Skip to main content

H2-antagonist in IgE-mediated type I hypersensitivity reactions: what literature says so far?

Abstract

Histamine is a monoamine synthesized from the amino acid histidine that is well-known for its role in IgE-mediated anaphylaxis but has shown pleiotropic effects on the immune system, especially in order to promote inflammatory responses. H1-receptor antagonist are common drugs used in mild/moderate allergic reactions whereas H2-receptor antagonist are commonly administered in gastric ulcer but showed some properties in allergy too. The EAACI guidelines for diagnosis and treatment of anaphylactic reactions recommend their use as third-line therapy in adjunct to H1-antagonists. The purpose of this article is to produce a complete summary of findings and evidence known so far about the usefulness of H2-receptor antagonist in allergic reactons.

To the editor,

According to EAACI guidelines for diagnosis and treatment of anaphylactic reactions [1], H2 anti-histamines are recommended as third-line therapy in adjunct to H1-antagonists. A recent systematic review evaluating acute and long-term management options for anaphylaxis concluded that this combination may require additional research prior to being included in recommended guidelines [2]. Histamine is a well-known immunomodulatory molecule that is able to influence the Th1/Th2 balance through a number of mechanisms and receptors [3, 4]. Among CD4+ T lymphocytes, Th1 cells are known to express higher levels of H1-receptor in contrast to Th2 cells that express a significantly greater proportion of H2-receptors. Through the binding of H1-receptor, histamine is able to activate a Th1-characterized response by increasing the release of interferon­γ. Alternatively, through H2-receptor, histamine is able to suppress a Th1 and/or Th2 response [5] by inhibition of IL-2, IL-4, IL-13, and interferon­γ production [6]. Within dendritic cells, histamine can drive an increase in expression of both MCH-II and the co-stimulatory molecules CD80 and CD86. Binding at the H2 receptor on both dendritic cells and monocytes, it can induce the production of IL-10, and, specific to monocytes, downregulate the release of IL-12, thus shifting the Th1/Th2 balance toward Th2-dominance [7]. Within eosinophilic granulocytes, histamine presents contrasting effects: low concentrations induce an increase in chemotaxis through H4-receptors, whereas greater concentrations are responsible for decreased chemotaxis via H2-receptors [6].

Despite their use in IgE-mediated reactions, especially in urticaria, H2-antagonists have only been documented to reduce wheal, flare, and itching sensation during skin prick test (SPT) procedures [8] and to improve cutaneous symptoms in small studies when administered in conjunction with H1-antagonists [9,10,11]. In an early study evaluating the use of anti-histamines in a mouse model of peanut-induced anaphylaxis, the co-administration of an H1- and H2-antagonist failed to demonstrate any improvement in the severity nor course of the anaphylactic reaction [12]. Findings from a recent retrospective study in humans have demonstrated that, when used alone, H2-antagonists appear unable to inhibit reactions associated with a histamine control during a SPT. Only when administered in conjunction with additional medications possessing anti-histamine properties the H2-antagonists demonstrate increased efficacy in suppression of histamine control-induced SPT reactions, likely due to the effects of the additional medications [13]. Research by Fedorowicz et al. are in agreement with these findings, concluding that the evidence supporting the use of H2-antagonists in the treatment of urticaria is weak and unreliable [14]. In addition, a small randomized, double-blind, placebo-controlled study suggested that the combination of cetirizine and ranitidine was not more effective than cetirizine alone in the treatment of chronic urticaria [15]. These findings are in contrast to a recent study specifically evaluating cholinergic urticaria suggesting that addition of an H2-antagonist (e.g. lafutidine) to ongoing H1-antagonist therapy could significantly reduce both objective and subjective symptoms and improve the patient’s quality of life [16]. This finding agrees with a previous retrospective cohort study that evaluated the efficacy and usefulness of adding lafutidine as an adjunct therapy in patients with idiopathic chronic urticaria that was not sufficiently controlled by an H1-antagonist alone. 74 % of patients considered lafutidine as useful or better after 3 months of treatment [17]. However, it should be noted that cholinergic urticaria is not solely an IgE-mediated disease, but can involve a complex pathogenesis including cholinergic stimuli, histamine-release, type-I hypersensitivity reactions to sweat and Malassezia globose, and poral occlusion [18].

