COVID-19 mortality and vaccine efficacy in nursing homes: does vitamin B12 deficiency play a role?

Henry Olders, P.Eng, MD, FRCPC

Affiliate Member, Dept of Psychiatry, McGill University, Montreal, Canada

Abstract

It is believed that nursing home residents experience more disease severity and higher mortality from COVID-19, compared to community-dwelling elderly with similar comorbidities. Among the possible explanations for this phenomenon is the difference in vitamin B12 (cobalamin) deficiency prevalences between these two groups, estimated at up to 24% for community-dwelling seniors and 46% for nursing home residents in the U.K.

While COVID-19 illness severity and mortality appear to be due to an acute inflammatory reaction mediated by the innate (native) immune response, overcoming an infection requires an adequately functioning adaptive (specific) immune system. Specific immunity is based on production of antibodies by lymphocytes whose numbers must increase rapidly after the infection. The rate at which these lymphocytes can replicate is likely to be reduced when B12 is deficient, as vitamin B12 is necessary for DNA synthesis and therefore impacts tissues with rapid cell turnover including RBCs and the lining of the GI tract, as well as lymphocytes involved in specific immunity.

This mechanism may also affect vaccine effectiveness, not only the COVID-19 vaccines currently being rolled out, but others including influenza vaccines.

Since 1998, Health Canada has recommended that all adults age 50 and over take synthetic B12; in the absence of foods fortified with B12, this means taking a B12 supplement. The hypothesis outlined above suggests a prudent approach would be to provide B12 supplements to all nursing home residents as well as other individuals at risk for severe COVID-19 illness, and to individuals prior to being vaccinated against SARS-CoV-2. Not only could this decrease the burden on hospitals to treat severe COVID-19, it may also forestall a crisis in public confidence in SARS-CoV-2 vaccines if a significant proportion of nursing home residents fail to be protected by these vaccines.

Conflict of Interest Statement

H. Olders owns 100 shares of Jamieson Wellness Inc., (Supplier of vitamins).

Introduction

Mortality due to COVID-19 infection is very high in nursing home residents¹²³⁴ perhaps even compared to seniors with similar comorbidities living in seniors’ residences or in the community⁵. Given that in U.K. community-dwelling seniors, vitamin B12 (cobalamin) deficiency is found in about 24%, with almost double that rate (46%) in nursing home residents⁶, could this difference in B12 deficiency prevalences play a role in the different mortality rates in the two settings?

Hypothesis: B12 deficiency increases COVID-19 mortality in nursing home residents

1. COVID-19 severity and mortality are determined by innate immunity

The severity of symptoms in infected individuals appears to be determined by inflammation due to the innate (native) immune response⁷; hence the usefulness of immune system suppressants such as dexamethasone⁸ in reducing symptom severity. However, multiple factors appear to play a role in ultimate mortality, including male sex⁹, frailty¹⁰ and cognitive impairment¹¹.

2. The specific immune response reduces inflammation

One of those other factors might be the quality of the specific (adaptive) immune response (as separate from the innate immune response) mounted by an individual against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19. When adaptive immunity is unable to bring the infection under control, the innate immune system may continue to produce high levels of inflammation resulting in more severe illness and possibly death.

3. Adaptive immunity requires rapid cell multiplication

A robust adaptive immune response is dependent on the rapid multiplication of lymphocytes producing specific antibodies. In contrast, acute inflammation produced by innate immunity is mediated by several different cell types already present in tissues. Basically, rapid cell multiplication is unnecessary for the acute inflammatory process, whereas it is essential for adaptive immunity.

4. Adaptive immunity is impaired by vitamin B12 deficiency

Synthesis of DNA, one of the cellular building blocks necessary for cell replication, is B12 dependent. Thus, rapidly dividing tissues are typically severely impacted by B12 deficiency, producing anemia and gastrointestinal symptoms. Another rapidly dividing tissue is the lymphocyte population when an adaptive immune response is called for; therefore, B12 deficiency can manifest as an impaired adaptive immune response eg, to Trypanosoma lewisi infection in rats¹², or to pneumococcal vaccine¹³, whereas B12 supplementation may improve adaptive immunity¹⁴. These findings should prompt us to ask whether B12 deficiency might impair an adaptive immune response to infection by SARS-CoV-2 or to a vaccine against this virus, and whether B12 supplementation might improve response in deficient individuals.

