Review and Feature Article
A Review of Adverse Reactions to Biologics Used in Allergy-Immunology Practice

https://doi.org/10.1016/j.jaip.2022.09.020Get rights and content

Biologic agents have become an integral therapeutic option for practicing allergists-immunologists for the management of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and various immunologic conditions. As these agents vary considerably from traditional small-molecule drugs, various adverse reactions have been noted. A different approach must be used to classify these reactions beyond the classic Gell-Coombs classification system as it does not capture many of the adverse events seen with biologic therapy. This article addresses the available literature on proposed classification systems and diagnostic modalities for adverse events associated with biologics and reviews each approved agent used frequently in allergy-immunology practice.

Section snippets

Overview of Biologics

Biologic therapies encompass a diverse range of products including vaccines, blood components, allergenic extract, somatic cells, gene therapy, cytokines, monoclonal antibodies, and fusion proteins.1 These therapies have revolutionized the treatment of conditions throughout the field of allergy and immunology. Widespread use has resulted in increased understanding of adverse reactions associated with these therapies including underlying mechanisms, classification, diagnostics, and management.

Classification of Adverse Reactions

Although various definitions of biologic therapies exist, biologics are derived from microorganisms or mammalian cells and are typically large complex molecules such as proteins or polypeptides.1 This contrasts with most drugs that are chemically synthesized, well-characterized small molecules, often with molecular weights less than 1 kDa. Furthermore, monoclonal antibodies and fusion receptor proteins have inherent immune-mediated effects that underlie their intended activity, whereas for most

Diagnostic Strategies

Careful clinical history is essential for determining subsequent diagnostic strategies. As discussed above, certain clinical features may suggest an underlying endotype to which targeted testing may be helpful; however, there is often a significant overlap of clinical symptoms across different endotypes, and diagnostic and management protocols have not yet been standardized.

Management

The proposed classification of infusion-related reactions (cytokine release reactions, type 1 reactions, mixed reactions, and delayed reactions) can help to direct the management approach. An example of 1 management algorithm is listed in Figure 1.

Injection site reactions can be treated with optimizing administration through rotating injection sites, avoiding sensitive locations, and if allowed, placing the biologic at room temperature before injection; furthermore, cold compresses, analgesics,

Omalizumab

Omalizumab was the first biologic agent approved for the treatment of allergic disease. First approved in 2003 for the treatment of moderate-to-severe asthma, further approvals have included indications for chronic spontaneous urticaria in 2014 and for adults with nasal polyps in 2020. Omalizumab is a chimeric human-mouse recombinant antibody that binds to the domain at which IgE binds to FϲεRI on mast cells and basophils.23,24 Its primary mechanism of action is binding of free IgE in the

Conclusion

As the use of biologic agents continues to rise across medicine especially within the field of allergy and immunology, adverse reactions will likely continue to be encountered with increasing frequency. Additional research is needed to better understand the utility of available testing, improved testing methods, and determine genetic factors that may increase the risk of AEs. Despite this, management tools such as rapid drug desensitizations can be used to safely administer biologics in many

References (72)

  • A. Sala-Cunill et al.

    One-dilution rapid desensitization protocol to chemotherapeutic and biological agents: a five-year experience

    J Allergy Clin Immunol Pract

    (2021)
  • M. Bernaola et al.

    Successful administration of omalizumab by desensitization protocol following systemic reactions in 12 patients

    J Allergy Clin Immunol Pract

    (2021)
  • P.L. Lieberman et al.

    Anaphylactic reactions associated with omalizumab administration: analysis of a case-control study

    J Allergy Clin Immunol

    (2016)
  • S.L. Limb et al.

    Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma

    J Allergy Clin Immunol

    (2007)
  • L. Cox et al.

    American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis

    J Allergy Clin Immunol

    (2007)
  • L. Cox et al.

    American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint Task Force follow-up report

    J Allergy Clin Immunol

    (2011)
  • D. Di Bona et al.

    Long-term “real-life” safety of omalizumab in patients with severe uncontrolled asthma: a nine-year study

    Respir Med

    (2017)
  • C. Iribarren et al.

    Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study in moderate to severe asthma

    J Allergy Clin Immunol

    (2017)
  • M. Shaker et al.

    Estimation of health and economic benefits of clinic versus home administration of omalizumab and mepolizumab

    J Allergy Clin Immunol Pract

    (2020)
  • I.D. Pavord et al.

    Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial

    Lancet

    (2012)
  • F. Roufosse et al.

    HES mepolizumab study group. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial

    J Allergy Clin Immunol

    (2020)
  • J. Corren et al.

    Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts

    Chest

    (2016)
  • K. Murphy et al.

    Long-term safety and efficacy of reslizumab in patients with eosinophilic asthma

    J Allergy Clin Immunol Pract

    (2017)
  • R. Kolbeck et al.

    MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function

    J Allergy Clin Immunol

    (2010)
  • M. Castro et al.

    Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study

    Lancet Respir Med

    (2014)
  • E.R. Bleecker et al.

    SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial

    Lancet

    (2016)
  • J.M. FitzGerald et al.

    CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial

    Lancet

    (2016)
  • W.W. Busse et al.

    BORA study investigators. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial

    Lancet Respir Med

    (2019)
  • Y. Han et al.

    Efficacy and safety of dupilumab for the treatment of adult atopic dermatitis: a meta-analysis of randomized clinical trials

    J Allergy Clin Immunol

    (2017)
  • C. Bachert et al.

    Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials

    Lancet

    (2019)
  • B. Geng et al.

    Respiratory infections and anti-infective medication use from phase 3 dupilumab respiratory studies

    J Allergy Clin Immunol Pract

    (2022)
  • F. Di Staso et al.

    Topical treatment of dupilumab-associated refractory conjunctivitis and keratitis

    Am J Ophthalmol Case Rep

    (2022)
  • A.S. Levin et al.

    Reactions to rituximab in an outpatient infusion center: a 5-year review

    J Allergy Clin Immunol Pract

    (2017)
  • L. de Wolff et al.

    Long-term abatacept treatment for 48 weeks in patients with primary Sjögren’s syndrome: the open-label extension phase of the ASAP-III trial

    Semin Arthritis Rheum

    (2022)
  • D. Egg et al.

    Therapeutic options for CTLA-4 insufficiency

    J Allergy Clin Immunol

    (2022)
  • T. Morrow et al.

    Defining the difference: what makes biologics unique

    Biotechnol Healthc

    (2004)
  • Cited by (1)

    No funding was received for this work.

    Conflicts of interest: S. R. Joshi has participated on advisory boards for Biocryst, Sanofi, Noho Allergy, Takeda, and Leo Pharma, and declares that he is a consultant and owns stock in Nectar Allergy. J. Oppenheimer declares that he is on the data and safety monitoring board for AstraZeneca, Amgen, GlaxoSmithKline, Sanofi/Regeneron, and Abbvie. He is a consultant for GlaxoSmithKline, Aquestive, Aimmune, and Amgen; and is an executive editor for Annals of Allergy, Asthma, and Immunology, UpToDate reviewer, and section editor for Medscape. T. G. Chow declares that he received the Allergists’ Foundation Community Grant (ACAAI) and was ACAAI Fellow-in-Training representative to the Board of Regents 2019-2021.

    View full text