The present study was the first to concern about the risk for malnutrition and provide evidence of nutritional risk screening in predicting outcomes for severe and critically ill patients infected with COVID-19. The present study showed that nutritional status, assessed using CONUT scores, GNRI, and PNI was significantly associated with poor in-hospital mortality in patients with COVID-19 in a multicenter setting, after adjusting for established risk factors. The results of this study suggested that the evaluation of risk for malnutrition was important for risk stratification.
The COVID-19 pandemic has spread throughout the world and has become a major public health threat. It is vital to offer optimal therapy to severe and critically ill patients and reduce the mortality caused by COVID-19. Recently, studies have shown that COVID-19 is largely dependent on certain socio-environmental factors, such as temperature [15,16,17,18], humidity [19,20,21], environmental pollution [22], and smoking [23], as well as clinical characteristics, such as comorbidity, laboratory test, symptoms, age, X-ray abnormality and functional status [13, 14]. To date, however, no studies have assessed the impact of objective nutritional parameters on COVID-19. Expert consensus on COVID-19 suggested that nutritional risk screening should be conducted among in-hospital COVID-19 patients [8, 24]. Given recent research gaps, the present study attempted to assess the impact of health status (i.e. nutritional status) on COVID-19 in China. The findings of the present study provided important evidence for recognizing patients at risk in addition to the established diagnostic criteria.
The nutritional status reflects the general condition of a patient, including physical condition, protein turnover, and immune-competence. Albumin, a component of the GNRI, CONUT score, and PNI, is the major protein in human plasma and the most abundant protein in the extracellular component [25]. Albumin synthesis is regulated by stimuli including nutrient intake, insulin levels, and oncotic pressure. Hypoalbuminemia is therefore thought to result from malnutrition, inflammation, or cachexia. Lymphocytopenia is considered to be related to physiological stress due to corticosteroid release and reflects a poorly regulated immune response [26].
The present study showed upward trends in inflammatory indexes along with the exacerbation of COVID-19, such as C-reactive protein and interleukin levels. Previous studies have theorized that inflammation might promote a generally catabolic state, stimulating protein degradation and the suppression of protein synthesis. Inflammation can also induce anorexia, aggravating the situation of malnutrition/undernutrition [27, 28]. Similarly, changes in metabolic indicators are also noteworthy. Reduced albumin, increased serum creatinine and blood urea nitrogen warn that severe and critically ill patients are at nutritional risk [7, 29]. 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 [30, 31]. However, it is worth noting that serum creatinine and blood urea nitrogen are more likely related to renal function especially in critically ill patients with complications in clinical practice. Therefore, composite indicators of nutritional status with high specificity are needed.
The risk for malnutrition among COVID-19 patients is caused by imbalances in energy intake and expenditure. Firstly, a high state of catabolism due to fever, over-activity of respiratory muscles, and the subsequent endocrine disorders result in the acceleration of gluconeogenesis, protein breakdown, and fat oxidation. Secondly, due to dyspnea mechanical ventilation and disturbance of consciousness, the patients may suffer from insufficient dietary intake. Thirdly, the direct attack of COVID-19 on the gastrointestinal tract results in nausea, diarrhea, and vomiting, with the prevalence of approximately 8.3%, 18.1 ~ 27.1%, and 4.0 ~ 5.9% [32, 33]. Finally, interventions such as mechanical ventilation and the use of antibiotics/antivirals cause hypoproteinemia and damage the digestive system [34,35,36,37].