Cimetidine, the first H2-antagonist introduced into clinical practice, has been shown to reduce the suppressor activity of Foxp3+ CD4+ CD25+ Treg cells through an increased degradation of Foxp3 [19]. Additional research has linked the use of cimetidine to an increase in Th1-type cytokine-mediated immune responses and delayed-type hypersensitivity reactions [20]. In a study involving mice sensitized with a ovalbumin, the administration of cimetidine resulted in a significant increase in both specific-IgE and IL-5 levels in the culture supernatants of spleen cells, whereas Th1-, Th2-, and Th17-type cytokines did not differ between treated and untreated mice [21]. Similar results were found in a mouse model of allergic rhinitis in which the mice were sensitized to ovalbumin: the group treated with ranitidine, an H2-antagonist, in conjunction with ovalbumin immunotherapy demonstrated higher levels of specific-IgE and IL-13 in their nasal lavage fluid, as well as greater levels of eosinophils in their nasal mucosa tissue, when compared to the untreated control group, suggesting a pro-inflammatory effect of the H2-antagonist on specific immunotherapy [22]. In studies of humans, cimetidine has demonstrated additional pro-inflammatory effects including the increased release of Th1-type cytokines, in particular IL-12 and IL-2 [23,24,25]. Pastorello et al. evaluated sixty-seven patients with systemic allergic reactions to amoxicillin, ranging from mild to severe, and, surprisingly, they found that treatment with an H2-antagonist was significantly related to severe reactions (p = 0.007) [26]. In monocytes and dendritic cells, the administration of ranitidine was associated with a reduction in histamine-associated suppression of IL-12 release via the H2 receptor [7, 27]. In addition to monocytes and dendritic cells, H2-receptor effects were evaluated in basophils collected from patients undergoing venom immunotherapy. Interestingly, the authors detected a rapid upregulation of H2-receptor and strong suppression of FcεRI-induced basophil activation and mediator release, including histamine and sulfidoleukotrienes, within the first 6 h of the build-up phase [28].

The majority of these findings appear to suggest that H2-antagonists may illicit pro-inflammatory effects, or effects that work in opposition to allergen immunotherapy; however, in 2016, Lee et al. demonstrated that roxatidine presents anti-allergic and tolerogenic effects through the inhibition of NF-κB, a transcription factor involved in immune regulation, apoptosis, cell differentiation, inflammation, and cancer [29]. In particular, roxatidine was able to suppress the release of inflammatory cytokines such as TNF-α, IL-6, and IL-1β from mast cells and delay the fatality rate in anaphylactic-induced mice. Moreover, the authors found that roxatidine significantly reduced ear swelling, mast cell accumulation, cytokine levels, and dendritic cell migration in sections of ear tissue in an animal model of allergen-induced contact hypersensitivity [30]. Additional findings by Geng et al. further support the anti-inflammatory effects of H2-antagonists, demonstrating that both systemic corticosteroids and H2-antagonists are associated with a significantly greater odds ratio for a negative outcome to the histamine control during SPT [31].

As summarized in Table 1, the scientific evidence supporting the role of H2-antagonists in the treatment of allergic reaction remains conflicted. It is possible that H2-antagonists may exert their effects more rapidly on H2-receptors located in vessels and on smooth muscles compared to those on immune-cells [16]. Alternatively, when administered as an adjunct to an H1-antagonist, it is feasible that they could increase the circulating blood levels via interference in drug metabolism and clearance [32]. Further investigations into the use of H2-antagonists during ongoing immunotherapy are needed to evaluate their use in the treatment or prevention of IgE-mediated allergic reactions.

Table 1 Summary of the research manuscripts assessing the role of H2-antagonist in IgE-mediated type I hypersensitivity reactions

Availability of data and materials

Not applicable.

Abbreviations

SPT:

Skin prick test

References

  1. 1.

    Muraro A, Roberts G, Worm M, Bilo MB, Brockow K, Fernandez Rivas M, et al. Anaphylaxis: guidelines from the European academy of allergy and clinical immunology. Allergy. 2014;69(8):1026–45.

    CAS  Article  Google Scholar 

  2. 2.

    Dhami S, Sheikh A, Muraro A, Roberts G, Halken S, Fernandez Rivas M, et al. Quality indicators for the acute and long-term management of anaphylaxis: a systematic review. Clin Transl Allergy. 2017;7:15.

    Article  Google Scholar 

  3. 3.

