Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation

Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation Naohisa Urabe, Susumu Sakamoto, Yui Shimanuki, Takumi Kanokogi, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1253953/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: The impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary Mycobacterium avium complex (MAC) disease has not been clearly demonstrated. This study sought to clarify clinical outcomes of co-infection with MAC after antimycobacterial therapy for MAC. Methods: Co-infection status was designated as the detection of pathogenic microorganisms other than MAC in at least two consecutive sputum cultures 6-24 months after initiation of treatment. Chest computed tomography (CT) findings and culture results were compared between co-infection and MAC alone groups. Results: The co-infection and MAC alone groups comprised 12 and 36 patients, respectively. The proportion of patients with sputum culture positive for MAC after 24 months of therapy did not differ significantly between the two groups [25% (3/12) vs. 16.7% (6/36); p =0.671]. The proportion of patients with improved chest CT score after 24 months of starting treatment compared to baseline was significantly lower for the co-infection group than for the MAC alone group [16.7% (2/12) vs. 79.4% (27/34); p <0.001]. In the co-infection group, mean CT score values at 12 and 24 months did not differ from baseline. However, the MAC alone group showed significant improvement at 12 and 24 months compared with baseline. Conclusions: Co-infection with other pathogenic microorganisms has no effect on the therapeutic efficacy of MAC but interferes with improvement in chest CT findings. Nontuberculous mycobacterium Mycobacterium avium complex Co-infection Pseudomonas aeruginosa Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Pulmonary nontuberculous mycobacteria (NTM) disease is increasing in incidence worldwide and has become an important concern [ 1 ]. In Japan, the incidence of pulmonary NTM disease has been gradually increasing and exceeded the incidence of mycobacterial tuberculosis for the first time in 2014 [ 2 ]. The type of NTM differs by region. In Japan, Mycobacterium avium complex (MAC) accounts for about 90% of the total [ 2 ]. Pulmonary MAC disease is a chronic lower respiratory tract infection caused by MAC. Chronic lower respiratory tract infections are a burden because of the difficulty with identifying the causative microorganism; co-infections with multiple microorganisms have also been reported [ 3 ]. In a previous study we report that 12.2% of patients with pulmonary MAC disease had co-infections with Haemophilus influenzae ( H. influenzae ) and Pseudomonas aeruginosa ( P. aeruginosa ) [ 4 ]. According to Fujita et al., 45.1% of patients with pulmonary MAC disease had chronic co-infection with other pathogenic microorganisms, and chronic P. aeruginosa co-infection increased after the initiation of treatment for pulmonary MAC disease [ 5 ]. However, the impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary MAC disease has not been clarified. Thus, we investigated the impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary MAC disease. Methods Study design This single-center retrospective cohort study included 48 patients with pulmonary MAC disease who had started treatment during the period from November 2014 through February 2019 at Toho University Omori Medical Center. All patients were required to fulfill the American Thoracic Society (ATS) criteria for the diagnosis of NTM [ 6 ], and they continued MAC treatment from baseline for at least 12 months (46 patients continued for at least 24 months; 2 patients continued for at least 12 months). Sputum culture for mycobacteria, other bacteria, and fungi was performed at least 3 times during the 6-24 months after treatment initiation for pulmonary MAC disease. Patients who had difficulty with sputum collection were excluded. Definition of co-infection and treatment failure in pulmonary MAC disease We defined co-infection as the detection of pathogenic microorganisms other than MAC in at least two consecutive sputum cultures 6-24 months after initiation of treatment for pulmonary MAC disease. At baseline, co-infection was defined as detection of pathogenic microorganisms other than MAC in at least two separate sputum cultures or at least one bronchoalveolar lavage. Co-infection at baseline was designated ‘base co-infection’. Treatment success was defined as sputum culture conversion to MAC negative within 12 months of treatment. Treatment failure was designated in patients with persistent MAC detection in sputum culture after 12 months of treatment We compared the results of high-resolution CT (HRCT) of the chest, microbiological tests, and subjective symptoms between the co-infection and MAC alone groups. Univariate and multivariate logistic regression analysis was also performed to identify factors independently associated with co-infection. Data collection The following patient data were collected: age, sex, body mass index (BMI), smoking history, serum anti-glycopeptidolipid-core IgA titer, comorbidities, chest and paranasal sinuses CT, and sputum and bronchoscopy culture results. Most patients underwent Chronic Obstructive Pulmonary Disease (COPD) assessment testing (CAT) to confirm subjective symptoms at the time of treatment initiation and at 6, 12, 18, and 24 months thereafter [ 7 ]. Chest CT score Chest HRCT score was reviewed as previously described with slight modification as follows [ 8 ]. We divided the lungs into 6 zones at the levels of the carina and inferior pulmonary vein. Using HRCT, we categorized the 4 types of pulmonary lesions in MAC (cavities, bronchiectasis, nodules, and infiltration) into 5 stages, according to the occupation area in each section (0: no lesion, 1: 1–24% occupied, 2: 25–49% occupied, 3: 50–74% occupied, and 4: 75–100% occupied). In addition, changes in cavity wall thickness were reflected by assigning +2 points for cavity wall thickening by more than 1 mm and -2 points for thinning (Figure, 1). Two respiratory physicians with over 13 years of experience reviewed Chest CT scores independently. Improved Chest CT score was defined as a decrease. We investigated the relationship of co-infection, treatment failure, and serial changes in chest CT findings. Statistical analysis Data are presented as the number of patients and percentages. Age, BMI, chest CT score, and CAT score are expressed as mean ± SD. Associations of categorical and continuous variables between patients in the co-infection and MAC alone groups were tested with the chi-squared or Fisher’s exact test, and the Mann–Whitney U test, respectively. Factors independently associated with co-infection were evaluated with univariate and multivariate logistic regression. Multivariate logistic regression was performed using a stepwise method. A P value of <0.05 was considered to indicate statistical significance. Statistical analyses were performed with SPSS software version 22 (IBM Corp., Armonk, NY). Results Clinical characteristics In total, 48 patients were included in this study; the co-infection group comprised 12 patients (mean age 72.1±6.9 years; 2 men, 10 women) and the MAC alone group included 36 patients (mean age 68.3±11.8 years; 7 men, 29 women). The characteristics of all 48 patients are shown in Table 1. At baseline, there were significant differences between the co-infection and MAC alone groups in scores for chest CT (12.6±3.3 vs. 9.1±4.1; p=0.007), bronchiectasis lesions score on chest CT (3.7±1.9 vs. 2.3±1.6; p=0.035), subjective cough symptoms (2.5±1.4 vs. 1.3±1.2; P =0.015), and sputum (2.6±1.8 vs. 1.1±1.0; p=0.021). The proportion of patients with cavitary lesions (25% vs. 50%; p=0.185), cavitary lesions score on chest CT (0.4±0.9 vs. 1.0±1.5; p=0.117) and the rate of base co-infection did not differ significantly between the two groups (50% vs. 38.9%; p=0.52). Both groups showed the same resistance