Variation in the prevalence of cough symptoms 4–5 days after infection with SARS‐CoV‐2 between seasons with different prevalent strains

Abstract Background The coronavirus disease 2019 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains a major global health concern in 2022. The association between the rapid spread of the variants, which eliminated the original strain, and clinical manifestations with the variants remains undetermined. Methods This was a population‐based longitudinal cohort study. Whole citizens in a city with approximately one million population who had contacted COVID‐19 patients and were tested by nasopharyngeal SARS‐CoV‐2 reverse transcription‐polymerase chain reaction (RT‐PCR) swab test between July 2020 and March 2021 were enrolled. Detailed contact episode and the presence of cough symptoms 4–5 days after contact with patients having COVID‐19 were evaluated. Results Among the 359 RT‐PCR test‐positive patients, 88 (24.5%) developed cough symptoms by 4–5 days from the infection. The same rate in RT‐PCR test‐negative cases was 8.6%. The prevalence of cough did not significantly differ by age, sex, and places or closeness of the contact episode. The rate of cough symptoms in RT‐PCR test‐positive patients increased in February–March 2021 with E484K variant predominance compared to that in July–December 2020 with the original strain (32.9% vs 19.4%, p = 0.0221), whereas the cough prevalence among RT‐PCR test‐negative population did not increase. Cough symptoms in COVID‐19 patients was associated with strong fatigability, but was independent from fever or dysosmia. Conclusions Cough symptoms 4–5 days after infection with SARS‐CoV‐2 was suggested to have increased with E484K variant, compared to the original strain.


| INTRODUC TI ON
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remained a major global health concern in 2021. 1 The continuous appearance and spread of new consequential variants has intermittently caused a large-scale pandemic. [2][3][4] In parallel with the intermittent appearance of consequential variants, many factors, such as predominant variants, prevalence, and social circumstances, have dynamically changed after the onset of the COVID-19 pandemic in various countries, including Japan. In 2020, Japan's major prevailing viral strain was the original strain that has been replaced by other strains of E484K or N501Y lines since February 2021. Subsequently, the dominant strains were replaced by the Delta and Omicron variants. 5 These consequential variants with increased transmissibility spread faster, but the reasons and mechanisms of their rapid spread have not yet been fully elucidated. For example, the symptoms of SARS-CoV-2 testpositive individuals in the early stages of the disease may have varied over time. Therefore, we aimed to investigate the difference in the symptoms of COVID-19 between the early and later phases of the pandemic to elucidate the symptom characteristics among patients with COVID-19. This population-based cohort study focused on the key COVID-19 symptoms 4-5 days after infection and compared the incidence of each symptom between different phases of the pandemic.

| Participants
The participants were the all individuals in Sendai City, Japan, who had contacted COVID-19 patients and checked for the in-

| Closeness of contact
A history of close contact with COVID-19 patients was judged by the local government staff in public health centers based on the fulfillment of all of the following four criteria: (1) contact from 2 days before to 14 days after the onset of symptoms or the positive RT-PCR test results; (2) not wearing masks; (3) <1 m distance; and (4) ≥15 min of contact. These criteria were not changed during the whole study period.

| Evaluated outcomes
Information regarding the age, sex, RT-PCR test results, and place and closeness of the contact episode were collected in advance upon registration before sampling. Body temperature and the presence of COVID-19-related key symptoms (cough, dyspnea, body temperature ≥37.5°C, fatigability, dysosmia, and dysgeusia) were self-reported and recorded at the time of the nasopharyngeal swab test, scheduled 4-5 days after contact with patients having COVID-19.

| Statistical analysis
Comparisons of the prevalence data were performed by chi-square test or Fisher exact test, according to the number of individuals in each cell. Comparisons of the quantitative data were performed by the Student's t-test or Mann-Whitney U test, according to the distribution patterns of the variables. p = 0.05 was used for the statistical significance. For each of the key COVID-19 symptoms, characteristics for estimating SARS-CoV-2 RT-PCR test positivity, such as sensitivity, specificity, positive predictive value, and negative predictive value, were calculated. The Wald method was used to estimate the 95% confidence intervals for the incidence of key COVID-19 symptoms in RT-PCR test-positive and test-negative individuals. 7 Statistical analyses were performed with R Statistical Software (version 4.0.5; R Foundation).

