Could docosahexaenoic acid (DHA), found in breast milk and artificial baby milks, protect infants and children from COVID-19 and make them less susceptible to COVID-19-related severe illness, as well as treat adult COVID-19 patients in combination with retinoic acid? A plan for observation and intervention

doi:10.21203/rs.3.rs-960227/v1

SARS-CoV-2, which causes COVID-19, is a new virus that has spread fast over the world. The severity of COVID-19 at different ages has been a notable and constant observation: severity, the requirement for hospitalization, and mortality all grow sharply with age, although severe disease and death are uncommon in children and young adults.. The majority of children infected with SARS-CoV-2 are asymptomatic or have moderate symptoms, which include fever, cough, pharyngitis, gastrointestinal symptoms, and changes in taste and smell. The question of whether children are less likely to be infected with SARS-CoV-2 is still being debated. Children make up only 1 to 2% of all SARS-CoV-2 cases, according to large epidemiological research. these numbers are heavily, depend on testing criteria, and in many reports, testing was limited to those who were symptomatic or required hospitalization, which is less common in children.. According to certain research, children are just as likely as adults to contract SARS-CoV-2.9. Recent research suggests that children are less likely to become infected after coming into touch with a SARS-CoV-2-positive person.According to some reports, children and adolescents have similar virus loads and are hence just as likely to transmit SARS-CoV-2 as adults. Furthermore, the viral load in asymptomatic and symptomatic people may be identical. Reassuringly, transmission of the virus from children to other children or adults in schools has been infrequent.Children are less likely to be infected with SARS-CoV-2 and have less severe symptoms, which is similar to what has been observed with SARS-CoV-1 and Middle East respiratory disease (MERS)-CoV. Infection with most other respiratory viruses (e.g., respiratory syncytial virus (RSV), metapneumovirus, parainfluenza, or influenza viruses), on the other hand, has a far higher prevalence and severity in youngsters. Dr. Mahmoud Elkazzaz and Dr Amr kamel khalil Ahmed, the lead investigators of this observational study, recently published a preprint that demonstrated Docosahexaenoic acid (DHA) had a high binding affinity and greatest interactions with ACE2 active sites, as well as a moderate binding affinity and moderate interactions with the active sites of IL-6. The Docosahexaenoic acid (DHA) interacts with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex.. A study proposed, a clinical benefit of targeting IL-17A signaling and the synergic inflammatory cytokine IL-6 to manage COVID-19 patients, particularly those presenting with cytokine storm syndrome.Hypercytokinemia, caused by notably high pro-inflammatory cytokines such as interleukin (IL)-1B, IL-6, IL-8, and IL-17, is mostly linked to the worsened clinical presentation of COVID-19 patients(14). In PBMCs from individuals with relapsing-remitting multiple sclerosis, a combination of docosahexaenoic acid (DHA) and all-trans-retinoic acid (ATRA) inhibits IL-17 gene expression.

Conclusions

Docosahexaenoic acid (DHA) was detected in abundance in breast milk and other algal sources milk supplement used for newborns and children's feeding. As a result, we believe that docosahexaenoic acid (DHA) may protect children and newborns thorough competing with COVID-19 for ACE2 receptors and inhibiting IL-6 activity and may possibly help them avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS- CoV-2 RBD attachment to ACE2. In addition to IL-17 was fond to increase COVID-19 inflammatory complication in this case DHA combined with retinoic acid is expected to be effective in inhibiting IL-6 and IL-17.

Virology

COVID-19

Children

Infants

Adults

DHA

Milk Formula

Retinoic Acid

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has infected over 235 million people causing over 4.8 million deaths over the world, and it is still expanding especially since current vaccines have not been able to completely end the pandemic because of existing new variants(1).
The world is still in an urgent need for targeted and effective COVID‐19 treatments which has put great pressure on researchers across the world for developing effective drugs. For severe acute respiratory syndrome coronavirus 2, the lower airway is the major target of infection (SARS-CoV-2). Pneumonia is almost always prevalent in COVID-19 patients(2,3). COVID-19 appears to be uncommon in youngsters, according to available reports(4,5,6,7). According to recent data from the Chinese Centers for Disease Control and Prevention, 416 (0.9%) of the 44,672 confirmed COVID-19 cases as of February 11, 2020 were aged 0–10 years and 549 (1.2%) were aged 10–19 years(8). Investigating the fundamental causes may aid in the understanding of COVID-19 pathophysiology.

Based on our recently published preprint , in which we found that Docosahexaenoic acid (DHA), a substance found abundantly in breast milk and added to other artificial milk formula had a high binding affinity and greatest interactions with ACE2 active sites, as well as a moderate binding affinity and moderate interactions with the active sites of IL-6(16). The Docosahexaenoic acid (DHA) interacts with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex(16) as showed in table 2 .

DHA is found in breast milk , the mean (+/-SD) concentration of DHA in breast milk (by wt) is 0.32 +/- 0.22% (range: 0.06-1.4%) and that of AA is 0.47 +/- 0.13% (range: 0.24-1.0%)(9). Docosahexaenoic acid (DHA) is found in breast milk and has a crucial function in the development of young children. Endogenous synthesis is insufficient to maintain tissue levels equal to breast-fed infants, hence a supply of these fatty acids in infant formula (usually following breast milk as a model with ARA > DHA) is regarded to be important. Numerous good developmental results (closer to breast-fed infants) have been found in intervention trials evaluating the influence of DHA- and ARA-supplemented formulas, including measurements of specific cognition functions, visual acuity, and immunological responses (10). In vitro and animal experiments, DHA has been shown to reduce the release of inflammatory cytokines(11). Calu-3 cells infected with Rhinovirus RV-43 and RV-1B released considerably less IL-6 and IP-10 after being supplemented with DHA (400 mM)(12).

