Comment on Shao et al.’s “risk factors associated with COVID‐19 pneumonia in Chinese patients with pre‐existing interstitial lung disease during the SARS‐CoV‐2 pandemic”Hsiu-Ming Lee 1, Po-Cheng Shih 2,3, James Cheng-Chung Wei, MD, PhD 2,4,51 School of Medicine, China Medical University, Taichung, Taiwan2 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan3 Department of Allergy, Immunology & Rheumatology, Changhua Christian Hospital, Changhua, Taiwan4 Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan5 Graduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanHsiu-Ming Lee and Po-Cheng Shih contribute equally.Correspondence： James Cheng-Chung Wei, MD, PhD.Address : No. 110, Sec. 1, Jianguo N. Rd., South District, Taichung City 40201, Taiwan.TEL : ＋886 4 24739595 #34718. (FAX) +886 4 24637389E-mail : [email protected] 0000-0002-1235-0679Word counts: 498Table counts: 0Figure counts: 0Funding Sources : noneConflicts of Interest : The authors declare no conflicts of interest.Dear Editor,We read the article with great interest by Shao et al, where a retrospective study analyzed the risk factors for pneumonia related to the 2019 coronavirus disease (COVID-19) in patients with various types of interstitial lung disease (ILD) caused by SARS-CoV-2 infection. According to Cox’s multivariate analysis, only male gender and the use of corticosteroids emerged as risk factors for developing new coronavirus pneumonia following illness. On the other hand, receiving two to three doses of vaccination proved protective for individuals with preexisting ILD who contracted COVID-19 pneumonia.[1] As a result, it is recommended that patients with preexisting ILD, especially those who are male and using corticosteroids, receive more than two doses of the vaccine for enhanced protection. Since 2019, WHO has reported 770 million confirmed COVID-19 cases and 6.9 million deaths globally.[2] Studies have linked interstitial lung disease to worse COVID-19 outcomes, showing a four-fold mortality increase.[3] Interstitial lung disease includes inflammatory and fibrotic conditions, with incidence rates of 7 to 1,650 per 100,000.[4, 5] In contrast, COVID-19 can also trigger interstitial lung disease.[6] As COVID-19 spreads, global lung disease rates will increase. Identifying risk factors for interstitial lung disease after a COVID-19 diagnosis is crucial for early prevention, resource allocation, and effective management. However, some details in the article still need to be further clarified.First, this paper analyzed several variables in developing pneumonia during COVID-19 infection, including age, sex, vaccination history, common immunosuppressants, antifibrotic agents, and corticosteroids. However, it should be noted that certain risk factors, such as smoking, diabetes mellitus, autoimmune diseases, and recurrent COVID-19 infections, still exhibit a high association with pneumonia and were not included in the analysis.[7-9] Therefore, we recommend that the authors consider incorporating these factors into future similar studies. The paper analyzed corticosteroid use as a potential risk factor but without mentioning the timing of administration. The Centers for Disease Control and Prevention (CDC) recommends steroids for COVID-19 cases beyond a sure severity threshold. Failing to differentiate when they were given may overestimate the proportion of pneumonia cases using steroids, affecting p-values. Some ILD patients use multiple immunosuppressants, impacting immune function and COVID-19 pneumonia risk. While the article lists common medications, it doesn’t analyze the number of patients receiving combined therapy. Therefore, we recommend that future studies assess the risk associated with concurrently using immunosuppressants to understand the implications of combination therapy better.Second, this paper reveals an intriguing shift, as sarcoidosis appears to become a protective factor against pneumonia following a COVID-19 diagnosis. It could be a groundbreaking revelation since the articles consistently state that sarcoidosis is an excessively high-risk factor for severe COVID-19 pneumonia.[10] No literature has delved into this phenomenon, its mechanisms, or potential implications. Given the substantial representation of sarcoidosis patients in this study, we recommended that authors separately analyze its subgroup, examining their disease site, activity, severity, and medication use differences. Furthermore, future research should focus on investigating the interaction mechanisms and conducting comprehensive comparative studies to unlock the full potential of this discovery.References:1. Shao, C., et al., Risk factors associated with COVID-19 pneumonia in Chinese patients with pre-existing interstitial lung disease during the SARS-CoV-2 pandemic. J Med Virol, 2023.95 (9): p. e29098.2. WHO Coronavirus (COVID-19) Dashboard . 2023 [cited 2023 Oct 10, 2023]; Available from:https://covid19.who.int/.3. Valenzuela, C., G. Waterer, and G. Raghu, Interstitial lung disease before and after COVID-19: a double threat? Eur Respir J, 2021.58 (6).4. Shah Gupta, R., et al., Incidence and prevalence of interstitial lung diseases worldwide: a systematic literature review.BMJ Open Respir Res, 2023. 10 (1).5. Lee, C.Y., Interstitial lung disease-From pulmonary perspective to pathogenesis, multidisciplinary approach and treatment. Int J Rheum Dis, 2023. 26 (5): p. 823-824.6. Myall, K.J., et al., Persistent Post-COVID-19 Interstitial Lung Disease. An Observational Study of Corticosteroid Treatment. Ann Am Thorac Soc, 2021. 18 (5): p. 799-806.7. Strzelak, A., et al., Tobacco Smoke Induces and Alters Immune Responses in the Lung Triggering Inflammation, Allergy, Asthma and Other Lung Diseases: A Mechanistic Review. Int J Environ Res Public Health, 2018. 15 (5).8. Wang, W., et al., Clinical characteristics of moderate or severe COVID-19 infection in patients with rheumatic diseases and analysis of risk factors leading to severe disease. Int J Rheum Dis, 2023. 26 (10): p. 1951-1959.9. Batu, E.D. and A. Erden, The outcome of COVID-19 in patients with autoimmune rheumatic diseases: Comparable to the general population or worse? Int J Rheum Dis, 2023. 26 (8): p. 1435-1439.10. Tana, C., et al., Sarcoidosis and COVID-19: At the Cross-Road between Immunopathology and Clinical Manifestation. Biomedicines, 2022.10 (10).

