Early onset hypersensitivity reactions (EHRs) are typically induced by the IgE-mediated mechanisms to various antigens, although they can be triggered by nonimmunologic mechanisms as well. Majority of reactions occurs within the first several hours of exposure to offending antigen, although delayed IgE-mediated reactions have been reported as well. Anaphylaxis, a potentially fatal systemic syndrome that results from the sudden release of mast cell and basophil-derived mediators into the circulation, represents the most serious EHR [1,2]. Lifetime prevalence of anaphylaxis from all triggers is currently projected to be 0.05–2%, although this incidence is believed to be underestimated because of failure to report or recognize every episode .
The current therapy of EHRs includes identification and avoidance of a trigger, as well as prompt medical treatment [1,4▪▪]. In those patients with recurrent bouts of anaphylaxis where a trigger is unknown or difficult to avoid, the treatment options are limited. Preventive therapy with glucocorticoids has been utilized, but is not optimal because of adverse effects [4▪▪].
The recognition of IgE antibody as a key mediator in the degranulation of mast cells and basophils has led to discovery of new therapeutic options, such as the development of humanized monoclonal anti-IgE antibodies . Omalizumab (Xolair, Novartis, Switzerland; and Genentech, San Francisco, California, USA) is a humanized monoclonal antibody that binds to the constant region of circulating IgE molecule, preventing activation of allergic effector cells . Omalizumab has been shown to have positive therapeutic effects in many IgE-mediated allergic disorders such as asthma, allergic rhinitis, and chronic urticaria . Various studies have attempted to identify whether anti-IgE therapy with omalizumab may also be beneficial in the prevention of EHRs.
MECHANISM OF ACTION OF OMALIZUMAB
IgE antibody combines with high-affinity IgE receptors (FcεRI) on the surface of mast cells through domain #3 of the constant Fc fragment. Cross-linking between two bound IgE molecules by allergen triggers the activation and degranulation of these cells. Interactions between IgE and FcεRI further upregulate FcεRI expression on cells, leading to rapid activation of effector cells .
Omalizumab is a humanized anti-IgE antibody with 95% human protein fused with 5% mouse protein at the Fab region. The Fab portion is directed to domain #3 of the Fc fragment of IgE and thus acts as a competitive inhibitor, binding only free IgE. Once bound to IgE, it forms a biologically inert molecule, preventing further reactions between IgE and FcεRI receptor (Fig. 1) . Omalizumab has been shown to rapidly reduce the levels of free IgE to nearly zero, with maintenance of this suppression for at least 4 months . In addition to the reduction in free IgE, omalizumab has been shown to lead to downregulation of FcεRI on effector cells, thus augmenting its neutralizing effects on IgE [11,12].
OMALIZUMAB IN THE PREVENTION OF HYPERSENSITIVITY REACTIONS
The advent of anti-IgE therapy has provided a novel therapeutic tool for the prevention of hypersensitivity reactions. In idiopathic anaphylaxis, for example, there is no clear trigger that may be targeted for avoidance or therapy. Several case reports have documented the effectiveness of omalizumab in preventing anaphylaxis in these patients [13–15]. All patients reported no further anaphylactic episode while on omalizumab therapy, though one patient did not tolerate extension of therapy from every 2 weeks to every 4 weeks with recurrent anaphylactic reaction , and another avoided presumed food triggers for anaphylaxis during the treatment period . Additionally, we recently reported successful use of omalizumab in the prevention of exercise-induced anaphylaxis in a patient who failed other prophylactic treatments. In all these cases, the proposed mechanism of omalizumab action was to decrease the serum concentration of IgE as well as stabilize the mast cells by downregulating the expression of the high-affinity IgE receptor .
