Assessment of Pulmonary Function in Children with Post-Acute Sequelae of COVID (PASC) Using Impulse Oscillometry and the Role of Vaccination

Assessment of Pulmonary Function in Children with Post-Acute Sequelae of COVID (PASC) Using Impulse Oscillometry and the Role of Vaccination | 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 Assessment of Pulmonary Function in Children with Post-Acute Sequelae of COVID (PASC) Using Impulse Oscillometry and the Role of Vaccination Chieh-Ho Chen, Pei-Chi Chen, Xiao-Ling Liu, Chi-Hung Wei, Yu-Lung Hsu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7135121/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID syndrome (LCS), is characterized by persistent symptoms following SARS-CoV-2 infection and poses significant health challenges, particularly impactingpulmonary function in children. This study aims to evaluate the effect of COVID-19 vaccination on pulmonary function in children with PASC using standardized spirometry and impulse oscillometry (IOS). Methods: This prospective, observational study was conducted from July to September 2022, at the tertiary medical center of children’s hospital in central Taiwan. Pediatric patients aged 6 to 18 years diagnosed with PASC were enrolled. Demographic data, vaccination status, and blood test results were collected. Pulmonary function was assessed using spirometry and IOS, measuring parameters such as respiratory resistance (R5, R20) and reactance (X5). Statistical analyses explored the association between IOS results and clinical symptoms, as well as vaccination status. Results: Among 209 children, 78.7% were vaccinated. IOS detected abnormalities in 74.6%, with 12.0% diagnosed with obstructive lung disease (OLD) and 62.9% with small airway disease (SAD). Fatigue (56.0%) and dyspnea (52.0%) were most common in OLD, while chest pain (45.0%) and cough (41.7%) prevailed in SAD. Vaccinated children showed significantly lower respiratory resistance (R5, R20, p<0.01) and improved reactance (X5, p<0.001). Vaccination did not significantly reduce respiratory-related symptoms but was associated with lower risks of decreased appetite (OR=0.399) and sleep disturbance (OR=0.345). Conclusion: COVID-19 vaccination may have a protective effect on pulmonary function in children with PASC, highlighting it’s in mitigating long-term respiratory complications. Further studies are needed to explore underlying mechanisms. Pediatrics Infectious Diseases SARS-CoV2 infection Post-acute sequelae of SARS-CoV-2 infection impulse oscillometry long COVID syndrome vaccination Figures Figure 1 1. Introduction: The global COVID-19 pandemic has impacted millions of people worldwide, including children and adolescents. While the acute phase of COVID-19 typically presents with respiratory symptoms and other systemic manifestations, a significant number of pediatric patients continue to experience symptoms long after the initial infection. This condition, known as post-acute sequelae of SARS-CoV-2 infection (PASC, persistent more than 4 weeks after infection), includes a range of symptoms such as fatigue, shortness of breath, chest pain, and neuropsychiatric issues, which can significantly impair the quality of life in affected children [ 1 ]. Studies have showed nearly 30% of COVID-19 victims suffer from PASC after recovery of acute COVID infection. PASC causes enormous damages in medical, mental, socioeconomical aspects, causing impaired quality of life. [ 2 , 3 ] Children, although generally experiencing milder acute COVID-19 symptoms compared to adults, are not immune to PASC. Recent studies have highlighted the presence of long-term symptoms in pediatric populations, raising concerns about the potential chronic health implications for children suffered with PASC. [ 4 , 5 ] Pulmonary function impairment is a notable concern, with reports indicating persistent respiratory issues in children long after recovery from the acute infection [ 6 ]. One meta-analysis based on seven articles reporting on 380 adult patients showed around 39% of patients with PASC have impairment in DLCO (diffusing capacity for carbon monoxide), 15% with restrictive lung pattern and 7% with obstructive pattern. [ 7 ] Nevertheless, similar research about lung function change in pediatric PASC patients is relatively uncommon. One small observation study from Turkey showed that there existed a significant decrease in FEV 1 /FVC and DLCO, with an increase in lung clearance index and ground-glass opacity (GGO) in chest CT scan in pediatric patients with respiratory PASC, indicating peripheral airway inflammation may play a role in respiratory LCS. [ 8 ] Assessing pulmonary function in pediatric patients with PASC or LCS is crucial for understanding the extent of respiratory involvement and guiding appropriate management. Traditional methods like spirometry can be challenging to perform in young children due to their need for active cooperation and effort. Impulse oscillometry (IOS) measures respiratory resistance (R) and reactance (X), providing insights into the mechanical properties of the lungs and airways, is a simple tool to measure the resistance and reactance of the entire respiratory system during tidal breathing, and it is sensitive to changes in peripheral airway function, which can be particularly relevant in children with early stage of various lung diseases.[ 9 ] Previous research has demonstrated that IOS can detect subtle changes in lung function, making it an ideal method for studying long-COVID-related pulmonary issues. Moreover, IOS may contribute early detection of subtle alternation of airway resistance, in various lung diseases, including cystic fibrosis [ 10 ], asthma [ 11 ] or chronic obstructive lung disease [ 12 ]. By monitoring these parameters longitudinally, healthcare professionals are able to identify any worsening of respiratory function and adjust treatment strategies accordingly. [ 13 , 14 ] This technique can provide valuable insights into the mechanism of pulmonary physiology, making it potentially useful in assessing children with PASC or LCS. Vaccination against COVID-19 has been shown to reduce the severity of the disease and the risk of hospitalization. However, its impact on long-COVID, particularly in children, remains under investigation. Preliminary data suggest that vaccinated individuals may experience fewer and less severe long-COVID symptoms [ 15 ]as well as the incidence of multisystem inflammatory syndrome in children (MISC) [ 16 ], yet it remains controversial about the protection of vaccination on long-COVID syndrome. Our previously report on 500 PASC children recruited from the DISCOVER study cohort ( Di agnosis and S upport for COV ID Children to E nhance R ecovery), a multidisciplinary combined-care program which was initiated to investigate the clinical conditions and to provide supportive management for PASC children, revealed that vaccinated subjects can lower chronic gastro-intestinal symptoms in post-acute phase of SARS-Cov2 infection. Whether vaccination was able to reduce the respiratory symptoms and impairment of lung function in PASC children is also the main concern of this study. Our study aim is to investigate the relationship between COVID-19 vaccination status and pulmonary function in children with long-COVID, utilizing IOS as the primary assessment tool. By comparing vaccinated and unvaccinated children, this research seeks to provide valuable insights into the potential protective effects of vaccination against long-term respiratory complications in the pediatric population. 