key: cord-1023828-11aftvrz authors: Shahbazi, Shaahin; Hajimohammadebrahim-Ketabforoush, Melika; Shariatpanahi, Maryam Vahdat; Shahbazi, Erfan; Shariatpanahi, Zahra Vahdat title: Evaluation of Anorexia and Analysis of Related Factors in Patients with COVID-19 date: 2021-10-14 journal: Nutrition Clinique et Métabolisme DOI: 10.1016/j.nupar.2021.08.001 sha: 99a51d5e1c868c357da853968d50a85e5d109c0c doc_id: 1023828 cord_uid: 11aftvrz Objective: COVID-19 may cause an anorexic situation. This in turn leads to underfeeding, puts the patient in an energy protein malnutrition state, develops the hyperinflammation, weakens the immunity, and makes COVID-19 conditions more dangerous. Meanwhile, the more severe inflammation conditions in the body, the more severe the anorexia, which in turn affect the disease severity. Studies evaluating appetite in COVID-19 patients are very rare; therefore, we evaluated anorexia and analyzed the related factors in patients with COVID-19. Material and Methods: In this cross sectional study, adult patients’ ≥18 years old with the positive real-time fluorescence polymerase chain reaction for COVID-19 were included. The patients were classified as mild, moderate, and severe based on the WHO classification. We measured the appetite score, weight, height, body mass index (BMI), depression and anxiety score, at admission for every patient. Results: A total of 301 patients participated in the study. The prevalence of admission anorexia was 58%, and this rate was significantly more in the severe group compared to the mild and moderate groups (P<0.001). Comorbidities, depression and anxiety were independently correlated with anorexia risk [(OR=3.6, 95% CI 1.68- 7.70, P=0.001), (OR=1.23, 95% CI 1.16- 1.30, P<0001), and (OR=1.24, 95% CI 1.17- 1.31, P<0001)], respectively. This correlation was adherence to a U-shape association for BMI, which means BMI<18.5 (OR=3.35, 95% CI 1.8- 10.42, P<0001) and BMI ≥30 (OR=2.45, 95% CI 1.02- 6.53, P=0.048) were related to higher risk of anorexia. Conclusion: We reported a high prevalence of anorexia (58%) in COVID-19 patients, which was positively correlated with disease severity. Furthermore, any factor worsening inflammatory state, including underweight, obesity, comorbidities, depression and anxiety can exacerbate anorexia in these patients. The current terrible pandemic (COVID-19) created by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects a huge number of people, and victims experience from mild to severe degrees of infection 1, 2 . The clinical manifestations of this infection have been attributed to the angiotensin-converting enzyme 2 (ACE2) receptor 3 . In addition to the lung alveolar type 2 cells, the mentioned receptor is highly expressed in many tissues, including the gastrointestinal tract 4, 5 . This theme explains the extra pulmonary symptoms of COVID- 19 . In this regard, some epidemiologic studies indicate that there are manifestations such as loss of appetite, diarrhea, nausea, and vomiting in COVID-19 patients 6, 7 . Among these gastrointestinal symptoms, loss of appetite has been reported as the most common symptom 8 . Appetite is associated with determinants such as food intake, weight, gender, age, acute illness, history of eating disorders, and psychological, family, and social situations. It has long been shown how inflammatory factors can lead to anorexia and reduced food intake, and subsequently predispose a human to malnutrition 9, 10 . Meanwhile, the more severe inflammation conditions in the body, the more severe the anorexia, which in turn affect the disease severity. Some factors involved in this process can be older age, obesity, smoking and comorbidities [9] [10] [11] [12] [13] . It appears that COVID-19 can cause this scenario by shifting the body to a hyper-inflammatory state, so that the loss of appetite and underfeeding put the patient in an energy protein malnutrition state, which in turn creates a proinflammatory state, weakens the immunity, and makes COVID-19 conditions more dangerous 14 . Recently, numerous studies have evaluated the olfactory and gustatory in COVID-19 patients, which indicate an impairment of these senses under the disease 15, 16 . However, the quantitative evaluation of J o u r n a l P r e -p r o o f appetite in these patients and its association with the disease severity have been neglected despite its special importance. Thus far, only one study measured appetite in COVID-19 patients using the appetite visual analogue scale (VAS), and found no significant difference between appetite in patients with and without weight loss 17 . The findings of this study indicated that patients with