key: cord-0811470-m334ohwm authors: Zhao, Xiaobo; Li, Yan; Ge, Yanyan; Shi, Yuxin; Lv, Ping; Zhang, Jianchu; Fu, Gui; Zhou, Yanfen; Jiang, Ke; Lin, Nengxing; Bai, Tao; Jin, Runming; Wu, Yuanjue; Yang, Xuefeng; Li, Xin title: Evaluation of Nutritional Risk and its Association With Mortality Risk in Severe and Critically Ill COVID‐19 Patients date: 2020-07-01 journal: JPEN J Parenter Enteral Nutr DOI: 10.1002/jpen.1953 sha: d05c30ca6ea31c17d1fa629601bf15479037426d doc_id: 811470 cord_uid: m334ohwm BACKGROUND: The nutritional status of COVID‐19 patients is unknown. This study evaluates the clinical and nutritional characteristics of severe and critically ill patients infected with SARS‐CoV‐2, and investigates the relationship between nutritional risk and clinical outcomes. METHODS: A retrospective, observational study was conducted at West Campus of Union Hospital in Wuhan. Patients confirmed with SARS‐CoV‐2 infection by a nucleic acid‐positive test and identified as severe or critically ill, were enrolled in this study. Clinical data and outcomes information was collected and nutritional risk was assessed by using Nutritional Risk Screening 2002 (NRS). RESULTS: Totally, 413 patients were enrolled in this study, including 346 severe patients and 67 critically ill patients. Most patients, especially critically ill patients, had significant changes in nutrition‐related parameters and inflammatory markers. As for nutritional risk, the critically ill patients had significantly higher proportion of high NRS scores (P<0.001), which were correlated with inflammatory and nutrition‐related markers. Among 342 patients with NRS score ≥3, only 84 (25%) received nutritional support. The critically ill patients and the patients with higher NRS score had a higher risk of mortality and longer stay in hospital. In logistic regression models, one unit increased in NRS score was associated with the risk of mortality increased by 1.23 times (adjusted OR = 2.23, 95% CI: 1.10, 4.51, P = 0.026). CONCLUSIONS: Most severe and critically ill patients infected with SARS‐CoV‐2 are at nutritional risk. The patients with higher nutrition risk have worse outcome, and require nutritional therapy. This article is protected by copyright. All rights reserved An outbreak of 2019 novel coronavirus diseases caused by a newly recognized novel coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly nationwide and worldwide [1] [2] [3] [4] [5] . As of Apr 17, 2020, there were 2,000,000 confirmed cases and nearly 130,000 deaths globally [6] . The clinical spectrum of COVID-19 ranges from mild to critically ill pneumonia. The severe patients aged over 60 years and those with underlying conditions (such as hypertension, diabetes, cardiovascular disease, and chronic respiratory disease) are at a higher risk of death and of great concern in clinical management and intensive care. Previous studies showed that patients with severe pneumonia were at risk of protein-calorie malnutrition, which severely impaired respiratory muscle contractility and immune defense system [7] . The COVID-19 patients also have some signs of malnutrition such as decreased albumin and prealbumin level and impaired liver and kidney function [8] . The nutritional risk screening and nutritional support have been recommended for critically ill COVID-19 patients [9] . However, clinical evidence of the nutritional risk and its association with clinical outcomes for COVID-19 patients is limited. Therefore, we performed an observational study to comprehensively evaluate the clinical and nutritional characteristics of severe and critically ill COVID-19 patients based on clinical data 9 This article is protected by copyright. All rights reserved. Coagulation Analyzer (Beijing Succeeder Technology Inc., China), interleukins were analyzed by BD FACSCanto™ II system (BD Biosciences,USA) and other blood biochemical indicators were detected by LABOSPECT008AS Automatic Analyzer (Hitachi High-Tech, Japan). The reference values were exhibited in Table S1. Nutritional risk was assessed within 48 hours of admission by using Nutritional Risk Screening 2002 (NRS), which was recommended by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the Chinese Society for Parenteral and Enteral Nutrition (CSPEN) to evaluate the nutritional risk for hospitalized patients, including COVID-19 [12] [13] [14] [15] [16] . NRS includes an assessment of the patient's nutritional status (based on weight loss, body mass index (BMI) and food intake) and disease severity (stress metabolism due to the degree of disease). Each parameter is scored from 0 to 3 points, and patients receive an extra point if they are 70 years or older. According to the severity of COVID-19, it was proposed that severe COVID-19 patients was scored 2 point, critically ill COVID-19 patient was scored 3 points. An NRS total score of ≥3 points was considered "at risk". The nutritional screening was performed by two trained specialists. Body weight and height was self-reported by patients. 