The present study was a large retrospective cohort study of 1263 patients diagnosed with NTMPD in Shanghai from 2014 to 2018 that investigated the incidence, bacterial species distribution, drug susceptibility tests, treatment outcome, and risk factors associated with treatment outcome. We found that the major causative species were MAC, M.abscessus, and M.kansasii. The treatment success rate and sputum culture conversion rate were much higher in patients with M.kansasii infections than in those with infections by the other two species. Among these patients, infection by M.abscessus, infection by MAC, having an elevated ESR, receipt of retreatment, middle-aged and elderly had significant and positive associations with treatment failure. These findings thus provide important additional information regarding the clinical prediction of prognosis in patients with NTMPD and may help to improve treatment outcomes in these patients.
The most common NTM species in the world are MAC, M.abscessus, and M.kansasii, identical to our findings in NTMPD patients in Shanghai from 2014 to 2018, although we also identified changing percentages of these species over time. In particular, we found that the percentages of M.kansasii and M.abscessus increased, and that the percentage of MAC decreased. We also found that multi-NTM infections were common, similar to a 2020 study that was conducted in Chongqing, China. However, the distribution of different NTM species varies in different countries. In Europe and North America, MAC, M.gordonae, M.xenopi, and M.fortuitum are the most common, but in South America, MAC, M.kansasii, M.gordonae, and M.fortuitum are the most common. These geographic differences may be due to various factors, such as temperature, humidity and living habit of local residents.
Previous studies reported that many NTM species had natural drug resistance, especially to conventional first-line anti-TB drugs[13, 14]. Our study has come to the same conclusion. Drug resistance is particularly notable in M.abscessus. This drug resistance may be due to the cell wall acting as a natural barrier, drug efflux systems, drug inactivation, mutation or deletion of drug target sites, plasmids, or a combination of factors. Therefore, in clinical practice, NTMPD patients require a long treatment course, but treatment efficacy is often low and the recurrence rate is often high. This present study showed that there were significant differences in the treatment success rates and sputum culture conversion rates of patients infected with different NTM species. In particular, patients infected with M.kansasii had significantly better outcomes than patients infected with MAC or M.abscessus.
Our large retrospective cohort study also analysed the risk factors for treatment failure in NTMPD patients from Shanghai. We found that the risk of treatment failure was greater for patients infected with M.abscessus(aOR = 9.355) and MAC(aOR = 2.970) compared to those with M.kansasii infections, consistent with previous studies[16, 17]. Among our three most common NTM species, M.kansasii was the most sensitive to common anti-TB drugs. Macrolides, quinolones, aminoglycosides and sulfonamides are also effective against M.kansasii; so it is easier to develop a regimen that includes more than three effective drugs. Relative to M.kansasii, MAC has much greater rates of resistance to amikacin, isoniazid, rifampicin, ethambutol, doxycycline, clarithromycin, linezolid, and moxifloxacin. M.abscessus is the most problematic species, because of its high rates of resistance to rifamycin, macrolides (including clarithromycin and azithromycin), and other key therapeutic drugs[19, 20], potentially due to induced drug resistance or drug resistance caused by mutations. Our results showed that M.abscessus had an extremely high drug resistance rate to all the first-line anti-TB drugs, only sensitive to amikacin (74.9%). The 2020 American Thoracic Society Guidelines recommended linezolid and clofazimine as suitable for treatment of M.abscessus infections. In this study, there were only 21(9.3%) patients with M.abscessus infection were treated with linezolid and 19(8.4%) patients were treated with clofazimine because these two drugs were not widely used for NTMPD treatment in Shanghai from 2014 to 2018. We believe this might be part of the reason for the low treatment success rate in patients infected with M.abscessus.
Previous studies of MAC lung disease (MAC-LD) found that female sex correlated with poor prognosis[22, 23]. Studies in the United States and Denmark showed that the mortality rate was significantly greater for elderly women with NTMPD[24, 25]. Our multivariate results indicated that treatment failure correlated with age, but not with female sex. Relative to patients younger than 45 years, the aOR for treatment failure was 1.661 for patients aged 45 to 60 years and 1.739 for patients older than 60 years.
A recent study suggested that a history of previous NTMPD might be related to unfavorable treatment outcomes in patients with lung disease due to M.abscessus infection. We found that the aOR for treatment failure was 2.074 for those who previously received NTMPD treatment. This may be because the initial structural damage of lung tissue caused by the sequelae of NTMPD and by low local drug bioavailability. In addition, during NTMPD retreatment, an increased drug resistance, high treatment cost, long treatment course, and psychological factors of the patient may contribute to poor patient compliance and increased treatment difficulties.
Gochi et al. found that patients who were older and had lower BMI values were more likely to experience aggravation of MAC-LD, and increased levels of serum inflammatory indicators. We found no effect of BMI on outcome, but patients with an elevated ESR had an notable risk for poor outcome(> 60mm/h: aOR = 2.658). ESR and C-reactive protein are common inflammatory markers, and increased levels may reflect the systemic inflammatory response caused by NTMPD infection, and often indicate disease progression. ESR > 50 mm/h was found to be a negative prognostic factor of radiologic deterioration in NTMPD complicated with rheumatoid arthritis. A previous animal study of MAC-LD found that the level of certain proinflammatory and anti-inflammatory cytokines, such as TNF-α and gamma interferon, were greater in mice with severe or advanced MAC infections.
An increasing number of studies have confirmed that chest imaging features are related to the prognosis of patients with NTMPD[23, 30, 31], such as bronchiectasis and pulmonary cavity. Patients with NTMPD often present with bronchiectasis[32–34]. There is also evidence that the occurrence of NTM may correlate with alpha-1-antitrypsin deficiency in patients with bronchiectasis and that bronchiectasis is a predisposing factor for reinfection with NTM species. Our univariate analysis identified bronchiectasis as a significant risk factor for treatment failure, but it was no longer significant in the multivariate analysis. Our results also showed infection by M.abscessus was significantly correlated with treatment failure. Because a high proportion of patients infected by M.abscessus have bronchiectasis, we consider bronchiectasis as a confounding factor for treatment failure.
This study found that the major species causing NTMPD in Shanghai during 2014 to 2018 were MAC, M.abscessus, and M.kansasii. The treatment success rate in patients with M.kansasii infections was much higher than in those infected by the other two species. Patients who were infected by M.abscessus or by MAC, had an elevated ESR, received retreatment and those were middle-aged or elderly had significant increased risk of treatment failure. We therefore recommend that when clinicians encounter a patient with any of these conditions, they should carefully evaluate disease status and perform drug susceptibility tests, and then implement the most appropriate treatment regimen. The Directly Observed Treatment Strategy which is applied in TB management should be considered for patients with NTMPD, and patients should be closely monitored for adverse drug reactions and compliance to minimize the risk of treatment failure. Our results provide valuable insights for the prediction of prognosis and improvement of treatment outcome in patients with NTMPD. The current study also has a few limitations. It had a retrospective cohort design, and complete clinical data, especially the drug susceptibility results such as clarithromycin, azithromycin, cefoxitin, doxycycline, clarithromycin, and linezolid were not available. We therefore suggest that the results of this study need verification by large, multi-center, prospective cohort studies.