Association between Serum Anti-glycopeptidolipid-core IgA Antibody Titers and Clinical Characteristics of Mycobacterium Avium Complex Pulmonary Disease

Association between Serum Anti-glycopeptidolipid-core IgA Antibody Titers and Clinical Characteristics of Mycobacterium Avium Complex Pulmonary Disease | 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 Association between Serum Anti-glycopeptidolipid-core IgA Antibody Titers and Clinical Characteristics of Mycobacterium Avium Complex Pulmonary Disease Norio Kodaka, Chihiro Nakano, Takeshi Oshio, Kayo Watanabe, Kumiko Niitsuma, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-283326/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Aug, 2021 Read the published version in International Journal of Infectious Diseases → Version 1 posted You are reading this latest preprint version Abstract Mycobacterium avium complex pulmonary disease (MAC-PD) can be serologically diagnosed according to the presence of anti-glycopeptidolipid (GPL)-core IgA antibodies. However, few studies have examined the association between serum anti-GPL-core IgA antibody titers and the clinical characteristics of patients with MAC-PD. From April 2014 to June 2019, we determined the level of anti-GPL-core IgA antibodies in 489 MAC-PD patients at our institute. Of them, 89 patients fulfilled the criteria of the American Thoracic Society and the Infectious Diseases Society of America statement on the diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. These patients were divided into antibody-positive ( n = 59) or -negative ( n = 30) groups according to their serum anti-GPL-core IgA antibody results. Additionally, the positive antibody group was further divided into a strong positive group ( n = 27) and a weak positive group ( n = 32), and their clinical characteristics were retrospectively compared. Disease progression requiring treatment during the 12 months following diagnosis and extensive radiological findings were significantly abundant in the strong positive group compared with the weak positive group. Our findings revealed that serum anti-GPL-core IgA antibody titers are useful not only for diagnosing MAC-PD but also for predicting the risk of exacerbation. Health Economics & Outcomes Research General Microbiology Pulmonology Mycobacterium avium complex pulmonary disease (MAC-PD) anti-glycopeptidolipid (GPL) antibodies nontuberculous mycobacterial diseases Figures Figure 1 Introduction The number of patients with Mycobacterium avium complex pulmonary disease (MAC-PD) is increasing globally [ 1 – 6 ]. In particular, there is an increasing number of cases of women with MAC-PD with central granular shadows of the middle lobe of the lung. Therefore, knowledge pertaining to its diagnosis, treatment, and management is essential for respiratory physicians. MAC-PD is the most frequently occurring nontuberculous mycobacteria (NTM) pulmonary disease [ 7 ], and it is often encountered in clinical practice. MAC-PD may have poor airway symptoms, and because the causative bacteria are not always detected in sputum samples, bronchoscopy may be essential for diagnosis. Furthermore, it may be difficult to detect bacteria by bronchoscopy, and some patients are hesitant to undergo bronchoscopy. Additionally, because MAC exists universally in soil, natural water, and tap water, it is difficult to distinguish between colonization and contamination [ 8 ]. MAC-PD is unlikely in patients who have a single positive sputum culture during the initial evaluation [ 9 – 11 ], but the rate of MAC-PD can be as high as 98% in those with ≥ 2 positive sputum cultures [ 9 ]. Therefore, a diagnosis of MAC-PD should be made if MAC is identified at least twice in sputum samples or once in bronchial washings. However, although relatively advanced MAC-PD easily meets the diagnostic criteria, sputum collection is not possible with asymptomatic patients, and a long period is required for a definitive diagnosis. In such cases, the level of serum anti-glycopeptidolipid (GPL)-core IgA is used for diagnosis and has been utilized in clinical practice in Japan since August 2011. The GPL core is part of the GPL antigen, which is found on the surface of the cell walls of MAC but not of Mycobacterium tuberculosis or Mycobacterium kansasii . It can be detected in the serum of patients with MAC infection using commercially available serodiagnostic kits that measure the antibody level. Several studies have reported a sensitivity of 58.6–85% and a specificity of 96.9–100% [ 12 – 17 ]. The presence of anti-GPL-core IgA antibody is useful as a tool for the auxiliary diagnosis of MAC-PD, but since it is only used for auxiliary diagnosis, there are few reports comparing the differences in antibody titers. Thus, we compared the clinical course of cases with antibody titers of ≥ 5.0 U/mL (strong positive), 0.7–5.0 U/mL (weak positive), and < 0.7 U/mL (negative). Results Table 1 shows the clinical characteristics of the 89 MAC-PD patients in our cohort, including the microbiological and radiological findings. Of them, two-thirds were positive for anti-GPL-core IgA antibodies. None of the patients were known to be seropositive for human immunodeficiency virus. The male sex, infection with M . intracellulare , a history of smoking, the presence of a cavitary lesion, a MAC-positive sputum smear, and the administration of medications for MAC during the year following diagnosis were reported in approximately one-fifth of patients, respectively. The median body mass index (BMI) was toward the lower range of normal, and the median number of abnormal lung zones was four. More than three-quarters of the patients had comorbidities (Table 1 ). Table 1 Baseline characteristics of MAC-PD patients with anti-GPL-core IgA antibody measured ( N = 89) Characteristic Baseline value Age (years) 75 (66–80) Female (%) 71 (79.8) BMI (kg/m 2 ) 19.1 (17.9–21.5) TP (g/dL) 7.4 (7.0–7.9) ALB (g/dL) 3.8 (3.15–4.05) CRP (mg/dL) 0.14 (0.04–1.21) IgG(mg/dL) 1380 (1,227–1,555) IgE(IU/mL) 70.8 (17.5–189.8) Smoking history 19 (21.3%) Previous tuberculosis 7 (7.9%) Comorbidity 69 (77.5%) Bloody sputum 13 (14.6%) Positive MAC smear 18 (20.2%) Mycobacterium intracellulare 17 (19.1%) Cavitary lesion 17 (19.1%) Zones with radiological findings 4 (3–4) Anti-GPL-core IgA antibody(strong/weak/negative) 27/32/30 Received treatment for MAC within 1 year of diagnosis 17 (19.1%) Data are expressed as medians (interquartile range) or numbers (%). ALB, serum albumin; BMI, body mass index; CRP, serum C-reactive protein; GPL, glycopeptidolipid; MAC, Mycobacterium avium complex; MAC-PD, Mycobacterium avium complex pulmonary disease; TP, serum total protein Regarding disease progression requiring treatment, extensive radiological findings were significantly abundant in the strong positive group compared with the weak positive group. Positive acid-fast bacilli (AFB) smears were significantly abundant in the strong positive group compared with the antibody-negative group. Those with weak positive antibody titers did not significantly differ from those in the antibody-negative group (Table 2 ). Table 2 Comparison of patient characteristics by anti-GPL-core IgA antibody titers ( N = 89) Characteristics Strong positive ( n = 27) Weak positive ( n = 32) Negative ( n = 30) P -value † Age, years 73 (62.5–77.5) 77.5 (69.75–82.25) 74 (67.5–79.0) 0.20 Sex (female, %) 23 (85.2%) 26 (81.3%) 22 (73.3%) 0.53 BMI (kg/m 2 ) 18.7 (17.2–19.8) 20.5 (18.1–22.4) 19.4 (16.6–21.0) 0.13 TP (g/dL) 7.4 (6.9–7.9) 7.5 (7.2–7.9) 7.4 (6.9–7.8) 0.80 ALB (g/dL) 3.7 (3.4–4.0) 3.9 (3.6–4.2) 3.6 (3.0–4.0) 0.16 CRP (mg/dL) 0.09 (0.03–0.61) 0.09 (0.03–0.90) 0.29 (0.11–2.6) 0.12 IgG (mg/dL) 1336 (1233–1507) 1387 (1242–1437) 1457 (1144–1609) 0.66 IgE (IU/mL) 75.3 (19.9–194.9) 37.4 (17.3–84) 73. 