10 This article is protected by copyright. All rights reserved. Treatment regimens including medication (such as antiviral, antibacterial, corticosteroid, etc.), respiratory support and nutritional support (parenteral and/or enteral) during entire hospital stay were recorded. Parenteral nutrition (PN) was defined as use of intravenous (peripheral or central) infusion of at least 2 of the energy providing nutrients including glucose, fat emulsion, and amino acids, for at least 3 days, supplying >10 kcal/kg/d of energy. Enteral nutrition (EN) was defined as the continuous use of commercial formulas via oral feeding or gavage for at least 3 days, providing >10 kcal/kg/d of energy. Use of dietary supplements or microecological modulators such as probiotics, prebiotics was also recorded. Hospital mortality was recorded. Information of clinical outcomes of each participant, either discharge or death date, was collected until March 31, 2020. The patients who met discharge standard of COVID-19 can be discharged from hospital. Hospital length of stay was calculated from the discharge date minus the date of admission. 11 This article is protected by copyright. All rights reserved. Prior to data analysis, all data were double-entered and logic-checked. Continuous variables were described using mean, median and interquartile range (IQR) values (P 25 -P 75 ). Categorical variables were described as frequency rates (%). Means for continuous variables were compared using independent group t test when the data were normally distributed between severe and critically ill groups or using the Mann-Whitney U test otherwise. Proportions for categorical variables were compared by χ² test or Fisher's exact test between two groups. Spearman's correlation test was used to analyze the association between Nutritional Risk Screening 2002 score and blood biomarkers. To present the results visually, Kaplan-Meier survival curves were used to visualize the results. Logistic regression models and linear regression models were used to analyze the association between NRS score (treated as a continuous variable) and outcomes after adjusted the covariates. All statistical analyses were performed using the SPSS software, version 22.0. A two-sided α of less than 0.05 was considered statistically significant. This article is protected by copyright. All rights reserved. In all, 413 patients admitted to West Campus of Union Hospital from Jan 29, 2020 to Feb 19, 2020 due to SARS-CoV-2 infection were enrolled in this study. Of these patients, 346 were diagnosed as severe and 67 were critically ill. Table 1 . The average age was 60.31±12.68 years, and 212 (51%) of them were men. The average BMI of patients was 23.73±3.24 kg/m 2 , and 35% of them were overweight (24.0 ≤BMI ≤27.9 kg/m 2 ) and 9% were obese (BMI ≥28.0 kg/m 2 ) according to the Chinese BMI cutoffs [17] . On average, days from illness onset to admission were 11.26±6.23 days. In addition, 175 (42%) patients had one or more comorbidities. The most common comorbidities were hypertension (28%), diabetes (11%), and cardiovascular diseases (11%). Fever (82%), cough (76%), impaired appetite (60%), and dyspnea (41%) were the most common symptoms at onset of illness. Compared with severe patients, patients who were critically ill were 13 This article is protected by copyright. All rights reserved. significantly older (P=0.003) and more likely to report sputum production (P=0.037). Other characteristics and symptoms had no significant difference between two groups. All patients received antiviral, and some patients received empirical antibacterial agents (318[77%]) and glucocorticoids (136[33%]) during entire hospital stay. In addition, 106 (26%) and 55 (13%) patients were given human albumin and immunoglobulin respectively. Of the patients, 383 (93%) received respiratory support. Furthermore, the proportion of nasal cannula or face mask use in severe group was significantly higher than that in critically ill group, while critically ill patients were more likely to receive high flow nasal cannula, non-invasive mechanical ventilation or invasive mechanical ventilation (P<0.001). The comparisons of treatment and medication between the two groups were shown in Table 1 . Laboratory