Dear Editors,
in the article “First and second COVID-19 waves in Japan: A comparison of disease severity and characteristics”, Saito et al. [1] presented a study on severity and characteristics of the first and second waves in Japan. Several countries have faced a two to three-wave pattern of COVID-19 during 2020–2021, previous reports suggesting that the subsequent waves of COVID-19 differ from the first one by the characteristics of both the virus [2] and the patients affected [1,[3], [4], [5]]. In order to compare the changes over time of COVID-19 patients and clinical outcomes in Italy, we assessed whether 28-day Intensive Care Unit admission (ICU) or mortality in a cohort of COVID-19 symptomatic hospitalised patients were changed over time, considering the roles of patients’ characteristics and severity of COVID-19 at hospital admission.
We analysed a prospective cohort of all symptomatic patients who were consecutively diagnosed with COVID-19 in the Città della Salute e della Scienza (CSS) – Molinette Hospital of Turin, from March 2020 to June 2021. The CSS Molinette is a large teaching hospital of about 1000 available beds for general inpatients. Patients data were collected using a standardized data collection form by a team of data managers and registered in the web EPICLIN platform.
According to the weekly frequency of Covid-19 admissions, two different waves were defined: a first wave from March to September 2020, and a second wave from October 2020 to June 2021 (supplementary figure 1). The primary outcome was 28-day intensive care unit (ICU) admission or mortality, and the secondary outcome was 28-day mortality only.
In the first wave period 311 symptomatic patients were admitted to the emergency department and hospitalized at the CSS Molinette hospital and 1270 in the second one (supplementary figure 2). Overall, the distribution of gender, hypertension and Charlson's comorbidity index was similar in the two waves (Table 1 ). During the first wave, there was a higher prevalence of patients with 85+ years and more severe COVID-19 disease. Median length of hospital stay was 2 days shorter in the first wave (10 days vs 12, p < 0.01) for all patients (13.5 days vs 12 days, p-value: 0.259, for patients discharged alive only). In the first wave ICU admission/death occurred in 107/311 (34.41%) patients and death in 91/311 patients (29.26%), whereas in the second wave the same figures were 301/1270 (23.70%) and 254/1279 (20.00%). Estimates for effects of waves and patients’ characteristics on outcomes are reported in Table 2 . Considering the combined outcome (28-days ICU admission/death) there was a risk reduction in the second wave with respect to the first wave (OR=0.69, 95%CI 0.50–0.95). In the adjusted model, older age, male gender, higher Charlson's index, NEWS2 score, WBC and creatinine levels were associated with higher 28-day mortality. Considering 28-day mortality, the associations between variables and outcomes were similar to the main analysis, but the reduction of risk of death in the second wave was less evident (OR=0.76, 95%CI 0.53–1.08).
Table 1.
Demographic and clinical characteristics at ED admission of symptomatic patients hospitalized for COVID19 at “Città della Salute e della Scienza di Torino hospital” by wave (March 2020–June2021).
| Total (N = 1581) | First wave (March 2020-Sept 2020) (N = 311) | Second wave (Oct 2020-June 2021) (N = 1270) | P-valuea | |
|---|---|---|---|---|
| Age: median (IQR) | 72 (60–81) | 73 (57–82) | 72 (60–80) | 0.832 |
| Age group: N (%) | ||||
| 0–59 | 391 (24.73) | 90 (28.94) | 301 (23.70) | 0.002 |
| 60–75 | 577 (36.50) | 91 (29.26) | 486 (38.27) | |
| 76–85 | 410 (25.93) | 76 (24.44) | 334 (26.30) | |
| ≥86 | 203 (12.84) | 54 (17.36) | 149 (11.73) | |
| Gender: N (%) | ||||
| Male | 983 (62.18) | 188 (60.45) | 795 (62.60) | 0.484 |
| Female | 598 (37.82) | 123 (39.55) | 475 (37.40) | |
| Body mass index (BMI): N (%) | ||||
| Underweight/Normal weight | 1277 (80.77) | 263 (84.57) | 1014 (79.84) | 0.058 |