rate to CAM of 8.3% at 24 months after treatment initiation. Overall treatment success rate for MAC was 81.2% (39/48) with no significant differences between the co-infection and MAC alone groups (75% vs 83.3%; p=0.671). Microbiological test results in the co-infection group Serial changes in microbiological test results in the co-infection group are shown in Table 2. At baseline, 6 of the 12 patients had base co-infection, namely 2 patients with H. influenzae , 2 with Methicillin-sensitive Staphylococcus aureus (MSSA), 1 with P. aeruginosa , and 1 with Escherichia coli ( E. coli ). In 3 of the 6 patients the same organism was detected in base co-infection and at 12-24 months after treatment for MAC (1 each with E. coli , P. aeruginosa , and MSSA). P. aeruginosa was the most common pathogenic microorganism in co-infections after the treatment for MAC, accounting for same in 7 of 12 (58.3%) patients. Serial changes in Chest CT score Table 3 shows the clinical course in patients with pulmonary MAC disease. In total, CT score was improved in 72.9% and 63% of patients at 12 months and 24 months after treatment initiation. At 24 months after treatment, the proportion of patients with improved chest CT score was significantly lower in the co-infection group than the MAC alone group (16.7% vs. 79.4%; p<0.001). Figure 2 shows serial changes in chest CT score in the 2 groups. In the co-infection group, mean CT score at 12 and 24 months did not differ compared with the baseline CT score (12.2±5.3 and 15.8±6.0 vs. 12.6±3.3; p=0.757 and p=0.55). However, in the MAC alone group, mean CT score at 12 and 24 months was significantly improved compared with the baseline score (5.6±5.0 and 5.9±6.5 vs. 9.1±4.1; p<0.001 and p<0.001). Figure 3 shows serial changes in chest CT score in the MAC alone and treatment success group (n=30); co-infection and treatment success group (n=9); and the treatment failure group (n=9). In the co-infection and treatment success group, mean values at 12 and 24 months did not differ significantly from baseline CT score (11.9±5.9 and 15.8±6.9 vs. 12.8±3.7; p=0.604 and p=0.196). In the treatment failure group, mean values at 12 and 24 months did not differ significantly compared with the baseline CT score (11.4±3.0 and 13.3±4.6 vs. 11.2±2.6; p=0.803 and p=0.220). However, the values at 12 and 24 months were significantly better than the baseline CT score (4.6±4.8 and 4.6±6.0 vs. 8.7±4.2; p<0.001 and p<0.001) in the MAC alone and treatment success group. Serial changes in CAT score At 12 and 24 months after initiation of MAC treatment, the proportion of patients with improved CAT scores did not differ significantly between the co-infection and MAC alone groups (70% vs. 54.8% and 40% vs. 48.3%; p=0.48 and p=0.726). The proportion of patients with improvement in relation to sputum score also did not differ significantly between the co-infection and MAC alone groups (50% vs. 35.5% and 20% vs. 24.1%; p=0.472 and p=1) (Table 3). Figure 4 shows serial changes in CAT score. The co-infection group showed no significant difference in mean CAT score at 12 and 24 months compared with baseline (11.6±9.8 and 13.8±10.9 vs. 11.1±7.2; p=0.576 and p=0.131); in the MAC alone group the CAT score at 12 and 24 months did not differ significantly from the baseline score (7.5±7.0 and 7.2±6.8 vs. 7.9±6.6; p=0.724 and p=0.845). Sputum score in CAT score was independently associated with co-infection (Table 4). Figure 5 shows serial changes in sputum score. In the co-infection group, the mean value at 12 and 24 months did not differ significantly compared with the baseline score (2.3±1.7 and 2.7±1.8 vs. 2.6±1.8; p=0.565 and p=1.0). Also, in the MAC alone group, the mean sputum score at 12 and 24 months, the score did not differ significantly from baseline (0.97±1.11, and 0.97±0.98 vs. 1.1±1.0; p=0.536 and p=0.345). Risk factors for co-infection Table 4 shows the results of univariate and multivariate logistic regression analysis of independent associations with co-infection. Higher chest CT score (Odds Ratio [OR], 1.27; 95% confidence interval [CI], 1.04-1.55; p=0.017), higher sputum score (OR, 2.35; 95% CI, 1.28-4.31; p=0.006), and higher cough score (ORs, 2.2; 95% CI, 1.17-4.14; p=0.014) were independently associated with co-infection in univariate analysis. Higher sputum score (ORs, 2.02; 95% CI, 1.08-3.79; p=0.028) was independently associated with co-infection in multivariate analysis. Discussion We demonstrated the impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary MAC disease. Although co-infection with other pathogenic microorganisms does not affect therapeutic efficacy in MAC, these organisms may interfere with improvement of chest CT findings. Few studies have investigated the impact of co-infection with other pathogenic microorganisms in pulmonary MAC disease [ 5 , 9 ]. Fujita et al. reported chronic co-infection with other pathogenic microorganisms including MSSA, P. aeruginosa, and Aspergillus spp. in 45.1% of patients with pulmonary MAC disease [ 5 ]. According to Kamata et al., chronic co-infection with P. aeruginosa was seen in 7.8% of patients with pulmonary MAC disease [ 9 ]. It is important to note that these were cross-sectional studies, and so did not clarify the impact of co-infection on the efficacy of MAC treatment. To our knowledge, this is the first report to investigate the impact of co-infection with other pathogenic microorganisms on clinical course after initiation of treatment for pulmonary MAC disease. This study showed that sputum culture conversion or treatment success rate was 81%, improvement in chest CT score was 63%, and the rate of CAM resistance was 8.3%. These results were consistent with those from previous studies. Earlier reports of macrolide-inclusive daily regimens have shown that the rate of sputum culture conversion was 42-92% [ 10 – 14 ], chest imaging improvement was 68-82% [ 12 , 13 ], and macrolide resistance was 9-15% [ 10 , 11 , 14 ]. In addition, the rates of MAC culture conversion and CAM resistance did not differ significantly between the co-infection and MAC alone groups. These results suggest that co-infection after the initiation of treatment for MAC did not affect the treatment efficacy. Nevertheless, the proportion of patients with improved chest CT scores was significantly lower in the co-infection group than in the MAC alone group at 24 months after initiation of treatment. Furthermore, serial changes in chest CT score in the co-infection group showed no significant improvement, even after excluding patients with MAC treatment failure. Thus, co-infection with other pathogenic microorganisms does not affect the outcome of MAC treatment but worsens chest CT findings. The worse chest CT findings may have been as a result of other pathogenic microorganisms that gained dominance due to weakening of the competing MAC. Among 6 of the 12 patients who had base co-infection in the co-infection group, only 3 had the same bacterial species detected until post MAC treatment. Clarithromycin-susceptible bacteria such as MSSA and H. influenzae decreased after MAC treatment while clarithromycin-resistant bacteria such as P. aeruginosa and Nocardia spp. increased after MAC treatment. We speculated that MAC treatment suppressed the proliferation of MAC and other clarithromycin (CAM)-susceptible bacteria, and this might foster a conversion of the bacteria to clarithromycin-resistant. This result is consistent with previous reports showing that P. aeruginosa was less frequently isolated from positive MAC sputum cultures and more often isolated after MAC sputum conversion [ 5 ]. Previous studies showed that patients with NTM bronchiectasis, including those with cystic fibrosis, had a lower rate of chronic P. aeruginosa infection compared with non-NTM infection [ 15 , 16 ]. MAC and other pathogenic microorganisms, especially P. aeruginosa , interact with each other and culture results may reflect the dominant pathogenic species at that time. Therefore, we speculate that the negative MAC culture