| Ethics
The institutional review board of Tohoku University approved the present study (IRB approval number: 2021-1-705). The need for informed consent was waived to minimize the risk of transmission at the testing center. Consent was secured in an opt-out manner.
Both of these processes were approved by the institutional review board. The whole process of this study was conducted in accordance with the Declaration of Helsinki of 1975, as revised in 2013.

| Participants
A total of 5042 individuals (2712 males and 2330 females), who had recently contacted COVID-19 patients and underwent RT-PCR screening test performed by the local government between July 2020 and March 2021 were enrolled in this population-based longitudinal observational study. Among them, 2639 (52.3%) were with high-risk contact history and 2403 (47.7%) were with low-risk contact history. All tested individuals were collected their nasopharyngeal swab samples at a single testing center located in the city.

| Cough symptoms during the whole study periods
In the whole 359 RT-PCR test-positive individuals, cough symptoms 4-5 days after infection was seen in 88 (24.5%) of them. The rate of cough symptoms was 18.3% (n = 11/60) in the patients aged The rate of cough symptoms 4-5 days after infection among RT-PCR test-positive cases in those who had household infection from other family members was 25.0% (n = 30/120), which was not significantly different from the rate among the whole patients after a high-risk contact or among the patients after a low-risk contact.
In the 4,683 RT-PCR test-negative individuals, cough symptoms 4-5 days after the contact history was seen in 404 (8.6%) of them.
The rate of cough symptoms was 7.3% (n = 174/2,383) among the RT-PCR test-negative individuals after a high-risk contact, and was 10.0% (n = 230/2298) among the test-negative individuals after a low-risk contact. The rate of cough symptoms 4-5 days after contact among RT-PCR test-negative cases was slightly higher among those who had low-risk contacts than those who had high-risk contact (p = 0.0010, chi-square test). This could be because of the background that all people who had high-risk contact underwent nasopharyngeal RT-PCR swab test, whereas some of the symptomfree individuals who had low-risk contacts with patients may have reserved to take the screening test. This could explain the slightly higher cough prevalence in the RT-PCR test-positive cases after a low-risk contact than in those after a high-risk contact, and may imply that some asymptomatic people after a low-risk contact with COVID-19 patients, who were actually with SARS-CoV-2 virus, did RT-PCR test-positive patients was higher in adults aged ≥18 years than in non-adults aged <18 years, suggesting that the rate of asymptomatic COVID-19 patients might be lower in non-adults aged <18 years than adults aged ≥18 years.

| Cough symptoms during each study period
Next, the prevalence of the aforementioned key COVID-19 symptoms in RT-PCR test-positive and test-negative individuals in four different seasons was evaluated (Table 1). In all seasons, the preva-   Table 2.

| Associations between the cough symptoms and other COVID-19 core symptoms
The development of cough symptoms at 4-5 days after infection among COVID-19 patients was associated with the increased rate of developing dyspnea and fatigability, but was not associated with an increased rate of developing dysosmia or dysgeusia.

| DISCUSS ION
Similar to other countries, Japan has also faced intermittent nationwide pandemic of COVID-19 infection with multiple consequential variants in 2021. Most of the consequential variants had mutations in genes encoding spike protein, supposedly causing an increased transmissibility after a contact with patients. Increased ability of immune escape in variants could be a major factor that facilitated the increased transmissibility of the variants. 8,9 The results of this study suggested that an increased prevalence of cough symptoms in the early disease stages could be another factor that could have facilitated the increased transmissibility of the variants. By now, it remains controversial whether the incidence of symptoms was changed with variants from the original strain. Meanwhile, some recent studies demonstrated that clinical TA B L E 1 Predictive impacts of each key COVID-19 symptom for RT-PCR test positivity

Specificity of each symptom PPV NPV
July-October 2020 (original strain predominant)

| Limitations
A limitation of this study was that a viral load in sputum from pa-

ACK N OWLED G M ENTS
The authors appreciate all medical staffs and local government staffs (Sendai City, Miyagi Prefecture) who joined and cooperated to the drive-through RT-PCR testing project. Also, the authors appreciate the local government staffs of Sendai City for offering the whole population data after a close contact with patients in the locality.

CO N FLI C T O F I NTE R E S T
The authors have stated explicitly that there are no conflicts of interest in connection with this article.