| Overweight/Obese | 304 (19.23) | 48 (15.43) | 256 (20.16) | |
| Hypertension: N (%) | ||||
| No | 760 (48.07) | 142 (45.66) | 618 (48.66) | 0.392 |
| Yes | 821 (51.93) | 169 (54.34) | 652 (51.34) | |
| Charlson comorbidity index: N (%) | ||||
| 0 | 676 (42.76) | 129 (41.48) | 547 (43.07) | 0.499 |
| 1 | 342 (21.63) | 70 (22.51) | 272 (21.63) | |
| 2 | 233 (14.74) | 39 (12.54) | 194 (15.28) | |
| 3 | 134 (8.48) | 27 (8.68) | 107 (8.43) | |
| 4+ | 196 (12.40) | 46 (14.79) | 150 (11.81) | |
| Creatinine (mg/dL): N (%) | ||||
| ≤1.30 | 1169 (73.94) | 223 (71.70) | 946 (74.49) | 0.314 |
| >1.30 | 412 (26.06) | 88 (28.30) | 324 (25.51) | |
| National Early Warning Score 2 risk: N (%) | ||||
| Low | 835 (52.81) | 152 (48.55) | 684 (53.86) | 0.008 |
| Low-medium | 202 (12.78) | 31 (9.97) | 171 (13.46) | |
| Medium | 268 (16.85) | 51 (16.40) | 217 (17.09) | |
| High | 276 (17.46) | 78 (25.08) | 198 (15.59) | |
| White blood cell count (WBC): N (%) | ||||
| <10 | 1229 (77.74) | 232 (74.60) | 997 (78.50) | 0.346 |
| ≥10 | 352 (22.26) | 79 (25.40) | 273 (21.50) | |
| C-reactive protein (CRP) (mg/L): N (%) | ||||
| <5.0 | 167 (10.56) | 24 (7.72) | 143 (11.26) | 0.069 |
| ≥5.0 | 1414 (89.44) | 287 (92.28) | 1127 (88.74) | |
| Length of hospital stay: median (IQR) | 12 (8–21) | 10 (6–21) | 12 (8–21) | 0.003 |
chi-square test for discrete variables, Kruskal-Wallis test for continuous variables.
Table 2.
Unadjusted and Adjusted effects on 28-days ICU admission or death and on 28-days mortality in symptomatic patients admitted for COVID19 at “Città della Salute e della Scienza di Torino hospital”.
| Outcome | 28-days ICU admission or death | 28-days mortality | ||
|---|---|---|---|---|
| Unadjusted OR (95% CI) | Adjusted model OR (95% CI) | Unadjusted OR (95% CI) | Adjusted model OR (95% CI) | |
| Period | ||||
| First (March 2020-Sept 2020) | 1 | 1 | 1 | 1 |
| Second (Oct 2020-June 2021) | 0.59 (0.45–0.78) | 0.69 (0.50–0.95) | 0.60 (0.45–0.79) | 0.76 (0.53–1.08) |
| Period (unit: month) | 0.96 (0.94–0.98) | 0.95 (0.93–0.98) | ||
| Age group | ||||
| 0–59 | 1 | 1 | 1 | 1 |
| 60–75 | 2.34 (1.60–3.41) | 2.17 (1.43–3.29) | 3.29 (1.99–5.45) | 2.87 (1.68–4.93) |
| 76–85 | 4.62 (3.15–6.77) | 3.73 (2.42–5.76) | 9.51 (5.80–15.60) | 7.50 (4.37–12.86) |
| ≥86 | 8.12 (5.31–12.42) | 6.12 (3.71–10.10) | 17.66 (10.42–29.92) | 13.26 (7.28–24.13) |
| Gender | ||||
| Male | 1 | 1 | 1 | 1 |
| Female | 0.76 (0.60–0.96) | 0.59 (0.44–0.78) | 0.81 (0.63–1.04) | 0.58 (0.42–0.80) |
| Body mass index (BMI) (N,%) | ||||
| Underweight/Normal weight | 1 | 1 | 1 | 1 |
| Overweight/Obese | 0.85 (0.63–1.14) | 1.07 (0.75–1.51) | 0.73 (0.53–1.01) | 1.01 (0.68–1.50) |
| Hypertension | ||||
| No | 1 | 1 | 1 | 1 |
| Yes | 1.46 (1.16–1.83) | 0.99 (0.75–1.31) | 1.52 (1.19–1.94) | 0.93 (0.69–1.26) |
| Charlson comorbidity index | ||||
| 0 | 1 | 1 | 1 | 1 |
| 1 | 1.84 (1.35–2.50) | 1.35 (0.95–1.94) | 2.39 (1.70–3.35) | 1.66 (1.11–2.46) |
| 2 | 1.81 (1.28–2.57) | 1.38 (0.93–2.06) | 2.41 (1.65–3.53) | 1.73 (1.12–2.68) |
| 3 | 2.34 (1.55–3.53) | 1.44 (0.90–2.31) | 3.06 (1.97–4.75) | 1.78 (1.07–2.97) |
| 4+ | 3.89 (2.76–5.50) | 2.36 (1.58–3.53) | 5.82 (4.04–8.40) | 3.48 (2.26–5.35) |
| Creatinine (mg/dL) | ||||
| ≤1.30 | 1 | 1 | 1 | 1 |
| >1.30 | 3.62 (2.84–4.62) | 1.84 (1.37–2.46) | 4.49 (3.48–5.79) | 2.12 (1.56–2.88) |
| National Early Warning Score 2 risk | ||||
| Low | 1 | 1 | 1 | 1 |
| Low-medium | 1.91 (1.31–2.79) | 1.62 (1.09–2.42) | 1.63 (1.08–2.46) | 1.33 (0.85–2.09) |
| Medium | 2.85 (2.06–3.94) | 2.79 (1.97–3.96) | 2.52 (1.79–3.55) | 2.51 (1.70–3.70) |
| High | 8.22 (6.04–11.18) | 6.40 (4.52–9.06) | 7.27 (5.31–9.95) | 5.70 (3.91–8.29) |
| White blood cell count (WBC) (N,%) | ||||
| <10 | 1 | 1 | 1 | 1 |
| ≥10 | 2.49 (1.93–3.20) | 1.50 (1.11–2.03) | 2.44 (1.87–3.17) | 1.40 (1.01–1.94) |
| C-reactive protein (CRP) (mg/L) | ||||
| <5.0 | 1 | 1 | 1 | 1 |
| ≥5.0 | 1.30(0.88–1.91) | 0.91 (0.59–1.42) | 1.37 (0.90–2.08) | 0.97 (0.60–1.59) |
