Incidence and Severity of Covid-19 in Patients with and without Previously Verified Infections with Common Cold Coronaviruses

Abstract

To the Editor—Several recent studies have proposed the existence of immune cross-reactivity between human common cold coronaviruses (CCCoVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Humans unexposed to SARS-CoV-2 may harbor antibodies that neutralize SARS-CoV-2 in cell culture [1], along with T cells that recognize epitopes shared between SARS-CoV-2 and CCCoVs [2, 3]. Henss et al [4] detected neutralizing antibodies against the NL63 CCCoV in serum from subjects with mild coronavirus disease 2019 (COVID-19), but not in those with severe disease. On the other hand, Schwaiger et al [5] reported that antibodies against CCCoVs had low functional avidity for SARS-CoV-2, which argues against clinically relevant cross-reactivity. These and other recent reports [6] emphasize that additional studies are required to determine whether cross-reactivity translates into clinically relevant cross-immunity. Findings of previous studies suggest that prior verified human respiratory infections with any of the 4 endemic CCCoVs (HKU1, OC43, NL63, and 229E) induce long-term protection against infection with the same (homologous) strain of CCCoV [7, 8]. In accordance, we reported that homologous infections of humans with CCCoV are approximately 10 times less common than heterologous infections [9], thus implying that infection with CCCoV entails significant protective immunity against the homologous virus. Analysis of the risk and severity of SARS-CoV-2 infection in patients with verified previous CCCoV infections might therefore inform the degree of clinically relevant cross-immunity. We interrogated a database of >75 000 respiratory samples obtained from >50 000 patients with respiratory tract infection diagnosed during 2013–2020. The database contains results from analyses of 18 respiratory pathogens with real-time polymerase chain reaction, including the 4 endemic CCCoVs described elsewhere [10]. Among patients in the database, we assessed the risk of subsequent SARS-CoV-2 infection, as determined by real-time polymerase chain reaction detection of SARS-CoV-2 RNA in respiratory specimens or by the presence in blood of immunoglobulin G antibodies against the nucleocapsid (Architect; Abbott) and the nucleocapsid/spike protein (iFlash; YHLO) of SARS-CoV-2. More than 100 000 patients were tested for SARS-CoV-2 at our department during February to November 2020 and of those, 8298 had ≥1 previous result in the above-referenced respiratory tract infection database before the COVID-19 pandemic. We also used hospital records to determine the severity of COVID-19 disease (hospitalization/intensive care unit referral or not). The proportion of SARS-CoV-2 positivity among patients with previous respiratory infections was compared against that in patients with no previously verified infection using χ 2 tests. The study was approved by the Swedish Ethical Review Board (application no. 2020–03276). As shown in Table 1, verified previous infections with CCCoV did not predict significantly reduced risk of SARS-CoV-2 infection. Similar results were observed when patients were grouped by previous infections with alpha-Coronaviridae (CCCoV NL63 and 229E) or beta-Coronaviridae (HKU1 and OC43). The incidence of SARS-CoV-2 infection was similar in patients with a history of CCCoV infection and in those with a previous common and immunologically unrelated respiratory infection (rhinovirus infection). The severity of COVID-19, as reflected by hospitalization and/or referral to intensive care, was not significantly reduced by previously verified CCCoV infections (Table 1). Infection with Severe Acute Respiratory Syndrome Coronavirus 2 in Patients with Previously Verified Common Cold Coronavirus Infection, Rhinovirus Infection, or Any Respiratory Infection and Coherent Odds Ratios Abbreviations: CCCoV, common cold coronavirus; CI, confidence interval; OR, odds ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. aPatients were tested for 18 airway pathogens from February 2013 to February 2020, before SARS-CoV-2 testing with real-time polymerase chain reaction or serology. bNo. of patients tested for SARS-CoV-2 and percentage of all patients with indicated previous infections. cOR and 95% CI for SARS-CoV-2 infection; the OR for patients with no previous infections (“negative for all”) was set to 1. dP values from χ 2 test comparing patients with indicated previous infections with those with no previous infections. ePatients hospitalized after ≥1 positive respiratory sample of SARS-CoV-2 (real-time polymerase chain reaction). Forty-five patients were SARS-CoV-2 positive but had no information regarding hospitalization. fOR and 95% CI for hospitalization after diagnosis of SARS-CoV-2; the OR for patients with no previous infections was set to 1. gOne patient had coinfection with an alphacoronavirus and a betacoronavirus before SARS-CoV-2 infection. In addition, the amount of SARS-CoV-2 in respiratory samples of patients with previously confirmed CCCoV infections (mean [standard error of the mean], 7.2 [2.07] log10 viral particles per swab; range 2.9–9.6) did not differ significantly from that of patients with previous rhinovirus infections (6.0 [1.95] log10 viral particles per swab; range, 0.7–10.61; P = .1, Student’s t test). Logistic regression analysis identified patient age as a risk factor for SARS-CoV-2 infection (P = .007) and hospitalization for COVID-19 (P < .001). In the adjusted analyses, previously verified infections, including those caused by CCCoV, did not confer significant protection against SARS-CoV-2 infection or hospitalization. Unexpectedly, patients with previously verified infection with alphacoronaviruses showed significantly higher risk for hospitalization after adjustment for age (odds ratio, 2.82, P = .03; Supplementary Table 1). A limitation to these analyses is that serial, systematic monitoring of CCCoV infections was not available. Our study, thus, likely underestimates the incidence of CCCoV infections in this patient cohort. Nevertheless, our results support the conclusions by Schwaiger et al [5], suggesting that past infection with the 4 endemic CCCoVs does not entail clinically significant protection against SARS-CoV-2. Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Financial support. This work was supported by the Swedish Governmental (ALF agreement ALFGBG-146611 to Sahlgrenska University Hospital). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Author contributions. The authors contributed jointly to the drafting of this manuscript.

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