characteristics of 409 patients were collected and present in Table 2 . On admission, white blood cell counts were below the normal range in 45 (11%) patients and above the normal range in 53 (13%) patients. White blood cell counts and neutrophil counts were lower in severe patients than in critically ill patients (P<0.001 and P<0.001 respectively). Most patients had remarkable lymphopenia, and critically ill patients demonstrated more severe lymphopenia and thrombocytopenia (P<0.001 and P<0.001 14 This article is protected by copyright. All rights reserved. respectively). The levels of coagulation function indexes such as D-dimer, prothrombin time and activated partial thromboplastin time on admission were higher in critically ill patients than in severe patients (P<0.001, P=0.001 and P<0.001 respectively). Regarding the inflammatory markers, procalcitonin (PCT) and C-reactive protein (CRP) levels were above the normal range in most patients. Notably, elevated PCT and CRP levels were observed in 96% and 94% critically ill patients, respectively. Similar results occurred in interleukins. IL-6 and IL-10 levels were significantly higher in critically ill patients (P<0.001 and P=0.005 respectively). As for nutrition-related indicators, the total protein, albumin and prealbumin levels of critically ill patients were significantly lower than those of severe patients (P=0.036, P<0.001 and P<0.001 respectively). Moreover, the levels of blood urea nitrogen, creatinine, glucose and total bilirubin were increased obviously in critically ill patients (P<0.001, P=0.043, P<0.001 and P=0.004 respectively). No significant differences in haemoglobin, total cholesterol or uric acid were observed between two groups. Other blood biochemistry results were present in Table S2 . Totally, 371 patients underwent an assessment of NRS, which considered age, disease severity and nutritional status. The assessment identified 342 (92%) patients with nutritional 15 This article is protected by copyright. All rights reserved. risk (NRS score ≥3) and 58 (16%) with high nutritional risk (NRS score ≥5). For critically ill patients, all of them were evaluated as at risk and 38 (62%) as high risk. Comparing to severe patients, critically ill patients had significantly higher proportion of high NRS scores (P<0.001). Among the three major parameters of NRS, critically ill patients tended to have higher scores of impaired nutritional status than severe patients did (P=0.005). The results of nutritional risk were presented in Table 3 . Table S3 demonstrated the correlations between blood parameters and NRS score. Most proinflammatory cytokines had positive correlations with NRS score. Among them, the correlation coefficient between procalcitonin and NRS score reached to 0.501, which meant they were strongly and positively correlated. When it came to nutrition-related markers, the correlations between NRS score and total protein, albumin, prealbumin were negative. Correlation coefficients were −0.153, −0.351 and −0.386, respectively. Other nutrition-related markers, such as blood urea nitrogen, creatinine glucose, were positively correlated with NRS score. 16 This article is protected by copyright. All rights reserved. The nutritional support or dietary supplements for severe and critically ill patients according to their nutritional status were shown in Table 4 respectively. For patients with NRS score ≥3, the ratio of receiving nutritional support, EN, PN or EN+PN in critically ill patients were higher than that in severe patients, respectively. However, the proportion of patients receiving nutritional support had no significant difference between the group of NRS score <3 and the group of NRS score ≥3. Until Mar 31, 2020, the clinical outcomes of 403 patients were collected, as displayed in Table 5 . The mortality was 9% in the whole population, and up to 47% in critically ill 17 This article is protected by copyright. All rights reserved. patients. The average hospital length of stay was 30.18±11.06 days. Critically ill patients had significantly higher mortality and longer stay in hospital than severe patients did (P<0.001 and P<0.001 respectively). In addition, great difference was also found in clinical outcomes among the patients in 3 ranks of NRS score. Those with higher NRS scores had significant higher mortality and longer stay in hospital (P<0.001 and P=0.002 respectively). These results were confirmed by Kaplan-Meier survival estimates, which showed a higher likelihood for mortality with increasing NRS scores (Fig. 1) . In logistic regression models, similar results were obtained after adjusted