[F] Multi-target therapies: Weight of evidence supporting nutritional therapies

The cytokine storm, which includes respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and microvascular thrombosis may be alleviated or prevented using nutritional therapies in co-ordination with medical treatment which enhance immunity.[i] Nutritional therapies, or adjuvant nutraceuticals can reduce infection risk through antiviral, immunostimulating and immunomoldulatory action. [ii]

Compared to medication nutrients have low interaction with other drugs and are much cheaper, these therapies present a favourable risk-benefit ratio. The current toolkit for doctors to treat patients who present with symptoms of COVID-19 can be broadened via discussion and debate on both medical and nutritional therapies that can be harnessed to best serve vulnerable populations who are frequently nutrient deficient. This ensures medical practitioners have a sufficiently broad toolkit to mitigate the multitude of conditions that present as Covid-19.

In addition to multi-target therapies used in hospitals, treatments can be developed to be home-based, which is often referred to as ambulatory or early outpatient treatment.[iii] [iv] [v] In this way individuals and households with early symptoms can respond swiftly to reduce the chance of hospitalisation and death.

Adjuvant nutraceuticals – micronutrients and supplements – for prevention of severe Covid-19, hospitalisation and death, are not considered curative by scientists, but are recommended as treatments to improve (augment) the therapeutic response.[vi] [vii]

Current treatment protocols for infected patients ignore persistent hyponutrition (under-nutrition) in high-risk groups. [viii] Those with the disease of obesity appear more at risk of deficiency.[ix] Relatively inexpensive nutritional therapies should be available as therapies to those who experience COVID-19 symptoms or are hospitalised. Nutrients recognised to be immune-supportive and which have been studied in the current pandemic include zinc[x] [xi] and vitamin C.[xii] [xiii] Nutrition-based guidelines and protocols may also reduce risk of thrombotic events, which, along with inflammation are an increased risk factor for groups with non-communicable multimorbid conditions including diabetes and heart disease.[xiv] Nutritional therapies also present a low risk for an adverse drug interaction.[xv]

Low vitamin D levels in blood serum may be a predictor, rather than a side effect of infection. [xvi] Vitamin D is a hormone that is essential to a robust immune system and it appears to decrease risk of an adverse COVID-19 outcome.[xvii] [xviii] [xix] Vitamin D plays an important role in preventing viruses shift from the upper to the lower respiratory tract, lessening risk for pneumonia and other symptoms of acute respiratory distress.’[xx] The evidence that vitamin D has an important role in improving the adaptive immune system and alleviating the serious hazards – the cytokine storm, lung disease and heart failure – is compelling.[xxi] [xxii]

Vitamin D levels can be measured, and the data has long supported healthy levels above 50 ng/mL (125 nmol/L). A recent analysis proposed that a vitamin D blood level above 50 ng/mL may prevent excess mortality.[xxiii]

Daily needs for vitamin D cannot be sourced from diets and roughly half of the New Zealand population is deficient in vitamin D, adults[xxiv] [xxv] [xxvi] and children.[xxvii] [xxviii] The New Zealand definition of vitamin D deficiency[xxix] is much lower than the recognised European level for deficiency.[xxx]

New Zealand governments’ Pharmaceutical update[xxxi] claims that use of vitamin D is ‘unsupported by current evidence’[xxxii] fails to consider decades of evidence that vitamin D is immune supportive. This may be a function of a ‘medical-mindset’. It may be a function of collegial relations where it feels easier and ‘less political’ to defer to medical regulatory processes in large countries such as the U.S.A., where these groups insist that trials demonstrating ‘evidence’ should come out of the current pandemic. Current approaches, which dismiss or downplay the nutrition-immune relationship, may be the result of a long-standing tendency in medical education to historically focus on symptoms, biological pathways and treatments – rather than on dietary and nutritional drivers of disease. We know that this is changing, but it is shifting too slowly in this pandemic to protect those at most risk.

The claim becomes more compelling when the data demonstrates that Māori, Pasifika and South Asian groups are more at risk of vitamin D deficiency[xxxiii] [xxxiv] [xxxv] [xxxvi] and obligations in law require that the New Zealand government take steps to reduce health disparities in the population.[xxxvii] When a therapy is low risk and patients present with COVID-19 and have an associated condition, it is important that doctors and frontline staff have access to a suite of medical and nutritional therapies that give them the best chance of not progressing to pneumonia and severe lung outcomes, what can slow or prevent the cytokine storm.

