Anaphylactic reactions associated with omalizumab administration: Analysis of a case-control study
Authors: Phillip L. Lieberman, Dale T. Umetsu, Gillis J. Carrigan, Abdelkader Rahmaoui
Journal: Journal of Allergy and Clinical Immunology (2016)

Treatment with omalizumab is associated with a small risk of anaphylaxis (∼0.2%). To clarify the circumstances and risk factors associated with anaphylaxis to omalizumab,1Limb S.L. Starke P.R. Lee C.E. Chowdhury B.A. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma.J Allergy Clin Immunol. 2007; 120: 1378-1381Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar we conducted a case-control study comparing cases with an adjudicated history of anaphylaxis to omalizumab with controls without a history of anaphylaxis (X-PAND study; ClinicalTrials.gov identifier NCT00813748 March 27, 2009, to April 3, 2014; see Methods and Fig E1 available in this article's Online Repository at www.jacionline.org). An evaluation of the association between the presence of antitherapeutic antibodies (ATAs) and the risk of anaphylactic reactions among patients with previous omalizumab exposure was included. An optional skin prick and intradermal testing substudy was offered using a previously published protocol.2Lieberman P. Rahmaoui A. Wong D.A. The safety and interpretability of skin tests with omalizumab.Ann Allergy Asthma Immunol. 2010; 105: 493-495Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Clinical histories for 30 consenting patients with a history of adjudicated anaphylaxis associated with omalizumab treatment (cases) were region matched to 88 consenting and current/former omalizumab-treated patients without anaphylaxis to omalizumab (controls). Anaphylaxis reactions were identified using a standard Medical Dictionary for Regulatory Activities query for all anaphylactic events from clinical studies and postmarketing reports. Cases eligible for the repository included those positively adjudicated and deemed causally related by an independent clinical expert (Phillip L. Lieberman) applying Sampson criteria,3Sampson H.A. Muñoz-Furlong A. Campbell R.L. Adkinson Jr., N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report–Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397Abstract Full Text Full Text PDF PubMed Scopus (1647) Google Scholar including the temporal association between omalizumab administration and the event. Controls received 1 or more doses of omalizumab within 18 months either before or after the matching case's first anaphylactic event and could not have had prior anaphylaxis or other hypersensitivity reactions to omalizumab. At least 1 control must have discontinued omalizumab treatment to ensure an adequate washout period for omalizumab (ie, 16 wk/∼4.5 elimination half-lives) for interpretable ATA data. Thirty cases of anaphylaxis and 120 controls were considered to give 79% power to detect a 4-fold increase in the risk for an anaphylactic reaction assuming a 10% prevalence for an identified risk factor and a 5% type I error (2-tailed). Prespecified potential clinically meaningful risk factors (eg, presence of food allergy, preomalizumab IgE levels, asthma severity, sex, and age) were assessed for effect on the frequency of anaphylaxis. The odds ratio (OR) was estimated for each risk factor using conditional logistic regression models with 95% CI calculated using Wald approximation. All analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, NC). All cases (n = 30) and 97.7% (n = 86) of the controls received omalizumab for asthma. Controls had 3 times as many omalizumab doses as did cases, indicating that we were comparing one population that tolerated omalizumab to another that did not. Most cases of anaphylaxis (24 of 30; 80%) included symptoms categorized as cutaneous/subcutaneous/mucosal (ie, lips, tongue, palate, uvula) and respiratory (ie, nose, laryngeal, lung). Most (70.0%) events occurred within 1 hour of omalizumab dosing (only 1 event occurred after 2 hours [ie, at 3.5 hours]). Median (range) time from the last dose of omalizumab to the anaphylactic event was 30 (0-210) minutes. Eleven of 28 (39.3%) patients in whom the number of previous doses had been recorded experienced anaphylaxis within the first 3 doses of omalizumab; anaphylaxis occurred after 4 to 20 doses in 8 (28.6%) cases and after more than 20 doses in 9 cases (1 case after >60 injections). Fig 1 provides a Kaplan-Meier plot of the time to anaphylaxis correlated to known lifetime doses of omalizumab. None of the anaphylactic events resulted in disability or death. Anaphylactic events were considered life-threatening in 12 of 30 (40.0%) cases and required hospitalization in another 6 (20.0%) cases. Treatment of anaphylaxis included the use of antihistamines (23 of 30; 76.7%), epinephrine (21 of 30; 70.0%), systemic corticosteroids (19 of 30; 63.3%), and inhaled β-agonists (13 of 30; 43.3%). No ATAs of IgG or IgE isotypes were detected among those eligible for ATA analysis (21 cases; 10 controls). None of the cases had a positive skin reaction to omalizumab or to excipient alone versus 2 of 7 controls (skin prick test; diluted 1:1,000, 1:100, 1:10, and undiluted: intradermal; diluted 1:100,000). Most patients in both groups were white and female, and