Objectives Very few investigations have explored the association between CHDs in offspring and mothers with autoimmune disease. In this study, we aimed to explore whether maternal autoimmune disease increases the risk of CHDs in newborns. Methods We analyzed 4780 offspring with maternal autoimmune disease and 9416 offspring without maternal autoimmune disease matching 1:2 with age and sex between 2009 and 2016 from databases including the National Health Insurance program, birth certificate applications, cause of death data, and Maternal and Child Health Database, which is managed by the Health and Welfare Data Science Center (HWDC) in Taiwan. Birth year, birth weight, gestational age, the children’s sex, mode of delivery, congenital defects, urbanization, insurance unit, maternal and paternal comorbidities, child or parents died within one year after birth and medication exposure during pregnancy were selected as covariates for further multivariate analysis. Also, multiple Cox regression analysis was performed to evaluate the adjusted hazard ratio (aHR) of CHDs. Results The incidence of CHDs was 5.35 per 10000 person-months in autoimmune mothers. The result of the multivariate Cox regression showed that the children whose mothers had autoimmune disease had a 1.57-fold risk of CHDs compared to children whose mothers did not have an autoimmune disease (crude hazard ratio: 1.57; 95% CI, 1.29-1.90, aHR: 1.51; 95% CI, 1.24-1.85). Conclusion Maternal autoimmune disease might be a risk factor for developing CHDs in offspring, especially in mothers with systemic lupus erythematosus or Sjogren’s syndrome. Further research is warranted to investigate the possible pathogenesis mechanisms of this association.

Background: Atopic dermatitis (AD) contributes to substantial social and financial costs in public health care systems. Antibiotic exposure during pregnancy has been proposed as a risk factor, but findings remain inconsistent. The aim of this study was to investigate the association between prenatal antibiotic use and childhood AD. Methods: We performed a population-based cohort study using data collected from the Taiwan Maternal and Child Health Database from 2009 to 2016. Associations were determined using Cox proportional hazards model and were adjusted for several potential covariates, including maternal atopic disorders and gestational infections. Subgroup analyses evaluated the influence of postnatal infant antibiotic/acetaminophen use on the association between prenatal antibiotic exposure and childhood AD diagnosed after 1 year of age. Results: A total of 1288343 mother-child pairs were identified and 39.5% received antibiotics prenatally. Maternal antibiotic use during pregnancy was slightly positively associated with childhood AD (aHR 1.05, 95% CI 1.04-1.06), especially in the first and second trimesters. An apparent dose-response pattern was observed with an 11% increased risk when the exposure was ≥5 courses prenatally (aHR 1.11, 95% CI 1.09-1.14). Subgroup analysis showed the positive association remained significant regardless of postnatal antibiotic use; however, a negative association was found in children without postnatal infant acetaminophen use (aHR 1.02, 95% CI 0.97-1.07). Conclusion: Maternal antibiotic use during pregnancy was associated with increased risk of childhood AD in a dose-related manner. Possible confounders existed between prenatal antibiotics and postnatal infant acetaminophen use in the subgroup analysis. Further research may be warranted to investigate this variable using a prospectively designed study, and also to examine whether or not this association is specifically related to pregnancy.

