key: cord-0849732-eli6f59y
authors: Li, F.; Cai, Y.; Gao, C.; Zhou, L.; Chen, R.; Zhang, K.; Li, W.; Zhang, R.; Zhang, X.; Wang, D.; Liu, Y.; Tao, L.
title: Clinical Course And Risk Factors For In-hospital Death In Critical COVID-19 In Wuhan, China
date: 2020-09-28
journal: nan
DOI: 10.1101/2020.09.26.20189522
sha: 506fc9279be89ce3b1ccd931896bef94e7b738d6
doc_id: 849732
cord_uid: eli6f59y

BACKGROUND The risk factors for mortality of COVID-19 classified as critical type have not been well described. OBJECTIVES This study aimed to described the clinical outcomes and further explored risk factors of in-hospital death for COVID-19 classified as critical type. METHODS This was a single-center retrospective cohort study. From February 5, 2020 to March 4, 2020, 98 consecutive patients classified as critical COVID-19 were included in Huo Shen Shan Hospital. The final date of follow-up was March 29, 2020. The primary outcome was all-cause mortality during hospitalization. Multivariable Cox regression model was used to explore the risk factors associated with in-hospital death. RESULTS Of the 98 patients, 43 (43.9%) died in hospital, 37(37.8%) discharged, and 18(18.4%) remained in hospital. The mean age was 68.5 (63, 75) years, and 57 (58.2%) were female. The most common comorbidity was hypertension (68.4%), followed by diabetes (17.3%), angina pectoris (13.3%). Except the sex (Female: 68.8% vs 49.1%, P=0.039) and angina pectoris (20.9% vs 7.3%, P = 0.048), there was no difference in other demographics and comorbidities between non-survivor and survivor groups. The proportion of elevated alanine aminotransferase, creatinine, D-dimer and cardiac injury marker were 59.4%, 35.7%, 87.5% and 42.9%, respectively, and all showed the significant difference between two groups. The acute cardiac injury, acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS) were observed in 42.9%, 27.8% and 26.5% of the patients. Compared with survivor group, non-survivor group had more acute cardiac injury (79.1% vs 14.5%, P<0.0001), AKI (50.0% vs 10.9%, P<0.0001), and ARDS (37.2% vs 18.2%, P=0.034). Multivariable Cox regression showed increasing hazard ratio of in-hospital death associated with acute cardiac injury (HR, 6.57 [95% CI, 1.89-22.79]) and AKI (HR, 2.60 [95% CI, 1.15-5.86]). CONCLUSIONS COVID-19 classified as critical type had a high prevalence of acute cardiac and kidney injury, which were associated with a higher risk of in-hospital mortality.

Beginning in December 2019, the COVID-19 has caused an international outbreak of respiratory illness. By March 30, 2020, the confirmed COVID-19 patients had exceeded 700 thousand. The soaring of COVID-19 has been seen as one of the most serious hazards to global health.

COVID-19 is clinically classified as four types: mild, moderate, severe and critical.

Critical patients have critical pulmonary injury, systemic inflammatory status and a very high mortality (1) (2) (3) , which leads to tremendous difference in clinical course, medical intervention and prognosis compared with mild to severe type. Illustration of demographics, clinical characteristics, complications and treatment outcome of critical patients is practically important to get further insights into the early origins of adverse outcomes and may ultimately be relevant for developing clinical prediction models. Although some COVID-19 case series and studies have been reported previously (4) (5) (6) , to our knowledge, there are limited studies only including critical patients and specifically focusing on adverse outcomes and the predictive factors.

In the present study, we retrospectively included 98 consecutive patients with critical COVID-19 in Huoshenshan hospital (Wuhan, China). We described the patient demographics, laboratory findings, treatment & complications and further explored risk factors of in-hospital death for these patients.

This is a single-center, retrospective cohort study. A total of 2074 consecutive patients with COVID-19 were screened in Huo Shen Shan Hospital from February 5, 2020 to March 4, 2020 . Huo Shen Shan Hospital was opened since February 3, 2020, designated by the government only for treating COVID-19. After excluding the mild, . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 28, 2020. 

The demographics, laboratory findings, treatment & complications for participants during hospitalization were collected from electronic medical records by 2 investigators. All data were independently reviewed and entered into the computer database by 2 analysts.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 28, 2020. . https://doi.org/10.1101/2020.09.26.20189522 doi: medRxiv preprint

The primary endpoint was all-cause mortality during hospitalization. Other endpoints included: 1) Cardiac injury , defined as blood levels of cardiac injury markers (hs-TNI or CK-MB) above the upper reference limit.; 2)Acute respiratory distress syndrome (ARDS), defined according to the Berlin definition(9); 3)Acute kidney injury, identified according to the Kidney Disease: Improving Global Outcomes definition (KDIGO) (10) .

