The discovery of human immunoglobulin E (IgE) in 1968 (Bennich et al., 1968) and an increased understanding of type 2 (T2) inflammatory pathways since the 1990s contributed to the development of today’s monoclonal antibodies (mAbs) targeted at T2 inflammation driven diseases (Fahy, 2015). Within asthma there is an endotype that is broadly characterized by T2 inflammation, namely, T2 asthma (Kuruvilla et al., 2019). T2 asthma demands a different treatment strategy than non-T2 asthma. Besides T2 asthma, also chronic urticaria, chronic rhinosinusitis with nasal polyps (CRSwNP), and atopic dermatitis are characterized by T2 inflammation (Garcovich et al., 2021; Matucci et al., 2021). While increased blood eosinophils are a biomarker for T2 asthma, a differential diagnosis is extensive and includes CRSwNP, vasculitis, and parasitic disease (Piggott et al., 2022). These eosinophils contribute to innate immune responses against helminths (i.e., multicellular parasitic worms) through phagocytosis, release of cytotoxic proteins and formation of extracellular traps (Klion, et al., 2020).

The availability of biologicals has aided patients with severe asthma in reducing exacerbations and oral corticosteroid use, while improving lung function and quality of life, especially in patients with T2 asthma (McGregor et al., 2019). The IgE-binding mAb omalizumab was approved in 2002 for the treatment of moderate-to-severe allergic asthma among adults and adolescents by the Therapeutic Goods Administration in Australia (BioDrugs, 2002). After that, more mAbs targeting T2 asthma were approved, namely, mepolizumab, reslizumab, benralizumab, and dupilumab (Papi et al., 2020). Dupilumab was primarily registered for the treatment of moderate-to-severe atopic dermatitis in 2017 (Shirley, 2017), for the treatment of asthma in 2018, and for the treatment of CRSwNP in 2019 (Boyle et al., 2020). Omalizumab was additionally registered for the treatment of chronic urticaria in 2014 (Kaplan et al., 2017). Clinical trials have shown that these biologicals contribute to disease control of T2 inflammatory diseases, especially in patients with T2 asthma (Agache et al., 2021; Matucci et al., 2021). While the effectiveness of these biologicals in real life has been demonstrated, further evaluation of the long-term safety of biologicals is needed as safety profiling studies are limited (Brusselle and Koppelman, 2022). In the clinical trials safety profiles were similar for patients in the intervention group and placebo group, with a low number of serious adverse events (AEs) (Ortega et al., 2014; Bleecker et al., 2016; Castro et al., 2018). More recently post-marketing studies confirm the low incidence of serious AEs in patients receiving anti-T2 biologicals, while identifying previously unknown risks (Sousa et al., 2020; Bettuzzi et al., 2022; Galletti et al., 2023). Anaphylaxis signals have been described for omalizumab, benralizumab, reslizumab, and mepolizumab (Li et al., 2021). Dupilmab has been linked with eye disorders, especially in patients with atopic dermatitis (Park et al., 2021).

In recent years, concerns were expressed for a hypothesized increased risk of parasitic infections among patients using biologicals affecting the T2 immune response (Tan et al., 2019). Such biologicals are dupilumab, omalizumab, mepolizumab, benralizumab, and reslizumab. Omalizumab binds to free IgE, inhibiting further binding of IgE to high-affinity IgE receptors on mast cells and basophils (Brusselle and Koppelman, 2022), while IgE is considered an important part of the multi-component T2 immune response towards parasitic infections (Cooper et al., 2008; Fitzsimmons et al., 2014). Dupilumab binds to interleukin (IL-) 4 receptor α, which inhibits IL-4 and IL-13 signaling (Brusselle and Koppelman, 2022), while both cytokines contribute to the elimination of parasites through increased mucus production and eosinophilic mucosal inflammation in the gut (Klion and Nutman, 2004; Braddock et al., 2018). Benralizumab binds to IL-5Rα, resulting into depletion of eosinophils in the blood and mucosal tissues via antibody-dependent cell-mediated cytotoxicity (Brusselle and Koppelman, 2022), and might thus interfere with the eosinophil-mediated killing and expulsion of gastro-intestinal helminths (Klion and Nutman, 2004). Reslizumab and mepolizumab bind to circulating interleukin IL-5 (Brusselle and Koppelman, 2022), likewise an important cytokine contributing to eosinophilic differentiation and activation (Klion and Nutman, 2004; Maizels and Adam, 2004).

In current clinical studies and routine practice, reporting of parasitic infections is based on spontaneous reporting, rather than systematic anamnestic or biochemical screening. Especially in endemic regions, routine screening for parasitic infections may be useful. So far, no studies were performed on the Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) investigating the risk of parasitic infections among patients using biologicals affecting the T2 immune response. Therefore, the objective of this study was to determine if parasitic infections are disproportionately reported for biologicals affecting the T2 immune response.

Even though a limited amount of AE case reports on parasitic infections were retrieved from the FAERS database, we demonstrated SDRs for parasitic infections associated with anti-IgE omalizumab and anti-T2 cytokine (receptor) antibodies dupilumab, mepolizumab, and benralizumab. In addition, we discovered that within the group of these biologicals parasitic infections were disproportionately reported for benralizumab. Given the mechanism of action of benralizumab [binding to IL-5R on eosinophils and basophils, and consequently depleting eosinophils in the blood and mucosal tissues such as the gastro-intestinal tract through antibody-dependent, cell-mediated toxicity] (Brusselle and Koppelman, 2022), it could be reasoned why proportionally more AE reports on parasitic infections were found in FAERS for benralizumab compared to the other biologicals. These SDRs should be taken seriously since a major clinical impact has been reported in the case reports, including death, life-threatening situations, hospitalizations, and other serious (unspecified) medical events.

