Long COVID therapies, tested partially beneficial, linked to EP-receptor profiles
Long COVID interventions; PGE2 hypothesis-driven mechanistic explanations
| Long COVID therapy trials | Published data | Hypothetical molecular mechanisms underlying symptom alleviation in LC |
DNA Aptamer drug BC007 Rovunaptabin Two cohort studies 1,2 and a case report 3 “The removal of GPCR-AAb might ameliorate the characteristics of the LCD, such as capillary impairment, loss of taste, and CFS.” 3 |
BC007 decreases IgG-autoantibody-activity 3 PGE2 stimulates autoantibodies through EP2 and EP4 4 5 6,7 |
Potentially beneficial for patients with “EP2 up” and/or “EP4 up” (“EP3 down”) |
Histamine receptor antagonists (HRA) Cohort study 8 “72% of patients with long COVID who received HRA reported clinical improvement.” |
HRA could decrease inflammatory PGE2 activity 8 Histamine reportedly upregulates COX-2/ PGE2 through H1 9 and through H2 10 HRA therapy antagonizes histamine activity 8 |
HRA could decrease inflammatory PGE2 activity by preventing histamine from upregulating PGE2 through H1 and H2 Potentially beneficial for patients with “EP3 down” |
Hyperbaric oxygen (HBOT) Cohort study 11 Review 12 “56-63% of long term-ill patients had a clinically relevant improvement in MCS/PCS 3 months after HBOT. However, 13-19% of the patients had a clinically relevant deterioration in MCS/PCS.” 11 |
HBOT decreases PGE2 level 13-15 HBOT alleviates predominantly cognitive symptoms 11 that we presume to be stimulated by EP1 (see section 10. And 11.1) “The symptoms that showed most improvement were predominantly in the cognitive domain 11.” |
Potentially harmful for patients with “EP3 up” & “EP1 down” |
Lidocaine Subcutaneous lidocaine-HP-β-CD: every other day or daily Cohort study 18 “Twenty-seven of 30 symptoms improved significantly at week 24 of treatment compared to pre-treatment. No serious adverse events were reported.” 18 |
Prolonged Lidocaïne administration reportedly decreases COX-2 / PGE2 activity 19 |
Prolonged Lidocaïne administration could hypothetically alleviate long COVID symptoms, decreasing PGE2 activity by binding to the Gq subunit of EP1 Potentially beneficial for patients with “EP1 up” potentially unbeneficial for patients with “EP1 down” |
Low Dose Naltrexon Cohort study 20 Case series with CFS patients 21 “We found a subset of 52 % of patients to be responders after 12 weeks of treatment.” Case series with CFS patients 21 “small-scale clinical trials have shown efficacy and low toxicity.” |
LDN decreases PGE2 activity through antagonizing TRL-4 activity 22 TRL-4 triggers PGE2 production 23 |
LDN could decrease inflammatory PGE2 activity through antagonizing TRL-4 activity 22 Potentially beneficial for patients with “EP3 down” |
| Stellate Ganglion Block (SGB) Cohort study 24 “Results indicated that a substantial proportion of patients (86%) experienced a reduction of their symptoms following SGB treatment.” 24 | In general, the SNS and PNS have opposing effects, and they interact 25 possibly through PGE2 activity: PGE2 binding to EP3 increases inflammatory SNS activity 26 27 and suppresses PNS activity 28 (see section 4.) |
SGB could decrease inflammatory PGE2 activity by inhibiting inflammatory SNS signaling 29 and stimulating anti-inflammatory PNS signaling May provide benefits across all four sub-phenotypes, but as it is expected to reduce PGE2 levels very effectively, it may pose a risk of raising blood pressure in patients with an “EP3-up” profile. |
Vagal Nerve Stimulation (VNS) Cohort study 30 “This pilot study provides preliminary evidence supporting the potential of t-VNS as a therapeutic intervention for female Long COVID patients.” |
PGE2 binding to EP3 suppresses PNS activity 28 and increases inflammatory SNS activity 26 27 VNS decreases brain COX-2/PGE2 31 |
VNS could decrease inflammatory PGE2 activity by stimulating anti-inflammatory PNS signaling decreasing inflammatory SNS activity May provide benefits across the four sub-phenotypes for patients with an “EP1-up” profile as expression of EP1 is expected to decrease with decerasing COX2/PGE2 levels in the brain and nervoussystem. |
1 Hohberger, B. et al. Safety, tolerability and clinical effects of rovunaptabin, also known as BC007 on fatigue and quality of life in patients with Post-COVID syndrome (reCOVer): a prospective, exploratory, placebo-controlled, double-blind, randomised phase IIa clinical trial (RCT). EClinicalMedicine 86, 103358 (2025). https://doi.org/10.1016/j.eclinm.2025.103358
2 Mardin, C. Y. et al. Influence on eye displacement in MRI after Rovunaptabin (BC007) in Post-COVID syndrome: reCOVer, a cross-over randomized controlled pilot trial. Investigative Ophthalmology & Visual Science 66, 1552-1552 (2025).