Backgrounds Appendectomy is one of the most commonly performed surgeries worldwide. Sepsis is an major etiology of morbidity and mortality in children. Our preliminary research revealed a positive correlation among appendectomy and future risk of sepsis in adults. However, to date, the relationship among appendectomy and future risk of sepsis in children remains unknown. The aim of this research was to investigate the relationship among appendectomy and hazard of future sepsis in children. Methods We applied a nationwide population-based cohort to assess whether children who received appendectomy were at increased risk of subsequent sepsis. Overall, 57261 subjects aged below 18 undergoing appendectomy as appendectomy group and 57261 matched controls were identified as non-appendectomy group from the National Health Insurance Research Database in Taiwan. We use propensity score analysis to match age, sex, urbanization level, and parental occupation at the ratio to 1:1. Multiple Cox regression and stratified analyses were used to appraise the adjusted hazard ratio (aHR) for developing sepsis in children. Results Children who received appendectomy had a 2.63 times higher risk of developing sepsis than those who did not, and the risk was even higher in children aged under 6 years. Patients with <1 year follow-up showed a 5.64-fold risk of sepsis in the appendectomy cohort. Patients with 1–4 and ≥5 years’ follow-up showed a 2.41- and 2.02-times risk of sepsis. Conclusion Appendectomy was correlative to a 2.63-fold increased future sepsis risk in children, and the risk in younger patients aged <6 years was even higher. More studies to interpret the possible biological mechanisms of the associations among sepsis and appendectomy are warrant

Background Among respiratory diseases, asthma is one of the most burdensome disorder worldwide. Growing evidence disclose gut dysbiosis may contribute to asthma via the gut-lung axis. Constipation can lead to alteration of the gut microflora. The clinical impact of constipation on asthma has not been researched. Therefore, we aim to assess the risk of asthma in constipated patients by a nationwide population-based cohort study. Methods We analyzed 82421 constipated patients and 82421 individuals without constipation between 1999 and 2013 from the Taiwanese National Health Insurance Research Database. Analysis of propensity score was utilized to match age, gender, comorbidities, and medications at a ratio of 1:1. Besides, multiple Cox regression analysis was performed to evaluate the adjusted hazard ratio of asthma. Furthermore, sensitivity tests and a stratified analysis were conducted. Results The incidence of asthma was 10.8 per 1,000 person-years in the constipation group, which was higher than the rate of 5.6 per 1,000 person-years observed in the non-constipation group. After adjustment for age, gender, comorbidities, and medications, constipated patients had a 1.91-fold greater risk of asthma compared to those without constipation (adjusted hazard ratio [aHR]: 1.91 (95% C.I. 1.84-1.99). In subgroup analyses, patients aged 20-39 years had a 2.04-fold highest risk of asthma in the constipation cohort (aHR:2.04, 95% CI, 1.84-2.26). Besides, the severity of constipation is associated with an increased risk of asthma; the aHR was 1.76 (1.69-1.85), 2.15(2.03-2.27), and 2.29(2.10-2.49) for < 3 times, 3-12 times, and ≥12 times of laxatives prescription within one year, respectively. (p<0.001) Moreover, constipated patients had a higher likelihood of asthma, regardless of gender, comorbidities, and medications. Conclusion Constipation relates to a significantly increased risk of asthma. Physicians should be aware of the possibility of asthma in constipated people. Further research is warranted to investigate the possible pathological mechanisms of this association.

