*Article* **Adherence to COVID-19 Nutrition Guidelines Is Associated with Better Nutritional Management Behaviors of Hospitalized COVID-19 Patients**

**Amelia Faradina 1, Sung-Hui Tseng 2,3, Dang Khanh Ngan Ho 1, Esti Nurwanti 4, Hamam Hadi 5,6,7, Sintha Dewi Purnamasari 5,6,7, Imaning Yulia Rochmah <sup>8</sup> and Jung-Su Chang 1,9,10,11,\***


**Abstract:** Good nutritional support is crucial for the immune system to fight against coronavirus disease 2019 (COVID-19). However, in the context of a pandemic with a highly transmissible coronavirus, implementation of nutrition practice may be difficult. A multicenter electronic survey involving 62 dieticians was conducted, in order to understand barriers associated with dieticians' adherence to nutrition guidelines for hospitalized COVID-19 patients in Indonesia. 69% of dieticians felt under stress when performing nutrition care, and 90% took supplements to boost their own immunity against the coronavirus. The concerns related to clinical practice included a lack of clear guidelines (74%), a lack of access to medical records (55%), inadequate experience or knowledge (48%), and a lack of self-efficacy/confidence (29%) in performing nutritional care. Half (52%) of the dieticians had performed nutrition education/counseling, 47% had monitored a patient's body weight, and 76% had monitored a patient's dietary intake. An adjusted linear regression showed that guideline adherence independently predicted the dieticians' nutrition care behaviors of nutrition counselling (ß: 0.24 (0.002, 0.08); *p* = 0.04), and monitoring of body weight (ß: 0.43 (0.04, 0.11); *p* = 0.001) and dietary intake (ß: 0.47(0.03, 0.10); *p* = 0.001) of COVID-19 patients. Overall, adherence to COVID-19 nutrition guidelines is associated with better nutritional management behaviors in hospitalized COVID-19 patients.

**Keywords:** COVID-19; nutrition care; guidelines adherence; length of stay; mortality; Indonesia

#### **1. Introduction**

Indonesia is among the 20 countries currently most severely affected by coronavirus disease 2019 (COVID-19) worldwide, with the fifth highest observed case–fatality ratio (3.0% per 100 confirmed cases) [1]. The clinical characteristics of COVID-19 are diverse,

**Citation:** Faradina, A.; Tseng, S.-H.; Ho, D.K.N.; Nurwanti, E.; Hadi, H.; Purnamasari, S.D.; Rochmah, I.Y.; Chang, J.-S. Adherence to COVID-19 Nutrition Guidelines Is Associated with Better Nutritional Management Behaviors of Hospitalized COVID-19 Patients. *Nutrients* **2021**, *13*, 1918. https://doi.org/10.3390/nu13061918

Academic Editors: Zafeiria Mastora and Dimitrios T. Karayiannis

Received: 6 April 2021 Accepted: 31 May 2021 Published: 3 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

and symptoms range from asymptomatic, mild with nonspecific symptoms (e.g., fever, cough, sore throat, and headaches), moderate/severe pneumonia with acute respiratory distress syndrome (ARDS) demanding mechanical ventilation, and multi-organ failure to death [2]. Currently, remdesivir is the only antiviral drug approved by the U.S. Food and Drug Administration (FDA) for treating COVID-19. Since there are limited effective antiviral drugs, supportive care with good nutritional support is crucial for the immune system to fight against coronavirus infection in hospitalized COVID-19 patients [2–5].

Dieticians are an integral part of healthcare systems, and are responsible for assessing the nutritional needs of hospitalized COVID-19 patients. However, one of the practical challenges of nutritional management with COVID-19 is the lack of clear guidelines, as the emerging coronavirus and its impacts on health are constantly evolving [2–5]. Although nutritional management of COVID-19 disease is, in principle, similar to that of hospitalized patients or patients in intensive care units (ICUs) [6], implementation of nutrition guidelines into clinical practice is a great challenge in the context of this pandemic with the highly transmissible coronavirus [7]. For example, dieticians might not be allowed to meet patients or perform nutritional assessments due to the risk of contracting or transmitting COVID-19. Frequently, some instruments for evaluating nutritional status are not readily available in most settings dedicated to COVID-19 patients. Indeed, dieticians should rely on rapid/alternative measures [8]. With the ongoing pandemic, health workers are burned out and are suffering from psychological symptoms (e.g., depression, anxiety, and insomnia), and these may also affect their motivation to implement nutrition guidelines [9,10]. Currently, little is known about the challenges and barriers that affect dieticians' implementation of COVID-19 nutritional guidelines. The broad aim of this study was to investigate barriers to dieticians' adherence to nutritional guidelines in hospitalized COVID-19 patients in Indonesia. Specific aims were: (1) to understand the practical challenges and concerns associated with nutritional care, and (2) to understand barriers (guideline knowledge, attitudes, and environmental factors) associated with nutritional management behaviors of dieticians (as indicated by monitoring a patient's body weight (BW) and dietary intake, as well as performing nutrition counseling/education).

#### **2. Materials and Methods**

#### *2.1. Study Participants*

This study was a multicenter electronic survey designed to understand the barriers associated with dieticians' adherence to clinical practice of nutrition care for hospitalized COVID-19 patients in Indonesia. This study was conducted during November 2020– January 2021. The link of the questionnaire (as a Google Form) was sent to social media groups of Indonesian dietetic association networks, where an estimated number of 210 of the group members were working as dieticians in a hospital. In total, 62 dieticians from 44 hospitals completed the online questionnaire, giving a response rate of 29.5%. Out of the 44 participating hospitals, 39 (88.6%) were located in Jakarta and Java Island, and had higher COVID-19 cases compared to other regions in Indonesia. In addition, 20 participating hospitals (45%) were hospitals designated for COVID-19 by the Indonesia Ministry of Health. The study was conducted anonymously, and no personal data were collected (e.g., name or contact address). Participants were informed of the purpose of the online survey, and their consent to participate in the study was assumed if they completed the online survey. Each participant was allowed to complete the online survey only once. Participants were included if they were of Indonesian nationality, were employed as a dietician in a hospital, had performed nutritional care for hospitalized COVID-19 patients, and completed the online surveys. Exclusion criteria were a non-Indonesian nationality, dieticians who never performed nutritional care for hospitalized COVID-19 patients, and those who did not complete the online survey questionnaires. The study was approved by the Research Ethic Committee of Alma Alta University, Indonesia (KE/AA/XI/10323/EC/2020).

#### *2.2. Survey Questionnaire: Barriers to Dietician Adherence to Nutrition Care for Hospitalized COVID-19 Patients*

The questionnaire was developed based on the framework of "barriers to physician adherence to practice guidelines in relation to behavior change", which was proposed by Cabana et al. and published in the Journal of the American Medical Association (JAMA) in 1999 [11]. The questionnaire consisted of four domains: knowledge (12 questions), attitudes (six questions), environmental factors (seven questions), and behaviors (three questions) (Supplementary Table S1). Depending on a participant's answers, each question was awarded 1 or 0 points, with a maximum of 28 points in total (Supplementary Table S1). For example, 1 point was awarded to a participant if they know "ESPEN guidelines on clinical nutrition in the intensive care unit" [6] or if they had "monitored the body weight of hospitalized COVID-19 patients". A higher total score of guideline knowledge, attitudes, environment, and behavior indicates better dietician adherence to clinical nutrition practices for hospitalized COVID-19 patients.

The "guideline knowledge section" (12 questions in total) included awareness of the guidelines (four questions) and familiarity with clinical nutrition practice of the guidelines (eight questions). The four guidelines were published between February 2019 and July 2020, and included the Coronavirus Disease 2019 (COVID-19) Treatment Guidelines (National Institutes of Health, USA) [2], ESPEN guidelines on clinical nutrition care in the intensive care unit (ICU) [6], ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2-infection [3], and Nutrition Therapy in the Patient with COVID-19 Disease Requiring ICU Care (reviewed and approved by the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition) [5]. Familiarity with clinical practice associated with the guidelines included questions such as "is it important to conduct nutritional screening and nutritional assessment for hospitalized COVID-19 patients?" and "must the nutritional assessment and early nutritional care management of COVID-19 patients be integrated into the overall therapeutic strategy?" Respondents answered with "agree" or "disagree".

The "attitude section" (six question in total) consisted of two parts: self-efficacy or confidence (three questions) and motivation (three questions) in performing nutritional care for hospitalized COVID-19 patients. Examples of the statements included: "lack of selfefficacy or confidence in performing nutrition care for hospitalized COVID-19 patients?", and "feel stress when performing nutrition care for hospitalized COVID-19 patients?" Respondents answered with "agree" or "disagree". "Environmental factors" included seven questions including "lack of time, lack of resources, limited budget, limited food supply, lack of access to meet hospitalized COVID-19 patients, lack of access to medical records, and inadequate authority to perform nutritional care for hospitalized COVID-19 patients". "Dieticians' behavior" mainly focused on three nutrition care behaviors: (1) "Do you give nutrition education/counseling to hospitalized COVID-19 patients? If yes, how do you give nutrition education/counseling: educational video, educational leaflet, phone call, or text message?"; (2) "Do you monitor COVID-19 patient's body weight change? If yes, who monitors body weight and how do you do it?"; and (3) "Do you monitor dietary intake of hospitalized COVID-19 patients? If yes, who monitors it and how do you do it?" Total guidelines adherence score (maximum 28 points) was defined as knowledge (12 points), attitudes (six points), environmental factors (seven points), and dieticians' nutrition practice behaviors (three points). A high total score indicated a better adherence to nutrition guidelines for hospitalized COVID-19 patients.

