Old Age, Number and Specic Comorbidities are Closely Related to Progression and Poor Prognosis in Patients with COVID-19

Background— Some patients with comorbidities and rapid disease progression have a poor prognosis. Aim—In this study, we aimed to investigate the distribution characteristics of comorbidities and their relationship with disease progression and outcomes of COVID-19 patients. Methods— A total of 718 COVID-19 patients were divided into ve clinical type groups and eight age-interval groups. The distribution characteristics of comorbidities were compared between the different clinical type groups and between the different age-interval groups, and their relationships with disease progression and outcomes of COVID-19 patients were assessed. Results—Approximately 88.62% (637/718) of the COVID-19 patients were twenty to fty-nine years old. Approximately 65.73% (554/718) had one or more comorbidities, and common comorbidities included non-alcoholic fatty liver disease (NAFLD), hyperlipidaemia, hypertension, diabetes mellitus (DM), chronic hepatitis B (CHB), hyperuricaemia and gout. COVID-19 patients with comorbidities were older, especially those with chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Hypertension, DM, COPD, chronic kidney disease (CKD) and CVD were mainly found in severe COVID-19 patients, and hypertension, CKD and CVD were primarily associated with those who died. Risk factors included the number of comorbidities and hyperlipidaemia for disease severity, age, the number of comorbidities, hyperlipidaemia, NAFLD and COPD for the virus negative conversion time, and the number of comorbidities and CKD for prognosis. Number of comorbidities played a predictive role in disease progression and outcomes. Conclusions—These ndings provide a reference for clinicians to focus on the number and specic comorbidities in COVID-19 patients to predict disease progression and prognosis. Clinical Trial Registry: Chinese Clinical Trial Register


Subjects
This study had a cross-sectional research design.
In total, 718 COVID-19 patients from the hospital isolation ward who presented to the Public and Health Clinic Centre of Chengdu from January 16, 2020, to April 30, 2021, were retrospectively recruited (Fig. 1). The Ethics Committee of the Public and Health Clinic Centre of Chengdu approved this study (ethics approval number: PJ-K2020-26-01). Written informed consent was waived by the Ethics Commission of the designated hospital because this study was related to emerging infectious diseases.

Clinical typing, disease diagnosis and cure criteria
The criteria for COVID-19 clinical typing and disease diagnosis were based on the seventh Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance. [7] 2.3 Grouping standards Seven hundred eighteen COVID-19 patients were enrolled (Fig. 1), including 681 and 37 non-severe (asymptomatic infection, light and common) and severe (severe and critical illness) cases, respectively (Table 1, Fig. 1). Of these patients, 710 and 8 cases were divided into a survival subgroup (those who survived) and a death subgroup (those who died), respectively (Table 1, Fig. 1).

Data collection
Demographic data, clinical data, and lymphocyte and subset counts for all 718 cases were collected and used to establish databases. The authenticity, accuracy and completeness of the data were strictly controlled.

Statistical analysis
Statistical analyses were performed using GraphPad Prism 8 (GraphPad, CA, USA) and SPSS 26.0 (SPSS, Chicago, IL, USA). Measurement data are expressed as x ± SD, and ANOVA was used for multigroup comparisons of the homogeneity of variance and normally distributed data. A least signi cant difference (LSD) t-test was used for further comparisons between two groups. An independent-sample t-test was employed for comparisons between two groups. A percentage or proportion was used to express enumeration data, and a chi-square test and Fisher's exact test were applied for comparisons of these data. Spearman correlation analysis was used for two-factor correlation analysis. Receiver operating characteristic (ROC) analysis for age was performed to assess the ability to distinguish between nonsevere and severe patients and between surviving patients and those who died. Statistical signi cance was de ned as P < 0.05. patients were twenty to fty-nine years old. A small number of patients were younger than 20 years old or older than 60 years old ( Fig. 2A).

General conditions
Patients in each comorbidity subgroup were older than those in the no-comorbidity subgroup (Fig. 3), especially those with COPD and CVD (Fig. 3). Except for the CKD subgroup and the cancer subgroup, the differences were statistically signi cant (all P<0.001).
Severe cases (critical illness and severe clinical type) were distributed in age-interval subgroups older than twenty years, especially in the subgroup of patients older than seventy years (Fig. 5A). Those who died were in the older than sixty age-interval subgroup, especially in those older than seventy (Fig. 5B). Common comorbidities were NAFLD, hyperlipidaemia, hypertension, DM, CHB, hyperuricaemia and gout ( Fig. 2B). Cancer, COPD, CVD, CKD and other comorbidities were rare (Fig. 2B).
Among COVID-19 patients, hypertension, DM, COPD and CVD were mainly found in patients with the critically ill clinical type (Fig. 6A, 6E, 6G, 6I), CKD and CVD were mainly found in patients with the common and severe clinical type (Fig. 6H, 6I), and hyperuricaemia and gout (

The relationship of comorbidities with disease progression and prognosis in COVID-19 patients
In the severe group, patients were older than those in the non-severe group and had a greater number of comorbidities (Table 2) (all P < 0.0001). However, there were no differences in comorbidities between the two groups ( Table 2) (P 0.05). In the non-surviving group, patients were older than those in the surviving group and had a greater number of comorbidities, more hypertension, more chronic kidney disease and more cardiovascular diseases (Table 3) (all P < 0.05). No differences in other comorbidities between the two groups were detected (Table 3) (P 0.05). According to Spearman correlation analysis, only the number of comorbidities correlated positively with disease severity (Table 4), though no speci c comorbidity correlated with disease severity (Table 4).
Moreover, the number of comorbidities, NAFLD, CHB and COPD were all correlated positively with virus negative conversion time (Table 4), and the number of comorbidities, CKD, CVD and hypertension correlated positively with prognosis (Table 4). According to multiple stepwise regression analysis for disease severity, risk factors included the number of comorbidities and hyperlipidaemia (Table 5). Risk factors for virus negative conversion time were the number of comorbidities, hyperlipidaemia, NAFLD and COPD (Table 5). Furthermore, risk factors for prognosis were the number of comorbidities and CKD (Table 5).

