Prevalence of persistent symptoms at least 1 month after SARS-CoV-2 Omicron infection in adults

Abstract

Background:

Persistent post-COVID-19 symptoms pose an important health care burden. The Omicron variant has rapidly spread across the world and infected millions of people, largely exceeding previous variants. The potential for many of these people to develop persistent symptoms is a major public health concern. The aim of this study was to determine the prevalence and risk factors of post-COVID-19 symptoms associated with Omicron.

Methods:

We conducted a single-centre prospective observational study in Quebec, Canada, between December 2021 and April 2022. Participants were adults enrolled in the Biobanque Québécoise de la COVID-19 (BQC19). Cases were considered Omicron cases as more than 85% were estimated to be attributable to Omicron variant during that period. Adults with polymerase chain reaction (PCR)-confirmed COVID-19 were recruited at least 4 weeks after the onset of infection.

Results:

Of 1,338 individuals contacted, 290 (21.7%) participants were recruited in BQC19 during that period. Median duration between the initial PCR test and follow-up was 44 days (IQR 31–56 d). A total of 137 (47.2%) participants reported symptoms at least 1-month post-infection. The majority (98.6%) had a history of mild COVID-19 illness. Most common persistent symptoms included fatigue (48.2%), shortness of breath (32.6%), and cough (24.1%). Number of symptoms during acute COVID-19 was identified as a risk factor for post-COVID-19 symptoms (OR 1.07 [95% CI 1.03% to 1.10%] p = 0.009).

Conclusions:

This is the first study reporting the prevalence of post-COVID-19 symptoms associated with Omicron in Canada. These findings will have important implications for provincial services planning.

Introduction

The COVID-19 pandemic has posed a major challenge for health systems, affected individuals, and policymakers. COVID-19 has become a global pandemic with 513 million cumulative cases worldwide (1) and close to 4 million confirmed cases in Canada as of May 27, 2022 (2). Omicron (B.1.1.529) is the most recent SARS-CoV-2 variant of concern to emerge during this pandemic. At the end of November 2021 in Quebec, Canada, Omicron rapidly replaced the previous circulating stain, the Delta variant (B.1.617.2) (3). Due to increased transmissibility and lower vaccine effectiveness (4–7), it has rapidly spread across the world within weeks, exceeding all previously reported cases. By mid-December 2021, it was estimated that most (86%) polymerase chain reaction (PCR)-confirmed cases reported in Quebec were associated with the Omicron variant and by mid-January 2022, it was nearly 100% of cases (3). However, the true magnitude of the Quebec Omicron surge was likely underestimated by routine SARS-CoV-2 surveillance because individuals who tested positive using an antigen test were not captured.

Following the onset of acute COVID-19, it has been observed that individuals may develop persistent post-COVID-19 symptoms well beyond the acute phase of the disease. An increasing number of patients are presenting with lingering symptoms (8–10). Most common symptoms include extreme fatigue, post-exertional malaise, shortness of breath, and neurocognitive symptoms, but more than 200 symptoms have been reported, affecting nearly any organ system (9). These persistent symptoms are often debilitating and usually have an important impact on the functional status of affected individuals (11,12). The prognosis has not been clearly established but symptoms may last for months if not years with little improvement (13). The prevalence of persistent post-COVID-19 symptoms reported by various studies before the Omicron surge has ranged from 13% to 76% (14–17). Reasons for these differences include the population studied, the methodological approaches used, the severity of the disease, the population size, and the vaccinal status.

The prevalence of persistent post-COVID-19 symptoms associated with the Omicron is unknown in Canada. As the number of new infections continue to grow, it is critical to assess the prevalence of post-COVID-19 sequelae because of the potential impact that affected individuals will have on health care systems. Symptoms associated with Omicron have been shown to differ from previous variants of concern, such as the Delta variant, during the acute phase of the disease (5). It is therefore possible that the prevalence of post-acute symptoms may also differ between these two variants. The aim of this study was to determine the prevalence of Omicron-associated symptoms 4 weeks or more after the onset of the disease and identify risk factors associated with persistent symptoms in adults.