5 (20.0–293) 0.52 Smoking history 6 (22.2%) 3 (9.4%) 10 (30.3%) 0.07 Previous tuberculosis 1 (3.7%) 3 (9.4%) 3 (10.0%) 0.63 Comorbidity 21 (77.8%) 27 (84.4%) 21 (70.0%) 0.40 Bloody sputum 6 (22.2%) 6 (18.8%) 1 (3.3%) 0.09 Positive MAC smear 11 (40.7%) ‡ 6 (18.8%) 1 (3.3%) 0.002 * Mycobacterium intracellulare 2 (7.4%) 9 (28.1%) 6 (20.0%) 0.13 Cavitary lesion 6 (22.2%) 7 (21.9%) 4 (13.3%) 0.62 Zones with radiological findings 4 (3–5) 3 (2–4) 3 (2–4) 0.03 * Anti-GPL-core IgA antibody titers 16 (9.5–32.1) 2.1 (1.28–3.1) ‡ ≤ 0.7 < 0.001 * Received treatment for MAC within 1 year of diagnosis 10 (37.0%) 4 (12.5%) 3 (10.0%) 0.02 * Data are expressed as medians (interquartile range) or numbers (%). ALB, serum albumin; BMI, body mass index; CRP, serum C-reactive protein; GPL, glycopeptidolipid; MAC, Mycobacterium avium complex; TP, serum total protein † P -values are for all comparisons. * P < 0.05. ¶ P < 0.05 for anti-GPL-core IgA antibody weak titers vs. anti-GPL-core IgA antibody-negative. ‡ P < 0.05 for anti-GPL-core IgA antibody strong titers vs. anti-GPL-core IgA antibody-negative. Discussion To our knowledge, this is the first report to describe the differences in clinical characteristics using an anti-GPL-core antibody titer threshold value of 5.0 U/mL. We set the threshold of the antibody-positive group to 5.0 U/mL, according to a previous report where the mean antibody titer that was considered the most reliable for MAC-PD diagnosis via bronchoscopy was 5.0 U/mL [ 18 ]. Among the antibody-positive MAC-PD patients in our study, the median value of anti-MAC antibodies was 4.5 U/mL, but considering the application to actual clinical practice and an objective evaluation, we selected 5.0 U/mL as the threshold between the strong positive and weak positive groups in our study. In our study, 66.3% of the patients newly diagnosed with MAC-PD were positive for anti-GPL-core IgA antibodies, which is comparable to the sensitivity reported in a previous review [ 19 ]. Furthermore, the clinical characteristics of the patients with MAC-PD in our study were consistent with those in previous reports (i.e., the patients were predominantly slim women with nodular bronchiectatic disease) [ 1 – 6 , 8 , 20 , 21 ]. Kitada et al . reported that the antibody titers reflect the disease activity to some extent [ 13 , 22 , 23 ] and found a weak correlation between the antibody levels and the extent of the disease on chest computed tomography (CT) [ 12 , 24 ]. Similarly, we found that both disease progression requiring treatment and extensive radiological findings were significantly abundant in the strong positive antibody group in our study cohort. However, there was no significant difference in the presence or absence of cavitary lesions. Thus, a strong positive anti-GPL-core IgA antibody result was associated with higher radiological scores for infiltration, although no difference was observed in cavitary lesions between patients with strong positive and weak positive results. This correlates with another study showing that the anti-GPL-core IgA antibody titer was not associated with the extent of disease in the fibrocavitary disease phenotype [ 22 ]. We found that a positive AFB smear in the strong positive group was significantly more abundant than in the antibody-negative group and slightly more abundant than in the weak positive group ( P = 0.053). Extensive radiological findings [ 23 , 25 ] and an AFB-positive sputum smear [ 8 , 25 , 26 ] have been reported as exacerbating factors of MAC-PD, which increases the likelihood that a high antibody titer is an exacerbating factor. However, the anti-GPL-core IgA antibody titer in patients with severe MAC-PD was sometimes low in our study, probably due to differences in individual immunity and immune response ability, but no significant difference was found in serum total protein, serum albumin, IgG, and IgE levels in our study. A lower BMI was considered an exacerbating factor in MAC-PD patients in previous studies [ 27 , 28 ]. In our study, although many patients with MAC-PD were thin on average, there was no significant difference in BMI between the three groups. In our study, M. intracellulare was found in 18.6% of patients with MAC-PD, and the infection rate was similar to other reports in Japan [ 29 ]. Regarding MAC species differentiation, some studies reported that patients with M. intracellulare infection experienced more frequent exacerbations than those with M. avium infection [ 30 ], but others reported that patients with M. intracellulare infection experienced a lower rate of recurrence than those with M. avium infection [ 31 ].Thus, the difference in the prognosis between M. avium and M. intracellulare infections remains uncertain. In our study, there was no significant relationship between the prognosis and the MAC species in all three groups. Additionally, there was no significant difference in clinical features between the MAC-PD patients with weak positive anti-GPL-core IgA antibodies and those who were antibody-negative. Thus, MAC-PD patients with weak positive antibody titers were considered to be of no clinical importance in our study other than in the diagnostic method that was used. Limitations Our study has several limitations. First, because the sample size was small, the number of MAC-PD patients may have been underestimated since patients who were not diagnosed according to the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA) guidelines were excluded from the analyses. Therefore, in reality, factors with clinical significance may have proven insignificant in the analyses due to reduced statistical power. Second, because data collection was retrospective, sputum cultures, laboratory data, and CT scans were performed according to clinical practice rather than according to strict schedules. Finally, the timing of the treatment was dependent on the decision of the attending physician. Conclusions Our study shows that anti-GPL-core IgA antibody titers > 5.0 U/mL can be used to both diagnose MAC-PD and to predict the risk of exacerbation. However, patients with weak positive antibody titers are not considered clinically significant other than in diagnostic methods. Although the anti-GPL-core IgA antibody is a qualitative test for MAC-PD, it can be useful as a quantitative test for MAC-PD severity. Methods Study Population and Design We retrospectively reviewed all patients seen in our hospital in Tokyo, Japan, from April 2014 to June 2019. There were 481 patients who underwent serologic testing for anti-GPL-core IgA antibodies. Of them, 119 newly diagnosed NTM-PD patients fulfilled the criteria of the ATS and the IDSA statement on the diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases [8, 26]. Those with a past history of NTM disease, NTM other than MAC, and no abnormal shadow on chest CT were excluded, and the remaining 89 MAC-PD patients were enrolled in our study (Fig. 1). We divided the study patients into two groups according to anti-GPL-core IgA antibody results: an antibody-positive group ( n = 59) and an antibody-negative group ( n = 30, antibody titer <0.7 U/mL). Then, the antibody-positive group was further divided into a strong positive group ( n = 27, antibody titer ≥5 U/mL) and a weak positive group ( n = 32, 5.0< antibody titer ≥0.7 U/mL). The antibody titers and the clinical characteristics of the patients, including age, sex, laboratory data, a past history of tuberculosis, comorbidities, and radiological findings, were retrospectively compared. Additionally, we investigated whether treatment was required for up to 1 year after diagnosis to determine if anti-GPL-core IgA antibody titers were associated with disease progression. Ethics Approval and Consent to Participate All methods were carried out in accordance with the declaration of Helsinki. The need of informed consent was waived by the Ethics Committee of Toho University Ohashi Medical Center due to the retrospective nature of the study. All protocols were approved by the Ethics Committee of Toho University Ohashi Medical Center (approval no. H20004). Serological Determination of Anti-GPL-core IgA Antibody Titers The titer of serum anti-GPL-core IgA