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Impact of SARS-CoV-2 viral load on restrictive spirometry patterns in mild COVID-19 recovered middle-aged individuals: a six-month prospective study
BMC Infectious Diseases volume 24, Article number: 1089 (2024)
Abstract
Background
Long term respiratory complications of Corona Virus Disease-2019 (COVID-19) are of great concern. Many studies have reported altered respiratory patterns in COVID-19 recovered individuals and most of them were from severe to critically ill patients. The association of viral load at the time of infection with symptoms of long COVID-19 specifically on pulmonary functions after months of recovery is still not known. This study was aimed to assess the impact of SARS-CoV-2 viral load during mild-moderate COVID-19 disease on pulmonary functions in middle-aged population after 6–8 months of acute infection.
Methods
This study included 300 (102 healthy controls and 198 COVID-19 recovered) individuals between age 30–60 of either gender. Mild-moderate COVID-19 recovered individuals were recruited between a period of 6–8 months post-acute infection. Spirometry was performed with MIR-Spirolab-III. The association of spirometry pattern was compared with SARS-CoV-2 viral loads during acute infection.
Results
We observed up to 70% of the participants presented with either shortness of breath (11.5%), body aches (23.5%), recurrent cough (4.4%), recurrent respiratory infections (9.5%) and/or fatigue (33.3%) at follow up. In our study, 35.5% of COVID-19 recovered individuals had abnormal respiratory patterns (33.5% had restrictive and 2% had obstructive patterns). Viral load ≤ 20 CT value was associated with restrictive respiratory patterns (p = 0.004). No association was found between viral load and disease severity (p = 0.23).
Conclusion
In this study, we found one third of mild-moderate COVID-19 recovered individuals have restrictive respiratory patterns after 6–8 months of recovery. These findings had a strong association with SARS-CoV-2 viral loads during acute infection which has been reported for the first time in our study. Studying the relationship between viral load and pulmonary functions can contribute to identifying potential risk factors for long COVID and developing preventive measures to mitigate the long-term impact on lung health.
Clinical trial number
Not applicable.
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causative pathogen of the COVID-19 pandemic [1]. According to World Health Organization (WHO), as of 25 May 2024, there were more than 7 billion cases and above 6 million cumulative deaths with COVID-19 worldwide [2]. The spectrum of disease severity is extremely heterogenous varying from asymptomatic cases to severe respiratory distress depending on multiple factors including host-pathogen interface, host immune response, and SARS-CoV-2 viral load [3]. Lungs are primary target of SARS-CoV-2 however other organs and systems have also been reported to be affected in COVID-19 including gastrointestinal tract, kidneys, liver, nervous system and cardiovascular system [4].
The SARS-CoV-2 virus affects the lungs in both acute and long-term conditions in several ways. In the acute phase, the virus enters the respiratory tract via ACE-2 receptors and leads to activation of host immune response. This can lead to inflammation and damage to the lung tissue, resulting in symptoms such as cough, shortness of breath, and in severe cases, may lead to respiratory distress [5]. In the long term, individuals may experience lingering effects on their lung function even after recovery. This may be characterized by reduced lung volumes and a decreased elasticity of the lungs impacting the lung volumes and capacities [6]. Several researches have been carried out to study the impact COVID-19 on pulmonary function post recovery ranging from 6 weeks to 12 months after recovery. It is a well established fact that significant number of severe-critical COVID-19 recovered individuals tend to present with restrictive respiratory pattern even after several months of being apparently covid-free [7]. Moreover, COVID-19 is also known to affect pulmonary function after recovery in mild-moderate individuals [8], which is comparatively less than severe-critical recovered patients.
The possibility that these effects are associated with the quantity of virus (viral load; measured in cycle threshold: the CT value) in the host is of great interest and rising concern among both scientists and clinicians. Studies have consistently shown that severe COVID-19 is associated with higher viral loads with severe respiratory symptoms [9]. This is crucial because the respiratory tract is a key area where the virus replicates and spreads. Understanding viral load dynamics during infection is vital in uncovering the complex relationship between SARS-CoV-2 and pulmonary function in the post infection era. To date, we could not find in literature, the association of viral load with post recovery pulmonary functions in mild-moderate COVID-19 recovered individuals. This study was performed to assess the impact of SARS-CoV-2 viral load at the time of infection on pulmonary functions after 6–8 months of recovery in middle-aged individuals.
