The worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, namely, coronavirus disease 2019 (COVID-19) presents a paramount and urgent threat to global health. (1–5) As of May 11, 2021, there were approximately 157,362,408 confirmed cases, including 3,277,834 deaths, reported worldwide (6). Although the overall prognosis of COVID-19 is good, (1–5) some patients with comorbidities or rapid disease progression have a poor outcome (7–12).

Previous studies have shown that approximately 66.67~70.70% of COVID-19 patients have comorbidities; common comorbidities are hypertension, cardiovascular disease (CVD), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), malignancy, chronic kidney disease (CKD), and obesity (13–15). DM, hypertension, CVD, active malignancy, and a high number of comorbidities are risk factors for a worse outcome (16–19). DM and hypertension, or CVD are common underlying diseases related to death in hospitalized cases (14).

The distribution characteristics of comorbidities in different age intervals and clinical types and whether other comorbidities are also related with the progression and prognosis of COVID-19 are unknown and worth studying.

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 30 years, especially older than seventy, and most deaths occurred in those older than 70 years. Overall, age correlated with severity. We also found that age played a predictive role in distinguishing severe cases from non-severe patients and in distinguishing dead cases from surviving cases. Older than 45 and 65 years predict disease progression, a poor prognosis, respectively. This finding 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 (16–19).

Approximately 64.76% of the patients in this COVID-19 cohort had one or more comorbidities, and 37.88% 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). The reason may be that the characteristics of the study population were different. The median age of hospitalized patients was 63 years old (minimum: 18, maximum: 94) and the majority of cases were in the age range of 60~79 years old, all of patients were Iranian in literature (14). And 59.4% of patients aged between 20 and 39 years, 30.6% of patients aged between 40 and 59 years, only 7.4% of patients were older than 60 years, all of patients were Saudi Arabian in literature (15). While 53.76% of patients aged between 20 and 39 years, 34.96% of patients aged between 40 and 59 years, 8.77% of patients were older than 60 years, all of patients were Chinese in this cohort.

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 findings 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. We found more types of comorbidities, especially metabolic diseases such as NAFLD, hyperlipidaemia, hyperuricaemia and gout in this COVID-19 cohort. The findings 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 76,993 patients that hypertension, CVD, DM, smoking, COPD, malignancy, and CKD, were most prevalent among patients with COVID-19 (13). But the findings are consistent with recent studies reported that 30.7–37.6% of COVID-19 patients from China had NAFLD, about 4.7 times higher than that of no-COVID-19 patients (22–24). Those NAFLD diagnosed of NASH increased 4.93 times the risk of COVID-19 (25).

Moreover, hypertension, DM, COPD, CKD and CVD were mainly present in patients with severe disease who were older than 50 years, especially among those 70 years old. Hypertension, CKD and CVD were common in patients who died and were older than 70 years. The number of comorbidities and age were correlated positively with disease severity, the number of comorbidities and NAFLD were correlated positively with virus negative conversion time, hypertension, CKD and CVD were primarily associated with those who died, and the above-mentioned correlation existed when age was controlled, and multiple stepwise regression analysis showed that the number of comorbidities and specific comorbidities and age were the risk factors for the disease severity and prognosis. These findings 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, (26) that impaired renal function is an independent predictor of in-hospital death, (27) and that risk of death is associated with pre-existing hypertension, diabetes, or chronic kidney disease (21).

In this study we found that hyperlipidaemia was risk factor for the disease severity, and NAFLD and hyperlipidaemia were the risk factor for with virus negative conversion time. These findings are consistent with studies reported that the presence of NAFLD is independently associated with severe COVID-19 (24, 28–30) independent of obesity (31), especially those the presence of liver fibrosis (32) and with high serum interleukin-6 (IL-6) levels (33). NAFLD was an independent predictor of mortality or COVID-19 severity (34).

In hyperlipidaemia and NAFLD patients systemic overexpression of genes involved in SARS-CoV-2 entry and cleavage (such as FURIN, angiotensin I converting enzyme 2, and transmembrane serine protease 2), (35–37) pro-inflammatory M1 phenotype polarization of macrophages mediated by interferon, circulating levels of pro-inflammatory cytokines elevated, increased neutrophil-to-lymphocyte ratio with activation of the pro- interleukin-17 axis, and enhanced production of pro-coagulant molecules, (38–43) these pathways increase susceptibility of severe COVID-19 in NAFLD patients. Therefore chronic low-grade inflammation is suggested as the main leading process to trigger immune dysregulation, cytokine storm, and hypercoagulability in NAFLD patients with COVID-19 (43).

Even if the mortality rate of young people due to COVID, NAFLD and hyperlipidemia is low, young people (at least under 60 years old) often have NAFLD, hyperlipidemia and hyperuricemia, so some communication and advice should be given to them: it is not recommended to consume high-fat, high-glucose and fried foods, healthy and regular eating habits, healthy lifestyle, smoking cessation, alcohol restriction, regular exercise, etc.

In this study we found that number of comorbidities and age all played a predictive role in distinguishing severe cases from non-severe patients and in distinguishing dead cases from surviving cases. More than three and more than four comorbidities predict disease progression, a poor prognosis, respectively. Older than 45 and 65 years predict disease progression, a poor prognosis, respectively.

Based on these findings, not only three or more comorbidities, and some specific comorbidities, such as hypertension, CKD and CVD, but also age are related to progression and death in hospitalized COVID-19 patients.

Our study had several limitations. First, it was a retrospective, single-center study. Second, the number of severe cases, particularly deaths, was small. Despite these limitations, we report several novel findings: 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. Independently of age, two or more comorbidities, and some specific comorbidities, such as hypertension, CKD and CVD, are related to progression and death in hospitalized COVID-19 patients.

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. Not only two or more comorbidities, and some specific comorbidities, such as hypertension, CKD and CVD, but also age are related to progression and death in hospitalized COVID-19 patients. These findings provide a reference for clinicians to focus on the number and specific comorbidities, and age in COVID-19 patients to predict disease progression and prognosis.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Public and Health Clinic Center of Chengdu approved this study (ethic approval number: PJ-K2020-26-01). Written informed consent was waived by the Ethics Commission of the designated hospital because this study is related to emerging infectious diseases. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. All participants understand that the information will be published without their child or ward's/their relative's name attached, but that full anonymity cannot be guaranteed. All participants understand that the text and any pictures or videos published in the article will be freely available on the internet and may be seen by the general public. The pictures, videos and text may also appear on other websites or in print, may be translated into other languages or used for commercial purposes. All participants have been offered the opportunity to read the manuscript.

DL, YZ, JK, DW, YM, GZ, HT, RZ, and LB: concept and design. DL, YZ, JK, DW, YM, and GZ: data acquisition, data analysis, and interpretation. YZ, JK, and DW: drafting the manuscript. YZ, JK, DW, HT, and LB: administrative, technical, or material support. HT, RZ, and LB: study supervision. All authors contributed to the article and approved the submitted version.

This research was supported by the Thirteenth Five-Year Project on Tackling Key Problems of National Science and Technology (2017ZX10305501008), the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2020-PT330-005), the Sichuan Science and Technology Program (2020YFS0564), the Chengdu Municipal Science and Technology Bureau Science and Technology Huimin Major Demonstration Project (00092), the Sichuan Province Health Commission (17PJ070), the Chengdu Municipal Health Commission (2019079), and the Chengdu Science and Technology Bureau (2020-YF05-00191-SN).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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