antibodies was determined using a Capilia MAC Ab ELISA serodiagnostic kit (TAUNS Laboratories, Inc., Shizuoka, Japan). The cutoff value was defined as 0.7 U/mL, according to the manufacturer’s instructions [22]. The test can be performed using a small amount of serum, and the turnaround time is approximately 4 hours [32]. Microbiological Examination AFB were cultured in mycobacteria growth indicator tubes using sputum samples or bronchial washings obtained by bronchoscopy. The sputum samples were obtained on two or more occasions after the initial presentation. The diagnosis of MAC-PD was made when MAC was identified in sputum at least twice or once in bronchial washings. MAC was confirmed when cultures were positive for AFB, and the cultured AFB were subsequently confirmed as MAC by polymerase chain reaction. Radiological Examination and Measurements High-resolution chest CT findings were classified as either showing or not showing a cavitary lesion. Additionally, chest CT findings at the time of initial diagnosis were scored, as previously described [33]. Briefly, the lung fields were divided into six lobes based on anatomical structures: right upper, right middle, right lower, left upper (S1+2 and S3), left lingular (S4 and S5), and left lower lobes. We assessed whether, at the time of diagnosis, each lung lobe had a shadow, such as cavities, bronchiectasis, small nodules, consolidations, or atelectasis. Statistical Analysis The patients’ characteristics are presented as medians (interquartile range). Numerical data are expressed as numbers (%). Intergroup differences (anti-GPL-core IgA antibody strong positive group vs. weak positive group vs. negative group) were compared using the Kruskal–Wallis test for numerical variables and the chi-square test or Fisher exact test for categorical variables where appropriate. All analyses were performed using SPSS Statistical software v22.0 (IBM Japan, Tokyo, Japan). P -values < 0.05 were considered significant. Declarations Author contributions N.K. collected the data, analyzed the data, created the tables, designed the study, and wrote the manuscript. C.N., T.O., K.W., K.N., C.I., N.S., H.Mo., and H.Ma. collected the data. H.Ma. critically revised the manuscript. All authors read and approved the final manuscript. Additional information Data availability statement The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to ethical restrictions. Competing interests The authors declare no competing interests. References Prevots, D. R. & Marras, T. K. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. Clin. Chest Med . 36 , 13-34 (2015). Tan, Y. et al . Epidemiology of pulmonary disease due to nontuberculous mycobacteria in Southern China, 2013–2016. BMC Pulm. Med . 18 , 168 (2018). Furuuchi, K. et al . Interrelational changes in the epidemiology and clinical features of nontuberculous mycobacterial pulmonary disease and tuberculosis in a referral hospital in Japan. Respir. Med . 152 , 74-80 (2019). Kendall, B. A. & Winthrop, K. L. Update on the epidemiology of pulmonary nontuberculous mycobacterial infections. Semin. Respir. Crit. Care Med . 34 , 87-94 (2013). Hoefsloot, W. et al . The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. Eur. Respir. J. 42 , 1604-1613 (2013). Simons, S. et al . Nontuberculous mycobacteria in respiratory tract infections, eastern Asia. Infect. Dis . 17 , 343-349 (2011). Hoefsloot, W. et al . The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. Eur. Respir. J. 42 , 1604-1613 (2013). Daley, C. L. et al . Treatment of nontuberculous mycobacterial pulmonary disease: an Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline: Executive Summary. Infect. Dis. 71 , e31-e36 (2020). Tsukamura, M. Diagnosis of disease caused by Mycobacterium avium Chest . 99 , 667-669 (1991). Koh, W. J. et al . Clinical significance of a single isolation of pathogenic nontuberculous mycobacteria from sputum specimens. Diagn. Microbiol. Infect. Dis. 75 , 225-226 (2013). Lee, M. R. et al . Factors associated with subsequent nontuberculous mycobacterial lung disease in patients with a single sputum isolate on initial examination. Clin. Microbiol. Infect. 21 ,e1-7 (2015). . Kitada, S. et al . Validation of a commercial serodiagnostic kit for diagnosing pulmonary Mycobacterium avium complex disease. Int. J. Tuberc. Lung Dis. 19 , 97-103 (2015). Numata, T. et al . Clinical efficacy of anti-glycopeptidolipid-core IgA test for diagnosing Mycobacterium avium complex infection in lung. Respirology . 20 , 1277-1281 (2015). Shu, C.-C. et al . Sero-diagnosis of Mycobacterium avium complex lung disease using serum immunoglobulin A antibody against glycopeptidolipid antigen in Taiwan. PLoS 8 , e80473 (2013). Kobashi, Y., Mouri, K., Obase, Y., Kato, S. & Oka, M. Serological assay by use of glycopeptidolipid core antigen for Mycobacterium avium Scand. J. Infect. Dis . 45 , 241-249 (2013). Kitada, S. et al . Serodiagnosis of Mycobacterium avium complex pulmonary disease in the USA. Eur. Respir. J . 42 , 454-460 (2013). Jeong, B. H. et al . Serodiagnosis of Mycobacterium avium complex and Mycobacterium abscessus complex pulmonary disease by use of IgA antibodies to glycopeptidolipid core antigen. Clin. Microbiol . 51 , 2747-2749 (2013). S. et al. Serodiagnosis of pulmonary disease due to Mycobacterium avium complex proven by bronchial wash culture. Chest . 138 , 236-237 (2010). Shibata, Y. et al . Diagnostic test accuracy of anti-glycopeptidolipid-core IgA antibodies for Mycobacterium avium complex pulmonary disease: systematic review and meta-analysis. Sci. Rep . 6 , 29325 (2016). Izumi K. et al . Epidemiology of adults and children treated for nontuberculous mycobacterial pulmonary disease in Japan. Ann. Am. Thorac. Soc . 16 , 341-347 (2018). Song, J. H., Kim, B. S., Kwak, N., Han, K., & Yim, J.-J. Impact of body mass index on development of nontuberculous mycobacterial pulmonary disease. Eur. Respir. J . 57 , 2000454 (2021). Kitada, S. et al . Serodiagnosis of Mycobacterium avium -complex pulmonary disease using an enzyme immunoassay kit. J. Respir. Crit. Care Med . 177 , 793-797 (2008). Kitada, S. et al . Use of glycopeptidolipid core antigen for serodiagnosis of Mycobacterium avium complex pulmonary disease in immunocompetent patients. Clin. Diagn. Lab. Immunol . 12 , 44-51 (2005). Kitada, S. et al . Serological test and chest computed tomography findings in patients with Mycobacterium avium complex lung disease. Eur. Respir. J. 29 , 1217-1223 (2007). Hwang, J. A., Kim, S., Jo K.-W. & Shim, T. S. Natural history of Mycobacterium avium complex lung disease in untreated patients with stable course. Eur . Respir . J . 49 , 1600537 (2017). Griffith, D. E. et al . An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. J. Respir. Crit. Care Med . 175 , 367-416 (2007). Kim, S. J. et al . Risk factors for deterioration of nodular bronchiectatic Mycobacterium avium complex lung disease. J. Tuberc. Lung Dis . 18 , 730-736 (2014). Kitada, S. et al . Long-term radiographic outcome of nodular bronchiectatic Mycobacterium avium complex pulmonary disease. Int . J . Tuberc . Lung Dis . 16 , 660-664 (2012). Morimoto, K. et al . A laboratory-based analysis of nontuberculous mycobacterial lung disease in Japan from 2012 to 2013. Ann. Am. Thorac. Soc . 14 , 49-56 (2017). Koh, W. J. et al . Clinical significance of the differentiation between Mycobacterium avium and Mycobacterium intracellulare in M avium complex lung disease. 142 , 1482-1488 (2012). Boyle, D. P., Zembower, T. R., Reddy, S. & Qi, C. Comparison of clinical features, virulence, and relapse among Mycobacterium avium complex species. J. Respir. Crit. Care Med. 191 , 1310-1317 (2015). Kitada S. Application of a commercial serodiagnostic kit that measures the serum anti-glycopeptidolipid core IgA antibody in Mycobacterium avium complex pulmonary disease. Respir Investig. 57 :410-414(2019). Kodaka, N. et al . Predictors of radiological aggravations of pulmonary MAC disease. PLoS One . 15 , e0237071 (2020). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 Aug, 2021 Read the published version in International Journal of Infectious Diseases → Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-283326","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":14896336,"identity":"6fad6eae-feba-4927-9d44-c236fdab8d3b","order_by":0,"name":"Norio Kodaka","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Norio","middleName":"","lastName":"Kodaka","suffix":""},{"id":14896337,"identity":"d9bcb246-c059-4291-9216-d2c5f9bc03ac","order_by":1,"name":"Chihiro Nakano","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chihiro","middleName":"","lastName":"Nakano","suffix":""},{"id":14896338,"identity":"4fec1c8d-8ce9-49cd-898d-62cfb8d08c88","order_by":2,"name":"Takeshi Oshio","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Oshio","suffix":""},{"id":14896339,"identity":"63c75de9-21da-4252-8d91-a1ef83ca75c5","order_by":3,"name":"Kayo Watanabe","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kayo","middleName":"","lastName":"Watanabe","suffix":""},{"id":14896340,"identity":"119eb0af-0910-49c3-8bb2-a4933d850bc5","order_by":4,"name":"Kumiko Niitsuma","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kumiko","middleName":"","lastName":"Niitsuma","suffix":""},{"id":14896341,"identity":"5dbd67e3-b070-49d3-91ea-6e67d63fa1bb","order_by":5,"name":"Chisato Imaizumi","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chisato","middleName":"","lastName":"Imaizumi","suffix":""},{"id":14896342,"identity":"63282113-edc1-4689-9aa1-3af66f9e7000","order_by":6,"name":"Nagashige Shimada","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nagashige","middleName":"","lastName":"Shimada","suffix":""},{"id":14896343,"identity":"7e6ef0a3-b9f2-4f72-b49b-fd811802b27a","order_by":7,"name":"Hirotsugu Morita","email":"","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hirotsugu","middleName":"","lastName":"Morita","suffix":""},{"id":14896344,"identity":"eccb3e81-266a-4991-886d-8fbb3b1b8469","order_by":8,"name":"Hiroto Matsuse","email":"data:image/png;base64,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","orcid":"","institution":"Toho University Ohashi Medical Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hiroto","middleName":"","lastName":"Matsuse","suffix":""}],"badges":[],"createdAt":"2021-02-27 11:29:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-283326/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-283326/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1016/j.ijid.2021.06.042","type":"published","date":"2021-08-01T21:01:45+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":6908320,"identity":"a8aed8e0-f603-484e-8b5e-7d8c272fe958","added_by":"auto","created_at":"2021-03-12 23:53:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37539,"visible":true,"origin":"","legend":"Flow chart of patients diagnosed with MAC pulmonary disease between April 2014 and June 2019 at our institution.\nMAC-PD, Mycobacterium avium complex pulmonary disease; CT, computed tomography; NTM, nontuberculous mycobacteria; MAC, Mycobacterium avium complex; GPL, glycopeptidolipid\n","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-283326/v1/521d00841c004b5f1e3d57c8.png"},{"id":19264160,"identity":"2fd0bb69-0f94-402c-824d-9599e020ad61","added_by":"auto","created_at":"2022-03-15 21:01:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":460588,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-283326/v1/023a9468-fe77-41c1-84b3-fbe45861c51e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eAssociation between Serum Anti-glycopeptidolipid-core IgA Antibody Titers and Clinical Characteristics of Mycobacterium Avium Complex Pulmonary Disease\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003eThe number of patients with \u003cem\u003eMycobacterium avium\u003c/em\u003e complex pulmonary disease (MAC-PD) is increasing globally [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In particular, there is an increasing number of cases of women with MAC-PD with central granular shadows of the middle lobe of the lung. Therefore, knowledge pertaining to its diagnosis, treatment, and management is essential for respiratory physicians. MAC-PD is the most frequently occurring nontuberculous mycobacteria (NTM) pulmonary disease [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and it is often encountered in clinical practice. MAC-PD may have poor airway symptoms, and because the causative bacteria are not always detected in sputum samples, bronchoscopy may be essential for diagnosis. Furthermore, it may be difficult to detect bacteria by bronchoscopy, and some patients are hesitant to undergo bronchoscopy. Additionally, because MAC exists universally in soil, natural water, and tap water, it is difficult to distinguish between colonization and contamination [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMAC-PD is unlikely in patients who have a single positive sputum culture during the initial evaluation [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], but the rate of MAC-PD can be as high as 98% in those with \u0026ge;\u0026thinsp;2 positive sputum cultures [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, a diagnosis of MAC-PD should be made if MAC is identified at least twice in sputum samples or once in bronchial washings. However, although relatively advanced MAC-PD easily meets the diagnostic criteria, sputum collection is not possible with asymptomatic patients, and a long period is required for a definitive diagnosis. In such cases, the level of serum anti-glycopeptidolipid (GPL)-core IgA is used for diagnosis and has been utilized in clinical practice in Japan since August 2011. The GPL core is part of the GPL antigen, which is found on the surface of the cell walls of MAC but not of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e or \u003cem\u003eMycobacterium kansasii\u003c/em\u003e. It can be detected in the serum of patients with MAC infection using commercially available serodiagnostic kits that measure the antibody level. Several studies have reported a sensitivity of 58.6\u0026ndash;85% and a specificity of 96.9\u0026ndash;100% [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The presence of anti-GPL-core IgA antibody is useful as a tool for the auxiliary diagnosis of MAC-PD, but since it is only used for auxiliary diagnosis, there are few reports comparing the differences in antibody titers. Thus, we compared the clinical course of cases with antibody titers of \u0026ge;\u0026thinsp;5.0 U/mL (strong positive), 0.7\u0026ndash;5.0 U/mL (weak positive), and \u0026lt;\u0026thinsp;0.7 U/mL (negative).\u003c/p\u003e "},{"header":"Results","content":" \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the clinical characteristics of the 89 MAC-PD patients in our cohort, including the microbiological and radiological findings. Of them, two-thirds were positive for anti-GPL-core IgA antibodies. None of the patients were known to be seropositive for human immunodeficiency virus. The male sex, infection with \u003cem\u003eM\u003c/em\u003e. \u003cem\u003eintracellulare\u003c/em\u003e, a history of smoking, the presence of a cavitary lesion, a MAC-positive sputum smear, and the administration of medications for MAC during the year following diagnosis were reported in approximately one-fifth of patients, respectively. The median body mass index (BMI) was toward the lower range of normal, and the median number of abnormal lung zones was four. More than three-quarters of the patients had comorbidities (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of MAC-PD patients with anti-GPL-core IgA antibody measured (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;89)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (66\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (79.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.1 (17.9\u0026ndash;21.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTP (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.4 (7.0\u0026ndash;7.