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.