In order to shift to favouring decades of supportive scientific literature, the New Zealand government look to the Bradford Hill criteria[xxxviii] and the Te Tiriti o Waitangi framework[xxxix] and recognise how nutrition-based therapies reflect the underlying principles of health equity embedded in the Whakamaua: Māori Health Action Plan.[xl]

The weight of evidence is in favour of improving access to vitamin D, a low-risk vitamin which reduces heart disease risk, increases lung function in asthmatics and smokers, reduces inflammation and cytokine upregulation, and prevents lower respiratory tract infections. [xli] [xlii] The approach can also be precautionary, as people with hyponutrition often show much greater benefit than those on better quality diets.

Vitamin D has a good risk-benefit profile and is already a high dose therapy in New Zealand for musculoskeletal disorders as side-effects are unlikely. There is a place to replace regulatory ambivalence[xliii] based on a narrow range of clinical data, with a greater recognition of the potential for protection.

New Zealand can adopt protocols used in Belgium, where the authorities recommend that those COVID-19 patients below 20 µg/litre in blood serum receive a loading dose (between 25,000 to 50,000 IU / week, i.e., 625 to 1,250 µg / week and that this is administered alongside other therapies for a few weeks.[xliv] Similarly, a European group recognising the broader benefits of Vitamin D for alleviating deficiency related harm including mental illness, recently noted that as a compliment to drug-based therapies ‘public health and public mental health point of view, based on the currently limited knowledge, for individuals with serious mental disorders, the benefits of Vitamin-D optimisation through supplementation seem to outweigh the risks’.[xlv]

There is concern that the officials with oversight in this pandemic have effectively devolved responsibility to other agencies who also have a ‘medical lens’ – they are biased against looking at the role of undernutrition[xlvi] and the potential for nutritional therapies, alongside conventional medical therapies. As an example, a recent Official Information Request to access scientific literature on vitamin D supplied to and held by the Executive Leadership Team. The response confirm or deny whether information had been forwarded from New Zealand scientists, but instead directed the author of the OIA request to the Pharmaceutical Update[xlvii] which states that vitamin D is currently unsupported by current evidence. After it was explained that the OIA request was not answered, a new one was established, which resulted in another wait.

NEXT: [G] Multi-target therapies: Weight of evidence supporting repurposed drugs

REFERENCES

[i] Peng et al. Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D. Int. J. Mol. Sci. (2021) 22:5251. https://doi.org/10.3390/ijms22105251

[ii] Costagliola et al. Could nutritional supplements act as therapeutic adjuvants in COVID-19? Italian Journal of Pediatrics. 47:32 https://doi.org/10.1186/s13052-021-00990-0

[iii] McCullough et al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Reviews in Cardiovascular Medicine (2020) 21:4: 517-530 DOI: 10.31083/j.rcm.2020.04.264

[iv] McCullough et al. Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection. Am J Med. (2021) 134(1): 16–22.

[v] The Association of American Physicians and Surgeons. A Guide to Home-Based COVID Treatment Step-By-Step Doctors’ Plan That Could Save Your Life https://faculty.utrgv.edu/eleftherios.gkioulekas/zelenko/aaps-Guide-to-Home-Based-Covid-Treatment.pdf

[vi] Derwand et al. COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study. International Journal of Antimicrobial Agents (2020) 56, 106214.

[vii] McCullough et al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Reviews in Cardiovascular Medicine (2020) 21:4: 517-530 DOI: 10.31083/j.rcm.2020.04.264

[viii] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[ix] Saternus R., Vogt T, Reichrath, J. 2019. A Critical Appraisal of Strategies to Optimize Vitamin D Status in Germany, a Population with a Western Diet. Nutrients. 11:2682 doi:10.3390/nu11112682

[x] Pal et al 2020. Zinc and COVID-19: Basis of Current Clinical Trials. Biological Trace Element Research 199:2882–2892

[xi] Anuk et al 2020. The Relation Between Trace Element Status (Zinc, Copper, Magnesium) and Clinical Outcomes in COVID-19 Infection During Pregnancy. Biological Trace Element Research 199;3608–3617

[xii] Coelho-Ravagnani 2021. Dietary Recommendations During the COVID-19 Pandemic: an Extract. Komp Nutr Diet 2021;1:3–7 DOI: 10.1159/000513449

[xiii] Ho et al 2021. Perspective Adjunctive Therapies for COVID-19:Beyond Antiviral Therapy. Int. J Med Sciences.18:2;314-324.

[xiv] Tsoupras et al. Thrombosis and COVID-19: The Potential Role of Nutrition. Front Nutr. (2020) doi 10.3389/fnut.2020.583080

[xv] E.g. the New Zealand Ministry of Health provides monthly high dose vitamin D to individuals with mulsculoskeletal health issues, because the vitamin presents low risk in high doses.