Similarly, in systemic mastocytosis or mast cell activation syndrome (MCAS), abnormal proliferation of mast cells and profound degranulation can lead to recurrent anaphylactic episodes without clear trigger [17,18]. Several case series and reports have described the successful use of omalizumab in patients with systemic mastocytosis or MCAS and recurrent anaphylactic episodes who have failed standard therapy [19–23]. A case report by Kontou-Fili et al. reports the successful use of omalizumab in a patient with systemic mastocytosis and unprovoked anaphylaxis, as well as bee-sting provoked anaphylaxis. In addition to having no episodes of unprovoked anaphylaxis, this patient tolerated three field stings (one bee sting and two unknown Hymenoptera stings), 100 μg bee venom subcutaneously, and controlled bee sting challenge without reaction. Mild decreases in serum tryptase were noted in two cases [21,23], whereas in the case series by Carter et al. and case report by Pitt et al., overall serum tryptase levels did not change [19,20]. These results suggest that the effect of omalizumab may be mediated through downregulation of FcεRI and a concurrent increase in activation threshold of mast cells and not through decreased mast cell numbers.
Omalizumab has also been used in patients with known triggers such as insect, drug, and food allergies. Case reports document the successful use of omalizumab therapy in patients with fire ant anaphylaxis and insulin allergy who had failed prior therapies including immunotherapy and desensitization, respectively. Once treated with omalizumab, patients were able to tolerate sting and insulin challenges [24,25]. In peanut allergy, in which unintended ingestion results in 50–100 deaths yearly, anti-IgE therapy has been studied as well. A double-blinded, randomized, placebo-controlled (DBRPC) study evaluated the effects of talizumab (TNX-901), another anti-IgE mAb not commercially available, in 84 patients with proven peanut hypersensitivity. By the end of treatment, all groups including the placebo group had a greater threshold of peanut tolerability, but only the high-dose TNX-901 group had a significant improvement from a threshold dose of 178 mg (1/2 peanut) to 2805 mg (9 peanuts). However, 25% of the high-dose group demonstrated no improvement . Sampson et al. studied children aged 6 years and older with peanut allergy using omalizumab; however, the trial was terminated prematurely and most children did not reach the study end point. Nevertheless, in 14 children who reached the study end point, a trend was noted: 44.4% of omalizumab-treated children versus 20% of children receiving placebo could tolerate a peanut challenge of greater than 1000 mg. A large proportion of children did not achieve the prespecified tolerability: five (55.6%) omalizumab-treated and four (80%) placebo-treated children experienced reactions at less than 1000 mg peanut flour . Finally, a DBPRC evaluating the effect of omalizumab in 16 patients with proven occupational latex allergy demonstrated a significant decrease in ocular and skin hypersensitivity reactions compared with placebo. The second, open-label phase of the trial confirmed this improvement in patients previously treated with placebo who were switched to omalizumab therapy .
In all of these cases, omalizumab use was well tolerated with limited side-effects, and in several instances, patients were able to discontinue additional therapies.
OMALIZUMAB IN COMBINATION WITH ALLERGEN IMMUNOTHERAPY
Specific immunotherapy (SIT) can be an effective treatment in a variety of allergic diseases, because of its ability to provide beneficial effects that persist for years after therapy is discontinued [29,30]. However, the potential for severe acute hypersensitivity reactions has limited its use [31▪▪,32]. The combination of omalizumab and SIT has been demonstrated to improve the efficacy of treatment and tolerability in patients in several clinical studies.
In a DBRPC trial of children and adolescents with seasonal allergic rhinitis and grass or birch pollen allergy, seasonal administration of omalizumab and SIT after preseasonal SIT treatment resulted in a significantly larger decrease in nasal and ocular symptoms and rescue medication use than either treatment alone . There was a significant decrease in local swelling and redness at SIT injection sites in the omalizumab group. In another DBRPC trial of adult patients, omalizumab pretreatment followed by rush immunotherapy for ragweed-induced seasonal allergic rhinitis significantly decreased symptom severity and also demonstrated a five-fold reduction in risk of anaphylaxis compared with immunotherapy alone . To analyze this further, a DBRPC trial of 9-week omalizumab pretreatment followed by 12-week immunotherapy for ragweed-induced seasonal allergic rhinitis alone or in combination with omalizumab demonstrated complete inhibition of allergen-specific IgE binding on CD23+ B lymphocytes measured by flow cytometry in groups treated with omalizumab compared with partial inhibition seen in the group treated with immunotherapy alone. Additionally, combined treatment with omalizumab and immunotherapy resulted in the inhibition of allergen–IgE binding after completion of therapy for up to 42 weeks compared with 30 weeks with omalizumab alone and 18 weeks with ragweed immunotherapy alone .