weight loss had more systemic inflammation, impaired renal function and longer disease duration, and only the disease duration was a predictor of weight loss 17 . Whereas, in other medical illnesses, it has been reported that history of decreased eating and low actual eating are associated with the low body mass index (BMI), which in turn is related to a 6-fold increase at a rate of 30-days in-hospital mortality 18 . Moreover, another study on patients admitted to a geriatric acute care ward suggested that inflammation was the underling predictor for poor appetite and food intake, whereas other factors such as infection, chronic inflammatory diseases, age and gender did not show any impact on appetite 10 . Overall, studies on anorexia and its related factors in inflammatory conditions have been rarely conducted in humans, particularly in COVID-19 patients. Therefore, we evaluated anorexia in COVID-19 patients and its relation to disease severity, hypoguesia and hyposmia, BMI, depression, anxiety, age, sex and comorbidity. The current cross sectional study was conducted from April 2020 to December 2020 in a university hospital. The study was approved by the Ethics Committee of the university. Adult 18 years and older patients with positive real-time fluorescence polymerase chain reaction (RT-PCR) for covid-19 were included in the study. Exclusion criteria were critical patients, lack of weight and height information, corticosteroid consumption, pills affecting the appetite, eating disorders, and history of depressive/anxiety disorder. Patients were classified as mild, moderate, and severe based on the WHO classification 19 . Mild patients were defined as symptomatic patients meeting the case definition for COVID -19 without the evidence of viral pneumonia or hypoxia. Moderate patients had clinical signs of pneumonia (fever, cough, dyspnea, fast breathing) but no signs of severe pneumonia, including SpO2 ≥ 90% on room air. Severe were defined as presence of clinical signs of pneumonia (fever, cough, dyspnea, fast breathing) plus one of the: 1-respiratory rate > 30 breaths/min; 2severe respiratory distress; or 3-SpO2 < 90% on room air. Critically patients defined as cases with respiratory failure, shock, or multiorgan dysfunction that should be treated in ICU were excluded, since their response to questionnaires were invalid or impossible. We measured the appetite score, weight, height, BMI, depression and anxiety score, at admission for every patients. To assess anorexia, the visual analogue scale (VAS) was performed for all patients on the day of admission. VAS is an applied simple tool, and the subject is asked to rate and mark his/her anorexia on a 0 to 10 analogue rating scale. There is no defined cutoff value on the VAS to diagnose anorexia. We defined a VAS score < 5 cm as indicative of anorexia 20, 21 . Anorexia was measured every day in hospitalized patients. In outpatient cases, it was measured at the first visit in the clinic of the hospital, and thereafter by telephone call daily to record the scores. Weight was measured without shoes while wearing light clothes using SECA digital scales with a precision of 0.1 kg. Height was measured barefoot using a meter attached to the wall with a precision of 1 cm. BMI was calculated as the weight in kilograms divided by the height in meters squared. Depression and anxiety on the day of admission were measured by the Hospital Anxiety and Depression Scale (HADS), which was a self-report instrument designed to measure the two related negative emotional states, namely depression and anxiety 22 . It consisted of 14 items comprising 2 subscales (depression and anxiety) of 7 items. Each item was rated on a 4-point Likert scale ranging from 0-3, with a score range of 0-21 for both subscales and higher scores indicated a greater anxiety and depression state. Data analysis was conducted by the SPSS 21 software for Windows. P values equal to or less than 0.05 were considered the level of significance. Kolmogorov-smirnov (K-S) test was conducted to examine the distribution normality of the variables. Continuous variables were regarded as means ± standard deviation (SD) or medians and interquartile ranges (IQR). Categorical data were presented as proportions (number and percentage). To find the difference between the three groups of COVID-19 concerning normal and abnormal distributed variables, ANOVA and Kruskal Wallis tests were used, respectively. In cases where reporting the difference between the two groups was needed, T test was used. Results were reported as the mean ± standard deviation for parametric tests as well as the median (Q1−Q3) for nonparametric