#### *2.3. Primary Outcome*

The primary outcomes were dieticians' behaviors of nutrition care and self-efficacy or confidence in providing nutrition care for hospitalized COVID-19 patients. The dieticians' behaviors of nutrition care included: (1) conducting nutrition counseling/education, (2) monitoring patients' weight changes, and (3) monitoring patients' dietary intake.

#### *2.4. Data Analysis*

Statistical analyses were conducted using SPSS 19 (IBM, Armonk, NY, USA). Continuous data are presented as the mean and standard deviation (SD), and categorical data are presented as the number (*n*) and percentage (%). Differences between two groups were analyzed by an unpaired *t*-test. Chi-squared or Fisher's exact test was employed to compare proportions. An age, gender, years of practice, and type of hospital-adjusted multivariate linear regression model was employed to examine relationships between dependent variables (dieticians' nutrition practice behaviors) and potential variables related to guideline adherence (total adherence score and its individual components: knowledge, attitude, and environmental factors). *p* < 0.05 was considered statistically significant.

#### **3. Results**

#### *3.1. Participant Characteristics*

Table 1 shows baseline characteristics of study participants. In total, 62 Indonesian dieticians participated in the survey; 89% were female and 56% had ≤5 years of clinical experience. Most participants worked in hospitals located in Jakarta (40%), East Java (21%), and Central Java (16%). All participants (100%) had experience in performing nutritional therapy for hospitalized COVID-19 patients, with 48% conducting nutritional therapy for severely and critically ill patients, 40% for patients with mild and moderate illness, and 12% for asymptomatic patients. However, 69% of dieticians felt stress when performing nutritional therapy for hospitalized COVID-19 patients. Ninety percent of participants took supplements or herbal remedies to boost their own immunity against COVID-19, with 63% taking vitamin C, 45% taking vitamin B complex, 30% taking multivitamins and minerals, and 25% consuming ginger (Table 1).

#### *3.2. Concerns Related to Nutritional Practices of COVID-19*

Table 2 shows concerns related to clinical practices of nutrition care of COVID-19 patients. The most commonly used nutritional screening tools were malnutrition universal screening tools (MUST) (34%) and malnutrition screening tools (MST) (34%), and nutrition assessments were mainly performed by nurses (58%) and dieticians (40%) (Table 2). Seventy-six percent of participants had monitored a patient's dietary intake; however, only half had monitored a patient's weight change (47%) or had provided nutrition education or counseling (52%). Ninety-seven percent of participants had recommended supplements for hospitalized COVID-19 patients, of which vitamin C (61%), vitamin B complex (60%), multivitamins/minerals (48%), zinc (40%), and omega 3 fatty acids (27%) were the most frequently recommended supplements. Sixty-eight percent of participants had experience in designing individual diets for hospitalized COVID-19 patients, with 68% modifying the protein content and 63% modifying the total energy. Concerns related to nutritional practices of hospitalized COVID-19 patients included a lack of clear guidelines (74%), a lack of access to meet COVID-19 patients (55%), inadequate experience or knowledge (48%), a lack of self-efficacy or confidence in performing nutrition care (29%), a lack of resources (29%), a limited food supply (29%), and a limited budget (26%) (Table 2).

#### *3.3. Barriers to Dieticians' Adherence to Nutrition Guidelines for COVID-19*

Next, we evaluated barriers to dieticians' adherence to clinical guidelines (Table 3). More than half of the dieticians were aware of "COVID-19 treatment guidelines" (total: 65%; among those with >5 years of experience: 74%; and among those with ≤5 years of experience: 57%) and "ESPEN guideline on clinical nutrition in the intensive care unit" (total: 58%; among those with >5 years of experience: 48%; and among those with ≤5 years of experience: 66%), but to a lesser extent, "nutrition therapy in the patient with COVID-19 disease requiring ICU care" (total: 35%; among those with >5 years of experience: 37%; and among those with ≤5 years of experience: 34%), and "ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection" (total: 24%; among those with >5 years of experience: 26%; and among those with ≤5 years

of experience: 23%). Most participants were familiar with knowledge of nutrition practice (95–100%) (Table 3). However, 74% of participants thought that there was a lack of clear guidelines for COVID-19, and this rate was slightly higher among junior dieticians (those with ≤5 years of experience: 83%) than senior (those with >5 years of experience: 63%) (*p* = 0.076) (Table 3: Knowledge: Familiarity with clinical practice). Junior dieticians also had lower agreement rates on questions of "I am knowledgeable about the role of nutrition therapy for hospitalized COVID-19 patients" (junior: 43% vs. senior: 81%, *p* = 0.004) and "self-efficacy or confidence in performing nutrition care for hospitalized COVID-19 patients" (junior: 57% vs. senior: 89%, *p* = 0.006), but had a higher rate of "feeling stress when performing nutrition care for hospitalized COVID-19 patients" (junior: 83% vs. senior: 52%, *p* = 0.009). Although 95% of participants agreed that "nutrition counseling is important for hospitalized COVID-19 patients" (Table 3: Knowledge: Familiarity of the guidelines), only half of dieticians (total: 52%) had conducted nutrition education/counseling for hospitalized COVID-19 patients, and this rate was much higher among junior dieticians (junior: 71% vs. senior: 26%; *p* < 0.0001). Only 47% (junior: 54% vs. senior: 37%, *p* = 0.177) had monitored BW changes and 76% (junior: 74% vs. senior: 78%) had monitored dietary intake of hospitalized COVID-19 patients (Table 3: Behavior)

**Table 1.** Characteristics of the study participants (*N* = 62).


Continuous variables are presented as the mean ± standard deviation (SD), and categorical data as the number (*n*) (percentage). Mortality rate (case fatality rate) was defined as the number of deaths divided by the number of confirmed cases.


**Table 2.** Nutrition practice and concerns related to hospitalized COVID-19 patients (*N* = 62).

Lack of clear guidelines 46 (74%) Lack of self-efficacy or confidence in performing nutritional care 18 (29%) Inadequate experience or knowledge 30 (48%) Limited budget 16 (26%) Lack of time 7 (11%) Lack of resources 18 (29%) Limited food supply 18 (29%) Lack of access to meet COVID-19 patients 34 (55%) Lack of access to medical records 9 (15%)

Continuous variables are presented as the mean ± standard deviation (SD). Categorical variables are presented as number (*n*) (percentage).

**Table 3.** Barriers to dietician adherence to nutritional guidelines in relation to nutritional practice behaviors of hospitalized COVID-19 patients.


All variables are expressed as the number (*n*), percentage (%). \* The *p* value was analyzed using unpaired Student's *t*-test for continuous variables or Chi-squared test for categorical variables.

#### *3.4. Factors Predicting Nutrition Care Behaviors of COVID-19 Patients* 3.4.1. Self-Efficacy or Confidence in Providing Nutrition Care

Next, we performed a multivariate linear regression analysis to identify factors associated with behaviors of nutrition care for hospitalized COVID-19 patients (Table 4). Age, gender and years of practice-adjusted regression showed that nutrition guideline adherence score (ß: −0.25 (−0.07, −0.01); *p* = 0.03) was negatively correlated with lack of self-efficacy, and, to a lesser extent, disease severity (ß: 0.22 (−0.01, 0.33); *p* = 0.057) (Table 4).

**Table 4.** Adjusted multivariate regression coefficient (ß) and 95% confidence intervals (CIs) of barriers of nutrition practice behaviors of COVID-19 patients.


Total adherence score (maximum 28 points) was defined as knowledge (12 questions), attitudes (six questions), environmental factors (seven questions), and behaviors (three questions). \* Results were adjusted for age, gender, years of practice, and type of hospital.

> 3.4.2. Nutrition Care Behaviors: Nutrition Counseling, and Monitoring of BW and Dietary Intake

A regression analysis adjusted for age, gender and years of practice showed that guideline adherence scores also independently predicted dieticians' nutrition care behaviors of nutrition counselling (ß: 0.24 (0.002, 0.08); *p* = 0.04), and monitoring of BW (ß: 0.43 (0.04, 0.11); *p* = 0.001) and dietary intake (ß: 0.47(0.03, 0.10); *p* = 0.001) of hospitalized COVID-19 patients (Table 4). Detail analysis of barriers to dieticians' adherence to nutrition guidelines found that awareness of guidelines was positively correlated with nutrition counselling (ß: 0.70 (0.18, 0.31); *p* < 0.0001), and monitoring patient's dietary intake (ß: 0.35 (0.03, 0.19); *p* = 0.01). Those dieticians who had better attitude (total score) (ß: 0.03 (0.02, 0.15); *p* = 0.012), self-efficacy or confidence (ß: 0.31 (0.03, 0.26); *p* = 0.013) or motivation (ß: 0.23 (0.02, 0.39); *p* = 0.04) in performing nutrition care were more likely to monitor a patient's BW (Table 4: adjusted for age, gender, years of practice, and type of hospital).