For reslizumab no AE reports were found on parasitic infections within FAERS, which could be attributed to a general low reporting rate for this biological and most probably due to lack of power. Indeed, spontaneous reports for the other biologicals were roughly a 12–16-fold more often received by the FDA than for reslizumab. The lower reporting rate for reslizumab might be due to a low number of patients receiving the drug because reslizumab has to be administered intravenously in the hospital. In contrast, other biologicals can be self-administered subcutaneously (e.g., at home), making treatment with reslizumab less practical and potentially more costly within the healthcare system (Kavanagh et al., 2021). Excluding drugs from the ATC drug group P in the 1st secondary analysis showed a slight increase in disproportionality for all the biologicals of interest, indicating a confounding effect.

Notably, 50 out of 79 parasitic infections were unspecified, raising concerns on the validity of the submitted reports. The parasitic infections might have been reported by individuals, such as consumers or even healthcare workers, with no experience in the diagnosis of parasitic infections. On the other hand, sufficient information might have been provided by an experienced or treating healthcare professional to the reporter of the AE. The validity of the start date of treatment, end date of treatment, and event date (i.e., date of parasitic infection) should be carefully interpreted, as in most cases these data elements were not reported, and in some cases the parasitic infection was reported before the start date of the mAb treatment. The latter would be unlikely as only primary drug suspects for the reported events were selected for analysis. Recently, a correspondence article by Lifar et al. (2023) has been published describing a disproportionality analysis of parasitic infections among omalizumab, mepolizumab, benralizumab, and dupilumab within the VigiBase using a case/noncase design in which the control group was represented by the disease concept “asthma” in combination with at the time approved inhalation therapies. Lifar et al. (2023) showed that only benralizumab among the biologicals of interest was disproportionately reported for parasitic infections compared to the control group. In comparison, our study showed disproportionality for all biologicals of interest, except for reslizumab, while utilizing the entire FAERS database representing a broader range of patients and medication.

While theoretically it can be expected that patients using these biologicals would be at an increased risk for parasitic infections, literature is relatively scarce on the topic, and evidence on the increased risk is weak. A 2007 clinical trial performed in Brazil reported that 50% (34 of 68) of the omalizumab arm experienced at least 1 intestinal helminth infection, compared to 41% (28 of 69) of the placebo arm (Cruz et al., 2007). The odds ratio (OR) was 1.47 with a 95% CI of 0.74–2.95. The OR was 2.2 (95% CI: 0.94–5.15) after adjusting for study visit, baseline infection status, sex, and age. In a 2013 omalizumab study in Turkey with 19 participants having severe asthma, 1 case of giardiasis was reported (Yalcin et al., 2013). An observational Italian study between 2007 and 2016 in which 91 patients received omalizumab did not report any parasitic infections (Di Bona et al., 2017). A 2021 clinical trial showed that 7 out of 271 (2.6%) children with uncontrolled moderate-to-severe asthma in the dupilumab arm experienced a non-severe parasitic infection compared to 0 out of 134 subjects in the placebo arm (Bacharier et al., 2021). A 2019 pooled analysis on infections in 1841 atopic dermatitis patients using dupilumab showed that no parasitic infections were reported (Eichenfield et al., 2019). In a review from 2019 by Tan et al. (2019) no cases of parasitic infections were reported in clinical trials assessing dupilumab, benralizumab, reslizumab, and mepolizumab in patients with severe asthma. A more recent 2021 review by Dragonieri and Carpagnano highlighted additional studies for mepolizumab and reslizumab, however, did not find reported cases with parasitic infections (Dragonieri and Giovanna Elisiana, 2021). In all of the summary of product characteristics (SmPCs) of the studied biologicals, it is recognized that IgE and eosinophils are involved in the immunological response for parasitic infections, hence some caution should be considered when individuals at high risk of parasitic infection are treated with the discussed biologicals (European Medicines Agency, 2015; European Medicines Agency, 2020; European Medicines Agency, 2021; European Medicines Agency 2022b; European Medicines Agency 2022a).

Besides the well-known shortcomings of randomized clinical trials (RCTs) compared to observational studies (Hannan, 2008), RCTs involving the discussed biologicals often excluded patients with a (history of) parasitic infection or a recent (or planned) visit to a country with prevalent parasitic infections (Hodsman et al., 2013; Wenzel et al., 2013; Beck et al., 2014; Braddock et al., 2018; Eichenfield et al., 2019; Paller et al., 2022). A 2022 open-label extension study on the safety and efficacy of dupilumab also excluded individuals which were suspected or at high risk of parasitic infections (Wechsler et al., 2022). Therefore, more real world studies on this topic should be performed to gain deeper understanding on the effect of anti-T2 immunity biologicals on parasitic infections.

Parasitic infections were disproportionately reported for mAbs targeting IgE, T2 cytokines, or T2 cytokine receptors. While the number of AE reports on parasitic infections in the FAERS database was relatively low, the resulting safety signals were disproportionate and warrant further investigation.