Epidemiology, risk factors and clinical course of SARS-CoV-2 infected patients in a Swiss university hospital: An observational retrospective study

Background This study aims to describe the epidemiology of COVID-19 patients in a Swiss university hospital. Methods This retrospective observational study included all adult patients hospitalized with a laboratory confirmed SARS-CoV-2 infection from March 1 to March 25, 2020. We extracted data from electronic health records. The primary outcome was the need to mechanical ventilation at day 14. We used multivariate logistic regression to identify risk factors for mechanical ventilation. Follow-up was of at least 14 days. Results 145 patients were included in the multivariate model, of whom 36 (24.8%) needed mechanical ventilation at 14 days. The median time from symptoms onset to mechanical ventilation was 9·5 days (IQR 7.00, 12.75). Multivariable regression showed increased odds of mechanical ventilation with age (OR 1.09 per year, 95% CI 1.03–1.16, p = 0.002), in males (OR 6.99, 95% CI 1.68–29.03, p = 0.007), in patients who presented with a qSOFA score ≥2 (OR 7.24, 95% CI 1.64–32.03, p = 0.009), with bilateral infiltrate (OR 18.92, 3.94–98.23, p<0.001) or with a CRP of 40 mg/l or greater (OR 5.44, 1.18–25.25; p = 0.030) on admission. Patients with more than seven days of symptoms on admission had decreased odds of mechanical ventilation (0.087, 95% CI 0.02–0.38, p = 0.001). Conclusions This study gives some insight in the epidemiology and clinical course of patients admitted in a European tertiary hospital with SARS-CoV-2 infection. Age, male sex, high qSOFA score, CRP of 40 mg/l or greater and a bilateral radiological infiltrate could help clinicians identify patients at high risk for mechanical ventilation.

. There is a wide spectrum of severity ranging from asymptomatic presentation to severe pneumonia requiring ventilator support and death [2]. Since March 2020, the pace of SARS-CoV-2 spread around the globe increased as the epidemic evolved to a pandemic [3]. In Europe, following a diminished caseload during summer 2020, new cases and deaths are increasing since September 2020 [4].
In the present study, we report the epidemiological and clinical characteristics of patients hospitalized for COVID-19 in a Swiss university hospital during the early phase of the pandemic as well as risk factors for progressive respiratory failure requiring mechanical ventilation.

Study design and participants
In this retrospective observational study, we included all adult patients consecutively hospitalized with a confirmed SARS-CoV-2 infection from March 1, 2020, to March 25, 2020. Patient's initial physicians used local guidelines to decide on admission (only patients with risk factors for severe disease or needing medical care were hospitalized). For all patients, we ensured a follow-up of 14 days or more during hospital stay or up to discharge or death if they occurred first.

Study setting
This study took place in Lausanne University Hospital (LUH), a one-thousand-bed tertiary university hospital in Lausanne, Switzerland. LUH serves as a primary-level community hospital for Lausanne (population circa 300'000 inhabitants) and as a referral hospital for Western Switzerland (population circa 1-1.5 million inhabitants). LUH increased its outbreak response capacity by setting up new intensive care units for the management of COVID-19 patients.

Data collection
LUH electronic health record (EHR) provided data on epidemiological, clinical, radiological and laboratory data.
Epidemiological data included age, sex, height, weight, and relevant comorbidities, including the Charlson Comorbidities Index (CCI). We collected data on clinical presentation, SARS-CoV-2 treatments, concomitant treatments, non-pharmacological interventions and clinical course within LUH.
We recorded radiological findings from reports of chest radiography or computed tomography (CT). We defined healthcare workers as professionals having direct contact with patients (nurses, physiotherapists, physicians, etc.) or patient samples.
We entered all data in an electronic clinical report form (eCRF) using the REDCap 1 platform (Research Electronic Data Capture v8.5.24, Vanderbilt University, Tennessee, USA) [6]. Fellows of the Infectious Diseases, Hospital Preventive Medicine and Internal Medicine Services at LUH entered the data and two of the authors (JR, MP) verified their integrity.

