Dynamic disease manifestations among individuals infected with SARS-CoV-2 Omicron variant

To the Editor: The unprecedented pandemic of coronavirus disease 2019 (COVID-19) has put tremendous pressure on healthcare resources and economic development worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron strain has become the dominant causative strain of COVID-19 in most countries since the end of 2021. Although a large cohort study comparing the symptomatic presentation of SARS-CoV-2 Omicron and Delta infection has been made in the UK,[1] features and evolution of symptoms of individuals infected with Omicron are rarely reported in other countries or regions, especially among Asian individuals. In late February 2022, the COVID-19 epidemic that was mainly caused by the Omicron subtype BA.2, a sub-lineage of the Omicron variant (B.1.1.529), rapidly emerged in Shanghai, China.[2] In this retrospective cohort study, we enrolled asymptomatic or mildly symptomatic patients (age ≥12 years) with polymerase chain reaction (PCR) confirmed COVID-19 admitted to the mobile cabin hospital in National Exhibition and Convention Center in Shanghai, between May 6 and May 14, 2022. COVID-19 was diagnosed based on the Diagnosis and Treatment Protocol for COVID-19 patients (Tentative 9th Edition) issued by the National Health Commission of the People's Republic of China.[3] Data on general information, characteristics of symptoms, the time of first positive nucleic acid test, vaccination status, and comorbidities were collected through a questionnaire [Supplementary Table 1, https://links.lww.com/CM9/B587]. This study was approved by Research Ethics Committees of the Shanghai Changzheng Hospital (No. 2022SL055). Informed consent to participate in the study was inferred based on submission of the questionnaire. A total of 2511 patients were admitted, among whom a total of 509 patients participated in filling-up the questionnaire; and these were followed up by telephone visit to supplement and verify the data provided in the questionnaire. Of these, 23 cases were excluded due to insufficiency of the data provided within the questionnaire or unavailability for providing supplementary information, resulting in a total of 486 patients getting accepted into the study [Supplementary Figure 1, https://links.lww.com/CM9/B587]. The demographic characteristics of the enrolled patients are shown in Supplementary Table 2, https://links.lww.com/CM9/B587. Eighty-eight patients (18.1%) were asymptomatic until discharge, and 398 patients (81.9%) exhibited at least one symptom. There were no statistically significant differences between the two groups in vaccination status, time since the last vaccine shot to the first positive nucleic acid test, vaccination status, history of alcohol consumption, body mass index (BMI), and education. Compared to the asymptomatic group, the symptomatic group had a higher proportion of females (46.0% [183/398] vs. 34.0% [30/88], P = 0.044) and a lower proportion of current smokers (16.6% [66/398] vs. 27.3% [24/88], P = 0.023). However, the risk of exposure, as stratified by gender and smoking history, was not chronicled on a symptomatic basis when age was taken into account. The median number of symptoms in the symptomatic population was four, with cough (57.6%), expectoration (46.7%), sore throat (44.2%), fever (42.0%), fatigue (36.0%), rhinorrhea (34.8%), headache (31.5%), and myalgia and arthralgia (33.3%) being the eight most common symptoms [Supplementary Figure 2A,https://links.lww.com/CM9/B587]. Among these, fever (32.9%, 131/398), cough (25.4%, 101/398), fatigue (23.4%, 93/398), sore throat (22.9%, 91/398), and headache (22.6%, 90/398) were the most common onset symptoms [Supplementary Figure 2B, https://links.lww.com/CM9/B587]. Cough and expectoration often occurred together in this group, and 72.5% of patients with cough had sputum (80.6% with low sputum volume) and 10.6% with sputum did not have cough. The majority (81.8%) of patients with cough progressed to the most severe cough within 2 days, with a median time to remission of 4 days, and lasting up to 26 days. Nearly half (101/203, 49.8%) had sputum that appeared more than 1 day later than cough, 88.1% had sputum that progressed to most severe within 2 days, median time to remission of sputum was 3 days and lasted up to 23 days, and 4.0% had symptoms that lasted until after discharge. A total of 204/486 (42.0%) presented with varying degrees of fever, and 64.2% as the onset symptom. Temperature was predominantly low (49.3%) and moderate (32.8%) with a median temperature of 38.0°C, and 68.5% had peak temperature on the first day of fever, the median duration of the fever being 2 days. All