2. Materials and Methods 2.1. Study Design and Participants: This cross-sectional study included children aged 5–17 years who were diagnosed with PASC based on persistent symptoms lasting more than 4 weeks post-acute COVID-19 infection. The study participants were recruited between January and December 2023 from the DISCOVER study cohort ( Di agnosis and S upport for COV ID Children to E nhance R ecovery), which was a multidisciplinary combined-care program initiated to investigate the clinical conditions and to provide supportive management [ 17 ]. The diagnosis of acute COVID-19 was confirmed through a positive reverse transcriptase-polymerase chain reaction (RT-PCR) or rapid antigen test, and PASC condition was defined as sequelae symptoms lasting longer than 4 weeks [ 18 ]. This study was approved by the Institutional Review Board of China Medical University Hospital (CMUH111-REC2-113 and CMUH111-REC2-122). Informed consent was obtained from all participants and their guardians. 2.2. Inclusion and Exclusion Criteria: Participants were included if they had a history of confirmed COVID-19 infection and persistent symptoms attributable to LCS. Exclusion criteria were the presence of pre-existing chronic respiratory conditions (e.g., asthma), other chronic diseases that could affect pulmonary function, and inability to perform impulse oscillometry (IOS) testing. 2.3. Data Collection All participants underwent a comprehensive medical history review and physical examination. Besides, we conducted a questionnaire for the participants and/or their parents to evaluate acute and chronic symptoms after COVID infection. Clinical data, including demographics, symptomatology, and vaccination status, were collected through structured interviews and medical record reviews. Symptoms were categorized into respiratory (e.g., cough, shortness of breath) and non-respiratory (e.g., fatigue, neuropsychiatric symptoms). On-line questionnaires were given to patients and their parents to survey their clinical symptoms. Blood tests including hemogram, liver and renal function, inflammatory makers, as well as IgE levels were obtained. 2.4. Impulse Oscillometry (IOS) Testing IOS was performed using a standard device (e.g., Jaeger Masterscreen IOS, CareFusion, Germany) in accordance with the American Thoracic Society (ATS) guidelines. Parameters measured included resistance at 5 Hz (R5) and 20 Hz (R20), reactance at 5 Hz (X5), the area of reactance (AX), and resonant frequency. Measurements were conducted in a seated position with participants breathing normally through a mouthpiece connected to the device. we classified examined children into three groups: normal, small airway dysfunction (SAD) and obstructive lung disease (OLD) based on the characterization of IOS results [ 19 , 20 ]. The normal subgroup was characterized by subjects displaying an R5 value less than 150% of predicted values and an R5 minus R20 (R5-R20) value equal to or less than 0.07 kPa. Conversely, the small airway disease subgroup showed an R5 value less than 150% of predicted values, accompanied by an R5-R20 value greater than 0.07 kPa. In contrast, the obstructive lung disease subgroup exhibited an R5 value surpassing 150% of predicted values. 2.5. Statistical Analysis Continuous data were presented by median and corresponding interquartile range (IQR), and categorical data were presented by counts and corresponding percentages. Kruskal-Wallis rank sum test was used for continuous variables and Fisher's exact test was used for categorical variables to investigate difference of baseline characteristics across IOS groups except for sex, which was used chi-square test to examine the difference across groups. We reported frequencies of the first twenty common clinical symptoms in the post-COVID-19 phase using heatmap plots in study children. We next performed logistic regression analysis with age adjustment to evaluate association between vaccination and IOS status, particularly, normal versus SAD and normal versus OLD, respectively. Similarly, logistic regression models with age adjustment were used to examine associations of clinical symptoms in post-COVID-19 phase with IOS status (normal versus SAD and normal versus OLD, separately) and with vaccination, respectively. P-value less than 0.05 was used to declare statistical significance. All analyses were performed using Stata v.14 (StataCorp, College Station, Texas, USA) and R statistical package. Heatmap plots were generated using the matplotlib and seaborn Python packages. A p-value of < 0.05 was considered statistically significant. 3. Results 3.1. Participants characteristics A total of 258 patients were enrolled in this study, and among them,49 patients were excluded due to refusal or incomplete surveillance, while 209 patients entered final analysis. 53 patients were in “Normal” group, 131 in SAD (small airway disease) group and 25 in OLD (obstructive lung disease) group. Table 1 presents the baseline characteristics of 209 participants categorized by their IOS status. The table includes demographic information such as age and sex distribution, hospitalization and vaccination status, and various biomedical test results. SAD group had the youngest median age, and the Normal group had the oldest one. (Normal vs. SAD vs. OLD: 14 vs. 9 v.s.11-year-old, P < 0.001). The distribution of sex among the groups shows a slight imbalance, with more males in the normal and SAD group than OLD group (Normal vs. SAD vs. OLD: 54% vs.. 60% v.s. 36%). The percentage of children requiring hospitalization were low across all groups, with a slightly higher rate in the OLD subgroup (Normal vs. SAD vs. OLD: 1% v.s.5%v.s 1%, P = 0.74). Children in SAD group were also less likely to be vaccinated compared to other two groups (Normal vs. SAD vs. OLD :90.57% v.s.72.09% v.s.88.0%, P = 0.01). In impulse oscillometry, the obstructive group had highest R5, R20, and R5-R20 values; while the SAD group had highest resonance frequency. n biochemical study, the median WBC count was significantly different among the groups, with the highest value in the OLD group, yet all within normal range. (Normal vs. SAD vs. OLD: 6.5 v.s. 7.2 v.s 7.85 x 103/uL, P = 0.01) The ESR and hsCRP levels did not show significant differences among the groups. Other tests such as Lactic Dehydrogenase (LDH), Ferritin, D-Dimer, Aspartate Aminotransferase (AST), Alanine Transaminase (ALT), Creatine Phospho Kinase (CPK), and Total Immunoglobulin E (IgE) also exhibited varying results among the groups. 3.2. PASC symptoms and IOS results Table 2 is the percentage of long-COVID symptoms in three groups, and Fig. 1 is the heatmap. Three most common symptoms in all patients were fatigue (44.83%), chest pain (41.84%) and limited daily activity (40.82%). Patients in normal group had highest risk to have neuropsychiatric symptoms, including lack of motivation (53.85%) and body weight change (38.46%), anxiety(42.31%), attention disturbance(37.52%), frustration(42.31%), dizziness(36%), memory disturbance(34.62%), depression(36.54%), headache(33.33%), and sleep disturbance(25%) compared to other two groups. Patients in SAD group were more likely to have chest pain (45.00%) and cough(41.67%) than other group. Patients in OLD group had highest percentage of fatigue (56.00%), limited daily activities(54.17%), short of breath(52.00%), and throat problem(37.50%). After adjustment of age, patients in OLD group had higher risk of fatigue beyond expectation (OR = 2.81) and short of breath (OR = 3.83) compared to Normal group; while the SAD group were more likely to experienced chest pain (OR = 2.625) Nevertheless, the ex-pulmonary symptoms were not statistically significant among three groups. 