Two additional DBRPC trials were performed to assess whether combined omalizumab and SIT could be used in patients with seasonal allergic rhinitis and comorbid symptomatic allergic asthma not controlled with inhaled corticosteroid therapy or with conventional pharmacotherapy, respectively [36,37]. Kopp et al. reported that omalizumab and SIT combination therapy reduced the symptom load by 39% (P = 0.0464) over SIT monotherapy. This difference was mainly because of reduced symptom severity (P = 0.0044), while rescue medication use did not change significantly. In Massanari et al.'s  cluster immunotherapy study, treatment with omalizumab before and during SIT resulted in a significant reduction in asthma symptom scores and decreased beta-agonist use. Additionally, 61.2% of patients experienced grade III (respiratory) allergic reactions to SIT with 12% in the omalizumab group vs. 49% in the placebo group (P = 0.017). Of note, 87% of patients were able to reach the target SIT dose compared with 72% with placebo (P = 0.04). There was no effect on the size of local reactions with omalizumab treatment.
A series of case reports has also found that omalizumab in combination with venom immunotherapy (VIT) decreased hypersensitivity reactions to VIT in patients who developed systemic reactions to VIT. In three cases, a single injection of omalizumab enabled rush VIT, though omalizumab use was continued in the maintenance phase [38,39]. One case, however, reported the development of diffuse myalgias and fatigue resulting in discontinuation of omalizumab therapy. The patient was unable to tolerate VIT after omalizumab discontinuation .
Similarly, one study [41▪] of omalizumab in combination with oral immunotherapy demonstrated that combined therapy was well tolerated and allowed rapid oral desensitization in patients with cow's milk allergy. Ultimately, 82% of patients (9 out of 11) underwent successful desensitization and were tolerating essentially normal amounts of milk (∼240 ml/day) in their diet [41▪]. The success, safety, and rapidity of desensitization indicate that omalizumab may improve outcome in oral food desensitization. This study was limited by small sample size, and there are ongoing larger studies looking at the role of omalizumab in oral food immunotherapy.
Although therapy with omalizumab is generally well tolerated, approximately 0.1–0.2% of patients have experienced anaphylaxis [42–44]. In 2006, the Omalizumab Joint Task Force (OJTF) was formed by the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) with the purpose of reviewing manufacturer clinical trials and postmarketing data on anaphylaxis. The OJTF concluded that the overall incidence of anaphylaxis during the period of review was approximately 0.09% (35 episodes out of 39 510 patients) . An update released by the OJTF reviewed additional manufacturer data from 2006 to 2008 and reported a similar prevalence . In contrast, a review of postmarketing adverse events reported to the U.S. Food and Drug Administration (USFDA) from 2003 to 2006 found a calculated prevalence of approximately 0.2% (2.6 new cases per month) [45▪]. A second investigation of postmarketing adverse events reported to the USFDA showed similar results with a case rate of 3.1 new case reports per month [45▪]. These data may have been skewed by the dependence on voluntary reporting of anaphylactic episodes and reviewer definition of anaphylaxis [45▪,46].
