Clinical Characteristics and Prognosis of patients with COVID-19 combineded with or without diabetes, hypertension or coronary

Bcakground: This study was to investigate the clinical characteristics and prognosis of COVID-19 patients combined with or without major chronic diseases like diabetes, hypertension or coronary. Methods: We retrospectively analyzed 183 patients with COVID-19 diagnosed at First People's Hospital of Jiangxia District (FPHJD) in Wuhan, China attended by Affiliated Hospital of Jiangsu University supporting medical team from February 1, 2020 to March 15, 2020. Patients were divided into simple COVID-19 group(n=134), COVID-19 combined with diabetes, hypertension or coronary group(n=49). Besides, COVID-19 patients with diabetes, hypertension or coronary were further classified into severe pneumonia group(n=23) and common pneumonia group(n=26), death group(n=17) and survival group(n=32). The prognosis of COVID-19 patients was evaluated by analyzing the clinical data and the results of laboratory tests. Results: 183 patients were included in this study, of whom 166 were discharged and 16 died in hospital. 49 (26.92%) patients had a comorbidity, with hypertension being the most common [37 (20.33%) patients], followed by diabetes [25 (13.74%) patients] and coronary heart disease [4 (2.2%) patients]. Compared with simple COVID-19 group, the proportion of history of chronic respiratory system disease, age, D-dimer, procalcitonin, C-reactive protein, myoglobin, cardiac troponin I, creatine kinase MB, lactate dehydrogenase, white blood cell count, neutrophil count, neutrophil percentage, blood urea nitrogen, creatinine and mortality rate were significantly higher in COVID-19 combined with chronic diseases group, whereas lymphocyte count, lymphocyte percentage and alanine transferase were significantly lower in COVID-19 combined with chronic diseases group. Among COVID-19 patients with chronic diseases, D-dimer, procalcitonin, C-reactive protein, myoglobin, cardiac troponin I, lactate dehydrogenase, white blood cell count, neutrophil count, D-dimer, procalcitonin, myoglobin, cardiac troponin I, creatine kinase MB, lactate dehydrogenase, neutrophil count, neutrophil percentage, blood urea nitrogen were significantly higher in death group compared with survival group, whereas lymphocyte count and lymphocyte percentage were significantly lower in survival group. In COVID-19 combined with chronic diseases group, univariate logistic regression showed that the risk for severe pneumonia were D-dimer, C-reactive protein, lactate dehydrogenase, white blood cell count, neutrophil count and neutrophil percentage. Univariate logistic regression also showed that the risk for death were D-dimer, lactate dehydrogenase, white blood cell count, neutrophil count, neutrophil percentage and blood urea nitrogen. Multivariate regression logistic showed that lactate dehydrogenase were independent risk factors for death among COVID-19 patients combined with chronic diseases. Cox regression analysis showed that compared with simple COVID-19 group, the RR(95% CI) in COVID-19 patients combined with diabetes, hypertension, and coronary were 2.187 (1.141~4.191) for death ( P <0.05). Conclusion: Among COVID-19 patients combined with diabetes, hypertension or coronary, the risk factors for severe pneumonia were D-dimer, C-reactive protein, lactate dehydrogenase, white blood cell count, neutrophil count and neutrophil percentage, whereas the risk factors for death were D-dimer, lactate dehydrogenase, white blood cell count, neutrophil count, neutrophil percentage and blood urea nitrogen. Moreover, lactate dehydrogenase were independent risk factors death. The mortality rate of COVID-19 patients combined hypertension or coronary was higher than that of simple COVID-19

Background: Coronavirus Disease 2019  has quickly progressed to a global health emergency. COVID-19 is a new type of coronavirus which belongs to the Betacoronavirus genera with the capacity for rapid mutation and recombination. [1]. The main clinical symptoms of COVID-19 are fever, fatigue, and a dry cough, and in severe cases, multiple organ failure [2][3]. COVID-19 has numerous transmission channels and humans are highly susceptible to infection. Cases of COVID-19 have been found across the whole of China and overseas [4]. Recent studies have found that COVID-19 patients with chronic diseases like diabetes, hypertension and coronary have higher critical illness rate and mortality rate [5][6].
However, the risk factors for mortality and a detailed clinical course of illness have not been well described. This paper reviews and summarizes the epidemiological and clinical characteristics of COVID-19 patients combined with or without diabetes, hypertension or coronary in order to provide a reliable basis for early diagnosis and treatment.

