Acute infections and post-infectious syndromes
As has been mentioned previously, according to the PHM hypothesis, PHM
colonization and associated hypersensitivity and stress often lead to
immune dysregulation and/or suppression. This could increase
susceptibility to infections.
Cardiovascular disease, diabetes and chronic lung diseases have been
associated with greater mortality from COVID-19[273]. These comorbid
diseases have all been associated with low grade inflammation, air
pollution, a westernized diet and increased levels of pathogenic or
dysbiotic microbes[133,274–276]. It is interesting to consider
whether the severe inflammatory component of COVID-19 could be related
to an intensified immune reaction to some of these colonizing microbes.
These microbes might be PHMs or opportunistic pathogens acquired
secondary to PHM colonization.
The PHM hypothesis proposes that before the viral infection, the immune
system was reacting to these colonizing/infecting microbes with
low-grade inflammation. Changes in the cytokine milieu occurring due to
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
might result in the low-grade inflammatory response to the PHMs being
transformed into a more intense inflammatory response (e.g., via isotype
switching). This could potentially contribute to or cause the excessive
inflammation in severe COVID-19. Elevated autoantibodies have recently
been found in a proportion of severe COVID-19[277]. This might
reflect increased reactions to PHMs that cross-react with self-tissue
Mast cells, traditionally known for their role in allergies, have been
proposed to be a potential target in COVID-19 to address excessive
immune reactions[278,279]. In fact, some early trials that targeted
the mast-cell product histamine generated positive
results[280–282]. These findings require validation in large,
randomized controlled trials.
Mast cells are being implicated in chronic inflammatory conditions as
well[283–285]. Beyond their role in allergy, mast cells have been
recognized as having a protective role against a broad range of
infectious agents[285]. The same may be true of IgE-mediated
responses, which are also being implicated in protection against
infections, as discussed above.
It may be relevant to consider the linkages that have been found between
COPD and asthma and/or allergic conditions[286–289]. A study showed
that 37% of adults between 65 and 86 years of age who had asthma or
COPD had asthma-COPD overlap syndrome[290], which was associated
with worse outcomes. The progression of asthma to asthma-COPD overlap
syndrome increased with higher exposure to fine particulate
matter[288] and workplace mold odor[291]. This is consistent
with the PHM hypothesis in that these environments likely contain
elevated PHM levels that could contribute to disease progression.
COPD’s underdiagnosis[292] and frequent connections with allergy
and/or asthma might be reason to investigate IgE levels in COVID-19. The
potential for local IgE elevations without elevated IgE levels in the
blood should also be considered[293].
Although patterns may differ with different viruses, IgE levels were
found to be higher at the beginning of a viral respiratory infection,
declining over the following 3 months[294]. However, perhaps the IgE
levels would stay high or be even more elevated in at least some of the
more severely ill COVID-19 patients and might contribute to the severity
of the inflammation. IgE elevation was observed to persist longer after
a viral infection if the patient was atopic[294]. Interestingly,
there is some evidence that IgE-targeting omalizumab is protective in
viral infections[295,296]. A patient with asthma who was taking
omalizumab was reported to recover from COVID-19 without undergoing any
severe effects[295]. This topic requires further investigation.
Liu et al[133] found that disease occurrence, exacerbation frequency
and inflammatory markers, such as IL-6 and IL-8, were associated with an
increase in pathogenic fungi in COPD patients’ lungs. The PHM hypothesis
suggests that these pathogenic species could be PHMs or occur secondary
to PHMs’ effects and might contribute to the greater susceptibility of
COPD patients to severe COVID-19.
It is still unclear how often bacterial and fungal co-infections are
involved in COVID-19[297,298]. A study[299] showed that
bacterial DNA and LPS in the plasma was significantly higher in patients
with the most severe disease. Bacterial DNA or LPS were also
significantly correlated with inflammatory mediators, such as
IL-6[299]. It is possible that this might be related, in some cases,
to PHMs in various tissues that might be influencing the course of the
disease. Of course, these are only speculative ideas to stimulate
research, and the latest recommendations are that antibiotics and
antifungals should be used judiciously in COVID-19[300].
