Clinical trial NCT04447144: Nutritional Habits, and Coronavirus Disease 2019 (COVID-19) Outcome
Official title: Nutritional Habits, Does it Affect Coronavirus Disease 2019 (COVID-19) Infection Outcome? An Egyptian Experience
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Covid19
Chronic Inflammation
Non-Communicable Chronic Diseases
Keywords: Covid19
noncommunicable diseases
chronic inflammation
Mediterranean diet
Lead sponsor: Cairo University
Sponsor class: OTHER
First posted: 2020-06-25
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study is a prospective cross-sectional single center National study, will include 200 Egyptian patients. The patients preliminary suggested to have COVID-19 of mild to moderate severity that is confirmed by laboratory and imaging studies.

Blood samples will be obtained for:

* CBC including lymphocyte count and absolute neutrophil count
* ALT, AST, bilirubin total and direct
* Serum creatinine, urea
* C- reactive protein
* LDH
* D-dimer
* Serum ferritin 4. ECG, CXR \& CT chest will be done and followed with Labs. 5. A questionnaire for the diet will be filled by the patient and will be analyzed.

  6. All patients will receive Hydroxychloroquine, Vitamin C, Zink tablets, acetylcysteine and lacorferrin according to The Egyptian Ministry of Health treatment protocol for COVID-19

Brief summary: As of May 30th more than 23,000 cases of COVID -19 cases were confirmed in Egypt with total deaths of 913. Post viral entry, intense immune response against the virus with infiltration of monocytes and macrophages into alveolar cells with decreasing number of lymphocytes in peripheral blood along with reduced lymphocytes in lymphoid organs, hypercoagulability, thrombosis and multiple organ damage, The gut microbiota and immune homeostasis seem to have a back and forth relationship.

Also, gut microbiota derived signals are known to tune the immune cells for pro and anti-inflammatory responses thereby affecting the susceptibility to various diseases. Healthy gut microbiome essentially could be pivotal in maintaining an optimal immune system to prevent an array of excessive immune reactions that eventually become detrimental to lungs and vital organ systems.

Numerous studies have shown that the patient's nutritional status have a significant effect on an individual's immunity and over all health status and it has been suggested that nutritional deficiencies may predispose to severe forms of COVID-19 infections.

Co-existing non-communicable chronic diseases (NCDs) in COVID-19 patients have been found to delay patients recovery and worsen their prognosis, the reason may be due to aggravated inflammatory pathology found in NCDs exacerbating COVID-19 infection.

The aim of the study is to evaluate the role dietary habits among COVID-19 Egyptian patients and whether type of diet (Mediterranean or Western) will affect disease outcomes

Detailed description: As of May 30th more than 23,000 cases of COVID -19 cases were confirmed in Egypt with total deaths of 913. There are over six million confirmed cases of COVID-19 and almost 370,000 deaths globally. COVID-19 originated from Wuhan city, China in early 2020, from their extending to the rest of the world. The virus belong to a large class of viruses known as β-coronaviruses with a large number of potential natural primary, intermediate and final hosts. Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is an enveloped RNA virus that typically spread by droplets causing pulmonary and extra-pulmonary complications.

COVID-19 can result in cytokine storm, which in severe cases can lead to acute respiratory distress syndrome (ARDS), sepsis and multiple organ dysfunction that can progress to death. Post SARS-CoV-2 entry, intense immune response against the virus with infiltration of monocytes and macrophages into alveolar cells with decreasing number of lymphocytes in peripheral blood along with reduced lymphocytes in lymphoid organs, hypercoagulability, thrombosis and multiple organ damage. This along with the fact that some patients of this disease have diarrhea points out towards a distinct possibility of involvement of gut-lung axis and may be the gut microbiota.

The gut microbiota and immune homeostasis seem to have a back and forth relationship. Also, gut microbiota derived signals are known to tune the immune cells for pro and anti-inflammatory responses thereby affecting the susceptibility to various diseases.

Many elderly and immune-compromised patients progress to serious adverse clinical outcomes, it is therefore tempting to speculate that in COVID-19, there is a possible cross-talk taking place between the lung and the gut microbiota which might influence the outcome of the clinical manifestation.

Healthy gut microbiome essentially could be pivotal in maintaining an optimal immune system to prevent an array of excessive immune reactions that eventually become detrimental to lungs and vital organ systems.

Several studies have shown that increased D-dimer levels are associated with severe forms of COVID-19 infection, this might be explained by diffuse alveolar damage, pneumocytes desquamation, pulmonary edema, interstitial mononuclear cells and lymphocytes infiltration causing intense inflammatory burden induced in severe COVID-19 infections.