in the co-infection group may not only be due to the effect of MAC treatment but also due to the suppression of MAC culture by other potentially infectious pathogenic microorganisms that became dominant. In this study, subjective symptoms were more severe in the co-infection group at baseline. Specifically, high sputum score at baseline was an independent risk factor for co-infection. According to Kamata et al., co-infection with P. aeruginosa worsened subjective symptoms in patients with pulmonary MAC [ 5 ]. Previous reports showed that P. aeruginosa colonization was an independent predictor of hospital admission in bronchiectasis [ 17 ]. But in our study, the rate of baseline co-infection showed no significant difference between the co-infection and MAC alone groups. We surmised that the presence of trace amounts of other bacteria undetectable by conventional culture in the co-infection group at baseline was the cause of the severe subjective symptoms, and that the bacteria may have become apparently detectable with MAC treatment. Several risk factors for developing co-infection in patients with MAC have been reported. This study showed that bronchiectasis score was significantly higher in the co-infection group than the MAC alone group. However, cavitary lesion score and the frequency of concomitant emphysema did not differ between the two groups. In addition, 7 out of 12 patients had P. aeruginosa co-infection and none had Aspergillus co-infection. In the Fujita study, of the 124 patients with co-infection, 18 and 35 patients had aspergillus and P. aeruginosa infection, respectively. Risk factors for co-infection were reported to be COPD and M. intracellulare infection [ 5 ]. Patients with M. intracellulare infection were more likely to have fibro-cavitary disease than those with M. avium infection [ 18 ] and cavitary lesions have been reported to be a risk factor for complications of chronic pulmonary aspergillus infection in pulmonary MAC [ 19 ]. In contrast, the Kamata study included 19 patients with MAC and P. aeruginosa exclusively. The severity of bronchiectasis, but not cavitary lesions, was associated with P. aeruginosa co-infection. The disparity in risk factors for co-infection in these studies may be due to the presence or absence of Aspergillus. A previous study showed that severity of bronchiectasis was significantly associated with the presence of chronic P. aeruginosa infection in patients with non-cystic fibrosis bronchiectasis [ 20 ]. We speculate that patients with cavitary lesions are more likely to have co-infection with Aspergillus , whereas those with severe bronchiectasis were more likely to be infected with certain types of bacteria including P. aeruginosa. These findings notwithstanding, this study had several limitations that should be mentioned. Firstly, it was a single-center study in a small number of patients. Thus, the findings may not be generalizable to a larger, more diverse population. Secondly, some patients were excluded from this study due to missing sputum examination and chest CT evaluations. These excluded patients might have had infections from a different type of pathogen. Thirdly, the potential presence of indigenous oral bacterial populations cannot be ruled out, and so this may not accurately reflect the status of the lower airway flora because not all patients underwent bronchoscopy. Conclusion Although co-infection with other pathogenic microorganisms does not affect the therapeutic efficacy in MAC, these organisms may interfere with improvement of chest CT findings. Abbreviations ATS American Thoracic Society BMI body mass index COPD Chronic Obstructive Pulmonary Disease CAT Chronic Obstructive Pulmonary Disease assessment testing CAM clarithromycin CT computed tomography CI confidence interval E. coli Escherichia coli H. influenzae Haemophilus influenzae HRCT high-resolution CT MSSA Methicillin-sensitive Staphylococcus aureus MAC Mycobacterium avium complex NTM Nontuberculous mycobacteria OR Odds Ratio P. aeruginosa Pseudomonas aeruginosa . Declarations Ethics approval and consent to participate This study was conducted in accordance with the amended Declaration of Helsinki and the Ethics Committee of Toho University Omori Medical Center approved the protocol (Approval No.M21218). All methods were carried out in accordance with relevant guidelines and regulations. All patients provided written informed consents to participate in the study. Consent for publication Not applicable Availability of data and materials All data generated or analysed during this study are included in this published article [and its supplementary information files]. Conflict of Interest Statement The authors have no conflicts of interest to declare. Competing interests The authors declare that they have no competing interests. Funding Sources This study received no funding. Author Contributions NU designed the study, analyzed, and drafted the manuscript, SS and KK designed the study and participated in editing the manuscript, SH confirmed the analyses, and revised the article for intellectual content, YS and TK conceptualized the study and revised the article for intellectual content, TM and NA conceptualized the study, supervised, CK, AY and NT participated in editing the manuscript and revised the article for intellectual content. All authors read and critically revised the first as well as the subsequent and final drafts of this manuscript. The author(s) read and approved the final manuscript. Acknowledgments Not applicable. References Brode SK, Daley CL, Marras TK. The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review. Int J Tuberc Lung Dis. 2014;18 (11): 1370–7. Namkoong H, Kurashima A, Morimoto K, Hoshino Y, Hasegawa N, Ato M, et al. 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Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis. Am J Respir Crit Care Med. 2013; 188 (7): 807–12. Aksamit TR, O'Donnell AE, Barker A, Olivier KN, Winthrop KL, Daniels MLA, et al. Adult Patients with Bronchiectasis: A First Look at the US Bronchiectasis Research Registry. Chest. 2017; 151 (5): 982–92. Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S, Davidson J, et al. The bronchiectasis severity index. An international derivation and validation study. Am J Respir Crit Care Med. 2014; 189(5): 576–85. Koh WJ, Jeong BH, Jeon K, Lee NY, Lee KS, Woo SY, et al. Clinical significance of the differentiation between Mycobacterium avium and Mycobacterium intracellulare in M. avium complex lung disease. Chest. 2012; 142(6): 1482–8. Song JW, Koh WJ, Lee KS, Lee JY, Chung MJ, Kim TS, et al. High-resolution CT findings of Mycobacterium avium-intracellulare complex pulmonary disease: correlation with pulmonary function test results. AJR Am J Roentgenol. 2008; 191 (4): W160. Dimakou K, Triantafillidou C, Toumbis M, Tsikritsaki K, Malagari K, Bakakos P. Non CF-bronchiectasis: Aetiologic approach, clinical, radiological, microbiological and functional profile in 277 patients. Respir Med. 2016; 116: 1–7. Tables Tables are available in the Supplemental Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx Table3.xlsx Table4.xlsx SupplementTable1.xlsx Additional file 1: Supplementary Table 1. Detailed sputum culture changes of all patients. SupplementTable2.