Another possibility involving a bacterial or fungal strain as a factor
in excessive inflammation in COVID-19 was suggested
recently[274]. It might be that another microbe that cross-reacts
with SARS-CoV-2 is present in the alveoli or other tissues in some
individuals with severe disease (L. Carrasco, UAM, personal
communication). This cross-reacting microbe could be a PHM and might
exhibit antimicrobial resistance, making recovery more difficult.
Relevant to the previous discussion of IgG4, Chen et al[301]
suggested that IgG4-RD patients may be more susceptible to severe
COVID-19. Also, elevated IgG4 was found in the fibrotic tissue of a
surgically resected tracheal ring in a patient with severe
COVID-19[302]. It might be that elevated IgG4 is a sign of chronic
antigenic stimulation by PHMs, as discussed above. Thus, these findings
might be supportive of a role for PHMs in COVID-19 severity.
Excessive inflammation can occur in connection with other infections,
such as influenza and sepsis[303]. Perhaps an intensified reaction
to PHMs might also contribute to the excessive inflammation in
conditions such as these.
PHMs might also be considered in post-infectious syndromes or other
diseases linked to infections, like multisystem inflammatory syndrome in
children and adolescents resulting from COVID-19 (MIS-C). Afrin et
al[304] proposed that MIS-C might be a form of mast cell activation
syndrome. Mast cell stabilization was proposed as a treatment to relieve
prolonged symptoms following acute infection with SARS-CoV-2[305].
It seems plausible, based on the PHM hypothesis, that mast cell
activation syndrome could be occurring as a response to antigens from
PHM colonizers[2].
Prolonged symptoms, often involving fatigue, following COVID-19 have
been compared to other post-infectious entities[306]. Myalgic
encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been reported to
often begin following an infection, stressful event and/or toxin
exposure[307]. A study of ME/CFS patients found elevated blood
Proteobacteria was part of a composite score associated with symptom
severity[308]. One might speculate that this reflects increased
blood PHM levels, since the phylum Proteobacteria includes diverse
environmental microbes. Some ME/CFS patients have reported that diet
changes have been helpful in symptom reduction[309–311], and a
trial of a diet and nutrient intervention led to patient
improvements[312].
It also is worth considering the relevance of recent insights into
Kawasaki disease (KD), a disease that closely resembles the multisystem
inflammatory response syndrome in children and adolescents associated
with SARS-CoV-2 infection. KD has been suggested to be linked to gut
dysbiosis[44,313], a westernized lifestyle/hygiene[44,313],
westernization-associated variants of normal flora[44], autoimmune
disease[314] and allergic disorders[315,316]. Some recent KD
research has implicated a microbe or its toxin transported by
tropospheric air currents, along with a triggering infection in
genetically susceptible individuals[317,318].
Increasing cedar pollen has been associated with increasing KD and other
diseases in Japan[319]. The role of pollen-associated PHMs might be
worth investigating. Pollen-associated microbial communities have been
found to be affected by urbanization-related pollution[320]. The
potential for detrimental effects from hypothesized pollen-associated
PHMs warrants investigation, especially given a recent study that found
an association between pollen levels and cancer incidence[321].
Thus, the possible involvement of westernization-associated gut
microbes, environmental microbes/antigens and triggering infections
suggest that the PHM hypothesis is potentially applicable to KD. And the
evidence for the involvement of an airborne component in KD causation is
reminiscent of the apparent association between severe COVID-19 and air
pollution[322–324].
Taken together, these findings are consistent with the hypothesis that
PHM colonization could be the underlying cause or a factor in
susceptibility or severity of a number of acute infections and their
sequelae.