tests. X 2 test was used to report the difference in categorical variables. Logistic regression analysis was used to assess the relationship between related variables as covariates and anorexia as the dependent variable. The VAS score for anorexia at admission was changed to a dichotomous variable with the cutoff point of 5 based on its median, and VAS score < 5 cm as indicative of anorexia. The covariates associated with J o u r n a l P r e -p r o o f anorexia in univariate regression were retained in the final model or multiple logistic regression. There was no correlation between these covariates, including age, obesity, being underweight, depression score and anxiety score. A total of 301 patients were included in the study. Table 1 presents the basal characteristics of the patients. Among the participants, 102 (34%) were with mild, 92 (31%) with moderate, and 107 (35%) with severe disease symptoms. Based on the VAS score, the prevalence of admission anorexia (VAS score < 5 cm) was 58%, and this rate was significantly higher in the severe group than in the mild and moderate groups ( Table 1) . Median duration of anorexia was 14 (12) (13) (14) (15) (16) days in the severe group, which was significantly longer than that of the moderate (10 (10-12), P=<0.001) and mild (10 (9-10), P=<0.001) groups. The participants' mean age was 61±12.8 years. The patients' mean age was significantly more in the severe group than in the mild group ( Table 1 ). The mean age was significantly more in patients with anorexia than in patients without anorexia (59.3±11.9 vs 62.5±13.4, P=0.03). Results of the logistic regression analysis showed a week correlation between age and anorexia. This correlation disappeared after adjustment by covariates ( Table 2) . Mean BMI was 23.5± 4.6 in the whole population. On admission, 8% of patients were underweight with BMI lower than 18.5 kg/m 2 , and 12.6% were obese with the BMI equal to and more than 30 kg/m 2 . Both underweight and obese patients had significantly involved more in the severe type of disease than normal and overweight patients ( Table 1) . Results of the logistic regression analysis showed that both obesity and underweight increased the risk of anorexia by 2 and 2.8 times, respectively. This value was increased to 2.45 and 3.3 folds after adjustment by covariates (Table 2) . In total, 63 (20.9%) patients had comorbidity, which was significantly more in the severe group than in the two other groups (Table 1) . Chronic obstructive pulmonary disease was observed in 15, 9 and 4 patients in severe, moderate and mild COVID patients, respectively. J o u r n a l P r e -p r o o f moderate and mild covid patients, respectively. Type 2 diabetes was observed in 14, 13 and 3 patients in severe, moderate and mild COVID patients, respectively. Admission anorexia was seen more in patients with comorbidity than in those without comorbidity (35 vs 28 patient, P= 0.01). Results of the logistic regression analysis indicated that the presence of comorbidity increased risk of anorexia by 3.2 times. This value was increased to 3.6 times after adjustment by covariates (Table 2) . The median admission depression score based on HADS was 5 (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) in the whole population. This score was significantly more in the severe group than in the mild group (Table 1) . Results of the Pearson correlation showed no relation between depression and anxiety scores (r= 0.03, P= 0.49). Results of the univariate logistic regression analysis showed that each point increase in depression score was associated with a 16% increase in the risk for anorexia. This value was increased by 23% in the multivariate logistic regression model (Table 2) . The median admission anxiety score based on HADS was 5 (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) in the whole population. This score was significantly more in the severe group than in the mild and moderate groups ( Table 1) . Results of the univariate logistic regression analysis showed that with each point increase in the anxiety score, the risk for anorexia increases by approximately 17%. This value is increased by 24% in the multivariate logistic regression model (Table 2) . In total, 42.3% (n=127) of patients had taste/smell impairment on admission. Based on the disease severity, the rate of hypogeusia/hyposmia had a trend to be more in the severe COVID group, but it was not significant (P= 0.06) ( Table 1 ). The median duration of Hypoguesia/Hyposmia was 10 (9-10), 10 (9-10) and 14 (12) (13) (14) (15) (16) in mild, moderate, and severe groups, respectively. This was significantly more in the severe group