more of the cases of anaphylaxis reported a history of anaphylaxis unrelated to omalizumab (56.7% vs 22.7%) and food allergies (60.0% vs 37.5%) compared with controls, respectively (Table I). Bivariate conditional logistic regression analysis indicated that among omalizumab users, a history of anaphylaxis to food, medication, or other causes increased the subsequent risk of anaphylaxis associated with omalizumab use (OR, 8.1; 95% CI, 2.7-24.3). The US Food and Drug Administration examined this information and advised including it in an updated Xolair US package insert. Total number of omalizumab doses, food allergies, female sex, presence of urticaria/hives, and race also were identified as potential risk factors for anaphylaxis associated with omalizumab. The absolute risks for anaphylaxis may be estimated on the basis of overall risks of 0.1% (based on clinical trial data) or 0.2% (based on postmarketing reports) of users. Assuming an overall 0.2% risk, the absolute increase in risk can be indirectly estimated from the OR, and it would be approximately 0.62% for patients with a history of anaphylaxis and 0.08% for patients with no history of anaphylaxis, resulting in a risk difference (ie, attributable risk) of 0.54%.Table IDemographic and baseline characteristicsCharacteristicCases of anaphylaxis(n = 30)Controls(n = 88)Mean ± SD age at time of event (y)∗For controls, age at the time of event was the age at the time of the adjudicated event experienced by the matched control.42.7 ± 16.445.4 ± 15.4Sex: female, n (%)27 (90.0)60 (68.2)Race, n (%) White26 (86.7)62 (70.5) Black1 (3.3)10 (11.4) Asian02 (2.3) Other3 (10.0)14 (15.9)Geographic region, n (%) West10 (33.3)33 (37.5) Midwest7 (23.3)19 (21.6) Northeast6 (20.0)12 (13.6) South7 (23.3)24 (27.3)Mean ± SD preomalizumab IgE (IU/mL)†Cases, n = 28; controls, n = 83.317.9 ± 416.0455.5 ± 758.5Mean ± SD best FEV1 (%)‡Cases, n = 20; controls, n = 79.79.3 ± 15.982.9 ± 15.9History of anaphylaxis or anaphylactoid episode, n (%)17 (56.7)20 (22.7)Mean ± SD age at asthma diagnosis (y)23.7 ± 19.520.2 ± 17.4Omalizumab frequency, n (%) Every 2 wk16 (53.3)40 (45.5) Every 4 wk13 (43.3)40 (45.5)Mean ± SD total no. of omalizumab doses§Total number of omalizumab doses taken during their lifetime up to the day of the event for cases and up to the day of enrollment for controls; cases, n = 28; controls, n = 84.18.6 ± 19.658.5 ± 59.7History of allergies/allergic rhinitis, n (%)29 (96.7)86 (97.7)History of food allergies, n (%)18 (60.0)33 (37.5)History of allergic reaction following any injection, n (%)10 (33.3)18 (20.5)∗ For controls, age at the time of event was the age at the time of the adjudicated event experienced by the matched control.† Cases, n = 28; controls, n = 83.‡ Cases, n = 20; controls, n = 79.§ Total number of omalizumab doses taken during their lifetime up to the day of the event for cases and up to the day of enrollment for controls; cases, n = 28; controls, n = 84. Open table in a new tab It should be noted that the overall incidence in our study population of a history of anaphylaxis was higher than in the general population.4Gupta R. Springston E. Warrier M. Smith B. Kumar R. Pongracis J. et al.The prevalence, severity, and distribution of childhood food allergy in the United States.Pediatrics. 2011; 128: e9-e17Crossref PubMed Scopus (1017) Google Scholar, 5Liu A.H. Jaramillo R. Sicherer S.H. Wood R.A. Bock S.A. Burks A.W. et al.National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006.J Allergy Clin Immunol. 2010; 126: 798-806.e13Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar However, in a study of nearly 8000 patients with moderate to severe asthma, a history of anaphylaxis was also frequent (∼22%), similar to the frequency observed in our control subjects. In our sample, the reasons for the high frequency of a history of anaphylaxis in the cases with anaphylaxis may reflect a true risk for subsequent anaphylaxis in patients treated with omalizumab or may be because these histories of anaphylaxis were not adjudicated and may be subject to recall bias, or because we evaluated a highly selected atopic population with asthma. These are key limitations of this small case-control study. Nevertheless, the results of our investigation are consistent with previous studies indicating that the likelihood of anaphylaxis in general is increased in patients with a history of asthma6Iribarren C. Tolstykh I.V. Miller M.K. Eisner M.D. Asthma and the prospective risk of anaphylactic shock and other allergy diagnoses in a large integrated health care delivery system.Ann Allergy Asthma Immunol. 2010; 104: 371-377Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 7Mullins R.J. Anaphylaxis: risk factors for recurrence.Clin Exp Allergy. 2003; 33: 1033-1040Crossref PubMed Scopus (203) Google Scholar or with a history of anaphylaxis.7Mullins R.J. Anaphylaxis: risk factors for recurrence.Clin Exp Allergy. 2003; 33: 1033-1040Crossref PubMed Scopus (203) Google Scholar In our study, we found that anaphylaxis occurred most frequently within the first 3 doses and within 1 hour of dosing. In contrast, in a previous analysis, a delay between the administration of omalizumab and the onset of anaphylaxis was observed.1Limb S.L. Starke P.R. Lee C.E. Chowdhury B.A. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma.J Allergy Clin Immunol. 2007; 120: 1378-1381Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar This delay prompted the suggestion of prolonged in office observation times.8Cox L. Lieberman P. Wallace D. Simons F.E. Finegold I. Platts-Mills T. 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; 128: 210-212Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar The reasons for this discrepancy between the current and previous studies are not apparent, but our observations indicate that it would be worthwhile to continue to collect data to see whether the prolonged observation time is justified. As in previous observations, we found no evidence to support an immunologic pathogenesis, specifically an IgE-mediated event, underlying anaphylactic episodes due to the administration of omalizumab.2Lieberman P. Rahmaoui A. Wong D.A. The safety and interpretability of skin tests with omalizumab.Ann Allergy Asthma Immunol. 2010; 105: 493-495Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 9Lieberman P. The unusual suspects: a surprise regarding reactions to omalizumab.Allergy Asthma Proc. 2007; 28: 259-261Crossref PubMed Scopus (20) Google Scholar, 10Price K.S. Hamilton R.G. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy.Allergy Asthma Proc. 2007; 28: 313-319Crossref PubMed Scopus (113) Google Scholar Although the mechanism causing these events remains unknown, the possibility that they are due to a reaction to polysorbate, an excipient in the preparation, has been suggested9Lieberman P. The unusual suspects: a surprise regarding reactions to omalizumab.Allergy Asthma Proc. 2007; 28: 259-261Crossref PubMed Scopus (20) Google Scholar, 10Price K.S. Hamilton R.G. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy.Allergy Asthma Proc. 2007; 28: 313-319Crossref PubMed Scopus (113) Google Scholar and cannot be ruled out. Although anaphylaxis associated with omalizumab remains a rare event, when prescribing omalizumab health care providers should consider these observations along with the clinical benefits, and should adhere to recommended clinical guidance regarding monitoring for anaphylaxis.8Cox L. Lieberman P. Wallace D. Simons F.E. Finegold I. Platts-Mills T. 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; 128: 210-212Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar The clinical data and serum repository was initiated on March 27, 2009, and closed on April 3, 2014 (ClinicalTrials.gov identifier NCT00813748). This study was conducted in accordance with US Food and Drug Administration regulations, the International Conference on Harmonisation E6 Good Clinical Practice guidelines, and applicable local, state, or federal laws. Institutional review board approval and informed consent were obtained for study participation. The health care provider (HCP) for each identified anaphylaxis case was instrumental in obtaining informed consent. The HCP for each positively adjudicated anaphylaxis case was asked to identify from the practice up to 4 current or former omalizumab-treated patients without anaphylaxis and/or hypersensitivity reactions to omalizumab to serve as control subjects. If 4 control patients could not be identified, supplementary controls from the same geographic region as the case were recruited. The primary exposure of interest for the repository was the detection of ATAs to omalizumab in all patients. Patients were evaluated by their HCP. Following a screening visit, the enrollment visit included data collection (demographic characteristics, clinical characteristics, anaphylaxis description [anaphylaxis cases only], history of hypersensitivity reactions, medication history, drug and allergy information) and a 5-mL blood sample for the ATA assay and IgE and IgG isotypes (anaphylaxis cases and assay controls). The presence of antiomalizumab IgG antibodies was determined using 2 omalizumab fragment–specific ELISAs using either the Fab or Fc fragment of omalizumab as the capture agent (Bureco AG, Reinach, Switzerland). An ELISA was designed to distinguish between bound and unbound omalizumab by IgE (Bureco AG) to account for the high affinity of omalizumab for the Fc fragment of human IgE. Because of omalizumab's mechanism of action, its effect on blunting skin test reactivity, and interference with the assay to detect ATAs against omalizumab, serum sample collections for the repository database were conducted at least 16 weeks after discontinuation of omalizumab to allow for washout of the drug. Omalizumab anaphylaxis occurring outside the recommended observation timesJournal of Allergy and Clinical ImmunologyVol. 139Issue 5PreviewIn a case-control study in the September 2016 issue of the Journal, Lieberman et al1 describe a series of 30 patients who had anaphylactic reactions associated with omalizumab administration, comparing them with 88 patients who received omalizumab without such reactions. Among their important findings is an increased risk for anaphylaxis to omalizumab in patients who have a history of anaphylaxis to food, medication, or other causes. Such a history would raise the overall 0.2% risk to 0.62%, but in those without such a history would lower the risk to 0.08%. Full-Text PDF