sex, age, comorbidity and BMI, and one unit increase in NRS score was associated with the risk of mortality increased by 1.23 times (adjusted OR=2.23, 95% CI: 1.10, 4.51, P=0.026). As for hospital length of stay, those with higher NRS scores had longer stay in hospital (β=1.23, 95%CI: 0.37, 2.10, P=0.005) in crude model. While adjusted covariates, this association disappeared (Table 6 ). WHO declared the COVID-19 a pandemic in March 11, 2020 [6] . The mortality of critically ill patients with COVID-19 is up to 61.5%, a considerable level [18] . Therefore, giving appropriate treatment and reducing mortality of severe and critically ill patients caused by coronavirus are of crucial importance. This study is the first to describe the clinical characteristics, especially the changes of nutritional metabolism, in severe and critically ill 18 This article is protected by copyright. All rights reserved. patients in detail, and explore the relationship between nutritional risk and clinical outcomes. The findings will provide important evidence for revising diagnosis and treatment scheme of critically ill patients to improve clinical outcomes. This study showed great alterations in clinical characteristics and laboratory findings, especially metabolic indexes related to nutrition, in critically ill patients and severe patients. The results showed that the infection led to a series of inflammatory reactions, indicated by an increase in PCT, C-reactive protein and interleukin levels, again consisting with other studies [8, 19, 20] . The changes in metabolic nutrition-related indicators was noteworthy. The reduction of albumin, prealbumin and total protein, and the elevation of creatinine and blood urea nitrogen warned that critically ill patients were at tremendous nutritional risk [8, 21] . It is worth mentioning that prealbumin, a protein also known as transthyretin, attracts much attention in nutritional status assessment these years. Due to the high sensitivity to inflammation, its ability of evaluating risk of malnutrition is often hampered [22, 23] . Nevertheless, an increasing body of evidence suggests that it is a good marker for prognosis associated with malnutrition, and is even better for monitoring refeeding efficacy despite inflammation [24] [25] [26] . Consistently, the prealbumin level decreased tremendously in both severe and critically ill patients and negatively correlated with NRS in the present study, indicating that this protein might be a good marker for nutritional risk. 19 This article is protected by copyright. All rights reserved. Some expert consensus proposed that nutritional risk screening should be conducted in admitted COVID-19 patients [9, 15] . In the present study, 90% of the patients underwent nutritional risk screening within 48 hours of admission using NRS score. Among them, 92% of the patients were considered with nutritional risk, meanwhile, all of the critically ill patients were at risk and 62% of them were identified as "high risk". The NRS score was determined by three parameters: impaired nutritional status, severity of disease, and age. Obesity has been considered as a risk factor to the severity of COVID-19 [27] . It was also observed that 44% of the patients were overweight or obesity in the present study, but BMI did not significantly affect the association between NRS and mortality in the logistic regression analysis. Only a few patients had lost weight prior to admission or had low BMI, indicating that they were not chronically malnourished. There exist three main reasons why COVID-19 patients have nutritional risk. Firstly, hypercatabolic status and endocrine disorders caused by acute severe infection such as inflammatory stress, hypoxia and bed rest result in increased gluconeogenesis, enhanced proteolysis, and accelerated fat oxidation. Secondly, loss of appetite and reduced dietary intake (as seen in 60% patients in this study) also exacerbate the nutrient deficiency. Finally, interventions such as mechanical ventilation and use of broad-spectrum antibiotics triggered severe hypoproteinemia and damaged the digestive system function, which delay or prevent recovery from illness and even aggravates the inflammatory stress of the body [28] [29] [30] [31] [32] . Those abnormalities of indicators above could 20 This article is protected by copyright. All rights reserved. further aggravate the course of the disease in return. Consistent with the results of previous studies, we found that an elevated nutritional risk, which was positively correlated with inflammatory and nutrition-related markers, was associated with adverse