To the best of our knowledge, the present study is the first to describe clinical and radiographic features in relation to species-specific pathogenic potential of respiratory NTM isolates in Belgium. The frequency of NTM-PD remained stable over an 8-year time period in the three participating reference centres, despite increasing isolation frequency. Pre-existing lung disease was the main risk factor for developing NTM-PD. NTM isolates were clinically significant in 43% of the patients. Symptoms like night sweats, fever, weight loss, and positive AFB staining, were more often associated with NTM-PD. Fibrocavitary lesions on chest CT are highly associated with clinical relevance. MAC was the commonest mycobacterial isolate and pathogen in our cohort.
Although there was an annual increase in new NTM isolates, numbers of newly diagnosed NTM-PD remained stable. This evolution over time is in line with study findings in Denmark and the Netherlands [20, 21], whereas reports from the UK, Germany, Canada and the USA report an increasing incidence of NTM-PD [11, 13, 14, 22, 23]. The increasing isolation of NTM from respiratory samples may be partly due to a rising awareness and screening, but may also be explained by environmental factors or an ageing population with more comorbidities and predisposition to NTM-PD. However, the real incidence of NTM-PD remains uncertain since NTM-PD is not a reportable disease in most countries. Therefore, longitudinal and prospective registries could be very informative concerning the true incidence of NTM-PD.
Less than half of pulmonary NTM isolates are considered clinically relevant according to the ATS/IDSA criteria. Over 40% of patients in our cohort met ATS/IDSA criteria, in contrast to lower reported numbers of 25-33% in similar studies from the Netherlands, the UK and South Korea [20, 24, 25]. This might be explained by the nature of referrals and underlying disease severity.
Patients in our study cohort were predominantly male and middle-aged, which is in concordance with some previous reports [6, 20] but in contrast to reports from the US and Japan where a different morphotype (white, middle-aged females) is described [12, 26, 27]. Pre-existing lung disease such as COPD and bronchiectasis were the most common comorbidities. Chronic respiratory disease is an important risk factor for NTM-PD, making it a pulmonologists issue: it has been associated with a 16-fold increased risk in a Danish population-based case-control study [28]. The finding was confirmed by Marras et al., reporting a nine times higher incidence of NTM-PD in COPD [8]. Closer surveillance for NTM in patients with pulmonary disease may be warranted.
Diagnosis of NTM-PD according to ATS-IDSA criteria can be challenging as symptoms are often nonspecific and partly overlapping with underlying illness. Fever, night sweats and weight loss tend to be present in advanced NTM-PD [4]. Similarly in our study, these symptoms were more likely to be associated with NTM-PD. Cough and fatigue also tended to be more frequently reported in patients with NTM-PD similar to findings from Aksamit et al., but these are rather non-specific symptoms which are often related to underlying diseases [4, 26]. The presence of nodular bronchiectatic lesions and especially fibrocavitary lesions on chest CT were significantly associated with NTM-PD. In the absence of either fibrocavitary or nodular bronchiectatic lesions, isolates were mostly not clinically relevant, a finding corroborating the ATS criteria. Fibrocavitary lesions are a marker of severe NTM-PD with worse prognosis [4, 29, 30]. Similarly, the majority of patients in our cohort with respiratory samples positive on AFB staining suffered from NTM-PD. This is in line with previous studies, where AFB stain positivity has been associated with a higher bacterial burden, more severe NTM-PD and poor outcome [5, 30]. A. fumigatus co-isolation was also associated with NTM-PD as suggested in previous studies by Kunst et al. and Provoost et al. [31, 32]. The value of this finding remains unclear. Is A. fumigatus co-isolation a risk factor or the consequence of NTM-PD? It could also be related to underlying lung disease or immunosuppression [31–33]. Prospective studies or registries could identify true risk factors or indicators which could help refining the current ATS/IDSA criteria for establishing the diagnosis of NTM-PD.
With MAC accounting for more than half of the isolates, its prevalence in our study is comparable with a 2008 report from the Belgian national reference lab in which 38% of all isolates were MAC [19]. In other European studies, MAC was the predominant species as well, although regional differences were noted [15, 19]. M. avium, M. intracellulare, M. gordonae and M. xenopi were the most frequently isolated species, in accordance with a national report by Soetaert et al. where M. avium, M. intracellulare and M. xenopi accounted for 20%, 21% and 15% of all (pulmonary and other) isolates respectively [17]. Of note, the same group previously showed that M. chimaera was frequently misidentified as M. intracellulare [34]. In our report we did not systematically re-evaluate these very closely related species. The difference for M. xenopi could be explained as our cohort did not properly cover the coast nor the southern half of the country which have a distinct environment. M. xenopi is a species mainly found in Europe with high concentrations in Southern Europe and along the English Channel [19, 35]. Accounting for only 3% of isolates, M. abscessus was rather rare which is similar to other European reports [12, 15]. Prevalence of M. abscessus isolates is substantially higher in Asia (16%) and Oceania (12%). These differences can be explained by different environmental factors and/or changing mycobacterial fauna over time [12, 15, 17, 19].
MAC was the main culprit (67.3%) for NTM-PD in this study cohort (Figure 3). The position of MAC as the main cause of NTM-PD is established worldwide although frequencies vary largely between studies [12, 15]. Of individual species M. szulgai, M. abscessus, M. malmoense, M. kansasii, M. intracellulare and M. avium were clinically relevant in more than 50% of cases, suggesting a higher pathogenic potential than other species (Figure 4). Compared to a Dutch study by Van Ingen et al., there are several similarities but also some differences [20]. Our M. abscessus and M. intracellulare isolates were more frequently considered clinically relevant than their Dutch counterparts (91.6% versus 33% and 64% versus 12.5%). In our cohort M. intracellulare had a higher probability of clinical relevance than M. avium (64% and 54.2% respectively) in contrast to the Dutch report (12.5% and 40.7%) [20]. Our findings, however, are in line with other reports about a higher pathogenicity of M. intracellulare [15, 36]. These differences support the hypothesis of regional variation and illustrate the value of local data.
Clinical relevance varies not only by species but also by radiological presentation. Clinically significant isolates of M. kansasii, M. malmoense and M. xenopi mostly presented with fibrocavitary changes while M. abscessus and MAC related NTM-PD more often presented with nodular bronchiectatic changes, which has already been described [37–39]. Our findings corroborate previous suggestions that when assessing NTM clinical relevance integration of radiological findings and species identification is useful [37, 38].
Our study has several limitations inherent to the retrospective study design. Selection bias cannot be excluded since data were collected from three major reference centres receiving the more complex cases. Additionally, increased awareness over time and more intense surveillance protocols for patients with pulmonary disease may have led to overestimation of NTM-PD risk. Our data are limited in scope, hence caution is warranted in generalising the findings. The lack of outcome data limit the predictive value of clinical significance.