3.3. IOS results and Vaccination Table 3 presents correlations of age, sex, impulse oscillometry with vaccination status. Vaccinated children tended have older age compared to non-vaccinated children (11 v.s. 9-year-old, OR = 2.08). Vaccinated children also had slightly higher R20 values (111.4 v.s. 102.23%, OR = 10.89), less R5-R20 (0.15 v.s.0.26 Kpa/L/S, OR=-0.056) and resonant frequency values. (17.39 v.s. 20.63, OR=-2.31). After adjustment of age, vaccination did not have significant influence on risk reduction of respiratory-related symptoms such as chronic cough (OR = 0.993), short of breath (0.646) or chest pain (OR = 0.523), yet vaccination alleviate risk of decreased appetite (OR = 0.399) and sleep disturbance (0.345). 4. Discussion 4.1. Our findings in Children with PASC using oscillometry In our study, patients in all ages successfully completed examination of impulse oscillometry after brief instruction, suggesting usefulness and convenience of impulse oscillometry to monitor respiratory condition of pediatric patients with long-COVID syndrome. Our study also reveals strong relationship between age and pulmonary function. Children with young age are more vulnerable to pulmonary LCS and become to have SAD or OLD in impulse oscillometry study. On the contrary, patients in Normal group are tended to be older, with more neuropsychiatric complaints than the rest of two groups. A pediatric study by Sansone et al also showed fatigue seems to be more frequent in older age children. [ 21 ] A retrospective cohort study in UK showed SARS-CoV-2 infection is not associated with elevated risk for mental distress in adolescents. [ 22 ] We hypothesize that younger children have small airway calibers and less lung reserve capacity than adolescents or adults in nature. Therefore, they are more vulnerable to develop respiratory manifestation of PASC. Besides, the incidence of predisposing allergic airway diseases might be more prevalent in children with young age, especially in boys. [ 23 ] Meanwhile, back to the pandemic outbreak period in 2021 to 2022, young children had lower chance to receive vaccination due to Taiwan’s national health policy and parental hesitation, leading to more severe infection in young children than adolescents or young adults. [ 24 , 25 ] While short of breath and fatigue are main complaint in OLD group, instead, chest pain and cough are more prevalent in patients with small airway disease, suggesting possible slightly different etiology between two groups. The mechanism of lung injury after acute COVID infection is complex. The COVID-19 virus enters human body through ACE-2 receptors in the epithelia of the lung, blood vessels, central nerve system, and gastrointestinal tracts, and trigger multiple immune responses. [ 26 ] Several hypotheses have been proposed to contribute PASC or LCS, including immune dysregulation, microbiota dysbiosis, autoimmunity and immune priming, blood clots and endothelial abnormalities, as well as dysfunctional neurological signaling.[ 27 ] Microscopically, hyaline membrane formation, diffuse alveolar epithelium destruction, alveolar septal fibrous proliferation, capillary damage and bleeding, or pulmonary consolidation have been observed in autopsy of victims with severe COVID infection. [ 28 ] Other than lung parenchyma, airway may also be the target for COVID infection. Pathological examination of in COVID victims reveal diffuse mucous plugging in bronchioles, with increased expression of MUC5B and MUC5AC RNA/protein driven by IL-1 signaling from COVID-19 virus [ 29 , 30 ]. These pathological switch in small airways lead to ventilation inhomogeneities, hyperresponsiveness, and airflow limitation, resulting in uneven ventilation and delayed gas clearance from the lungs, requiring increased respiratory effort. [ 31 ] Numerous residual thromboembolisms in pulmonary capillary beds may also lead to secondary alveolar ventilation dysfunction in individuals with COVID-19 infection. [ 32 ] Studies have shown that around 28.2% of non-hospitalized adult patients with mild COVID-19 may exhibit persistent ventilation and perfusion abnormalities in VQ SPECT/CT scan, indicative of strong relationship of small airway disease and pulmonary micro-thrombosis. [ 33 ] Further research is essential to uncover the underlying mechanisms of small airway diseases in the context of COVID-19 and other respiratory disorders, aiming to improve diagnostic precision and enhance treatment strategies for affected individuals. Though many studies have proven vaccination could reduce risk of severe infection, its effectiveness in prevention of long-COVID syndrome remains controversial. [ 15 ] One large meta-analysis by Byambasuren et al [ 34 ] showed covid-19 vaccines for at least one dose might have protective and therapeutic effects on long covid, yet this review also pointed out huge heterogeneity of the research among the studies it included. Another systemic review by Notarte et al showed low level of evidence (grade III, case-controls, cohort studies) that vaccination before SARSCoV-2 infection could reduce the risk of subsequent long-COVID. [ 35 ] In our study, vaccination failed to show protective effects on impulse oscillometry result and clinical symptoms after adjustment of age. One possible explanation is that vaccine may have partial protection to certain inflammatory process but not the entire immune system. An in vivo study by using dynamic contrast-enhanced magnetic resonance imaging shows that blood brain barrier dysfunction is associated with long COVID-induced cognitive impairment. Individuals with brain fog also had dysregulation of the coagulation system and a dampened adaptive immune response in peripheral blood. However, the pulmonary symptoms arise from lung parenchymal fibrosis and micro thrombo-embolism of pulmonary capillary systems. An adult cohort study by Ayoubkhani et al also shows that two doses of vaccination significantly reduce incidence of fatigue, headache, and sleep disturbance, while symptoms of difficulty in breathing is unchanged.[ 36 ] Anther cross-sectional study by Kuodi from Isarel demonstrates similar results. [ 37 ] Yet, in our study, young children were less likely to be fully vaccinated due to national health policy during pandemic period. Further investigation should be done to clarify long-term protective of vaccination in children. 5.2. Limitations and Advantages There exist several limitations in our study. First, it is an observational study without patients’ baseline health conditions and their pulmonary function studies prior to COVID infection. Second, this is a single center study with relatively sample size, which potentially impacts the generalizability of the findings to a broader pediatric population with PASC. The study duration is also relatively short, ranging from July 1st, 2022, to September 30th, 2022, may not capture long-term effects of PASC in children, limiting the understanding of chronic implications. Despite the limitation mentioned above, our study still brings up a comprehensive evaluation of respiratory function in children with PASC by using Impulse oscillometry, providing valuable insights into potential pulmonary abnormalities. The findings may have clinical utility in early detection and monitoring of lung function abnormalities in symptomatic children with PASC. These advantages and limitations should be considered when interpreting the results and implications of the study on Impulse oscillometry for children with PASC. Further large-scale prospective study related to impulse oscillometry should be conducted to clarify pathophysiology change of pediatric PASC with pulmonary manifestation. 