key: cord-0719581-1p0p0hi5
authors: Terada, M.; Ohtsu, H.; Saito, S.; Hayakawa, K.; Tsuzuki, S.; Asai, Y.; Matsunaga, N.; Kutsuna, S.; Sugiura, W.; Ohmagari, N.
title: Risk factors for severity on admission and the disease progression during hospitalization in a large cohort of COVID-19 patients in Japan
date: 2021-04-07
journal: nan
DOI: 10.1101/2021.04.02.21254809
sha: 42167f26ee2af6a16c90d6f102e046379b0c58e0
doc_id: 719581
cord_uid: 1p0p0hi5

Objectives: To investigate the risk factors contributing to severity on admission. Additionally, risk factors on worst severity and fatality were studied. Moreover, factors were compared based on three points: early severity, worst severity, and fatality. Design: A observational cohort study utilizing data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP. Setting: As of August 31, 2020, 7,546 cases from 780 facilities have been registered. Participating facilities cover a wide range of hospitals where COVID-19 patients are admitted in Japan. Participants: Participants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests, and were admitted to participating healthcare facilities. A total of 3,829 cases were identified from January 16 to May 31, 2020, of which 3,376 cases were included in this study. Primary and secondary outcoe measures: Primary outcome was severe or non-severe on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2, or respiratory rate. Secondary outcome was the worst severity during hospitalization, judged by the requirement of oxygen and/or IMV/ECMO. Results: Risk factors for severity on admission were older age, male, cardiovascular disease, chronic respiratory disease, diabetes, obesity, and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumor, and hyperlipidemia did not influence severity on admission ; however it influenced worst severity. Fatality rates for obesity, hypertension, and hyperlipidemia were relatively lower. Conclusions: This study segregated the comorbidities driving severity and death. It is possible that risk factors for severity on admission, worst severity, and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidemia, and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation. Trial registration: UMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045453

obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation. 

In this article, we studied the disease progression of COVID-19, by comparing the risk factors on three points: early severity, worst severity, and fatality.

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The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint Our results are useful from a public health perspective, as we provide risk factors for predicting the severity on admission and disease progression from patients' background factors.

This study pointed out the possibility that risk factors of the severity on admission, worst severity, and fatality are not consistent and may be propelled by different factors.

Our data were collected from hundreds of healthcare facilities; thus data accuracy may be questionable.

Also, treatment type, dosage, duration, and combination varied immensely across the facilities and we did not consider treatments prior to and during hospitalization in the analysis.

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused a major global public health crisis. As of October 3, 2020, >34 million people had been infected in over 230 countries 1,2 . Japan experienced two pandemic waves after the first case reported on January 16, 2020. During the first wave, a state of emergency was declared on April 7, which ended on May 25, settling the first wave. Nearly thrice as many SARS-CoV-2 positive cases were detected in the second wave, which emerged from the end of June 3 . The fatality rate in the second wave has generally been lower in many countries, including Japan 4 .

When the number of patients explodes, hospital beds were in great shortage; hotels were utilized as isolation facilities in many countries [5] [6] [7] . Likewise, in Japan, mild patients were transferred to hotels from April 2020 8 . About two-thirds of cases did not require oxygen support throughout thier illness 9 . However, some cases initiated non-severe may instantly plunge into a serious state and require aggressive care 10 . Therefore, public health centers are in demand for indicators to identify those at a higher risk of aggravation in the early phase and determine the destination-hospital, hotel, or home. Depicting the clinical course-from onset to worst severity and the outcome-is imperative to appropriately allocate patients to healthcare resources. Analyses considering the severity on admission and the disease progression thereafter . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint has not been conducted are of interest to physicians globally.

We obtained nationwide data from a COVID-19 inpatient registry, "COVID-19 REGISTRY JAPAN (COVIREGI-JP)" 11 , and conducted a study to identify the independent risk factors contributing towards severity on admission. We aimed to determine the risk factors on admission, namely demographics and comorbidities. Progression of severity was inspected in detail on different time points. Cases identified within the period of the first pandemic wave were studied.