Continuous data are presented as mean SD or median (interquartile range) and compared using the Student's t-test or the Mann-Whitney test depending on their distributions. Categorical variables were expressed as frequencies with percentages and compared with the Chi-square or Fisher exact tests as required. Kaplan-Meier curves were constructed to estimate the cumulative incidence of death and were compared using the log-rank test. Cox proportional hazards models were used to identify risk factors for the occurrence of death. Results are reported as HRs and 95%

CIs. Only covariates associated with the risk of death at a univariate analysis with P <0.1 were then included in the multivariate analysis of in-hospital death. All statistical tests were two-tailed, and P values were statistically significant at <0.05. All data were analyzed with SPSS version 19.0 software (SPSS, Inc, Chicago, Illinois, USA). 

The percentages of use of noninvasive ventilation and invasive mechanical ventilation were 52.0% (51patients) and 40.8% (40 patients). Of the 40 patients who received invasive mechanical ventilation, 33 patients (80.5%) died, 7 patients (12.3%) are still in hospital, and no patient was discharged. The proportion of antiviral therapy was the highest (86.7%), followed by antibiotics (80.6%), corticosteroids (65.3%) and

traditional Chinese medicine treatment (28.6%). Only 3 patients (3.1%) received continuous renal replacement therapy, and 2 patients (2.0%) received ECMO therapy.

Overall, the acute cardiac injury observed in 42.9% of the patients, followed by AKI (Table 3) . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 28, 2020. (Figure 1 )

Our present retrospective cohort study demonstrated a 43.9% of in-hospital death rate and identified several risk factors for in-hospital death in patients with critical COVID-19. Of a particular note, high incidence of acute cardiac injury and AKI was observed in our study population of patients with critical COVID-19, which are associated with a high risk of mortality during hospitalization.

By March 30, 2020, the number of COVID-19 had dramatically increased. According to the COVID-19 diagnosis and treatment program (trial sixth edition) issued by the National Health Commission of China (7), the patients were classified as clinically four types: mild, moderate, severe and critical type. For its rapidly progress in pulmonary injury and subsequently systemic complications (11) , it is still the emphasis and difficulty in the treatment of critical type of COVID-19 (12) . At early stage of the COVID-19 outbreak, a descriptive study of 99 patients with moderate to critically ill presentation reported a 11% of mortality (5) . A cohort study including 191 all . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 28, 2020. . https://doi.org/10.1101/2020.09.26.20189522 doi: medRxiv preprint hospitalized patients with a definite outcome (dead or discharged) reported a 28.3% of mortality (13) . An observational study enrolled 21 critically ill patients from a public hospital in Washington State reported a 52.4% in-hospital death (1) . A retrospective single-center study included 52 critically ill patients (3), and 32 (61·5%) patients had died at 28 days after hospitalization. In the present study, we enrolled 98 consecutive patients with critical COVID-19, and reported a 43.9% of in-hospital death rate.

Taking into account of 18 patients still in hospital, we could infer that the mortality will continue to rise.

For the first time, we reported that AKI acted as an independent predictor for in-hospital death in COVID-19. Although studies reported that AKI occurred in COVID-19 patients, the association between AKI and risk of mortality has not be found yet. In the 1099 COVID-19 patients recently reported by Guan et al, the AKI incidence observed in unselected cases was 0.5% (14) . A cohort study by Zhou et al in 191 patients reported an incidence of 15% (13) . The difference in the prevalence rate of AKI may be attributed to the differences in enrolled patient populations. In the present study, the incidence of AKI is 27.8% in total, with an AKI incidence of 50% in the non-survivor group, which is consistent with Zhou's study (13) . Furthermore, even after adjusting for confounding factors, the multivariable adjusted Cox proportional hazard regression model still showed a significantly higher risk of death in patients with AKI than in those without AKI. The mechanism of coronavirus infection leading to AKI is not clear. According to existing studies (15, 16) , in addition to virus particles directly interacting with ACE2 receptor and overreacted immune responses, AKI in critical type of patients may also be caused by the following factors: hypotension, hypoxemia, electrolyte disorders, and massive use of immunosuppressive agents. However, more research is needed to clarify this issue.

Cardiac injury in COVID-19 has been reported in several studies (6, 17, 18) . A report on 138 inpatients with COVID-19 showed that 7.2% of patients developed acute . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted September 28, 2020. Therefore, their role might be underestimated in predicting in-hospital death.

Although we have adjusted for various variables that were associated with death in Cox regression analysis, there may be other potential confounders.

A high incidence of acute cardiac injury and AKI were presented in COVID-19 classified as critical type, which were associated with high risk of in-hospital mortality.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 28, 2020. . https://doi.org/10.1101/2020.09.26.20189522 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 28, 2020. . https://doi.org/10.1101/2020.09.26.20189522 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted September 28, 2020. . https://doi.org/10.1101/2020.09.26.20189522 doi: medRxiv preprint

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