ABSTRACT
The potential impact of combined COVID-19 and influenza vaccination on long COVID remains uncertain. In the present cross-sectional study, we aimed to investigate the plausible association between them in middle-aged and older Europeans based on the Survey of Health, Ageing, and Retirement in Europe (SHARE). A total of 1910 participants were recruited in the analyses. The study outcome was long COVID. Participants were divided into 4 groups through the self-reported status of COVID-19 and influenza vaccination. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. 1397 participants experienced long COVID. After multivariable adjustment, those vaccinated with neither COVID-19 nor influenza vaccine had higher risk of long COVID (OR, 1.72; 95% CI, 1.26–2.35) compared to those vaccinated with both vaccines. Furthermore, adding the 4 statuses of COVID-19 vaccination/influenza vaccination to conventional risk model improved risk reclassification for long COVID (continuous net reclassification improvement was 16.26% [p = .003], and integrated discrimination improvement was 0.51% [p = .005]). No heterogeneity was found in the subgroup analyses (all p-interaction ≥0.05). Our study might provide a strategy for people aged 50 and over to reduce the occurrence of long COVID, that is, to combine the use of the COVID-19 vaccine and influenza vaccines.
Introduction
By November 8, 2023, the global incidence of Corona Virus Disease 2019 (COVID-19) had surpassed 771 million confirmed cases, resulting in approximately 7 million deaths, thereby imposing a substantial societal burden.Citation1 The post COVID-19 conditions, commonly referred to as “long COVID,” presented enduring challenges for individuals infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prior studies indicated a prevalence of long COVID in no less than 10% of afflicted individuals, manifesting through a spectrum of physical, psychological, or cognitive symptoms, such as fatigue, cough, sleep disturbances, memory loss, and in some cases, exhibiting symptoms even several months post-infection.Citation2,Citation3 Long COVID is acknowledged as an impending public health crisis,Citation4 underscoring its significant implications for public health.
Several studies have identified older age, female gender, overweight/obesity, and disease severity as predisposing factors for long COVID, while vaccination emerged as a potential risk mitigator.Citation5,Citation6 A survey conducted by Mayssam Nehme et al. at Geneva University Hospitals in Switzerland revealed a correlation between vaccination and a diminished incidence of long COVID.Citation7 Some systematic reviews indicated a substantial reduction in the occurrence of cognitive dysfunction, kidney complications, sleep disorders, and other long COVID-related risks following COVID-19 vaccination.Citation8 Seasonal influenza is a respiratory infectious disease that has many similarities with COVID-19 in terms of clinical symptoms, epidemiology, and management. Both of these diseases pose elevated risks of morbidity and mortality among the elderly. Several studies demonstrated a linkage between influenza vaccination and decreased susceptibility to SARS-CoV-2 infection, mitigated intensive care needs, reduced dependence on invasive respiratory support, and shorter hospitalization durations,Citation9,Citation10 posited to be associated with trained immunity.Citation11 Co-infection involving SARS-CoV-2 and influenza viruses increased the likelihood of severe illnessCitation12 and the chances of long COVID. The World Health Organization (WHO) advocated the concurrent administration of inactivated seasonal influenza and COVID-19 vaccines at different anatomical sites,Citation13 noting no safety concerns or minimal interactions with the combined vaccination approach.Citation14 Nonetheless, the impact of combined vaccination on long COVID remains uncertain. Consequently, this cross-sectional study aimed to explore the potential associations among influenza vaccination, COVID-19 vaccination, combined COVID-19-influenza vaccination, and long COVID by leveraging data from the Survey of Health, Ageing, and Retirement in Europe (SHARE).