5.3. Conclusion As PASC in children is relatively new, the most effective treatments are still being explored. Impulse Oscillometry might be able help track how a child's respiratory function responds to different interventions, allowing for adjustments in treatment plans based on objective data. PASC is still not fully understood, especially in pediatric populations. Incorporating Impulse Oscillometry into research studies can contribute to a better understanding of the respiratory manifestations of Long COVID in children and may help identify patterns or subgroups within this population. Declarations Not applicable Acknowledgement I would like to express my sincere thankfulness to all members of this research project. Their dedication, expertise, and commitment were instrumental in the realization of our research objectives. I am appreciated for their valuable insights, collaborative spirit, and unwavering support throughout the project. Ethical Approval The study was approved by the Institutional Review Board of China Medical University Hospital (CMUH111-REC2-113). Funding This study was supported by following grants: NSTC 113-2314-B-039-057-from the National Science and Technology Council, Taiwan; a research grant (1JA8) from the Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan; DMR-113-114, DMR-114-024, and DMR-114-109 from the China Medical University Hospital, Taichung, Taiwan. 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J Inflamm Res 14:175–189. 10.2147/JIR.S271292 Fahy JV, Dickey BF (2010) Airway mucus function and dysfunction. N Engl J Med 363(23):2233–2247. 10.1056/NEJMra0910061 Jing H, Wu X, Xiang M, Liu L, Novakovic VA, Shi J (2022) Pathophysiological mechanisms of thrombosis in acute and long COVID-19. Front Immunol 13:992384. 10.3389/fimmu.2022.992384 Evbuomwan O, Endres W, Tebeila T, Engelbrecht G (2023) Identification and Follow-up of COVID-19 Related Matching Ventilation and Perfusion Defects on Functional Imaging Using VQ SPECT/CT. Nuclear Med Mol Imaging 57(1):9–15. 10.1007/s13139-022-00776-0 Byambasuren O, Cardona M, Bell K, Clark J, McLaws M-L, Glasziou P (2020) Estimating the extent of asymptomatic COVID-19 and its potential for community transmission: Systematic review and meta-analysis. Journal of the Association of Medical Microbiology and Infectious Disease Canada = Journal Officiel De l’Association Pour La Microbiologie Medicale Et L’infectiologie Canada. 5(4):223–234. 10.3138/jammi-2020-0030 Notarte KI, Catahay JA, Velasco JV, Pastrana A, Ver AT, Pangilinan FC, Peligro PJ, Casimiro M, Guerrero JJ, Gellaco MML et al (2022) Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: A systematic review. EClinicalMedicine 53:101624. 10.1016/j.eclinm.2022.101624 Ayoubkhani D, Bermingham C, Pouwels KB, Glickman M, Nafilyan V, Zaccardi F, Khunti K, Alwan NA, Walker AS (2022) Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study. BMJ (Clinical research ed). 377:e069676. 10.1136/bmj-2021-069676 Kuodi P, Gorelik Y, Zayyad H, Wertheim O, Wiegler KB, Abu Jabal K, Dror AA, Nazzal S, Glikman D, Edelstein M (2022) Association between BNT162b2 vaccination and reported incidence of post-COVID-19 symptoms: cross-sectional study 2020-21, Israel. NPJ vaccines 7(1):101. 10.1038/s41541-022-00526-5 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7135121","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":486050524,"identity":"e8850dc7-c2e1-4f30-9ba0-c86e27649312","order_by":0,"name":"Chieh-Ho Chen","email":"","orcid":"","institution":"6.Department of Pediatric Pulmonology, China Medical University Children's Hospital, China Medical University, Taichung 404327, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Chieh-Ho","middleName":"","lastName":"Chen","suffix":""},{"id":486050525,"identity":"7626bd29-e528-4e67-8be8-fffc179f0f43","order_by":1,"name":"Pei-Chi Chen","email":"","orcid":"","institution":"Department of Microbiology \u0026 Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Pei-Chi","middleName":"","lastName":"Chen","suffix":""},{"id":486050526,"identity":"dd276e52-5de3-4fa6-9694-9cc92a803340","order_by":2,"name":"Xiao-Ling Liu","email":"","orcid":"https://orcid.org/0009-0000-3860-975X","institution":"Research Center of Allergy, Immunology and Microbiome (A.I.M.), China Medical University Hospital, China Medical University, Taichung 404327, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Xiao-Ling","middleName":"","lastName":"Liu","suffix":""},{"id":486050527,"identity":"55c06a49-f684-43b6-bbf3-86fb4d450861","order_by":3,"name":"Chi-Hung Wei","email":"","orcid":"","institution":"Department of Teaching and Research, China Medical University Children’s Hospital, China Medical University, Taichung 404327, Taiwan","correspondingAuthor":false,"prefix":"","firstName":"Chi-Hung","middleName":"","lastName":"Wei","suffix":""},{"id":486050528,"identity":"fa475a67-8c5b-42dc-8d24-488aceb6f0b5","order_by":4,"name":"Yu-Lung Hsu","email":"","orcid":"","institution":"5.Department of Pediatric Infectious Diseases, China Medical University Children’s Hospital, China Medical University, Taichung 404327, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Yu-Lung","middleName":"","lastName":"Hsu","suffix":""},{"id":486050529,"identity":"6e8799ff-9f4d-4921-b3f3-fbb3eaee69a5","order_by":5,"name":"Chien-Heng Lin","email":"","orcid":"","institution":"6.Department of Pediatric Pulmonology, China Medical University Children's Hospital, China Medical University, Taichung 404327, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Chien-Heng","middleName":"","lastName":"Lin","suffix":""},{"id":486050530,"identity":"00387a50-6f24-4ffa-a9be-929d9b72c99e","order_by":6,"name":"Wen-Jue Soong","email":"","orcid":"","institution":"6.Department of Pediatric Pulmonology, China Medical University Children's Hospital, China Medical University, Taichung 404327, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Wen-Jue","middleName":"","lastName":"Soong","suffix":""},{"id":486050531,"identity":"e2e85021-10c6-4d22-83df-7f01ca39acab","order_by":7,"name":"Lawrence Shih-Hsin Wu","email":"","orcid":"","institution":"Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan","correspondingAuthor":false,"prefix":"","firstName":"Lawrence","middleName":"Shih-Hsin","lastName":"Wu","suffix":""},{"id":486050532,"identity":"3f7daa7e-a5c8-4687-96a7-7143fd2e5e89","order_by":8,"name":"Hui-Ju Tsai","email":"","orcid":"","institution":"Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Hui-Ju","middleName":"","lastName":"Tsai","suffix":""},{"id":486050533,"identity":"5f63947e-27f5-4924-a205-1759fc0bf87a","order_by":9,"name":"Shen-Mao, Chang","email":"","orcid":"","institution":"Department of Statistics, National Taipei University, Sanxia, New Taipei, Taiwan.","correspondingAuthor":false,"prefix":"","firstName":"Chang","middleName":"","lastName":"Shen-Mao","suffix":""},{"id":486050534,"identity":"a52abe5b-0c4d-47c3-8fee-fa00ee8bc528","order_by":10,"name":"Jiu-Yao Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYLACCQYbBgZm5gYoN4EoLWlALYxIWg4Q1nQYiInVYnD87OEXlm3no/nbgVp+5hxm4GfPMWD+2IZHy5m8NAvJttu5Mw4zNjD2bjvMINnzxoDhIB4tZgdyzAxAWhqAWpgZgVoMbuQAtWzDo+X8G5CWc7nzYVrsCWq5kWP8QLLtQO4GuC0SBLTY33hjxiBxLjl3I1DLwd5t6TwSZ54VHDj7D7cWyf4c488SZXa5884fPvjg5zZrOf725I0PKs7g1gIEbNKSbBDWASDmgTHwAeaPH/4QUDIKRsEoGAUjGwAA42xZL1gBYJYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-4540-9822","institution":"Department of Allergy \u0026 Immunology, China Medical University Children's Hospital, China Medical University, Taichung 404327, Taiwan","correspondingAuthor":true,"prefix":"","firstName":"Jiu-Yao","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-07-16 02:58:46","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7135121/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7135121/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87053586,"identity":"b2e5b229-7faf-4ac0-a4ca-b213738cd54f","added_by":"auto","created_at":"2025-07-18 15:13:37","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":353825,"visible":true,"origin":"","legend":"\u003cp\u003eHeatmap of clinical symptoms across three groups.