{"id":4380,"date":"2026-08-15T13:36:34","date_gmt":"2026-08-15T13:36:34","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=4380"},"modified":"2026-09-30T14:17:13","modified_gmt":"2026-09-30T14:17:13","slug":"handout-reverse-side","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=4380","title":{"rendered":"Handout reverse side"},"content":{"rendered":"\t\t
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Clinical phenotypes and potential biomarkers<\/h2>\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t
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Many therapies investigated for Long COVID have been reported to reduce PGE2 activity, either directly or indirectly see potential PGE2-lowering therapies<\/a>. The PGE2 hypothesis proposes that persistent PGE2 activity, together with altered expression of its receptors (EP1\u2013EP4), may contribute to the development and maintenance of Long COVID and related fatigue syndromes.\u00a0However, chronic PGE2 overactivity may not affect all patients in the same way. Differences in EP-receptor expression and cellular adaptation could result in different PGE2 signaling profiles, potentially contributing to the clinical heterogeneity observed in Long COVID.
If biological responses to PGE2 differ between patients because of differences in their EP-receptor expression profiles, a therapy that influences PGE2 signaling may be beneficial for some patients but less effective in others. In this context, partially successful clinical studies may not necessarily indicate that a treatment is ineffective overall, but could point to the need for biological stratification of patients.<\/p>

Several techniques may potentially be used to assess EP-receptor expression and function, as well as other biological features related to PGE2 signaling. The table below summarizes potential clinical and biochemical biomarkers that could help identify biologically distinct patient subgroups and support the development of future precision-medicine approaches.<\/p>

For further information and references, see our hypothesis publication DOI:<\/em>10.1016\/j.bbrep.2026.102518<\/em><\/a> or visit the website: pge2-hypothesis.com<\/em><\/p>

Hypothetical biomarkers for two or four subgroups of LC patients\u00a0<\/h3>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t
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Two observed subphenotypes<\/th>More male patients<\/th>More female patients<\/th><\/tr>

More often hospitalized<\/p><\/th>

More often mild infection<\/th><\/tr><\/thead>

(PGE2 stimulates the sickness syndrome through EP3)<\/em><\/p>

Proposed EP3-receptor-expression<\/a><\/p><\/th>

+EP3<\/p><\/td>

-EP3<\/p><\/td><\/tr>

Four observed subphenotypes<\/th>Cardiovascular, kidney, allergy<\/span><\/td>Gastro-intestinal, urinary tract, respiratory<\/span><\/td>Musculo-skeletal, nervous system, auto-immune<\/span><\/td>Fatigue, Respiratory\/asthma, mental and cognitive problems<\/span><\/td><\/tr>
Proposed full EP-receptor-profile (in view of their functions)<\/th>

+EP1<\/p>

-EP2<\/p>

+EP3<\/span><\/p>

-EP4<\/p><\/td>

-EP1<\/p>

-EP2<\/p>

+\/-EP3<\/p>

+EP4<\/span><\/p><\/td>

-EP1<\/p>

+EP2<\/span><\/p>

-EP3<\/p>

+EP4<\/span><\/p><\/td>

+EP1<\/span><\/p>

+EP2 (internalized)<\/span><\/p>

-EP3<\/p>

+EP4 (internalized)<\/p><\/td><\/tr>

Matching reported EP-expression in the immune cells listed below\u2074<\/th>

-EP2<\/p>

-EP4<\/p><\/td>

+EP1<\/p>

+EP3<\/p><\/td>

-EP2<\/p>

+EP4<\/p><\/td>

+EP2<\/p>

+EP4<\/p><\/td>

+EP2<\/p>

-EP4<\/p><\/td><\/tr>

Proposed matching predominant immune cell type<\/p>

and immune response\u2077-\u00b9\u00b9<\/p><\/th>

Na\u00efve CD4+ cells<\/p>

Innate<\/p><\/td>

(mastcells)<\/p><\/td>

Classical Monocytes<\/p>

Th1<\/p><\/td>

Non classical Monocytes<\/p>

Th17<\/p><\/td>

Intermediate Monocytes<\/p>

Th2<\/p><\/td><\/tr>

Matching clusters of cytokines\u00b9<\/th>Pro-inflammatory cytokines<\/td>IFN-\u03b3\/IL-1\u03b2<\/td>IL-17<\/td>Anti-inflammatory cytokines<\/td><\/tr><\/tbody><\/table><\/div>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t
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Published data on PGE2, immune cells, and cytokines<\/h3>

The following findings from the literature are relevant to the proposed relationship between PGE2 signaling, immune-cell function, cytokine profiles, and fatigue in Long COVID.<\/p>

Cytokines and clinical subphenotypes<\/h6>