key: cord-0726029-11ch08kz
authors: Del Riccio, M.; Lorini, C.; Bonaccorsi, G.; Paget, J.; Caini, S.
title: The association between influenza vaccination and the risk of SARS-CoV-2 infection, severeillness, and death: a systematic review of the literature.
date: 2020-09-27
journal: nan
DOI: 10.1101/2020.09.25.20201350
sha: 983f4f04350d054b3c23c01b8412997da99ac622
doc_id: 726029
cord_uid: 11ch08kz

We reviewed the association between seasonal influenza vaccination and the risk of SARS-CoV-2 infection or complicated illness or poor outcome (e.g. severe disease, need for hospitalization or ventilatory support, or death) among COVID-19 patients. None of the studies that were reviewed (n=12) found a significant increase in the risk of infection or in the illness severity or lethality, while some reported significantly inverse associations. Our findings support measures aimed at raising influenza vaccination coverage in the coming months.

There has been an important debate recently in the media and scientific community and in the media about the relationship between influenza vaccination and COVID-19. Influenza and COVID-19 are respiratory viral illnesses that may be clinically indistinguishable and tend to be lifethreatening in largely overlapping population subgroups (e.g. the elderly and people suffering from chronic health conditions). Moreover, being respiratory virus illnesses, their peak of activity may occur in the same period of the year (i.e. winter months in temperate countries). Based on the above considerations, most health professionals have advocated in favour of strengthening influenza vaccination programmes, arguing that rising vaccine coverage could help improve COVID-19 patient management by allowing easier differential diagnosis and reducing the overload of the healthcare systems, particularly intensive care units (ICUs) [1] . Public health decisions should be based as much as possible on the best available evidence regarding any benefits and drawbacks that the proposed intervention may be expected to entail, and since the influenza season is fast approaching in the northern hemisphere, a literature review on this topic is urgently needed. Here, we conducted a systematic review of the articles that examined whether influenza vaccination affects the risk of being infected with the SARS-CoV-2 virus, and the risk of complicated illness or poor outcome (e.g. severe disease, need for hospitalization or ventilatory support, or death) among COVID-19 patients.

The literature search was performed on 31 August, 2020, by interrogating the MEDLINE, Embase and medRxiv databases for both peer-reviewed and non-peer-reviewed articles using the following string: 'SARS-CoV-2 OR COVID' AND 'influenza OR flu AND 'vaccin*'. All identified articles were first independently screened by two researchers (MDR and SC) based on their title, and any considered as potentially eligible for inclusion by either researcher was then obtained and read in full text. Any disagreement on the eligibility of a given article was resolved by consensus. The literature search was then extended to the reference lists of all the articles that were obtained in full copy (regardless of their final inclusion in the review). To be eligible for inclusion, . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. . https://doi.org/10.1101/2020.09.25.20201350 doi: medRxiv preprint an article had to be an original report based on individual-level data; studies relying on aggregated data (e.g. ecological studies reporting correlations [2] [3] ) were not retained because of their higher proneness to bias and confounding. Letters and commentaries with no original data were discarded as well.

The literature search identified 1,619 non-duplicate entries, of which 1,461 were excluded based on their title. The remaining 158 articles were read in full copy, and an additional article was identified in their reference lists. Finally, twelve independent articles met all inclusion criteria and were retained (Figure 1 ). Seven articles [6] [7] [8] [9] [10] [11] [12] focused on the association between influenza vaccination and the risk of SARS-CoV-2 infection (Table 1) : these encompassed a total of 242,323 subjects, of which 56.6% were contributed by Pawlowski et al. [11] and 32.6% by Vila-Córcoles A et al. [12] . Most studies were based on subjects from the general population, except the two smallest studies, which included 203 firefighters and paramedics from the USA is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. . https://doi.org/10.1101/2020.09.25.20201350 doi: medRxiv preprint association (hazard ratio 0.63, 95%CI 0.43-0.92, p=0.015) emerged among adults aged ≥50 years enrolled in the study by Vila-Córcoles et al. [12] . The study by Santos et al. [4] was excluded due to probable overlap of the study population with the article by Fink et al. [5] . Both studies were based on data from hospitalizations for COVID-19 patients in Brazil registered in a national surveillance system. The study by Santos et al. was less recent and based on a smaller population, and examined fewer outcomes, compared to Fink et al, and, unlike the latter, performed no statistical adjustments. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. HR: hazard ratio. OR: odds ratio. RR: relative risk. CI: confidence intervals.

Five articles [5, [13] [14] [15] [16] reported on the association between influenza vaccination and the risk of severe illness and/or death among COVID-19 patients ( Table 2 ). The total number of patients was 111,820 of which the majority (82.9%) were contributed by Fink et al. [5] . The latter was the only study encompassing a minority (16%) of non-laboratory-confirmed patients. Jehi et al. [13] and Murillo-Zamora et al. [14] found that the likelihood of being vaccinated against influenza was significantly (p<0.001) or, respectively, nearly significantly (p=0.073) lower among patients who required to be hospitalized compared to those who did not. Likewise, Fink et al. [5] reported a significantly lower odds of requiring intensive care or respiratory support among influenza vaccinees vs. non-vaccinees. The latter study also found that vaccinated COVID-19 patients were at significantly reduced risk of dying compared to non-vaccinated ones (OR 0.82, 95%CI 0.75-0.89, p<0.01), but this finding was not confirmed in the studies by Ortiz-Prado et al. [15] and Poblador-Plou et al. [16] . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. . https://doi.org/10.1101/2020.09.25.20201350 doi: medRxiv preprint Table 2 . Main features and results of studies on the association between influenza vaccination and the risk of severe illness or death among COVID-19 patients.

Jehi et al. [13] Laboratory-confirmed COVID-19 patients in Ohio and Florida, USA (n = 2,852) (a)

Severe cases (requiring hospitalization) were significantly less likely to be vaccinated than non-severe cases (p < 0.001) (b) None

Laboratory-confirmed COVID-19 patients in Ohio and Florida, USA (n = 1,684) (a)

Severe cases (requiring hospitalization) were significantly less likely to be vaccinated than non-severe cases (p < 0.001) (b) None

Murillo-Zamora et al. [14] Laboratory-confirmed COVID-19 patients aged ≥ 15 years in Mexico (n = 740)

Severe cases (dyspnoea requiring hospitalization) were non-significantly less likely to be vaccinated than non-severe cases (p = 0.073) None

Fink et al. [5] All clinically confirmed COVID-19 patients in Brazil (n = 92,664, of which 84% laboratoryconfirmed)

Severe illness Ortiz-Prado et al. [15] All laboratory-confirmed COVID-19 patients in Ecuador (n = 9,468) Death No statistically significant association (OR among vaccinated patients: 0.71, 95% CI 0.23-2.17)

Poblador-Plou et al [16] All laboratory-confirmed COVID-19 patients in Aragon, Spain, with follow-up ≥ 30 days (n = 4,412)

Death No significant differences in the proportion of vaccination between deceased and alive patients after adjusting by age (p = 0.110 among men, p= 0.126 among women).

Age (a) COVID-19 patients diagnosed from 8 Mar to 1 May were included in a "development" cohort (used to build a predictive model), and patients diagnosed afterwards (until 5

Jun) were included in a "validation" cohort (for model validation). Results were only provided separately for the two cohorts. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. . https://doi.org/10.1101/2020.09.25.20201350 doi: medRxiv preprint

There was no funding for this manuscript.

. CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 27, 2020. . https://doi.org/10.1101/2020.09.25.20201350 doi: medRxiv preprint

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