3 Hohberger, B. et al. Case Report: Neutralization of Autoantibodies Targeting G-Protein-Coupled Receptors Improves Capillary Impairment and Fatigue Symptoms After COVID-19 Infection. Front Med (Lausanne) 8, 754667 (2021). https://doi.org/10.3389/fmed.2021.754667
4 Stein, S. H. & Phipps, R. P. Antigen-specific IGG2A production in response to prostaglandin E2, immune complexes, and IFN-gamma. The Journal of Immunology 147, 2500-2506 (1991). https://doi.org/10.4049/jimmunol.147.8.2500
5 Fedyk, E. R. & Phipps, R. P. Prostaglandin E2 receptors of the EP2 and EP4 subtypes regulate activation and differentiation of mouse B lymphocytes to IgE-secreting cells. Proc Natl Acad Sci U S A 93, 10978-10983 (1996). https://doi.org/10.1073/pnas.93.20.10978
6 Ishihara, Y. et al. Regulation of Immunoglobulin G2 Production by Prostaglandin E<sub>2</sub> and Platelet-Activating Factor. Infection and Immunity 68, 1563-1568 (2000). https://doi.org/doi:10.1128/iai.68.3.1563-1568.2000
7 Roper, R. L. & Phipps, R. P. Prostaglandin E2 and cAMP inhibit B lymphocyte activation and simultaneously promote IgE and IgG1 synthesis. J Immunol 149, 2984-2991 (1992).
8 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
9 Tan, X. et al. Histamine directly and synergistically with lipopolysaccharide stimulates cyclooxygenase-2 expression and prostaglandin I(2) and E(2) production in human coronary artery endothelial cells. J Immunol 179, 7899-7906 (2007). https://doi.org/10.4049/jimmunol.179.11.7899
10 Uotila, P. Inhibition of prostaglandin E2 formation and histamine action in cancer immunotherapy. Cancer Immunology, Immunotherapy 37, 251-254 (1993). https://doi.org/10.1007/BF01518519
11 van Berkel, J., Lalieu, R. C., Joseph, D., Hellemons, M. & Lansdorp, C. A. Hyperbaric oxygen therapy for long COVID: a prospective registry. Sci Rep 15, 28351 (2025). https://doi.org/10.1038/s41598-025-11539-0
12 Wu, B. Q. et al. Effects of Hyperbaric Oxygen Therapy on Long COVID: A Systematic Review. Life (Basel) 14 (2024). https://doi.org/10.3390/life14040438
13 Su, J. J., Chen, H. T., Wang, X., Jin, Q. & Wang, L. [The relationship between the expression of PGE2 and COX-2 and the osteogenic activity and oxygen level of alveolar bone]. Shanghai Kou Qiang Yi Xue 33, 85-89 (2024).