    Packard KA, Khan MM. Effects of histamine on Th1/Th2 cytokine balance. Int Immunopharmacol. 2003;3(7):909–20.

    CAS  Article  Google Scholar 

  4. 4.

    Ahmad SF, Zoheir KM, Ansari MA, Korashy HM, Bakheet SA, Ashour AE, et al. Stimulation of the histamine 4 receptor with 4-methylhistamine modulates the effects of chronic stress on the Th1/Th2 cytokine balance. Immunobiology. 2015;220(3):341–9.

    CAS  Article  Google Scholar 

  5. 5.

    Baumer W, Rossbach K. [Histamine as an immunomodulator]. J Dtsch Dermatol Ges. 2010;8(7):495–504.

    PubMed  Google Scholar 

  6. 6.

    Thurmond RL, Gelfand EW, Dunford PJ. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov. 2008;7(1):41–53.

    CAS  Article  Google Scholar 

  7. 7.

    Elenkov IJ, Webster E, Papanicolaou DA, Fleisher TA, Chrousos GP, Wilder RL. Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors. J Immunol. 1998;161(5):2586–93.

    CAS  PubMed  Google Scholar 

  8. 8.

    Kupczyk M, Kuprys I, Bochenska-Marciniak M, Gorski P, Kuna P. Ranitidine (150mg daily) inhibits wheal, flare, and itching reactions in skin-prick tests. Allergy Asthma Proc. 2007;28(6):711–5.

    CAS  Article  Google Scholar 

  9. 9.

    Runge JW, Martinez JC, Caravati EM, Williamson SG, Hartsell SC. Histamine antagonists in the treatment of acute allergic reactions. Ann Emerg Med. 1992;21(3):237–42.

    CAS  Article  Google Scholar 

  10. 10.

    Lin RY, Curry A, Pesola GR, Knight RJ, Lee HS, Bakalchuk L, et al. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med. 2000;36(5):462–8.

    CAS  Article  Google Scholar 

  11. 11.

    Dhanya NB, Rai R, Srinivas CR. Histamine 2 blocker potentiates the effects of histamine 1 blocker in suppressing histamine-induced wheal. Indian J Dermatol Venereol Leprol. 2008;74(5):475–7.

    CAS  Article  Google Scholar 

  12. 12.

    Arias K, Baig M, Colangelo M, Chu D, Walker T, Goncharova S, et al. Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions. J Allergy Clin Immunol. 2009;124(2):307–14. 14 e1-2.

    CAS  Article  Google Scholar 

  13. 13.

    Shah KM, Rank MA, Dave SA, Oslie CL, Butterfield JH. Predicting which medication classes interfere with allergy skin testing. Allergy Asthma Proc. 2010;31(6):477–82.

    Article  Google Scholar 

  14. 14.

    Fedorowicz Z, van Zuuren EJ, Hu N. Histamine H2-receptor antagonists for urticaria. Cochrane Database Syst Rev. 2012;3:8596.

    Google Scholar 

  15. 15.

    Guevara-Gutierrez E, Bonilla-Lopez S, Hernandez-Arana S, Tlacuilo-Parra A. Safety and efficacy of cetirizine versus cetirizine plus ranitidine in chronic urticaria: Double-blind randomized placebo-controlled study. J Dermatolog Treat. 2015;26(6):548–50.

    Article  Google Scholar 

  16. 16.

    Hatakeyama M, Fukunaga A, Washio K, Ogura K, Yamada Y, Horikawa T, et al. Addition of lafutidine can improve disease activity and lead to better quality of life in refractory cholinergic urticaria unresponsive to histamine H1 antagonists. J Dermatol Sci. 2016;82(2):137–9.

    CAS  Article  Google Scholar 

  17. 17.

    Ogawa Y, Ichinokawa Y, Hiruma M, Machida Y, Funakushi N, Sadamasa H, et al. Retrospective cohort study on combination therapy with the histamine H2-receptor antagonist lafutidine for antihistamine-resistant chronic urticaria. J Dermatolog Treat. 2013;24(6):463–5.

    CAS  Article  Google Scholar 

  18. 18.

    Fukunaga A, Washio K, Hatakeyama M, Oda Y, Ogura K, Horikawa T, et al. Cholinergic urticaria: epidemiology, physiopathology, new categorization, and management. Clin Auton Res. 2018;28(1):103–13.

    Article  Google Scholar 

  19. 19.

