Risk Factors for In-hospital Progression of Ordinary COVID-19 in Wuhan, China: A Retrospective Cohort Study


 Objective: To describe the clinical characteristics and outcomes of ordinary COVID-19 when admitted, to describe how these patients were treated and risk factors for in-hospital progression.Methods: In this retrospective study, we included 291 adult patients diagnosed as ordinary COVID-19 on admission who had been discharged or had died between Jan 20, 2020 and Mar 16, 2020 from General Hospital of Central Theatre Command (Wuhan, China).Results: Of the 291 patients diagnosed as ordinary COVID-19 when admitted, 65 (22.34%) had been recorded COVID-19 progressing at least once, and 226 (77.66%) had been recorded COVID-19 improving during hospitalization. The median time from admission to disease progressed was 5.0 days (2.0-7.0). Multivariable regression showed increasing odds of in-hospital progression associated with male (odds ratio 2.333, 95% CI 1.135-4.395; P=0.020), preexisting cardiovascular diseases (2.433, 1.044-5.671; P=0.039), and lymphopenia (3.482, 1.783-6.799; P<0.001), elevated IL-6 (2.669, 1.084-6.574; P=0.033), d-dimer (2.829, 1.420-5.636; P=0.003) and lactate dehydrogenase (2.855, 1.458-5.591; P= 0.002) on admission.Conclusions: The potential risk factors of male, preexisting cardiovascular disease, lymphopenia, elevated IL-6, and lactate dehydrogenase, d-dimer could help clinicians to identify in-hospital progression among ordinary COVID-19 at early stage to optimize medical treatment.


Introduction
In December 2019, a group of patients with acute respiratory illness of unknown cause appeared in Wuhan, China, which was confirmed to be caused by a novel corona virus. Full-genome sequencing and phylogenic analysis indicated that the novel corona virus is closely related to bat-derived SARSlike corona viruses 1 and officially named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by International Committee on Taxonomy of Viruses. WHO declared the disease caused by SARS-CoV-2 was officially named as corona virus disease 2019 . Epidemiological studies confirmed human-to-human transmission of COVID-19 2,3 . As of Apr 5, 2020, COVID-19 has been described in 208 countries, areas or territories, involving 1,093,349 individuals and causing 58,620 deaths. COVID-19 spread rapidly and has threatened global public health 4 .
The incubation period of COVID-19 infection was 1-14 days, mostly 3-7 days. Most severe patients develop dyspnea and / or hypoxemia one week after onset and may lead to organ dysfunction (such as shock, acute respiratory distress syndrome, septic shock, acute heart injury and acute kidney injury) and death 5 . Huang first reported 41 cases of COVID-19 infection, 22(55%) developed into dyspnoea (median time from illness onset to dyspnoea 8.0 days (IQR 5·0-13·0), 13 (32%) patients were admitted to an Intensive Care Unit (ICU) and six (15%) died 6 . In another single-center case series of 138 COVID-19patients, 26% received ICU care with a median time of 8.0d for initial symptoms to acute respiratory distress syndrome (ARDS), and 6 deaths (mortality rate 4.3%) 7 . Therefore, early detection, early treatment, prevention of disease progression to severity, and reduction of mortality are the focus of clinical diagnosis and treatment.
Current studies have demonstrated that age, sex, comorbidities, some early onset of symptoms and laboratory findings may be risk factors for poor outcome of COVID-19. [7][8][9] However, there are some disagreements between those studies. Chen et al found older males with comorbidities were more likely to be affected and resulted in sever and even acute respiratory ARDS 8 , while Wang et al found no male difference between ICU patients and non-ICU patients 7 . A recent study including 78 COVID-19 patients reported several factors led to the progression of COVID-19, but there was no significance in any comorbidities, probably because of the small sample size 9 . Therefore, it is necessary to include more patients to evaluate the possible risk factors associated with COVID-19 progression. As reported that COVID-19 patients were more common to be ordinary cases when admitted to hospital 9-11 , but until now, there is no study focus on ordinary COVID-19 in-hospital progression. So, we represent a quantitative analysis of 291 COVID-19 patients who were clinically classified as ordinary cases on admission to identify possible risk factors for in-hospital progression and hope to provide an insight into the treatment for high-risk severe COVID-19 patients.

Ethical approval
The study was approved by the Research Ethics Commission of General Hospital of Central Theatre Command ([2020]016-1) and the requirement for informed consent was waived by the Ethics Commission.