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 07 Mar, 2022 Reviews received at journal 01 Mar, 2022 Reviews received at journal 11 Feb, 2022 Reviewers agreed at journal 02 Feb, 2022 Reviewers agreed at journal 02 Feb, 2022 Reviewers invited by journal 02 Feb, 2022 Editor assigned by journal 02 Feb, 2022 Editor invited by journal 27 Jan, 2022 Submission checks completed at journal 27 Jan, 2022 First submitted to journal 12 Jan, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1253953","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":79651848,"identity":"411bd7a4-a7bf-4303-bbc3-78473e3f5ef1","order_by":0,"name":"Naohisa Urabe","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Naohisa","middleName":"","lastName":"Urabe","suffix":""},{"id":79651849,"identity":"3c091d0d-5fdc-4635-a4bb-260edc344c02","order_by":1,"name":"Susumu Sakamoto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYPACCR5+9uYDIIYMsVos5CR7jiWA9RKrpcLY4EaOAYhFWIv8jPRnUjfbJBIbbuR8fnWjxoKHgf3w0Q34tAANN5POBWpp7Hm7zTrnGNBhPGlpN/BqkchhA2tpZs/dZpzDBtQiwWOGVwvIYWAtbQw5z4xz/hGhheFGAthhxjwcOcyPgQzCWgzOvDG2zjknISfBc8yMObdPgoeNkF/k29Mf3s4pq+OxP978+HPOtzo5fvbDx/A7DAmwSYBJYpWDAPMHUlSPglEwCkbByAEApPBEdSUaBDMAAAAASUVORK5CYII=","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Susumu","middleName":"","lastName":"Sakamoto","suffix":""},{"id":79651850,"identity":"f5a0c5a5-7af9-402d-a3e5-f09308fdd5a4","order_by":2,"name":"Yui Shimanuki","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yui","middleName":"","lastName":"Shimanuki","suffix":""},{"id":79651851,"identity":"294f7f11-ff7e-42a5-9d01-7b776dc9525c","order_by":3,"name":"Takumi Kanokogi","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takumi","middleName":"","lastName":"Kanokogi","suffix":""},{"id":79651852,"identity":"70a9f45f-fb06-44e3-9cb7-3c718fff115b","order_by":4,"name":"Takumi Motohashi","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takumi","middleName":"","lastName":"Motohashi","suffix":""},{"id":79651853,"identity":"3162eeb5-3f82-423a-b53d-ba4ba97bbc98","order_by":5,"name":"Nanami Anzai","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nanami","middleName":"","lastName":"Anzai","suffix":""},{"id":79651854,"identity":"bce33e30-d4fc-429d-9660-548a96cf0508","order_by":6,"name":"Chiaki Kato","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chiaki","middleName":"","lastName":"Kato","suffix":""},{"id":79651855,"identity":"c98ecf9e-007d-414f-9cca-6112d0c723c0","order_by":7,"name":"Asuka Yamaguchi","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Asuka","middleName":"","lastName":"Yamaguchi","suffix":""},{"id":79651856,"identity":"041954ad-42dd-4573-87f6-b4550be0c842","order_by":8,"name":"Nozomi Tokita","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nozomi","middleName":"","lastName":"Tokita","suffix":""},{"id":79651857,"identity":"a535fbc6-5661-45ba-a545-20849400256e","order_by":9,"name":"Sakae Homma","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sakae","middleName":"","lastName":"Homma","suffix":""},{"id":79651858,"identity":"5f5438b8-47e9-4f44-9464-3a2fd6e07f69","order_by":10,"name":"Kazuma Kishi","email":"","orcid":"","institution":"Toho University Omori Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kazuma","middleName":"","lastName":"Kishi","suffix":""}],"badges":[],"createdAt":"2022-01-12 13:44:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1253953/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1253953/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":17820493,"identity":"76d654db-1cdf-4026-9d5f-65e8b01a8f9c","added_by":"auto","created_at":"2022-01-31 19:14:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":451373,"visible":true,"origin":"","legend":"\u003cp\u003eStages of pulmonary lesions in MAC disease by chest CT score. Cavity wall thickness was assigned +2 points if the thickness increased by more than 1 mm and -2 points were given for thinning.\u0026nbsp;\u003c/p\u003e","description":"","filename":"FIgure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/f789d2fec4a0a13309335c1d.png"},{"id":17821018,"identity":"c0523ff7-9df6-4ca3-8549-3a37fb55ce94","added_by":"auto","created_at":"2022-01-31 19:17:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":398173,"visible":true,"origin":"","legend":"\u003cp\u003eSerial changes in chest CT score. Gray lines indicate change in chest CT score in each patient after initiation of treatment for pulmonary MAC disease. Black lines indicate the mean for all patients. A paired t-test was used to compare values at 12 and 24 months with baseline.\u003c/p\u003e","description":"","filename":"FIgure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/e474c2e6781e8fd9882e0554.png"},{"id":17821016,"identity":"9d5c88d4-e004-48c0-b917-099599a59796","added_by":"auto","created_at":"2022-01-31 19:17:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":168128,"visible":true,"origin":"","legend":"\u003cp\u003eGray lines indicate change in Chest CT score in each patient after initiation of treatment for pulmonary MAC diseases. Black lines indicate the mean for all patients. A paired t-test was used to compare values at 12 and 24 months with baseline values.\u003c/p\u003e","description":"","filename":"FIgure3.png","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/2ba9a235d0bee321194ce864.png"},{"id":17820500,"identity":"09466dc9-edf8-4555-913e-e30bb64b2cbf","added_by":"auto","created_at":"2022-01-31 19:14:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":176443,"visible":true,"origin":"","legend":"\u003cp\u003eGray lines indicate change in CAT score in each patient after initiation of treatment for pulmonary MAC disease. Black lines indicate the mean for all patients. A paired t-test was used to compare values at 12 and 24 months with baseline values.\u003c/p\u003e","description":"","filename":"FIgure4.png","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/159fe49f705b928b4f991463.png"},{"id":17821020,"identity":"2c454cf5-67dd-4bfb-aff2-f6785360ed66","added_by":"auto","created_at":"2022-01-31 19:17:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":142308,"visible":true,"origin":"","legend":"\u003cp\u003eGray lines indicate change in sputum score in each patient after initiation of treatment for pulmonary MAC disease. Black lines indicate the mean for all patients. A paired t-test was used to compare values at 12 and 24 months with baseline values.\u003c/p\u003e","description":"","filename":"FIgure5.png","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/8a422e59e557bcf836d6a686.png"},{"id":17821021,"identity":"c7940fc3-34e0-4112-a8a1-3780f9c4b114","added_by":"auto","created_at":"2022-01-31 19:17:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":350134,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/71ec6e3e-2bb5-40af-b92f-b26adb664122.pdf"},{"id":17821017,"identity":"f1d4a8fb-a055-4b04-bf20-b0476cb85073","added_by":"auto","created_at":"2022-01-31 19:17:06","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15038,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/c7ea7456f176761eb792a98a.xlsx"},{"id":17820496,"identity":"3b2dd0ad-043e-4e8e-8380-38d590bf49d0","added_by":"auto","created_at":"2022-01-31 19:14:06","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12114,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/5bf80226441a6e2885b316a9.xlsx"},{"id":17820498,"identity":"4aac9efc-be5a-42fd-b35f-2aa03bc6ef61","added_by":"auto","created_at":"2022-01-31 19:14:06","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":11046,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/136af47ecd6a82c98d8b8451.xlsx"},{"id":17821019,"identity":"add468be-a445-417d-99c2-4d5575b953d5","added_by":"auto","created_at":"2022-01-31 19:17:06","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":11178,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/c2909f90c33d09c0067b0112.xlsx"},{"id":17820503,"identity":"e645e91f-0068-4d32-99fd-c9065c827eee","added_by":"auto","created_at":"2022-01-31 19:14:06","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":14857,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 1: Supplementary Table 1. \u003c/strong\u003e\u003c/p\u003e\u003cp\u003eDetailed sputum culture changes of all patients.\u0026nbsp;\u003c/p\u003e","description":"","filename":"SupplementTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/cbef329b944c07c39208507a.xlsx"},{"id":17820505,"identity":"8d5cad00-cdab-43ad-9564-725e2fe93402","added_by":"auto","created_at":"2022-01-31 19:14:06","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":38331,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1253953/v1/75bb7e24777e132606492c85.