key: cord-1021799-uqiflkg7 authors: Cengiz, Mahir; Uysal, Betul Borku; Ikitimur, Hande; Ozcan, Erkan; Islamoğlu, Mehmet Sami; Aktepe, Emre; Yavuzer, Hakan; Yavuzer, Serap title: Effect of oral L-Glutamine supplementation on Covid-19 treatment date: 2020-07-29 journal: Clin Nutr Exp DOI: 10.1016/j.yclnex.2020.07.003 sha: c38142a089beccdd9040f7947c042f91f95b131d doc_id: 1021799 cord_uid: uqiflkg7 Summary Objectives The aim of this study is to investigate the effect of oral L-Glutamine supplementation on hospitalization time, need for intensive care unit and Coronavirus Disease-19 (Covid-19) mortality. Methods The study included 30 Covid-19 patients using L-Glutamine and 30 Covid-19 patients who did not use L-Glutamine with similar age, gender and clinical status. Diagnostic tests, laboratory examinations, clinical findings and computed thorax tomography imaging of the patients were evaluated. Results Hospitalization time was 10.4 ± 1.9 days in Covid-19 without L-Glutamine group and 8.9 ± 1.8 days in Covid-19 with L-Glutamine group (p = 0.005). In Covid-19 without the L-Glutamine group, the requirement of the intensive care unit was significantly higher (p = 0.038). Conclusions In Covid-19 cases, nutritional assessments of patients should not be overlooked in addition to the currently used treatments. Some nutritional supplements provide immune nutritional support by inhibition of inflammatory responses and regulation of immune functions in infectious diseases. Larger-scale studies are needed on L-Glutamine, which is added to normal nutrition in the early period of infection, may lead to shortened hospital stay and lead to less need for intensive care. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus first discovered in December 2019 in Wuhan, province of China [1] . The disease was called Coronary Virus Disease-19 (Covid-19) on February 11, 2020. On March 11, 2020 , the World Health Organization announced the Covid-19 as a pandemic [2] . As of the end of April, the disease affected more than 3 million people in the worldwide and caused more than 200 thousand of deaths. In the treatment of Covid-19, antiviral agents such as lopinavir, ritonavir, remdesivir, antibacterial drugs such as macrolides and antimalarial drugs such as hydroxychloroquine are used. While international studies are ongoing to find a curative treatment in the disease, there is still no effective treatment that improves the course of the disease and reduces mortality. The main approach, especially in those with lower respiratory tract involvement, is focused on optimizing respiratory functions. The most effective treatment approach in the course of the disease appears to be supportive therapy. The morbidity and mortality of the disease is higher, especially in the elderly patients with low immune function, in individuals with nutritional deficiencies and in people with chronic diseases [3, 4] . As in other acute diseases, since the catabolic process continues in Covid-19, normal protein intake is not sufficient to support recovery. Promoting acute stress-decreasing levels of specific amino acids, such as cysteine, arginine and glutamine enhances immunity in such patients [5] . Acting as signal molecules and mediators at the cellular level, these featured amino acids are known to regulate many functions in the cell and help recovery [6] . Glutamine is the most abundant amino acid in the body, containing 60% of the total pool of free amino acids. The main synthesis sources of glutamine circulating in plasma are skeletal muscle, adipose tissue and lungs. Glutamine performs most of the transport of nitrogen from the skeletal muscle to the visceral tissues. Glutamine is used as a glucoseefficient primary fuel for many rapidly dividing cells, including enterocytes, colonocytes, lymphocytes, and fibroblasts [7] . It has been shown that glutamine, whose many functions are known, plays a role in acid-base balance through the production of ammonia in the kidney, its oxidized form provides the substrate for the synthesis of purines and pyrimidines necessary for DNA, RNA and mesenger RNA. Glutamine is also a precursor to glutathione, a powerful antioxidant produced endogenously. It is one of the most researched amino acids on multiple aspects of medical nutritional care, including conditions such as gastrointestinal diseases, oncology, burn injury, HIV / AIDS, and chronic wound management [8] . Giving all the nutrition to be provided with glutamine support, which is very important in immune nutrition, on time and as much as necessary, is very important for recovery. However, it should not be forgotten that in all diseases, timely recognition and correction of malnutrition has the potential to improve the outcome in a cost-effective way [4] . The aim of this study is to investigate the effect of oral L-Glutamine supplementation on hospitalization time, intensive care unit requirement and mortality in Covid19 patients, over 50 years of age who