Next, we investigated the relationship between dieticians' adherence to nutrition guidelines, length of stay and COVID-19 mortality. Adjusted linear regression analysis showed that guideline awareness was negatively correlated with the length of stay for moderate symptoms (ß: −0.51 (−1.22, −0.14); *p* = 0.017), severe symptoms (ß: −0.31 (−1.48, −0.26); *p* = 0.04) and critical illness (ß: −0.46 (−1.45, −0.16); *p* = 0.029), but not mild symptoms. Guideline familiarity also independently predicted COVID-19 mortality (ß: −40.95 (−63.95, −17.95); *p* = 0.001) (Supplementary Table S2).

#### **4. Discussion**

Our study results indicated that adherence to COVID-19 nutrition guidelines is associated with better nutritional management and, possibly, related to clinical outcome. Studies showed that adherence to nutrition guidelines in critically ill patients is associated with better survival outcomes [12,13]. Currently, Indonesia is not only facing capacity constraints in the health care sector (e.g., man power, funding and facility) but also the unprecedented economic burden of the direct medical cost of COVID-19. It is estimated that median lengths of stay of hospitalized COVID-19 patients were 4~53 days in China

and 4~21 days outside of China [14]. In the United States, a single symptomatic COVID-19 infection would cost a direct medical cost of USD 3,045 and one hospitalized case would cost a median of USD 14,366, which only covers costs during the course of the infection and not the follow-up care [15]. The importance of appropriate nutritional assessments and treatments cannot be overstated. The health of COVID-19 patients may rapidly deteriorate after being hospitalized, and patients may develop progressive hypermetabolism 1 week after being intubated in the ICU, which may require 1.6~1.8-times higher energy inputs by the third week post-intubation [16]. Screening and monitoring of a patient's BW and dietary intake can help doctors and dieticians identify patients at risk of poor outcomes, and also allow planning of individualized nutrition care to support a patient's immune system in fighting the coronavirus [17]. This is of particular importance for COVID-19, since supportive care is the major treatment method for hospitalized COVID-19 patients, and most severe and critically ill COVID-19 patients are at risk of malnutrition [18,19].

Awareness of guidelines also predicts a dietician's adherence to nutrition guidelines for COVID-19. In the context of a constantly evolving and highly contagious coronavirus, implementation of nutrition guidelines might not be straightforward. Dieticians need to quickly adapt to a wide range of work environments and upgrade their nutrition care programs through training, self-study, or discussing practical problems in real-time through online social networks with fellow dieticians to provide optimal service to COVID-19 patients. Our study found that major concerns related to the nutrition care of COVID-19 patients were a lack of clear guidelines (74%), a lack of self-efficacy (29%), and inadequate experience or knowledge (48%). Dissemination of COVID-19 guidelines with their management algorithm may improve dieticians' knowledge and promote adherence to guidelines. However, passive dissemination of guidelines might not be effective in the context of the ever-changing COVID-19 pandemic, as the guidelines need to be adapted to local healthcare environments. It is likely that active dissemination or targeted approaches together with supportive networks would improve awareness of, and adherence to, guidelines. For example, Canadian dieticians launched a "COVID-19 response group" on Facebook for dieticians and nutrition students to discuss nutrition care issues, share experiences, and seek advice. Online supportive networks may be particularly important for junior dieticians as our study showed that they had lower self-efficacy/confidence and knowledge than senior dieticians.

Currently, Indonesian hospitals are overwhelmed by COVID-19 and our study found that most Indonesia dieticians, in particularly junior dieticians, are suffering from psychological stress when performing nutritional care for hospitalized COVID-19 patients. Increased psychological stress among junior dieticians is likely due to the combination factors of a higher rate of performing nutritional counseling and a lack of self-efficacy/confidence in performing nutritional care for hospitalized COVID-19 patients. The current study found that psychological stress not only predicted dieticians' self-efficacy/confidence but also their behaviors of nutrition care of COVID-19. Lu and Dollahite showed that years of nutrition counselling experience significantly predicted self-efficacy scores [20]. Currently, we do not know why Indonesian junior dieticians had a higher rate of performing nutritional counseling for hospitalized COVID-19 patients than senior dieticians, despite the lack of clinical experience. Another interesting finding is that most of dieticians (90%) took supplements as well as recommending supplements (Vitamins C and B complex, multivitamins and zinc) to COVID-19 patients, despite the fact that the COVID-19 Treatment Guidelines stated that there are insufficient data for the panel to recommend the use of vitamins or minerals for the treatment of COVID-19 [2]. Using Google Trends to analyze worldwide concerns with immune-boosting nutrients/herbs during the COVID-19 pandemic, our previous study found that vitamin C, D, E and zinc were the most searched nutrients during the first wave of COVID-19 pandemic [21]. Vitamins and minerals have anti-inflammatory and antioxidant properties, which may support a healthy immune system against coronavirus infection. However, the effects of vitamin and mineral supplementation on COVID-19 remain inconclusive [22,23]. It is very important to prevent

or treat nutritional deficiencies. However, supplementation with a supraphysiologic or supratherapeutic amount of micronutrients has not been recommended in the prevention or improvement of clinical outcomes of COVID-19 infection. Therefore, the provision of daily allowances for vitamins and trace elements has been suggested [3,24].

Our study found that environmental factors such as a lack of access to meet COVID-19 patients in person was not a barrier to nutrition care practice. To overcome physical barriers, Indonesian dieticians have employed telemedicine to perform nutrition counseling and monitor patients' food intake and weight changes. However, feeling stress when independently performing nutrition care predicts the behavior of monitoring a patient's BW. This suggests that, even when upgrading one's skills through telehealth channels, dieticians still suffer from psychological stress when dealing with COVID-19. Health organizations need to identify sources of stress and adapt their clinical practice to support nutrition care. Another barrier that predicts the behavior of monitoring a patient's food intake is the lack of access to medical records. Nutrition care might not be considered a priority in the COVID-19 pandemic, as acknowledged by Thibault and colleagues [7]. Based on their experiences with the COVID-19 pandemic in France, those authors emphasized the need to adapt protocols of nutrition care that are simple and easily applied [7]. Overall, our study results suggest that dieticians need to upgrade their skills in telemedicine and adapt to the local healthcare environment in order to strategize plans for performing individualized nutrition care during the ever-changing COVID-19 pandemic.

The strength of this study includes its novelty, as it is the first to investigate barriers affecting COVID-19 nutrition care, as well as being a multicenter survey with all participants having experience in nutrition care of hospitalized COVID-19 patients. The present study also has several limitations. Firstly, there was a relatively small sample size (*n* = 62) with only one country surveyed (Indonesia) and a low response rate (29.5%). We recognized that a regional study with small sample size may not provide a complete picture of dietetic practice in Indonesia and other countries during the COVID-19 outbreak. The low response rate in our study is due, in part, to the exclusion of dieticians who never performed nutritional care for hospitalized COVID-19 patients in Indonesia. The COVID-19 outbreak itself may also contribute to the low response rate. A recent study in UK also found a limited number of dietitians was able to participate in the online survey due to COVID-19 outbreak, though no response rate was reported [25]. Secondly, information was collected online and not through face-to face interviews. Limitations of online surveys have been noted and intensively discussed [26]. The major strengths of the online survey were its cost effectiveness and the ability to be conducted in a short period of time with no regional restrictions; however, there were concerns about internet accessibility, a lack of control of the sampling or response rate, and ethical issues (e.g., consent, anonymity, and confidentiality) [26]. Nonetheless, it was performed in the context of social distancing during the COVID-19 pandemic, and consent was obtained through participation in the online survey, and all responses were anonymous; the research ethics committee in Indonesia approved the current study. Other limitations include the fact that more confounding factors are needed for the linear regression model when analyzing the relationship between the predictive effect of dieticians' adherence to nutrition guidelines and the clinical outcomes (survival and length of stay).

#### **5. Conclusions**

Our study results indicate that adherence to COVID-19 nutrition guidelines is associated with better nutritional management and, possibly, better clinical outcomes. A further validation study is needed in order to provide some definitive guidance on how to implement nutrition guidelines, as well as how the adherence to COVID-19 nutrition guidelines may affect medical cost and economy during the ever-changing COVID-19 pandemic.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/nu13061918/s1, Supplementary Table S1: Barriers to dietician adherence to clinical practice of nutrition guidelines for hospitalized COVID-19 patients. Supplementary Table S2: Adjusted multivariate regression coefficient (β) and 95% Confidence Intervals (95% CI) for length of stay and mortality of hospitalized COVID-19 patients in Indonesia.

**Author Contributions:** A.F., D.K.N.H., S.-H.T., H.H. and J.-S.C. designed the study and conducted the initial searches. A.F., E.N., S.D.P. and I.Y.R. contributed to recruitment of dieticians. Data were analyzed by A.F. and J.-S.C. drafted the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** Jung-Su Chang was supported by grants from Taipei Medical University Hospital (110TMU-TMUH-09) and the Ministry of Science and Technology, Taiwan (MOST 107-2320-B-038-010-MY3 and MOST 109-2923-B-038-001-MY3).

**Institutional Review Board Statement:** The study was approved by the Research Ethic Committee of Alma Alta University, Indonesia (KE/AA/XI/10323/EC/2020).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data are not publicly available due to participant confidentiality.

