated from specimens and assess the frequency and clinical relevance of isolation of NTM in the Regional Center of Pulmonology in Bydgoszcz, hospital of Northern Poland. Clinical, radiological, and microbiological data were collected from all patients from whom NTM was isolated between 2013 and 2022. Data were reviewed retrospectively. Diagnostic criteria for NTM-LD published by the American Thoracic Society (ATS) were used to determine clinical relevance. The study comprised 81,985 clinical specimens submitted for mycobacterial culture in the Department of Microbiology at the Regional Center of Pulmonology in Bydgoszcz between 2013 and 2022. Clinical specimens were processed according to the standard procedure in mycobacteria laboratories in Poland. NTM strains were identified using analysis of mycolic acids by chromatography as well as GenoType NTM-DR, GenoType Mycobacterium AS, and GenoType Mycobacterium CM. There were 395 patients with NTM strains between 2013 and 2022. Out of them, 149 cases met the diagnostic criteria of NTM-LD and were classified as definite cases. M. kansasii (n = 77) was the most common species in the group (51.68%), followed by M. avium complex (n = 46). Patients with NTM-LD were 22-88 years old (median age was 60 years). There were 81 men and 68 women. The most common symptoms were cough, hemoptysis, and fever. Radiological X-ray images were dominated by infiltrative lesions in the upper and middle lobe of the right lung with cavities; the changes were in the upper lobe of the left lung and on both sides of the chest. They were smokers in 61%. The most common concomitant diseases were chronic obstructive pulmonary disease (COPD), diabetes mellitus, pulmonary carcinoma, and human immunodeficiency virus (HIV) infection, and other immunodeficiencies. The most common treatment was isoniazid, ethambutol, rifampicin, and ofloxacin for 18 months with a minimum of 12 months of culture negativity. NTM-LD infections are present with other pulmonary illnesses and extrapulmonary diseases and may be connected to primary immunologic deficiencies. These diseases concern patients of all ages and have various clinical manifestations. M. kansasii and MAC are the most prevalent NTM isolates among respiratory samples in Northern Poland. In addition, an increase in MAC and a decrease in M. kansasii both in cultivation and the cause of NTM-LD were reported.

Prevalence and risk factors of non-tuberculous mycobacterial pulmonary isolates and infection in interstitial lung disease associated with systemic autoimmune disease.

Non-tuberculous mycobacterial (NTM) lung disease (NTM-LD) prevalence is increasing worldwide. In this study, we aimed to evaluate the clinical significance of NTM pulmonary isolates (NTM-PI) and NTM-LD in patients with systemic autoimmune disease (SAD) who had a concurrent interstitial lung disease (ILD) diagnosis. We retrospectively identified patients with SAD who had a concurrent ILD diagnosis (SAD-ILD) and from whom clinically indicated sputum specimens were collected for NTM culture between 2003 and 2018 at a tertiary referral hospital. We analysed the prevalence and risk factors of NTM pulmonary isolates (NTM-PI; ≥1 positive culture) and NTM-LD (≥2 positive cultures). This study included 258 patients. Rheumatoid arthritis and Sjögren's syndrome were the most common SADs (32.2% and 26.7%, respectively). The NTM-negative subgroup had 204 patients (79.1%) and the NTM-PI subgroup had 54 patients (20.9%). In the NTM-PI subgroup, 33 patients had one NTM positive set of specimens (NTM 1+, 12.8% of the entire sample) and 21 had NTM-LD (8.1% of the entire sample). In a multivariable analysis, chronic kidney disease (CKD; adjusted odds ratio [aOR]: 3.10 [1.53, 6.29]) and chronic obstructive pulmonary disease (COPD; aOR: 2.59 [1.16, 5.78]) were significantly associated with NTM-PI. For NTM-LD, CKD (aOR: 2.79 [1.00, 7.76]) and COPD (aOR: 3.70 [1.23, 10.72]) remained significant risk factors. In patients with SAD-ILD, the NTM-PI and NTM-LD prevalence rates were 20.9% and 8.1%, respectively. COPD and CKD were independent risk factors of both NTM-PI and NTM-LD. Previous use of biological agents was associated with NTM-PI.