Excess of Post-Acute Sequelae of COVID-19 After the First Wave of the Pandemic.

INTRODUCTION: To compare the time distribution of initial COVID-19 among patients with self-reported post-acute sequelae of COVID-19 (PASC).
METHODS: We compared the distribution of the date of the reported initial COVID-19 among patients with self-reported PASC and the COVID-19 cases in France between the first wave (January 1-May 11, 2020) and the later period (May 12, 2020-June 30, 2021) using the chi-squared test. COVID-19 cases in France were assessed using previous modeling of COVID-19 burden in France for the first time period, and positive RT-PCR testing for the second time period.
RESULTS: The study included 567 individuals with PASC (median age 44, [IQR 37-50]; 83.4% women). A total of 293 (51.7%) patients reported an initial COVID-19 infection during the first period while 272 (48%) reported it during the later period (missing data, n = 2; 0.3%). Patients with PASC were 82% more likely to report initial COVID-19 during the first pandemic wave than afterward (OR 1.82, 95% CI [1.55-2.15]; p < 0.0001).
CONCLUSIONS: The incidence of self-reported PASC wave was significantly higher when initial COVID-19 happened during the first pandemic wave than afterward, suggesting the importance of non-viral factors in PASC development.

Key Summary Points

Introduction

SARS-CoV-2 has infected hundreds of millions people since the beginning of the pandemic in early 2020, resulting in the death of millions. Among a proportion of convalescent individuals, a condition called post-acute sequelae of COVID-19 (PASC) or long COVID has emerged. Since then, the medical and scientific community has been working together with patient associations to define PASC and identify mechanisms underlying its pathogenesis [1, 2]. Several studies have shed some light on the potential role of central nervous system invasion by SARS-CoV-2 [3], autoimmunity/dysregulated inflammation [4], or metabolic abnormalities in the pathogenesis of PASC [1, 5]. Additionally and in similitude with other chronic diseases, associated mental health disorders such as depression and anxiety have been described in PASC and may affect its prognosis [6].

In our PASC clinic, we were surprised that the majority of patients reported the date of their initial COVID-19 with a perfect precision, although it happened months to years earlier. Moreover, we were struck by the high proportion of patients reporting an initial COVID-19 infection during the first wave. Should it be substantiated, this observation would inform research into the causes of PASC, orientating toward factors that differentiate the first wave from subsequent waves.

The aim of this study was to evaluate if the incidence PASC was uniformly distributed between the first COVID-19 pandemic wave and the later time period, up to June 2021.

Methods

Study Population

We evaluated a population of individuals with self-reported PASC included in a study conducted in August 2021 assessing the effect of SARS-CoV-2 vaccination on their symptom [7]. The patients were recruited through social media (Twitter, LinkedIn, Facebook) and with the help of a French association of patients with PASC (#AprèsJ20 Covid Long France). Although the study was conducted before the publication of the clinical definition of the post COVID-19 condition by the World Health Organization (WHO) [8], we used a similar definition. All patients gave informed consent and the study was approved by an independent ethics committee (CE-2021-106).

Incidence of COVID-19 in France

During the first wave, SARS-CoV-2 RT-PCRs were not widely available and cannot be used to evaluate COVID-19 incidence. We therefore used a nationwide model conducted by the Pasteur Institute which took into account the number of hospitalizations and deaths due to COVID-19 to infer the number of cases in France [9]. By May 11, 2020, 5.3% of the French population was estimated to have been infected since the beginning of the pandemic. For the later period (May 12, 2020–June 30, 2021), we used widely available data of positive SARS-CoV-2 RT-PCR tests (Our World in Data [10], Supplementary File 1) as a surrogate for new COVID-19 cases.

Statistical Analysis

Quantitative data are given as median with interquartile range (IQR) and qualitative data as percentages. The odds ratio (OR) for the risk of development of PASC after COVID-19 reported during or after the first period was calculated using the chi-squared test. A p value less than 0.05 was considered statistically significant. The analysis was conducted using STATA MP 13.0 (STATACORP, USA).