**Acknowledgments:** We thank all Indonesian dieticians who participated in the survey.

**Conflicts of Interest:** The authors declare that no competing interest exists.

#### **References**


## *Review* **The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19**

**Sotirios Kakavas 1, Dimitrios Karayiannis 2,\* and Zafeiria Mastora <sup>3</sup>**


**Abstract:** There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection. Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Consequently, mast cell histamine and its receptors represent promising pharmacological targets. At the same time, nutritional modulation of immune system function has been proposed and is being investigated for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy. Several studies indicate that several immunonutrients can regulate mast cell activity to reduce the de novo synthesis and/or release of histamine and other mediators that are considered to mediate, at least in part, the complex pathophysiology present in COVID-19. This review summarizes the effects on mast cell histamine of common immunonutrients that have been investigated for use in COVID-19.

**Keywords:** immunonutrition; COVID-19; histamine

**Citation:** Kakavas, S.; Karayiannis, D.; Mastora, Z. The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19. *Nutrients* **2021**, *13*, 3458. https://doi.org/10.3390/nu13103458

Academic Editor: Arved Weimann

Received: 3 September 2021 Accepted: 27 September 2021 Published: 29 September 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped singlestranded positive-sense ribonucleic acid (RNA) virus that was first detected in China and has caused an ongoing global pandemic [1]. SARS-CoV-2 comprises four identified structural proteins, namely, spike (S), membrane (M), envelope (E), and nucleocapsid (N) [2]. In general, the virus infects by binding its S protein to the host's angiotensin-converting enzyme 2 (ACE2) receptors, then entering by endocytosis into airway epithelium cells, lung macrophages, alveolar epithelial cells, and vascular endothelial cells [3,4]. Patients may remain asymptomatic or develop symptoms of varying severity [5,6]. In the resulting coronavirus disease 2019 (COVID-19), activation of the innate immunity, specific antibodies, and activated T cells represent basic defensive factors, while in more severe cases, lung injury progresses and leads to respiratory failure [5,7]. Severe lung injury in SARS-CoV-2 patients is considered the result of immune hyperreaction that involves both innate and adaptive immune responses [6,8]. Briefly, coronavirus infection activates antigen-presenting cells, such as macrophages, that display viral antigens to T and B cells resulting in antibody production and increased cytokine secretion in the form of a cytokine storm. Other immune cells are also implicated, including mast cells, which are important coordinators for both innate and adaptive immunity [9]. Endothelial injury and microthromboses ensue in the lungs and other organs of COVID-19 patients [10,11]. Patients may require mechanical ventilation and develop multiple organ failure [5,6].

Histamine is an endogenous biogenic amine that functions as a neurotransmitter and an immunoregulatory factor. In the immune system, histamine is mainly stored in cytoplasmic granules of mast cells and basophils and is released upon triggering along with other mediators such as serotonin, proteases (e.g., tryptase and chymase), heparin, a variety of cytokines, and angiogenic factors [12]. Histamine release can be activated by numerous innate signals or exogenous triggers [13] including allergens, toxins, and viruses [14]. The high-affinity immunoglobulin (Ig)E receptor, FcepsilonRI (FcεRI), is the primary receptor in mast cells that mediates IgE-dependent (allergic) reactions [12]. Yet, it is apparent that non-IgE-mediated mechanisms of mast cell activation also exist [13]. Histamine exerts its biological actions through four types of G protein-coupled histamine receptors (i.e., H1 receptor, H2 receptor, H3 receptor, and H4 receptor) [15]. It also activates acute immune-mediated reactions and enhances vascular smooth muscle contraction and the migration of other immune cells, antibodies, and mediators to the site of insult [7]. The release of histamine by perivascular mast cells may also affect adjacent lymphatic vessel function inducing immune cell trafficking through its lumen, which potentially contribute to acute inflammatory stimulus [16]. In the lungs, this may cause bronchoconstriction, increased mucus production, increased vasopermeability with edema, microthrombosis, and infiltration by leukocytes, predominantly neutrophils [17]. Histamine can regulate the balance between Th1 and Th2 effector cells [18]. During histamine-mediated lung inflammation, secretion of Th2 cytokines is enhanced, while production of Th1 cytokines is suppressed [19]. This response may increase susceptibility to viral and bacterial infections of the respiratory tract [5]. In addition, viral remnants may prolong and exaggerate the inflammatory process, causing a histamine-induced release of more pro-inflammatory Th2 cytokines through an IgE-mediated positive feedback vicious cycle [5].

A growing body of evidence has implicated histamine and mast cells in COVID-19 [20–22]. In animal models of COVID-19, mast cells detected in the lungs were chymase positive [23]. Mast cells are shown to express histamine receptors by themselves which, in an autocrine fashion, can potentially ensue a feedback regulation further enhancing inflammatory response [16,24]. The SARS-CoV-2 infection has been shown to activate mast cells leading to histamine release that increases IL-1 levels, causing hyper-inflammation and cytokine storm [25]. Mast cell degranulation has been reported in alveolar septa of deceased patients with COVID-19 and in SARS-CoV-2-infected mice and non-human primates [23,26]. Furthermore, this mast cell activation was associated with interstitial edema and immunothrombosis [27], while the levels of the mast cell-specific protease, chymase, correlated significantly with disease severity [23]. Moreover, studies have reported that H1 as well as H2 receptor antagonists, such as famotidine, are associated with a reduced risk of infection and deterioration leading to intubation or death from COVID-19 [28,29]. These agents are considered to improve pulmonary symptoms of SARS-CoV-2 infection by blocking the histamine-mediated cytokine storm [30]. Nevertheless, these observational findings need further validation by the ongoing randomized clinical trials.

Given that limited therapeutic modalities are available for the treatment of COVID-19, nutritional modulation of the immune system function has been proposed and is being investigated [31–34]. It is widely accepted that normal nutritional status is vital for immune homeostasis [35], while a number of recently published key studies suggest promising effects of immunonutrition on acute respiratory infections [36,37]. Briefly, immunonutrition can be defined as modulation of either the activity of the immune system or modulation of the consequences of activation of the immune system by nutrients or specific food items fed in amounts above those normally encountered in the diet [38]. Until now, specific immunonutrients have been proposed as effective for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy [39]. At the same time, these nutraceuticals have been reported to modulate mast cell activation and histamine release with similar potency to pharmacological interventions [40,41]. This review summarizes the effects on mast cell and histamine signaling of common immunonutrients that have been investigated for use in COVID-19.

#### **2. Vitamins**

#### *2.1. Vitamin D*

Vitamin D has been linked to the susceptibility to SARS-CoV-2 infection and the prognosis of COVID-19 based on a series of data [32]. There is evidence that vitamin D inhibits the entry and replication of SARS-CoV-2 and suppresses the levels of proinflammatory cytokines while enhancing the production of anti-inflammatory cytokines and antimicrobial peptides [42]. According to epidemiological observations, vitamin D deficiency has been associated with a higher risk, severity, and mortality rate of COVID-19 [43,44]. However, conflicting results have been reported concerning the effects of vitamin D supplementation in outpatients and hospitalized patients after COVID-19 diagnosis in terms of disease severity, hospital length of stay, ICU admission, or mortality rate [45–48]. Although, no official guidelines exist, it has been proposed to aim for adequate serum 25(OH)D levels of at least 30 ng/mL (75 nmol/L) during the pandemic [49]. Further results are pending ongoing clinical trials [50].

Vitamin D seems to preserve the stability of mast cells, possibly by maintaining the expression of vitamin D receptors. In a vitamin D-deficient environment, mast cell activation occurs automatically, even in the absence of specific triggering [51]. In addition, it has been shown that vitamin D inhibits histamine release from mast cell activation including IgE-mediated activation [52]. Likewise, decreased levels of serum histamine have been found after the antigenic challenging of sensitized mice previously receiving a vitamin D supplemented diet [51]. According to this study, vitamin D receptor binding inhibits mast cell activation by blocking the non-receptor tyrosine kinase Lyn. Lyn is recruited immediately during mast cell activation following the crosslinking of FcεRI–IgE complexes by multivalent antigens or exposure to the bacterial lipopolysaccharide [53,54]. Furthermore, the phosphorylation of the Syk tyrosine kinase was also suppressed by vitamin D receptor binding to the β chain of FcεRI. Syk activation can be triggered by Lyn and is involved in mast cell degranulation [55]. Recent data also indicate a positive effect of vitamin D supplementation on functional humoral immunity levels as determined by IgG levels [56].

#### *2.2. Vitamin E*

Vitamin E is a lipid-soluble vitamin with antioxidant and immunomodulatory properties. In addition to scavenging free radicals, vitamin E can affect immune function by modulating signal transduction and gene expression [57–59]. In this way, vitamin E has been found to reduce susceptibility to respiratory infections as well as allergy-related diseases such as asthma [59]. Vitamin E has been implicated in the treatment of SARS-CoV-2 infection in an effort to minimize oxidative damage in these patients [33]. However, limited evidence exists on the use of vitamin E as an adjuvant agent for the treatment of COVID-19 patients, and information resulting from clinical trials is wanted [60].

