The table below lists reported biomedical characteristics of Long COVID patients that are consistent with PGE2 activity associated with either an “EP3-up” or “EP3-down” profile, according to the literature.

Candidate biomarkers for two subgroups of LC patients based on the PGE2 hypothesis

Hypothetical biomarkers for LC Category A – “EP3 up” enhanced capacity of EP3 as compared to healthy subjects “seropositive Long COVID”	Hypothetical biomarkers for LC Category B – “EP3 down” insufficient capacity of EP3 as compared to healthy subjects “seronegative Long COVID”	References
Data compared to presumed category B patients:	Data compared to presumed category A patients:
higher percentage was hospitalized for COVID-19	higher percentage experienced a mild infection	11
higher percentage of male patients	higher percentage of female patients	11,150
more antibodies against Sars	less antibodies against Sars	153 159,160
more activity of CD4+ cells	less activity of CD4+ cells 161	153
more proinflammatory activity	more anti-inflammatory activity	153
more sympathetic activity	less sympathetic activity	52
can develop a high fever	not prone to high fever	51,162
higher blood pressure – measured in adolescence (before age-induced changing PGE2 levels that could stimulate BP and atherosclerosis)	lower blood pressure – measured in adolescence (before age-induced changing PGE2 levels that could stimulate BP and atherosclerosis)	22,163
more thrombotic problems	less thrombotic problems	164
less lipolysis, more evenly distributed (brown) adipose tissue 126	more lipolysis leading to more ectopic adipose tissue 165	166
more insulin sensitivity	less insulin sensitivity	165
attenuated insulin secretion	insulin secretion is less attenuated	167
less β-cell proliferation and survival	more β-cell proliferation and survival	168
lower glucose level	higher glucose level	169

150         Danesh, V. et al. Symptom Clusters Seen in Adult COVID-19 Recovery Clinic Care Seekers. J Gen Intern Med 38, 442-449 (2023). https://doi.org/10.1007/s11606-022-07908-4

151         Aronoff, D. M. et al. E-prostanoid 3 receptor deletion improves pulmonary host defense and protects mice from death in severe Streptococcus pneumoniae infection. J Immunol 183, 2642-2649 (2009). https://doi.org/10.4049/jimmunol.0900129

152         Maher, S. A., Birrell, M. A. & Belvisi, M. G. Prostaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy. Am J Respir Crit Care Med 180, 923-928 (2009). https://doi.org/10.1164/rccm.200903-0388OC

153         Kervevan, J. et al. Divergent adaptive immune responses define two types of long COVID. Frontiers in Immunology 14 (2023). https://doi.org/10.3389/fimmu.2023.1221961

154         Okano, M. et al. E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2. Immunology 118, 343-352 (2006). https://doi.org/10.1111/j.1365-2567.2006.02376.x

155         Muenchhoff, M. & Goulder, P. J. Sex differences in pediatric infectious diseases. J Infect Dis 209 Suppl 3, S120-126 (2014). https://doi.org/10.1093/infdis/jiu232

156         Blesson, C. S., Büttner, E., Masironi, B. & Sahlin, L. Prostaglandin receptors EP and FP are regulated by estradiol and progesterone in the uterus of ovariectomized rats. Reproductive Biology and Endocrinology 10, 3 (2012). https://doi.org/10.1186/1477-7827-10-3

157         Gross, R. S. et al. Characterizing Long COVID in Children and Adolescents. Jama 332, 1174-1188 (2024). https://doi.org/10.1001/jama.2024.12747

158         Kikkenborg Berg, S. et al. Long COVID symptoms in SARS-CoV-2-positive children aged 0-14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study. Lancet Child Adolesc Health 6, 614-623 (2022). https://doi.org/10.1016/s2352-4642(22)00154-7

159         Queiroz, M. A. F. et al. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front Cell Infect Microbiol 12, 922422 (2022). https://doi.org/10.3389/fcimb.2022.922422

160         Kaspersen, K. A. et al. Symptoms reported by SARS-CoV-2 seropositive and seronegative healthcare and administrative employees in Denmark from May to August 2020. Int J Infect Dis 109, 17-23 (2021). https://doi.org/10.1016/j.ijid.2021.06.017

161         Glynne, P., Tahmasebi, N., Gant, V. & Gupta, R. Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines. J Investig Med 70, 61-67 (2022). https://doi.org/10.1136/jim-2021-002051

162         Machado, N. L. S., Bandaru, S. S., Abbott, S. B. G. & Saper, C. B. EP3R-Expressing Glutamatergic Preoptic Neurons Mediate Inflammatory Fever. J Neurosci 40, 2573-2588 (2020). https://doi.org/10.1523/JNEUROSCI.2887-19.2020

163         Cipollone, F. et al. Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human. Arterioscler Thromb Vasc Biol 25, 1925-1931 (2005). https://doi.org/10.1161/01.Atv.0000177814.41505.41

164         Mawhin, M. A., Tilly, P. & Fabre, J. E. The receptor EP3 to PGE2: A rational target to prevent atherothrombosis without inducing bleeding. Prostaglandins Other Lipid Mediat 121, 4-16 (2015). https://doi.org/10.1016/j.prostaglandins.2015.10.001

165         Inazumi, T. et al. Prostaglandin E(2)-EP4 Axis Promotes Lipolysis and Fibrosis in Adipose Tissue Leading to Ectopic Fat Deposition and Insulin Resistance. Cell Rep 33, 108265 (2020). https://doi.org/10.1016/j.celrep.2020.108265

166         Inazumi, T. & Sugimoto, Y. Metabolic Regulation in Adipocytes by Prostanoid Receptors. Biological and Pharmaceutical Bulletin 45, 992-997 (2022). https://doi.org/10.1248/bpb.b22-00270

167         Kimple, M. E. et al. Prostaglandin E2 Receptor, EP3, Is Induced in Diabetic Islets and Negatively Regulates Glucose- and Hormone-Stimulated Insulin Secretion. Diabetes 62, 1904-1912 (2013). https://doi.org/10.2337/db12-0769

168         Bosma, K. J. et al. Pharmacological blockade of the EP3 prostaglandin E(2) receptor in the setting of type 2 diabetes enhances β-cell proliferation and identity and relieves oxidative damage. Mol Metab 54, 101347 (2021). https://doi.org/10.1016/j.molmet.2021.101347

169         Püschel, G. P., Kirchner, C., Schröder, A. & Jungermann, K. Glycogenolytic and antiglycogenolytic prostaglandin E2 actions in rat hepatocytes are mediated via different signalling pathways. Eur J Biochem 218, 1083-1089 (1993). https://doi.org/10.1111/j.1432-1033.1993.tb18468.x