Methods
Study description
In this follow up study, a total of 300 participants were recruited from Dow University Hospital (DUH) and Sindh Infectious Diseases Hospital & Research Center (SIDHRC) of Karachi Pakistan from February 2022 to June 2023. The sample size was estimated from a reference study [10]. We took controls and cases with 1:2 respectively.
Ethical statement
The study was conducted as per ethical guidelines of declaration of Helsinki. It was approved by Institutional Review Board (IRB) of DUH. The ERC approval reference number is IRB-2342/DUHS/Approval/2021 − 713. The participants were recruited in the study after written informed consent.
Recruitment of participants
COVID-19 recovered (CR) group
A sum of 198 participants having age 30–60 years (middle-aged) with either gender, who had recovered from COVID-19 pneumonia after six-eight months of onset of symptoms, who came for follow-up were included in the study. Those who had mild or moderate disease were included. The disease categorization was done according to WHO criteria [11]. We also used another approach for including participants in our study, where we retrospectively collected data of positive RT-PCR for COVID-19 from our laboratory and recruited participants by calling them. Those who fulfilled inclusion criteria and provided consent to participate, were called to the clinics.
Exclusion criteria were asymptomatic or severe-critical COVID-19 disease, smokers, known case of respiratory diseases including chronic obstructive pulmonary disease (COPD), restrictive lung patterns including Idiopathic Pulmonary Fibrosis (IPF), Interstitial Lung Disease (ILD), sclerosis, history of diabetes, known history (based on verbal recollection) of recent acute viral infection or chronic (Hepatitis B / C / HIV) infection, history of active TB and pregnancy.
Healthy control (HC) group
In total, 102 healthy individuals of either gender were included in the study with the same exclusion criteria. HC group were either attendants of the patients or volunteer staff from the same hospital who never got a positive RT-PCR or related symptoms of COVID-19 during the study period.
Data collection
In all participants, at the time of recruitment, data regarding age, gender, symptoms of COVID-19, COVID-19 severity, current presenting complains related to COVID-19 was collected.
Assessment of viral load at the time of infection
Only those who got tested from Dow Diagnostic Research and Reference Lab (DDRRL) were included in the study. The Data regarding viral load in CT value was retrieved from the lab retrospectively. Viral load was categorized into CT value ≤ 20, 20.1 to 30 and > 30. RT-PCR performed within 72 h of development of COVID-19 symptoms were included in the study.
Pulmonary function test by Spirometry
The spirometry was performed in willing participants with the help of a trained staff with portable MIR-Spirolab-III machine. Those who were able to complete the spirometry were further included in the study. The respiratory patterns were defined as normal or abnormal (restrictive or obstructive) as per American Thoracic Society/European Respiratory Society (ATS/ERS) as FEV1/FVC and FVC lying above or below 5th percentile respectively [12].
Statistical analysis
Statistical analysis was carried out using the Statistical Packages for Social Sciences (SPSS) version 22 and GraphPad PRISM version 8.1. The Pearson Chi square test was used to compare categorical data. While independent T test was used to compare the continuous data. We further used regression analysis to study the association and predictors of respiratory patterns with SARS-CoV-2 viral load and other variables of the study.
Results
Demographic characteristics of the participants
In total, our study included 300 participants, of which 198 were COVID 19 recovered (CR) individuals, and the remaining were healthy controls (HC). Among total, 60% of them were male, and 40% were female. The most prominent respiratory symptoms at the time of infection were cough (42.4%) followed by Flu (24.7%), Shortness of Breath (SOB;15.6%), and fever (12.1%). Of the total CR individuals, 128/198 (64.6%) had mild covid (Table 1). The presenting complains by study participants at the time of recruitment are shown in Fig. 1.
Spirometry patterns of study participants
We found 35.5% and 5.5% of participants having abnormal respiratory patterns in CR and HC groups respectively (p < 0.05, having 33.5% and 2% of restrictive and obstructive respiratory patterns in CR group respectively). Normal respiratory pattern was found in 94.5% and 64.5% of HC and CR groups respectively (p < 0.05; Fig. 2).
Association of respiratory patterns with study variables
The mean age of CR group was 43.32 ± 6.76. There were 128 (64.5%) individuals with normal spirometry results and 70 (35.5%) participants with abnormal respiratory pattern (restrictive and obstructive were combined). There was no difference in age or gender between individuals with normal and abnormal respiratory patterns (p = 0.51) Cough was the predominant symptom (42.4%) among CR group. Of the 70 participants with abnormal respiratory patterns, 40 (57.2%) had moderate COVID 19 while remaining had mild COVID-19 (Table 2). A higher number of moderate COVID-19 diseased were found to have abnormal respiratory patterns as compared to mild diseased (57% vs. 23.5%; p value < 0.001: Fig. 3).