clinical outcomes [33] [34] [35] [36] . Thus, it is crucial to reduce nutritional risk in alleviating COVID-19 and improving clinical outcomes, especially for the patients with high nutritional risk (NSR 2002 score ≥5). Although there was limited supportive evidence that specific interventions, such as nutritional support, could decrease mortality in acute respiratory distress syndrome (ARDS) [37] , some studies on severe community-acquired pneumonia have shown that adequate and reasonable nutritional support was beneficial. It reduces nutritional risk by correcting inadequate calorie intake and reducing oxidative damage and inflammatory response. These will enhance immunity, improve respiratory function, and thus improve the prognosis of disease [31, 38] . Considering the positive effects of nutritional support, some expert consensus also recommended nutritional support, especially on critically ill patients infected with SARS-CoV-2 [10] . Nonetheless, it could not be implemented in many designated hospitals. In this study, only about 25% of the patients received nutritional support regardless of the nutritional risk, even in those who would benefit most from it with nutritional risk (NRS ≥3), the proportion was 25% as well which should reach to 92%. That means the implementation of nutritional support here was not based on the results of NRS. This situation of low proportion of nutritional support was caused by several factors, including the limited 21 This article is protected by copyright. All rights reserved. Additionally, 33% patients were given probiotics in the present study, as recommended by the Guideline for the treatment of COVID-19 [10, 11] . It has been mentioned that microecological preparation can be used to keep the equilibrium for intestinal microecology and prevent secondary bacterial infection as other treatments of COVID-19. However, further high quality clinical trials are needed to conclusively prove the benefits of probiotics administration in COVID-19. Our study is the first to concern about nutritional risk and provide evidence to explore nutrition strategies in improving outcomes for severe and critically ill patients infected with SARS-CoV-2. However, this study has several limitations. Firstly, the critically ill patients who had been admitted to the intensive care unit were not enrolled in the present study and the scores (such as acute physiology and chronic health evaluation) that usually used to 22 This article is protected by copyright. All rights reserved. evaluate the severity and predict the prognosis of the critically ill patients were not available. Therefore, there were selection bias in the inclusion of critically ill patients. Next, owing to the inconvenience of measurement in emergency, the information of body height and weight was self-reported by the patients. Thus, possible recall biases existed in the process of collecting data. Furthermore, retrospective design was used in this study. As a consequence, we only descriptively demonstrated the relationship between the nutritional risk and clinical outcomes. To further investigate the role of nutritional support in the prognosis of COVID-19 patients, more well-designed randomized controlled trial are needed. In conclusion, most severe and critically ill patients infected with SARS-CoV-2 are at nutritional risk, and those who are at a higher nutritional risk tend to have worse outcomes. Adequate and reasonable nutritional support to patients with high nutritional risk could effectively improve the nutritional status and clinical outcomes of COVID-19 patients. 23 This article is protected by copyright. All rights reserved. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare that they have no competing interests. This article is protected by copyright. All rights reserved. a Continuous variables were presented as mean ± SD (n), categorical variables were showed as n (%). BMI, body mass index. This article is protected by copyright. All rights reserved. Medication and respiratory support information was recorded during entire hospital stay, other information was recorded at admission. b P-values were from t test for continuous data and from χ² test for categorical data. This article is protected by copyright. All rights reserved. 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Dietary supplements included vitamins (vitamin C, vitamin D or vitamin E) or minerals (calcium, iron). b P-values were from χ² test between severe cases and critically ill cases. c P-values were from χ² test between NRS score <3 and NRS score ≥3. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.