Some possible implications of microbiome and immune system interactions for treatment of severe COVID-19

The drugs that are currently being tested to treat severe COVID-19 infection are primarily focused on preventing or slowing viral replication or blocking the actions of IL-6 or other cytokines. In order to consider a wide range of possibilities to help achieve the greatest potential for benefit, it seems worth considering the role of other immune cells that contribute to the production of IL-6 and other inflammation-related changes.
As mentioned previously, the tendency for severe COVID-19 to be most common in individuals with chronic diseases that may involve infections/dysbiosis that produce low-grade inflammation would suggest that other approaches might also be beneficial. Previously, the growing evidence for a significant role for mast cells in a number of chronic conditions that involve elevated pro-inflammatory cytokines and hypersensitivity responses was discussed[12]. Mast cells also appear to play an important role in cardiovascular disease[105], diabetes[106] and COPD[107]. The many effects of mast cells on inflammatory processes in cardiovascular disease, obesity, insulin resistance and diabetes, as well as established and experimental medications to prevent or block these effects, was reviewed by Theoharides et al[108].
Hypertension, associated with elevated angiotensin II, has been linked to mast cells[109], and mast cell stabilization has lowered angiotensin II in animal models[110]. It has been suggested that an approach to treating hypertension that is focused on mast cells might be worth studying in humans[110]. Activation of the renin angiotensin aldosterone system (RAAS) has been found to occur as a result of acute psychosocial stress[111] and may also occur as a result of chronic stress[112]. Elevated angiotensin II appears to be associated with more severe COVID-19[113]. The elevation is thought to be due to the actions of the coronavirus binding ACE2 in a way that reduces its ability to degrade angiotensin II[114]. The fact that hypertension seems to be found at a higher level among the most severe COVID-19 cases, suggests that processes that were occurring before the viral infection might be relevant as well. It is interesting to consider the possibility that a prior elevation of angiotensin II in hypertensive patients might play a role in the severity of COVID-19. Research has shown that inflammation is interconnected extensively with activation of the RAAS[115]. It seems reasonable to speculate that the prior inflammation and stress associated with an increased activation of the RAAS might arise from low grade infections and/or dysbiotic microbiotas, as discussed above[114], and might be a contributing factor leading to the development of severe COVID-19.
Mast cell stabilization has shown benefits in a randomized controlled trial of diabetes in humans[116] and is discussed in a recent review on cardiovascular disease[105]. Additional research on the role of IgE and mast cells has been reviewed[106,117], indicating a potential beneficial role of mast cell stabilization in obesity and diabetes as well.
Besides their role in allergies/hypersensitivities, mast cells are important in the immune response to viral, bacterial, fungal and parasitic infections[118] and there is evidence that they play a role in the immunopathology in coronavirus infections[119,120]. Mast cells are important in immune defense; however, when mast cell activation is excessive, it can cause more harm than benefit. Studies in mice support the role of excessive activation of mast cells in viral respiratory illnesses, such as influenza, that cause death largely due to excessive inflammation[121]. Sodium cromoglycate, which stabilizes mast cells, has been shown to be beneficial in a mouse model of H5N1 influenza[122]. Mast cell stabilization using ketotifen reduced lung lesions and apoptosis in another study using a mouse model of H5N1 influenza[123]. Kritas et al[119] has suggested that a possible treatment approach to control the mast cell contribution to the high level of inflammation in severe COVID-19 might involve anti-inflammatory cytokines of the IL-1 family.
Mast cell activation appears to be important in lung diseases[107], like COPD, one of the diseases that is a risk factor for severe COVID-19 outcomes. Fibroproliferation that occurs in the acute respiratory distress syndrome may not be initiated by mast cells; however, mast cells still appear to play an important role in the increased inflammation[124]. Overed-Sayer[125] et al reviewed studies on the mast cell role in idiopathic pulmonary fibrosis and fibrotic diseases of other organs, indicating that the role of mast cells is a promising area of investigation.
Sepsis occurs in a subset of severe COVID-19 cases[126]. In animal models, sepsis has been linked to mast cell involvement[127] and has been improved by mast cell stabilization[128] and histamine receptor blockers[129]. Mast cell activation seems to be beneficial at the local level or more moderate disease, but was detrimental at the systemic level in the severe cecal ligation and puncture (CLP) mouse model of sepsis[118,130,131]. On the whole, these and other studies and reviews suggest that mast cell focused approaches are worth investigating as treatment approaches in COVID-19.