Clinical management
Treating physicians made all decisions regarding supportive care. Specialists in infectious diseases reviewed all SARS-CoV-2 treatment decisions according to the local recommendations. These included protease inhibitors (ritonavir-boosted lopinavir or atazanavir), hydroxychloroquine or remdesivir. Selected critically ill patients with high inflammatory markers (CRP, Ddimers, PCT and ferritin) received tocilizumab. The choice of treatment depended on drug availability, safety profile drug-drug interactions.
Treating physicians discussed advance planning of care and do not resuscitate orders with all patients. Limitations of care were decided upon admission according to the patient's values and goals and the treating physician's appreciation. Treating physicians documented all inpatients' limitation of care in LUH EHR. We categorized these limitations into two levels: 1) no limitation; 2) limitation to the best supportive care provided in non-monitored wards or intermediate care units but without mechanical ventilation (MV).

Definition
We defined a confirmed SARS-CoV-2 infection as a positive test for SARS-CoV-2 using realtime polymerase chain reaction (qPCR) technology in any respiratory sample.
We defined obesity either as a body mass index (BMI) of 30 kg/m 2 or higher, or, when missing anthropometric data, a medical diagnosis of obesity.
We used the Berlin definition for Acute Respiratory Distress Syndrome (ARDS) [7]. We defined shock as refractory hypotension requiring infusion of vasopressors. Acute kidney injury (AKI) was identified and classified according to the 2012 Kidney Disease Improving Global Outcome guidelines [8]. We defined liver injury as a 3-fold or greater increase in transaminase levels.
We defined MV as invasive respiratory support through a laryngeal or a tracheostomy tube

Outcome
The primary outcome was the use of MV for respiratory failure attributed to SARS-CoV-2 pneumonia, within 14 days after admission.

Statistics
For the descriptive analysis, we first described patient's characteristics. We summarized categorical variables as numbers (percentages), normally distributed continuous variables as mean ± standard deviation (SD) and continuous variables with a skewed distribution as median [interquartile range (IQR)]. We then tested for associations between patient's characteristics and MV. We used Pearson's chi-square test for binary characteristics, Student t-test for normally distributed variables and Mann-Whitney-Wilcoxon test for continuous variables with a skewed distribution. We used a general linear model based on univariate logistic regression to calculate odds ratio for MV. We finally performed a multivariate logistic regression with a LASSO (Least Absolute Shrinkage and Selection Operator) penalisation. We used LASSO regression analysis, as the number of MV cases was low and did not allow us to obtain a multivariate regression model with more than four predictors. LASSO provides the most parsimonious model for high number of covariates and small sample size [12]. In addition, it accounts for collinearity. For multivariate analysis, we selected relevant clinical, biological and radiological parameters as well as patients characteristics previously identified in the literature and after authors consensus (clinical knowledge). To identify the optimal penalization parameter (lambda), we used a bootstrap resampling procedure: 1000 bootstrap samples of the same size of the full database (lambda = 4). We retained as the model the one with the lowest AIC (Akaike Information Criterion).
We excluded from the analysis, patients whose care was limited to the best supportive care and patients already mechanically ventilated on admission. As we did not have treatments starting date, we did not include SARS-CoV-2 specific treatments as variables in the model.
For the inflammatory biomarkers, we converted continuous variables to categorical variables using cut-off values previously identified in the literature: 1000 ng/ml for D-dimer, 40 mg/L for CRP, 0.5 μg/l for procalcitonin and 300 μg/l for ferritin [13][14][15].
We did not impute any values for missing data. Statistical analyses were performed using R software v3.6.2 (R Foundation for Statistical Computing; www.r-project.org).

Ethics
This project was conducted in accordance with the Declaration of Helsinki, the principles of Good Clinical Practice and the Swiss Human Research Act (HRA). The project received approval from the Ethics Committee of canton Vaud, Switzerland (2020-00657) that waived the need for informed consent. All data were anonymized before analysis.