than in the two other groups (P<0.001). There was no correlation between taste/smell impairment and admission anorexia analyzed with the logistic regression analysis (OR= 1.37, CI: 0.86-2.17, p=0.17). In total, 7.3% (n=22) of the patients were smoker with no difference in terms of type of disease (Table 1) . There was no difference in the rate of admission anorexia between nonsmokers 9 (7.1%) and smokers 13 (7.4%) (P=0.92). Logistic regression analysis did not show any correlation between smoking and anorexia ( Table 2) . Sixty percent of the patients were female. There was no difference in the sex involvement between subtypes of disease (Table 1) . There was no difference in the rate of the admission anorexia according to their sex (41% male vs. 59% female. P=0.87). Logistic regression analysis did not show any correlation between sex and anorexia ( Table 2 ). The present study was conducted to evaluate anorexia and analyze related factors in patients with COVID-19. The percentages related to the disease severity among all of our patients were 34%, 31%, and 35%, which belonged to mild, moderate, and severe disease, respectively. Totally, the prevalence of admission anorexia was 58%, and this rate was significantly more, patients was positively associated with the scores of depression and anxiety. In our study, we found the scores of depression and anxiety to be higher in the severe type of COVID-19 than in mild to moderate types. In addition to the mentioned factors, surprisingly, we found that being underweight (BMI<18.5) was also associated with severe COVID-19. It is explained that malnutrition and underweight, like obesity, put the body in a proinflammatory state, and levels of C-reactive protein (CRP) and other inflammatory markers are higher in these patients than in normal and overweight patients 34, 35 . Moreover, by analyzing the factors associated with anorexia, we found that BMI had a U-shaped correlation with anorexia risk, so that both underweight and obesity were associated with lower VAS scores, being representative of severe anorexia. Previously, such an association shape of BMI was observed with the inflammation in hemodialysis patients 35 . In addition, Forli et al. 36 revealed systemic inflammation in underweight patients with advanced pulmonary disease. Therefore, it appears that the found U-shape association of BMI with anorexia in the present study can be justified by considering the inflammatory status of the body. This is also true for comorbidities, depression and anxiety, which, according to what has been mentioned thus far, leads to an inflammatory situation and anorexia. In our study, older patients were more affected by severe COVID-19, being consistent with the results of previous studies [23] [24] [25] 37 . However, considering the effect of confounding variables, we did not find a significant correlation between age and anorexia risk in patients with COVID-19. A possible reason for this finding could be that the J o u r n a l P r e -p r o o f age difference between our patients was very negligible. In this regard, our results are consistent with those obtained by Kalantar-Zadeh et al. 38 However, our study had certain limitations. It was better to use different validated appetite tools and evaluate the relationship between the VAS score and self-reports of food intake, because food intake is the major criterion measure of anorexia. This study was conducted to evaluate the anorexia and analysis of related factors in patients with COVID-19. We reported a high prevalence of anorexia (58%) in COVID-19 patients that was positively correlated with the disease severity. Furthermore, any factor worsening inflammatory state such as underweight, obesity, comorbidities, depression and anxiety can exacerbate anorexia in these patients. It is recommended that eating behaviors and nutritional intake be considered in order to prevent underweight and worsening of COVID-19 patients' inflammatory state. It is also important to reduce the patients' fear in order to reduce anxiety/depression and consequently anorexia. 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All authors contributed to the study conception and design. Material preparation, data The authors did not receive support from any organization for the submitted work. The authors declare that the study was performed in a manner conforming to the Helsinki declaration of 1975, as revised in 2000 and 2008 concerning human and animal rights. The study was approved by the Ilam University of Medical Sciences ethics committee. Written informed consent was obtained from all the patients before being enrolled in the study.