Vitamin E has been shown to have an inhibitory effect on the proliferation, secretion, and survival of mast cells [61]. This effect originates from the modulation of protein kinase C, protein phosphatase 2A, and protein kinase B in mast cells. Furthermore, in vitro studies in various mast cell lines have shown that vitamin E affects mast cell activation, resulting in a decreased release of proinflammatory mediators including histamine [62,63]. The effects of vitamin E on mast cell function could be related with the antioxidative properties of the vitamin [61]. Interestingly, oxidative stress and mast cells interact and participate in acute lung injury. Reactive oxygen species generation promotes pulmonary mast cell degranulation which, in turn, can increase oxidative stress and inflammation during acute lung injury [64].

#### *2.3. Vitamin C*

Vitamin C or ascorbic acid is a water-soluble antioxidant vitamin that possesses antiinflammatory and immunomodulatory properties [5]. Although the value of vitamin C has not yet been demonstrated in COVID-19, it has gained interest in this context because of its

antiviral action [65] and beneficial effects in oxidative damage and inflammation [66]. Vitamin C has previously been implicated in sepsis and ARDS, both of which represent major complications of COVID-19 [67]. Although low levels of vitamin C have been reported in sepsis, conflicting results have been produced by studies evaluating vitamin C supplementation in septic shock and ARDS [68,69]. At present, we are awaiting the results of several ongoing trials evaluating the value of oral or intravenous vitamin C supplementation in the treatment of COVID-19. A daily oral dosage of 1–2 g/day of vitamin C has been proposed as beneficial for the prevention or treatment of COVID-19, while higher doses of intravenous vitamin C, up to 24 gm/day, are being evaluated in critically ill patients with COVID-19. Proposed mechanisms for the ability of vitamin C to benefit patients with COVID-19 point to the prevention of IL-6 increase in several (pro)inflammatory conditions and the inhibition of increases for a range of inflammatory cytokines [70,71].

Previous studies have shown that vitamin C administration attenuates a robust immune response [72]. In fact, mast cell-mediated bronchial hypersensitivity caused by the common cold was inhibited by the administration of vitamin C [73]. These patients exhibited decreased bronchial hypersensitivity to histamine and bronchoconstriction after vitamin C administration [40]. Both preclinical [74–76] and clinical studies [76–78] have evaluated histamine blood levels after vitamin C administration. In a recent study, 7.5 g of vitamin C administered intravenously in 89 patients with allergies or upper respiratory infections caused a significant reduction in serum histamine [79]. Several mechanisms may be responsible for the inhibitory effect of vitamin C on histamine [79,80]; vitamin C may inhibit mast cell activation, increase histamine degradation by diamine oxidase or, alternatively, decrease histamine production by inhibiting histidine decarboxylase [81].

#### **3. Minerals**

#### *3.1. Zinc*

Zinc is the second most abundant essential trace element that plays important roles in the development, differentiation, and function of immune cells [33]. The perceived antiviral properties of zinc against upper respiratory tract viral infections derive from its participation in metallothioneins [82]. In this context, zinc may interfere with viral infection in many ways [83,84]. First, zinc may prevent viral attachment to nasopharyngeal mucous as well as fusion with the host's membrane and virus entry into cells. In particular, zinc has been shown to decrease the activity of the ACE2 receptor, which is essential for SARS-CoV-2 binding and the provocation of cytokine storm. Moreover, this trace element has been shown to hinder SARS-CoV-1 viral replication by inhibiting SARS-CoV RNA polymerase [85]. Further antiviral effects of zinc include the impairment of viral protein translation and the blockade of viral particle release [86]. Zinc deficiency is common in COVID-19 patients and is associated with more complications and increased mortality [42]. In older adults, supplementation with 45 mg elemental zinc per day has been shown to reduce the risk of infection [31]. In summary, it has been proposed that zinc supplementation may be beneficial in the prevention and treatment of SARS-CoV-2 infection and the associated inflammation [87–89]. At present, a series of clinical trials have been registered to test the efficacy of various regimens containing zinc against COVID-19.

Zinc deficiency has been demonstrated to affect the function of various types of immune cells including mast cells [90,91]. Zinc seems to be essential for mast cell activation. In an in vitro study, the release of histamine from human basophils and lung mast cells was inhibited from physiological concentrations of zinc [92]. A possible mechanism may include the blockade of Ca2+ influx induced by the IgE-mediated activation of mast cells [6]. On the other hand, a zinc chelator (N,N,N,N-tetrakis (2-pyridylmethyl) ethylenediamine) has been recently shown to contribute to the inhibition of histamine release from mast cells and this effect was reversed by zinc supplementation [93]. Zinc may regulate mast cell activation and function by modulating the PKC/NF-κB signaling pathway [90]. Various mechanisms have been suggested, but modulation of the NF-kB pathway could be the result of the inhibition of cyclic nucleotide phosphodiesterase, cross activation of protein kinase

A, and inhibitory phosphorylation of protein kinase Raf-1 [94]. In addition, activation of NF-kB can also activate mast cells thereby releasing histamine secretion and an ensuing inflammatory response along with cytokine secretion [95].

#### *3.2. Selenium*

Selenium is a trace element that serves as an essential component of antioxidant enzymes. In this way, it exhibits a protective effect against respiratory infections including viral infections [96,97] (33, 97, 98). It has been suggested that selenium deficiency might be implicated in the evolution of SARS-CoV-2 [87]. Moreover, a number of studies have linked selenium with SARS-CoV2 infection and recovery rates [98–100]. Selenium may halt oxidative stress in patients with COVID-19 [33,39]. Interestingly, oxidative stress and mast cells show a bidirectional interaction. Intracellular reactive oxygen species production is the result of mast cells by various triggers [101], while mast cell degranulation can be controlled via the decrease in reactive oxygen species generation using antioxidants [62]. In accordance with this, an in vitro study showed that selenium can suppress the IgEmediated release of inflammatory mediators in a murine mast cell line, although histamine release only slightly decreased [102]. The regulation of redox-sensitive transcription factors is considered the responsible mechanism by which selenium affects mast cell histamine release [103]. Published data also highlight the important role of biological functions that occur via incorporation of selenium into selenoproteins in the form of selenocysteine amino acid residue. Selenocysteine (Sec-Cys) is involved in a variety of prostanoid metabolism processes and, therefore, have an impact on immunity [104].

#### **4. Omega-3 Fatty Acids**

Omega-3 fatty acids are polyunsaturated fatty acids (PUFAs) obtained mainly from two dietary sources: marine and plant oils. These fatty acids incorporate into the biphospholipid layer of the cell membrane and result in the reduced production of proinflammatory mediators [105]. To date, sparse evidence has implicated omega-3 fatty acids in the prevention and treatment of COVID-19 [106,107]. Nevertheless, it has been shown that the omega-3 PUFAs inactivate enveloped viruses like SARS-CoV2 and inhibit ACE2-mediated binding and cellular entry of SARS-CoV-2 [108]. Furthermore, beneficial reports of omega-3 PUFAs have been reported in patients with sepsis and sepsis-induced ARDS [109,110]. Several clinical trials assessing the effect of omega-3 PUFAs in COVID-19 management are currently registered (ZPD37). In a recent double-blind, randomized clinical trial, enteral supplementation with omega-3 PUFAs significantly improved respiratory and renal function indices as well as one-month survival rates in critically ill patients with COVID-19 [111].

Similar to other immune cells, fatty acids are incorporated into mast cell membranes and can differentially influence mast cell secretive properties [62,112,113]. Collectively, the actions of omega-3 PUFAs on mast cells are mainly inhibitory. A series of studies in animal models and in human cells has demonstrated the inhibitory effect of omega-3 PUFAs on IgE-mediated activation of mast cells [26,114,115]. This effect is mediated by the inhibition of GATA transcription factors in mast cells and leads to suppressed Th2 cytokine expression [116]. As expected, this action of omega-3 PUFAs was tested to ameliorate the severity of mast cell-associated diseases [117,118]. In a canine atopic dermatitis model mast cell histamine release was reduced after treatment by γ-linolenic acid or α-linolenic acid. On the other hand, linoleic acid or arachidonic acid enhanced histamine release [113,119]. However, in a model of stress-induced visceral hypersensitivity in maternally separated rats, neither mast cell degranulation nor hypersensitivity were affected by the administration of an omega-3 PUFA-enriched diet [120]. Clinical trials of the dietary omega-3 supplementation in asthma patients have reported beneficial effects on airway inflammation but inconsistent clinical benefits in terms of lung function indices [121]. Nonetheless, it should be noted that two of these studies reported clinical benefits of dietary

supplementation with omega-3 PUFAs in asthma patients without an accompanying decrease in mast cell activation and histamine release [122,123].

#### **5. Phytochemicals**

#### *5.1. Flavonoids*

Flavonoids are a group of naturally occurring polyphenolic substances with antioxidative and anti-inflammatory actions in various disease states [124]. They may also have antiviral properties and several representatives of this family, such as quercetin, have been proposed as a potential treatment of COVID-19 [125,126]. Luteolin from Veronica linariifolia may also be beneficial, since it has been shown to prevent viral entry into the host cell by inhibiting the binding of the SARS-CoV spike protein [127]. A potential antiviral activity via the inhibition of the SARS-CoV helicase has been reported for luteolin, myricetin (from Myricanagi), and scutellarin (from Scutellaria barbata) [128]. Finally, the antiviral activity of kaempferol has been suggested to derive from the inhibition of the 3a-channel protein of SARS-CoV [129].