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation","fulltext":[{"header":"Background","content":"\u003cp\u003ePulmonary \u003cem\u003enontuberculous mycobacteria\u003c/em\u003e (NTM) disease is increasing in incidence worldwide and has become an important concern [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In Japan, the incidence of pulmonary NTM disease has been gradually increasing and exceeded the incidence of \u003cem\u003emycobacterial tuberculosis\u003c/em\u003e for the first time in 2014 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The type of NTM differs by region. In Japan, \u003cem\u003eMycobacterium avium\u003c/em\u003e complex (MAC) accounts for about 90% of the total [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Pulmonary MAC disease is a chronic lower respiratory tract infection caused by MAC. Chronic lower respiratory tract infections are a burden because of the difficulty with identifying the causative microorganism; co-infections with multiple microorganisms have also been reported [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In a previous study we report that 12.2% of patients with pulmonary MAC disease had co-infections with \u003cem\u003eHaemophilus influenzae\u003c/em\u003e (\u003cem\u003eH. influenzae\u003c/em\u003e) and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (\u003cem\u003eP. aeruginosa\u003c/em\u003e) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. According to Fujita et al., 45.1% of patients with pulmonary MAC disease had chronic co-infection with other pathogenic microorganisms, and chronic \u003cem\u003eP. aeruginosa\u003c/em\u003e co-infection increased after the initiation of treatment for pulmonary MAC disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, the impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary MAC disease has not been clarified.\u003c/p\u003e \u003cp\u003eThus, we investigated the impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary MAC disease.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003cdiv id=\"Sec3\" class=\"Section3\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis single-center retrospective cohort study included 48 patients with pulmonary MAC disease who had started treatment during the period from November 2014 through February 2019 at Toho University Omori Medical Center. All patients were required to fulfill the American Thoracic Society (ATS) criteria for the diagnosis of NTM [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and they continued MAC treatment from baseline for at least 12 months (46 patients continued for at least 24 months; 2 patients continued for at least 12 months). Sputum culture for mycobacteria, other bacteria, and fungi was performed at least 3 times during the 6-24 months after treatment initiation for pulmonary MAC disease. Patients who had difficulty with sputum collection were excluded.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDefinition of co-infection and treatment failure in pulmonary MAC disease\u003c/h2\u003e \u003cp\u003eWe defined co-infection as the detection of pathogenic microorganisms other than MAC in at least two consecutive sputum cultures 6-24 months after initiation of treatment for pulmonary MAC disease. At baseline, co-infection was defined as detection of pathogenic microorganisms other than MAC in at least two separate sputum cultures or at least one bronchoalveolar lavage. Co-infection at baseline was designated \u0026lsquo;base co-infection\u0026rsquo;. Treatment success was defined as sputum culture conversion to MAC negative within 12 months of treatment. Treatment failure was designated in patients with persistent MAC detection in sputum culture after 12 months of treatment\u003c/p\u003e \u003cp\u003eWe compared the results of high-resolution CT (HRCT) of the chest, microbiological tests, and subjective symptoms between the co-infection and MAC alone groups. Univariate and multivariate logistic regression analysis was also performed to identify factors independently associated with co-infection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eThe following patient data were collected: age, sex, body mass index (BMI), smoking history, serum anti-glycopeptidolipid-core IgA titer, comorbidities, chest and paranasal sinuses CT, and sputum and bronchoscopy culture results. Most patients underwent Chronic Obstructive Pulmonary Disease (COPD) assessment testing (CAT) to confirm subjective symptoms at the time of treatment initiation and at 6, 12, 18, and 24 months thereafter [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eChest CT score\u003c/h2\u003e \u003cp\u003eChest HRCT score was reviewed as previously described with slight modification as follows [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. We divided the lungs into 6 zones at the levels of the carina and inferior pulmonary vein. Using HRCT, we categorized the 4 types of pulmonary lesions in MAC (cavities, bronchiectasis, nodules, and infiltration) into 5 stages, according to the occupation area in each section (0: no lesion, 1: 1\u0026ndash;24% occupied, 2: 25\u0026ndash;49% occupied, 3: 50\u0026ndash;74% occupied, and 4: 75\u0026ndash;100% occupied). In addition, changes in cavity wall thickness were reflected by assigning +2 points for cavity wall thickening by more than 1 mm and -2 points for thinning (Figure, 1). Two respiratory physicians with over 13 years of experience reviewed Chest CT scores independently. Improved Chest CT score was defined as a decrease. We investigated the relationship of co-infection, treatment failure, and serial changes in chest CT findings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData are presented as the number of patients and percentages. Age, BMI, chest CT score, and CAT score are expressed as mean \u0026plusmn; SD. Associations of categorical and continuous variables between patients in the co-infection and MAC alone groups were tested with the chi-squared or Fisher\u0026rsquo;s exact test, and the Mann\u0026ndash;Whitney U test, respectively. Factors independently associated with co-infection were evaluated with univariate and multivariate logistic regression. Multivariate logistic regression was performed using a stepwise method. A P value of \u0026lt;0.05 was considered to indicate statistical significance. Statistical analyses were performed with SPSS software version 22 (IBM Corp., Armonk, NY).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eClinical characteristics\u003c/h2\u003e \u003cp\u003eIn total, 48 patients were included in this study; the co-infection group comprised 12 patients (mean age 72.1\u0026plusmn;6.9 years; 2 men, 10 women) and the MAC alone group included 36 patients (mean age 68.3\u0026plusmn;11.8 years; 7 men, 29 women). The characteristics of all 48 patients are shown in Table 1. At baseline, there were significant differences between the co-infection and MAC alone groups in scores for chest CT (12.6\u0026plusmn;3.3 vs. 9.1\u0026plusmn;4.1; p=0.007), bronchiectasis lesions score on chest CT (3.7\u0026plusmn;1.9 vs. 2.3\u0026plusmn;1.6; p=0.035), subjective cough symptoms (2.5\u0026plusmn;1.4 vs. 1.3\u0026plusmn;1.2; \u003cem\u003eP\u003c/em\u003e=0.015), and sputum (2.6\u0026plusmn;1.8 vs. 1.1\u0026plusmn;1.0; p=0.021). The proportion of patients with cavitary lesions (25% vs. 50%; p=0.185), cavitary lesions score on chest CT (0.4\u0026plusmn;0.9 vs. 1.0\u0026plusmn;1.5; p=0.117) and the rate of base co-infection did not differ significantly between the two groups (50% vs. 38.9%; p=0.52). Both groups showed the same resistance rate to CAM of 8.3% at 24 months after treatment initiation. Overall treatment success rate for MAC was 81.2% (39/48) with no significant differences between the co-infection and MAC alone groups (75% vs 83.3%; p=0.671).