This is an observational cohort study that utilizes the data accumulated in the nationwide "COVID-19 REGISTRY JAPAN (COVIREGI-JP)" 11 . As of September 28, 2020, 10,048 cases from 802 facilities have been registered. Participating facitilies covers a wide range of hospitals where COVID-19 patients are admitted in Japan. Enrolled cases satisfied two eligibility criteria: a positive test result for COVID-19 and being admitted to a healthcare facility.

Registration started on March 2, 2020, and is ongoing, at present.

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The copyright holder for this preprint this version posted April 7, 2021. 

Comorbidities were collected based on Charlson comorbidity index 15,16 with modifications. Some comorbidities were combined as follows: Cardiovascular disease (CVD)-myocardial infarction, congestive heart failure, and peripheral vascular disease; Chronic respiratory disease (CRD)-chronic obstructive pulmonary disease (COPD) and other chronic lung diseases; Renal disease or dialysis-moderate to severe renal disorder (creatinine ≥ 3mg/dL, nephropathy, post-renal transplantation, or on dialysis), and maintenance hemodialysis or peritoneal dialysis before hospitalization; and Solid tumor-solid tumor with or without metastasis. Obesity was . CC-BY-NC-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)

The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint diagnosed based on physician's judgement, and body mass index (BMI) was not considered in this study.

Steroids, chemotherapy, and immunosuppressants administered prior to hospitalization were collected as pre-hospitalization treatments. Steroids included those equivalent to 20 mg/day prednisolone for ≥ 1 month and are not considered as immunosuppressants. Chemotherapy and immunosuppressants was applicable if administered 3 months prior to hospitalization.

Treatment during hospitalization was studied on systemic steroids, favipiravir, ciclesonide, heparin, and tocilizumab, due to the frequent use in Japan. Heparin use included those given for both prophylactic and treatment purposes.

We defined the first wave period as January 16 to May 31, 2020 17 , and cases from the first wave was included in this analysis. Therefore, data extraction conditions were: (1) cases admitted to healthcare facilities between January 16 and May 31, 2020, and (2) all CRF items completed on dataset generation. The dataset was generated and fixed on September 2, 2020.

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Severity on admission was converted into bivariate variables: severe and non-severe. Cases met at least one of the following criteria were categorized as severe: (1) requiring invasive or non-invasive mechanical ventilation, (2) requiring supplemental oxygen, (3) SpO 2 ≤ 94% in room air, or (4) tachypnea with respiratory rate (RR) ≤ 24 breaths per minute 18 . Those who did not meet the aforementioned were classified as non-severe.

The worst severity was grouped into three categories: no-oxygen, oxygen, and IMV/ECMO. The worst state during hospitalization was adopted on categorization, and each was defined as follows:

No-oxygen-No requirement of supplemental oxygen throughout hospitalization.

Oxygen-Required supplemental oxygen (including high-flow oxygen devices) or non-invasive mechanical ventilation during hospitalization.

IMV/ECMO-Required invasive mechanical ventilation or extracorporeal membrane oxygenation during hospitalization.

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The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint Continuous variables are presented in median and interquartile range (IQR) and categorical variables in number of cases and percentages. We classified the disease progression into three stages: severity on admission, worst severity, and clinical outcomes. We used Mann-Whitney U tests (for two groups) or Kruskal-Wallis tests (for three groups) for continuous variables and chi-squared tests for categorical variables.

We conducted a multivariable logistic regression analysis to identify the factors associated with the patients' severity on admission. We included age, sex, comorbidities (CVD, cerebrovascular disease, CRD, asthma, liver disease, diabetes, obesity diagnosed by physicians, renal disease or dialysis, solid tumors, leukemia, lymphoma, hypertension, and hyperlipidemia), use of systemic steroids in the past month, chemotherapy in the past three months, and use of immunosuppressants other than steroids as independent variables. Multicollinearity was evaluated using the variance inflation factor (VIF). Variables of VIF > 3 were excluded from the model; however, no variables demonstrated obvious multicollinearity. R version3.6.3 (R core team, 2020) 19 was used for all the analyses performed in this study.

The National Center for Global Health and Medicine ethics board approved this study (referral . CC-BY-NC-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)

The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint number NCGM-G-003494-08), and waived the need for informed consent from individual patients owing to the non-invasive, non-interventional nature of this observational study according to the local Ethical Guidelines 20 . Information regarding opting out of our study is available on the website 11 . Although it is not mandatory, the study is also being registered on Demographics and clinical characteristics of the study population are shown in Table 1 .