COPD is a condition associated with severe outcomes of COVID-19 and may be linked to other risk factors for severe COVID-19, such as diabetes[132] and heart disease[133]. It is estimated that an increasing portion of the U.S. population has reduced airway function related to COPD and that 70% of these cases remain undiagnosed[134,135]. Many cases are related to tobacco use; however, research[136] has also implicated other factors, such as occupational and other environmental exposures, such as air pollution and mold exposure[137].
It is also interesting to consider a potential role for hypersensitivity-related mechanisms and treatments. Asthma is often associated with reactions to allergens or chemicals/irritants, and asthma can be difficult to distinguish from COPD, especially in the elderly[138]. It has even been proposed that asthma and COPD may be part of the same disease process, particularly because prior asthma is associated with the development of COPD[139]. Asthma-COPD overlap syndrome is increasingly being recognized and is found to benefit from the IgE-blocking monoclonal antibody, omaluzimab[139]. Atopy has been found at a significant level in dairy farmers with COPD[140].
Both allergic and non-allergic rhinitis are common comorbid conditions in COPD, and even though IgE may not be elevated in the serum in many rhinitis patients, non-allergic rhinitis has been associated with local elevations of IgE[141]. IgE levels are thought to decline to some degree with age, like other immunoglobulins, as part of immunosenescence. However, allergic diseases can still be significant in the elderly, despite the fact that they are often given less attention[142].
It is interesting to consider whether IgE responses might, under certain circumstances, shift over time, toward excessive IgG responses that have the potential for pathogenic effects, as has been suggested in eosinophilic esophagitis[143] and possibly other conditions[12]. Both IgE and IgG responses might be targeting at least some microbes within the tissue microbiota and possibly cross-reacting self-antigens. Trost et al has found cross-reactivity between microbes and tissue antigens to be extensive[144].
In severe viral infections, such as COVID-19, the activation of the immune system in response to the coronavirus might cause an increased immune response to the dysbiotic microbiota and cross-reacting self-tissues and could be hypothesized to be a factor in the development of the acute respiratory distress syndrome and multiple organ failure in COVID-19.
Based on the above connections between COPD and allergic conditions, IgE levels might be measured in COVID-19 patients, especially in those with prior lung disease, like asthma or COPD. Typically, IgE levels are high at the beginning of a viral respiratory infection and they decline over a 3-month period. But perhaps, they would stay high in more severely ill COVID-19 patients. This pattern was found in atopic individuals with viral infections[145]. If this were the case, or if local IgE levels were elevated, the IgE-targeting monoclonal antibody drug, omaluzimab, might be considered in some patients as a treatment for severe COVID-19 inflammation. Omaluzimab is thought to work through stabilizing mast cells as well as binding IgE. The large numbers of those with undiagnosed COPD mentioned above might be reason to consider this approach even in those without known prior chronic lung disease.
Other inflammatory markers are also being implicated in severe COVID-19 and a detailed discussion of this topic is beyond the scope of this review. However, among 3 markers that Yang et al[146] found were associated with worse outcomes of COVID-19 was IP-10 (aka interferon gamma-induced protein-10 or CXCL-10 or C-X-C motif chemokine 10). They suggested IP-10 might be a therapeutic target to consider in the treatment of COVID-19. This marker has also been associated with cardiovascular disease and risk of diabetes[147] as well as the recruitment of mast cells in asthma[148]. Evidence suggests that IP-10 also plays a role in COPD[149].
Another consideration relevant to a role for the microbiome or other infectious agents in COVID-19 is the possibility of a bacterial or fungal strain being present in the alveoli of some individuals that might cross-react with SARS-CoV-2 and thus might contribute to inflammatory symptoms (L. Carrasco, UAM, personal communication). Interestingly, hydroxychloroquine has been found to have antifungal and antibacterial effects. For instance, there was a case report of a skin infection with Aspergillus niger resolving in the weeks after hydroxychloroquine was instituted for a rheumatic condition only to return when the patient had to stop the hydroxychloroquine due to tinnitus[150]. There have been promising reports regarding the use of hydroxychloroquine in SARS-CoV-2 with a focus on its antiviral effects[151]. Other recent studies have failed to show benefit[152,153], however, further large randomized controlled trials are being conducted. If shown to be effective in at least a proportion of patients, it might be acting via multiple antimicrobial mechanisms. It might be that hydroxychloroquine or another antimicrobial would be most beneficial if administered before the severe inflammatory stage that requires anti-inflammatory medications. Since antimicrobials also may have harmful effects, including disruptive effects on the microbiome, caution needs to be used. Microbiome studies would be useful to test this hypothesis.