Materials and methods
Study design and sample
Data from the ongoing multinational SHARE study, initiated in 2004,Citation15 formed the basis of this investigation. The SHARE target population consisted of all persons aged 50 years and over at the time of sampling from 27 European countries and Israel, collecting data biennially. In addition – in all waves – current partners living in the same household were interviewed regardless of their age. All SHARE respondents who were interviewed in any previous wave were part of the sample. The current analyses used data from Waves 8 and 9, integrated with the SHARE COVID-19 Survey.Citation16–18 Typically, SHARE employs computer-assisted personal interviewing (CAPI) to facilitate physical tests. The interviewers conduct face-to-face interviews using a laptop on which the CAPI instrument has been installed. However, due to the abrupt cessation of fieldwork during Wave 8 in March 2020 amid the COVID-19 outbreak, Wave 8 transitioned to the SHARE Corona Survey 1 and the SHARE Corona Survey 1 was conducted via telephone (Computer Assisted Telephone Interview, CATI).Citation16,Citation17 The SHARE Corona dataset contains data collected by the SHARE Corona Survey 1 (between June and September 2020) and Wave 9 SHARE Corona Survey 2 (between June and August 2021).Citation17,Citation18 Participants aged below 50 were excluded, aligning with SHARE’s focus on the 50+ population.Citation15 A total of 49,058 participants with COVID-19-influenza vaccination information were included. 17758 participants were excluded, of which 953 were with COVID-19 symptoms or were COVID-19 positive in Wave 8 and 16,805 being younger than 50 years, and finally 31,300 participants were eligible at baseline. Additionally 29,390 individuals were excluded due to absence of information on long COVID and without being COVID-19-positive in Wave 9. Eventually, 1910 participants met the eligibility criteria in the cross-sectional study ().
Figure 1. Flow chart of participants’ selection. SHARE, survey of health and retirement in Europe; COVID-19, corona virus disease 2019.
Exposure: COVID-19 and influenza vaccination
Information on COVID-19 and influenza vaccination status was sourced from SHARE Wave 9, utilizing questions querying participants about their COVID-19 and flu vaccination within the last 12 months, respectively, with response options of “yes” or “no.”
Outcome: long COVID
Long COVID data from SHARE Wave 9 were collected via a query asking participants about long-term or lingering effects attributed to their COVID illness (fatigue, cough, congestion, shortness of breath, loss of taste or smell, headache, body aches, joint pain, chest or abdominal pain, diarrhea, nausea, confusion and other). The respondents were considered to have long COVID if they reported one or more of these symptoms, which could be a continuation of the same symptoms during the initial onset of COVID-19 and lasted for at least 2 months.Citation19–21
Covariates
Control variables encompassed demographics (age, sex, smoking history, current drinking), pneumonia vaccination history, medical history (e.g., heart disease, hypertension, dyslipidemia), clinical and functional data (e.g., BMI, grip strength, activities of daily living), and the Euro-Depression scale. Except for pneumonia vaccination history from Wave 9, all other variables were sourced from Wave 8. Dominant hand grip strength was determined using a handheld dynamometer (Smedley, S Dynamometer, TTM, Tokyo, 100 kg) twice and the detailed description of the procedure could be viewed from Wave 8. Information regarding limitations in activities of daily living (ADL) or instrumental activities of daily living (IADL) were assessed by asking the participants whether they had difficulties in independently performing one or more of six ADLs (namely, dressing, bathing, walking across a room, eating, getting into or out of bed, and toileting) or with one or more of IADLs (namely, using a map, preparing a meal, shopping for groceries, using the phone, taking medications, doing housework, managing money, using transport, and doing personal laundry). Euro-Depression scale (EURO-D scale) was used to assess depression, with twelve items covering depressed mood, pessimism, suicidality, guilt, sleep, (lack of) interest, irritability, (loss of) appetite, fatigue, (lack of) concentration, (lack of) enjoyment and tearfulness.Citation22 Total score ranged from 0 to 12 and a higher score indicated more depressive symptoms.
