Zhang et al. investigated the incidence and reproducibility of specific Long Covid-symptoms in individuals who contracted COVID19 (in the pre-Omicron period) ¹. In a development cohort of 20.881 and a validation cohort of 13.724 patients, they identified over 137 Long Covid symptoms and conditions in four reproducible subphenotypes ¹.

• Type 1 “Cardiac and renal”: Compared to the other subphenotypes patients were older, mean age 65 yrs, predominantly men, with more severe illness and the highest hospitalization rate. They also had the highest burden of comorbidities, ao cardiac and circulatory problemsand kidney problems
• Type 2 “Respiratory, sleep and anxiety”: consisted of more women, mean age 51 yrs. 
• Type 3 “Musculoskeletal and nervous”:more women and higher baseline comorbidity of autoimmune and allergy conditions, mean age 57 yrs.
• Type 4 “Digestive and respiratory”, smallest cohort, mainly female patients, digestive system, urinary and respiratory conditions, lower burden of underlying conditions, mean age 54 yrs. 

We considered Zhang’s data according to our ‘EP receptor up and down’ approach (Data-set 1.). We collected evidence that the symptoms of Zhangs “Type 1” can be correlated with “EP3 up”. The symptoms of the other three types can be linked to “EP3 down” combined with “EP1 up”, “EP2 up” and “EP4 up” respectively (see for references Data-set 2).
Of significance:  EP1, EP2 and EP4 are expected to upregulate by infections while EP3 expression is expected to downregulate, looking at the reported effect of PGE2/COX-2 upregulation on EP receptor expressions (see full hypothesis article, section 3.1)

Data-set 1. Hypothetical EP receptor distribution in four subphenotypes of LC patients

Zhangs 4 types of Long COVID patients	Characteristic LC subphenotypes according to Zhangs research and terminology	Male/female ratio	Proposed distribution patterns of four EP expression based on our literature searches (see references in Data-set 1) compared with the presumed profiles of the other types and average EP expressions
Type 1	“Cardiac and renal”	Mostly  male	EP3 up
Type 2	“Respiratory, sleep  and anxiety”	Mostly female	EP1 up	EP3 down
Type 3	“Musculoskeletal and nervous”	Mostly female	EP2 up	EP3 down
Type 4	“Digestive and respiratory”	Mostly female	EP4 up	EP3 up/down*
* EP4 expression (↑cAMP) up = EP3 capacity (↓cAMP) down, even when EP3 expression is up

Data-set 2. Four LC symptom clusters hypothetically associated with dominance of a distinct EP receptor

Type 1 “Cardiac and renal” EP3 up PGE2-EP3 activity contributes to high blood pressure 2,3 and cardiac 4-8 and renal 9-12 problems	Type 4 “Digestive and respiratory”  EP4 up  PGE2-EP4 activity stimulates bile 13 and reportedly contributes to gastrointestinal 14-16 and airway 17,18 problems – bile stimulates both 19,20
Type 2 “Respiratory, sleep and anxiety” EP1 up PGE2-EP1 activity contributes to respiratory problems 21-24 and mediates elevated anxiety 25. PGE2 and COX-2 derived PGD2 through EP1 have opposing roles in sleep regulation 26	Type 3 “Musculoskeletal and nervous”  EP2 up  PGE2-EP2 activity stimulates oligodendrocyte apoptosis and demyelination, possibly contributing to musculoskeletal 27-30,31 and nervous 32-35 problems. PGE2-EP2 stimulates aldosterone 36 and aldosterone upregulation is associated with damages to skeletal muscle cells 37,38

These models might help finding the right treatment for more specific types of Long COVID patients.