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eMicrobiological test results in the co-infection group\u003c/h2\u003e \u003cp\u003eSerial changes in microbiological test results in the co-infection group are shown in Table 2. At baseline, 6 of the 12 patients had base co-infection, namely 2 patients with \u003cem\u003eH. influenzae\u003c/em\u003e, 2 with \u003cem\u003eMethicillin-sensitive Staphylococcus aureus\u003c/em\u003e (MSSA), 1 with \u003cem\u003eP. aeruginosa\u003c/em\u003e, and 1 with \u003cem\u003eEscherichia coli\u003c/em\u003e (\u003cem\u003eE. coli\u003c/em\u003e). In 3 of the 6 patients the same organism was detected in base co-infection and at 12-24 months after treatment for MAC (1 each with \u003cem\u003eE. coli\u003c/em\u003e, \u003cem\u003eP. aeruginosa\u003c/em\u003e, and MSSA). \u003cem\u003eP. aeruginosa\u003c/em\u003e was the most common pathogenic microorganism in co-infections after the treatment for MAC, accounting for same in 7 of 12 (58.3%) patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSerial changes in Chest CT score\u003c/h2\u003e \u003cp\u003eTable 3 shows the clinical course in patients with pulmonary MAC disease. In total, CT score was improved in 72.9% and 63% of patients at 12 months and 24 months after treatment initiation. At 24 months after treatment, the proportion of patients with improved chest CT score was significantly lower in the co-infection group than the MAC alone group (16.7% vs. 79.4%; p\u0026lt;0.001).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows serial changes in chest CT score in the 2 groups. In the co-infection group, mean CT score at 12 and 24 months did not differ compared with the baseline CT score (12.2\u0026plusmn;5.3 and 15.8\u0026plusmn;6.0 vs. 12.6\u0026plusmn;3.3; p=0.757 and p=0.55). However, in the MAC alone group, mean CT score at 12 and 24 months was significantly improved compared with the baseline score (5.6\u0026plusmn;5.0 and 5.9\u0026plusmn;6.5 vs. 9.1\u0026plusmn;4.1; p\u0026lt;0.001 and p\u0026lt;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows serial changes in chest CT score in the MAC alone and treatment success group (n=30); co-infection and treatment success group (n=9); and the treatment failure group (n=9). In the co-infection and treatment success group, mean values at 12 and 24 months did not differ significantly from baseline CT score (11.9\u0026plusmn;5.9 and 15.8\u0026plusmn;6.9 vs. 12.8\u0026plusmn;3.7; p=0.604 and p=0.196). In the treatment failure group, mean values at 12 and 24 months did not differ significantly compared with the baseline CT score (11.4\u0026plusmn;3.0 and 13.3\u0026plusmn;4.6 vs. 11.2\u0026plusmn;2.6; p=0.803 and p=0.220). However, the values at 12 and 24 months were significantly better than the baseline CT score (4.6\u0026plusmn;4.8 and 4.6\u0026plusmn;6.0 vs. 8.7\u0026plusmn;4.2; p\u0026lt;0.001 and p\u0026lt;0.001) in the MAC alone and treatment success group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSerial changes in CAT score\u003c/h2\u003e \u003cp\u003eAt 12 and 24 months after initiation of MAC treatment, the proportion of patients with improved CAT scores did not differ significantly between the co-infection and MAC alone groups (70% vs. 54.8% and 40% vs. 48.3%; p=0.48 and p=0.726). The proportion of patients with improvement in relation to sputum score also did not differ significantly between the co-infection and MAC alone groups (50% vs. 35.5% and 20% vs. 24.1%; p=0.472 and p=1) (Table 3).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows serial changes in CAT score. The co-infection group showed no significant difference in mean CAT score at 12 and 24 months compared with baseline (11.6\u0026plusmn;9.8 and 13.8\u0026plusmn;10.9 vs. 11.1\u0026plusmn;7.2; p=0.576 and p=0.131); in the MAC alone group the CAT score at 12 and 24 months did not differ significantly from the baseline score (7.5\u0026plusmn;7.0 and 7.2\u0026plusmn;6.8 vs. 7.9\u0026plusmn;6.6; p=0.724 and p=0.845).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSputum score in CAT score was independently associated with co-infection (Table 4). Figure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows serial changes in sputum score. In the co-infection group, the mean value at 12 and 24 months did not differ significantly compared with the baseline score (2.3\u0026plusmn;1.7 and 2.7\u0026plusmn;1.8 vs. 2.6\u0026plusmn;1.8; p=0.565 and p=1.0). Also, in the MAC alone group, the mean sputum score at 12 and 24 months, the score did not differ significantly from baseline (0.97\u0026plusmn;1.11, and 0.97\u0026plusmn;0.98 vs. 1.1\u0026plusmn;1.0; p=0.536 and p=0.345).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRisk factors for co-infection\u003c/h2\u003e \u003cp\u003eTable 4 shows the results of univariate and multivariate logistic regression analysis of independent associations with co-infection. Higher chest CT score (Odds Ratio [OR], 1.27; 95% confidence interval [CI], 1.04-1.55; p=0.017), higher sputum score (OR, 2.35; 95% CI, 1.28-4.31; p=0.006), and higher cough score (ORs, 2.2; 95% CI, 1.17-4.14; p=0.014) were independently associated with co-infection in univariate analysis. Higher sputum score (ORs, 2.02; 95% CI, 1.08-3.79; p=0.028) was independently associated with co-infection in multivariate analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe demonstrated the impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary MAC disease. Although co-infection with other pathogenic microorganisms does not affect therapeutic efficacy in MAC, these organisms may interfere with improvement of chest CT findings. Few studies have investigated the impact of co-infection with other pathogenic microorganisms in pulmonary MAC disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Fujita et al. reported chronic co-infection with other pathogenic microorganisms including MSSA, \u003cem\u003eP. aeruginosa, and Aspergillus\u003c/em\u003e spp. in 45.1% of patients with pulmonary MAC disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. According to Kamata et al., chronic co-infection with \u003cem\u003eP. aeruginosa\u003c/em\u003e was seen in 7.8% of patients with pulmonary MAC disease [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. It is important to note that these were cross-sectional studies, and so did not clarify the impact of co-infection on the efficacy of MAC treatment. To our knowledge, this is the first report to investigate the impact of co-infection with other pathogenic microorganisms on clinical course after initiation of treatment for pulmonary MAC disease.\u003c/p\u003e \u003cp\u003eThis study showed that sputum culture conversion or treatment success rate was 81%, improvement in chest CT score was 63%, and the rate of CAM resistance was 8.3%. These results were consistent with those from previous studies. Earlier reports of macrolide-inclusive daily regimens have shown that the rate of sputum culture conversion was 42-92% [\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], chest imaging improvement was 68-82% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and macrolide resistance was 9-15% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In addition, the rates of MAC culture conversion and CAM resistance did not differ significantly between the co-infection and MAC alone groups. These results suggest that co-infection after the initiation of treatment for MAC did not affect the treatment efficacy.\u003c/p\u003e \u003cp\u003eNevertheless, the proportion of patients with improved chest CT scores was significantly lower in the co-infection group than in the MAC alone group at 24 months after initiation of treatment. Furthermore, serial changes in chest CT score in the co-infection group showed no significant improvement, even after excluding patients with MAC treatment failure. Thus, co-infection with other pathogenic microorganisms does not affect the outcome of MAC treatment but worsens chest CT findings. The worse chest CT findings may have been as a result of other pathogenic microorganisms that gained dominance due to weakening of the competing MAC.