Statistical analysis
Participants were categorized into four groups (COVID-19 vaccination/influenza vaccination, COVID-19 vaccination/no influenza vaccination, no COVID-19 vaccination/influenza vaccination, no COVID-19 vaccination/no influenza vaccination) based on COVID-19 and influenza vaccination status. Baseline characteristics were compared across these groups. Given the nonevent properties of long COVID, multivariable logistic regression models were used to estimate its risk concerning COVID-19 and influenza vaccination status. All these analyses were adjusted for the following covariates: age, sex, smoking history, current drinking in model 1; adding pneumonia vaccination history and medical history (heart disease, hypertension, dyslipidemia, cerebrovascular disease, diabetes mellitus, lung disease, cancer, Parkinson, hip fracture, Alzheimer, emotional problem and chronic kidney disease) in model 2; adding BMI, dominant hand grip strength, ADL scale, IADL scale and EURO-D scale in model 3. The likelihood ratio tests were performed to test the integrity of the models.Citation23 We evaluated the ability of individual COVID-19 vaccine, individual influenza vaccine, COVID-19 vaccine and influenza vaccine, the four statuses of COVID-19 and influenza vaccines to reclassify risks based on basic model with established risk factors. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated.Citation24
In addition, to test the robustness of our findings, we conducted subgroup analyses stratified by age (<65 and ≥65 years), sex, smoking history, current drinking, hypertension, dyslipidemia, diabetes mellitus and lung disease. The third multivariable logistic model was used to test the statistical significance of COVID-19 and Influenza vaccination category × potential modified factors category on long COVID by the likelihood ratio test. We additionally performed a sensitivity analysis, that was, adding COVID-19 vaccination status in the original model 3 to further explore the association between influenza vaccine and long COVID. Statistical significance was set at p value < .05, and SAS statistical software (version 9.4) was used for data analysis.
Results
Baseline characteristics
A total of 1910 participants (male accounted for 40.25%; mean age 67.01 ± 8.68 years) met the eligibility criteria for analysis. The participants vaccinated against COVID-19 exhibited a higher prevalence of smoking and drinking habits. Moreover, individuals receiving the influenza vaccine showed an increased likelihood of also receiving the pneumonia vaccine. Participants who solely received the influenza vaccine, in contrast to those not vaccinated against COVID-19, demonstrated lower grip strength and a higher prevalence of heart disease, dyslipidemia, and lung disease ().
Table 1. Characteristics of the study participants according to the vaccination status of COVID-19 and influenza vaccines.
Long COVID and vaccination
demonstrated the correlation between COVID-19 and influenza vaccinations and the occurrence of long COVID. The risk of long COVID was significantly higher by 28% (OR, 1.28; 95% CI, 1.00–1.63) for individuals not receiving the COVID-19 vaccine in comparison to those vaccinated against it (Model 3). Similarly, those not receiving the influenza vaccine displayed a 52% heightened risk (OR, 1.52; 95% CI, 1.19–1.96) in contrast to their vaccinated counterparts. When compared with participants vaccinated with both COVID-19 and influenza vaccines, those solely vaccinated against COVID-19 exhibited a 1.70-fold increased risk (OR, 1.70; 95% CI, 1.27–2.26), individuals solely vaccinated against influenza showed a 2.06-fold heightened risk (OR, 2.06; 95% CI, 1.17–3.63), and those unvaccinated for both demonstrated a 1.72-fold increased risk (OR,1.72; 95% CI, 1.26–2.35) of long COVID. Combined Groups 2, 3, and 4, the result showed that the participants who had not received at least one of the COVID-19 and influenza vaccines had a 1.73 times greater risk (OR, 1.73; 95% CI, 1.34–2.25) of developing long COVID than those vaccinated with both (). In addition, we also added COVID-19 vaccination status in Model 3 to analyses the association between influenza vaccine and long COVID. The participants who did not receive the influenza vaccine had a 47% higher risk (OR, 1.47; 95% CI, 1.14–1.89) in contrast to those vaccinated against it (Supplementary Table S1). Incorporating the four statuses of COVID-19 and influenza vaccines into a model containing traditional risk factors significantly improved risk reclassification for long COVID (continuous net reclassification improvement was 16.26% [p = .003], and integrated discrimination improvement was 0.51% [p = .005]) ().
Table 2. Odds ratios and 95% confidence intervals of the correlation between COVID-19 and influenza vaccinations and the occurrence of long COVID.
Table 3. Reclassification and discrimination statistics for long COVID in participants with different COVID-19 and influenza vaccination.