Results

The study included 567 French individuals with self-reported PASC. The median age was 44 years (IQR 37–50) and 83.4% were female. Other demographic and clinical characteristics can be found in Table 1. A total of 293 (51.7%) patients reported an initial COVID-19 infection during the January 1–May 11, 2020 period while 272 (48%) reported it during the May 12, 2020–June 30, 2021 period (missing infection date, n = 2 [0.3%]). In total 6.6% of patients reported being hospitalized for COVID-19 without difference between the first and second time period (8.1% vs. 5.1%, respectively; p = 0.15). In accordance with our hypothesis that SARS-CoV-2 RT-PCR is not a good surrogate for COVID-19 evaluation during the first wave, RT-PCR was performed in 22.2% of patients during the first period (65/293) compared to 85.3% (232/272) during the later period (p < 0.0001). Instead, we used a previously published estimation that 5.3% of the French population (67 millions; N = 3,551,000 cases) had been infected with SARS-CoV-2 as of May 11, 2020 [9]. Between May 12, 2020 and June 30, 2021, a total of 6,007,213 COVID-19 cases were diagnosed using RT-PCR (Our World in Data; Supplementary File 1).

Table 1

Characteristics of the analysis population

	PASC population (n = 565)
Female sex, % (n)	83.4% (471)
Age, mean (SD)	43.3 (10.0)
COVID-19 severity, % (n)
Ambulatory	94.9% (536)
Need for oxygen therapy	4.4% (25)
Intensive care hospitalization	0.7% (4)
Confirmed COVID-19, % (n)	64.4% (364)
Positive RT-PCR	45% (254)
Positive lung CT	22.7% (128)
Positive serology	32.6% (183)
Positive antigen test	8.7% (49)
Number of persisting symptoms, mean (SD)	12.1 (3.9)
Reported symptom, % (n)
Fatigue	96.5% (445)
Brain fog	87.1% (492)
Headaches	70.8% (400)
Irritability	62.8% (355)
Sleeping issues	70.3% (397)
Thoracic pain/oppression	62.8% (355)
Shortness of breath	81.8% (462)
Cough	32.9% (186)
Palpitations	65.8% (372)
Muscle pain	77% (435)
Arthralgia	67.6% (382)
Paresthesia/tingling	58.6% (331)
Anosmia/agueusia	37.7% (213)
Abdominal pain	54.7% (309)
Diarrhea	42.7% (241)
Spontaneous ecchymosis	27.8% (157)
Pruritus	32% (181)
Fever/shivering	30% (226)
Professional activity
Unchanged	45% (254)
Adapted to PASC	17.9% (101)
Interrupted	37.1% (210)

We plotted the date of initial COVID-19 of our population study (red dots) together with the incident COVID-19 cases in France (blue dots; Fig. 1). The risk to self-report PASC was 82% higher (odds ratio 1.82, 95% CI [1.55–2.15], p < 0.0001) if the initial COVID-19 happened during the first wave than afterward. In contrast to the modeling of COVID-19 cases during the first wave, the number of COVID-19 cases diagnosed using PCR (second period) did not include asymptomatic cases, which were reported to account for 20–25% of cases in France during the same period [11]. We therefore conducted a sensitivity analysis taking into account different percentages of asymptomatic COVID-19 (missed by PCR) for the second period and computed the corresponding odds ratio which ranged from 1.91 [1.62–2.26] to 2.28 [1.93–2.69] (Table 2; data in Supplementary File 2). Strikingly, the maximal incidence of initial COVID-19 in individuals with self-reported PASC aggregated around the date of the presidential speech announcing the lockdown in France (March 16, 2020; Supplementary File 2).

Fig. 1

Distribution of initial COVID-19 in patients with self-reported PASC compared to the incidence of new COVID-19 cases in France. Concerning the incidence of COVID-19 during the first wave, only the mean number of cases is shown since their distribution was not modeled (straight blue line instead of a Gaussian curve). The lockdown was announced by an unprecedented presidential address on March 16, 2020

Table 2

Sensitivity analysis taking into account asymptomatic COVID-19 cases undiagnosed by PCR during the second time period

% of asymptomatic cases	0	5	10	15	20	25
Diagnosed COVID-19 cases during time period 2	6,007,213	6,307,590	6,607,949	6,908,306	7,208,653	7,509,076
Odds ratio to report PASC after COVID-19 during the first wave [95% CI]	1.82 [1.55–2.15]	1.91 [1.62–2.26]	2.00 [1.70–2.36]	2.10 [1.78–2.47]	2.19 [1.85–2.58]	2.28 [1.93–2.69]

Discussion

In the present ancillary study, we show that French patients with self-reported PASC were significantly more likely to report an initial COVID-19 infection during the first pandemic wave than afterward.