Days between onset and admission were similar in both groups (non-severe 6.0 vs severe 7.0 days). Over ten times as many severe cases on admission underwent IMV/ECMO than . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint non-severe cases (2.0% vs 26.4%). Severe cases were older (50.0 vs 67.0), had higher BMI (22.9 vs 24.1), greater male dominance (56.3% vs 70.5%), and a higher prevalence of comorbidities excluding leukemia, compared to the non-severe group. The most prevalent symptoms in both groups were fever (non-severe 49.5%, severe 73.7%), cough (non-severe 53.8%, severe 64.9%), and fatigue (non-severe 40.3%, 59.9%), but was greater in the severe group. Conversely, prevalence of dysgeusia (25.9% vs 13.2%), dysosmia (22.6% vs 11.5%), headache (18.1% vs 14.7%), and runny nose (11.9% vs 8.9%) was higher in the non-severe group.

Results of the multivariate logistic regression to determine the risk of severity on admission are shown in Table 2 between onset to admission were non-significant (p = 0.376); the timing of admission did not affect the severity on admission. Table 3 depicts the study population from a different angle and is categorized by the worst severity (n=3,336) and fatality (n=3,376). Oxygen and IMV/ECMO cases were predominantly severe at admission (65.5% and 87.9%, respectively), whereas most no-oxygen . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint cases come from non-severe group (90.2%). Prevalence of comorbidities was lowest in no-oxygen cases; however, prominent difference was not observed for asthma. Similarly, fatal cases were more severe at admission (84.0% vs 31.1%) and had higher prevalence of oxygen and IMV/ECMO cases (oxygen: 56.4% vs 29.0%, IMV/ECMO: 41.9% vs 8.2%, respectively).

Days between onset and admission was longer in non-fatal cases (5-days vs 7-days).

More non-severe cases with any comorbidity underwent treatment with oxygen or IMV/ECMO compared to non-severe cases with no comorbidities. In figure 1, only 11.9% underwent oxygen therapy or IMV/ECMO in non-severe cases without any comorbidities.

However, among the non-severe cases with comorbidity, the rates of oxygen or IMV/ECMO were higher in most comorbidities, including CVD (34.7%), CRD (38.9%), liver disease Among the cases without comorbidity, 75.2% of cases that were severe on admission required oxygen or IMV/ECMO; however, the fatality rate was low, and only 8.0% resulted in death ( Figure 2 ). Fatality rates were approximately 3-5 times higher when the following comorbidities were present: renal disease or dialysis (44%), CVD (40.5%), cerebrovascular . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint disease (39.5%), CRD (30.4%), solid tumor (30.4%), diabetes (25.8%), and liver disease (25.6%). Even among non-severe cases, relatively high fatality rate was observed in cases with solid tumor, CRD, cerebrovascular disease, CVD, and renal disease or dialysis, with fatality rates ranging from 8.1% to 11.1%. Collectively, obesity, hypertension, and hyperlipidemia influenced the worst severity; however, their influence on fatality was relatively lower than that mentioned earlier.

Older age was relevant to both worst severity and fatality, as shown in supplemental figures 1 and 2. The combined proportion of oxygen and IMV/ECMO increased gradually by age from 5.3% in 20s to 69.3% in ≥ 80s. Conversely, the fatality rate leaped between 60s (2.2%) and 70s (8.6%). Likewise, supplemental figure 3 shows the combined proportion of oxygen and IMV/ECMO and fatality rates as higher in older individuals, irrespective of underlying comorbidities.

Predominant comorbid cases required more drug administration than those without comorbidities (Supplementary Table 1 ). Systemic steroids were most frequently used in cases with CRD (27.9%). Heparin was used most often in renal disease (12.8%), hypertension (11.2%), diabetes (10.9%), and CVD (10.4%).

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The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint

We took disease progression into consideration and evaluated the study population based on severity on admission, worst severity, and the outcome. To our knowledge, studies have predominantly reported worst severity, whereas disease progression has not been considered. Our findings, therefore, are novel, augmenting the evidence needed to depict the clinical course and trajectory from onset to worsening condition. Specifically, this study segregated the comorbidities influencing severity and death. Based on our findings, it may be possible that the early severity, worst severity, and death are propelled by different factors, whilst confirmation is necessary by multivariate analysis.