Material and Methods

Study design and participants

The Biobanque Québécoise de la COVID-19 (BQC19) is a biobank initiative undertaken in Quebec, Canada, of individuals with confirmed SARS-CoV-2 infection. Study design and procedures have been described in detail elsewhere (18). Enrolment of participants with different disease severity has been ongoing since March 26, 2020, in different centres including ours, throughout Quebec. Taking advantage of this biobanking effort, we conducted a single centre, prospective observational study, in the Estrie region of Quebec, between December 13, 2021, and April 24, 2022. This study included adults that were diagnosed with COVID-19 infections by the microbiological laboratory of the Centre Hospitalier Universitaire de l’Estrie (CHUS), which deserves a population of 300,000. Individuals who were diagnosed by a rapid antigen test were not included in this study. Patients were first contacted by phone during acute infection to determine whether they would be willing to participate to Biobanque Québécoise COVID-19 (BQC19). Those who were enrolled in BQC19 were contacted again at least 30 days after their positive test and interviewed for new or persistent symptoms. Phone and in-person interviews (determine by participant's choice) were conducted by trained research personal in administrating the standardized questionnaire. We excluded all patients who died within the first 30 days following their diagnosis of COVID-19 (n = 3). All vaccinated participants received mRNA-based vaccines (Pfizer or Moderna). This study was approved by the ethic review board of the Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CRCHUS ME0-02-2021-3172; MP-02-2020-8929).

Data Collection

The questionnaire included details on demographic data including age, sex, weight, height, BMI, COVID-19 vaccination status, and injection dates, smoking status, history of hypertension, history of chronic cardiovascular disease, history of chronic pulmonary diseases (excluding asthma), asthma, history of hepatic disease, history of kidney disease, history of chronic neurologic disease, history of active cancer, HIV status, asplenia, and history of immunosuppressive drugs (18). Acute and persistent symptoms were captured using a 28-symptom questionnaire. Acute SARS-CoV-2 infection severity was categorized as asymptomatic, mild, moderate, and severe according to the World Health Organization definition (19).

Statistical Analysis

Data were presented using descriptive statistics for the complete sample, but also separated for the presence of persistent symptoms. Continuous variables were expressed as mean (SD) when data was normally distributed and as median (Interquartile ranges). Nominal variables were presented as frequency and percentage. Normality was assessed visually with histogram and Q-Q plots. No imputation method was used, missing data were only reported when present. A significative level of 5% was used. Results were obtained using SP55 v.26 (IBM Corp., Armonk, NY) and R v.4.0.2 (R Core Team, Vienna, Austria).

With regards to the main objective, prevalence of persistent symptoms was reported using frequency and percentage with a 95% CI. For the secondary aim, simple log-binomial regressions models were used to separately analyze the strength of association between participant baseline characteristics and persistent symptoms. Effect sizes were presented as relative risk ratios (RR) with their 95% CI. All variables were then added in a multiple log-binomial regression model and presented using adjusted relative risk ratio (aRR) with 95% CI. Results were obtained using R logbin package.

Results

A total of 1,338 individuals in the Estrie region who tested positive for SARS-CoV-2 by PCR were contacted between December 13, 2021 and April 24, 2022. Of those, 453 (33.9%) agreed to participate. The remaining (n = 885, 66.1%) refused to participate or could not be reached for their 1-month follow-up. The main reasons for refusing to participate to BQC19 included lack of interest and lack of time. Among the 453 who agreed to participate, 163 had missing data leaving out a total of 290 participants which were included in this study. These cases were considered Omicron cases as more than 86% of SARS-CoV-2 infections during the study period were attributable of the Omicron variant in Quebec (5). To examine sub-sample for attrition bias, we compared the baseline data of the study participants to those who were contacted but refused to participate and those who accepted to participate but for which data were missing. There was no significant difference between those who refused to participate, those with missing data, and those who participated regarding age, sex, initial COVID-19 severity, proportion vaccinated, and health care worker proportion.

Mean age of 290 BQC19 participants was 41.5 years (range 19.2–87.7 y). Most were female (215 participants; 74.1%), and the majority was health care workers (71.7%). Most participants had mild COVID-19 (98.6%) and were symptomatic (97.6%). Overall, 97 (33.4%) participants reported having a comorbidity. Most participants were fully vaccinated (>96%).

