This study describes the phenotype of patients with NTM-positive bronchiectasis in Israel. We found that among the whole cohort with bronchiectasis, the patients with positive NTM cultures were older than the patients with negative NTM cultures, tended to be female, and had indicia of advanced disease including lower body mass index, more extensive bronchiectasis, and a greater propensity for exacerbations.

Our findings are consistent with prior studies. Patients with NTM pulmonary infection are generally characterized by older age [11,12,13, 19] which may entail an age-dependent decrease in respiratory muscle strength and mucocilliary clearance and an association with other factors such as impaired cell-mediated immunity, cytokine production, and phagocytosis [20]. The pathophysiologic mechanisms underlying the association of NTM infection and female gender, also reported by others [11, 12, 21], are not fully understood. It is noteworthy that there is a similar gender bias of bronchiectasis in general. Possible explanations include age-related deficiency of estradiol in women [20] and a higher prevalence of autoimmune disorders requiring immunosuppressive treatment among females than males with bronchiectasis that may contribute to susceptibility to NTM.

Similarly, the association of lower BMI with NTM pulmonary infection has been previously reported [11, 12, 19, 21]. While lower BMI may simply be a result of the NTM infection itself, it has been suggested that decreased fat mass with corresponding regulatory dysfunction of adipokines that participate in the immune response, such as leptin and adiponectin, may increase susceptibility to NTM infection [21, 22]. Moreover, we observed a relatively greater reduction in serum albumin among patients in the NTM-positive group, attributable to reduced protein synthesis, accelerated catabolism, and altered body distribution of albumin resulting from the combined effects of NTM infection, inflammation, and impaired nutritional status [22]. Both lower BMI and hypoalbuminemia are associated with disease progression [22] and mortality [23].

Among the various comorbidities, we identified an association of NTM infection with GERD, noted in an earlier study as well [12]. While GERD may contribute to the progression of bronchiectasis due to repeated insult of refluxed gastric contents to the bronchial tree [24], NTM pulmonary disease may predispose patients to GERD because of the frequent coughing and impaired mucus clearance [24].

One of the novel findings of our study was the more frequent use of muco-active medications by patients who had NTM pulmonary infection compared to those who did not. By contrast, the single pertinent study in the literature reported more common muco-active therapy in patients free of NTM pulmonary infection [12]. The reason for this discrepancy is unclear and may be related to differences in study design or in the prevalence of the relevant comorbidities. It is difficult to conclude on the basis of our data whether NTM-infected patients with bronchiectasis are more likely to need muco-active treatment due to excessive mucus production or whether the increased muco-ciliary secretion associated with bronchiectasis makes these patients more susceptible to NTM infection.

Of note, patients in the NTM group had more exacerbations in the 12 months prior to bronchoscopy, in agreement with the findings of Yin et al. [11]. However, Aksamit et al. [12] noted a lower incidence of exacerbations leading up to diagnosis in patients with NTM infection. This issue warrants further investigation.

The main novel finding of the present study was the association of NTM infection in patients with bronchiectasis with lower values of several routine laboratory parameters, such as serum albumin and blood counts of lymphocytes and eosinophils. Importantly, the presence of hypoalbuminemia in patients with NTM lung disease has been reported to predict disease progression [22] and mortality [23]. The lower levels of serum albumin in our NTM-positive patients may be explained mainly by reduced synthesis, accelerated catabolism, and altered body distribution of albumin resulting from the combined effects of a more severe infection, inflammation, and poor nutritional status [22].

Regarding the lower counts of lymphocytes and eosinophils, to our knowledge, no studies of patients with bronchiectasis to date compared these parameters between those who were positive or negative for NTM infection. While lymphopenia likely reflects a decreased host immune and nutritional status, the lymphopenia in MAC lung disease has been associated with recurrence following treatment [25] and a worse prognosis [26]. The pathogenesis of the lower eosinophil counts in the NTM-positive group is unclear. We suggest that it may indicate a more severe clinical status compared to patients without NTM infection. Notably, a previous study of a patient population with bronchiectasis found that a higher eosinophil count (>1.0x109/l) was associated with better nutritional status, lung function, and clinical outcomes [27].

An additional interesting observation in our investigation was the significantly higher isolation rate of Staphylococcus aureus from BAL cultures in the NTM-positive than the NTM-negative group (17.0% vs. 8.6%) relative to the other bacteria and fungi evaluated for which isolation rates were comparable in the two groups. Respiratory culture data are scarce in patients with bronchiectasis with and without NTM pulmonary infection [10]. Only a single study reported positive cultures rates for Staphylococcus aureus, and in contradiction to our results, they were significantly lower in the patients with NTM infection than in those without (10.0% and 15.0%, respectively).

Moreover, spirometry values (FEV1, FVC) and DLCO were decreased in the patients with NTM pulmonary infection. This finding is likely attributable to their more the extensive bronchiectasis and the attendant destruction of the lung parenchyma compared to the NTM-negative group. Similarly, others reported an association of NTM infection with a greater decline in spirometry overtime [28], more extensive radiological findings, and involvement of multiple lobes [10,11,12,13,14].

Finally, we found no statistically significant association between inhaled corticosteroids (ICS) and NTM infection. This finding contrasts with other research reports that show an association between high-dose ICS inhaler usage and acquiring NTM infection [29, 30]. Several explanations for this discrepancy may exist. First, our findings may be influenced by the criteria we used for diagnosing NTM pulmonary infection rather than NTM pulmonary disease. Second, the small sample size of the NTM group may have limited our ability to detect a significant difference. It is worth noting a trend towards a higher proportion of NTM culture-positive results in the ICS group (33% vs. 26%), which may become significant with a larger sample size. Third, a recent meta-analysis and systematic review found that the correlation between ICS and NTM infection was especially significant in the higher-dose ICS group. In our study, we did not perform a subanalysis based on ICS dose [31].

The strengths of our study are the large sample of cases and the diagnosis of NTM infection on the basis of BAL, performed in all patients. In addition, the evaluated data included wide spectrum of variables which made it possible to determine the NTM infection risk.

The limitations of the study include its retrospective, observational design, and single-center setting. We only included patients experiencing bronchiectasis exacerbation who were unresponsive to empiric therapy and lacked evidence of a pathogen, which represents a specific patient population and may restrict the generalizability of the results.