Epidemiological characteristics
Overall, 200 patients with confirmed SARS-CoV-2 infection were hospitalized at LUH during the study period. In 54 (28.5%), care was agreed to be limited to best supportive care on admission, these patients were older and with more comorbidities (Table 1).
We excluded 54 patients with limitation of care and one patient already mechanically ventilated of admission and included 145 (72.5%) patients in the statistical analysis (Fig 1).
The presence of a radiological infiltrates increased the odds of mechanical ventilation (odds ratio 11.0, 95% confidence interval 3.14 to 70.45) as did the presence of a bilateral infiltrates (odds ratio 7.05, 95% confidence interval 2.75 to 21.87). Acute kidney injury on admission (odds ratio 4.27, 95% confidence interval 1.87 to 9.91), D-dimers of 1000 ng/ml or greater (odds ratio 3.28, 95% confidence interval 1.37 to 8.25), CRP of 40 mg/l or greater (odds ratio 6.79, 95% confidence interval 1.51 to 18.58) and PCT of 0.5 μg/l or greater (odds ratio 5.99, 95% confidence interval 1.52 to 29.66) increased the unadjusted odds of mechanical ventilation. Table 8

Discussion
Our study identified several risk factors for unfavourable disease progression leading to MV in patients admitted with COVID-19 to a Swiss university hospital. A quarter of the patients for which there were no limitation of care eventually required MV. MV occurred early during the course of hospitalization and the median duration of MV was shorter than previously reported [16,17]. This effect is likely due to the limited duration of follow-up and could also result from a selection bias towards patients without limitations of care.
As infection with SARS-CoV-2 may cause an excessive host immune response, leading to ARDS and death [18], we would expect biomarkers of inflammation to be associated with unfavourable outcomes. In this study, CRP >40 mg/L on admission was associated with higher odds of MV, suggesting that an unfavourable course is more frequent in patients with a severe inflammatory response. Several studies have identified an increased risk of mortality in COVID-19 patients with elevated CRP [15,19]. We believe that CRP is an ubiquitously measured biomarker whose result could potentially help clinicians assess the risk of MV in patients with COVID-19. Its use could be easily scaled up, and it is available as a point-of-care test.
In our study, the risk of mechanical ventilation increased with higher score values for NEWS, CRB-65 and qSOFA. qSOFA has been proven a useful predictor of mortality among patients with suspected infection [9], mainly of bacterial aetiology [20], but also influenza [21,22]. We opted for including qSOFA in our final multivariate analysis, since it is widely used by clinicians in our institution, and is quick and easy to apply. A higher Sequential Organ Failure Assessment score (SOFA) has been previously linked to increased mortality due to COVID-19 [13]. Data for its calculation are not routinely collected for all patients outside the ICU, making it a less pragmatic tool to quickly evaluate the risk of MV in this patient population.
Age as a categorical variable was not significantly associated with MV in our univariate model but was significantly associated with MV when included as a continuous variable in our multivariate model. Numerous studies have linked age to mortality and to MV for SARS-CoV-2 patients [2,13,23]. The lack of significant association in the univariate model could be due to the small size of our sample and to limitations of care agreed to in older patients.
We additionally identify male sex as a predictor of unfavourable outcome in patients with COVID-19, as previously described [24][25][26]. A study recently underlined different immune response in male and female SARS-CoV-2 patients, which could explain more severe evolution in male patients [27].
Several factors such as obesity, pregnancy, healthcare worker status, previous ACE inhibitors or ARB II treatment and immunosuppressive drugs before admission were not associated with severe disease in this study.
Our study has several limitations to be acknowledged. First, due to its very nature the sample size is limited, which could lead to observation bias in the analyses, with some findings likely to evolve over time. The follow-up period was also limited and several patients were still hospitalised at the time of data analysis. Finally, due to the constantly evolving nature of the epidemic, the clinical care of patients likely evolved during their hospitalisation as changes were made to the recommendations for treatments administered at LUH. The single centre nature of the study limits the generalisability of the results.
However, this study gives some insights in the epidemiology and clinical course of patients admitted in our institution with SARS-CoV-2 infection. We found that age, male sex, bilateral SARS-CoV-2 pneumonia, elevated CRP and qSOFA equal or greater to two increased the risk of mechanical ventilation. The timely identification of these patients could help us target treatment and better manage the attribution of resources.
Supporting information S1