Study population
This retrospective cohort study included patients with COVID-19 diagnosed at the First People's Hospital of Jiangxia District (FPHJD) in Wuhan, China attended by Affiliated Hospital of Jiangsu University supporting medical team from February 1, 2020 to March 15, 2020. In this study, patients who were hospitalised for COVID -19 and had a definite outcome (dead or discharged) at the early stage of the outbreak.
The study was approved by the Research Ethics Commission of FPHJD (Approval No.

Data collection
After taking medical history, necessary investigations like blood examinations which included complete blood count, serum biochemical tests (including renal and liver function, creatine kinase, creatine kinase MB and lactate dehydrogenase), myocardial enzymes(including myoglobin and cardiac troponin I), D-dimer, C-reactive protein and procalcitonin were performed upon hospital admission. All data were checked by two physicians (JZ and JZ).

Definitions
All patients were up to 18 years old and received throat swab samples which were gathered for SARS-CoV-2 RNA detection by gene sequencing or real-time RT-PCR and the results were positive at least once. Diabetes mellitus was defined as a medical history of diabetes or the use of oral hypoglycemic medication or insulin or patients with a fasting glucose ≥7.0 mmol/L or a two-hour postprandial serum glucose ≥11.1 mmol/L [7]. Hypertension was defined as a medical history of hypertension or the use of antihypertensive, a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of ≥90 mmHg [8]. Coronary diagnosis was defined as ischemic symptoms or coronary computed tomographic angiography (CTA) or percutaneous coronary interve ntion (PCI) and defined as angiographic evidence of more than 50% luminal narrowing in at least one segment of a main epicardial coronary artery [9]. The illness severity of pneumonia was defined according to the Chinese management guideline for COVID-19 (version 6.0) [10]. All the subjects were exclude from malignancy, pregnancy, blood disease, autoimmune disease and patients who failed to complete relevant blood examinations.

Statistical Analysis
All statistical analyses were performed using SPSS version16.0 (SPSS Inc., Chicago, IL). Data were summarized as means ± standard deviations for normally distributed variables, medians plus percentiles (25 th ; 75 th ) for nonnormally distributed variables, and frequencies for categorical variables. For comparisons between two groups, independent Student t test was used. Categorical variables were examined by x 2 test.
To explore the risk factors associated with severe pneumonia and death, univariable and multivariable logistic regression models were used. To identify the chronic diseases affecting the mortality rate, we used a multivariate Cox regression analysis model. All calculated p values were two-sided, and p values < 0.05 were considered statistically significant.

COVID-19 combined with chronic diseases group
Compared with simple COVID-19 group, the proportion of history of chronic respiratory system disease, age, D-dimer, procalcitonin, C-reactive protein, myoglobin, cardiac troponin I, creatine kinase MB, lactate dehydrogenase, white blood cell count, neutrophil count, neutrophil percentage, blood urea nitrogen, creatinine and mortality rate were significantly higher in COVID-19 combined with chronic diseases group, whereas lymphocyte count, lymphocyte percentage and alanine transferase were significantly lower in COVID-19 combined with chronic diseases group (Table 1). Data are means±SD, n, and median (25 th and 75 th percentiles).* P<0.05.

Clinical and biochemical characteristics among COVID-19 patients with chronic diseases
Among COVID-19 patients with chronic diseases, D-dimer, procalcitonin, C-reactive protein, myoglobin, cardiac troponin I, lactate dehydrogenase, white blood cell count, neutrophil count, neutrophil percentage, blood urea nitrogen and mortality rate were significantly higher in severe pneumonia group than common pneumonia group.
While lymphocyte count and lymphocyte percentage were significantly lower in severe pneumonia group than common pneumonia group (Table 2). Besides, we found that the proportion of history of chronic respiratory system disease, D-dimer, procalcitonin, myoglobin, cardiac troponin I, creatine kinase MB, lactate dehydrogenase, neutrophil count, neutrophil percentage, blood urea nitrogenwere significantly higher in death group compared with survival group, whereas lymphocyte count and lymphocyte percentage were significantly lower in survival group (Table 3).  Data are means±SD, n (%), and median (25 th and 75 th percentiles).* P<0.05.

Univariate and multivariate analysis of the risk factors for severe pneumonia and death in COVID-19 patients combined with chronic diseases
The distribution of COVID-19 patients combined with diabetes, hypertension or coronary was showed in Table 4. We calculated the individual comorbidity percentage in common pneumonia group and severe pneumonia group, survival group and death group, and plotted them versus each other as shown in Figure 1 and Figure 2. In

COVID-19 combined with chronic diseases group, univariate logistic regression
showed that the risk for severe pneumonia were D-dimer, C-reactive protein, lactate dehydrogenase, white blood cell count, neutrophil count and neutrophil percentage( Table 5). Univariate logistic regression also showed that the risk for death were D-dimer, lactate dehydrogenase, white blood cell count, neutrophil count, neutrophil percentage and blood urea nitrogen (Table 6). Multivariate logistic regression showed that lactate dehydrogenase were independent risk factors for death among COVID-19 patients combined with chronic diseases (Table 7).