Several flavonoids inhibit in vitro the expression and/or release of mediators, such as histamine, by human and rodent mast cells [130–132]. More specifically, quercetin inhibits mast cell activation and release of histamine and may modulate airway inflammation [133,134]. Likewise, luteolin or a structural analog of luteolin inhibit mast cell activation and histamine release from animal and human mast cells [135–137]. The modulatory action of flavonoids on mast cell secretory function affects both IgE-dependent and independent processes and appears to be selective [130]. Some flavonoids, such as caffeic acid, inhibit selective histamine release, while others, such as luteolin and myricetin, inhibit both histamine and β-hexosaminidase release [138]. This inhibitory action may involve the suppression of NF-κB activation [137,139]. The inhibition of calcium influx and protein kinase C translocation and activity mediate the actions of luteolin and quercetin on histamine release from murine bone marrow-derived mast cells, rat peritoneal mast cells, and human cultured cord blood-derived mast cells [131,140,141]. Similarly, quercetin, kaempferol, and myricetin suppressed IgE-mediated activation and histamine release from human umbilical cord blood-derived cultured mast cells. The proposed mechanism includes the decrease of intracellular calcium influx and the inhibition of protein kinase Ctheta isoenzyme signaling [140]. Finally, luteolin inhibits neuropeptide (non-IgE mediated) stimulation of mast cells via the mammalian target of rapamycin (mTOR) signaling [142].

#### *5.2. Curcumin*

Curcumin is a natural yellow constituent of turmeric or curry powder that is derived from the rhizome of Curcuma longa plants [143]. Curcumin has been reported as a pleiotropic molecule with various biological actions including antioxidant and antiinflammatory effects [144]. The oral or intranasal administration of curcumin has been shown to suppress airway inflammation and remodeling and to inhibit airway hyperreactivity to histamine and bronchoconstriction in animal models of asthma [145,146]. Curcumin may also exhibit antiviral activities and has been shown to hamper the replication and proliferation of SARS-CoV-1, the first beta-coronavirus that caused the 2003 SARS outbreak and shares a substantial genetic similarity with SARS-CoV-2 [147]. Moreover, in a rat experimental model, curcumin administration resulted in the attenuation of myocardial fibrosis by modulating angiotensin receptors and ACE2 [4,148]. A similar role could be proposed in the fibrotic process that emerges as a secondary event in severe COVID-19 [148]. Along with its well-known anti-inflammatory effects, curcumin has been reported to inhibit mast cell degranulation and histamine release in vitro and in vivo [149–151]. A possible mechanism may include the in vivo suppression of the Syk-dependent phosphorylations, which are critical for mast cell activation. Although the phosphorylation of Syk itself was not affected, curcumin directly inhibited Syk kinase activity in vitro [149]. Curcumin also inhibited the phosphorylation of additional down-stream signaling molecules including Akt, p38, and JNK [149].

#### **6. Conclusions**

There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection that continues to spread rapidly around the world. Mounting evidence shows that hyper-inflammation is the hallmark of COVID-19 pathophysiology leading to significant morbidity and mortality. The majority of the histamine secreted by mast cells may play an important role in the pathophysiology of COVID-19 and is regarded as a promising pharmacological target. The activation of pulmonary mast cells releases mediators with proinflammatory, fibrotic, and thrombogenic properties. Moreover, observational studies have shown the potential benefits of H2 receptor antagonists in patients with COVID-19. However, given the relative paucity of agents targeting mast cells, it may be rational to consider alternative treatments with pleiotropic properties including the modulation of histamine release. Mast cell-derived histamine can regulate not only adaptive and immune system responses but also vasodilatation by binding to endothelial H1 receptors and enhancing NO production. In an inverse way, histamine-induced NO can negatively modulate mast cell activation, mediator expression, and secretion, thus creating an autocrine loop [152]. In this context, several in vivo and in vitro studies indicate that mast cell activity can be regulated by various nutraceuticals that have gained interest for the treatment of COVID-19. In this way, immunonutrition could lead to a reduction in the de novo synthesis and/or release of histamine and other mast cell mediators that are considered to mediate, at least in part, the immune and microvascular alterations present in COVID-19 (Figure 1). These regimens could be used prophylactically or adjunctively to the conventional treatment of patients infected with SARS-CoV-2. We should point out that for other nutrients, such as glutamine and arginine that have been extensively studied for their immune modifying effect, there are no data available regarding their role on mast cells and histamine during SARS-CoV-2 infection. Nevertheless, the clinical evidence is still limited, and further investigations are necessary to validate the efficacy of nutraceuticals in managing the immune response in COVID-19, and, in particular, modulating mast cell activity.

**Figure 1.** Schematic representation of the modulatory activity of immunonutrients with potential use in COVID-19 on mast cells and histamine during SARS-CoV-2 infection. APC: antigen-producing cells (macrophages or dendritic cells).

**Author Contributions:** D.K. and S.K. contributed equally to this work. S.K. drafted the manuscript and D.K. and Z.M. revised it. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**


#### **References**


## *Review* **Ketogenic Diet as a Preventive and Supportive Care for COVID-19 Patients**

**Elena Gangitano 1,\*,†, Rossella Tozzi 2,†, Orietta Gandini 2, Mikiko Watanabe 1, Sabrina Basciani 1, Stefania Mariani 1, Andrea Lenzi 1, Lucio Gnessi <sup>1</sup> and Carla Lubrano 1,\***


**Abstract:** Severe obesity is associated with an increased risk of admission to intensive care units and need for invasive mechanical ventilation in patients with COVID-19. The association of obesity and COVID-19 prognosis may be related to many different factors, such as chronic systemic inflammation, the predisposition to severe respiratory conditions and viral infections. The ketogenic diet is an approach that can be extremely effective in reducing body weight and visceral fat in the short term, preserving the lean mass and reducing systemic inflammation. Therefore, it is a precious preventive measure for severely obese people and may be considered as an adjuvant therapy for patients with respiratory compromise.

**Keywords:** SARS-CoV-2; COVID-19; obesity; ketogenic diet; VLCKD; inflammation; viral infections; respiratory failure

#### **1. Introduction**

Coronavirus 2019 disease (COVID-19), caused by SARS-CoV-2 virus, has spread worldwide causing a pandemic since March 2020, now leading to new waves of infection. Overall fatality rate reached 2.3% [1] and, to date, 2,343,069 cases of COVID-19 and 80,253 (3.4%) deaths have been registered in Italy [2].

In most cases the clinical presentation is characterized by fever, dry cough, fatigue and mild pneumonia, although critical forms with desaturation and respiratory failure, septic shock, and/or multiple organ dysfunction can also occur; it has been estimated that moderate and severe forms can affect 14% and 5% of patients, respectively [1]. COVID-19 management consists of supportive therapy and preventing respiratory insufficiency through oxygen therapy or positive ventilation. The most widely adopted therapeutic protocol is based on the use of antibiotic prophylaxis, steroids and anticoagulant therapy, although there is no conclusive evidence supporting their role [3]. In order to limit the typical coagulative hyperactivation and the well-known condition of thrombosis susceptibility [4,5], heparin is now used in early stage COVID-19 patients; however, intensive care units are gradually filling up again, fearing the national health system collapse.

COVID-19 mortality is highly correlated to the severity of the inflammation-related cytokine storm and to the presence of multiple comorbidities (obesity, type 2 diabetes, hypertension, chronic obstructive pulmonary disease) increasing the risk of developing critical forms of infection [6]. In light of these considerations, it is therefore mandatory to pursue new strategies to reduce risk factors and to limit the development of the cytokine storm syndrome (CSS) in order to prevent patients' worsening and access to emergency rooms.

The nutritional approach to COVID-19 patients is extremely important to ensure the correct amount of nutrients, necessary to face the infection and the body's capacity to

**Citation:** Gangitano, E.; Tozzi, R.; Gandini, O.; Watanabe, M.; Basciani, S.; Mariani, S.; Lenzi, A.; Gnessi, L.; Lubrano, C. Ketogenic Diet as a Preventive and Supportive Care for COVID-19 Patients. *Nutrients* **2021**, *13*, 1004. https://doi.org/10.3390/ nu13031004

Academic Editors: Dimitrios T. Karayiannis and Zafeiria Mastora

Received: 24 February 2021 Accepted: 16 March 2021 Published: 20 March 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

face and fight the virus. Current European Society for Clinical Nutrition and Metabolism (ESPEN) expert statements for COVID-19 patients recommend considering energy needs of 27–30 kcal per kg body weight and day, and 1–1.3 g per Kg of proteins, depending on disease status. Fat and carbohydrate ratio are currently suggested to be 30:70 for patients without respiratory deficiency and 50:50 for ventilated patients [7].

The ketogenic diet (KD), reducing carbohydrates oral intake, allows the hepatic production of ketone bodies and the onset of nutritional ketosis as a result of an increased utilization of fat as metabolic fuel when the availability of glucose is low. Ketone bodies are attracting more and more attention for their anti-inflammatory role and immune metabolism modulation [8]. Besides the well-known metabolic advantages (better hyperglycemia control, reduction of insulin resistance, improvement of hepatic steatosis), several "non-classical" beneficial effects have been attributed to KDs, including growth factors, leptin or IGF-1 modulation [9], together with the protection of renal, brain function and anti-viral effects [10].