Study design and participants
All adult patients included in this retrospective cohort study were diagnosed with COVID-19 laboratory-confirmed positive for COVID-19 by testing the nucleic acid of respiratory specimens, who were discharged or died between Jan 20, 2020 and Mar 16, 2020. The illness severity of all patients was evaluated and classified clinically upon admission, according to the Chinese management guideline for COVID-19 (version 7.0) 5 . Our study enrolled all patients who were clinically classified as ordinary cases when admitted and had a definite outcome (dead or discharged). We excluded patients whose disease has improved, meanwhile the results for COVID-19 nucleic acids have returned negative before admission, and patients diagnosed as mild, severe or critical on the day of admission.
According to the Chinese management guideline for COVID-19 (version 7.0), the clinical classifications of the disease included: (1) mild cases: the clinical symptoms are mild and no pneumonia manifestation can be found in imaging; (2) ordinary cases: patients have symptoms like fever and respiratory tract symptoms, etc., and pneumonia manifestation can be seen in imaging; (3) sever cases (meeting any of the following): respiratory distress, RR ³30 breaths/min; the oxygen saturation is less than 93% at a rest state; arterial partial pressure of oxygen (PaO 2 ) / oxygen concentration (FiO 2 ) £300 mmHg (1 mmHg=0.133 kPa); (3) critical cases (meeting any of the following): respiratory failure occurs and mechanical ventilation is required monitoring and treatment in ICU 5 .
All patients were evaluated and classified clinically upon admission and during the treatment. Based on the clinical records, patients were included in the disease progression group when the disease progressed to a serious or critical state during the treatment, patients who did not progress were included in the improvement group.

Data collection
Epidemiological, demographic, clinical, laboratory, radiological, treatment and outcomes data for all patients with confirmed COVID-19 were obtained from electronic medical records by a trained team.
We used a standardized case record form to collect clinical data. If information was not clear, the investigators would contact the doctor responsible for the treatment of the patient for clarification.

Laboratory procedures and treatment
COVID-19 in respiratory specimens was detected by real-time RT-PCR methods. Throat-swab specimens were collected for SARA-CoV-2 re-examination according to the condition of patients (improved or progressive).
Blood count (white blood cell, lymphocyte count), serum biochemical tests (including liver and renal function, myocardial enzymes, lactate dehydrogenase, troponin, myoglobin), C-reactive protein, procalcitonin, interleukin6 (IL6), erythrocyte sedimentation rate and d-dimer were tested with routine blood examinations. Chest imaging was done for all inpatients. The frequency of examinations was based on the patient's condition.
The most common treatment of antivirals included lopinavir/ritonavir, Interferon, Arbidol, and Ribavirin combined with Traditional Chinese Medicine. Patients received glucocorticoid for 3-5 days according to the severity of respiratory distress and the progress of chest imaging. In addition, Respiratory support was used for preventing acute hypoxic respiratory failure.
The criteria for discharge were with normal body temperature for more than 3 days, significantly recovered respiratory symptoms, obvious absorption in both lungs in chest CT, negative results of the nucleic acid tests of respiratory specimens for consecutive two times at least 24 h apart.

Statistical analysis
Mean, medians and inter quartile ranges (IQRs) were calculated as continuous variables. Categorical variables were presented as percentages of patients in each category. Independent group t test or Mann-Whitney U test were used to compare distributions of continuous variables on admission where appropriate. The c 2 test or Fisher exact test were used to compare the proportions for categorical variables where appropriate. Univariate and multivariate logistic regression analysis were adopted to identify risk factors of disease progression. P< 0.05(bilateral) was considered statistically significant.
We excluded variables from the univariable analysis if there were no significant difference between the two groups. All statistical analyses were performed using SPSS (Statistical Package for the Social Science) version 22.0 software (SPSS Inc).

Baseline characteristics
By Mar 16, 2020, 311 patients were identified as laboratory-confirmed COVID-19, of that 12 (3.8%) were classified as mild cases, 291(93.6%) were classified as ordinary cases, and 8(2.6%) were classified as severe cases when admitted. All have been discharged or died. Finally, the 291 ordinary cases were included in this study( Table 1   There was no significant difference in duration from illness onset to first admission between the two groups (P >0.05).