\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7135121/v1/4398a111ef507fc46d17a67d.jpeg"},{"id":87054045,"identity":"49467efb-1e88-4b9e-a04c-89b34d92f709","added_by":"auto","created_at":"2025-07-18 15:21:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":953458,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7135121/v1/92c72bcc-6feb-4d5f-a6cc-179fb86d07f7.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAssessment of Pulmonary Function in Children with Post-Acute Sequelae of COVID (PASC) Using Impulse Oscillometry and the Role of Vaccination\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction:","content":"\u003cp\u003eThe global COVID-19 pandemic has impacted millions of people worldwide, including children and adolescents. While the acute phase of COVID-19 typically presents with respiratory symptoms and other systemic manifestations, a significant number of pediatric patients continue to experience symptoms long after the initial infection. This condition, known as post-acute sequelae of SARS-CoV-2 infection (PASC, persistent more than 4 weeks after infection), includes a range of symptoms such as fatigue, shortness of breath, chest pain, and neuropsychiatric issues, which can significantly impair the quality of life in affected children [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Studies have showed nearly 30% of COVID-19 victims suffer from PASC after recovery of acute COVID infection. PASC causes enormous damages in medical, mental, socioeconomical aspects, causing impaired quality of life. [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Children, although generally experiencing milder acute COVID-19 symptoms compared to adults, are not immune to PASC. Recent studies have highlighted the presence of long-term symptoms in pediatric populations, raising concerns about the potential chronic health implications for children suffered with PASC. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e\u003cp\u003ePulmonary function impairment is a notable concern, with reports indicating persistent respiratory issues in children long after recovery from the acute infection [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. One meta-analysis based on seven articles reporting on 380 adult patients showed around 39% of patients with PASC have impairment in DLCO (diffusing capacity for carbon monoxide), 15% with restrictive lung pattern and 7% with obstructive pattern. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Nevertheless, similar research about lung function change in pediatric PASC patients is relatively uncommon. One small observation study from Turkey showed that there existed a significant decrease in FEV\u003csub\u003e1\u003c/sub\u003e/FVC and DLCO, with an increase in lung clearance index and ground-glass opacity (GGO) in chest CT scan in pediatric patients with respiratory PASC, indicating peripheral airway inflammation may play a role in respiratory LCS. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eAssessing pulmonary function in pediatric patients with PASC or LCS is crucial for understanding the extent of respiratory involvement and guiding appropriate management. Traditional methods like spirometry can be challenging to perform in young children due to their need for active cooperation and effort. Impulse oscillometry (IOS) measures respiratory resistance (R) and reactance (X), providing insights into the mechanical properties of the lungs and airways, is a simple tool to measure the resistance and reactance of the entire respiratory system during tidal breathing, and it is sensitive to changes in peripheral airway function, which can be particularly relevant in children with early stage of various lung diseases.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Previous research has demonstrated that IOS can detect subtle changes in lung function, making it an ideal method for studying long-COVID-related pulmonary issues. Moreover, IOS may contribute early detection of subtle alternation of airway resistance, in various lung diseases, including cystic fibrosis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], asthma [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] or chronic obstructive lung disease [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. By monitoring these parameters longitudinally, healthcare professionals are able to identify any worsening of respiratory function and adjust treatment strategies accordingly. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] This technique can provide valuable insights into the mechanism of pulmonary physiology, making it potentially useful in assessing children with PASC or LCS.\u003c/p\u003e\u003cp\u003eVaccination against COVID-19 has been shown to reduce the severity of the disease and the risk of hospitalization. However, its impact on long-COVID, particularly in children, remains under investigation. Preliminary data suggest that vaccinated individuals may experience fewer and less severe long-COVID symptoms [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]as well as the incidence of multisystem inflammatory syndrome in children (MISC) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], yet it remains controversial about the protection of vaccination on long-COVID syndrome. Our previously report on 500 PASC children recruited from the \u003cb\u003eDISCOVER\u003c/b\u003e study cohort (\u003cb\u003eDi\u003c/b\u003eagnosis and \u003cb\u003eS\u003c/b\u003eupport for \u003cb\u003eCOV\u003c/b\u003eID Children to \u003cb\u003eE\u003c/b\u003enhance \u003cb\u003eR\u003c/b\u003eecovery), a multidisciplinary combined-care program which was initiated to investigate the clinical conditions and to provide supportive management for PASC children, revealed that vaccinated subjects can lower chronic gastro-intestinal symptoms in post-acute phase of SARS-Cov2 infection. Whether vaccination was able to reduce the respiratory symptoms and impairment of lung function in PASC children is also the main concern of this study.\u003c/p\u003e\u003cp\u003eOur study aim is to investigate the relationship between COVID-19 vaccination status and pulmonary function in children with long-COVID, utilizing IOS as the primary assessment tool. By comparing vaccinated and unvaccinated children, this research seeks to provide valuable insights into the potential protective effects of vaccination against long-term respiratory complications in the pediatric population.