Evolution of symptoms compatible with post-acute sequelae of SARS-CoV-2 (PASC) after Wild-type and/or Omicron BA.1 infection: A prospective healthcare worker cohort

•Long COVID symptoms after Wild-type infection can persist over 18 months.•Primary or secondary Omicron infection did not increase long COVID risk.•COVID-19 vaccination before Omicron infection was not associated with long COVID.•A potential protective effect of physical/social activities should be further studied. In this Journal, Lippi and colleagues provided some early indication that symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) Omicron infection are less severe compared to Wild type infection.1Lippi G. Nocini R. Henry B.M. Analysis of online search trends suggests that SARS-CoV-2 Omicron (B.1.1.529) variant causes different symptoms.J Infect. 2022; 84: e76-e77Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Similarly, the risk of long COVID after SARS-CoV-2 Omicron infection is lower compared to previous variants.2Kahlert C.R. Strahm C. Güsewell S. Cusini A. Brucher A. Goppel S. et al.Post-acute sequelae after severe acute respiratory syndrome coronavirus 2 infection by viral variant and vaccination status: A multicenter cross-sectional study.Clin Infect Dis. 2023; 77: 194-202Crossref PubMed Scopus (13) Google Scholar, 3Antonelli M. Pujol J.C. Spector T.D. Ourselin S. Steves C.J. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2.Lancet. 2022; 399: 2263-2264Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar However, data on the impact of reinfection with Omicron on post-acute sequelae of COVID-19 (PASC) is scarce. A study based on a US Veterans healthcare database suggests that reinfection increases the risk of PASC. However, not only reinfections with Omicron, but also with pre-Omicron variants were included.4Bowe B. Xie Y. Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection.Nat Med. 2022; 28: 2398-2405Crossref PubMed Scopus (175) Google Scholar For reinfections with Omicron, UK data show that the risk of reporting new-onset long COVID symptoms is nearly 30% reduced.5Bosworth M.L. Shenhuy B. Walker A.S. Nafilyan V. Alwan N.A. O’Hara M.E. et al.Risk of new-onset long COVID following reinfection with severe acute respiratory syndrome coronavirus 2: A community-based cohort study.Open Forum Infect Dis. 2023; 10ofad493Crossref PubMed Scopus (0) Google Scholar The role of SARS-CoV-2 vaccination in the prevention of PASC after secondary infection remains unknown. Herein, the evolution of PASC symptoms in healthcare workers (HCW) infected with SARS-CoV-2 Wild-type and/or the Omicron BA.1 variant and the influence vaccination and other co-variables are reported. The SURPRISE open cohort was launched in August 2020 (baseline) within nine Swiss healthcare networks. Via electronic questionnaires, HCW repetitively reported clinical and laboratory data including dates/results of SARS-CoV-2 swabs and vaccinations. The infecting viral variant was extrapolated from public sequencing data.2Kahlert C.R. Strahm C. Güsewell S. Cusini A. Brucher A. Goppel S. et al.Post-acute sequelae after severe acute respiratory syndrome coronavirus 2 infection by viral variant and vaccination status: A multicenter cross-sectional study.Clin Infect Dis. 2023; 77: 194-202Crossref PubMed Scopus (13) Google Scholar A PASC questionnaire was asked in March 2021 (Q1), September 2021 (Q2), and June 2022 (Q3), and included questions on PASC symptoms and the Fatigue Severity Scale (FSS) score. At the same timepoints, SARS-CoV-2 anti-nucleocapsid (anti-N) antibodies were determined (Table S1).2Kahlert C.R. Strahm C. Güsewell S. Cusini A. Brucher A. Goppel S. et al.Post-acute sequelae after severe acute respiratory syndrome coronavirus 2 infection by viral variant and vaccination status: A multicenter cross-sectional study.Clin Infect Dis. 2023; 77: 194-202Crossref PubMed Scopus (13) Google Scholar We excluded individuals without positive swab who had positive anti-N (unknown infection time) and those with infection during Alpha/Delta circulation, i.e. January 21 to January 22 (low numbers). HCW without any positive swab and consistently negative anti-N served as controls. As outcomes, we used the number of PASC symptoms and the FSS score. The PASC symptoms asked varied slightly across time points (Table S1). To account for the background noise of these symptoms, we calculated the sum of PASC and FSS symptoms relative to uninfected controls, expressed as rate ratio (RR) with 95% confidence intervals (CI). The outcomes were compared i) between HCW with primary infection during Wild-type- and Omicron-dominating periods (i.e. Omicron BA.1 