The majority of comorbidities we studied did not influence severity on admission. On admission, severity was driven by age, sex, CVD, CRD, diabetes, obesity, and hypertension.

The trend was similar for the worst severity, as cases with these factors had higher rate of oxygen or IMV/ECMO. However, all comorbidities appeared to influence the worst severity.

Within the comorbidities, the prognosis of cases with obesity, hypertension, or hyperlipidemia was relatively favorable. In contrast to our results, hypertension and obesity are reportedly related to an increased risk of severity and mortality 21-24 . However, a large cohort reported a trend similar to our results 25 . Another study reported that obesity is be confounded by age and sex 26,27 . Obesity was judged by a physician in our study, and the results may change after incorporating BMI. Several other evidences suggest that the association of these . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint comorbidities with poorer outcome of COVID-19 needs further investigation. BMI, on average, is lower in the Asia-Pacific region than in other global regions 28 ; therefore, the degree of obesity may have been milder in our study population. Extreme obesity may worsen the prognosis, and confounders should be addressed in consecutive analyses. On the other hand, the presence of hypertension and the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers act contrarily 29-31 , while ACE2 mediates the entry of SARS-CoV-2 into host cells 32,33 , making the COVID-19 pathophysiology in hypertensive patients intricate. Our study suggested that hypertension, hyperlipidemia, and obesity could be less detrimental on fatality.

In accordance with previous studies, CVD, CRD, liver disease, diabetes, cerebrovascular disease, renal disease or dialysis, and solid tumor were associated with to fatality and worst severity. Two meta-analyses have reported common risk factors for worst severity during hospitalization, which include, diabetes, COPD, malignancy, CVD, and cerebrovascular disease 34, 35 . Other studies have also reported chronic liver disease and renal disease as risk factors 36-38 . Studies have elucidated that acute respiratory distress syndrome and coagulation dysfunction are related to the renin-angiotensin-aldosterone system and blood coagulation pathways, which are altered by SARS-CoV-2 host cell invasion via ACE2 39-41 .

Clinical and non-clinical studies revealed an association between these comorbidities; while SARS-CoV-2 infection decreases ACE2 expression, ACE2 deficiency is reported to cause . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint cardiac overload and kidney inflammation [41] [42] [43] [44] . Elevated blood glucose is also associated with mortality 45 . Although risk factors vary among studies, the comorbidities we identified are highly likely associated with fatality, backed up by clinical and non-clinical results.

Different trends were seen in the rates of IMV/ECMO and death for each comorbidity.

Although rates of IMV/ECMO were comparable in all comorbid cases, those with obesity, asthma, hyperlipidemia, and hypertension showed a lower fatality rate, suggesting that the fatality rates within the IMV/ECMO cases with these comorbidities were lower than expected.

Contrarily, fatality rates in cases with CVD, cerebrovascular disease, renal dysfunction, tumor, and CRD were comparable or higher than IMV/ECMO rates. The number of death actually exceeded the number of IMV/ECMO cases in patients with tumor, cerebrovascular disease, or CVD. These comorbidities likely have caused a higher risk of death and some even died without intubation. Healthcare nearly overwhelmed in the first wave in Japan but ICU capacity was maintained 46 , and thus intubation may have been unperformed due to a medical judgment. A detailed examination of these issues is necessary in the future.

Our results did not show prominent difference in fatality between males and females.

Oftentimes, males are considered to develop severe conditions and increased fatality 37,38,47-49 .

However, according to Global Health 5050, sexual disparity in incidence of COVID-19 is low 50 .

Additionally, ACE2 expression is affected by sexual hormones, whereby higher expression is . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint observed in men, possibly explaining the sexual disparity 51-53 . Moreover, the immunological response to produce antibodies is more favorable in females 54 . These studies support the rationale that males are more susceptible to severe COVID-19, which contravene our results.

The lower-than-expected fatality rate in our male population may be attributed to comorbidity prevalence, treatments, age, and/or degree of obesity. Our results could be useful to roughly identify those at a risk of aggravation or death.