---

References

1          Zhang, H. et al. Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes. Nature Medicine 29, 226-235 (2023). https://doi.org/10.1038/s41591-022-02116-3

2          Bryson, T. et al. The Deleterious Role of the Prostaglandin E 2 EP3 Receptor in Angiotensin II Hypertension. American Journal of Physiology-Heart and Circulatory Physiology 318 (2020). https://doi.org/10.1152/ajpheart.00538.2019

3          Wu, J. et al. EP3 (E-Prostanoid 3) Receptor Mediates Impaired Vasodilation in a Mouse Model of Salt-Sensitive Hypertension. Hypertension 77, 1399-1411 (2021). https://doi.org/doi:10.1161/HYPERTENSIONAHA.120.16518

4          Bryson, T. D. et al. Targeted Gene Deletion or Antagonism of the Prostaglandin E2 EP3 Receptor Protects Against Cardiac Injury Postmyocardial Infarction. Circulation: Heart Failure 17, e011089 (2024). https://doi.org/doi:10.1161/CIRCHEARTFAILURE.123.011089

5          Schaid, M. D., Wisinski, J. A. & Kimple, M. E. The EP3 Receptor/G(z) Signaling Axis as a Therapeutic Target for Diabetes and Cardiovascular Disease. Aaps j 19, 1276-1283 (2017). https://doi.org/10.1208/s12248-017-0097-1

6          Gu, X. et al. Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9 (2016). https://doi.org/10.1161/CIRCHEARTFAILURE.116.003291

7          Meyer-Kirchrath, J. et al. Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart. Cardiovasc Res 81, 310-318 (2009). https://doi.org/10.1093/cvr/cvn312

8          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

9          Jing, L., Wen, Z. & Bin, L. The role of E-type prostaglandin receptor EP3 in acute renal injury induced by ischemia-reperfusion. Journal of Molecular and Cellular Cardiology 140, 56 (2020). https://doi.org/https://doi.org/10.1016/j.yjmcc.2019.11.135

10        Leng, J. et al. E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation. Kidney International 103, 100-114 (2023). https://doi.org/https://doi.org/10.1016/j.kint.2022.08.019

11        Hassouneh, R. et al. PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes. Diabetologia 59, 1318-1328 (2016). https://doi.org/10.1007/s00125-016-3916-5

12        Vio, C. P., Quiroz-Munoz, M., Cuevas, C. A., Cespedes, C. & Ferreri, N. R. Prostaglandin E2 EP3 receptor regulates cyclooxygenase-2 expression in the kidney. Am J Physiol Renal Physiol 303, F449-457 (2012). https://doi.org/10.1152/ajprenal.00634.2011

13        Ying, F. et al. EP4 emerges as a novel regulator of bile acid synthesis and its activation protects against hypercholesterolemia. Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids 1863, 1029-1040 (2018). https://doi.org/https://doi.org/10.1016/j.bbalip.2018.06.003

14        Dey, I., Giembycz, M. A. & Chadee, K. Prostaglandin E(2) couples through EP(4) prostanoid receptors to induce IL-8 production in human colonic epithelial cell lines. Br J Pharmacol 156, 475-485 (2009). https://doi.org/10.1111/j.1476-5381.2008.00056.x

15        Crittenden, S. et al. Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells.  (2020).

16        Maseda, D. et al. mPGES-1-Mediated Production of PGE2 and EP4 Receptor Sensing Regulate T Cell Colonic Inflammation. Frontiers in Immunology Volume 9 – 2018 (2018). https://doi.org/10.3389/fimmu.2018.02954

17        Akaba, T. et al. Activating prostaglandin E2 receptor subtype EP4 increases secreted mucin from airway goblet cells. Pulmonary Pharmacology & Therapeutics 48, 117-123 (2018). https://doi.org/https://doi.org/10.1016/j.pupt.2017.11.001

18        Aso, H. et al. Prostaglandin E2 enhances interleukin-8 production via EP4 receptor in human pulmonary microvascular endothelial cells. American Journal of Physiology-Lung Cellular and Molecular Physiology 302, L266-L273 (2011). https://doi.org/10.1152/ajplung.00248.2011

19        Reen, F. J. et al. Bile signalling promotes chronic respiratory infections and antibiotic tolerance. Sci Rep 6, 29768 (2016). https://doi.org/10.1038/srep29768

20        Flynn, S. et al. Bile Acid Signal Molecules Associate Temporally with Respiratory Inflammation and Microbiome Signatures in Clinically Stable Cystic Fibrosis Patients. Microorganisms 8 (2020). https://doi.org/10.3390/microorganisms8111741