Subgroup analyses
No heterogeneity was found in the subgroup analyses (all p-interaction ≥0.05) ().
Table 4. Subgroup analysis of ORs (95% CI) of vaccination status of COVID-19 and influenza vaccines for long COVID.
Discussion
To our knowledge, this cross-sectional study is the first large-scale multicenter investigation to explore the impact of COVID-19 and influenza vaccination on the incidence of long COVID in individuals aged 50 and above among the European population. Utilizing data from the SHARE study, our findings revealed a significant reduction in the risk of long COVID associated with the combined administration of COVID-19 and influenza vaccines compared to their singular use.
Controversy surrounds the influence of COVID-19 vaccination on long COVID. Studies by Maxime Taquet et al.Citation25 in the older American veterans,Citation26 and some systematic reviewsCitation27 presented varied conclusions. While some suggested no robust associations between prior COVID-19 vaccination and post-acute sequelae in older individuals, others proposed partial protection or emphasized the need for further exploration, particularly among those displaying long COVID symptoms. Elena Azzolini et al.Citation28 a case-control study in Britain,Citation29 and a cross-sectional study in the USACitation30 supported that COVID-19 vaccination, especially in older populations, could mitigate the risk of long COVID, which corroborated with our findings from the SHARE study.
As far as we know, no prior studies have delved into the correlation between influenza vaccination and long COVID. Our study bridged this gap by demonstrating a significant effect of influenza vaccination in reducing the incidence of long COVID among individuals aged 50 and older. Earlier researches have highlighted the efficacy of influenza vaccines in reducing SARS-CoV-2 positivity, symptomatic presentations, and hospitalizations related to COVID-19, and potentially alleviated its long-term burden.Citation31 A recent study in the NetherlandsCitation32 found that tetravalent inactivated influenza vaccines could induce enhanced cytokine responses against SARS-CoV-2, hinting at a mechanism for potential cross-reactivity and heterologous immunity against unrelated pathogens.Citation33
Despite the emergence of the Omicron variant, which seemingly decreases the likelihood of long COVID, the rising number of long COVID cases amidst the Omicron surge is a concern. The precise mechanisms underlying the impact of COVID-19 and influenza vaccines on long COVID remain unclear. While our study did not elucidate these mechanisms, a plausible hypothesis posited that these vaccines might rectify dysregulated immune or inflammatory responses or aid in the elimination of persistent viral remnants of SARS-CoV-2.Citation34 Presently, long COVID lacks specific treatment and our study’s implication for individuals aged 50 and above suggested the combined use of COVID-19 and influenza vaccines as a potential strategy to reduce its occurrence.
This study’s strengths lie in its large-scale representative prospective nature across European countries and Israel, standardized data collection methods across the countries, and robust efforts to control potential confounding factors in multivariable models, providing high-quality evidence regarding the association between COVID-19, influenza vaccination, and long COVID. However, several limitations warrant acknowledgment. Self-reported exposure, outcomes, and some covariates might introduce information bias. The cross-sectional design precluded causal inferences. Due to the setting of the questions in the questionnaires, we were unable to collect the doses and time of vaccinations, and could not analyze the time sequence of vaccination and long COVID outcome. The prior influenza virus infection history was unfortunately not available. These, to some extent, limit the ability to ascertain the relationship between vaccination and long COVID. When compared with participants vaccinated with both COVID-19 and influenza vaccines, the higher risk of long COVID was observed in individuals receiving influenza but not COVID-19 vaccines than those unvaccinated for both. This might be attributed to a smaller sample size, those who received an influenza vaccination more likely to have received a greater number of COVID-19 vaccinations (i.e., to be fully vaccinated) and missing specific treatment information, which all potentially biasing the study outcome.
In conclusion, our study might provide a strategy for people aged 50 and over to reduce the occurrence of long COVID, that is, to combined use the COVID-19 vaccine and influenza vaccine.
Ethical statement
The study adhered to the ethical principles outlined in the World Medical Declaration of Helsinki and received approval from the University of Valencia’s Ethics Committee for Human Research (register code 1510464).
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Supplementary material
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2345505
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Funding
References
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