KDs provide for a deprivation of carbohydrate content equal to 5–10% of total kcal daily intake, although the specific macronutrient composition may vary. As reported by Watanabe et al. [11], ketogenic diets differ mainly in calorie intake and protein content. High Fat Ketogenic Diets (HFKD) are characterized by a restriction of carbohydrates (CHO) < 50 g per day with unrestricted intake of fat, a relative increase of protein (0.8–1.2 g per day), and ad libitum caloric intake; very low-calorie ketogenic diets (VLCKD) are characterized by approximately the same amount of CHO and protein as in HFKDs, but significantly lower fat and therefore calorie intake, which goes as low as 600 kcal/daily. Very low-calorie diets (VLCD), providing a marked restriction of daily calorie intake, are characterized instead by a variable amount of carbohydrate intake which may or may not be able to induce ketosis [12] (Table 1).

**Table 1.** Main differences between ketogenic and low-carbohydrate diets (with the kind permission of Watanabe et al. [11]).


While HFKDs are still used in refractory epilepsy in children, VLCKD are now recommended in severe or sarcopenic obesity, prior to bariatric surgery, to improve glycemic control, dyslipidemia and for a rapid reduction of cardiovascular risk factors in obese patients, not responsive to standard diets [12].

Current contraindications to the VLCKD include type 1 diabetes mellitus, kidney or liver failure, heart failure, cardiac arrhythmias, recent stroke, myocardial infarction, pregnancy and breastfeeding. Of note, active/severe infections and respiratory failure are currently among the conditions not recommended for implementing a VLCKD regimen for a hypothesized immunosuppression and acidosis risk, respectively [13]. Nevertheless, studies conducted in the past have reported good results, also highlighting some benefits derived from ketosis [13]. As per HFKDs, patients with CVD, heart, liver or kidney disease need close medical supervision in order to safely undergo such regimen, and those with severe dyslipidemia or a history of hypertriglyceridemia associated pancreatitis are recommended against undergoing this dietary regimen [14].

The aim of this work is to highlight the potential role of KDs in the management and prevention of COVID-19, focusing on the beneficial effects that may exert on inflammation, immune system and respiratory function.

#### **2. Low Chronic Inflammation, COVID-19 and Ketogenic Diet**

As described above, severe forms of COVID-19 are characterized by an ineffective adaptive immune response that leads to a persistence in C-reactive protein (CRP) and interleukin (IL) -6 elevation [15]. This pattern falls within the so-called chronic low-grade inflammatory phenotype (CLIP), a phenomenon that underlies many of the diseases associated with more critical forms of COVID-19, such as diabetes, obesity, insulin-resistance, hypertension and atherosclerosis [16]. All these metabolic derangements are closely related to inflammation triggered by the abnormal expansion of visceral adipose tissue, which has been shown to predict poor COVID-19 prognosis as well as respiratory indicators [17]. Specifically, the white adipose tissue M1 macrophages secretion of pro-inflammatory cytokines including tumor necrosis factor (TNF) alpha, IL-6, CRP, IL-1, is increased, whereas a steep decline occurs in the production of anti-inflammatory cytokines like IL-10, the interleukin-1 receptor antagonist (IL-1RA), and adiponectin. Not only the adipose tissue, but also the immune cells, liver, brain, muscles and pancreas suffer from the inflammatory insult in subjects with obesity. Macrophage-like Kupffer cells initiate the inflammatory process in the liver preceding the inflammatory signals produced by the white adipose tissue, which may further lead to hepatic-necro-inflammation [18]. Moreover, role of P-loop domain belonging to the STAND class of NTPases with homology to the oligomerization module found in AAA+ ATPases (NACHT), Leucine-rich repeat (LRR), and NOD-like receptors (NLRs) Pyrin Domain-Containing 3 Protein (NLRP3) for maintenance of chronic inflammation is crucial. In fact, in response to activation of innate immune receptors by stimuli such as microbial ligands, transcription of pro-inflammatory genes, including those encoding NLRP3 and pro-IL1β, is induced [19].

KDs inhibit aerobic glycolysis, which has been proven to occur following inflammatory activation of cells from both myeloid and lymphoid lineage; in particular, KDs prevent the differentiation and effector functions of inflammatory cells, while promoting the differentiation of regulatory subsets. Moreover, the ketone body β- hydroxybutyrate blocks NLRP3 inflammasome activation [20].

#### **3. Immune System, COVID-19 and Ketogenic Diet**

SARS-CoV-2 infects lung cells and enters host epithelial cells through Transmembrane Serine Protease 2 (TMPRSS2) action and spike protein binding Angiotensin Converting Enzyme 2 (ACE-2) receptor. After alveolar epithelial cells pyroptosis-induced death and damage-associated molecular patterns (DAMPs) release, macrophages and monocytes are recruited and cytokines secreted. More specifically, in case of a dysfunctional immune response, we observe an abnormal monocytes, macrophages and T-cells infiltration favored by vascular permeability, a systemic cytokine storm (IL-6, IFN gamma, IL-2, IL-10, Granulocyte colony-stimulating factor G-CSF, TNF), clinical worsening (pulmonary oedema and pneumonia) and widespread inflammation and/or multiorgan damage due to excessive TNF and reactive oxygen species (ROS) production. On the contrary, in a healthy immune system, initial inflammation attracts virus specific T-cells to the site of infection, where they can eliminate the infected cells before the virus spreads. Neutralizing antibodies in these individuals can block viral infection resulting in early recovery [15]. Noteworthy, viral infection can also result in an aberrant cytokine production by the immune cells such as monocytes and macrophages. Elderly people seem to be more susceptible to critical forms of COVID-19 due to an ageing lung microenvironment causing altered dendritic cell maturation and migration to the lymphoid organs and to an inefficient IFN response [21].

Karagiannis et al. [22] demonstrated that restricting dietary glucose by feeding mice a HFKD (72% fat, 2.4% sugar) largely ablates lung-resident type 2 Innate Lymphoid Cells (ILC-2) and reduces airway inflammation by impairing fatty acid metabolism and the formation of lipid droplets. Chronic activation of ILCs, typical of allergenic airway inflammation, needs exogenous fatty acids which are transiently stored in lipid droplets and therefore converted into phospholipids to promote ILCs proliferation. This metabolic program, imprinted by IL-33 and regulated by the genes Peroxisome proliferator-activated receptor gamma (PPAR-γ) and Diacylglycerol O-Acyltransferase 1 (Dgat1), is controlled by glucose availability as well as mammalian target of rapamycin (mTOR) signaling. Moreover, Goldberg et al. reported that a HFKD allows for better survival and increased protective IL-17-secreting γδ T cells in the lungs of mice with influenza virus [10], while Ryu et al. have recently provided preclinical evidence that a HFKD is capable of providing a protective effect against the animal equivalent of COVID-19 in aged mice, with the maintenance of a better oxygen saturation and an increase in γδ T cells [23].

#### **4. Obesity, Viral Infections and Respiratory Function**

Weight excess is associated with a higher susceptibility to viral infections [3], as seasonal and H1N1 influenza [24,25], and a higher risk of hospitalization for these conditions [26–29]. In recent years, during the H1N1 influenza pandemic, obesity has been shown to be associated with hospitalization and death [29] and critically ill patients were frequently morbidly obese [25]. Similarly to other viral infections, severe obesity is associated with a high risk of COVID-19 complications [30]. Among obesity comorbidities, hypertension, dyslipidemia, prediabetes and insulin resistance might predispose individuals to cardiovascular events and increased susceptibility to infection via atherosclerosis. Resulting cardiac dysfunction and kidney failure can more easily lead to pneumoniaassociated organ failures [31]. Moreover, visceral adipose tissue—a reliable and specific marker of insulin resistance—has been independently associated with the need of intensive care unit (ICU) resulting as the strongest predictor of worse prognosis in patients with COVID-19 [17]. Considered this, a nutritional approach that can break down insulin resistance such a HFKD, might have beneficial implications in COVID-19 prognosis likely without any detrimental effects.

Obese patients are predisposed to the development of chronic and acute respiratory illnesses [32,33], including respiratory tract infections [34]. The reasons for this susceptibility to respiratory disease are many and not completely elucidated yet [35,36]. Obese people have alterations in respiratory physiology [37] and immune response [24,33] and, consequently, develop a lower response to antiviral therapies and vaccinations [24]. The alterations in respiratory physiology consist in a decreased functional residual capacity and reduced expiratory reserve volume, hypoxemia and ventilation perfusion abnormalities [28,37]. The presence of Obstructive Sleep Apnea Syndrome (OSAS), which is common in obese people, may predispose the patients to COVID-19 complications [38].

Obesity is characterized by low-grade systemic inflammation, that may be related to the pathogenesis of respiratory conditions [33]. Fat tissue may accumulate within the lungs, as observed in the airways of obese humans [39] and in the alveolar interstitium of obese diabetic rats [40]. Adipose tissue accumulation in the outer wall of large airways positively correlated with inflammatory infiltrate of eosinophils and neutrophils in patients with fatal asthma [39].

Animal models of obesity showed that during influenza infection there is increased lung permeability, leading to protein leakage into the bronchoalveolar lavage fluid. For the resolution of the infection, the repair of the damaged epithelial surface is required, but wound repair is impaired. Increased lung oedema and oxidative stress have been observed as well [24].