\u003c/p\u003e \u003cp\u003eAmong 6 of the 12 patients who had base co-infection in the co-infection group, only 3 had the same bacterial species detected until post MAC treatment. Clarithromycin-susceptible bacteria such as \u003cem\u003eMSSA\u003c/em\u003e and \u003cem\u003eH. influenzae\u003c/em\u003e decreased after MAC treatment while clarithromycin-resistant bacteria such as \u003cem\u003eP. aeruginosa\u003c/em\u003e and \u003cem\u003eNocardia\u003c/em\u003e spp. increased after MAC treatment. We speculated that MAC treatment suppressed the proliferation of MAC and other clarithromycin (CAM)-susceptible bacteria, and this might foster a conversion of the bacteria to clarithromycin-resistant. This result is consistent with previous reports showing that \u003cem\u003eP. aeruginosa\u003c/em\u003e was less frequently isolated from positive MAC sputum cultures and more often isolated after MAC sputum conversion [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious studies showed that patients with NTM bronchiectasis, including those with cystic fibrosis, had a lower rate of chronic \u003cem\u003eP. aeruginosa\u003c/em\u003e infection compared with non-NTM infection [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. MAC and other pathogenic microorganisms, especially \u003cem\u003eP. aeruginosa\u003c/em\u003e, interact with each other and culture results may reflect the dominant pathogenic species at that time. Therefore, we speculate that the negative MAC culture in the co-infection group may not only be due to the effect of MAC treatment but also due to the suppression of MAC culture by other potentially infectious pathogenic microorganisms that became dominant.\u003c/p\u003e \u003cp\u003eIn this study, subjective symptoms were more severe in the co-infection group at baseline. Specifically, high sputum score at baseline was an independent risk factor for co-infection. According to Kamata et al., co-infection with \u003cem\u003eP. aeruginosa\u003c/em\u003e worsened subjective symptoms in patients with pulmonary MAC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Previous reports showed that \u003cem\u003eP. aeruginosa\u003c/em\u003e colonization was an independent predictor of hospital admission in bronchiectasis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. But in our study, the rate of baseline co-infection showed no significant difference between the co-infection and MAC alone groups. We surmised that the presence of trace amounts of other bacteria undetectable by conventional culture in the co-infection group at baseline was the cause of the severe subjective symptoms, and that the bacteria may have become apparently detectable with MAC treatment.\u003c/p\u003e \u003cp\u003eSeveral risk factors for developing co-infection in patients with MAC have been reported. This study showed that bronchiectasis score was significantly higher in the co-infection group than the MAC alone group. However, cavitary lesion score and the frequency of concomitant emphysema did not differ between the two groups. In addition, 7 out of 12 patients had \u003cem\u003eP. aeruginosa\u003c/em\u003e co-infection and none had \u003cem\u003eAspergillus\u003c/em\u003e co-infection. In the Fujita study, of the 124 patients with co-infection, 18 and 35 patients had aspergillus and \u003cem\u003eP. aeruginosa\u003c/em\u003e infection, respectively. Risk factors for co-infection were reported to be COPD and \u003cem\u003eM. intracellulare\u003c/em\u003e infection [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Patients with \u003cem\u003eM. intracellulare\u003c/em\u003e infection were more likely to have fibro-cavitary disease than those with \u003cem\u003eM. avium\u003c/em\u003e infection [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and cavitary lesions have been reported to be a risk factor for complications of chronic pulmonary aspergillus infection in pulmonary MAC [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In contrast, the Kamata study included 19 patients with MAC and \u003cem\u003eP. aeruginosa\u003c/em\u003e exclusively. The severity of bronchiectasis, but not cavitary lesions, was associated with \u003cem\u003eP. aeruginosa\u003c/em\u003e co-infection. The disparity in risk factors for co-infection in these studies may be due to the presence or absence of Aspergillus. A previous study showed that severity of bronchiectasis was significantly associated with the presence of chronic \u003cem\u003eP. aeruginosa\u003c/em\u003e infection in patients with non-cystic fibrosis bronchiectasis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. We speculate that patients with cavitary lesions are more likely to have co-infection with \u003cem\u003eAspergillus\u003c/em\u003e, whereas those with severe bronchiectasis were more likely to be infected with certain types of bacteria including \u003cem\u003eP. aeruginosa.\u003c/em\u003e\u003c/p\u003e \u003cp\u003eThese findings notwithstanding, this study had several limitations that should be mentioned. Firstly, it was a single-center study in a small number of patients. Thus, the findings may not be generalizable to a larger, more diverse population. Secondly, some patients were excluded from this study due to missing sputum examination and chest CT evaluations. These excluded patients might have had infections from a different type of pathogen. Thirdly, the potential presence of indigenous oral bacterial populations cannot be ruled out, and so this may not accurately reflect the status of the lower airway flora because not all patients underwent bronchoscopy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough co-infection with other pathogenic microorganisms does not affect the therapeutic efficacy in MAC, these organisms may interfere with improvement of chest CT findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eATS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Thoracic Society\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic Obstructive Pulmonary Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic Obstructive Pulmonary Disease assessment testing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclarithromycin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eE. coli\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eEscherichia coli\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eH. influenzae\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eHaemophilus influenzae\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh-resolution CT\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMSSA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eMethicillin-sensitive Staphylococcus aureus\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eMycobacterium avium complex\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNTM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003eNontuberculous mycobacteria\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOdds Ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cem\u003eP. aeruginosa\u003c/em\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the amended Declaration of Helsinki and the Ethics Committee of Toho University Omori Medical Center approved the protocol (Approval No.M21218). All methods were carried out in accordance with relevant guidelines and regulations. All patients provided written informed consents to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received no funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNU designed the study, analyzed, and drafted the manuscript, SS and KK designed the study and participated in editing the manuscript, SH confirmed the analyses, and revised the article for intellectual content, YS and TK conceptualized the study and revised the article for intellectual content, TM and NA conceptualized the study, supervised, CK, AY and NT participated in editing the manuscript and revised the article for intellectual content. All authors read and critically revised the first as well as the subsequent and final drafts of this manuscript. The author(s) read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrode SK, Daley CL, Marras TK. The epidemiologic relationship between tuberculosis and non-tuberculous mycobacterial disease: a systematic review. Int J Tuberc Lung Dis. 2014;18 (11): 1370\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNamkoong H, Kurashima A, Morimoto K, Hoshino Y, Hasegawa N, Ato M, et al. Epidemiology of Pulmonary Nontuberculous Mycobacterial Disease, Japan. Emerg Infect Dis. 2016; 22 (6): 1116\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCox MJ, Turek EM, Hennessy C, Mirza GK, James PL, Coleman M, et al. Longitudinal assessment of sputum microbiome by sequencing of the 16S rRNA gene in non-cystic fibrosis bronchiectasis patients. PLoS One. 2017;12(2): e0170622.