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALB (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.8 (3.15\u0026ndash;4.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.14 (0.04\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG(mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1380 (1,227\u0026ndash;1,555)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgE(IU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.8 (17.5\u0026ndash;189.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (21.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious tuberculosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (7.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (77.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBloody sputum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (14.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive MAC smear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (20.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMycobacterium intracellulare\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (19.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCavitary lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (19.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZones with radiological findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (3\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-GPL-core IgA antibody(strong/weak/negative)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27/32/30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReceived treatment for MAC within 1 year of diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (19.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are expressed as medians (interquartile range) or numbers (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eALB, serum albumin; BMI, body mass index; CRP, serum C-reactive protein; GPL, glycopeptidolipid; MAC, \u003cem\u003eMycobacterium avium\u003c/em\u003e complex; MAC-PD, \u003cem\u003eMycobacterium avium\u003c/em\u003e complex pulmonary disease; TP, serum total protein\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding disease progression requiring treatment, extensive radiological findings were significantly abundant in the strong positive group compared with the weak positive group. Positive acid-fast bacilli (AFB) smears were significantly abundant in the strong positive group compared with the antibody-negative group. Those with weak positive antibody titers did not significantly differ from those in the antibody-negative group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of patient characteristics by anti-GPL-core IgA antibody titers (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;89)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStrong positive (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeak positive (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (62.5\u0026ndash;77.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77.5 (69.75\u0026ndash;82.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (67.5\u0026ndash;79.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (female, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (85.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (81.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (73.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.7 (17.2\u0026ndash;19.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.5 (18.1\u0026ndash;22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.4 (16.6\u0026ndash;21.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTP (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.4 (6.9\u0026ndash;7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5 (7.2\u0026ndash;7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.4 (6.9\u0026ndash;7.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALB (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7 (3.4\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9 (3.6\u0026ndash;4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.6 (3.0\u0026ndash;4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.09 (0.03\u0026ndash;0.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.09 (0.03\u0026ndash;0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29 (0.11\u0026ndash;2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1336 (1233\u0026ndash;1507)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1387 (1242\u0026ndash;1437)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1457 (1144\u0026ndash;1609)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgE (IU/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75.3 (19.9\u0026ndash;194.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.4 (17.3\u0026ndash;84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73. 5 (20.0\u0026ndash;293)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (22.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (30.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious tuberculosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (77.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (84.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (70.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBloody sputum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (22.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (18.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive MAC smear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (40.7%)\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (18.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMycobacterium intracellulare\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (28.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCavitary lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (22.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (21.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZones with radiological findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (3\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (2\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-GPL-core IgA antibody titers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (9.5\u0026ndash;32.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.1 (1.28\u0026ndash;3.1)\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReceived treatment for MAC within 1 year of diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (37.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are expressed as medians (interquartile range) or numbers (%).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eALB, serum albumin; BMI, body mass index; CRP, serum C-reactive protein; GPL, glycopeptidolipid; MAC, \u003cem\u003eMycobacterium avium\u003c/em\u003e complex; TP, serum total protein\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026dagger;\u003cem\u003eP\u003c/em\u003e-values are for all comparisons.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e\u0026para;\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for anti-GPL-core IgA antibody weak titers vs. anti-GPL-core IgA antibody-negative.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for anti-GPL-core IgA antibody strong titers vs. anti-GPL-core IgA antibody-negative.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first report to describe the differences in clinical characteristics using an anti-GPL-core antibody titer threshold value of 5.0 U/mL. We set the threshold of the antibody-positive group to 5.0 U/mL, according to a previous report where the mean antibody titer that was considered the most reliable for MAC-PD diagnosis via bronchoscopy was 5.0 U/mL [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Among the antibody-positive MAC-PD patients in our study, the median value of anti-MAC antibodies was 4.5 U/mL, but considering the application to actual clinical practice and an objective evaluation, we selected 5.0 U/mL as the threshold between the strong positive and weak positive groups in our study.