Persistent Post-COVID-19 Symptoms in Study Participants

Of the 290 COVID-19-positive participants recruited in this study, 137 (47.2% [41.6%–53.0%]) reported having symptoms at least 30 days after testing positive (Table 1). Median duration between the SARS-CoV-2 PCR positive test and phone interview was 44 days (IQR 31–56 d). There was no difference between participants without persistent and participants with persistent 30 days symptom groups, regarding sex, initial COVID-19 severity, proportion vaccinated, overall number of comorbidities, and health care worker proportion (Table 1). Participants with persistent symptoms were slightly older (43.8 versus 40.3 years; p = 0.012) and had a higher BMI (26.6 kg/m² versus 25.2 kg/m²; p = 0.012). Among those who reported having a comorbidity, the most common was asthma, followed by hypertension, and diabetes. Asthma was more prevalent in the group with persistent symptoms (16.1% versus 8.5%; p = 0.048). However, there was no difference with regards to the prevalence of comorbidities between the two groups. The most common persistent symptoms included fatigue (48.2%), shortness of breath (32.8%), cough (24.1%), and headaches (18.2%) (Figure 1). There was a significant reduction in the median number of symptoms from 7 (IQR 5–9) at disease onset to 2 (IQR 1–3) after 4 weeks.

Table 1:

Characteristics of study population according to 30 days symptoms

Characteristics	No persistent symptoms	Persistent symptoms	p-value
COVID-19 infections, no. (%)	153 (52.8)	137 (47.2)
Mean (SD) age, y	40.3 (11.7)	42.8 (12.0)	0.071
Female sex, no. (%)	111 (72.5)	104 (75.9)	0.514
BMI, kg/m2, median (IQR)	25.2 (22.2–29.6)	26.6 (23.5–30.9)	0.012
Active smoking status, no. (%)	8 (5.2)	7 (5.1)	0.936
Health care workers, no. (%)	113 (73.9)	95 (69.3)	0.394
Comorbidities, no. (%)
Hypertension	15 (9.8)	14 (10.2)	0.934
Diabetes	5 (3.3)	10 (7.3)	0,122
Cardiovascular disease	9 (5.9)	2 (1.5)	0.490
Pulmonary disease	0 (0.0)	0 (0.0)	0
Asthma	13 (8.5)	22 (16.1)	0.048
Cancer	4 (2.6)	4 (2.9)	0.874
Comorbidities median (IQR)	0 (0–1)	0 (0–1)	0.660
Hospitalization	2 (1.3)	2 (1.5)	0.911
Vaccinated, ≥2 doses, no. (%)	148 (96.7)	132 (96.4)	0.821

Figure 1:

Spectrum of acute and post-COVID-19 symptoms

Note: The blue line graph represents the participants with symptoms (in percentage) during the acute infection and the red line represents participants with symptoms (in percentage) beyond 4 weeks from diagnosis

Clinical Risk Factors Associated with Development of Persistent Symptoms

We assessed the strength of association between the risk of having persistent post-COVID-19 symptoms. Different baseline factors including sex, age, BMI, vaccine dose (1, 2, or 3), number of comorbidities, and number of symptoms during acute COVID-19 were examined. On univariate analysis, only the BMI (RR 1.03 [95% CI 1.01% to 1.04%] p = 0.046) and the number of symptoms during acute COVID-19 (RR 1.07 [95% CI 1.05% to 1.11%] p = 0.001) were associated with an increased risk of having persistent post-COVID-19 symptoms (Table 2). In multivariable analysis, the number of symptoms during COVID-19 remained a significant risk factor for the development of persistent symptoms after 30 days (RR 1.07 [95% CI 1.01% to 1.10%] p = 0.009) (Table 2). Each additional symptom during the acute phase increases the risk of having persistent symptoms by 9%.

Table 2:

Univariate and multiple analysis of risk factor associated with persistent symptoms

Risk factors	RR (95% CI)	p-value	aRR (95% CI)	p-value
Sex	1.10 (0.82% to 1.47%)	0.635	1.01 (0.75% to 1.37%)	0.947
Age	1.01 (1.01% to 1.04%)	0.190	1.01 (1.00% to 1.02%)	0.300
Vaccination (dose number)	0.89 (0.76% to 1.04%)	0.314	0.92 (0.79% to 1.98%)	0.489
BMI	1.03 (1.01% to 1.04%)	0.046	1.02 (0.99% to 1.04%)	0.162
Number of symptoms during acute COVID*	1.08 (1.05% to 1.11%)	0.001	1.07 (1.03% to 1.10%)	0.009
Number of comorbidities*	1.05 (0.93% to 1.20%)	0.581	0.98 (0.86% to 1.12%)	0.838