Omalizumab-associated anaphylaxis typically occurs within the first 2 h of injection. In the OJTF report, 68% of episodes occurred within the first 2 h. If we disregard five episodes in which the timing of anaphylaxis was unknown, the number of anaphylactic episodes within the first 2 h after injection rises to 78% . Similarly, the two studies [44,46] reviewing USFDA data between 2003–2006 and 2007–2008 noted the majority of documented episodes occurring within the first 2 h (60 and 20%, respectively). Additional cases with the onset of anaphylaxis outside of this 2-h postdose interval have been described [43,44,47,48]. In the case series by Limb et al., 33 of 124 episodes (27%) occurred after 6 or more hours. Ten patients (8%) demonstrated a protracted progression of symptoms, describing itching or flushing initially followed by bronchospasm minutes to hours later, and finally systemic manifestation of angioedema, hypotension, and syncope minutes to hours beyond that.
Most reactions also occurred within the first several injections; of the 41 episodes identified by the OJTF, 78% occurred within the first three injections . There is, however, a continued risk of anaphylaxis in those patients who have previously tolerated omalizumab. Several case reports have identified patients who had been receiving omalizumab therapy and describe anaphylactic reaction after over a year of therapy .
The mechanism underlying omalizumab-associated anaphylaxis remains unclear. Polysorbate, an additive used to enhance drug solubility in omalizumab formulation, has been associated with hypersensitivity reactions when used in formulation of erythropoietin or darbepoetin . A case report of two omalizumab-associated anaphylactic episodes also concluded that the likely cause was the polysorbate component of the formulation . Other hypotheses suggested the presence of preexisting or developed antiallotypic or anti-idiotypic antibody against omalizumab or IgE binding to glycosylation products of the Chinese hamster ovary cell line from which part of monoclonal antibody is produced .
Given the risk of acute hypersensitivity reaction to omalizumab, a skin test protocol has been published to assess the concentration of omalizumab that would not produce an adverse event, irritant reaction, or detectable IgG response to omalizumab. It was found that skin prick testing at all saline dilutions and intradermal testing with a concentration of 1 : 100 000 (1.2 mg omalizumab/ml) could be safely performed without producing an irritant response .
DESENSITIZATION TO OMALIZUMAB
Omalizumab-associated hypersensitivity reactions represent a contraindication to continued therapy, though in those patients in whom omalizumab provides profound clinical benefit, desensitization may be considered. One report of desensitization to omalizumab in a 32-year-old woman with chronic idiopathic urticaria and asthma resulted in continued pruritus and generalized erythema, which resolved after pretreatment with nonsteroidal anti-inflammatory drugs. Ultimately, however, the patient developed a serum sickness-like reaction after her seventh dose of omalizumab and therapy was discontinued .
In our institution, we have developed a new outpatient omalizumab desensitization protocol (Table 1) and have successfully desensitized three steroid-dependent severe asthmatics to omalizumab. All patients developed transient mild-to-moderate reactions during desensitization, but were able to tolerate the remainder of the desensitization. Patients continued on omalizumab therapy for 12 months after desensitization without any reported adverse events. They reported significant improvement in their asthma control and were able to decrease or discontinue systemic steroids .
A large proportion of IgE-mediated hypersensitivity reactions result from episodes in which a trigger is unknown, difficult to avoid, or part of preferred medical treatment. In these patients, treatment with omalizumab has been found to be an effective and well tolerated therapy, though there does remain a risk of hypersensitivity reaction to the medication itself. To date, omalizumab use is approved only for patients with moderate-to-severe asthma, although benefits have been seen in other allergic conditions as well. Additional studies are needed to identify the exact mechanisms underlying the efficacy of this medication in various conditions, as well as the mechanisms of omalizumab-associated hypersensitivity reactions.
Conflicts of interest
Dr Petrov has received research support from Genentech and has participated on Genentech Advisory Board. For T. Shankar, none was declared.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 120).
1. Sampson HA, Muñoz-Furlong A, Campbell RL, 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; 117:391–397.
2. Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002; 110:341–348.
3. Lieberman P, Camargo CA, Bohlke K, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol 2006; 97:596–602.
4▪▪. Simons FER, Ardusso LRF, Bilò MB, et al. 2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol 2012; 12:389–399.
This review article represents a great summary of the latest World Allergy Organization Guidelines for the assessment and management of anaphylaxis.