Association SARS-CoV-2 viral load with study variables
We further evaluated the association of SARS-CoV-2 viral load with age, gender, disease severity and respiratory patterns. We found no association of viral load with age, gender, and disease severity of study participants (p = NS; Table 3).
Association of SARS-CoV-2 viral load with spirometry pattern at follow up
We then retrospectively saw the viral load at the time of infection of the recovered individuals. We categorized the viral load as mentioned above (methods). There were 42/198 (21.2%) participants with CT value ≤ 20. However, there were 100/198 (50.5%) who had CT value 20.1 to 30 while 56/198 (28.3%) had CT value of > 30. We found a strong association of viral load during the time of infection with restrictive spirometry patterns after 6–8 months follow up in these middle-aged individuals (p = 0.004). Those who had viral load ≤ 20, we found 24/42 (57.14%) had abnormal respiratory patterns (Fig. 4).
Regression analysis of respiratory patterns with study variables
We further explored the variation in respiratory patterns associated with our study variables through regression analysis. Multivariate analysis revealed disease severity and SARS-CoV-2 viral load as strong predictors of abnormal respiratory patterns. We found moderate disease severity to be a significant predictor of abnormal respiratory patterns (p < 0.001 with odds of 1.231) while CT value ≤ 20 was also associated with increased odds of having abnormal respiratory patterns (p < 0.001 with odds of 2.140). We did not find any relation with age, gender or time since acute COVID-19 disease (data not shown).
Discussion
In our study, we found 33.5% of COVID-19 recovered middle-aged individuals with restrictive respiratory patterns at time point of six months post infection. This was found more frequently among moderate as compared to mild COVID-19 recovered individuals. We also found a strong association of restrictive respiratory patterns with SARS-CoV-2 viral load at the time of infection.
We found presenting complaints were significantly more prevalent in the COVID-19 recovered group as compared to the controls with the most prevalent respiratory symptoms being shortness of breath, flu and cough. COVID-19 is known to have long term impact on multiple organ systems other than respiratory system even after recovery [13]. Persistence of respiratory symptoms like dyspnea, chest pain, flu and cough after acute COVID-19 are possibly due to long-term lung damage and unresolved inflammation even after several months of infection [14]. The persistence of these symptoms is not necessarily related to severity of initial infection, hence indicating a complex interplay of factors which are not fully understood yet. However, residual viral particles or immune response to the initial infection may continue to affect the respiratory system [15]. Furthermore, we also found fatigue, myalgia, muscle weakness and arthralgia in COVID-19 recovered participants. Musculoskeletal symptoms after COVID-19 are more commonly observed in recovered individuals. Fatigue and myalgia are often linked to chronic inflammation, ongoing immune dysregulation, microvascular dysfunctional and neuroinflammation affecting muscle tissues leading to pain and discomfort [16]. Our results are in accordance with large-scale studies in China and the United Kingdom identifying fatigue as the most common Post-COVID symptom [17, 18]. In another study, Augustin et al. has shown up to 50% of non-hospitalized COVID-19 recovered patients with presence of any one symptom among anosmia, ageusia, fatigue or dyspnea up to seven months of recovery [19]. Davis et al. depicted fatigue and cognitive dysfunction to be among the most commonly encountered symptoms at 6 months post mild to moderate COVID-19 infection [20] however, we did not assess the cognitive functions of the study individuals. Carfi et al. reported most common post COVID-19 symptoms which consisted of shortness of breath, fatigue, dyspnea and cough [21] and this is also in concordance with our study.
We further investigated the respiratory patterns in mild-moderate COVID-19 recovered participants after 6 months of recovery. We found a significant number of individuals (33.5%) with restrictive respiratory patterns. Among those, 42.4% were from mild and 57.6% were from moderate COVID-19 recovered individuals. Changes in the morphology and function of pulmonary endothelial cells are characteristic features of COVID-19 [22]. SARS-CoV-2 has profound impact on interstitial lung changes which reduces lung volume and compliance leading to respiratory symptoms [23]. Persistent inflammation, endothelial dysfunction, and microvascular damage contribute to these changes leading to reduced lung capacity and impaired gas exchange [24]. Our data has shown a higher number of affected individuals than in a Mexican study which has shown restrictive lung impairment as most common spirometry measurement in 17% (20/115), of whom 65% (13/20) had mild COVID-19 [25]. However, our results have shown a higher number (57.6%) of individuals with restrictive respiratory patterns who had moderate COVID-19. Arturo et al. also reported 20% of mild COVID-19 recovered participants having restrictive respiratory patterns even after 2 months of recovery [26] and their numbers were less as compared to our study.