There is evidence that immune system functioning is altered in obesity. T-cells diversity is reduced and this may be related to the T-cells poor response to influenza virus [24]. CD8+ T memory cells has been shown to be impaired, with consequent exacerbates lung complications and mortality [33]. These cells are responsible for an efficient immune response to vaccination [33], with consequent reduced response to vaccination in obese

people [24]. Moreover, obesity may be a factor that exacerbates the aging of the immune system [24].

In addition, the high ACE-2 expression in adipose tissue may play a role in obese patients' susceptibility to COVID-19 infection, since SARS-CoV-2 shows high affinity for this enzyme [41].

Therefore, interventions aimed to weight loss in obese patients are warranted to prevent viral infection susceptibility and their complications and theoretically may ameliorate respiratory function.

#### **5. Low-Carbohydrate Ketogenic Diets and Respiratory Function**

VLCKDs are, to date, contraindicated for obese patients with respiratory failure [12]. However, some studies reported some beneficial effects from high-fat low-carbohydrate diets and detrimental effects of carbohydrate loads on respiratory parameters. These studies, anyway, often did not specify if patients were in ketosis, but used low amount of CHO, possibly leading to ketosis.

Two studies on a total of 40 healthy patients [42,43] reported that a VLCKD (848 kcal/day; protein: carbohydrate: fat = 43:14:43%) and a HFKD (10% calories from carbohydrate) diet reduced CO2 output without modifying oxygen uptake. Moreover, Rubini et al. compared a VLCKD regimen to a hypocaloric Mediterranean diet showing that only the VLCKD significantly decreased respiratory exchange ratio (*p* < 0.05) in addition to higher fat mass loss in healthy patients. Therefore, these diets may be helpful in respiratory patients for reducing CO2 body stores levels and dyspnea at rest. On the other hand, a study on 17 healthy women who were administered a HFKD (2400 kcal/day), reported earlier muscle fatigue during daily life activities [44].

Chronic Obstructive Pulmonary Disease (COPD) is often accompanied with hypercapnia and hypoxemia. A reduction in carbon dioxide production would reduce the workload of respiratory muscles and therefore be beneficial for these patients. Some studies focused on the administration of HFKD in COPD patients, and beneficial or, at least, neutral results were observed.

In twelve clinically stable COPD patients, the administration of a high-fat meal had a small effect on gas exchange parameters compared to 12 healthy controls, whereas a high-carbohydrate diet was detrimental on gas exchange parameters, especially in COPD patients [45]. No differences in pulmonary function were detected in 36 COPD patients comparing the administration of a moderate-fat meal with a high-fat meal [46]. On the other hand, the administration of a HFKD in COPD patients with hypercapnia led to an amelioration of respiratory parameters in an overall sample of 74 underweight patients [47,48].

In patients with respiratory failure, providing an adequate protein intake is extremely important to preserve skeletal muscle mass and function [7]. A high-fat low-carbohydrate diet has been reported as a potential useful tool to ameliorate respiratory failure [49–51].

In the literature, there are some evidences of a beneficial effect of a high-fat lowcarbohydrate diet in mechanically ventilated patients [52–54], since it was able to reduce PaCO2 levels [52,53,55] and the time of mechanical ventilation [52,53].

#### **6. COVID-19, Lockdown and KDs**

Both HFKD and VLCKD represent valuable treatments despite being characterized by the presence of contraindications and capable of causing side effects. Therefore, they should be followed under strict medical supervision and be considered similar to pharmacologic treatment. A concern may be that during the isolation imposed during the pandemic, it is difficult to monitor a patient on the ketogenic diet undergoing rehabilitation. Just a few studies reporting the administration of a ketogenic diet during this pandemic have been published, and to the best of our knowledge none published results on its use in COVID-19 infected and/or respiratory patients yet.

Kossof et al. [56] administered a HFKD to patients with uncontrolled seizures, mainly children, during the pandemic, using a combined approach with in person meetings and telemedicine. The authors and the other members of the International Ketogenic Diet Study Group, pediatric consensus group, reported no issues regarding the maintenance of ketosis and seizure control in their group, and raised no questions about the safety of the ketogenic diet in case of respiratory infection. A similar approach in similar setting was used by Ferraris et al. [57] and no major issues were reported, but they did not specify if any of their patients was infected by COVID-19.

Soliman et al. [58] proposed the use of a ketogenic diet and intermittent fasting, with administration of medium-chain triglycerides, as a prophylactic measure and an adjuvant therapy for COVID-19. In fact many viruses, as the varicella-zoster [59], the cytomegalovirus [60] and the hepatitis C [61], need the fatty acid metabolism pathway for their replication, therefore the diet-induced metabolic switch leading to a reduction in the fatty acid synthesis pathways may help in reducing viral replication [58].

#### **7. Conclusion and Future Perspective**

#### *7.1. KDs in COVID-19 Prevention*

Obesity, and in particular visceral abdominal fat, has been indicated as an independent risk factor for worse prognosis in COVID-19, often associated with the need for intensive care [17,30,41,62]. These may be due to the impaired respiratory mechanics, increased airway resistance and impaired gas exchange [25,28,54], as well as obesity-related comorbidities [63], which appear to be directly related to the onset of complications and severe course of COVID-19. In particular, OSAS [38], metabolic syndrome, hypertension, Non-Alcoholic Fatty Liver Disease (NAFLD) and diabetes or insulin resistance have all shown to affect COVID-19 outcome negatively [55–58]. Finally, it should not be overlooked that obesity is associated with low chronic inflammation within a state of immunological dysfunction that can lead to increased risk of allergies [64] or ineffective response against infections [35] and vaccines [65].

KDs, and specifically VLCKDs, demonstrated to induce weight loss and diabetes remission. VLCKDs are currently used in bariatric surgery preparation [12] thanks to the ability in reducing hepatic volume [11] with a subsequent improvement in intra and post-operative care. Recent findings underlined immune advantages derived from ketone bodies, such as blockage NLRP3 inflammasome [20], reduction in chronic activation of ILCs and induction of protective γδ T-cells against infections [10]. Taken together, in addition to the benefit of airway inflammation prevention by impairing the formation of lipid droplets [22], KDs could be an excellent tool to prevent the infection and stem the damage induced by COVID-19 in the fragile population affected from obesity.

#### *7.2. KDs in Supportive Care of COVID-19*

Studies conducted in mice highlighted the beneficial effect of HFD- induced ketone bodies in COVID-19 models [10,23]. In humans, HFKDs has been experimented in Intensive Care Units (ICU) and good results have been reported in mechanically ventilated patients [52,55]. Moreover, telemedicine achieved good results in pediatric epileptic patients under HFKDs, either for safety and compliance, proving that it can be a valid tool to be adopted even in the event of quarantine and fiduciary isolation. On the basis of these considerations, several authors proposed KDs in COVID-19 management and some clinical trials are ongoing [66,67].

#### *7.3. KDs during Rehabilitation Post SARS-CoV-2 Infection*

Patients affected from COVID-19, especially elderly ones, often require ICU for a longer period (up to 20 days) than other more typical uses of ICU. Among Post Intensive Care Syndrome (PICS), impaired exercise tolerance, neuropathies, muscle weakness/paresis, severe fatigue are responsible for decreased exercise capacity, disability and compromised quality of life for months, even years after intensive care [68]. Muscle atrophy, as well as obesity and immune dysregulation, is associated with Growth Hormone/Insulin-like Growth Factor 1 (GH/IGF-1) impaired axis and might be a link

between IGF-1 downregulation and COVID-19 severity [69]. Preserving muscle mass is essential in order to improve rehabilitation and to reduce costs for recovering people.

VLCKDs preserved muscle mass in obese patients [70,71] when a protein intake of at least 1.2 gr of protein/Kg was ensured; the same results have been confirmed when isocaloric KDs have been used in patients affected from multiple sclerosis, reporting a superiority compared to Mediterranean diet [72]. Furthermore, HFKD (75–80% calories from fat, carbohydrates <50 g per day and <10 g per meal) improves quality of life, lean mass and metabolic parameters (included IGF-1) in oncologic patients, compared to standard diet [73].

In conclusion, VLCKDs administration might be considered in severely obese patients as an effective adjuvant therapy for COVID-19, first of all as a preventive measure, to achieve a fast weight loss [67], and secondly as an adjuvant therapy during rehabilitation (see Figure 1). More challenging is the hypothesis of administering HFKD during hospitalization or even more in delicate settings such as an intensive care unit or during positive ventilation; although several data support the evidence that limiting carbohydrate intake and promoting ketone formation may be helpful in ameliorating respiratory parameters. Furthermore, as extensively discussed, HFKDs show a strong anti-inflammatory effect and some data suggest that they may be useful for reducing viral replication. However, many studies are old, the samples small, and the ketosis not specifically addressed, therefore new clinical trials are needed. Hoping that the promising results observed in animal studies can be passed on to humans, we herein suggest considering KDs as an option to be considered for COVID-19 management within the current indications.

**Figure 1.** Mechanisms through which VLCKD with its consequent weight loss may reduce the susceptibility to severe SARS-CoV-2 infection and stem the damage induced by the virus.

**Author Contributions:** Conceptualization, L.G., A.L. and C.L.; writing—original draft preparation, E.G., R.T., M.W. and S.B.; writing—review and editing, O.G., S.M., L.G. and C.L.; supervision, L.G. and C.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** Data sharing not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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