are hospitalized with lower respiratory tract involvement. The sample collection protocol was approved by the Ethics Committee of the Biruni University Faculty of Medicine (Authorization Number: 2020/39-39) and carried out in accordance with the requirements of the Second Declaration of Helsinki. Before the written consent, all patients were given complete information about the study procedures. Patients with kidney and liver dysfunction, alcoholism, malignancy, connective tissue diseases, cardiovascular diseases (hypertension, ischemic heart disease, arrhythmia, serious valvular disease), diabetes mellitus, neurological and psychiatric problems (Parkinson's disease, cerebrovascular disease, delirium, bipolar disorder, depression), or severe disease that can not be measured their weight or height were excluded from the study. When the patient was classified with or at risk of malnutrition at the beginning or in the following period of the hospital stay, we planned a nutritional care plan and excluded them from the study. Thorax CT screenings of all patients, included in the study, were taken at the time of hospital admission. As stated in the guidelines of Turkish Ministry of Health, an oropharyngeal sample was first taken with a swab, then a nasal sample was taken using the same swab, and placed in the same transport medium for diagnosis. Samples were tested by RT-PCR assay developed from the virus sequence. Fasting blood samples were taken at the time of admission. Serum CRP levels were measured by a nephelometric method (Immage 800, Beckman Coulter, Istanbul, Turkey). The other biochemical parameters as complete blood count (CBC), creatinine, sodium, potassium, alanine aminotranferase (ALT), aspartate aminotransaminase (AST), lactate dehydrogenase (LDH), D-dimer, ferritin, troponin were measured by routine methods with commercial kits. The nutritional status of all our patients were investigated with the Nutritional Risk severe that were converted to a numeric score between 1 to 3 according to recommendations. A total score under 3 suggested no nutritional risk. A data collection sheet was used to obtain all informations according to the ESPEN guidelines [9] . All given meals for the studied patients were prepared in accordance with the appropriate guidelines in COVID-19 and consisted with equal protein and calori contents [10] . To the group using L-Glutamine, 10 grams L-Glutamine available in powder forms (Resource Glutamine, Nestle) were given 3 times a day with meals. Data on patients' gender, age, clinical symptoms, treatments used, swab sample and presence of thorax CT findings, laboratory results, vital signs, the results of nutritional status screenings and the results of Pneumonia Severity Index Grades on the day of diagnosis, the number of hospitalization days, need of ICU and mortality were recorded [9, 11] . A sample size of n=29 per group is required to provide 80% power to detect a difference in the mean levels with a significance of 0.05 (2-sided α). The normal distribution of the data was tested using the one-sample Kolmogorov-Smirnov test. Continuous variables are presented as mean±standard deviation. Categorical variables are presented as counts. The statistical comparisons were performed using the two-sided Student's t-test. Categorical variables were compared using the Chi-square test or Fisher exact test for small samples. Values of p<0.05 were considered to be statistically significant. The statistical analyses were performed using SPSS 20.0 software (SPSS, Chicago, IL, USA) for Windows. Demographic features and laboratory findings of the study groups are given in Table 1 . Age, gender distribution, smoking and laboratory findings were similar between the groups. Symptoms, medications for Covid-19 and physical examination findings of the study groups are given in Table 2 . All of the symptoms, medications and physical examination findings of the study groups were similar between the groups. Duration of hospitalization, necessity of intensive care unit and number of mortality of the study groups are given in Table 3 . Duration of hospitalization was found as 10.4±1.9 days in Covid-19 without L-Glutamine group and 8.9±1.8 days in Covid-19 with L-Glutamine group (p=0.005). The number of necessity of intensive care unit was significantly higher in Covid-19 without L-Glutamine group (p=0.038). Although there was no difference in mortality rates between the groups, a death was observed in the Covid-19 group, which did not receive L-Glutamine. This study evaluates the effects of L-Glutamine supplementation on hospitalization time, intensive care requirement, and mortality in Covid-19 patients followed by lower respiratory tract involvement. The results of our study showed that in Covid-19 cases using L-Glutamine, the duration of hospitalization was shorter and the need for intensive care was less than those who did not use L-Glutamine. Leukocytes fight endotoxin, cytokine and free oxygen