Laboratory indices
Compared with the improvement group, the patients in the progression group had decreased peripheral blood lymphocyte count ( P <0.001)( Table 2)

Treatments and outcomes
Among the 291 patients, the most common treatment was antivirals including lopinavir/ritonavir, Interferon, Arbidol, and Ribavirin combined with Traditional Chinese Medicine ( Table 3). The proportion of patients treated with lopinavir/ritonavir, glucocorticoid, and antibacterial were higher in the progression group than improvement group (all P <0.05).  (13,23) In addition, respiratory support was used for preventing acute hypoxic respiratory failure. 13 patients used noninvasive ventilator, and two patients used invasive ventilator. Moreover, one patient was treated with extracorporeal membrane oxygenation (ECMO). The progression group had more severe hypoxia and was significantly more likely to receive higher levels of respiratory support compared to the improvement group (P <0.001).
Hospitalization day were longer in the progression group than that in the improvement group (P <0.001).

Risk factors for in-hospital progression in COVID-19 patients
The   13 . Previous studies have also reported that advanced age, male sex were associated with a high case-fatality rate and independent predictors of adverse outcome in SARS [15][16][17] . The results in our study partially supported previous reports that advanced age and male sex were associated with COVID-19 progression in univariable analysis, male sex was also independent predictor in multivariable analysis, but advanced age was not. The age-dependent defects in physical condition and immune system were more likely to lead to poor outcomes of viral pneumonia 18,19 . The probable reason of our result maybe because only ordinary cases on admission enrolled in our study, of which 49 (16.8%) were older than 70 years. Older patients classified as severe or critical cases when admitted were excluded from our study, while they more easily progressed to adverse outcomes during hospitalization 20 .
Our results found that patients with preexisting cardiovascular disease more easily developed into severe condition and showed more severe damage to heart which was evaluated by significantly elevated myoglobin and creatine kinase. Recently a meta-analysis including six studies with 1527 COVID-19 patients reported that the incidence of cardia-cerebrovascular diseases was three-folds higher in ICU/sever cases than in non-ICU/ sever counterparts, and COVID-19 can, in turn, aggravate the damage to the heart 21 . This result just proved our findings. Full-genome sequencing and phylogenic analysis indicated SARS-CoV-2 has a similar receptor-binding domain structure to that of SARS-CoV, which binds to the angiontensin-coverting enzyme 2 (ACE2) in humans 1 . ACE2 expressed on myocyte and vascular endothelial cells 22,23 , and some studies found circulating ACE2 has been shown to be increased in patients with cardiovascular disease and activity increased in patients with left ventricular systolic dysfunction 24,25  playing in predicting in-hospital death. In our study, we found high initial lactate dehydrogenase, and IL6 are independent risk factors to predict in-hospital COVID-19 progression. This found should be attached importance to and need further evaluated by more studies. It was common to be found increased coagulation activity in patients with pneumonia, marked by increased level of d-dimer. Ddimer greater than 1mg/L was associated with fatal outcome of COVID-19 12 . In this study, we found high initial d-dimer is associated with COVID-19 progression. Lymphopenia has been reported in SARS, Ebola, and COVID-19, thus there seems to be a connection between viral infections and lymphopenia, whether the viruses directly causes lymphopenia is still a question 27 . Many studies reported that lymphopenia was a high-risk factor for adverse outcomes of SARS 15,28 , and our result shows lymphopenia is an independent predictor for COVID-19 progression.
In our study, all patients received antiviral treatment, but the types of drugs used varied. Given the retrospective nature of our study, it is difficult to determine whether there is any therapeutic benefit to the treatment regimens used in treating COVID-19, specifically lopinavir/ritonavir, glucocorticoids.
Recently, the result of the randomized clinical trial for lopinavir/ritonavir (ChiCTR2000029308) has been published that no benefit was observed among in-hospital patients with severe COVID-19 29 .
Therefore, the effectiveness and safety of lopinavir/ritonavir needs to be evaluated by more research.
There are some disagreements between using and not using glucocorticoids during the treatment of viral pneumonia, due to the conflict of anti-inflammatory and immunosuppression 30,31 . So, the time and dose of glucocorticoids use is important for disease development.
Our study still has some limitations. Firstly, certain data may have based on patient memory, such as timing of onset of symptoms that may be affected by recall bias, and certain laboratory tests were not done in all patients, such as troponin and myoglobin, that may be underestimated their role in predicting disease progression. Secondly, lack of effective antivirals, and high-dose glucocorticoids use might have contributed to the progression in some patients.

Conclusions
As we described that most COVID-19 patients were just ordinary cases when admitted, nearly 23% of those had been recorded progressing or even death. Early detection and treatment is important for prevention of COVID-19 progression to severity and reduction of mortality. In this study, male, preexisting cardiovascular disease, lymphopenia, elevated IL-6, and lactate dehydrogenase, d-dimer on admission were potential risk factors associated with progression which could help clinicians to identify in-hospital progression at early stage to optimize medical treatment.