individuals recovered to normal temperature within 10 days, and less than 5.0% had fever for more than 5 days. Among patients presenting with sore throat, 76.3% progressed to the worst symptom within 1 day, with a median time to remission of 3 days, and 3.0% had sore throat lasting more than 10 days. Among patients presenting with fatigue, 84.0% progressed to its maximum severity within 1 day of fatigue presentation. The median time to remission of fatigue was 2 days, and the duration of the disease could extend to more than 1 month. Headache, and myalgia and arthralgia, occurred in more than 30.0% of cases. These were most severe on the same day or the next day in more than 90.0% of patients and resolved within 3 days in about 80.0% of patients [Figure 1A and Supplementary Figure 2C, https://links.lww.com/CM9/B587]. All patients enrolled were successfully discharged, and none developed severe symptoms or died. Cluster analysis [Supplementary Figure 3,https://links.lww.com/CM9/B587] showed that cough, expectoration, sore throat, and rhinorrhea formed a cluster of upper respiratory syndromes, while headache, fatigue, and myalgia and arthralgia formed a separate cluster. Both symptom clusters were closely related to fever.Figure 1: Characteristics of symptoms and virology in COVID-19 patients. (A) Time distribution of different stages of symptoms since initial symptom began. The left and the right ends of the rectangle represent the IQR at each stage of time, the vertical lines inside the rectangle represent the median time, and the rhombuses represent the individuals with time beyond the IQR. (B) The Ct values of ORF1ab and N gene detected by RT-PCR in pharyngeal swab from asymptomatic (n = 88) and symptomatic (n = 398) groups. (C) The Kaplan–Meier method was used to estimate the positive rate of viral RNA, and the two-sided log-rank test was applied to assess the significant difference in viral shedding time between the asymptomatic and symptomatic groups. * P <0.0001. COVID-19: Coronavirus disease 2019; 95%CI: 95% confidence interval; IQR: Interquartile range; RT-PCR: Reverse transcription-polymerase chain reaction; Ct: Cycle threshold.The median overall symptom duration was 7 days (interquartile range [IQR] 4–10 days), and risk factors for overall symptom duration longer than 10 days were analyzed by multivariate logistic regression. Random forest plots [Supplementary Figure 4,https://links.lww.com/CM9/B587] showed that the presence of comorbidities (odds ratio [OR]: 2.72, 95% confidence intervals [CI]: 1.19–6.22, P = 0.017), cough (OR: 3.50, 95% CI: 1.39–8.78, P = 0.008), myalgia and arthralgia (OR: 2.18, 95% CI: 1.08–4.41, P = 0.030), and olfactory taste loss (OR: 2.81, 95% CI: 1.13–7.01, P = 0.026) are independent risk factors. Additionally, the risk of overall symptom duration more than 10 days was 3.61 and 3.14 times higher in patients aged <30 years and 30–50 years, respectively, than in patients aged >50 years (P <0.050). We also analyze the relationship between symptom evolution, viral load, and the duration of viral shedding. The pharyngeal swab viral load was at a high level during symptom onset and early stage of illness [Supplementary Figure 5,https://links.lww.com/CM9/B587]. Viral shedding could be observed as symptoms resolved, especially with regard to upper respiratory tract symptoms. Cycle threshold (Ct) values increased with the remission of cough, expectoration, and rhinorrhea compared with the onset and worst symptom (P <0.01) [Supplementary Figure 5,https://links.lww.com/CM9/B587]. After admission, we compared the minimal Ct values in 398 symptomatic and 88 asymptomatic individuals enrolled [Figure 1B]. The minimum Ct values after admission were significantly lower in symptomatic patients than in asymptomatic patients (ORF1ab 33.00 ± 5.77 vs. 36.49 ± 5.28, P <0.001; N gene 31.92 ± 6.30 vs. 35.49 ± 6.11, P <0.001), suggesting a higher viral load in symptomatic patients. The median duration of viral shedding time was 6 days (IQR 3–9 days) in all patients, 3 days (IQR 1–6 days) in asymptomatic patients, and 7 days (IQR 4–10 days) in symptomatic patients. The symptomatic group had a significantly longer duration of viral shedding than the asymptomatic group (Hazard ratio: 1.50, 95% CI: 1.18–1.89, log-rank P = 0.001) [Figure 1C]. In conclusion, Omicron infection causes clusters of symptoms, most of which resolve in 7–10 days. Symptomology is associated with the longer duration of illness and prolonged shedding of the virus. Our findings may help physicians understand the characteristics of Omicron infection and be informative for the adaptation of workplace health policies and public health guidelines. Conflicts of interest None.