The dynamics of SARS CoV-2 viral load and its association with different clinical parameters remain poorly characterized in the patient population. Viral load might propose the disease prognosis in individuals with less effective immune system however, high viral load has been shown even in asymptomatic or mild COVID-19 individuals [27]. We did not find any association of viral load with disease severity, symptoms at the time of infection or time since recovery. Individuals with older age and comorbid conditions like diabetes mellitus tend to have poor COVID-19 prognosis associated with high viral loads [28]. In younger population, the association of viral load with disease outcome have not been well established till date. A study has shown no difference in viral load between asymptomatic and symptomatic COVID-19 disease in middle-aged Korean population [29]. In contrast, a study has shown high viral load to be associated with severe COVID-19 and hospitalization of individuals [30] however, hospitalized individuals were of older age in that cohort.
Several pathways including hypoxia, inflammation and complement activation have been proposed as possible drivers of pulmonary vascular injury mediated by SARS-CoV-2 infection. The long term affects of the viral load acquired during acute COVID-19 and its lasting impact on potential to further damage the pulmonary function over the years has not been studied yet. Hence, we further retrospectively collected the data of individuals for the viral load in CT values of RT-PCR during acute infection. We found high SARS-CoV-2 viral load has a strong association with restrictive respiratory pattern. Individuals with viral load ≤ 20 CT tend to have restrictive breathing patterns. This was further confirmed by regression analysis that viral load being a strong predictor of abnormal respiratory pattern. To the best of our knowledge, our study is the first one which has reported the association of viral load at the time of infection with respiratory patterns after 6 months of acute infection. The impact of COVID-19 infection on lung functions lasts even after 12 months of recovery which impacts the quality of life of the patients [31]. How the viral load impacts the pulmonary functions in apparently less severe diseased individuals after 6 months of recovery and the pathophysiology behind it is yet to be understood.
Conclusion
Viral load at the time of infection has an association with respiratory patterns in mild-moderate middle-aged individuals at six months post recovery. With further analysis, the viral load at the time of acute infection was known to be a strong predictor of restrictive respiratory pattern. Studying the relationship between viral load and pulmonary functions can contribute to identify potential risk factors for long COVID and developing preventive measures to mitigate the long-term impact on respiratory health. Furthermore, studying the viral loads during acute infection may also be helpful in understanding the lasting effects of COVID-19 in population suffering from long COVID.
Limitations of the study
The study has a limitation as there were no previous or pre-COVID-19 spirometry results available from the study participants. Furthermore, unrecognized pre-existing conditions or lifestyle factors or exposures that could affect the pulmonary functions could not be ruled out as clinical history was based on verbal information provided by the participants; however, we tried our best to exclude the conditions mentioned in exclusion criteria. Moreover, the viral load was collected from a single laboratory which might have introduced a selection bias.
Data availability
All data has been included in the study however it is available with the corresponding author and may be provided on request.
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Acknowledgements
We acknowledge the study participants of the study. We also acknowledge the faculty and staff of Sindh Institute of Infectious Diseases & Research and department of Physiology, Dow International Medical College, Karachi, Pakistan.
Funding
No funding was applied for this study.
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Contributions
Conception/design of the work: UA, IA, SA, SF. Data collection, data analysis and interpretation: UA, AA, FR, NH. Drafting the article: UA, PK, IAB, MY, NH, ZHJ, SF. Critical revision of the article, and final approval: UA, AA. All authors have read and approved the final manuscript.
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Ethics approval and consent to participate
This study was approved by the Institutional Review Board (IRB) of Dow University of Health Sciences. Approval no. DUHS/2022/2342. Written informed consent was obtained from all the participants for the study.
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The authors declare no competing interests.
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Abbas, U., Ahmed, I., Afshan, S. et al. Impact of SARS-CoV-2 viral load on restrictive spirometry patterns in mild COVID-19 recovered middle-aged individuals: a six-month prospective study. BMC Infect Dis 24, 1089 (2024). https://doi.org/10.1186/s12879-024-09959-w
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DOI: https://doi.org/10.1186/s12879-024-09959-w