From 5 February 2020 to 8 October 2020, a total of 16 077 COVID-19 cases over the age of 40 years old (47.5% male, 21.8% aged ≥ 70 years, 71.7% from Wuhan) were recruited in 31 provinces in the mainland of China (Table 1). Severe and fatal outcomes were recorded from 1 792 and 837 cases, giving a SR of 11.1% and CFR of 5.2%, respectively. Compared with other regions in China, Wuhan had a higher proportion of patients aged ≥ 70 years (23.6% vs. 17.4%), as well as significantly higher rates of severe outcome and deaths. As the rapid decline of ODI from about 40 days in early January 2020 to < 3 days in early March, both COVID-19 related CFR and SR largely decreased, till to below 5% (Fig. 1). The ODI, as well as the SR and CFR were maintained at a similar level among most provinces of China during the entire epidemic period except Wuhan (Additional file 1: Fig. S1).
ODI and related factors
We profiled the ODIs in terms of age and sex for Wuhan and outside Wuhan separately. The overall median ODI was 4 days (IQR 2‒7), while Wuhan had longer median ODIs than outside Wuhan (Table 1, Additional file 1: Fig. S2). In general, the ODI appeared to be slightly longer in female cases and cases aged 60‒69 years, and notably longer in Wuhan and among both severe cases than their counterparts (all P < 0.001, Table 1). However, fatal cases did not appear to have a longer ODI relative to non-death cases.
Multivariate linear regression model further revealed significantly longer ODIs in female, cases aged 60‒69 years and cases in Wuhan (Additional file 1: Table S1). Subgroup analysis showed that the pattern of a longer ODI in sex was consistently seen in both regions, but cases aged 60‒69 years did not have a longer ODI in Wuhan.
Profile of SR in relate to ODI
As a whole the SR increased from 7.0% to 20.0% and then decreased to 8.0%, corresponding to the increase of ODI from 0 to 20 days, with a turning point observed at Day 10 of the ODI. Before the turning point, the APC of SR was 8.61% (P < 0.05), but after that it was -6.66% (P < 0.05) (Fig. 2A).
With the increase of ODI, earlier appearing of turning points and higher APCs of SR were found in patients of males over females (10 days vs. 13 days for the turning points, and 10.50% vs. 8.25% for APCs), in patients aged 40‒59 years, 60‒69 years, and aged ≥ 70 years (10 days, 9 days and 13 days for the turning points, 13.47%, 14.90% and 4.85% for APCs), and outside Wuhan over Wuhan (10 days vs. 13 days for the turning points, 10.64% vs. 5.53% for APCs), respectively (Fig. 2B‒D). Given the same ODI, older age and from Wuhan both led to a higher SR (Fig. 2C‒D). The turning points of ODI for those aged < 70 years were significantly longer outside Wuhan than in Wuhan, while it was comparable and those aged ≥ 70 years between two regions (Additional file 1: Fig. S3).
Impact of ODI on severity of patients with COVID-19
A serial of SR-related ORs and AFs were evaluated based on two-day grouping of ODIs, and also separately delineated by sex, age and region over the whole study period (Fig. 3A‒D, Additional file 1: Tables S2‒S3). All-data based ODI risk functions showed a monotonic pattern, with the highest OR of 2.95 (95% CI 2.37‒3.66) at Day 10–11 and AF of 29.1% (95% CI 22.2%‒36.1%) for severe outcome of COVID-19 cases observed at Day 8–9 after adjusting for age, sex and region (Fig. 3A). A similar pattern was observed for the sex- or age-specific ORs and AFs of severe outcome, disclosing more robust adverse effects of ODI for younger cases (Fig. 3B‒3C). The effect of ODIs on SR was comparable between two regions until to prolonged ODI of Day 8‒9 (Fig. 3D). The magnitude of the association between ODI and severe disease was continuously elevated in Wuhan, with the highest OR and AF observed at Day 10–11 and Day 8–9, while the OR and AF were elevated to the highest level at Day 12–13 and Day 2–3 outside Wuhan. Lower ORs of ODI for severe outcome in cases aged ≥ 70 years were observed both in Wuhan and outside Wuhan (Additional file 1: Fig. S4).