5. Fahy JV, Boushey HA. Targeting IgE with monoclonal antibodies: the future is now. Clin Exp Allergy 1998; 28:664–667.
6. Casale TB, Stokes JR. Immunomodulators for allergic respiratory disorders. J Allergy Clin Immunol 2008; 121:288–296.
7. Kopp MV. Omalizumab: anti-IgE therapy in allergy. Curr Allergy Asthma Rep 2011; 11:101–106.
8. MacGlashan D, Lichtenstein LM, McKenzie-White J, et al. Upregulation of FcεRI on human basophils by IgE antibody is mediated by interaction of IgE with FcεRI. J Allergy Clin Immunol 1999; 104 (2 Pt 1):492–498.
9. Shields RL, Whether WR, Zioncheck K, et al. Inhibition of allergic reactions with antibodies to IgE. Int Arch Allergy Immunol 1995; 107:308–312.
10. Casale TB, Bernstein IL, Busse WW, et al. Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol 1997; 100:110–121.
11. MacGlashan DW, Bochner BS, Adelman DC, et al. Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997; 158:1438–1445.
12. Chang TW, Shiung Y-Y. Anti-IgE as a mast cell-stabilizing therapeutic agent. J Allergy Clin Immunol 2006; 117:1203–1212.
13. Warrier P, Casale TB. Omalizumab in idiopathic anaphylaxis. Ann Allergy Asthma Immunol 2009; 102:257–258.
14. Jones JD, Marney SR, Fahrenholz JM. Idiopathic anaphylaxis successfully treated with omalizumab. Ann Allergy Asthma Immunol 2008; 101:550–551.
15. Demirtürk M, Gelincik A, Colakoğlu B, et al. Promising option in the prevention of idiopathic anaphylaxis: omalizumab. J Dermatol 2012; 39:552–554.
16. Bray S, Fajt M, Petrov A. Successful treatment of exercise induced anaphylaxis with omalizumab. Ann Allergy Asthma Immunol 2012; 109:279–285.
17. Robyn J, Metcalfe DD. Systemic mastocytosis. Adv Immunol 2006; 89:169–243.
18. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126:1099–1104.
19. Carter MC, Robyn JA, Bressler PB, et al. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol 2007; 119:1550–1551.
20. Pitt TJ, Cisneros N, Kalicinsky C, Becker AB. Successful treatment of idiopathic anaphylaxis in an adolescent. J Allergy Clin Immunol 2010; 126:415–416.author reply 416.
21. Kontou-Fili K, Filis CI, Voulgari C, Panayiotidis PG. Omalizumab monotherapy for bee sting and unprovoked ‘anaphylaxis’ in a patient with systemic mastocytosis and undetectable specific IgE. Ann Allergy Asthma Immunol 2010; 104:537–539.
22. Bell MC, Jackson DJ. Prevention of anaphylaxis related to mast cell activation syndrome with omalizumab. Ann Allergy Asthma Immunol 2012; 108:383–384.
23. Douglass JA, Carroll K, Voskamp A, et al. Omalizumab is effective in treating systemic mastocytosis in a nonatopic patient. Allergy 2010; 65:926–927.
24. Tartibi HM, Majmundar AR, Khan DA. Successful use of omalizumab for prevention of fire ant anaphylaxis. J Allergy Clin Immunol 2010; 126:664–665.
25. Matheu V, Franco A, Perez E, et al. Omalizumab for drug allergy. J Allergy Clin Immunol 2007; 120:1471–1472.author reply 1472–1473.
26. Leung DYM, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 2008; 348:986–993.
27. Sampson HA, Leung DY, Burks AW, et al. A phase II, randomized, double-blind, parallel-group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J Allergy Clin Immunol 2011; 127:1309.e1–1310.e1.
28. Leynadier F, Doudou O, Gaouar H, et al. Effect of omalizumab in healthcare workers with occupational latex allergy. J Allergy Clin Immunol 2004; 113:360–361.
29. Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999; 341:468–475.
