key: cord-0866399-ro1a41zk authors: Zhang, Fengqin; Xiong, Ying; Wei, Yanqiu; Hu, Yi; Wang, Feng; Li, Gang; Liu, Kui; Du, Ronghui; Wang, Cong‐Yi; Zhu, Wenzhen title: Obesity predisposes to the risk of higher mortality in young COVID‐19 patients date: 2020-05-21 journal: J Med Virol DOI: 10.1002/jmv.26039 sha: 463ab09dfb999272aa3c72877a4c10b651309441 doc_id: 866399 cord_uid: ro1a41zk BACKGROUND: Although emerging data demonstrated mortality of young COVID‐19 patients, but no data reported the risk factors of mortality for those young patients, and whether obesity is a risk for young COVID‐19 patients remains unknown. METHODS: We conducted a retrospective study including 13 young patients died of COVID‐19 and 40 matched survivors. Logistic regression was employed to characterize the risk factors of mortality in young obese COVID‐19 patients. RESULTS: Most of the young deceased COVID‐19 patients were mild cases at the time of admission, but the disease progressed rapidly featured by the higher severity of Patchy shadows (100.00% vs. 48.70%, P = 0.006), pleural thickening (61.50% vs. 12.80%, P = 0.012), mild pericardial effusion (76.90% vs. 0.00%, P < 0.001). Most importantly, the deceased patients manifested higher BMI (OR = 1.354, 95% CI = 1.075‐1.704, P = 0.010), inflammatory‐related index CRP (OR = 1.014, 95% CI = 1.003‐1.025, P = 0.014), cardiac injury biomarker hs‐cTnI (OR = 1.420, 95% CI = 1.112‐1.814, P = 0.005), and increased coagulation activity biomarker D‐Dimer (OR = 418.7, P = 0.047), as compared to that of survivors. CONCLUSIONS: Our data support that obesity could be a risk factor associated with high mortality in young COVID‐19 patients, while aggravated inflammatory response, enhanced cardiac injury and increased coagulation activity are likely to be the mechanisms contributing to the high mortality. This article is protected by copyright. All rights reserved. Since the initial outbreak of 2019 novel coronavirus (SARS-CoV-2), approximately 2.7-million people have been diagnosed with coronavirus disease 2019 (COVID- 19) , which endowed 190,000 death worldwide 1, 2 . Earlier data suggested that aged subjects, particularly for those with comorbidities, are at higher risk to develop severe or critical type of COVID-19 than that of younger subjects 3 . In contrast, young subjects are considered to only have mild type of COVID-19 without hospitalized treatment, and is unlikely to cause death 4 . As such, the infected young subjects usually were usually arranged with more optimistic and less apprehensive treatment. The truth that we observed, however, was unfulfilling. A 33-year-old young obese male patient was diagnosed as COVID-19 based on the nucleic acid assays, and was then arranged by the Outbreak Control Center for hospitalized treatment in Tongji Hospital at the end of January, 2020. He had stable vital signs and mild flu-like symptoms without underlying disease on admission. Moreover, his CT imaging only manifested slight ground-glass opacity. In general, we considered this patient to be optimistic during the conversation of his first day of admission. Unexpectedly, the disease progressed so rapidly and he died of respiratory failure within the week of admission, which really surprised us remarkably. To dissect the causative factors relevant to rapid disease progression and death, our team reviewed all of his clinical records. We first noted that he was in a state of overweight. This finding brought Accepted Article to our attention for the first time of obesity in young COVID-19 patients. Indeed, obesity has been suggested with increase risk for influenza complications, such as cardiovascular disorders along with reduced natural killer cell activity, thereby leading to higher morbidity and mortality following viral infection [5] [6] [7] [8] [9] . However, whether obesity is a risk for young COVID-19 patients remains unknown. As the pandemic progresses, more and more young COVID-19 patients ( functional failure of other organs and ICU care was required. Epidemiological data including patients' age, sex, body mass index (BMI), clinical symptoms, blood routine results, and CT scans were collected through the standardized data collection tables from the electronic medical records. BMI was calculated using self-reported height and weight from the NPHS or CCHS. In general, there is high correlation between self-reported and measured height and weight 12 . Overweight and obesity were calculated by BMI definition recommended by Working Group on Obesity in China (BMI: normal weight, 18.5-23.9; overweight, 24-27.9; and obesity, ≥28) 13 . In case some of the data were missed from the records or specific clarification was necessary, those data were obtained by directly communicating with the attending doctors and health-care providers. Continuous variables were presented as median and interquartile range (IQR) for skewed distributed data or mean and standard deviation (SD) for normal distributed data. Categorical variables were expressed as number (%). For continuous variables, the Student's t-test was used for normal distributed data, whereas Mann-Whitney U non-parameter test was used for skewed distributed data. The Pearson's χ² test or Fisher's exact test were applied for categorical variables. Unconditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between factors and the clinical outcomes of COVID-19. A two-sided P value<0.05 was considered statistically significant. All statistical analyses were performed using the SPSS (22.0) software. Generally, the mortality rate of COVID-19 patients admitted in Tongji Hospital was 8.9% Table 1) . The typical CT images derived from either