Profile of CFR in relate to ODI
There appeared to be only a slight decrease in CFR as ODI increased from 0 to 20 days (P > 0.05) (Fig. 2E). In addition to a slight increase in CFR in male cases, a slight decrease in CFR was also observed in all age and gender subgroups, with increasing ODI (Fig. 2F‒G). However, the linear correlation between CFR and ODI was significant both in Wuhan and outside Wuhan, with APCs of − 2.17 and − 12.12, respectively (Fig. 2H). When two regions were considered respectively, only female cases and cases aged 60‒69 years outside Wuhan had a significant positive association between CFR and ODI, with APCs of 6.99% and 7.88%, respectively (Additional file 1: Fig. S3).
Impact of ODI on CFR of COVID-19
A serial of CFR-related ORs and AFs were evaluated based on two-day grouping of ODIs, and were also separately delineated by sex, age and region over the whole study period (Fig. 3E‒H, Additional file 1: Table S4‒S5). Although ODIs of 2‒3 days were shown to have significant impacts on death outcome (P < 0.05), the magnitude of this risky effect was minor, with OR of 2.17 and AFs from 12.4%. Significant differences were observed for sex-, age-, and region-specific ORs and AFs of death outcome, disclosing the adverse effects of ODI on death outcome were only seen among male cases, younger cases aged 40‒59 years, and cases from Wuhan (Fig. 3F‒H). Notably, male cases displayed an increasing risk of COVID-19 death as the increase of ODI, with the highest OR of 1.39 (95% CI 1.05–1.85) and AF of 16.9% (95% CI 0.8–33.1%) at the ODIs of Day 2–3, while no such effect was observed for female cases (Fig. 3F, Additional file 1: Table S4‒S5). An increased risk of death from the increase of ODI was observed from patients aged 40–59 years, with the OR of 2.03 (95% CI 1.20–3.46) and AF of 33.6% (95% CI 9.0–58.2%) at the ODIs of Day 2–3, while no such effect was observed for other age groups (Fig. 3G, Additional file 1: Table S4‒S5). The effect of ODI on fatal outcome was only observed in Wuhan, with the OR of 1.31 (95% CI 1.03–1.67) and AF of 13.9% (95% CI − 0.3 to 28.2%) at the ODIs of Day 2–3, while no such effect was observed outside Wuhan (Fig. 3H, Additional file 1: Tables S4‒S5). Among the cases in Wuhan, higher ORs of ODI for fatal outcome were demonstrated in male than in female, in the 40–59 years group than in the ≥ 60 years group (Additional file 1: Fig. S5). Among the cases outside Wuhan, insignificant associations were observed in most two-day groups of ODI stratified by sex and age.
Prediction of overall numbers of severe cases and deaths for different scenarios
The estimated overall numbers of severe cases ranged from 1 236 (95% CI 683‒2 047) to 1 801 (95% CI 1 553‒2 076) under the 16 scenarios, which were significantly increasing with the prolonged ODI. If all cases were diagnosed within 10 days after symptom onset, the predicted severe cases were estimated to be 1.4 times of the scenario when all cases were diagnosed with 0 or 1 day after symptom onset (Fig. 4 and Additional file 1: Table S6). If all cases were diagnosed within 15 days after symptom onset, the predicted number of severe cases was further increased to 1 801 (95% CI 1 553‒2 076). For prediction of deaths in different scenarios, the estimated overall numbers ranged from 764 (95% CI 405‒1 422) to 844 (95% CI 692‒1 029), which slightly increased in relate to the prolonged ODI, and with much lower magnitude than those of severe cases. If all cases were diagnosed before 3 days after symptom onset, only little reduction of death cases was obtained, which was close to the actual number of death cases reported.