variant); ii) between Wild-type infected HCW with and without Omicron reinfection; and iii) according to vaccination doses received after Wild-type infection (ie, none, 1-2 doses, ≥3 doses), irrespective of Omicron reinfection. For those after Wild-type infection, we used multivariable negative binomial regression (complete case analysis) to estimate the effects of Omicron reinfection and SARS-CoV-2 vaccination (received after primary Wild-type infection) on PASC symptoms at Q3, adjusting for symptoms at Q1 and for potential confounders (Table S2). Among 5,792 HCW, 3,334 answered the questionnaire at Q1, 3,417 at Q2, and 1,935 at Q3. We considered only participants answering at least Q1 and Q3 (n = 1,600). After exclusions (Alpha/Delta (n = 139); anti-N without positive swab (n = 255), multiple Omicron infections (n = 5)), 1,201 participants remained (median age 43.6 years; 81.4% female). Baseline characteristics differed slightly in included HCW (Table S3). Of the 1,201 participants, 176 had primary Wild-type, 458 primary Omicron, and 59 Omicron after Wild-type infection, and 508 were uninfected controls (Table S4). After Wild-type infection, PASC symptoms were higher compared to controls both at Q1 (RR 1.67, 95% CI 1.31-2.13) and Q3 (RR 1.37, 95% CI 1.08-1.73); FSS scores decreased from Q1 (RR 1.45, 95% CI 1.18-1.80) to Q3 (RR 1.11, 95% CI 0.90-1.37). Neither primary Omicron infection nor Omicron reinfection after Wild-type infection influenced PASC and FSS scores compared to controls (Fig. 1). Likewise, SARS-CoV-2 vaccination had no influence on the outcomes (Fig. S1/Table S5). In multivariable analysis, social activities at baseline were negatively associated with PASC symptoms at Q3 (adjusted for those at Q1) (aRR 0.46 for sport, 0.50 for others); vaccination after Wild-type infection (aRR 0.96, 95% CI 0.51-1.83) and Omicron reinfection (aRR 1.19, 95% CI 0.74-1.91) showed no significant effect (Table 1).Table 1Results of multivariable negative binomial regression analysis regarding post-acute sequelae of SARS-CoV-2 (PASC) symptom frequency number at Q3 among HCW with primary Wild-type infection (n = 220).Adjusted rate ratio (95% CI)p ValueSymptom number Q1 (log scale)5.59 (3.96-8.08)<0.001Body mass index >30 kg/m21.57 (0.93-2.69)0.085Active smoking1.81 (0.97-3.46)0.066Social leisure activities: sport vs. none0.46 (0.27-0.75)0.002Social leisure activities: only other vs. none0.50 (0.30-0.86)0.011Any comorbidity1.32 (0.86-2.04)0.200Vaccination after Wild-type infection0.96 (0.51-1.83)0.902Omicron reinfection after Wild-type infection1.19 (0.74-1.91)0.471 Open table in a new tab In this prospective cohort of mostly white, female HCW, neither Omicron BA.1 reinfection nor SARS-CoV-2 vaccination altered the risk of PASC symptoms after Wild-type infection. PASC symptoms declined, but did not resolve, over a median of 18 months after Wild-type infection. Omicron BA.1 reinfection did not influence PASC symptoms, contrasting data from US veterans.4Bowe B. Xie Y. Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection.Nat Med. 2022; 28: 2398-2405Crossref PubMed Scopus (175) Google Scholar This discrepancy might be due to the younger median age in our population, with SARS-CoV-2 causing less severe acute disease, a major risk factor for PASC, in younger individuals. Furthermore, the US study included reinfections with pre-Omicron variants, which per se are associated with a higher risk for long COVID.2Kahlert C.R. Strahm C. Güsewell S. Cusini A. Brucher A. Goppel S. et al.Post-acute sequelae after severe acute respiratory syndrome coronavirus 2 infection by viral variant and vaccination status: A multicenter cross-sectional study.Clin Infect Dis. 2023; 77: 194-202Crossref PubMed Scopus (13) Google Scholar Primary Omicron infection was not associated with higher PASC symptoms compared to uninfected controls in our cohort. This contrasts with several other studies which have in fact shown an increased long COVID risk after Omicron infection.6Nehme M. Vetter P. Chappuis F. Kaiser L. Guessous I. Nehme M. et al.Prevalence of post-coronavirus disease condition 12 weeks after omicron infection compared with negative controls and association with vaccination status.Clin Infect Dis. 2023; 76: 1567-1575Crossref PubMed Scopus (14) Google Scholar, 7Thaweethai T. Jolley S.E. Karlson E.W. Levitan E.B. Levy B. McComsey G.A. et al.Development of a definition of postacute sequelae of SARS-CoV-2 infection.JAMA. 2023; 329: 1934-1946Crossref PubMed Scopus (88) Google Scholar Again, our distinct study population as well as the relatively small sample size could explain this unexpected finding. PASC symptoms after SARS-CoV-2 reinfection were not influenced by vaccination status in our study, which is in line with Bowe et al.4Bowe B. Xie Y. Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection.Nat Med. 2022; 28: 2398-2405Crossref PubMed Scopus (175) Google Scholar In contrast, vaccination before primary SARS-CoV-2 infection has been shown to reduce the risk of long COVID in a previous meta-analysis, although included studies were predominantly from the pre-Omicron period.8Tsampasian V. Elghazaly H. Chattopadhyay R. Debski M. Naing T.K.P. Garg P. et al.Risk factors associated with post−COVID-19 condition.JAMA Intern Med. 2023; 183 (Jun 1): 566-580Crossref PubMed Scopus (101) Google Scholar We also confirm previous findings showing persistence of PASC symptoms in some individuals after infection with pre-Omicron variants, even at a median of 18 months after infection.9Fjelltveit E.B. Blomberg B. Kuwelker K. Zhou F. Onyango T.B. Brokstad K.A. et al.Symptom burden and immune dynamics 6 to 18 months following mild Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2): A case-control study.Clin Infect Dis. 2023; 76: e60-e70Crossref PubMed Scopus (11) Google Scholar Interestingly, baseline physical and other social activities were associated with reduced PASC symptoms, a finding which has been reported before.10Wang S. Li Y. Yue Y. Yuan C. Kang J.H. Chavarro J.E. et al.Adherence to healthy lifestyle prior to infection and risk of post–COVID-19 condition.JAMA Intern Med. 2023; 183: 232-241Crossref PubMed Scopus (16) Google Scholar Whether physical activity itself or social aspects are important in this context remains unknown. The prospective nature with repetitive measurements of PASC symptoms and SARS-CoV-2 anti-N to detect a-/oligosymptomatic infections are important strengths of our study. The restriction to professionally active HCW (excluding those incapacitated for work by PASC) is an important study limitation, which might have underestimated the burden of long COVID. In conclusion, we did not observe any increased burden of PASC after infection or reinfection with the SARS-CoV-2 Omicron BA.1 variant in our population of mostly young and healthy white HCW, while PASC symptoms after Wild-type infection can persist over 18 months. The presumed protective effect of baseline physical and other social activities should be further studied. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. SURPRISE+ study group: We thank the participants of the SURPRISE+ study and the members of the study group (in alphabetical order): Ulrike Besold, MD (Geriatric Clinic St. Gallen), Elsbeth Betschon (Clienia Littenheid), Angela Brucher, MD (Psychiatry Services South, St. Gallen), Alexia Cusini, MD (Cantonal Hospital Graubünden), Andrée Friedl, MD (Cantonal Hospital Baden), Stephan Goppel, MD (Psychiatry Services North, St. Gallen), Fabian Grässli, MSc (Cantonal Hospital St. Gallen), Christian R. Kahlert, MD (Children's Hospital of Eastern Switzerland, St. Gallen), Joelle Keller (Hirslanden Clinic Zurich), Simone Kessler (Cantonal Hospital St. Gallen), Philipp Kohler, MD MSc (Cantonal Hospital St. Gallen), Stefan P. Kuster, MD MSc (Cantonal Hospital St. Gallen), Onicio Leal, PhD (University of Zurich), Eva Lemmenmeier, MD (Clienia Littenheid), Allison McGeer, MD MSc (Mount Sinai Hospital, Toronto), Dorette Meier Kleeb, MD (Cantonal Hospital Baden), Elisabeth Möller (Clienia Littenheid), J. Carsten Möller, MD (Clinic Zihlschlacht), Maja F. Müller (Hirslanden Clinic Zurich), Vaxhid Musa (Cantonal Hospital St. Gallen), Manuela Ortner (Rheintal Werdenberg Sarganserland Hospital Group, Grabs), Philip Rieder, PhD (Hirslanden Clinic Zurich), Lorenz Risch, MD PhD (Laboratory Risch Buchs), Markus Ruetti, MD (Fuerstenland Toggenburg Hospital Group Wil), Matthias Schlegel, MD (Cantonal Hospital St. Gallen), Hans-Ruedi Schmid, PhD (Cantonal Hospital Baden), Reto Stocker, MD (Hirslanden Clinic Zurich), Pietro Vernazza, MD (Cantonal Hospital St. Gallen), Matthias von Kietzell MD (Clinic Stephanshorn St. Gallen), Danielle Vuichard-Gysin, MD MSc (Thurgau Hospital Group Muensterlingen), and Benedikt Wiggli, MD (Cantonal Hospital Baden). This work was supported by the Swiss National Sciences Foundation (grant number 31CA30_196544; grant number PZ00P3_179919 to PK), the Federal Office of Public Health (grant number 20.008218/421-28/1), the Health Department of the Canton of St. Gallen, and the research fund of the Cantonal Hospital of St. Gallen. Funding institutions did not have any role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Download .docx (.17 MB) Help with docx files Supplementary material.

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