5. B12 deficiency may decrease vaccine effectiveness

The mechanism described above may help explain the reduced adaptive immune response to other vaccines in seniors, including the influenza vaccine. An important and pressing public health issue, then, will be the possibility of B12 deficiency in individuals who will receive one of the candidate vaccines against SARS-CoV-2 currently in the development, approval, or rollout stages.

One caveat is that the impairment of DNA synthesis caused by B12 deficiency can be overcome by folic acid supplementation, but doing so may increase the risk of neurological impairment from low B12¹⁵.

6. B12 deficiency may increase inflammation

In addition to the role that B12 plays in adaptive immunity, it may also influence the innate immune response. Low B12 is associated with increased IL-6 production by peripheral blood mononuclear cells in Alzheimer disease patients¹⁶, and causes an elevation in homocysteine, associated with oxidative stress and increased release of inflammatory cytokines¹⁷¹⁸. “Hyperhomocysteinemia can result in systemic and vascular inflammation which leads to many health disorders” according to one review¹⁹. Conversely, adding methylcobalamin to the culture medium of peripheral mononuclear cells suppressed production of IL-6 and interferon-gamma²⁰. Elevated IL-6 is associated both with ICU admission and mortality in COVID-19 patients²¹, and it is thought that IL-6 blockade may decrease the cytokine release syndrome which plays a major role in COVID-19 pathology²².

Vitamin B12 deficiency is also implicated in thrombotic microangiopathy (TMA) syndromes²³, which may contribute to the organ damage in severe COVID-19.

7. B12 supplementation may improve COVID-19 outcomes

The author was able to identify only one study addressing this issue:

A cohort observational study in Singapore which looked at the effects of administering a combination of vitamin D, magnesium, and vitamin B12 orally to patients admitted with COVID-19 but not requiring oxygen. The cohort receiving this combination ultimately required less oxygen therapy than the control group²⁴. Unfortunately, this was not a randomized controlled trial, and as a combination intervention was used, the contribution of B12 alone could not be determined.

8. Many nursing home residents have B12 deficiency

While the U.K. study cited in the introduction found that 46% of nursing home residents were B12 deficient, there is a lot of disagreement between studies. Given that other effects of B12 deficiency such as dementia or falling with their attendant risks of hip fracture and loss of mobility²⁵ may cause nursing home admission, even when the B12 deficiency remains undiagnosed, a high prevalence can be expected.

Those with deficiency may be at risk for more severe disease if infected with the COVID-19 virus, and may be inadequately protected by vaccines. Both scenarios constitute a public health crisis, as described in the abstract.

Recommendations

1. Health Canada’s recommendation that adults over 50 should take a B12 supplement needs to be widely promulgated

Even in the absence of direct evidence that B12 deficiency contributes to COVID-19 mortality in nursing home residents, it may be reasonable to provide B12 supplements to vulnerable individuals in any case. In 1998, Health Canada together with the U.S. Institute of Medicine, recommended “Because 10 to 30 percent of older people may malabsorb food-bound vitamin B12, it is advisable for those older than 50 years to meet the RDA mainly by consuming foods fortified with vitamin B12 or a supplement containing vitamin B12”(see Table 3, Footnote d). In Canada, as no B12 fortified foods are available, supplements are the only avenue to get synthetic B12. Unfortunately, it appears the vast majority of Canadians, including physicians and other health care providers, are unaware of this recommendation.

2. B12 supplementation should not be based on laboratory confirmation of deficiency

Nevertheless, this recommendation that all adults over 50 take a B12 supplement is critical, because lab testing to diagnose B12 deficiency is highly problematic. The four tests available (total B12, holotranscobalamin II, total homocysteine, and methylmalonic acid) have important limitations²⁶, and recent studies use all four tests ²⁷²⁸, or even a combined index of B12 deficiency (4cB12)²⁹, with the goal of improving accuracy.

Given these difficulties, laboratory confirmation of B12 deficiency as a prerequisite to supplementation may impose undesirable delays and problems with false negative results. With one possible exception, there do not appear to be any negative consequences of vitamin B12 supplementation, even in large amounts³⁰. The exception refers to diminished survival in breast cancer patients who took B12 supplements either before or during chemotherapy³¹.