21        McGraw, D. W. et al. Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex. J Clin Invest 116, 1400-1409 (2006). https://doi.org/10.1172/jci25840

22        Okazaki, A. et al. Role of prostaglandin E2 in bronchoconstriction-triggered cough response in guinea pigs. Pulmonary Pharmacology & Therapeutics 48, 62-70 (2018). https://doi.org/https://doi.org/10.1016/j.pupt.2017.09.003

23        Tilley, S. L. et al. Receptors and pathways mediating the effects of prostaglandin E2 on airway tone. American Journal of Physiology-Lung Cellular and Molecular Physiology 284, L599-L606 (2003). https://doi.org/10.1152/ajplung.00324.2002

24        Okazaki, A. et al. Role of prostaglandin E(2) in bronchoconstriction-triggered cough response in guinea pigs. Pulm Pharmacol Ther 48, 62-70 (2018). https://doi.org/10.1016/j.pupt.2017.09.003

25        Kitaoka, S. & Furuyashiki, T. [Roles of inflammation-related molecules in emotional changes induced by repeated stress]. Nihon Shinkei Seishin Yakurigaku Zasshi 34, 109-115 (2014).

26        Yoshida, Y. et al. Prostaglandin E (EP) receptor subtypes and sleep: promotion by EP4 and inhibition by EP1/EP2. Neuroreport 11, 2127-2131 (2000). https://doi.org/10.1097/00001756-200007140-00014

27        Gao, X. et al. Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin−/−/Utrophin−/− Double-Knockout Mice. Cells 14, 116 (2025).

28        Nango, H. et al. Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis. Transl Neurodegener 12, 32 (2023). https://doi.org/10.1186/s40035-023-00366-w

29        Wang, P., Zhu, F., Lee, N. H. & Konstantopoulos, K. Shear-induced interleukin-6 synthesis in chondrocytes: roles of E prostanoid (EP) 2 and EP3 in cAMP/protein kinase A- and PI3-K/Akt-dependent NF-kappaB activation. J Biol Chem 285, 24793-24804 (2010). https://doi.org/10.1074/jbc.M110.110320

30        Sato, T. et al. Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes. Ann Rheum Dis 70, 221-226 (2011). https://doi.org/10.1136/ard.2009.118620

31        Ota, H. et al. EP2 receptor plays pivotal roles in generating mechanical hyperalgesia after lengthening contractions. Scand J Med Sci Sports 28, 826-833 (2018). https://doi.org/10.1111/sms.12954

32        Lushington, R., Camilli, S., Pascual, F., Lockey, R. F. & Kolliputi, N. EP2 inhibition restores myeloid metabolism and reverses cognitive decline. Journal of Allergy and Clinical Immunology: Global 2, 100082 (2023). https://doi.org/https://doi.org/10.1016/j.jacig.2023.100082

33        Kang, X. et al. Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype. Scientific Reports 7, 9459 (2017). https://doi.org/10.1038/s41598-017-09528-z

34        Minhas, P. S. et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 590, 122-128 (2021). https://doi.org/10.1038/s41586-020-03160-0

35        Palumbo, S., Toscano, C. D., Parente, L., Weigert, R. & Bosetti, F. The cyclooxygenase-2 pathway via the PGE₂ EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination. J Neurochem 121, 418-427 (2012). https://doi.org/10.1111/j.1471-4159.2011.07363.x

36        Csukas, S., Hanke, C. J., Rewolinski, D. & Campbell, W. B. Prostaglandin E2-induced aldosterone release is mediated by an EP2 receptor. Hypertension 31, 575-581 (1998). https://doi.org/10.1161/01.hyp.31.2.575

37        Kang, B. et al. Elevated Myoglobin in Patients With Primary Aldosteronism: A Cross-Sectional Study. Front Endocrinol (Lausanne) 13, 799174 (2022). https://doi.org/10.3389/fendo.2022.799174

38        Palmer, B. F. & Clegg, D. J. Extrarenal Effects of Aldosterone on Potassium Homeostasis. Kidney360 3, 561-568 (2022). https://doi.org/10.34067/kid.0006762021