Cox regression analysis and survival curve
Cox regression analysis showed that compared with simple COVID-19 group, the RR significantly shorter than that in the simple COVID-19 group (Fig 4).

Discussion
Patients with hypertension, diabetes and coronary heart disease have worse clinical outcomes when infected with coronavirus [11][12][13][14]. From previous studies of the fatal cases of severe acute respiratory syndrome coronavirus (SARS-CoV) pneumonia, the comorbidities of hypertension, diabetes and coronary heart disease were found to be dangerous factors that resulted in death [15][16]. Also, a systematic analysis of 637 Middle East respiratory syndrome coronavirus (MERS-CoV) cases suggests that diabetes and hypertension are equally prevalent in approximately 50% of the patients while coronary heart disease are present in 30% [17]. However, the mechanisms for high morbidity and mortality of patients with comorbidities are unknown. The SARS-CoV-2, a positive strand RNA virus, has been seen to infect humans through the angiotensin converting enzyme -2 (ACE-2) receptor [18][19]. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of proposed as a potential therapeutic approach in COVID-19 pneumonia [21].
There is growing literature exploring that myocardial injury is one of the important pathogenic features of COVID-19 [22][23][24][25]. In a cohort of 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital, 12 patients (23%) had cardiac injury which was defined as an elevated serum level of high-sensitivity cardiac troponin I (hs-TnI) [26]. In concert with previous studies, we found that increased cardiac biomarkers mainly myoglobin and cardiac troponins T in the COVID-19 patients combined with chronic diseases especially those with severe pneumonia or death. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia [27][28][29]. We suggest that myocardial injury is a problem that cannot be ignored in patients with COVID-19. It has also been proposed that in patients with COVID-19 had increased coagulation activity, marked by increased D-dimer concentrations [30]. Study has proved that D-dimer might help in early recognition of these high-risk patients and also predict outcome [31]. We also observed that D-dimer is one of the risk factors for severe pneumonia or death among COVID-19 patients combined with chronic diseases. Contributory mechanisms include systemic pro-inflammatory cytokine responses that are mediators of atherosclerosis directly contributing to plaque rupture through local inflammation, induction of procoagulant factors, and haemodynamic changes, which predispose to ischaemia and thrombosis [32]. However, due to the limitations of existing evidence, future research is needed to elaborate on the potential mechanisms.
In this study, lactate dehydrogenase (LDH) were independent risk factors for death among COVID-19 patients combined with chronic diseases. LDH is a cytoplasmic glycolytic enzyme found in all most every tissue. Its elevation generally indicates tissue damage. Raised LDH was a common findings in patients infected with MERS-CoV [33][34][35]. High LDH levels has previously been shown to be an independent prognostic indicator of SARS infection which can help clinicians to predict adverse clinical outcome [36][37][38]. It was also reported to be one of the factors tightly associated with mortality of acute respiratory distress syndrome (ARDS) [39].
Our finding of increased LDH in severe pneumonia group and death group indicated the possibility of subclinical tissue damage. As the disease progresses, not only the damage of lung but also involvement in multiple tissues and organs can be observed in severe patients, which indicates systemic organ damage caused by the excessive reaction of the immune response. Thus, we suggest that LDH levels could be used as a surrogate marker help to locate damaged tissues or organs.
Our study has some limitations. First, we no doubt missed patients who were asymptomatic or had mild cases and who were treated at home, so our study cohort may represent the more severe end of Covid-19. Second, some specific information was missing in this study, such as symptoms, chest CT scans, supportive treatment and living status. Third, data generation was clinically driven and not systematic. Last but not least, interpretation of our findings might be limited by the sample size, which may have some impact on the statistical results. Based on the limitations above, a multicenter study will be needed to expand the sample size and to conduct more rigorous randomized controlled trials.

Conclusions:
In summary, our results indicate that the risk factors for severe pneumonia were D-dimer, C-reactive protein, lactate dehydrogenase, white blood cell count, neutrophil count and neutrophil percentage, whereas the risk factors for death were D-dimer, lactate dehydrogenase, white blood cell count, neutrophil count, neutrophil percentage and blood urea nitrogen among COVID-19 patients combined with diabetes, hypertension or coronary. Lactate dehydrogenase were independent risk factors for death. The mortality rate of COVID-19 patients combined with diabetes, hypertension or coronary was higher than that of simple COVID-19 patients.