By Dr. Liji Thomas, MD

The COVID-19 pandemic that began in late December 2019 has spread to over 188 countries and territories, causing over 6.5 million cases and 385,000 deaths. With no effective therapeutic COVID-19 drug or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in sight, researchers are exploring different strategies to limit its spread and mortality.

A recent study published on the preprint server medRxiv* in May 2020 shows that a combination of the readily available and inexpensive vitamins D3, B12, and the mineral magnesium can reduce the progression of the disease to severe or fatal stages.

Hyperinflammation in COVID-19 Disease
The current thinking on the pathogenesis of the condition is that hyperinflammation plays a crucial role in patient outcomes. In other words, direct viral injury is not the only or even primary player in organ dysfunction related to COVID-19. Rather, it is the result of the organ toxicity caused by the unregulated release of pro-inflammatory cytokines like IL-6 and IL-8, in response to the immune induction by the virus.

Immunomodulation is thus an attractive option in the treatment of COVID-19 and may prevent the progression of the patient to severe or critical illness. Various biologic molecules have been tried, such as the IL-6 blocker tocilizumab.

The DMB Protocol
The present study was an observational cohort study of a consecutive series of hospitalized COVID-19 patients aged 50 years and above, who were given a combination of the above micronutrients (DMB), comparing the rate of progression of disease in this group to another cohort of patients who were not given DMB.

Vitamin D protects the respiratory epithelium structure and function. Magnesium promotes vitamin D functions, acting as a cofactor in multiple enzymes involved in vitamin D metabolism, while also having independent bronchodilator and vasodilator activity. Vitamin B12 improves the health of the gut bacteria, which in turn is vital for an active and effective immune system. All are safe and well-tolerated by patients.

How Was the Study Done?
The current study aimed at testing the effect of a short course of supplementation of DMB in COVID-19 patients who are not yet in the severe or critical phase of the illness. The aim was to find out if this could prevent poor patient outcomes.

The study included all patients with COVID-19 who were at least 50 years old, admitted to Singapore General Hospital, between 15 January and 15 April 2020. All of them had a positive RT-PCR test. The study outcome was to assess how many progressed to need oxygen in any mode, or intensive care unit (ICU) admission.

From 6 April 2020, all patients fitting these criteria were administered DMB and formed the study cohort. DMB consisted of one daily dose of vitamin D3 1000 IU, magnesium 150mg, and vitamin B12 500mcg for up to 14 days. It was stopped if the patient either recovered symptomatically and two successive PCR tests were negative, or if the patient deteriorated clinically.

Related Stories
Does vitamin D deficiency increase COVID-19 risk?
Dead virus fragments are causing COVID-19 reinfection false positives
Kawasaki disease outbreak in children with COVID-19
Most patients in the study arm received DMB on the first day of admission and had continued therapy for 5 days (median).

The patients admitted in the same period but who did not receive DMB were the controls. The study arm comprised 17 patients while the control arm had 26 patients, both arms being similar concerning demographics, and clinical features.

Did the DMB Improve the Clinical Course?
The researchers found that only 3/17 patients in the study arm required supplemental oxygen, compared to 16/26 in the control group.

In both groups, the requirement for oxygen also signaled a high risk for ICU, with 2/3 in the DMB group and 16/16 in the non-DMB group requiring ICU admission. Of the 3 patients in the DMB group who deteriorated, one needed oxygen supplementation after 3 days on DMB but remained stable on the ward.

Of the 9 patients who received early DMB (in the first week of hospitalization), only one deteriorated, being among the 2, which required oxygen early (within 24 hours of starting DMB). These 2 are likely to have already gone downhill, judging from their rapid deterioration, and the DMB was probably too late to affect events either way.

The analysis showed that the odds of requiring oxygen went up with age and the presence of other illnesses, but went down significantly with DMB treatment, even after adjusting for age, gender, and other illnesses. The odds would have been even more impressive if the two patients who received DMB late in their clinical course were excluded. Importantly, there were no adverse effects that could be traced to DMB.

The Implications of the DMB Study
Available data from around the world shows that up to a fifth of COVID-19 patients experience life-endangering complications. IL-6 blockers and anti-thrombotic agents may be little better than a Band-aid in this situation, addressing the late events and mostly ineffective. However, the current study sought to make use of pre-emptive immunoregulatory, safe, and well-tolerated agents to reduce the cytokine storm associated with terminal organ damage and death.

The apparent success of this strategy could allow it to be adopted as a safe, easily administered, and early intervention in the primary care setting. It could also be equally effectively used to prevent symptomatic or severe disease among high-risk contact clusters traced during an outbreak. It is extremely cost-effective, making it suitable for low- and middle-income countries, even when vaccines or therapeutic drugs may be too costly to afford.

Lastly, the use of DMB may be equally effective in other viral infections that also produce high levels of cytokines and thus cause injury independent of the direct tissue injury.

The small sample size and absence of biologic assays to support the clinical improvement in the study cohort are limitations. However, the authors conclude, “It is a proof-of-principle effort with very promising results. Our findings would need to be further validated in a well-designed randomized study.”

*Important Notice
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Tan, C. W. et al. (2020). A Cohort Study To Evaluate The Effect Of Combination Vitamin D, Magnesium And Vitamin B12 (DMB) On Progression To Severe Outcome In Older COVID-19 Patients. medRxiv preprint. doi: https://doi.org/10.1101/2020.06.01.20112334. https://www.medrxiv.org/content/10.1101/2020.06.01.20112334v1