Numerous studies have shown that the patient's nutritional status have a significant effect on an individual's immunity and over all health status and it has been suggested that nutritional deficiencies may predispose to severe forms of COVID-19 infections. Adequate Fruits and vegetables consumption have been studied for their potential protective effects against respiratory diseases and anti-inflammatory effects, furthermore, fruits and vegetables are also rich sources of fibers that have favorable effects on gut microbiome. One of very familiar water-soluble vitamins; Vitamin C (ascorbic acid) , that can be found in citrus fruits, barriers, leafy greens, tomatoes, and various other fruits and vegetables. Indeed, 1-2 g supplementation of vitamin C was found to shorten the duration of common cold by 18%, according to the United states National Institute of health (NIH) the recommended daily allowances (RDA) of vitamin C for healthy adults is 75-90 mg/d.

The Sunshine vitamin (Vitamin D) which is found in mushrooms, eggs, salmon and milk was found in a meta-analysis of 25 randomized controlled trails conducted over more than 11,000 participants, an overall protective effect of vitamin D supplementation in acute respiratory infections and, also, COVID-19, studies also suggested to possible role of Vitamin D as an antiviral immunomodulator through anti-inflammatory properties, for this reason, Vitamin D have been suggested to have a beneficial effects against SARS-CoV-2 infection (16), another study done in Switzerland on SARS-CoV-2 positive patients found to have significant lower levels (mean value 11.1 ng/mL) of 25-hydroxyvitamin D. The recommended RDA of vitamin D according to NIH 15-20 ug/d (600-800 IU with tolerable upper limit of 4000 IU). Another vitamin with anti-inflammatory benefits, fat soluble vitamin E (œ-tocopherol) found in seeds, green leafy vegetables, nuts, and fortified cereals. Vitamin E has been labeled as immunoenhancing vitamin by with anti-inflammatory properties by regulating the production of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) and modulating signal transduction, thus protecting The polyunsaturated fatty acids (PUFAs) in the cell membranes, for this reason, it has been suggested that the combination of Vitamins C, D \& E may be useful in COVID-19 patients. The RDA of Vitamin E for healthy adults according to the NIH is 15 mg/d (tolerable upper level 1000 mg/d).

Regarding minerals, Zinc has been found to have a critical role in maintaining immune cells integrity and important cofactor for numerous enzyme, zinc deficiency can cause impaired cell-mediated immunity predisposing to various infections, especially respiratory infections, available food sources of zinc including; meats, legumes and diary products, the RDA of zinc according to NIH is 8-11 mg/d (with 40 mg/day tolerable upper intake level).

Another essential trace element is Copper that can be found in nuts and offal and, in lesser concentrations in cereals and fruits, copper has a pivotal role in maintaining DNA integrity by its antioxidant effects, studies have shown that adequate copper supplementation can reduce lung inflammation in mice, according to NIH, the RDA of copper is 900 ug/d (tolerable upper limit of 10 mg/d).

Regular intake of prebiotic foods such as oligosaccharides, fermentable fibers, and resistant starches can beneficially affect the gut microbiota, prebiotic fibers are considered selective substrates for specific beneficial colonic bacteria as they are neither hydrolyzed nor absorbed in the proximal gut. Dietary fibers have been suggested as immunity modulators as they lower incidence of bacterial translocation by maintaining integrity of the gut barrier, available sources include; oat, barley, seeds, nuts, peas and some fruits, the recommended daily intake is 25-38 g/day. Probiotic foods (from dairy products as yogurt\& sour cream) and supplements have the ability to modify the gut microbiota and potentially modulate gut inflammatory response.

D-dimer is a fibrin degradation product (FDP) that reflects bath thrombin production and activation, elevated levels have been linked to increased risk of coronary artery disease, cerebrovascular strokes and total mortality, so far the link between dietary habits and D-dimer levels has been poorly explored. Studies have reported, that adherence to a Mediterranean diet was found to be associated with decreased levels of D-dimer, with possible antithrombotic effects due to high content of fibers, antioxidants, mono and polyunsaturated fatty acids.

Co-existing non-communicable chronic diseases (NCDs) in COVID-19 patients have been found to delay patients recovery and worsen their prognosis, the reason may be due to aggravated inflammatory pathology found in NCDs exacerbating COVID-19 infection. Such patients with underlying cardiovascular, respiratory disease were found to have worse prognosis, diabetes, hypertension and hypercholesterolemia are considered major risk factors for thrombotic complications, which in COVID-19 patients may account for higher risk of serious disease outcome and is associated with two-folds increase in mortality.

Fish and fish oils are considered very beneficial to individual health especially in patients with NCDs including cardiovascular diseases. Omega-3-polyunsaturated fatty acids (PUFA) are integral component of the cell membrane thus having anti-inflammatory effects, however, substantial human trials in this area are lacking.

