The occurrence of MCA symptoms in LC patients has previously not been examined in a detailed manner. In the present study, there was a high prevalence of MCA symptoms in LC patients prior to MCAS treatment. The symptom data and spider web plots illustrated that LC patients’ symptoms are virtually identical to those experienced by MCAS patients. These results support, but do not provide definitive proof of, our earlier hypothesis that LC might often arise out of a SARS-CoV-2-driven provocation of primary or secondary MCAS (Afrin et al., 2020a). Theories to explain promotion of MCA in LC include: 1) complex interactions of stressor-induced cytokine storms with epigenetic-variant-induced states of genomic fragility to induce additional somatic mutations in stem cells or other mast cell progenitors; (Afrin et al., 2020a) 2) cytokine or SARS-CoV-2 coronavirus activation of mast cells and microglia; (Theoharides and Conti, 2020) 3) dysregulation of genes by SARS-CoV-2 coronavirus leading to loss of genetic regulation of mast cells; (Maxwell et al., 2021) 4) development of autoantibodies which react with immunoglobulin receptors on mast cells; (Liu et al., 2021, Vojdani et al., 2021) and 5) increase in Toll-like receptor activity by the coronavirus (Mukherjee et al., 2021).
Potential limitations of our study include gender recruitment imbalance. LC females outnumbered LC males. This is likely due to the makeup of the LC Facebook group and/or gender preference for recruitment. In a concurrent study to ours with a similar design/methodology, 78.9% of 3762 LC Internet responders were women (Davis et al., 2021). In the largest study to date, LC was more common in women (FAIR Health White Paper, 2021). With respect to gender imbalance in the general population control, it is likely that more women than men were recruited because of gender imbalance of employees at the hospital and endoscopy center and these individuals may not have recruited male spouses. In our studies and clinical practices, we have observed that MCAS patients have a significantly higher percentage of women (Afrin et al., 2017, Molderings et al., 2013). We recognize that members of most social media groups are largely self-selected and do not constitute a randomly selected population and may not necessarily represent the general population of patients who have LC. Subjects who join a medical support group might be more ill than other patients. Yet, examination of such groups may provide preliminary insights which may provide useful guidance for further research. The fact that the MCAS patients were diagnosed at a gastroenterology clinic that subspecializes in MCAS could have biased the comparison group by having increased severity of gastrointestinal symptoms. Nonetheless, MCAS patients often present to gastroenterologists as well as many other specialists (e.g., allergists, cardiologists, neurologists, and urologists) (Weinstock et al., 2021). Retrospective data entered by the MCAS patients was not ideal methodology. Their symptoms, however, were experienced within a 2-year period of the study and MCAS symptoms often are present for decades. Another potential problem is that the LC group completed their pre-COVID-19 questionnaire by recall, and thus this part of the study was retrospective. This was a limitation of the study design, yet the spider symptom/severity plots at baseline were remarkably similar to the general population control group, likely negating this issue.