[xvi] Borsche et al. COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis. Nutrients 2021. 13:3596 DOI 10.3390/nu13103596

[xvii] Merzon 2020 Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. FEBS Journal 287:17

[xviii] Dror et al 2021. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. medRxiv

[xix] Lakkireddy et al 2021. Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease. Scientific Reports. 11:10641

[xx] Vasheghani et al 2021. The relationship between serum 25-hydroxyvitamin D levels and the severity of COVID-19 disease and its mortality. Scientific Reports 11:17594. | https://doi.org/10.1038/s41598-021-97017-9

[xxi] Peng et al 2021. Immunological Aspects of SARS-CoV-2 Infection and the Putative Beneficial Role of Vitamin-D. Int. J. Mol. Sci. 2021, 22, 5251. https://doi.org/10.3390/ijms22105251

[xxii] Yisak et al 2021. Effects of Vitamin D on COVID-19 Infection and Prognosis: A Systematic Review. Risk Management and Healthcare Policy 14:31-38

[xxiii] Borsche et al. COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis. Nutrients 2021. 13:3596 DOI 10.3390/nu13103596

[xxiv] Ministry of Health 2012. Vitamin D Status of New Zealand Adults: Findings from the 2008/09 New Zealand Adult Nutrition Survey. Wellington: Ministry of Health.

[xxv] University of Otago. Otago reveals concerning prevalence of vitamin D deficiency in Southern New Zealand women. January 22nd, 2018. https://www.otago.ac.nz/news/news/otago673255.html

[xxvi] Wheeler et al 2018. A Longitudinal Study of 25-Hydroxy Vitamin D and Parathyroid Hormone Status throughout Pregnancy and Exclusive Lactation in New Zealand Mothers and Their Infants at 45 ◦ S. . Nutrients. 10, 86; doi:10.3390/nu10010086

[xxvii] Delshad et al 2019. Wintertime Vitamin D status and its related risk factors among children living in Auckland, New Zealand. NZMJ 132:1504

[xxviii] Cairncross et al 2017. Predictors of vitamin D status in New Zealand preschool children. Maternal & Child Nutrition (2017), 13, e12340

[xxix] Ministry of Health 2012. Vitamin D Status of New Zealand Adults: Findings from the 2008/09 New Zealand Adult Nutrition Survey. Wellington: Ministry of Health.

[xxx] European Food Safety Authority. 2016 Dietary reference values for vitamin D: EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA Journal 2016;14(10):4547www p.17

[xxxi] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[xxxii] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf

[xxxiii] Narang et al 2021. A prediction tool for vitamin D deficiency in New Zealand adults. Archives of Osteoporosis 15: 172

[xxxiv] Delshad et al 2019. Wintertime Vitamin D status and its related risk factors among children living in Auckland, New Zealand. NZMJ 132:1504

[xxxv] Wheeler et al 2018. A Longitudinal Study of 25-Hydroxy Vitamin D and Parathyroid Hormone Status throughout Pregnancy and Exclusive Lactation in New Zealand Mothers and Their Infants at 45 ◦ S. . Nutrients. 10, 86; doi:10.3390/nu10010086

[xxxvi] Cairncross et al 2017. Predictors of vitamin D status in New Zealand preschool children. Maternal & Child Nutrition (2017), 13, e12340

[xxxvii] New Zealand Public Health and Disability Act 2000 3 Purpose (1) (b)

[xxxviii] Fedak et al 2015. Applying the Bradford Hill criteria in the 21st century.

[xxxix] Ministry of Health 2020. Te Tiriti o Waitangi and the health and disability system. https://www.health.govt.nz/system/files/documents/pages/whakamaua-tiriti-o-waitangi-framework-a3-aug20.pdf

[xl] Ministry of Health. 2020. Whakamaua: Māori Health Action Plan 2020–2025. Wellington: Ministry of Health.

[xli] Batmaz et al 2018. Seasonal variation of asthma control, lung function tests and allergic inflammation in relation to vitamin D levels: a prospective annual study. Adv Dermatol Allergol 2018; XXXV (1): 99–105

[xlii] Sluyter 2017. Effect of Monthly, High-Dose, Long-Term Vitamin D on Lung Function: A Randomized Controlled Trial

[xliii] E.g. NIH Vitamin D Recommendation April 21, 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitamin-d/

[xliv] Conseil Supérieur de la Santé Vitamine D, Zinc et coViD-19 janVier 2021 cSS n° 9620

[xlv] Wernenke et al 2021. Vitamin D in the time of the coronavirus (COVID-19) pandemic – a clinical review from a public health and public mental health perspective. Ther Adv Psychopharmacol. 11:1-27

[xlvi] Clemente- Suárez et al 2021. Nutrition in the Actual COVID-19 Pandemic. A Narrative Review. Nutrients 13:1924

[xlvii] Ministry of Health. Covid-19 Science Updates. July 9 2021. https://www.health.govt.nz/system/files/documents/pages/csu_09_july_2021_covid-19_pharmaceutical_treatments.pdf