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Viral dynamics during SARS-CoV-2 omicron infection highlight presymptomatic and asymptomatic infectiousness

2022; Elsevier BV; Volume: 86; Issue: 5 Linguagem: Inglês

10.1016/j.jinf.2022.11.026

1532-2742

Li Jiang, Lu Tang, Linyu Zhu, Yufang Zhu, Song Yang, Wenjie Chen, Fan Yi, Xuejiao Yang, Shuai Yang, Yulan Zheng, Yunsheng Xu, Peng Hong,

COVID-19 Clinical Research Studies

•Asymptomatic and symptomatic omicron infections had comparable peak viral loads.•Viral loads peaked before symptom onset in 21% symptomatic omicron infections.•Public health interventions were associated with lower peak viral loads. Peaking of SARS-CoV-2 viral shedding usually correlates with high infectiousness.1Hakki S. Zhou J. Jonnerby J. Singanayagam A. Barnett J.L. Madon K.J. et al.Onset and window of SARS-CoV-2 infectiousness and temporal correlation with symptom onset: a prospective, longitudinal, community cohort study.Lancet Respir Med. 2022; 10 (NovPubMed PMID: 35988572. Pubmed Central PMCID: PMC9388060. Epub 20220818): 1061-1073Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Despite of early awareness of prevalent presymptomatic viral shedding that may evade control measures and drive stealth transmission,2He X. Lau E.H.Y. Wu P. Deng X. Wang J. Hao X. et al.Temporal dynamics in viral shedding and transmissibility of COVID-19.Nat Med. 2020; 26 (MayPubMed PMID: 32296168. Epub 20200415): 672-675Crossref PubMed Scopus (2744) Google Scholar SARS-CoV-2 viral kinetics during presymptomatic stage or asymptomatic infections was still poorly understood due to requiring repeated tests in asymptomatic population. SARS-CoV-2 omicron infections were more likely to be asymptomatic or milder comparing to delta infections,3Olaiz-Fernandez G. Vicuna de Anda F.J. Diaz-Ramirez J.B. Fajardo Dolci G.E. Bautista-Carbajal P. Angel-Ambrocio A.H. et al.Effect of Omicron on the prevalence of COVID-19 in international travelers at the Mexico city international airport. December 16th, 2021 to January 31st, 2022.Travel Med Infect Dis. 2022; 49 (May 29PubMed PMID: 35640809. Pubmed Central PMCID: PMC9148423. Epub 20220529)102361Crossref PubMed Scopus (4) Google Scholar, 4Nyberg T. Ferguson N.M. Nash S.G. Webster H.H. Flaxman S. Andrews N. et al.Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study.Lancet. 2022; 399 (Apr 2PubMed PMID: 35305296. Pubmed Central PMCID: PMC8926413. Epub 20220316): 1303-1312Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar, 5Iuliano A.D. Brunkard J.M. Boehmer T.K. Peterson E. Adjei S. Binder A.M. et al.Trends in disease severity and health care utilization during the early Omicron variant period compared with previous SARS-CoV-2 high transmission periods - United States, December 2020-January 2022.MMWR Morb Mortal Wkly Rep. 2022; 71 (Jan 28PubMed PMID: 35085225. Epub 20220128): 146-152Crossref PubMed Scopus (208) Google Scholar which were associated with shifting virological characteristics of omicron in animal models,6Yuan S. Ye Z.W. Liang R. Tang K. Zhang A.J. Lu G. et al.Pathogenicity, transmissibility, and fitness of SARS-CoV-2 Omicron in Syrian hamsters.Science. 2022; 377 (Jul 22PubMed PMID: 35737809. Epub 20220623): 428-433Crossref PubMed Scopus (59) Google Scholar, 7Suzuki R. Yamasoba D. Kimura I. Wang L. Kishimoto M. Ito J. et al.Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.Nature. 2022; 603 (MarPubMed PMID: 35104835. Pubmed Central PMCID: PMC8942852. Epub 20220201): 700-705Crossref PubMed Scopus (252) Google Scholar, 8Shuai H. Chan J.F. Hu B. Chai Y. Yuen T.T. Yin F. et al.Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron.Nature. 2022; 603 (MarPubMed PMID: 35062016. Epub 20220121): 693-699Crossref PubMed Scopus (288) Google Scholar and might offer key evolutionary advantage over prior variants.9Berkhout B. Herrera-Carrillo E. SARS-CoV-2 evolution: on the sudden appearance of the Omicron variant.J Virol. 2022; 96 (Apr 13PubMed PMID: 35293771. Pubmed Central PMCID: PMC9006888. Epub 20220316)e0009022Crossref PubMed Scopus (23) Google Scholar Here, we provided evidence of peak viral shedding at presymptomatic stage and during asymptomatic omicron infections by analyzing viral RNA kinetics during the entire infection course. 