Treatable traits and challenges in the clinical management of non-tuberculous mycobacteria lung disease in people with cystic fibrosis.

INTRODUCTION: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce. MAIN BODY: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies. CONCLUSIONS: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition.

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.

Idiopathic pulmonary fibrosis: pathogenesis and management.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open. MAIN BODY: Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities. CONCLUSIONS: Building on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.

Nontuberculous mycobacterial infections during cancer therapy with immune checkpoint inhibitors: a systematic review.

Immune checkpoint inhibitors (ICIs) are drugs growingly employed in the treatment of cancers, but there are still uncertainties about their possible role in the risk of developing nontuberculous mycobacteria (NTM) infections. To understand this, we performed a systematic review of the literature including studies published between 20 June 2012 and 20 June 2022 which described the occurrence of NTM infections among patients treated with ICIs. Overall, we included seven studies describing nine patients with NTM infection occurring during ICIs therapy. NTM infections occurring during ICIs therapy are mainly caused by germs belonging to the Mycobacterium avium complex, involve primarily the lungs, on average 1 year after the start of treatment, and are not associated with immunosuppressive treatments.

Nontuberculous mycobacteria infection and pulmonary disease in bronchiectasis.

Background: Although interest in nontuberculous mycobacteria (NTM) infection has increased in the last decades, published data vary according to different geographical areas, diagnostic facilities and quality of study design. This study aims at assessing both prevalence and incidence of NTM infection and NTM pulmonary disease (NTM-PD) among adults with bronchiectasis, to describe patients' characteristics, therapeutic options and clinical outcomes. Methods: Bronchiectasis adults who had been tested for NTM were enrolled at the Bronchiectasis Program of the Policlinico Hospital in Milan, Italy, from 2016 to 2018. Results: Among the 373 patients enrolled, 26.1% had at least one respiratory sample positive for NTM and 12.6% reached a diagnosis of NTM-PD. Incidence rates for NTM infection and NTM-PD were 13 (95% CI 10-16) and 4 (95% CI 2-6) per 100 person-years, respectively. The most prevalent NTM species causing NTM-PD were M. intracellulare (38.3%), M. avium (34.0%), M. abscessus (8.5%) and M. kansasii (8.5%). Once treatment for NTM-PD was initiated, a favourable outcome was documented in 52.2% of the patients, while a negative outcome was recorded in 32.6%, including recurrence (17.4%), treatment failure (10.9%), re-infection (2.2%) and relapse (2.2%). Treatment halted was experienced in 11 (23.9%) patients. Conclusions: NTM infection is frequent in bronchiectasis patients and the presence of NTM-PD is relevant. The low success rate of NTM-PD treatment in bronchiectasis patients requires a call to action to identify new treatment modalities and new drugs to improve patients' outcomes.

Stenting versus balloon dilatation in patients with tracheal benign stenosis: The STROBE trial.

Background: It is well known that benign tracheal stenosis represents an obstacle to open surgery, and that its treatment could be challenging. Two endoscopic techniques have so far been adopted to restore tracheal patency: balloon dilatation (BA) through laryngoscopy, and tracheal stenting (ST) with rigid bronchoscopy. The main objective of this study was to compare the efficacy of BA and ST to treat benign tracheal stenosis not eligible for surgery. We also compared the rate of adverse events in the two treatment groups. Methods: A retrospective, observational cohort study was carried out at the University Hospital of Modena (Italy) from November 2012 to November 2017 in two separate departments. Patients were considered to be "stabilized" (primary outcome) if they did not report significant respiratory symptoms, or restenosis in the long-term (2 years) following the endoscopic procedure. Results: Sixty-six patients were included in the study (33 in the BA and 33 in the ST group, respectively). Unadjusted Kaplan-Meier estimates showed a greater therapeutic effect of ST compared to BA at 2 years (hazard ratio = 3.9 95%CI [1.5-9.8], p = .01). After adjusting for confounders, stratified analyses showed that this effect was significant in patients with complex stenosis, idiopathic etiology, and degree of stenosis >70%. Compared with BA, ST showed a higher rate of adverse events (p = .01). Conclusions: Compared to BA, ST seems to be more effective in achieving stabilization of tracheal patency in complex benign tracheal stenosis, although burdened with a significantly higher number of adverse effects. These findings warrant future prospective study for confirmation. Level of evidence: 3.

Pulmonary nontuberculous mycobacterial infections and environmental factors: A review of the literature.

BACKGROUND: Pulmonary nontuberculous mycobacterial (pNTM) infection is mainly acquired through the inhalation of bioaerosols. Nevertheless, behavioural restrictions are rarely given by clinicians to susceptible populations, in part because the available guidelines for pNTM management emphasize more diagnosis and treatment than prevention. Aim of this review is to clarify if pNTM prevention should routinely include recommendations about risk reducing behaviors. METHODS: We used PubMed as biomedical database. We limited our search to the publication period 2000 to 2020 with selected keyword combinations including "nontuberculous mycobacteria", "water", "soil", and "exposure". Titles and abstract of selected articles were systematically screened. Articles were included in the analysis if they were published under free access through the digital library of the University of Brescia (Italy), and provided full text either in English, French, German or Italian. Articles were excluded if the topic was beyond the aim of our study. Finally, we selected 20 articles. RESULTS: Studies disagree in identifying the type of aerosol posing the highest risk for the development of pNTM infection. In the retrieved publications the colonization of household niches has been associated with a higher risk of pNTM disease, such as in the exposure to shower aerosols. Considering the non-household settings, the exposure to aerosols in indoor swimming and the higher soil exposure (>2 h/week) seem to correlate with a higher risk to develop pNTM disease. According to our findings, randomized behavioural intervention studies are missing. CONCLUSIONS: Stringent scientific evidence is missing to formulate recommendations on behavioural risk reduction for pNTM.

Mindfulness-based stress reduction in patients with interstitial lung diseases: a pilot, single-centre observational study on safety and efficacy.

BACKGROUND: Chronic, progressive respiratory symptoms are associated with great psychological and emotional impact in patients suffering from interstitial lung disease (ILD). This single-centre pilot study evaluated for the first time the safety, feasibility and efficacy of a Mindfulness Based Stress Reduction Program (MBSR) in a group of patients with ILD. METHODS: Prospective observational study set in a university hospital ILD outpatient clinic. Nineteen patients with different ILDs were recruited 2 months prior to the start of the 8-week MBSR program and followed up for 12 months. Primary outcomes were program safety and feasibility, while secondary outcomes were changes in moods and stress (assessed by Profile Of Mood State (POMS) and Perceived Stress Scale (PSS) questionnaires), symptoms (Shortness Of Breath (SOB) and Cough And Sputum Assessment (CASA-Q) questionnaires), lung function and exercise tolerance at 12 months. RESULTS: Two patients (10.5%) dropped out in the observational period before the start of the MBSR intervention because of non-respiratory causes. All 17 patients who entered the 8-week MBSR program managed to complete it with an adherence average of eight sessions of nine. No adverse events related to the mindfulness training were reported. Statistically significant improvements in the POMS total score and in several individual items of POMS and PSS were observed throughout the study. However, respiratory questionnaire scores, lung function and exercise tolerance did not show a significant difference over time. CONCLUSIONS: An MBSR program appears to be safe and feasible in patients with ILD, and might affect perceived moods and stress producing a positive and lasting improvement in several stress-related negative domains. These findings pave the way to larger (possibly multicentre), randomised, controlled confirmatory trials.