^* Each one unit increase

RR = Relative risk; aRR = adjusted Relative risk

Discussion

The recent Omicron variant has affected millions of people in Canada. In that context, it is critical to estimate the prevalence of individual who will suffer from persistent post-COVID-19 symptoms, as this will increase the burden on health care resources. We believe this is the first study to report on persistent symptoms associated with infection by the Omicron variant from Canada. To reflect the current pandemic, our study included mostly individuals with mild disease. We found that nearly one out of two infected individuals reported having symptoms at least 30 days after their infection. This is in the same range of previous estimates of prevalence in the pre-Omicron surge, which ranged from 13% to 76% (14–17). This high rate of persistent symptoms was observed despite the high proportion of vaccination among participants. Among those having symptoms at 30 days, it is estimated that 50% to 75% will recover within 3 months. However, those who do not recover will show a significant and persistent alteration of their functional status for months and even years (19,20). Therefore, even if half of the individuals who show post-Omicron persistent symptoms at one month recover within 3 months, that still leave out a substantial number of people with limited recovery that will potentially seek health services in the next few months.

Consistent with existing literature with previous variant, the most reported symptoms after 30 days, were fatigue, shortness of breath, and cough. Neurocognitive symptoms such as brain fog, memory loss, and difficulty concentrating have been frequently reported as post-COVID-19 sequelae in other studies (21,22). In this study, there was a low prevalence of these symptoms in during acute infection and in those with persistent symptoms. The low prevalence in the persistent symptom group could be related to the limited time between diagnostic and recruitment (<60 days). It has been reported that neurocognitive symptoms often appear >120 days after acute infection (23).

Among other important findings that we observed was association between persistent symptoms at >30 days and the number of symptoms during the acute infection. Early disease features (number of symptoms with first week) have been previously associated with an increased risk of persistent symptoms at 30 days (24). It is important to identify risk factors for post-COVID-19 sequelae as this will help stratify patients who may benefit the most from follow up post-COVID-19 visits to initiate early interventions.

Study limitations include a relatively small sample size, single study location, lack of control group, overrepresentation of health care workers, and inclusion of PCR-confirmed infections. Given the low participation rate, there is a concern for a potential selection bias to favour those who had a more severe acute infection. However, individuals who refused to participate were comparable to the BQC19 participants regarding age, sex, and disease severity. Although we cannot rule out that people who had more comorbidities may have been more likely to participate, either because they had a more severe acute infection, or they were more concerned about longer term consequences, it is unlikely to have played a significant role as most participants (67%) reported no comorbidity. Most studies have included participants previously hospitalized for severe COVID-19, even though the vast majority of those who acquire SARS-CoV-2 do not require hospitalization. In that context, one advantage of our study is the fact that most participants had a mild infection.

Comprehensive long-term follow up investigation will be necessary to fully understand the impact of Omicron-associated post-acute sequelae. Nonetheless, our study provides, for the first time, an estimate for the potential health care burden related to Omicron in Quebec.

In conclusion, persistent COVID-19 symptoms were common and seen in 47.2% of patients after a diagnosis of COVID-19. The most common among the spectrum of persistent symptoms included fatigue, shortness of breath, and cough. The number of symptoms during COVID-19 was a risk factor for persistent symptoms after 1 month.

Funding Statement

Funding: The participants in this study were enrolled in the BQC19 biobank. This biobank is financially supported by the Fonds de recherche du Quebec—Santé (FRQS), Genome Quebec and the Public Health Agency of Canada (PHAC). The BQC19 funders initiated the project to support the research community facing the COVID-19-related sanitary emergency.

Contributors:

Conceptualization, A Piché; Data Curation, M Gallant, K Mercier, C Rioux-Perreault; Formal Analysis, S Lemaire-Paquette; Funding Acquisition, A Piché; Investigation, A Piché; Methodology, A Piché; Project Administration, C Rioux-Perreault; Resources, C Rioux-Perreault; Software, M Gallant, K Mercier, S Lemaire-Paquette; Validation, M Gallant, K Mercier, S Lemaire-Paquette; Supervision, C Rioux-Perreault; Writing – Original Draft: A Piché; Writing– Review & Editing, M Gallant, K Mercier, C Rioux-Perreault, S Lemaire-Paquette.

Ethics Approval:

The manuscript has been reviewed by the ethics review board of the Centre de Recherche du CHUS (CRCHUS).

Informed Consent:

N/A

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

All data will not be made publicly available. Researchers who require access to the study data can contact the corresponding author for further information.

Funding:

The participants in this study were enrolled in the BQC19 biobank. This biobank is financially supported by the Fonds de recherche du Quebec—Santé (FRQS), Genome Quebec and the Public Health Agency of Canada (PHAC). The BQC19 funders initiated the project to support the research community facing the COVID-19-related sanitary emergency.

Disclosures:

The other authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A