There is no universally accepted definition of malnutrition or a gold-standard methodology for nutritional screening. In the present study, a per point increase in the CONUT score was associated with an increased risk of in-hospital death, as well as age, level of total bilirubin, and chest CT findings at admission. The present study indicated that nutritional screening using the CONUT score should be taken into consideration for COVID-19 patients. The CONUT score was first reported by Ignacio de Ulı’barri et al. as an objective screening tool for identifying undernutrition in a hospital population [9]. GNRI was first reported by Bouillanne et al. [11] in 2005 as a simple and accurate tool for predicting the risks of morbidity and mortality in hospitalized elderly patients. They defined 4 grades of nutrition-related risk: major risk (GNRI < 82), moderate risk (GNRI 82 to < 92), low risk (GNRI 92 to 98), and no risk (GNRI > 98). Many of the previous studies adopted GNRI cut-off points of 92 or 98. In the present study, the cut-off of GNRI was within the normal range, but the decrease of GNRI still predicted worse clinical outcomes after adjusting for important covariates. A possible explanation for this could be that patients in the present study had a better baseline clinical condition than patients in previous studies, and not only elderly or chronic kidney disease patients but also young or nonchronic kidney disease patients were included. It has been reported that GNRI is an independent prognostic factor for short-term in-hospital mortality in elderly patients with sepsis [38] since the 28-day mortality of very high-risk patients (GNRI < 82) has been increased sixfold [39]. Also, Wang et al. emphasized that GNRI should be of concern to clinicians as a potential prognostic predictor of COVID-19 based on the recently published preliminary results [40]. Given that GNRI was a simple, objective, and rapid method relating to patients’ nutritional status with short- and long-term outcomes, it should be considered as a potential predictor of COVID-19 severity and survival, regardless of patients’ comorbidities.
To date, several nutrition indicators have been reported, such as serum albumin, total cholesterol level, the Mini- Nutritional Assessment (MNA) [41], the Subjective Global Assessment (SGA) [42]. Assessments using a single indicator of malnutrition, such as serum albumin or total cholesterol level, may be affected by various factors and not provide adequate information. The MNA and SGA require subjective data evaluated by medical staff. A previous study demonstrated that inflammatory response reduced albumin synthesis [43]. A retrospective, observational study conducted by Zhao et al. showed that the most severe and critically ill patients infected with SARS-CoV-2 were at nutritional risk assessed by Nutritional Risk Screening 2002 (NRS) [44]. Frailty is one of the potential important junctions between poor nutritional status and worsened health outcomes. It is defined as a clinically identifiable state of increased physiologic vulnerability and dysfunction [45, 46]. Frailty is a measure of overall health and due to its relevance to immune function and risk of respiratory viral infection [47], could be also used as a significant prognostic factor for COVID-19. Besides, functional status could be a promising prognostic factor for patients suffering from COVID-19, as impaired physical function was independently associated with the worst outcomes in hospitalized patients with community-acquired pneumonia, according to a recent prospective study [48].
The aforementioned findings suggest that the incorporation of patients’ functional status measurement into patient assessment may improve the prognostic ability of current risk classification systems to predict mortality from COVID-19 pneumonia. The CONUT score includes serum albumin, total cholesterol levels, and total lymphocyte count for the assessment of nutritional status, while the PNI includes only albumin and lymphocyte count. GNRI is measured using both serum albumin and BMI. These three indexes, CONUT score, PNI, and GNRI, can be calculated using objective parameters and are originally developed to assess the nutritional status of patients with malignant diseases. The results of the discrimination analysis did not show significant improvement after adding the nutritional status. One possible reason was that the incident rate of in-hospital death was 8.5%. However, multivariate logistic regression analysis clearly showed that worse nutritional status was related to the higher risk of in-hospital mortality.
In the present study, the GNRI had a relatively high and significant OR for in-hospital mortality compared to the CONUT score and the PNI. These factors should be considered for risk stratification to detect high-risk individuals. However, further research should be carried out to elucidate this promising, time-saving method.
The present study had several limitations. First, this was a retrospective, observational study with a small sample size, and unknown confounders might influence the outcomes irrespective of the analytical adjustments. Besides, all of the patients were Chinese, so patients of different ethnicities/races needed to establish their reference. Second, the present study evaluated the risk for malnutrition once at admission and did not assess its changes. Meanwhile, only in-hospital mortality was analyzed. Thus, it was not possible to determine the long-term effects of nutrition risk. Third, the interaction between risk for malnutrition and the presence of the severity of COVID-19, which could affect especially the lymphocyte count, was not further explored. Finally, a validation study of the screening tool, however, was not examined. A prospective, long-term cohort study was needed to further verify the findings of the present study.
This was the first study to describe the risk for malnutrition in patients with COVID-19 using three nutritional indices. From the overall analysis, it was clear that nutritional status affected in-hospital mortality. The study was conducted in the hotspot cities in China. The results of this study are not only a major public health concern for these cities, but also for those that are likely to withstand a pandemic in the coming days during the current COVID-19 outbreak.