\u003c/p\u003e\u003cp\u003eIn our study, 66.3% of the patients newly diagnosed with MAC-PD were positive for anti-GPL-core IgA antibodies, which is comparable to the sensitivity reported in a previous review [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Furthermore, the clinical characteristics of the patients with MAC-PD in our study were consistent with those in previous reports (i.e., the patients were predominantly slim women with nodular bronchiectatic disease) [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eKitada \u003cem\u003eet al\u003c/em\u003e. reported that the antibody titers reflect the disease activity to some extent [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and found a weak correlation between the antibody levels and the extent of the disease on chest computed tomography (CT) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Similarly, we found that both disease progression requiring treatment and extensive radiological findings were significantly abundant in the strong positive antibody group in our study cohort. However, there was no significant difference in the presence or absence of cavitary lesions. Thus, a strong positive anti-GPL-core IgA antibody result was associated with higher radiological scores for infiltration, although no difference was observed in cavitary lesions between patients with strong positive and weak positive results. This correlates with another study showing that the anti-GPL-core IgA antibody titer was not associated with the extent of disease in the fibrocavitary disease phenotype [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe found that a positive AFB smear in the strong positive group was significantly more abundant than in the antibody-negative group and slightly more abundant than in the weak positive group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.053). Extensive radiological findings [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and an AFB-positive sputum smear [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] have been reported as exacerbating factors of MAC-PD, which increases the likelihood that a high antibody titer is an exacerbating factor.\u003c/p\u003e\u003cp\u003eHowever, the anti-GPL-core IgA antibody titer in patients with severe MAC-PD was sometimes low in our study, probably due to differences in individual immunity and immune response ability, but no significant difference was found in serum total protein, serum albumin, IgG, and IgE levels in our study. A lower BMI was considered an exacerbating factor in MAC-PD patients in previous studies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In our study, although many patients with MAC-PD were thin on average, there was no significant difference in BMI between the three groups.\u003c/p\u003e\u003cp\u003eIn our study, \u003cem\u003eM. intracellulare\u003c/em\u003e was found in 18.6% of patients with MAC-PD, and the infection rate was similar to other reports in Japan [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Regarding MAC species differentiation, some studies reported that patients with \u003cem\u003eM. intracellulare\u003c/em\u003e infection experienced more frequent exacerbations than those with \u003cem\u003eM. avium\u003c/em\u003e infection [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], but others reported that patients with \u003cem\u003eM. intracellulare\u003c/em\u003e infection experienced a lower rate of recurrence than those with \u003cem\u003eM. avium\u003c/em\u003e infection [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].Thus, the difference in the prognosis between \u003cem\u003eM. avium\u003c/em\u003e and \u003cem\u003eM. intracellulare\u003c/em\u003e infections remains uncertain. In our study, there was no significant relationship between the prognosis and the MAC species in all three groups. Additionally, there was no significant difference in clinical features between the MAC-PD patients with weak positive anti-GPL-core IgA antibodies and those who were antibody-negative. Thus, MAC-PD patients with weak positive antibody titers were considered to be of no clinical importance in our study other than in the diagnostic method that was used.\u003c/p\u003e"},{"header":"Limitations","content":" \u003cp\u003eOur study has several limitations. First, because the sample size was small, the number of MAC-PD patients may have been underestimated since patients who were not diagnosed according to the American Thoracic Society (ATS) and the Infectious Disease Society of America (IDSA) guidelines were excluded from the analyses. Therefore, in reality, factors with clinical significance may have proven insignificant in the analyses due to reduced statistical power. Second, because data collection was retrospective, sputum cultures, laboratory data, and CT scans were performed according to clinical practice rather than according to strict schedules. Finally, the timing of the treatment was dependent on the decision of the attending physician.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eOur study shows that anti-GPL-core IgA antibody titers\u0026thinsp;\u0026gt;\u0026thinsp;5.0 U/mL can be used to both diagnose MAC-PD and to predict the risk of exacerbation. However, patients with weak positive antibody titers are not considered clinically significant other than in diagnostic methods. Although the anti-GPL-core IgA antibody is a qualitative test for MAC-PD, it can be useful as a quantitative test for MAC-PD severity.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003eStudy Population and Design\u003c/h2\u003e\n\u003cp\u003eWe retrospectively reviewed all patients seen in our hospital in Tokyo, Japan, from April 2014 to June 2019. There were 481 patients who underwent serologic testing for anti-GPL-core IgA antibodies. Of them, 119 newly diagnosed NTM-PD patients fulfilled the criteria of the ATS and the IDSA statement on the diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases [8, 26]. Those with a past history of NTM disease, NTM other than MAC, and no abnormal shadow on chest CT were excluded, and the remaining 89 MAC-PD patients were enrolled in our study (Fig. 1). We divided the study patients into two groups according to anti-GPL-core IgA antibody results: an antibody-positive group (\u003cem\u003en\u003c/em\u003e = 59) and an antibody-negative group (\u003cem\u003en\u003c/em\u003e = 30, antibody titer \u0026lt;0.7 U/mL). Then, the antibody-positive group was further divided into a strong positive group (\u003cem\u003en\u003c/em\u003e = 27, antibody titer \u0026ge;5 U/mL) and a weak positive group (\u003cem\u003en\u003c/em\u003e = 32, 5.0\u0026lt; antibody titer \u0026ge;0.7 U/mL). The antibody titers and the clinical characteristics of the patients, including age, sex, laboratory data, a past history of tuberculosis, comorbidities, and radiological findings, were retrospectively compared. Additionally, we investigated whether treatment was required for up to 1 year after diagnosis to determine if anti-GPL-core IgA antibody titers were associated with disease progression.\u003c/p\u003e\n\u003ch2\u003eEthics Approval and Consent to Participate\u003c/h2\u003e\n\u003cp\u003eAll methods were carried out in accordance with the declaration of Helsinki. The need of informed consent was waived by the Ethics Committee of Toho University Ohashi Medical Center due to the retrospective nature of the study. All protocols were approved by the Ethics Committee of Toho University Ohashi Medical Center (approval no. H20004).\u003c/p\u003e\n\u003ch2\u003eSerological Determination of Anti-GPL-core IgA Antibody Titers\u003c/h2\u003e\n\u003cp\u003eThe titer of serum anti-GPL-core IgA antibodies was determined using a Capilia MAC Ab ELISA serodiagnostic kit (TAUNS Laboratories, Inc., Shizuoka, Japan). The cutoff value was defined as 0.7 U/mL, according to the manufacturer\u0026rsquo;s instructions [22]. The test can be performed using a small amount of serum, and the turnaround time is approximately 4 hours [32].