Discussion
Previous studies in patients with bronchiectasis have shown that H. influenzae and P. aeruginosa were the more prevalent pathogens and that S. aureus was a less common pathogen.12 ,19 ,24 ,25 In contrast, a previous study in patients with bronchiectasis and NTM infection reported that P. aeruginosa (51%) and S. aureus (28%) were often isolated, whereas H. influenzae (12%) was rarely isolated.19 As compared with these previous studies, our study showed that chronic and intermittent microorganism co-infection was observed in 45.1% and 14.9%, respectively, of patients with pulmonary MAC disease. The majority of co-infecting microorganisms were MSSA, followed by P. aeruginosa and Aspergillus spp. We found that co-infection with Aspergillus spp is the third most prevalent infection in patients with pulmonary MAC disease.
CNPA was occasionally complicated during a long course of MAC disease.26 Kunst et al reported that Aspergillus-related lung disease was more common in patients with bronchiectasis and NTM. Although they used serological markers but not sputum culture for the diagnosis of Aspergillus-related lung disease, they showed that NTM infection predisposed patients with bronchiectasis to Aspergillus-related lung disease.20 In this study, most of our participants had bronchiectasis, and all 18 patients with chronic Aspergillus infection had culture-proven Aspergillus-related lung disease (15 patients with CNPA and 3 patients with ABPA).
In patients with cystic fibrosis, chronic Methicillin-resistant Staphylococcus aureus (MRSA) infection caused a rapid decline in lung function, and chronic Aspergillus infection was more frequently associated with both low lung function and increased risk of hospitalisation than intermittent Aspergillus infection or no infection.17 ,18 In patients with bronchiectasis, the baseline lung function of patients with chronic P. aeruginosa infection was lower than that of patients either with intermittent P. aeruginosa infection or without an infection.16 Others reported that chronic P. aeruginosa infection was associated with an accelerated decline in lung function.13 ,27 Therefore, we divided our group of co-infected patients into those with chronic co-infections and those with intermittent co-infections. In this study, we found that these three microorganisms were predominantly isolated from chronically co-infected patients (71.9% with an MSSA infection, 77.8% with a P. aeruginosa infection and 62.1% with an Aspergillus infection).
Previous studies have demonstrated that the risk factors for microorganism infection in patients with bronchiectasis and cystic fibrosis include COPD,21 rheumatoid arthritis,22 a long duration of the disease12 and the use of immunosuppressive agents.18 ,22 Compared with these previous studies, our study found that patients with COPD were at an increased risk of chronic infection with any pathogenic microorganisms or with MSSA or P. aeruginosa individually. A long duration of MAC disease (≥8 years) was significantly associated with chronic MSSA co-infection. The use of systemic corticosteroids was significantly associated with chronic Aspergillus spp co-infection. These factors for microorganism co-infection in patients with pulmonary MAC disease are similar to those in patients with bronchiectasis and cystic fibrosis.
Since COPD and systemic corticosteroid use also increased the risk of pulmonary NTM disease,28–30 close attention to pulmonary MAC disease and other co-infections is needed in these patients.
A recent study comparing the features of patients with pulmonary M. avium and M. intracellulare disease showed that patients with pulmonary M. intracellulare disease had more severe symptoms including the FC form of the disease and a worse prognosis.5 In this study, we found that pulmonary M. intracellulare disease was significantly associated with intermittent co-infection and chronic co-infection, especially Aspergillus co-infection. Patients with pulmonary M. intracellulare disease more frequently had the host traits of severe pneumonia, malignant disease and autoimmune disease, systemic corticosteroid use and more cavity findings (FC form and NB+FC form) in the HRCT than patients with pulmonary M. avium disease (table 2). Therefore, patients with pulmonary M. intracellulare disease potentially may have more lung deterioration than patients with pulmonary M. avium disease and thus be predisposed to the development of microorganism co-infection.
In our study participants, clarithromycin, rifampicin and ethambutol were the most commonly used drugs for MAC treatment. The historical use of these antibiotics in patients with MAC disease did not differ among patients with MSSA, P. aeruginosa and Aspergillus co-infections (table 6). However, since clarithromycin and rifampicin decrease susceptibility to MSSA, MAC treatment markedly suppressed the sputum isolation of MSSA but only during MAC treatment. In contrast, P. aeruginosa and Aspergillus were isolated during MAC treatment due to the lack of susceptibility of Pseudomonas and Aspergillus to these drugs.
Recently, Binder et al31 reported that cystic fibrosis patients with MAC were less likely than those without MAC to be colonised with P. aeruginosa. Winthrop et al also showed that non-cystic fibrosis bronchiectasis patients with NTM were less likely than those without NTM to be colonised with Pseudomonas spp as indicated in the US Bronchiectasis Registry.32 In this study, MSSA was similarly isolated in MAC-positive sputum cultures and after MAC sputum conversion (table 9). However, we found that P. aeruginosa was less frequently isolated from positive MAC sputum cultures and more often isolated after MAC sputum conversion (tables 6 and 9). Although we investigated only patients with pulmonary MAC disease and did not include patients without MAC disease in this study, we found that P. aeruginosa was increasingly isolated after negative sputum conversion of MAC in patients who were originally MAC-positive and that P. aeruginosa was less likely to be isolated concurrently with MAC. Therefore, our data support these previous studies.31 ,32
The existence of lung nodules was associated with chronic MSSA co-infection in this study. Morikawa et al previously reported that centrilobular nodules (63.9%) were more common than consolidation (51.8%) and bronchiectasis (12.0%) in patients with MSSA pneumonia. Since MSSA was rarely isolated during the antibiotic treatment of MAC in this study, some of the nodules found in patients with chronic MSSA co-infection might have been associated with MSSA pneumonia.33
Patients with chronic P. aeruginosa infection had greater areas of lung involvement in the lower lobes than patients without co-infection in this study. Previous studies showed that P. aeruginosa pneumonia was predominantly involved in the lower lung zone.34 ,35 Even after negative sputum conversion of MAC, P. aeruginosa remained positive in sputum cultures (table 9), and these areas of lower lung involvement were observed in follow-up CTs (data not shown). Therefore, some of the areas of lower lobe involvement in patients with chronic P. aeruginosa infection were most likely due to P. aeruginosa infection.
This study had the limitation of retrospective observation. We could not regularly follow sputum examination or chest CT evaluation for every participant. More than half of the patients were excluded from our cohort due to missing sputum examinations and chest CT evaluations. These excluded patients might have had a different frequency of microorganism isolation from the participants in this study. Therefore, the recruitment of additional patients and collection of additional sputum samples might allow more pathogenic microorganisms to be isolated and thus alter the prevalence of specific co-infections. However, since most of the excluded patients had few symptoms and less expectoration of sputum, the results in this study would reflect a symptomatic population. Also, since the university hospital is the tertiary referral hospital, more patients with severe conditions or with multiple complications are likely to be referred. Furthermore, this study was conducted only at a single centre. These may cause the patient selection bias. In this study, multiple statistical tests were applied to the different co-infection subgroups, and this carries a risk of false-positive associations—hence, the findings of this subgroup analysis should be viewed as hypothesis-generating rather than definitive. Finally, since we did not analyse an association of co-infection with the outcome or prognosis, we could not show the clinical significance of co-infection in this study.
In conclusion, we showed a high prevalence of chronic co-infections of pathogenic microorganisms in patients with pulmonary MAC disease. MSSA, P. aeruginosa and Aspergillus were the most prevalent isolated microorganisms. COPD and pulmonary M. intracellulare disease were risk factors for chronic co-infection.