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Study Design and Participants:\u003c/h2\u003e\u003cp\u003eThis cross-sectional study included children aged 5\u0026ndash;17 years who were diagnosed with PASC based on persistent symptoms lasting more than 4 weeks post-acute COVID-19 infection. The study participants were recruited between January and December 2023 from the \u003cb\u003eDISCOVER\u003c/b\u003e study cohort (\u003cb\u003eDi\u003c/b\u003eagnosis and \u003cb\u003eS\u003c/b\u003eupport for \u003cb\u003eCOV\u003c/b\u003eID Children to \u003cb\u003eE\u003c/b\u003enhance \u003cb\u003eR\u003c/b\u003eecovery), which was a multidisciplinary combined-care program initiated to investigate the clinical conditions and to provide supportive management [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The diagnosis of acute COVID-19 was confirmed through a positive reverse transcriptase-polymerase chain reaction (RT-PCR) or rapid antigen test, and PASC condition was defined as sequelae symptoms lasting longer than 4 weeks [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This study was approved by the Institutional Review Board of China Medical University Hospital (CMUH111-REC2-113 and CMUH111-REC2-122). Informed consent was obtained from all participants and their guardians.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Inclusion and Exclusion Criteria:\u003c/h2\u003e\u003cp\u003eParticipants were included if they had a history of confirmed COVID-19 infection and persistent symptoms attributable to LCS. Exclusion criteria were the presence of pre-existing chronic respiratory conditions (e.g., asthma), other chronic diseases that could affect pulmonary function, and inability to perform impulse oscillometry (IOS) testing.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Data Collection\u003c/h2\u003e\u003cp\u003eAll participants underwent a comprehensive medical history review and physical examination. Besides, we conducted a questionnaire for the participants and/or their parents to evaluate acute and chronic symptoms after COVID infection. Clinical data, including demographics, symptomatology, and vaccination status, were collected through structured interviews and medical record reviews. Symptoms were categorized into respiratory (e.g., cough, shortness of breath) and non-respiratory (e.g., fatigue, neuropsychiatric symptoms). On-line questionnaires were given to patients and their parents to survey their clinical symptoms. Blood tests including hemogram, liver and renal function, inflammatory makers, as well as IgE levels were obtained.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Impulse Oscillometry (IOS) Testing\u003c/h2\u003e\u003cp\u003e IOS was performed using a standard device (e.g., Jaeger Masterscreen IOS, CareFusion, Germany) in accordance with the American Thoracic Society (ATS) guidelines. Parameters measured included resistance at 5 Hz (R5) and 20 Hz (R20), reactance at 5 Hz (X5), the area of reactance (AX), and resonant frequency. Measurements were conducted in a seated position with participants breathing normally through a mouthpiece connected to the device. we classified examined children into three groups: normal, small airway dysfunction (SAD) and obstructive lung disease (OLD) based on the characterization of IOS results [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The normal subgroup was characterized by subjects displaying an R5 value less than 150% of predicted values and an R5 minus R20 (R5-R20) value equal to or less than 0.07 kPa. Conversely, the small airway disease subgroup showed an R5 value less than 150% of predicted values, accompanied by an R5-R20 value greater than 0.07 kPa. In contrast, the obstructive lung disease subgroup exhibited an R5 value surpassing 150% of predicted values.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Statistical Analysis\u003c/h2\u003e\u003cp\u003eContinuous data were presented by median and corresponding interquartile range (IQR), and categorical data were presented by counts and corresponding percentages. Kruskal-Wallis rank sum test was used for continuous variables and Fisher's exact test was used for categorical variables to investigate difference of baseline characteristics across IOS groups except for sex, which was used chi-square test to examine the difference across groups. We reported frequencies of the first twenty common clinical symptoms in the post-COVID-19 phase using heatmap plots in study children. We next performed logistic regression analysis with age adjustment to evaluate association between vaccination and IOS status, particularly, normal versus SAD and normal versus OLD, respectively. Similarly, logistic regression models with age adjustment were used to examine associations of clinical symptoms in post-COVID-19 phase with IOS status (normal versus SAD and normal versus OLD, separately) and with vaccination, respectively. P-value less than 0.05 was used to declare statistical significance. All analyses were performed using Stata v.14 (StataCorp, College Station, Texas, USA) and R statistical package. Heatmap plots were generated using the matplotlib and seaborn Python packages. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Participants characteristics\u003c/h2\u003e\u003cp\u003eA total of 258 patients were enrolled in this study, and among them,49 patients were excluded due to refusal or incomplete surveillance, while 209 patients entered final analysis. 53 patients were in \u0026ldquo;Normal\u0026rdquo; group, 131 in SAD (small airway disease) group and 25 in OLD (obstructive lung disease) group. \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e presents the baseline characteristics of 209 participants categorized by their IOS status. The table includes demographic information such as age and sex distribution, hospitalization and vaccination status, and various biomedical test results. SAD group had the youngest median age, and the Normal group had the oldest one. (Normal vs. SAD vs. OLD: 14 vs. 9 v.s.11-year-old, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The distribution of sex among the groups shows a slight imbalance, with more males in the normal and SAD group than OLD group (Normal vs. SAD vs. OLD: 54% vs.. 60% v.s. 36%). The percentage of children requiring hospitalization were low across all groups, with a slightly higher rate in the OLD subgroup (Normal vs. SAD vs. OLD: 1% v.s.5%v.s 1%, P\u0026thinsp;=\u0026thinsp;0.74). Children in SAD group were also less likely to be vaccinated compared to other two groups (Normal vs. SAD vs. OLD :90.57% v.s.72.09% v.s.88.0%, P\u0026thinsp;=\u0026thinsp;0.01). In impulse oscillometry, the obstructive group had highest R5, R20, and R5-R20 values; while the SAD group had highest resonance frequency. n biochemical study, the median WBC count was significantly different among the groups, with the highest value in the OLD group, yet all within normal range. (Normal vs. SAD vs. OLD: 6.5 v.s. 7.2 v.s 7.85 x 103/uL, P\u0026thinsp;=\u0026thinsp;0.01) The ESR and hsCRP levels did not show significant differences among the groups. Other tests such as Lactic Dehydrogenase (LDH), Ferritin, D-Dimer, Aspartate Aminotransferase (AST), Alanine Transaminase (ALT), Creatine Phospho Kinase (CPK), and Total Immunoglobulin E (IgE) also exhibited varying results among the groups.