How does Covid lead to long-Covid? Part I

One suggestion, by someone who has also likened long-Covid to beriberi, is that this is a slightly more virulent virus than usual, one that we have not had any experience of before, and that the high morbidity and mortality is due to the generally poor nutritional state of sufferers.¹

The influenza pandemic ‘Spanish Flu’ from 1918 onwards was thought to be particularly deadly as it happened at the end of World War I when there was a significant amount of malnutrition.

Another explanation was that the Spanish Flu triggered a cytokine storm—an over-reactive immune response.

These two things—exaggerated immune response and poor nutritional status are not mutually exclusive. One study in patients having surgery for colorectal cancer showed that malnourished patients had a higher interleukin 6 (IL-6) level.² Interestingly, IL-6 is one of the key drivers of inflammation and the cytokine storm in Covid.

Another well-known cytokine is IL-17, produced by Th17 cells. The Th stands for helper T cells. These cells are very important in infections. They help activate the B cells—the ones that produce antibodies. Th17 or helper T cells also help to activate the cytotoxic T cells that can kill cells that are infected to clear the virus.

The cytokine IL-17 protects individuals from bacterial infections, but in excess it can cause the inflammation in the lungs—ARDS or adult respiratory distress syndrome—seen in Covid. IL-17 promotes the downstream production of other pro-inflammatory molecules, such as IL-6 and TNF-α (tumour necrosis factor).

Wernicke’s encephalopathy is a well-established model of thiamine deficiency. Patients with this disorder develop instability walking, eye muscle abnormalities and mental changes, and it occurs in a proportion of alcoholics, as well as patients with very poor nutrition, such as gut disorders, severe sickness in pregnancy, malignancy and AIDS.

Thiamine deficiency is associated with increased pro-inflammatory cytokines; IL-6, TNF-α and IL-17. Increased IL-6 and TNF-α were found in post-mortem brains of patients who had died of a thiamine deficient, non-alcohol-associated state called Wernicke’s encephalopathy.³ Another recently reported study showed that treatment with thiamine in patients with Wernicke’s Encephalopathy significantly lowered IL-17.⁴

In critically ill patients thiamine deficiency has been found to be present in as many as 71% of patients.⁵ Certain medical conditions, such as alcoholism, diabetes, gut resection, predispose patients to thiamine deficiency.   

In summary: Covid is associated with an exaggerated immune response. Critical illness, of any cause, can lead to thiamine deficiency and certain conditions, such as diabetes are associated with thiamine deficiency, and also with increased risk of mortality from Covid. Thiamine deficiency is associated with an increased immune response as seen in patients with Covid. Hence long-Covid could be caused by an overactive immune system in addition to thiamine deficiency resulting from a severe infection or underlying condition or nutritional state.

Next week: how does Covid lead to long-Covid? Part II. Does Covid damage nerves?

References

1. Olney RW. Long covid: How to define it and how to manage it. BMJ 2020; 370: m3489.

2. Hatada T and Miki C. Nutritional status and postoperative cytokine response in colorectal cancer patients. Cytokine. 2000; 12(9): 1331-6.

3. Neri M, Cantatore S, Pomara C, Riezzo I, Bello S, Turillazzi E and Fineschi V. Immunohistochemical expression of proinflammatory cytokines IL-1β, IL-6, TNF-α and involvement of COX-2, quantitatively confirmed by Western blot analysis, in Wernicke’s encephalopathy.  Pathol Res Pract. 2011; 207(10): 652-8

4. Vatsalya V, Li F, Frimodig J, Gala KS, Srivastava S, Kong M, Ramchandani VJ, Feng W, Zhang X and McClain CJ. Repurposing treatment of Wernicke-Korsakoff syndrome for Th-17 cell immune storm syndrome and neurological symptoms in Covid-19: thiamine efficacy and safety, in-vitro evidence and pharmacokinetic profile. Front Pharmacol. 2020; 11: 598128.

5. Costa NA, Gut AL, de Souza Dorna M, Pimentel JAC, Cozzolino SMF, Azevedo PS, Fernandes AAH, Zornoff LAM, de Paiva SAR and Minicucci MF. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care. 2014; 29(2): 249-52.