14 Niu, K. C., Lin, M. T. & Kao, C. H. Prevention and suppression of pyrogenic fever in rabbits by hyperbaric oxygen. Eur J Pharmacol 570, 229-234 (2007). https://doi.org/10.1016/j.ejphar.2007.05.056
15 Niu, K. C., Huang, W. T., Lin, M. T. & Huang, K. F. Hyperbaric oxygen causes both antiinflammation and antipyresis in rabbits. Eur J Pharmacol 606, 240-245 (2009). https://doi.org/10.1016/j.ejphar.2009.01.013
16 Heyboer Rd, M., Wojcik, S. M., Smith, G. & Santiago, W. Effect of hyperbaric oxygen therapy on blood pressure in patients undergoing treatment. Undersea Hyperb Med 44, 93-99 (2017). https://doi.org/10.22462/3.4.2017.2
17 Wang, L., Wu, Y., Jia, Z., Yu, J. & Huang, S. Roles of EP Receptors in the Regulation of Fluid Balance and Blood Pressure. Front Endocrinol (Lausanne) 13, 875425 (2022). https://doi.org/10.3389/fendo.2022.875425
18 Oostwouder, C. J. et al. Effect of subcutaneous lidocaine-hydroxypropyl-β-cyclodextrin (HP-β-CD) on quality of life in patients with post-COVID condition: a 36-week observational interrupted time series study. EClinicalMedicine 90, 103681 (2025). https://doi.org/10.1016/j.eclinm.2025.103681
19 Cook, V. L. et al. Anti-inflammatory effects of intravenously administered lidocaine hydrochloride on ischemia-injured jejunum in horses. Am J Vet Res 70, 1259-1268 (2009). https://doi.org/10.2460/ajvr.70.10.1259
20 Isman, A. et al. Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain Behav Immun Health 36, 100733 (2024). https://doi.org/10.1016/j.bbih.2024.100733
21 Bolton, M. J., Chapman, B. P. & Van Marwijk, H. Low-dose naltrexone as a treatment for chronic fatigue syndrome. BMJ Case Rep 13 (2020). https://doi.org/10.1136/bcr-2019-232502
22 Zhang, X. et al. Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists. J Chem Inf Model 58, 816-825 (2018). https://doi.org/10.1021/acs.jcim.7b00717
23 Sun, Q., Liu, Q., Zheng, Y. & Cao, X. Rapamycin suppresses TLR4-triggered IL-6 and PGE(2) production of colon cancer cells by inhibiting TLR4 expression and NF-kappaB activation. Mol Immunol 45, 2929-2936 (2008). https://doi.org/10.1016/j.molimm.2008.01.025
24 Pearson, L. et al. Stellate Ganglion Block Relieves Long COVID-19 Symptoms in 86% of Patients: A Retrospective Cohort Study. Cureus 15, e45161 (2023). https://doi.org/10.7759/cureus.45161
25 Luo, D., Pan, W., Li, Y., Feng, K. & Liu, G. The Interaction Analysis between the Sympathetic and Parasympathetic Systems in CHF by Using Transfer Entropy Method. Entropy (Basel) 20 (2018). https://doi.org/10.3390/e20100795
26 Zhang, Z. H. et al. EP₃ receptors mediate PGE₂-induced hypothalamic paraventricular nucleus excitation and sympathetic activation. Am J Physiol Heart Circ Physiol 301, H1559-1569 (2011). https://doi.org/10.1152/ajpheart.00262.2011
27 Yokotani, K. et al. Elevation of plasma noradrenaline levels in urethane-anaesthetized rats by activation of central prostanoid EP3 receptors. Br J Pharmacol 115, 672-676 (1995). https://doi.org/10.1111/j.1476-5381.1995.tb14985.x
28 Reinheimer, T., Harnack, E., Racke, K. & Wessler, I. Prostanoid receptors of the EP3 subtype mediate inhibition of evoked [3H]acetylcholine release from isolated human bronchi. Br J Pharmacol 125, 271-276 (1998). https://doi.org/10.1038/sj.bjp.0702057
29 Deng, J. J. et al. Treatment of stellate ganglion block in diseases: Its role and application prospect. World J Clin Cases 11, 2160-2167 (2023). https://doi.org/10.12998/wjcc.v11.i10.2160
30 Zheng, Z. S., Simonian, N., Wang, J. & Rosario, E. R. Transcutaneous vagus nerve stimulation improves Long COVID symptoms in a female cohort: a pilot study. Frontiers in Neurology 15 (2024). https://doi.org/10.3389/fneur.2024.1393371
31 Revathikumar, P., Maître, E. L., Jakobsson, P.-J., Korotkova, M. & Lampa, J. A2.7 Effects of Vagus Nerve Stimulation on the Central Prostaglandin System and Substance P Following Peripheral Inflammation. Annals of the Rheumatic Diseases 72, A6-A7 (2013). https://doi.org/https://doi.org/10.1136/annrheumdis-2013-203215.7