In the present study, a reduction of 28-day ICU admission or death in patients with symptomatic COVID-19 of an Italy Hospital was showed (from 29.3% in the period to March-September 2020 to 20.0% in the period October 2020-June 2021). Patients admitted to the ED of our hospital in the first period were older, reflecting also the frequent outbreaks in nursing-home residents. In Italy access for visitors of nursing-homes was forbidden in April 2020 and isolation protocols for staff and patients were implemented. Furthermore, patients in the first period were more hypertensive, had a higher co-morbidity burden and presented at the ED with more severe symptoms and a worse inflammatory profile. However, adjustment for all these factors did not explain the period effect on mortality.
Consistently with Saito's Japanese cohort, the severity of Italian patients at ED presentation (measured with NEWS 2 score and two markers related to mortality [6]) was reduced in the second wave. Furthermore, as expected, higher level and lower levels of WBC counts, higher levels of CRP and more severe clinical conditions (NEWS2 score >=7) were associated with higher mortality in COVID-19 patients. Low severity at admission has been associated to a reduction of death risk in the second wave coherently with other previous studies [1,4]. Anyway, in our experience also patients with very severe presentation at the ED had an improved prognosis in the second wave, probably due to better organization and experience gained along the whole care pathway of more critical patients.
The excess mortality observed in the first period of pandemics could be due, at least in part, to distinct factors not related to the characteristics of the patients. I) Knowledge about the clinical course of the disease and evidence on effective and ineffective treatments rapidly accumulated during the first pandemic wave. In the peak of the first phase, emergency rooms, hospitals and intensive care units were challenged by the need of simultaneously providing care to a high number of critically ill patients. In the second wave, hospitals were better organized to receive COVID-19 patients with dedicated pathways, wards, beds, respiratory supports and protective devices. [7]. II) The treatment approach changed over the two periods, i.e., those admitted to hospital in the second phase were less likely to receive antivirals and more likely to be treated with steroids and antithrombotic prophylaxis or therapy [8]. Furthermore, in the second wave, a more timely and non-invasive ventilation support was employed [9]. The second wave captured a predominance of patients affected by the alpha variant of SARS-COV-2. The alpha variant was described as more contagious than wild type SARS-COV-2 and probably a cause of a more severe disease [10]. This is in contrast with our findings because, in the second wave, when a higher prevalence of alpha variant of SARS-COV-2 was expected, we noticed a lower mortality rate. However, it must be noticed that the genomic determination of SARS-COV-2 subfamilies was not performed routinely in Italy, so that we can only speculate on the genomic family of SARS-COV-2 among infected patients.
In conclusion, in a cohort of COVID-19 patients admitted to an Italian hospital a decreased risk of ICU admission or mortality was documented after the first wave that was only marginally attenuated by adjustment for patients’ characteristics and severity of COVID-19 at hospital admission.
Declaration of Competing Interest
None.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jinf.2022.06.023.
Contributor Information
Giovannino Ciccone & COVID-EASYNET working group:
Grazia Maria Auzzas, Cristina Balestro, Carol Brentisci, Francesco Brunetti, Umberto Fiandra, Claudia Galassi, Manuela Gangemi, Lisa Giacometti, Marco Gilardetti, Fulvio Lazzarato, Vitor Hugo Martins, Matteo Papurello, Francesca Ponti di Sant’Angelo, Stefano Roggero, Fabio Saccona, Carlo Silvestre, Antonella Stura, Danila Turco, Federico Vischia, and Susanna Zozzoli
Appendix. Supplementary materials
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