Days from onset to admission was not a risk factor; early hospitalization will not influence the disease progression or outcome, and severity on admission was mostly driven by age and the presence of a few comorbidities. Several studies have created a scoring system to predict the . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint risk of severity or mortality [66] [67] [68] . However, these utilize laboratory data collected on admission and are seldom practical for estimating the severity of illness prior to medical visits or when test results are not promptly available. While these are useful to predict prognosis more precisely, our results are useful from a public health perspective, as they provide risk factors for predicting the severity on admission and disease progression from patients' background factors.

Our study has several limitations. In some of our analyses, confounders were not eliminated. We did not consider treatments prior to and during hospitalization. As our data were collected from hundreds of healthcare facilities, treatment type, dosage, duration, and combination varied immensely. We plan to deliberate the analytical methodology further to evaluate the outcomes which are prone to be affected by in-hospital treatments. Data were collected from numerous facilities; therefore, accuracy may be questionable. Additionally, hotels were utilized as isolation facilities from April 2020, and participant selection might have altered thereafter. COVIREGI-JP is continuously open for new entry; the number of registrations is increasing, and subsequent results may vary from ours.

On admission, factors that influence severity were age, sex, and comorbidities, including CVD, CRD, diabetes, obesity, and hypertension. Risk factors for severity on . CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint admission, worst severity, and fatality were not consistent, and it is likely that they are each propelled by different factors. Our results are practically useful for predicting the progression and preparing for the worst, based on patients' backgrounds. Moreover, based on our predictions, healthcare resources can be allocated to patients in the most suitable way.

We thank all the participating facilities for their care towards COVID-19 patients and cooperation during data entry. We are especially grateful for the 299 facilities that contributed to the dataset used in this study. 

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The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint This study was funded by Health and Labor Sciences Research Grant, "Research for risk assessment and implementation of crisis management functions for emerging and re-emerging infectious diseases", provided by the Japanese Ministry of Health, Labour, and Welfare. The funding agency did not assume any role in this study or COVIREGI-JP.

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; H.O. reports personal fees as a statistician and as an external consultant for clinical trials from EPS International, outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work.

The corresponding author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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Data on an individual level is shared with limitation to participating healthcare facilities through applications to COVIREGI-JP 11 .

No patient was involved in the setting of research question, outcome measures, or study design, nor were they involved in the recruitment to and conduct of the study.

The study results will be shared with all the healthcare facilities which participated and registered data in COVIREGI-JP. It will also be shared with the public on the website 11 .

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The copyright holder for this preprint this version posted April 7, 2021. 12. International Severe Acute Respiratory and Emerging Infection Consortium ISARIC).

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The copyright holder for this preprint this version posted April 7, 2021. (Article in Japanese). https://www.mhlw.go.jp/content/10900000/000662183.pdf. Accessed

October 3, 2020.

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The copyright holder for this preprint this version posted April 7, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2021. . CC-BY-NC-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-NC-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 preprint this version posted April 7, 2021. . CC-BY-NC-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-NC-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)

The copyright holder for this preprint this version posted April 7, 2021. immunosupprenssants other than steroids . CC-BY-NC-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)

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Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2

Inhaled corticosteroids in virus pandemics: a treatment for COVID-19?

Dexamethasone in the management of covid-19

Prediction model and risk scores of ICU admission and mortality in COVID-19

Scoring systems for predicting mortality for severe patients with COVID-19

A novel simple scoring model for predicting severity of patients with SARS-CoV-2 infection

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The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint . CC-BY-NC-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)The copyright holder for this preprint this version posted April 7, 2021. . CC-BY-NC-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)The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint . CC-BY-NC-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)The copyright holder for this preprint this version posted April 7, 2021. . CC-BY-NC-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.

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The copyright holder for this preprint this version posted April 7, 2021. Use of steroid in one 10 (0) 5 (2) 4 (0) 8 (1) 4 (1). CC-BY-NC-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.

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The copyright holder for this preprint this version posted April 7, 2021. immunosupprenssants other than steroids . CC-BY-NC-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 preprint this version posted April 7, 2021. 

. CC-BY-NC-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 preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint

Top bars represent non-severe cases at admission and bottom bars represent severe cases at admission. Each group of cases was divided based on the presence of comorbidities. Dark gray represents fatal cases while light gray represents non-fatal cases.. CC-BY-NC-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. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted April 7, 2021. ; https://doi.org/10.1101/2021.04.02.21254809 doi: medRxiv preprint