Vitamin B12 and D deficiency as cofactors of COVID-19 vaccine-induced chronic neurological adverse reactions: Two cases and a hypothesis

Background: The COVID-19 vaccines have been an essential measure to help reduce COVID-19-related injury and death. However, in some cases, vaccination has caused severe and chronic reactions, akin to post-acute sequelae of COVID-19 (long COVID). Cases: In Version 1 of this manuscript, we presented two cases (Case 1: male, age 43 years, Pfizer BNT162b2 vaccination; Case 2: female, age 30 years, Oxford-AstraZeneca ChAdOx1nCoV-19 vaccination) with severe neurological adverse reaction post-vaccine and concomitant vitamin B12 deficiency. Both cases presented with non-textbook symptomatology of vitamin B12 deficiency. Case 1 had full symptom resolution with vitamin B12 replacement therapy, including after a second vaccine whereby symptoms returned. In Case 2, frank vitamin D deficiency and chronically elevated D-dimer were also found. Here we elaborate on further tests done on Case 2 only. Upon additional investigation due to significantly incomplete recovery with B12 and vitamin D replacement, Case 2 was diagnosed with a vaccine-induced long COVID-like syndrome, with evidence of microclots and perfusion imaging that was diffusely abnormal with widespread small defects, some areas of which were mismatched to ventilation, reported as possibly due to small pulmonary emboli; as well as mast cell activation syndrome; postural orthostatic tachycardia syndrome and dysautonomia; endocrine dysfunction; and worsened myalgic encephalomyelitis. Additionally, homocysteine remained elevated even after extensive B12 replacement, requiring folic acid supplementation despite no evidence of relevant genetic variants. Discussion: Vaccines, including the COVID-19 vaccines, are known to cause severe and/or chronic neurological reactions in some cases. We support research into screening for vitamin B12 deficiency prior to vaccination in high-risk groups (e.g. those following an animal produce free diet), those suffering atypical/chronic vaccine reactions, and those with similar conditions, such as post-acute sequelae of COVID-19 (long COVID). Here we demonstrate (to our knowledge) the first in-depth clinical exploration of a long COVID-like syndrome—in this case induced from vaccination—using established clinical pathways to make multiple diagnoses. Key lessons for clinicians seeing patients with (vaccine- or infection-induced) long COVID-like symptoms are: breathlessness should not be assumed to be dysautonomia, rather clotting should be fully explored; check for autonomic nervous system dysfunction; check for signs of mast cell activation syndrome and myalgic encephalomyelitis; and be aware that leaving these pathologies untreated can seemingly cause ongoing endocrine and metabolic dysfunction. Clinical and scientific investigation is warranted to understand how these pathologies interact in order to identify optimum treatment targets on a case-by-case basis. Case 2 is continuing to be monitored and the paper will be updated accordingly if necessary.