    Zhang Y, Chen Z, Luo X, Wu B, Li B, Wang B. Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells. Hum Vaccin Immunother. 2016;12(10):2512–8.

    Article  Google Scholar 

  20. 20.

    Avella J, Madsen JE, Binder HJ, Askenase PW. Effect of histamine H2-receptor antagonists on delayed hypersensitivity. Lancet. 1978;1(8065):624–6.

    CAS  Article  Google Scholar 

  21. 21.

    Arae K, Oboki K, Ohno T, Hirata M, Nakae S, Taguchi H, et al. Cimetidine enhances antigen-specific IgE and Th2 cytokine production. Allergol Int. 2011;60(3):339–44.

    CAS  Article  Google Scholar 

  22. 22.

    Shin JH, Kim BG, Kim SW, Cho JH, Park YJ, Kim SW. Immunomodulatory role of histamine H2 receptor in allergen-specific immunotherapy: a mouse model of allergic rhinitis. Otolaryngol Head Neck Surg. 2011;144(4):500–5.

    Article  Google Scholar 

  23. 23.

    Ishikura H, Fukui H, Takeyama N, Tanaka T. Cimetidine activates interleukin-12, which enhances cellular immunity. Blood. 1999;93(5):1782–3.

    CAS  Article  Google Scholar 

  24. 24.

    Hahm KB, Kim WH, Lee SI, Kang JK, Park IS. Comparison of immunomodulative effects of the histamine-2 receptor antagonists cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells in gastric cancer patients. Scand J Gastroenterol. 1995;30(3):265–71.

    CAS  Article  Google Scholar 

  25. 25.

    Jafarzadeh A, Nemati M, Rezayati MT, Ebrahimi M, Hassan ZM. Cimetidine enhances delayed-type hypersensitivity responses and serum interleukin (IL)-2, -10, -12, and IL-17 levels after burn injury in an animal model. J Immunotoxicol. 2013;10(2):201–9.

    CAS  Article  Google Scholar 

  26. 26.

    Pastorello EA, Stafylaraki C, Mirone C, Preziosi D, Aversano MG, Mascheri A, et al. Anti-amoxicillin immunoglobulin E, Histamine-2 receptor antagonist therapy and mast cell activation syndrome are risk factors for amoxicillin anaphylaxis. Int Arch Allergy Immunol. 2015;166(4):280–6.

    CAS  Article  Google Scholar 

  27. 27.

    van der Pouw Kraan TC, Snijders A, Boeije LC, de Groot ER, Alewijnse AE, Leurs R, et al. Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. J Clin Invest. 1998;102(10):1866–73.

    Article  Google Scholar 

  28. 28.

    Novak N, Mete N, Bussmann C, Maintz L, Bieber T, Akdis M, et al. Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2. J Allergy Clin Immunol. 2012;130(5):1153–8 e2.

    CAS  Article  Google Scholar 

  29. 29.

    Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001;11(9):372–7.

    CAS  Article  Google Scholar 

  30. 30.

    Lee M, Lee NY, Chung KS, Cheon SY, Lee KT, An HJ. Roxatidine attenuates mast cell-mediated allergic inflammation via inhibition of NF-kappaB and p38 MAPK activation. Sci Rep. 2017;7:41721.

    CAS  Article  Google Scholar 

  31. 31.

    Geng B, Thakor A, Clayton E, Finkas L, Riedl MA. Factors associated with negative histamine control for penicillin allergy skin testing in the inpatient setting. Ann Allergy Asthma Immunol. 2015;115(1):33–8.

    CAS  Article  Google Scholar 

  32. 32.

    Simons FE, Sussman GL, Simons KJ. Effect of the H2-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine and cetirizine in patients with chronic urticaria. J Allergy Clin Immunol. 1995;95(3):685–93.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Not Applicable.

Funding

No funding.

Author information

Affiliations

Authors

Contributions

MB wrote the manuscript, GM collected all the materials, SN reviewed the structure of the article, AL verified for grammar errors, SC designed the article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Matteo Borro.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Borro, M., Negrini, S., Long, A. et al. H2-antagonist in IgE-mediated type I hypersensitivity reactions: what literature says so far?. Clin Mol Allergy 19, 4 (2021). https://doi.org/10.1186/s12948-021-00143-y

Download citation

Keywords

  • H2-receptor antagonist
  • Histamine
  • Type-I hypersensitivity reaction
  • Allergy