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2. PASC symptoms and IOS results\u003c/h2\u003e\u003cp\u003e\u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e is the percentage of long-COVID symptoms in three groups, and \u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e is the heatmap. Three most common symptoms in all patients were fatigue (44.83%), chest pain (41.84%) and limited daily activity (40.82%). Patients in normal group had highest risk to have neuropsychiatric symptoms, including lack of motivation (53.85%) and body weight change (38.46%), anxiety(42.31%), attention disturbance(37.52%), frustration(42.31%), dizziness(36%), memory disturbance(34.62%), depression(36.54%), headache(33.33%), and sleep disturbance(25%) compared to other two groups. Patients in SAD group were more likely to have chest pain (45.00%) and cough(41.67%) than other group. Patients in OLD group had highest percentage of fatigue (56.00%), limited daily activities(54.17%), short of breath(52.00%), and throat problem(37.50%). After adjustment of age, patients in OLD group had higher risk of fatigue beyond expectation (OR\u0026thinsp;=\u0026thinsp;2.81) and short of breath (OR\u0026thinsp;=\u0026thinsp;3.83) compared to Normal group; while the SAD group were more likely to experienced chest pain (OR\u0026thinsp;=\u0026thinsp;2.625) Nevertheless, the ex-pulmonary symptoms were not statistically significant among three groups.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3. IOS results and Vaccination\u003c/h2\u003e\u003cp\u003e\u003cb\u003eTable\u0026nbsp;3\u003c/b\u003e presents correlations of age, sex, impulse oscillometry with vaccination status. Vaccinated children tended have older age compared to non-vaccinated children (11 v.s. 9-year-old, OR\u0026thinsp;=\u0026thinsp;2.08). Vaccinated children also had slightly higher R20 values (111.4 v.s. 102.23%, OR\u0026thinsp;=\u0026thinsp;10.89), less R5-R20 (0.15 v.s.0.26 Kpa/L/S, OR=-0.056) and resonant frequency values. (17.39 v.s. 20.63, OR=-2.31). After adjustment of age, vaccination did not have significant influence on risk reduction of respiratory-related symptoms such as chronic cough (OR\u0026thinsp;=\u0026thinsp;0.993), short of breath (0.646) or chest pain (OR\u0026thinsp;=\u0026thinsp;0.523), yet vaccination alleviate risk of decreased appetite (OR\u0026thinsp;=\u0026thinsp;0.399) and sleep disturbance (0.345).\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e4.1. Our findings in Children with PASC using oscillometry\u003c/h2\u003e\u003cp\u003eIn our study, patients in all ages successfully completed examination of impulse oscillometry after brief instruction, suggesting usefulness and convenience of impulse oscillometry to monitor respiratory condition of pediatric patients with long-COVID syndrome. Our study also reveals strong relationship between age and pulmonary function. Children with young age are more vulnerable to pulmonary LCS and become to have SAD or OLD in impulse oscillometry study. On the contrary, patients in Normal group are tended to be older, with more neuropsychiatric complaints than the rest of two groups. A pediatric study by Sansone et al also showed fatigue seems to be more frequent in older age children. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] A retrospective cohort study in UK showed SARS-CoV-2 infection is not associated with elevated risk for mental distress in adolescents. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] We hypothesize that younger children have small airway calibers and less lung reserve capacity than adolescents or adults in nature. Therefore, they are more vulnerable to develop respiratory manifestation of PASC. Besides, the incidence of predisposing allergic airway diseases might be more prevalent in children with young age, especially in boys. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Meanwhile, back to the pandemic outbreak period in 2021 to 2022, young children had lower chance to receive vaccination due to Taiwan\u0026rsquo;s national health policy and parental hesitation, leading to more severe infection in young children than adolescents or young adults. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eWhile short of breath and fatigue are main complaint in OLD group, instead, chest pain and cough are more prevalent in patients with small airway disease, suggesting possible slightly different etiology between two groups. The mechanism of lung injury after acute COVID infection is complex. The COVID-19 virus enters human body through ACE-2 receptors in the epithelia of the lung, blood vessels, central nerve system, and gastrointestinal tracts, and trigger multiple immune responses. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] Several hypotheses have been proposed to contribute PASC or LCS, including immune dysregulation, microbiota dysbiosis, autoimmunity and immune priming, blood clots and endothelial abnormalities, as well as dysfunctional neurological signaling.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] Microscopically, hyaline membrane formation, diffuse alveolar epithelium destruction, alveolar septal fibrous proliferation, capillary damage and bleeding, or pulmonary consolidation have been observed in autopsy of victims with severe COVID infection. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Other than lung parenchyma, airway may also be the target for COVID infection. Pathological examination of in COVID victims reveal diffuse mucous plugging in bronchioles, with increased expression of MUC5B and MUC5AC RNA/protein driven by IL-1 signaling from COVID-19 virus [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. These pathological switch in small airways lead to ventilation inhomogeneities, hyperresponsiveness, and airflow limitation, resulting in uneven ventilation and delayed gas clearance from the lungs, requiring increased respiratory effort. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] Numerous residual thromboembolisms in pulmonary capillary beds may also lead to secondary alveolar ventilation dysfunction in individuals with COVID-19 infection. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] Studies have shown that around 28.2% of non-hospitalized adult patients with mild COVID-19 may exhibit persistent ventilation and perfusion abnormalities in VQ SPECT/CT scan, indicative of strong relationship of small airway disease and pulmonary micro-thrombosis. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] Further research is essential to uncover the underlying mechanisms of small airway diseases in the context of COVID-19 and other respiratory disorders, aiming to improve diagnostic precision and enhance treatment strategies for affected individuals.\u003c/p\u003e\u003cp\u003eThough many studies have proven vaccination could reduce risk of severe infection, its effectiveness in prevention of long-COVID syndrome remains controversial. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] One large meta-analysis by Byambasuren et al [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] showed covid-19 vaccines for at least one dose might have protective and therapeutic effects on long covid, yet this review also pointed out huge heterogeneity of the research among the studies it included. Another systemic review by Notarte et al showed low level of evidence (grade III, case-controls, cohort studies) that vaccination before SARSCoV-2 infection could reduce the risk of subsequent long-COVID. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] In our study, vaccination failed to show protective effects on impulse oscillometry result and clinical symptoms after adjustment of age. One possible explanation is that vaccine may have partial protection to certain inflammatory process but not the entire immune system. An in vivo study by using dynamic contrast-enhanced magnetic resonance imaging shows that blood brain barrier dysfunction is associated with long COVID-induced cognitive impairment. Individuals with brain fog also had dysregulation of the coagulation system and a dampened adaptive immune response in peripheral blood. However, the pulmonary symptoms arise from lung parenchymal fibrosis and micro thrombo-embolism of pulmonary capillary systems. An adult cohort study by Ayoubkhani et al also shows that two doses of vaccination significantly reduce incidence of fatigue, headache, and sleep disturbance, while symptoms of difficulty in breathing is unchanged.[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] Anther cross-sectional study by Kuodi from Isarel demonstrates similar results. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] Yet, in our study, young children were less likely to be fully vaccinated due to national health policy during pandemic period. Further investigation should be done to clarify long-term protective of vaccination in children.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e5.2. Limitations and Advantages\u003c/h2\u003e\u003cp\u003eThere exist several limitations in our study. First, it is an observational study without patients\u0026rsquo; baseline health conditions and their pulmonary function studies prior to COVID infection. Second, this is a single center study with relatively sample size, which potentially impacts the generalizability of the findings to a broader pediatric population with PASC. The study duration is also relatively short, ranging from July 1st, 2022, to September 30th, 2022, may not capture long-term effects of PASC in children, limiting the understanding of chronic implications. Despite the limitation mentioned above, our study still brings up a comprehensive evaluation of respiratory function in children with PASC by using Impulse oscillometry, providing valuable insights into potential pulmonary abnormalities. The findings may have clinical utility in early detection and monitoring of lung function abnormalities in symptomatic children with PASC. These advantages and limitations should be considered when interpreting the results and implications of the study on Impulse oscillometry for children with PASC. Further large-scale prospective study related to impulse oscillometry should be conducted to clarify pathophysiology change of pediatric PASC with pulmonary manifestation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e5.3. Conclusion\u003c/h2\u003e\u003cp\u003eAs PASC in children is relatively new, the most effective treatments are still being explored. Impulse Oscillometry might be able help track how a child's respiratory function responds to different interventions, allowing for adjustments in treatment plans based on objective data. PASC is still not fully understood, especially in pediatric populations. Incorporating Impulse Oscillometry into research studies can contribute to a better understanding of the respiratory manifestations of Long COVID in children and may help identify patterns or subgroups within this population.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI would like to express my sincere thankfulness to all members of this research project. Their dedication, expertise, and commitment were instrumental in the realization of our research objectives. I am appreciated for their valuable insights, collaborative spirit, and unwavering support throughout the project.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Review Board of China Medical University Hospital (CMUH111-REC2-113).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by following grants: NSTC 113-2314-B-039-057-from the National Science and Technology Council, Taiwan; a research grant (1JA8) from the Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan; DMR-113-114, DMR-114-024, and DMR-114-109 from the China Medical University Hospital, Taichung, Taiwan.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBurns MD, Bartsch YC, Davis JP, Boribong BP, Loiselle M, Kang J, Kane AS, Edlow AG, Fasano A, Alter G et al (2023) Long-term humoral signatures following acute pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children. 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NPJ vaccines 7(1):101. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41541-022-00526-5\u003c/span\u003e\u003cspan address=\"10.1038/s41541-022-00526-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"China Medical University Children's Hospital","isAcceptedByJournal":false,"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":"SARS-CoV2 infection, Post-acute sequelae of SARS-CoV-2 infection, impulse oscillometry, long COVID syndrome, vaccination","lastPublishedDoi":"10.21203/rs.3.rs-7135121/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7135121/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID syndrome (LCS), is characterized by persistent symptoms following SARS-CoV-2 infection and poses significant health challenges, particularly impactingpulmonary function in children. This study aims to evaluate the effect of COVID-19 vaccination on pulmonary function in children with PASC using standardized spirometry and impulse oscillometry (IOS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This prospective, observational study was conducted from July to September 2022, at the tertiary medical center of children’s hospital in central Taiwan. Pediatric patients aged 6 to 18 years diagnosed with PASC were enrolled. Demographic data, vaccination status, and blood test results were collected. Pulmonary function was assessed using spirometry and IOS, measuring parameters such as respiratory resistance (R5, R20) and reactance (X5). Statistical analyses explored the association between IOS results and clinical symptoms, as well as vaccination status.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 209 children, 78.7% were vaccinated. IOS detected abnormalities in 74.6%, with 12.0% diagnosed with obstructive lung disease (OLD) and 62.9% with small airway disease (SAD). Fatigue (56.0%) and dyspnea (52.0%) were most common in OLD, while chest pain (45.0%) and cough (41.7%) prevailed in SAD. Vaccinated children showed significantly lower respiratory resistance (R5, R20, p\u0026lt;0.01) and improved reactance (X5, p\u0026lt;0.001). Vaccination did not significantly reduce respiratory-related symptoms but was associated with lower risks of decreased appetite (OR=0.399) and sleep disturbance (OR=0.345).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eCOVID-19 vaccination may have a protective effect on pulmonary function in children with PASC, highlighting it’s in mitigating long-term respiratory complications. Further studies are needed to explore underlying mechanisms.\u003c/p\u003e","manuscriptTitle":"Assessment of Pulmonary Function in Children with Post-Acute Sequelae of COVID (PASC) Using Impulse Oscillometry and the Role of Vaccination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 15:05:32","doi":"10.21203/rs.3.rs-7135121/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":"56180e89-e9ba-4b40-9db1-75884f3490b0","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51597302,"name":"Pediatrics"},{"id":51597303,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2025-07-18T15:05:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 15:05:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7135121","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7135121","identity":"rs-7135121","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}