\u003c/p\u003e\n\u003ch2\u003eMicrobiological Examination\u003c/h2\u003e\n\u003cp\u003eAFB were cultured in mycobacteria growth indicator tubes using sputum samples or bronchial washings obtained by bronchoscopy. The sputum samples were obtained on two or more occasions after the initial presentation. The diagnosis of MAC-PD was made when MAC was identified in sputum at least twice or once in bronchial washings. MAC was confirmed when cultures were positive for AFB, and the cultured AFB were subsequently confirmed as MAC by polymerase chain reaction.\u003c/p\u003e\n\u003ch2\u003eRadiological Examination and Measurements\u003c/h2\u003e\n\u003cp\u003eHigh-resolution chest CT findings were classified as either showing or not showing a cavitary lesion. Additionally, chest CT findings at the time of initial diagnosis were scored, as previously described [33]. Briefly, the lung fields were divided into six lobes based on anatomical structures: right upper, right middle, right lower, left upper (S1+2 and S3), left lingular (S4 and S5), and left lower lobes. We assessed whether, at the time of diagnosis, each lung lobe had a shadow, such as cavities, bronchiectasis, small nodules, consolidations, or atelectasis.\u003c/p\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eThe patients\u0026rsquo; characteristics are presented as medians (interquartile range). Numerical data are expressed as numbers (%). Intergroup differences (anti-GPL-core IgA antibody strong positive group vs. weak positive group vs. negative group) were compared using the Kruskal\u0026ndash;Wallis test for numerical variables and the chi-square test or Fisher exact test for categorical variables where appropriate. All analyses were performed using SPSS Statistical software v22.0 (IBM Japan, Tokyo, Japan). \u003cem\u003eP\u003c/em\u003e-values \u0026lt; 0.05 were considered significant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor contributions\u003c/h2\u003e\n\u003cp\u003eN.K. collected the data, analyzed the data, created the tables, designed the study, and wrote the manuscript. C.N., T.O., K.W., K.N., C.I., N.S., H.Mo., and H.Ma. collected the data. H.Ma. critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAdditional information\u003c/h2\u003e\n\u003ch2\u003eData availability statement\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to ethical restrictions.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePrevots, D. R. \u0026amp; Marras, T. K. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review. \u003cem\u003eClin. Chest Med\u003c/em\u003e. \u003cstrong\u003e36\u003c/strong\u003e, 13-34 (2015).\u003c/li\u003e\n\u003cli\u003eTan, Y. \u003cem\u003eet al\u003c/em\u003e. Epidemiology of pulmonary disease due to nontuberculous mycobacteria in Southern China, 2013\u0026ndash;2016. \u003cem\u003eBMC Pulm. Med\u003c/em\u003e. \u003cstrong\u003e18\u003c/strong\u003e, 168 (2018).\u003c/li\u003e\n\u003cli\u003eFuruuchi, K. \u003cem\u003eet al\u003c/em\u003e. Interrelational changes in the epidemiology and clinical features of nontuberculous mycobacterial pulmonary disease and tuberculosis in a referral hospital in Japan. \u003cem\u003eRespir. Med\u003c/em\u003e. \u003cstrong\u003e152\u003c/strong\u003e, 74-80 (2019).\u003c/li\u003e\n\u003cli\u003eKendall, B. A. \u0026amp; Winthrop, K. L. Update on the epidemiology of pulmonary nontuberculous mycobacterial infections. \u003cem\u003eSemin. Respir. Crit. Care Med\u003c/em\u003e. \u003cstrong\u003e34\u003c/strong\u003e, 87-94 (2013).\u003c/li\u003e\n\u003cli\u003eHoefsloot, W. \u003cem\u003eet al\u003c/em\u003e. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. \u003cem\u003eEur. Respir. J.\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 1604-1613 (2013).\u003c/li\u003e\n\u003cli\u003eSimons, S. \u003cem\u003eet al\u003c/em\u003e. Nontuberculous mycobacteria in respiratory tract infections, eastern Asia. \u003cem\u003e Infect. Dis\u003c/em\u003e. \u003cstrong\u003e17\u003c/strong\u003e, 343-349 (2011).\u003c/li\u003e\n\u003cli\u003eHoefsloot, W. \u003cem\u003eet al\u003c/em\u003e. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. \u003cem\u003eEur. Respir. J.\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 1604-1613 (2013).\u003c/li\u003e\n\u003cli\u003eDaley, C. L. \u003cem\u003eet al\u003c/em\u003e. Treatment of nontuberculous mycobacterial pulmonary disease: an Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline: Executive Summary. \u003cem\u003e Infect. Dis.\u003c/em\u003e \u003cstrong\u003e71\u003c/strong\u003e, e31-e36 (2020).\u003c/li\u003e\n\u003cli\u003eTsukamura, M. Diagnosis of disease caused by \u003cem\u003eMycobacterium avium\u003c/em\u003e \u003cem\u003eChest\u003c/em\u003e. \u003cstrong\u003e99\u003c/strong\u003e, 667-669 (1991).\u003c/li\u003e\n\u003cli\u003eKoh, W. J. \u003cem\u003eet al\u003c/em\u003e. Clinical significance of a single isolation of pathogenic nontuberculous mycobacteria from sputum specimens. \u003cem\u003eDiagn. Microbiol. Infect. Dis.\u003c/em\u003e \u003cstrong\u003e75\u003c/strong\u003e, 225-226 (2013).\u003c/li\u003e\n\u003cli\u003eLee, M. R. \u003cem\u003eet al\u003c/em\u003e. Factors associated with subsequent nontuberculous mycobacterial lung disease in patients with a single sputum isolate on initial examination. \u003cem\u003eClin. Microbiol. Infect.\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e,e1-7 (2015).\u003c/li\u003e\n\u003cli\u003e. Kitada, S. \u003cem\u003eet al\u003c/em\u003e. Validation of a commercial serodiagnostic kit for diagnosing pulmonary \u003cem\u003eMycobacterium avium\u003c/em\u003e complex disease. \u003cem\u003eInt. J. Tuberc. Lung Dis.\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 97-103 (2015).\u003c/li\u003e\n\u003cli\u003eNumata, T. \u003cem\u003eet al\u003c/em\u003e. Clinical efficacy of anti-glycopeptidolipid-core IgA test for diagnosing \u003cem\u003eMycobacterium avium\u003c/em\u003e complex infection in lung. \u003cem\u003eRespirology\u003c/em\u003e. \u003cstrong\u003e20\u003c/strong\u003e, 1277-1281 (2015).\u003c/li\u003e\n\u003cli\u003eShu, C.-C. \u003cem\u003eet al\u003c/em\u003e. Sero-diagnosis of \u003cem\u003eMycobacterium avium\u003c/em\u003e complex lung disease using serum immunoglobulin A antibody against glycopeptidolipid antigen in Taiwan. \u003cem\u003ePLoS \u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, e80473 (2013).\u003c/li\u003e\n\u003cli\u003eKobashi, Y., Mouri, K., Obase, Y., Kato, S. \u0026amp; Oka, M. Serological assay by use of glycopeptidolipid core antigen for \u003cem\u003eMycobacterium avium\u003c/em\u003e \u003cem\u003eScand. J. Infect. Dis\u003c/em\u003e. \u003cstrong\u003e45\u003c/strong\u003e, 241-249 (2013).\u003c/li\u003e\n\u003cli\u003eKitada, S. \u003cem\u003eet al\u003c/em\u003e. Serodiagnosis of \u003cem\u003eMycobacterium avium\u003c/em\u003e complex pulmonary disease in the USA. \u003cem\u003eEur. Respir. J\u003c/em\u003e. \u003cstrong\u003e42\u003c/strong\u003e, 454-460 (2013).\u003c/li\u003e\n\u003cli\u003eJeong, B. H. \u003cem\u003eet al\u003c/em\u003e. Serodiagnosis of \u003cem\u003eMycobacterium avium\u003c/em\u003e complex and Mycobacterium abscessus complex pulmonary disease by use of IgA antibodies to glycopeptidolipid core antigen. \u003cem\u003e Clin. Microbiol\u003c/em\u003e. \u003cstrong\u003e51\u003c/strong\u003e, 2747-2749 (2013).\u003c/li\u003e\n\u003cli\u003eS. \u003cem\u003eet al.\u003c/em\u003e Serodiagnosis of pulmonary disease due to \u003cem\u003eMycobacterium avium\u003c/em\u003e complex proven by bronchial wash culture. \u003cem\u003eChest\u003c/em\u003e. \u003cstrong\u003e138\u003c/strong\u003e, 236-237 (2010).\u003c/li\u003e\n\u003cli\u003eShibata, Y. \u003cem\u003eet al\u003c/em\u003e. Diagnostic test accuracy of anti-glycopeptidolipid-core IgA antibodies for \u003cem\u003eMycobacterium avium complex\u003c/em\u003e pulmonary disease: systematic review and meta-analysis. \u003cem\u003eSci. Rep\u003c/em\u003e. \u003cstrong\u003e6\u003c/strong\u003e, 29325 (2016).