Objective: This study aimed to investigate the risk of Graves’ disease in Polycystic ovary syndrome (PCOS) patients. Design: Population-based retrospective cohort study. Setting: We utilized the medical records randomly selected from the Taiwan National Health Insurance Research Database (NHIRD) during period between 2000 and 2013. Population: We included women aged between 20 and 50 who have no previous Graves’ disease diagnosis records. Methods: We matched the baseline characteristics and the index date of the PCOS-free cohort to the PCOS cohort at a ratio of 4:1 by propensity score matching method. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Main outcome measure: To analyze the cumulative incidence and the hazard ratio of Graves’ disease events in both PCOS group and PCOS-free cohort. Results: We identified 5927 patients as the PCOS cohort, and included 23708 patients as the PCOS-free cohort. The PCOS group had a significant increased risk of Graves’ disease with an adjusted hazard ratio (aHR) of 1.34 (95% CI= 1.00-1.81). The p-value was 0.03 in log-rank test. PCOS patients without anxiety, chronic obstructive pulmonary disease, hypertension or hyperlipidemia had a higher risk of Graves’ disease in the stratification analysis. Conclusions: This study revealed a significant association between PCOS and subsequent risk of developing Graves’ disease. Funding: Nil. Tweetable abstract: PCOS increase the risk of Graves’ disease. Keywords: Polycystic ovary syndrome, PCOS, Graves’ disease, GD, hyperthyroidism, autoimmune thyroiditis, cohort, hazard ratio, epidemiology, Taiwan National Health Insurance Research Database

Background Atopic dermatitis (AD) is the chronic inflammatory disorder that affects both in childhood and adulthood. Mounting evidence indicates that gut dysbiosis contributes to AD via the gut-skin axis. Constipation can result in alteration of the gut microflora. The clinical impact of constipation on AD has not been researched. Therefore, we aim to assess the risk of AD in constipated patients by the population-based cohort study. Methods We collected 87015 constipated people and 87015 people without constipation between 1999 and 2013 from the Taiwanese National Health Insurance Research Database. Propensity score analysis was administrated to match age, gender, comorbidities, and medications at a ratio of 1:1. Multiple Cox regression analysis was utilized to evaluate the adjusted hazard ratio of AD. In addition, sensitivity tests and a stratified analysis were conducted. Results The incidence of AD was 4.7 per 1,000 person-years in the constipation group, which was higher than the rate of 2.2 per 1,000 person-years observed in the non-constipation group. After adjustment for age, gender, comorbidities, corticosteroids, and antihistamine, constipated people had a 2.11-fold greater risk of AD compared to those without constipation (adjusted hazard ratio [aHR]: 2.11 (95% C.I. 1.98-2.24). Moreover, constipated people had a higher likelihood of AD, regardless of gender, comorbidities, as well as the usage of corticosteroids, and antihistamines. Conclusion Constipation is associated with a significantly risk factor of AD. Clinicians should be careful of the possibility of AD in constipated people. Further study is warranted to investigate the possible pathological mechanisms of this relationship.

Aim: Insulin is highly recommended for diabetes management in persons with liver cirrhosis. However, insulin has some deleterious side effects, and only few studies have evaluated its long-term effects in persons with cirrhosis. We conducted this cohort study to compare the risks of all-cause mortality, liver-related complications, cardiovascular events, and hypoglycemia between insulin users and nonusers with type 2 diabetes mellitus (T2DM) and compensated liver cirrhosis. Methods: From January 1, 2000, to December 31, 2012, we selected 2047 insulin users and 4094 propensity score-matched nonusers from Taiwan’s National Health Insurance Research Database. Cox proportional hazard models with robust sandwich standard error estimates were used to assess the risks of main outcomes between insulin users and nonusers. Results: The mean follow-up time was 5.84 years. The death rate during the follow-up period was 5.28 and 4.07 per 100 person-years for insulin users and nonusers, respectively. In insulin users, the hazard ratios and 95% confidence intervals (CIs) of all-cause mortality, hepatocellular carcinoma, decompensated cirrhosis, hepatic failure, major cardiovascular events, and hypoglycemia were 1.31 (1.18-1.45), 1.18 (1.05-1.34), 1.53 (1.35-1.72), 1.26 (1.42-1.86), 1.41 (1.23-1.62), and 3.33 (2.45-4.53), respectively. Conclusions: This retrospective cohort study indicated that among persons with T2DM and compensated liver cirrhosis, insulin users demonstrated with higher risks of death, liver-related complications, cardiovascular events, and hypoglycemia compared with insulin nonusers. Therefore, vigilance is recommended when such persons use insulin.