3. B12 injections are the gold standard, but sublingual methylcobalamin or intranasal hydroxocobalamin are also better absorbed than oral B12

What route of administration is advisable for B12 supplements? The B12 malabsorption in older adults referred to by Health Canada has multiple causes. Autoimmune gastritis is an increasingly prevalent³² cause of pernicious anemia (PA), defined as B12 deficiency due to absence of intrinsic factor (IF). In individuals with PA, about 1% of an oral dose of B12 will be absorbed³³ by passive mechanisms, but even when IF is present, the oral route of IF-dependent absorption is limited to about 1 to 2 micrograms every several hours³⁴. An intranasal preparation of hydroxocobalamin has been shown to be well absorbed³⁵³⁶, but is not readily available. Sublingual (SL) methylcobalamin in children produces B12 levels close to those achieved by intramuscular cyanocobalamin³⁷ but may be difficult to use for seniors with cognitive impairment. The gold standard is subcutaneous (SC) or intramuscular (IM) injection; however, intradermal delivery via an almost painless microneedle injection has almost equal bioavailability³⁸.

4. High daily doses are advisable for elderly persons

What doses should be used in seniors? Many elderly persons respond poorly to daily oral doses under 500 micrograms (mcg), even if they do not have classical malabsorption³⁹. A common protocol for treating diagnosed B12 deficiency when clinical symptoms are present is to inject (SC or IM) 1000 mcg cyanocobalamin daily for a week, then weekly for 4 weeks, followed by monthly injections for life. While adequate to reverse hematological manifestations of B12 deficiency, monthly injections may be insufficient to prevent neurological problems such as cognitive impairment, in PA patients. This is because B12, as well as inactive B12 analogues, are secreted into the bile; normally, IF binds the B12 so it can be resorbed, and the inactive analogues are eliminated via the feces. In PA patients, lacking IF, active B12 also is eliminated in feces; these individuals therefore have higher losses of B12 compared to those with IF⁴⁰.

Clinicians no longer attempt to distinguish PA from other types of B12 deficiency, so it is important to use doses adequate for PA. In practice, this suggests up to 5000 mcg daily, orally or sublingually, for elderly individuals with symptoms ascribable to B12 deficiency (probably most nursing home residents), and 1000 mcg per day for asymptomatic individuals.

5. Injections may be available without prescription

In some jurisdictions, including Canada, it is possible to obtain B12 for injection without a physician’s prescription, if parenteral administration is desired. The protocol above may be used for symptomatic patients, continuing however with weekly rather than monthly injections of 1000 mcg.

While many community-dwelling seniors take vitamin supplements, the B12 dosage may be insufficient, especially in multivitamin preparations. In nursing homes, physician prescriptions are usually required so that staff can distribute vitamin supplements to residents; unfortunately, many physicians in this situation, unaware of Health Canada’s recommendation, refuse to prescribe supplements in the absence of laboratory evidence for deficiency.

6. Nursing home residents and their families play a role

While people living in the community can easily obtain and take B12 supplements without the necessity of involving health professionals, nursing home residents may need to depend on their families to make the case to staff that supplements are both recommended and potentially lifesaving.

Conclusions

Given the magnitude of the potential benefits from B12 supplementation of nursing home residents and other at-risk elderly, and the low risks, it seems prudent to commence with supplementation as soon as practicable. Failure to do so risks continuing with high severity of COVID-19 illness in nursing homes and a high rate of hospital admissions in the second and subsequent waves; this may overwhelm already stretched health care systems. If, as hypothesized, B12 deficiency also reduces effectiveness of vaccines, the high prevalence of B12 deficiency in nursing homes means continuing high rates of infection in those settings even after mass vaccination. This could prompt a loss of confidence in those vaccines, an increase in vaccine hesitancy and refusal, and a resulting failure to achieve herd immunity.

Given that Health Canada has for 22 years been recommending B12 supplementation for all older adults, prompt supplementation of nursing home residents, especially those receiving vaccines, is called for. Simultaneously, the additional research that is urgently needed should be undertaken⁴¹.

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