1,085 SARS-CoV-2 PCR-positive cases in Guang'an city of western China, who were admitted to West China Guang'an Hospital between 2022/5/9 and 2022/6/3 were enrolled in this study. Characteristics of the cohort were summarized in Table 1. Methods of population screening for omicron infections and in-hospital procedures including PCR testing and symptom monitoring were detailed in the Supplementary Materials. The human study protocols have been approved by West China Guang'an Hospital and all patient identifications were replaced by anonymous codes during abstraction as stipulated by the Declaration of Helsinki.Table 1Demographic and clinical characteristics of the cohort.All cases (n = 1085)Asymptomatic (n = 766)Symptomatic (n = 319)P*Categorical variables were assessed by Fisher's exact test or Chi-square test and continuous variables were assessed by Mann-Whitney U test. Tests were performed between asymptomatic and symptomatic groups. Abbreviations: IQR, interquartile range.Age in years, median (IQR)43 (17–56)42 (16–55)47 (18–57).039 95% vaccine coverage. Patient zero with asymptomatic infection of omicron BA.2.2 sub-variant arrived in Guang'an on 2022/5/4 and was the index of and outbreak that lead to more than 1,000 cases despite early interventions (Fig. S1). Viral RNA kinetics of 962 cases showed prevalent asymptomatic and presymptomatic peaks (Fig. S2). 69% (668/962) of them, who were asymptomatic till the end of follow-up, showed comparable peak viral RNA levels (geometric mean 4.4 × 105 vs 2.7 × 105 copies/ml, p=.173) and peak timing (median 5 vs 5 days, p=.378) with symptomatic cases (Fig. 1A and B). Interestingly, 21% (61/294) symptomatic cases showed pre-symptomatic peaking of viral RNA, which were rarely seen in pre-alpha and alpha variant infections,1Hakki S. Zhou J. Jonnerby J. Singanayagam A. Barnett J.L. Madon K.J. et al.Onset and window of SARS-CoV-2 infectiousness and temporal correlation with symptom onset: a prospective, longitudinal, community cohort study.Lancet Respir Med. 2022; 10 (NovPubMed PMID: 35988572. Pubmed Central PMCID: PMC9388060. Epub 20220818): 1061-1073Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar with higher peak viral loads than other symptomatic (geometric mean 1.1 × 106 vs 1.9 × 105 copies/ml, p<.001) or asymptomatic cases (geometric mean 1.1 × 106 vs 4.4 × 105 copies/ml, p=.014) (Fig. 1C). Simultaneous or post-symptomatic peaks were dominant in pre-alpha and alpha variant infections,1Hakki S. Zhou J. Jonnerby J. Singanayagam A. Barnett J.L. Madon K.J. et al.Onset and window of SARS-CoV-2 infectiousness and temporal correlation with symptom onset: a prospective, longitudinal, community cohort study.Lancet Respir Med. 2022; 10 (NovPubMed PMID: 35988572. Pubmed Central PMCID: PMC9388060. Epub 20220818): 1061-1073Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar whereas they were less common in early-stage (≤5 days post-lockdown, 41/83) than late-stage omicron cases in our cohort (192/211, p<.0001). Intriguingly, late-stage infections had lower peak viral loads (geometric mean 1.3 × 106 vs 1.5 × 105 copies/ml, p<.0001) at the time of increased preventive measures (Fig. 1D), whereas among those infected, vaccination was not associated with peak viral load, duration of viral clearance, or symptomatic disease (Fig. S3). Of note, endocrine disorders such as diabetes were associated with higher peak viral loads, whereas chronic infections such as HBV infections were also associated with higher peak viral loads despite of not reaching statistical significance due to small number of positive cases (Fig. S3). These findings together provided evidence of an early and asymptomatic window of infectiousness during some omicron infections. Such front-loaded infectiousness of omicron poses significant challenges to pandemic control policies, and measure undertaken earlier were less likely to be effective in this circumstance. Symptom-based testing and extended quarantine used to be an effective strategy to block SARS-CoV-2 transmission in pre-omicron era due to the long infectious window post-symptom onset.10Mefsin Y.M. Chen D. Bond H.S. Lin Y. Cheung J.K. Wong J.Y. et al.Epidemiology of infections with SARS-CoV-2 Omicron BA.2 variant, Hong Kong, January-March 2022.Emerg Infect Dis. 2022; 28 (SepPubMed PMID: 35914518. Pubmed Central PMCID: PMC9423929. Epub 20220801): 1856-1858Crossref PubMed Scopus (45) Google Scholar However, ongoing epidemic in countries with strict COVID-19 policies suggested that omicron carriers may already spread infections before being quarantined,10Mefsin Y.M. Chen D. Bond H.S. Lin Y. Cheung J.K. Wong J.Y. et al.Epidemiology of infections with SARS-CoV-2 Omicron BA.2 variant, Hong Kong, January-March 2022.Emerg Infect Dis. 2022; 28 (SepPubMed PMID: 35914518. Pubmed Central PMCID: PMC9423929. Epub 20220801): 1856-1858Crossref PubMed Scopus (45) Google Scholar which had exactly happened in Guang'an and could only be contained by early detection and interventions. Hopefully, upcoming omicron-adapted vaccines could control the pandemic; otherwise, more efficient and cost-effective screening techniques for asymptomatic population might be needed for future variants with high virulence. This study was supported by the National Natural Science Foundation of China (grants 82072862 and 82272949 to YX).