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUrabe N, Sakamoto S, Sano G, Ito A, Homma S. Characteristics of patients with bronchoscopy-diagnosed pulmonary Mycobacterium avium complex infection. J Infect Chemother. 2018; 24 (10): 822\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujita K, Ito Y, Hirai T, Kubo T, Togashi K, Ichiyama S, et al. Prevalence and risk factors for chronic co-infection in pulmonary Mycobacterium avium complex disease. BMJ Open Respir Res. 2014;1(1): e000050.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGriffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175 (4): 367\u0026ndash;416.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJones PW, Tabberer M, Chen WH. Creating scenarios of the impact of COPD and their relationship to COPD Assessment Test (CAT\u0026trade;) scores. BMC Pulm Med. 2011; 11: 42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorimoto K, Yoshiyama T, Kurashima A, Sasaki Y, Hoshino Y, Yoshimori K, et al. Nutritional indicators are correlated with the radiological severity score in patients with Mycobacterium avium complex pulmonary disease: a cross-sectional study. Intern Med. 2014; 53 (5): 397\u0026ndash;401.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamata H, Asakura T, Suzuki S, Namkoong H, Yagi K, Funatsu Y, et al. Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease. BMC Pulm Med. 2017; 17(1): 198.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallace RJ, Jr., Brown BA, Griffith DE, Girard WM, Murphy DT. Clarithromycin regimens for pulmonary Mycobacterium avium complex. The first 50 patients. Am J Respir Crit Care Med. 1996; 153(6 Pt 1): 1766\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGriffith DE, Brown BA, Cegielski P, Murphy DT, Wallace RJ, Jr. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis. 2000; 30 (2): 288\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeong BH, Jeon K, Park HY, Kim SY, Lee KS, Huh HJ, et al. Intermittent antibiotic therapy for nodular bronchiectatic Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2015; 191 (1): 96\u0026ndash;103.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiwa S, Shirai M, Toyoshima M, Shirai T, Yasuda K, Yokomura K, et al. Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. A preliminary study. Ann Am Thorac Soc. 2014; 11 (1): 23\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto Y, Miwa S, Shirai M, Kanai M, Fujita K, Ohba H, et al. Macrolide resistant Mycobacterium avium complex pulmonary disease following clarithromycin and ethambutol combination therapy. Respir Med. 2020; 169: 106025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBinder AM, Adjemian J, Olivier KN, Prevots DR. Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons with cystic fibrosis. Am J Respir Crit Care Med. 2013; 188 (7): 807\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAksamit TR, O'Donnell AE, Barker A, Olivier KN, Winthrop KL, Daniels MLA, et al. Adult Patients with Bronchiectasis: A First Look at the US Bronchiectasis Research Registry. Chest. 2017; 151 (5): 982\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S, Davidson J, et al. The bronchiectasis severity index. An international derivation and validation study. Am J Respir Crit Care Med. 2014; 189(5): 576\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoh WJ, Jeong BH, Jeon K, Lee NY, Lee KS, Woo SY, et al. Clinical significance of the differentiation between Mycobacterium avium and Mycobacterium intracellulare in M. avium complex lung disease. Chest. 2012; 142(6): 1482\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSong JW, Koh WJ, Lee KS, Lee JY, Chung MJ, Kim TS, et al. High-resolution CT findings of Mycobacterium avium-intracellulare complex pulmonary disease: correlation with pulmonary function test results. AJR Am J Roentgenol. 2008; 191 (4): W160.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDimakou K, Triantafillidou C, Toumbis M, Tsikritsaki K, Malagari K, Bakakos P. Non CF-bronchiectasis: Aetiologic approach, clinical, radiological, microbiological and functional profile in 277 patients. Respir Med. 2016; 116: 1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Nontuberculous mycobacterium, Mycobacterium avium complex, Co-infection, Pseudomonas aeruginosa","lastPublishedDoi":"10.21203/rs.3.rs-1253953/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1253953/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: The impact of co-infection with other pathogenic microorganisms after initiation of treatment for pulmonary \u003cem\u003eMycobacterium avium\u003c/em\u003e complex (MAC) disease has not been clearly demonstrated. This study sought to clarify clinical outcomes of co-infection with MAC \u003c/p\u003e\u003cp\u003eafter antimycobacterial therapy for MAC.\u003c/p\u003e\u003cp\u003eMethods: Co-infection status was designated as the detection of pathogenic microorganisms other than MAC in at least two consecutive sputum cultures 6-24 months after initiation of treatment. Chest computed tomography (CT) findings and culture results were compared between co-infection and MAC alone groups. \u003c/p\u003e\u003cp\u003eResults: The co-infection and MAC alone groups comprised 12 and 36 patients, respectively. The proportion of patients with sputum culture positive for MAC after 24 months of therapy did not differ significantly between the two groups [25% (3/12) vs. 16.7% (6/36); \u003cem\u003ep\u003c/em\u003e=0.671]. The proportion of patients with improved chest CT score after 24 months of starting treatment compared to baseline was significantly lower for the co-infection group than for the MAC alone group [16.7% (2/12) vs. 79.4% (27/34); \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001]. In the co-infection group, mean CT score values at 12 and 24 months did not differ from baseline. However, the MAC alone group showed significant improvement at 12 and 24 months compared with baseline.\u003c/p\u003e\u003cp\u003eConclusions: Co-infection with other pathogenic microorganisms has no effect on the therapeutic efficacy of MAC but interferes with improvement in chest CT findings.\u003c/p\u003e","manuscriptTitle":"Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-01-31 19:14:04","doi":"10.21203/rs.3.rs-1253953/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-03-07T15:42:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-03-01T19:49:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-02-11T10:42:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"d0988325-36ca-43c5-ac99-15c7e6ad0e46","date":"2022-02-02T19:14:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2711950e-f842-4001-b225-abaaa5f1206a","date":"2022-02-02T13:06:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-02-02T12:59:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-02-02T07:24:17+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-01-27T15:22:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-01-27T15:13:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2022-01-12T13:35:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5dcb2369-8864-4004-97be-64a04f2e52f4","owner":[],"postedDate":"January 31st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-04-14T07:44:24+00:00","versionOfRecord":[],"versionCreatedAt":"2022-01-31 19:14:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1253953","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1253953","identity":"rs-1253953","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}