radicals, which increase in serious inflammation situations such as sepsis, polytrauma and acute respiratory failure and also damage the functions of cell. In these acute stress situations, heat shock proteins 70 (Hsp70) expressed from leukocytes only have a positive effect on complications and mortality in the presence of sufficient glutamine. Therefore, Hsp70 and leukocyte functions, which decrease with glutamine levels falling below physiological doses in these patients, are considered as one of the causes of immune indulgence [12, 13] . Increased metabolic stress period, free glutamine release from skeletal muscle, resulting in intracellular glutamine concentration drops more than 50% [14, 15] . In their study, Roth et al. found that survival in patients with intra-abdominal sepsis is associated with free intracellular glutamine concentration [16] . Glutamine is normally synthesized endogenously, however, it is considered as an essential amino acid in catabolic processes. Thus, the body's glutamine synthesis becomes unable to meet higher requirements during Glutamine supplementation during oncology therapy is an exciting area of current research. The data show that glutamine can support the host by regenerating glutathione levels, preventing or repairing tissue damage, and improving some side effects [18] . With parenteral glutamine-supplemented nutrition given to patients undergoing bone marrow transplantation, the duration of hospitalization and the rate of developing infections have decreased. Estimated cost savings per patient was about $ 22,000 [19] . In our study, it was observed that the duration of hospitalization was shortened and the need for intensive care was reduced by giving L-Glutamine to patients with lower respiratory tract involvement due to Covid-19. Therefore, this decrease in morbidity also reduces health expenses. In the literature, there are many randomized controlled studies and meta-analyzes investigating the effectiveness of glutamine in supplementary therapy in acute stressful diseases, and sometimes the results can be confusing. However, an umbrella study examining the results of meta-analyzes on this subject has recently been published. In many of the metaanalyzes, it was stated that glutamine, which became essential amino acid by decreasing its level in critical acute patients, had a positive effect on recovery time, development of secondary infection and mortality in parenteral or enteral ways [20] . Parenteral glutamine given in rats with in vivo polymicrobial sepsis, and glutamine given enterally and/or parenterally to patients diagnosed with sepsis in vitro studies have also been shown to have positive effects on the immune system [21, 22] . In the light of these studies, in Covid-19 with lower respiratory tract involvement, which is the most important pandemic of the last century and has yet no curative treatment, we designed our study considering that glutamine supplementation, which can be given orally to the patients, will provide positive efficacy on immune modulation. The results of our study were also positive similarly to the literatüre. However, more comprehensive studies on this subject are needed to reconfirm the results from our study The current study has some limitations. First, the results cannot be generalized to the whole population because the study was conducted in a single center and included only patients over 50 years of age without comorbidity. Second, more patients should be included in the study to demonstrate the effect of L-Glutamine supplementation on mortality. Third, to demonstrate the improvement of pathophysiological changes in the lung, patients should undergo pulmonary function tests and CT examinations after 6-8 weeks. The last limitation is that the Covid-19 without L-Glutamine group's not using placebo creates a separate bias. In conclusion, the use of L-Glutamine in Covid-19 cases can shorten the length of hospital stay and reduce the need for intensive care unit. Larger studies are needed to demonstrate the effect of L-Glutamine supplementation on Covid-19-related mortality. The authors declare that they have no conflict of interest. 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Influence of intercurrent infection Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle Influence of amino acid supply on nitrogen and plasma amino acid metabolism in severe trauma Glutamine, cancer, and its therapy A cost-evaluation of glutamine-supplemented parenteral nutrition in adult bone marrow transplant patients Therapeutic benefits of glutamine: An umbrella review of metaanalyses The effects of intravenous, enteral and combined administration of glutamine on malnutrition in sepsis: a randomized clinical trial Glutamine Administration in Early or Late Septic Phase Downregulates Lymphocyte PD-1/PD-L1 Expression and the Inflammatory Response in Mice With Polymicrobial Sepsis The authors declare that they have no conflict of interest.