\u003c/li\u003e\n\u003cli\u003e\u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/30339468\"\u003eIzumi K. \u003cem\u003eet al\u003c/em\u003e. Epidemiology of adults and children treated for nontuberculous mycobacterial pulmonary disease in Japan. \u003cem\u003eAnn. Am. Thorac. Soc\u003c/em\u003e. \u003cstrong\u003e16\u003c/strong\u003e, 341-347 (2018).\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eSong, J. H., Kim, B. S., Kwak, N., Han, K., \u0026amp; Yim, J.-J. \u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/32817261/\"\u003eImpact of body mass index on development of nontuberculous mycobacterial pulmonary disease.\u003c/a\u003e \u003cem\u003eEur. Respir. J\u003c/em\u003e. \u003cstrong\u003e57\u003c/strong\u003e, 2000454 (2021).\u003c/li\u003e\n\u003cli\u003eKitada, S. \u003cem\u003eet al\u003c/em\u003e. Serodiagnosis of \u003cem\u003eMycobacterium avium\u003c/em\u003e-complex pulmonary disease using an enzyme immunoassay kit. \u003cem\u003e J. Respir. Crit. Care Med\u003c/em\u003e. \u003cstrong\u003e177\u003c/strong\u003e, 793-797 (2008).\u003c/li\u003e\n\u003cli\u003eKitada, S. \u003cem\u003eet al\u003c/em\u003e. Use of glycopeptidolipid core antigen for serodiagnosis of \u003cem\u003eMycobacterium avium \u003c/em\u003ecomplex pulmonary disease in immunocompetent patients. \u003cem\u003eClin. Diagn. Lab. Immunol\u003c/em\u003e. \u003cstrong\u003e12\u003c/strong\u003e, 44-51 (2005).\u003c/li\u003e\n\u003cli\u003eKitada, S. \u003cem\u003eet al\u003c/em\u003e. Serological test and chest computed tomography findings in patients with \u003cem\u003eMycobacterium avium \u003c/em\u003ecomplex lung disease. \u003cem\u003eEur. Respir. J.\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 1217-1223 (2007).\u003c/li\u003e\n\u003cli\u003eHwang, J. A., Kim, S., Jo K.-W. \u0026amp; Shim, T. S. Natural history of \u003cem\u003eMycobacterium avium\u003c/em\u003e complex lung disease in untreated patients with stable course. \u003cem\u003eEur\u003c/em\u003e. \u003cem\u003eRespir\u003c/em\u003e. \u003cem\u003eJ\u003c/em\u003e. \u003cstrong\u003e49\u003c/strong\u003e, 1600537 (2017).\u003c/li\u003e\n\u003cli\u003eGriffith, D. E. \u003cem\u003eet al\u003c/em\u003e. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. \u003cem\u003e J. Respir. Crit. Care Med\u003c/em\u003e. \u003cstrong\u003e175\u003c/strong\u003e, 367-416 (2007).\u003c/li\u003e\n\u003cli\u003eKim, S. J. \u003cem\u003eet al\u003c/em\u003e. Risk factors for deterioration of nodular bronchiectatic \u003cem\u003eMycobacterium avium\u003c/em\u003e complex lung disease. \u003cem\u003e J. Tuberc. Lung Dis\u003c/em\u003e. \u003cstrong\u003e18\u003c/strong\u003e, 730-736 (2014).\u003c/li\u003e\n\u003cli\u003eKitada, S. \u003cem\u003eet al\u003c/em\u003e. Long-term radiographic outcome of nodular bronchiectatic \u003cem\u003eMycobacterium avium\u003c/em\u003e complex pulmonary disease. \u003cem\u003eInt\u003c/em\u003e. \u003cem\u003eJ\u003c/em\u003e. \u003cem\u003eTuberc\u003c/em\u003e. \u003cem\u003eLung Dis\u003c/em\u003e. \u003cstrong\u003e16\u003c/strong\u003e, 660-664 (2012).\u003c/li\u003e\n\u003cli\u003eMorimoto, K. \u003cem\u003eet al\u003c/em\u003e. A laboratory-based analysis of nontuberculous mycobacterial lung disease in Japan from 2012 to 2013. \u003cem\u003eAnn. Am. Thorac. Soc\u003c/em\u003e. \u003cstrong\u003e14\u003c/strong\u003e, 49-56 (2017).\u003c/li\u003e\n\u003cli\u003eKoh, W. J. \u003cem\u003eet al\u003c/em\u003e. Clinical significance of the differentiation between \u003cem\u003eMycobacterium avium\u003c/em\u003e and Mycobacterium intracellulare in M avium complex lung disease. \u003cstrong\u003e142\u003c/strong\u003e, 1482-1488 (2012).\u003c/li\u003e\n\u003cli\u003eBoyle, D. P., Zembower, T. R., Reddy, S. \u0026amp; Qi, C. Comparison of clinical features, virulence, and relapse among \u003cem\u003eMycobacterium avium\u003c/em\u003e complex species. \u003cem\u003e J. Respir. Crit. Care Med.\u003c/em\u003e \u003cstrong\u003e191\u003c/strong\u003e, 1310-1317 (2015).\u003c/li\u003e\n\u003cli\u003eKitada S. \u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/31085120/\"\u003eApplication of a commercial serodiagnostic kit that measures the serum anti-glycopeptidolipid core IgA antibody in Mycobacterium avium complex pulmonary disease.\u003c/a\u003e Respir Investig. \u003cstrong\u003e57\u003c/strong\u003e:410-414(2019).\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eKodaka, N. \u003cem\u003eet al\u003c/em\u003e. Predictors of radiological aggravations of pulmonary MAC disease. \u003cem\u003ePLoS One\u003c/em\u003e. \u003cstrong\u003e15\u003c/strong\u003e, e0237071 (2020).\u003c/li\u003e\n\u003c/ol\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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Mycobacterium avium complex pulmonary disease (MAC-PD), anti-glycopeptidolipid (GPL), antibodies, nontuberculous mycobacterial diseases","lastPublishedDoi":"10.21203/rs.3.rs-283326/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-283326/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eMycobacterium avium\u003c/em\u003e complex pulmonary disease (MAC-PD) can be serologically diagnosed according to the presence of anti-glycopeptidolipid (GPL)-core IgA antibodies. However, few studies have examined the association between serum anti-GPL-core IgA antibody titers and the clinical characteristics of patients with MAC-PD. From April 2014 to June 2019, we determined the level of anti-GPL-core IgA antibodies in 489 MAC-PD patients at our institute. Of them, 89 patients fulfilled the criteria of the American Thoracic Society and the Infectious Diseases Society of America statement on the diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. These patients were divided into antibody-positive (\u003cem\u003en\u003c/em\u003e = 59) or -negative (\u003cem\u003en\u003c/em\u003e = 30) groups according to their serum anti-GPL-core IgA antibody results. Additionally, the positive antibody group was further divided into a strong positive group (\u003cem\u003en\u003c/em\u003e = 27) and a weak positive group (\u003cem\u003en\u003c/em\u003e = 32), and their clinical characteristics were retrospectively compared. Disease progression requiring treatment during the 12 months following diagnosis and extensive radiological findings were significantly abundant in the strong positive group compared with the weak positive group. Our findings revealed that serum anti-GPL-core IgA antibody titers are useful not only for diagnosing MAC-PD but also for predicting the risk of exacerbation.\u003c/p\u003e","manuscriptTitle":"Association between Serum Anti-glycopeptidolipid-core IgA Antibody Titers and Clinical Characteristics of Mycobacterium Avium Complex Pulmonary Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-12 23:53:54","doi":"10.21203/rs.3.rs-283326/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"522f442a-0db9-4496-8a96-2ee59254a04f","owner":[],"postedDate":"March 12th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":2927124,"name":"Health Economics \u0026 Outcomes Research"},{"id":2927125,"name":"General Microbiology"},{"id":2927126,"name":"Pulmonology"}],"tags":[],"updatedAt":"2022-03-15T21:01:45+00:00","versionOfRecord":{"articleIdentity":"rs-283326","link":"https://doi.org/10.1016/j.ijid.2021.06.042","journal":{"identity":"international-journal-of-infectious-diseases","isVorOnly":true,"title":"International Journal of Infectious Diseases"},"publishedOn":"2021-08-01 21:01:45","publishedOnDateReadable":"August 1st, 2021"},"versionCreatedAt":"2021-03-12 23:53:54","video":"","vorDoi":"10.1016/j.ijid.2021.06.042","vorDoiUrl":"https://doi.org/10.1016/j.ijid.2021.06.042","workflowStages":[]},"version":"v1","identity":"rs-283326","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-283326","identity":"rs-283326","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}