deceased young COVID-19 patients or survivors were characterized by the ground-glass opacity (76.90% vs. 61.50%). Remarkably, those deceased young COVID-19 patients were featured by the higher severity of patchy shadows (100.00% vs. 48.70%, P = 0.006), pleural thickening (61.50% vs. 12.80%, P = 0.012), mild pericardial effusion (76.90% vs. 0.00%, P < 0.001), and lymphadenia (76.90% vs. 7.70%, P < 0.001), as compared to the young counterparts. Collectively, these findings suggest that obesity could be a risk factor contributing the high mortality in young COVID-19 patients. In addition, we interestingly observed that ACE2 is widely expressed in adipocytes by the analyses of single-cell sequencing data ( Figure S1 ). In this retrospective study, we compared clinical features between those deceased young COVID-19 patients absent of preexisting diseases and their survival counterparts in Tongji hospital and Wuhan Pulmonary Hospital from February 7 to March 27 of 2020. A total of 53 young COVID-19 patients were included, and 13 of whom were died from COVID-19, while the rest of them are survivors. Among those deceased patients, 9 cases were mild type, and 3 cases with severe type and 1 case with critical type in terms of disease severity at the time of admission, but all patients were died of COVID-19 within the week of admission. Remarkably, obesity was characterized as the critical factor contributing to the death of these patients, as evidenced by the fact that the body mass index (BMI) of the young deceased patients is significantly higher than that of the survivors. Previous studies have revealed that, during the 2009 H1N1 influenza pandemic [14] [15] [16] [17] , obesity was epidemiologically associated with an increased risk of the disease. Furthermore, obese individuals had a greater risk of hospitalization and death for H1N1 than individuals with normal weight 18 . Notably, the prevalence of pneumonia by COVID-19 (53%) was higher than H1N1 influenza (11%) 19 , therefore, the risk of COVID-19 patients with obesity should not be underestimated. Moreover, according to the data analysis of single cell sequencing, the expression of SARS-CoV-2 receptor ACE2 in fat cells is found to be high, which supported the assumption that obesity may be a risk factor for the poor prognosis of young COVID-19 patients. Despite that the deceased COVID-19 patients (77.80%) and the survivors (82.50%) shared similar primary symptoms such as fever, the deceased patients, however, were more likely to couple with cough, sputum, and dyspnea. Ground glass-like opacity was visible in the CT scans in both two groups, but the severity in deceased patients was significantly higher. This discrepancy was mainly reflected by the increase of inflammation and enlarged lymph nodes. More significantly, pericardial effusion occurred in 7 out of 13 patients (77.80%), and laboratory results further illustrated these phenomena. The significant abnormality of the laboratory results secondary to obesity in the deceased young patients was the expression of inflammatory factors. Specifically, their IL-10, TNF-α and CRP were much higher than those of the survivors, which logically explained the increase in consolidation and enlarged lymph nodes in CT scans 20 . Moreover, both hs-cTnI and BNP, indicators of myocardial damage 21 , were much higher than those of young survivors. Furthermore, the D-D dimer, an indicator of secondary fibrinolysis, was also significantly increased, suggesting that the patients had abnormal coagulation and fibrinolysis such as disseminated intravascular coagulation (DIC), pulmonary embolism, and so on 21 Similarly, Cao and his colleagues revealed that the significant increase in D-Dimer is one of the high risk factors for higher mortality in COVID-19 patients 24 . Therefore, it is of great importance to restrain and treat microcirculation disorders as soon as possible so as to reduce the risk. In addition, the number of lymphocytes and eosinophils of in the deceased young COVID-19 patients was significantly lower. Previous studies suggested that lymphocytes could be directly infected by COVID-19 virus and are consumed greatly during the Accepted Article antiviral process 25 . However, the underlying mechanism of reduced eosinophils in COIVD-19 patients is currently unknown. There is evidence that eosinophils act as innate immune cells, and are able to efficiently eliminate respiratory syncytial virus (RSV) 26 , while our studies revealed that SARS-CoV-2 could also directly infect eosinophils 27 . Therefore, it would be logical to assume that the reduction of eosinophils could also be the exhaustion caused by infection of SARS-CoV-2. A logistic regression model was adopted to identify the factors for addressing the mechanisms underlying obesity in predisposition to the death of young COVID-19 patients. Through which, the inflammation-related index CRP, cardiac damage, and increased coagulation activity are characterized to be significantly associated with the adverse clinical outcomes in young COVID-19 patients with abnormal BMI. Moreover, the decrease of lymphocytes and eosinophils or total globulin levels is also correlated with the poor prognosis in those COVID-19 patients. One major limitation for our study is the limited patient numbers included in the study. Therefore, the cardiac insufficiency This article is protected by copyright. All rights reserved. Fibrinogen, g/L Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering Estimates of the severity of coronavirus disease 2019: a model-based analysis Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. 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