Management of post-acute covid-19 in primary care

Dear Editor

Who would have imagined, just a few months ago, that we would be brought to our knees by a pandemic of the common cold; albeit a common cold which can cause severe systemic disease in a minority of those infected. SARS-Cov-2 causes a mild upper respiratory tract infection (URTI) in most young healthy people. The virus replicates in mucosal epithelial cells and induces a T cell immune response which leads to viral elimination. Mucosal secretory IgA is produced which is expected to prevent re-infection (10). This is typical of the common cold.

Severe covid-19, however, is a different disease. The risk of severe inflammation rises as a power function of age, with an exponent which is similar to that of ageing in general. The risk is also increased in a number of pre-existing conditions: ischaemic heart disease, hypertension, type 2 diabetes mellitus, and obesity. These conditions are associated with low grade chronic inflammation, and evidence in recent years indicates that pathogenic bacteria growing within our tissues contribute to the inflammation (2, 3).

In the 1980s there were approximately 1500 deaths per annum, in England and Wales, from sudden infant death syndrome (SIDS). There was a clear seasonal pattern and death was clearly related to the prevalence of URTI in the community. The link between SIDS and the common cold was complex. Prone sleeping and URTI led to increased pooling of nasopharyngeal secretions, increased growth of nasopharyngeal bacteria, toxin production and toxin induced sudden death in infants who at 2 to 3 months of age had low levels of protective anti-toxin IgG antibodies in their blood stream. The prime suspect was alpha-haemolysin produced by Staphylococcus aureus (4 -6).

We can make sense of covid-19 if we think about it in the same way. The coronavirus triggers a cytokine cascade in a minority of those exposed; it does not mean that the virus is the direct cause. SARS-CoV-2 amplifies the low-grade chronic inflammation which is associated with the above pre-existing conditions. In certain patients this can cause a cytokine cascade with the clinical features of sepsis.

Sepsis, with negative blood cultures, unresponsive to antibiotics, but mitigated by steroids is strongly indicative of toxic shock syndrome (7). The commonest cause is S. aureus. This is also the commonest cause of a cytokine cascade. Pathogenic bacteria, which grow within our tissues, need genetic mechanisms to prevent immune rejection and to protect their niche. Certain strains of S. aureus produce pyrogenic toxins, which are superantigens. They cause non-specific T cell proliferation with cytokine secretion and induce severe inflammation (2). An uneasy truce follows and the immune system leaves the organisms alone. But when the cytotoxic T cells come to eliminate the infected epithelial cells, S. aureus will defend its niche and severe inflammation will follow.

This concept fits with the observation that severe symptoms develop as the virus is eliminated. The idea also fits with the observation that symptoms of inflammation can persist for weeks or months after the virus is totally cleared from the system. There is experimental evidence that the common cold in infancy leads to increased S. aureus carriage and increased pyrogenic toxin production (8). There is no reason to believe that it is different in adults. Post-acute covid-19 could therefore leave the patient with increased carriage of S. aureus, and with intermittent release of pyrogenic toxins leading to prolonged fatigue.

I am sure I will be accused of speculation. But as a retired pathologist I am not in a position to organise the relatively simple tests which could be used to prove or disprove this hypothesis. If one of my relatives had post-acute covid-19 I would want the primary care physician to submit a specimen of faeces to the laboratory and ask for selective culture for S. aureus. Any isolates should then be submitted for genotyping to see if the strain is potentially pyrogenic (8). I would then suggest consumption of natural yoghurt daily to bring the microbial flora back to an optimal condition (9). I acknowledge that these unproven assumptions should be subject to rigorous test. But there is no excuse for the medical profession to continue to ignore the possible role of pyrogenic staphylococcal toxaemia in this pandemic.

References
1. Burgess S, Ponsford MJ, Dipender G. Are we underestimating seroprevalence of SARS-CoV-2? BMJ 2020;370:m3364.
2. Morris JA. Staphylococcus aureus bacteraemia: a hidden factor in the pathogenesis of human disease. JSM Microbiology, 2017; 5: 1037.
3. Morris JA. A cacophony of cytokines explains the biopsychosocial interaction model of mental and physical disease. Archives of Depression and Anxiety 2018; 4: 56 – 64.
4. Morris JA, Haran D, Smith A. Hypothesis: common bacterial toxins are a possible cause of the sudden infant death syndrome. Medical Hypotheses 1987; 22: 211 – 222.
5. Harrison LM, Morris JA, Telford DR, Brown SM, Jones K. The nasopharyngeal bacterial flora in infancy, effects of age, gender, season, viral upper respiratory infection and sleeping position. FEMS Immunology and Medical Microbiology 1999; 25: 19 – 28.
6. Morris JA, Harrison LM. Sudden unexpected death in infancy: evidence of infection. Lancet 2008; 371: 1815 – 1816.
7. Todd J, Fishault M, Kapral F, Welch T. Toxic shock syndrome associated with phage group 1 staphylococci. Lancet 1978; ii: 1116 – 1118.
8. Harrison LM, Morris JA, Lauder RM, Telford DR. Staphylococcal pyrogenic toxins in infant urine samples: a possible marker of transient bacteraemia. J Clin Pathol 2009; 62: 735 – 738.
9. Morris JA. Optimise the microbial flora with milk and yoghurt to prevent disease. Medical Hypotheses 2018; 114: 13 – 17.