Introduction
Nontuberculous mycobacteria (NTM) are opportunistic bacterial pathogens [
1‐
4]. Some populations are more susceptible to infection with NTM, particularly chronic respiratory disease (CRD) patients [
3,
5‐
8]. The most common clinical manifestation of NTM disease (NTMD) is lung disease [
2]. Previous studies have found that patients with chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, and cystic fibrosis (CF) experience higher NTMD burden than patients without those diseases [
1,
7,
9‐
11].
National guidelines for the treatment of NTMD have changed over time and significant differences in recommended therapies were seen between the two major guidelines available during our study period [
1,
12]. The new British Thoracic Society 2017 guidelines [
2] have explicitly recommend specialist management of NTMD, unlike previous guidelines [
1,
12].
Few studies have investigated the clinical burden of NTM infection in the UK; these small, secondary care-based studies found large variation in the proportion of isolates that resulted in actual clinical disease, but do not provide insight into NTMD at a national level [
6,
13].
This is the first study to characterise NTMD patients, treatment regimens, and burden of NTMD, in the general population and in CRD patients, managed in UK primary care.
Discussion
This is the first national-scale study to look at the incidence and prevalence of NTMD managed within UK primary care, and investigate this within a CRD population.
Prevalence of NTMD was slightly higher in males than females in both strict cohorts, in keeping with most other studies [
3,
7,
13,
19‐
22]. The average ages of our general cohorts are similar to other European populations [
11,
21,
22]; however, there was an unusually large proportion of young persons in our strict general cohort. This may be indicative of young, healthier, milder disease being managed in primary care, whereas older, frailer, more severe disease is managed in secondary care. As in previous studies, a notable proportion of patients were underweight [
23].
Just under 40% of both general NTMD cohorts had a CRD. COPD was the most common in the strict cohort, followed by asthma, following previous studies [
11,
13,
21,
22]. However, bronchiectasis was slightly lower in our cohorts than seen previously and could be due to our primary care population as NTMD-bronchiectasis patients may be more likely seen in secondary care [
11,
13,
21,
22]. ILD was fourth in both cohorts and we found no previously published studies to explicitly estimate the amount of comorbid NTMD and ILD. We found, as expected, a very low proportion of CF patients with NTMD, most likely as CF is uncommon, our adult-only cohort, and CF patients being treated predominantly by specialists.
In our study, 14.8% of patients in our general strict cohort had no evidence of NTMD treatment, less than a recent German study [
24]. Treatment of NTMD in UK primary care appeared to follow guidelines available during our study period only half of the time [
1,
12]; however, when considering only the ATS07 [
1], the most commonly used worldwide [
25], treatments were concordant only 36% of the time. Many treated patients meeting guidelines (16%) were taking rifampicin/rifabutin and ethambutol, a combination recommended by BTS00 [
2], but not subsequent guidelines [
1,
2]. Patients without a history of CRD were more often treated than those with CRD; however, patients with CRD were more likely to be on recommended NTMD treatment regimens than patients without CRD. This suggests that patients with CRD may be more likely to be treated in secondary care and/or treated in consultation with a specialist than those without CRD.
Incidence in our strictly defined NTMD general cohort decreased over time, running counter to evidence that isolation of NTM from clinical samples and NTMD is increasing globally [
11,
26‐
32]. Specifically, in the UK, excluding Scotland, isolation from clinical samples has grown almost tenfold [
3,
20]. Scotland and Denmark [
19,
33] have seen stable NTM occurrence and nowhere has seen decreases. Decreasing NTMD in our strictly defined general cohort, requiring evidence of appropriate therapy or repeated testing, could suggest that the management of NTMD patients in the UK is shifting towards secondary care. This is supported by findings observing steep increases in NTM isolation in UK secondary care [
3,
34]. This may be due to changing risk factors, particularly increased use of immunosuppressant drugs and inhaled corticosteroids associated with acquisition of NTM infection [
35,
36] and requiring more complicated management. For example, guidelines recommend immunosuppressant drugs for the treatment of rheumatoid arthritis [
37] and inflammatory bowel syndrome [
38], and appear in clinical trials for treatment of asthma [
39] with some recommended for use [
40]. Increasing complexity of NTMD management is reflected in the most recent BTS guidelines, which explicitly recommend specialist management of NTMD [
2].
As in previous studies [
19], incidence of NTMD increased with increasing age in all our cohorts. For both definitions of NTMD, incidence was higher in patients with CRD than in the general population; this could suggest that patients with a history of CRD are more likely to suffer from, or be monitored for, NTM infection than the wider population.
Contrarily, incidences in our expanded definition cohorts increased over time. Our expanded definition of NTMD included all eligible CPRD patients with any NTMD code, including a single test, suggesting general practitioners (GPs) may be testing for NTMD more. This study provides a baseline for understanding the impact of the BTS17 guidelines, which explicitly recommend management by NTMD specialists; however, discrepancies between our strict and expanded cohorts may indicate that NTMD in the UK may already be principally managed in secondary care. Additionally, we found 14.8% of our patients with likely NTMD had no evidence of treatment within primary care; indicating that management coding in primary care is incomplete, management of NTMD is shared by primary and secondary care, and/or identification of NTMD occurs in primary care but is managed solely in secondary care.
Limitations
This study only used primary care data to identify patients with NTMD, limiting generalisability to the wider UK population. Microbiological data was not available, limiting our accuracy in identifying NTMD cases. Several steps were taken to limit misclassification of patients, as described in the methods and limitations
Supplementary Material. We used an expanded definition to try to capture all NTMD, including patients who were only partly managed within primary care, but undoubtedly the use of this definition included patients who were only investigated, but not diagnosed.
We are limited to reporting NTMD managed in primary care and cannot generalise to the whole UK population. Unfortunately, available secondary care data was not granular enough to pick up TB clinics, where NTMD patients are most likely managed. Without detailed secondary care and microbiology data, it cannot be known whether a shift in NTMD management from primary to secondary care has occurred, although other findings support our hypothesis [
3,
34].
Compliance with ethical standards