The prediction of number of comorbidities on disease progression and the outcomes of COVID-19 patients
According to the ROC analysis, number of comorbidities could predict disease progression and patient outcomes (Table 6, 7). The best cutoff point for distinguishing the severe cases from the non-severe cases was more than three comorbidities (Table 6). Its area under the curve was 0.864, (Table 6, Fig. 8).
Its sensitivity was 75.70% (Table 6). Its speci city was 88.00% (Table 6). The best cutoff point for distinguishing the dead cases from the survival cases was more than four comorbidities (Table 7). Its area under the curve was 0.947, (  Fig. 9). Its sensitivity was 85.70% (Table 7). Its speci city was 91.60% (Table 7). Abbreviations: AUC, area under the curve; CI, con dence interval. Abbreviations: AUC, area under the curve; CI, con dence interval.

Discussion
In this COVID-19 cohort, the prevalence of severity was 5.16%, and mortality was 1.11%. Most patients with severe disease were older than thirty years, especially older than seventy, and most deaths occurred in those older than seventy years. Overall, age correlated with severity. This nding is consistent with the literature that old age is associated with the progression of COVID-19 and is an independent risk factor for progression [20] and that advanced age is a risk factor for a worse outcome in association with higher death rates. [16][17][18][19] Approximately 65.73% of the patients in this COVID-19 cohort had one or more comorbidities, and 37.85% had two or more. This is consistent with a report that one-third of patients have no comorbidity according to medical records, [14] but it is lower than the report that 70.7% of patients have one chronic condition and higher than the report that 20.9% patients have 2 or more. [15] Further analysis found that severe cases had more comorbidities than non-severe cases; those who died had more comorbidities than surviving patients. An increased number of comorbidities correlated positively with disease severity and poor prognosis and was also an independent risk factor for progression and poor prognosis. This was consistent with previous ndings that the number of comorbidities is a risk factor for a worse outcome [16-18, 21] In this study, common comorbidities were mainly NAFLD, hyperlipidaemia, hypertension, DM, CHB, hyperuricaemia and gout; cancer, COPD, CVD, CKD and other comorbidities were not common. The ndings are not completely consistent with the report of common comorbidities in hospitalized patients of hypertension, CVD, DM, asthma, COPD, and other underlying diseases, [14] or the systematic review and meta-analysis of 76993 patients that hypertension, CVD, DM, smoking, COPD, malignancy, and CKD, were most prevalent among patients with COVID-19. [13] We found more types of comorbidities, especially metabolic diseases such as NAFLD, hyperlipidaemia, hyperuricaemia and gout, in our cohort. Moreover, hypertension, DM, COPD, CKD and CVD were mainly present in patients with severe disease who were older than fty years, especially among those seventy years old. Hypertension, CKD and CVD were common in patients who died and were older than seventy years. These ndings were not completely consistent with the literature report that DM and HBP or CVD are common underlying diseases related to death in hospitalized cases, [14] that COPD increases the risks of death and negative outcomes in patients with severe COVID-19, [22] that impaired renal function is an independent predictor of in-hospital death, [23] and that risk of death is associated with pre-existing hypertension, diabetes, or chronic kidney disease. [21] In this study we found that number of comorbidities played a predictive role in distinguishing severe cases from nonsevere patients and in distinguishing dead cases from surviving cases. More than three and more than four comorbidities predict disease progression, a poor prognosis, respectively.
Based on these ndings, advanced age, three or more comorbidities, and some speci c comorbidities, such as hypertension, CKD and CVD, are related to progression and death in hospitalized COVID-19 patients.
Our study had several limitations. First, it was a retrospective, single-centre study. Second, the number of severe cases, particularly deaths, was small. Despite these limitations, we report several novel ndings: in addition to the common comorbidities reported in the literature, more types of comorbidities, especially metabolic diseases such as NAFLD, hyperlipidaemia and hyperuricaemia, were present in this COVID-19 cohort. Advanced age, two or more comorbidities, and some speci c comorbidities, such as hypertension, CKD and CVD, are related to progression and death in hospitalized COVID-19 patients.

Conclusion
In addition to the common comorbidities reported in the literature, there were more types of comorbidities, especially metabolic diseases such as NAFLD, hyperlipidaemia and hyperuricaemia, in this COVID-19 cohort. Advanced age, two or more comorbidities, and some speci c comorbidities, such as hypertension, CKD and CVD, are related to progression and death in hospitalized COVID-19 patients. These ndings provide a reference for clinicians to focus on the number and speci c comorbidities in COVID-19 patients to predict disease progression and prognosis.
6. Declarations Patient data. Non-severe refers to the clinical type of COVID-19 that is asymptomatic, light and common.
Severe refers to the clinical type of COVID-19 that is associated with severe and critical illness.