For this reason, an effective approach to reduce person's risk of developing NCDs is to halt underlying inflammation via modifiable risk factors including; diet, exercise and healthy lifestyle choices. To date, there is no single food or natural remedy that has been used for preventing COVID-19 infections. Healthy diets containing adequate amounts of necessary macro and micronutrients, prebiotics and probiotics that can maintain and restore immune system, therefore increasing protection against chronic inflammation-related NCDs. Foods with anti-inflammatory and immunomodulatory compounds including essential vitamins (C, D \& E) and minerals (Zinc, Copper, Calcium \& Selenium) are considered protective foods, these micronutrients can act in harmony to prevent thrombotic and reactive oxygen species (ROS) complications by their anti-inflammatory properties. They are present in fair amounts in Mediterranean Diet, which is characterized by increased dietary consumption of legumes, olive oil, whole grains, nuts, and monounsaturated fats, minimally processed fruits, vegetables, associated with low to moderate consumption of fermented dairy products, fish, poultry. Antithrombotic advantages of Mediterranean diet have been explained by reduced levels of factor VII, tissue factor, platelets and leucocytes counts in individuals consuming Mediterranean diet. On the other hand, The "Western" dietary pattern, which is characterized by high consumption of saturated fats, refined carbohydrates, red meat, deserts and sweets, that may be associated with hyperglycemia, hyperlipidemia and chronic inflammatory state.

The aim of the study is to evaluate the role dietary habits among COVID-19 Egyptian patients and whether type of diet (Mediterranean or Western) will affect disease outcomes.

The current study also trying to determine if balanced diet maintaining healthy gut microbiota can have a role in avoiding disease progression and deterioration in COVID-19 cases.

Dietary pattern questionnaire for COVID 19 patient Name:- Age :- The work:- height :- Weight :- BMI :-

* Did you lose weight during the previous 3 months?
* Do you smoke?
* What is your usual breakfast before the injury and when to take it ?
* What is your usual lunch before the injury and when to take it ?
* What is your usual dinner before the injury and when to take it ?
* Did you eat between meals and what you eat?
* How many cups of water you drink daily?
* Do you eat salads or fresh vegetables daily (type and amount)?
* Do you eat fruit daily (type and amount )?
* Do you drink milk daily ?
* Do you eat yogurt daily?
* Do you drink fermented milk daily?
* Do you eat cheese daily(type and amount)?
* Do you eat fish weekly ( type and amount)?
* Do you eat pickles daily(amount) ?
* Are you exposed to the sun daily ( duration and time)?
* Number of spoons of sugar taken per day ( and sweets)?
* Types of drinks daily and their times ?
* Frequency of eating out ( weekly)?
* Do you eat any of these food daily ( cocoa , cashew , cheddar, chicken , meat, Milk , almond , salmon , yogurt)?
* Number of times eating eggs per week ?
* The type and amount of fats used in cooking :-
* Number of hours of sleep per day :-
* Antibiotic intake rate:-
* Have you take any supplements and vitamins for the past months?

The analysis of the above food habits questionnaire Will be fitted to a scoring system from 0 to 32 points covering the following

1. Probiotic in food
2. Prebiotic in food
3. Vitamins and minerals in food
4. Mediterranean type of food
5. Antibiotics intake that affect gut microbiota
6. Tea frequency and amount intake with respecting it's role on microbiota
7. Exercise daily and it's effect on immune system and lung capacity

All patients will be followed up for 14 days For disease recovery or progression to severe category.

Statistical analysis will be done after tabulation of the results to correlate with microbiome as well as the clinical status of patients.

Aim and Expected outcomes: The novelty of this study is that the investigators will get information about the role and type of diet on COVID-19 outcome and clarifying the role certain macro and micronutrients in inducing chronic inflammation, protecting from thrombosis The investigators also hope through this research to modify dietary habits in the Egyptian society encouraging healthy nutrition with the pre and probiotics food role to retain normal healthy life.

Eligibility criteria: Inclusion Criteria:

- Patients (18 -80 years) with mild to moderate COVID-19 cases consented to home or hospital isolation to follow them.

Exclusion Criteria:

Severe cases not fulfilling the definition of mild and moderate cases.

Definition of mild cases according to The Egyptian Ministry Of Health: (MOH)

1. Age \< 60
2. Temperature \<38.5
3. SaO2 \>92%
4. Heart Rate \<110
5. Respiratory Rate \<25 /min.
6. Neutrophil / lymphocyte ratio on CBC \< 3.1
7. No co-morbidities that necessitates hospital admission: Pregnancy, severe uncontrolled Diabetes, Chronic lung disease, Chronic kidney disease, Chronic liver disease, Serious heart diseases (arrythmia, Ischemic heart disease, uncontrolled hypertension), immunocompromised: prolonged use of corticosteroids and other immunosuppressive drugs/ organ transplantation/ HIV/ Immunodeficiency, Obesity (BMI \> 40) Any patient not fulfilling the above mild criteria is considered having moderate disease as well as any positive pulmonary imaging findings

Primary outcomes:
measure: Western versus Mediterranean diet in COVID-19 outcome
timeFrame: 2 months
measure: Gut- Lung axis in COVID-19
timeFrame: 2 months
measure: Protective role of minerals and vitamins in COVID-19 patients
timeFrame: 2 months
measure: non-communicable diseases and COVID-19
timeFrame: 2 months
Secondary outcomes:
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Faculty of Medicine Cairo University
Study officials:
affiliation: Lecture of Internal Medicine Hepatology & gastroenterology Unit
name: Ahmed M Abdul Ghani, MD
role: STUDY_DIRECTOR
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