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.