30. Des Roches A, Paradis L, Knani J, et al. Immunotherapy with a standardized dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation. Allergy 1996; 51:430–433.
31▪▪. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011; 127 (1 Suppl):S1–S55.
The practice parameter is a great resource for practicing allergists-immunologists. It provides an update to established guidelines for well tolerated and effective use of allergen immunotherapy.
32. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol 2006; 117:169–175.
33. Kamin W, Kopp MV, Erdnuess F, et al. Safety of anti-IgE treatment with omalizumab in children with seasonal allergic rhinitis undergoing specific immunotherapy simultaneously. Pediatr Allergy Immunol 2010; 21 (1 Pt 2):e160–e165.
34. Casale TB, Busse WW, Kline JN, et al. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2006; 117:134–140.
35. Klunker S, Saggar LR, Seyfert-Margolis V, et al. Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: inhibition of IgE-facilitated allergen binding. J Allergy Clin Immunol 2007; 120:688–695.
36. Kopp MV, Hamelmann E, Zielen S, et al. Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma. Clin Exp Allergy 2009; 39:271–279.
37. Massanari M, Nelson H, Casale T, et al. Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma. J Allergy Clin Immunol 2010; 125:383–389.
38. Galera C, Soohun N, Zankar N, et al. Severe anaphylaxis to bee venom immunotherapy: efficacy of pretreatment and concurrent treatment with omalizumab. J Investig Allergol Clin Immunol 2009; 19:225–229.
39. Schulze J, Rose M, Zielen S. Beekeepers anaphylaxis: successful immunotherapy covered by omalizumab. Allergy 2007; 62:963–964.
40. Kontou-Fili K. High omalizumab dose controls recurrent reactions to venom immunotherapy in indolent systemic mastocytosis. Allergy 2008; 63:376–378.
41▪. Nadeau KC, Schneider LC, Hoyte L, et al. Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy. J Allergy Clin Immunol 2011; 127:1622–1624.
This report of omalizumab use in combination with oral desensitization for cow's milk allergy indicates that omalizumab may play an important role in oral food immunotherapy.
43. Cox L, Platts-Mills TAE, Finegold I, 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; 120:1373–1377.
44. Limb SL, Starke PR, Lee CE, Chowdhury BA. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol 2007; 120:1378–1381.
45▪. Cox L, Lieberman P, Wallace D, 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; 128:210–212.
This follow-up report to the 2007 Joint Task Force report on omalizumab-associated anaphylaxis reviewed additional postmarketing data from the manufacturer which demonstrate no change in the initially reported prevalence of anaphylaxis (∼0.09%).
46. Lin RY, Rodriguez-Baez G, Bhargave GA. Omalizumab-associated anaphylactic reactions reported between January 2007 and June 2008. Ann Allergy Asthma Immunol 2009; 103:442–445.
47. Barry PJ, O’Mahony A, Finnegan C, O’Connor TM. Delayed allergic reactions to omalizumab: are patients reporting all cases? J Allergy Clin Immunol 2008; 121:785–786.author reply 786.
48. Lanier BQ. Unanswered questions and warnings involving antiimmunoglobulin E therapy based on 2-year observation of clinical experience. Allergy Asthma Proc 2005; 26:435–439.
49. Price KS, Hamilton RG. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy. Allergy Asthma Proc 2007; 28:313–319.
50. Steele RH, Limaye S, Cleland B, et al. Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoetin. Nephrology (Carlton) 2005; 10:317–320.
51. Lieberman P, Rahmaoui A, Wong DA. The safety and interpretability of skin tests with omalizumab. Ann Allergy Asthma Immunol 2010; 105:493–495.
52. Dreyfus DH, Randolph CC. Characterization of an anaphylactoid reaction to omalizumab. Ann Allergy Asthma Immunol 2006; 96:624–627.
53. Owens G, Petrov A. Successful desensitization of three patients with hypersensitivity reactions to omalizumab. Curr Drug Saf 2011; 6:339–342.