High-dose (1.5 g/day EPA and 1.0 g/day DHA) n-3 supplementation can lower plasma levels of both IL-6 and IL-1ß, according to the findings of a randomised, controlled trial published in 2018(12).

Naturally, cow's milk does not provide a rich source of DHA however in North America whole milk and partially skimmed milk (2%) are fortified with DHA by adding DHA rich feed additive to cattle's diet. Skim milk or low fat milk (1%) cannot be fortified with DHA because DHA is contained in the milk fat(13).

Supplementing with EPA and DHA appears to have an anti-inflammatory impact, which is consistent with the majority of previous clinical findings as in table 1 (12).

A study proposed, a clinical benefit of targeting IL-17A signaling and the synergic inflammatory cytokine IL-6 to manage COVID-19 patients, particularly those presenting with cytokine storm syndrome(14).Hypercytokinemia, caused by notably high pro-inflammatory cytokines such as interleukin (IL)-1B, IL-6, IL-8, and IL-17, is mostly linked to the worsened clinical presentation of COVID-19 patients(14). In PBMCs from individuals with relapsing-remitting multiple sclerosis, a combination of docosahexaenoic acid (DHA) and all-trans-retinoic acid (ATRA) inhibits IL-17 and RORt gene expression(15).

Table 1

Table 2. Docosahexaenoic acid (DHA) binding affinities with ACE2 and IL-6 in addition to its other therapeutic properties

Docosahexaenoic acid (DHA) binding affinities with ACE2 and IL-6 could make it a potent protective factor against COVID-19 in children and Infants
Binding Affinity with ACE2 receptor	-6.3
Binding Affinity with IL-6	-5.3
Hydrogen bonds with ACE2	Two strong hydrogen bonds
Hydrogen bonds with IL-6	One strong hydrogen bond
Type	Omega-3 fatty acid
Anti-inflammatory properties	Inhibition of Interleukin-6(IL-6) (Rehman K et al.,2016) Inhibition of tumor necrosis factor-alpha (TNF-α) and nuclear factor-κB (NF-κB) (Yang YC et al.,2013)
Smell, taste and GPCRs	Protective for the olfactory system ( Gao MG et al.,2021) DHA levels affect ad modulates G protein-coupled receptors (GPCRs) function (Guixà-González R et al., 2016)
Sources	Breast Milk, Fish oils, Single cell oils (SCO) ( Algal source like Crypthecodinium and Schizochytrium)( Z.Cohen et al,. 2010)
Anti-clotting properties	Inhibition of platelet aggregation (DiNicolantonio JJ et al.,2019)
DHA for children	DHA has many health benefits for both mother and baby (Juber et al,.2016) Enhances brain function and vision. (Horrocks LA.,1999) Treats allergies, asthma, and attention deficit-hyperactivity disorder (ADHD). (Miyata J et al., 2015)
DHA , COVID-19 and Children	According to our findings DHA found in breast milk (Juber et al,.2016), could act as a protective factor against COVID-19 via inhibiting both ACE2 receptors and IL-6

Groups/Cohorts

300 Newborn feeding on Breast Milk or Artificial Milk Formula from birth to

about 2 months of age

The electronic patient record of 300 Newborn feeding on Breast Milk or Artificial Milk Formula from birth to about 2 months of age would be examined and followed between March 2020 and October 2021 and compare their rates of Covid-19 infection, hospitalization and complications with the rates of the Control Groups

300 Infant feeding on Breast Milk or Artificial Milk Formula from 2 months to

1 year

The electronic patient record of 300 Infant feeding on Breast Milk or Artificial Milk Formula from 2 months to 1 year would be examined and followed between March 2020 and October 2021 and compare their rates of Covid-19 infection, hospitalization and complications with the rates of the rates of the Control Groups

300 child feeding on Breast Milk or Artificial Milk Formula from 1 year to 5

year

The electronic patient record of 300 child feeding on Breast Milk or Artificial Milk Formula from 1 year to 5 year would be examined and followed between March 2020 and October 2021 and compare their rates of Covid-19 infection, hospitalization and complications with the rates of the rates of the Control Groups

300 child feeding on Breast Milk or Artificial Milk Formula from 5 year up to

15 year

The electronic patient record of 300 child feeding on Artificial Milk Formula or any source of DHA from 5 year up to 15 year would be examined and followed between March 2020 and October 2021 and compare their rates of Covid-19 infection, hospitalization and complications with the rates of the Control Groups

300 adult patients from 15 years to 25 years infected with COVID-19 will be treated by taking Milk formula supplement or capsules

contain DHA for one month

300 adult patients from 15 years to 25 years infected with COVID-19 will be treated by taking Milk formula supplement or capsules

contain DHA and retinoic acid capsules(Tretinoin 10mg soft capsules) for one month

Control Group

The electronic patient record of 150 infant and child patients who feed on only cow's milk which does not provide a rich source of DHA and did not feed on any Artificial Milk Formula or any source of DHA would be examined and followed between March 2020 and October 2021 and compare their rates of Covid-19 infection, hospitalization and complications with the rates of the cohorts that feed on Breast Milk or Artificial Milk Formula
The electronic patient record of 150 adult patients from 15 years to 25 years who did not feed on any Artificial Milk Formula or any source of DHA would be examined and followed between March 2020 and October 2021

Anticipated Results and Outcome Measures of children and infants

Primary Outcome Measure:

. Susceptibility for COVID-19.

Did infants and children who were fed breast milk or artificial milk formula have a lower risk of infection with Covid-19? in comparison with the control groups