Several hypotheses may concur to explain time differences in the incidence of PASC. First, it is possible that viral factors (i.e., viral variants) may impact the risk of subsequent PASC. Data from the UK Office of National Statistics (ONS) suggest that the Omicron variant, which appeared after the study period, is linked to a 49.7% lower risk of PASC development [12]. Variant studies conducted in France indicate that the alpha variant became highly prevalent in early 2021 (after the second wave, Fig. 1) [13], suggesting that viral factors cannot fully explain these observed differences. Second, the vaccination against SARS-CoV-2 may decrease the risk of PASC, and observational data from the ONS indicate a 41.1% risk reduction among double vaccinated patients [14]. However, vaccination cannot explain the observed differences in our analysis since none of the included individuals had been vaccinated before developing PASC. Finally, the first wave was arguably the most stressful period of the pandemic, considering uncertainties surrounding the emergence of a previously unknown virus, its lethality, and the lack of testing capacities and prevention strategies (i.e., masks). The related anxiety may have catalyzed the onset or persistence of PASC. Supporting this hypothesis, a recent study identified that self-reported previous infection was associated with several PASC symptoms regardless of SARS-CoV-2 serology test results [15]. A recent study conducting multimodal evaluation of self-referred adults with a history of COVID-19 found that anxiety was associated with the reporting of symptoms consistent with PASC while the immunologic, virologic, and cardiopulmonary studies were inconclusive in differentiating individuals with PASC and those without PASC [16]. The underlying mechanisms are likely diverse including a nocebo effect through increased attention toward bodily sensations, incorrect causal attribution of new symptoms to PASC, or chronicization of physical symptoms, either related to SARS-CoV-2 or not, through negative conditioning [17] and avoidant behavior. These mechanisms may result in the persistence of functional somatic disorders after an acute medical episode, such as a viral infection [18, 19]. Furthermore, stress-related disorders are known to be associated with the development of a wide range of conditions including autoimmune [20] and cardiovascular diseases [21]. Finally, anxiety may participate in a “false admittance” of PASC without any previous SARS-CoV-2 infection. Overall, the links between anxiety and PASC deserve further study.

Our study has some limitations. First, we included patients with self-reported and not medically confirmed PASC, and 35.6% of the patients did not have virological confirmation of the initial COVID-19. However, considering that the clinical definition of PASC is permissive (i.e., no need for virological diagnosis), and that patients reporting an alternative diagnosis were excluded, we believe that the included population satisfies the WHO post-COVID condition definition [8]. Second, the study population was recruited through social media, which may not represent the diversity of patients with PASC. However, PASC is characterized by a structured and supportive patient community, and the recruitment was conducted with the help of one patient association (#AprèsJ20 Covid Long France), promoting a wider recruitment. Therefore, this population is likely to be representative of at least one important subgroup of patients seeking medical advice for PASC. Importantly, 27 patients with PASC (4.8%) reported an initial COVID-19 infection during the January–February 2020 time period, at which point very few cases had been reported in France [22], shedding doubt on the fact that the reported viral infections were COVID-19. Finally, 64 patients (11.3% of the population; 21.8% of those reporting COVID-19 during the first wave) indicated a COVID-19-like illness on the days surrounding the first wave presidential address (March 15–17). This address was unprecedented in the lives of most adults in France in regards to the uncertainties evoked and the wording used (“We are at war, at war against the virus”). However, while the stress induced by this address may have taken its toll, it may also have induced a recall bias which could explain the aggregations of reported COVID-19 cases around it.

In conclusion, we show that a majority of patients with self-reported PASC report an initial COVID-19 infection during the first wave of the pandemic, supporting the potential role of non-viral factors in the onset of PASC. Further studies in other countries and populations will need to confirm these preliminary findings.

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 198 KB)

In France, patients with post-acute sequelae of COVID-19 (PASC) were 82% more likely to report an initial infection during the first pandemic wave, and aggregated around the lockdown announcement.

Viral factors (i.e. variants) or prior vaccination were unlikely to explain the observed differences in PASC incidence considering the study period.

We hypothesize that the stress induced by the first wave of the pandemic may have fostered the onset or chronicization of symptoms in a subset of patients with PASC.