Skip to main content

Anaphylaxis to three humanized antibodies for severe asthma: a case study



Omalizumab, mepolizumab, benralizumab, and dupilumab are the currently available biologics used to treat asthma in Japan. Anaphylaxis following treatment with mepolizumab or benralizumab is considered rare.

Case presentation

We report the case of a 35-year-old woman with severe asthma, who experienced anaphylaxis following the administration of benralizumab, mepolizumab, and omalizumab, separately. The therapy with biologics was chosen to avoid the repeated use of systemic corticosteroids for asthma exacerbations. The mechanisms underlying anaphylaxis caused by these three biologics remain unclear. The patient’s asthma symptoms and lung function improved after treatment with bronchial thermoplasty.


To our knowledge, this is the first report of an asthmatic patient developing anaphylaxis after commencement of benralizumab, mepolizumab, and omalizumab therapy. These three biologics should be administered carefully, and patients should be monitored for anaphylaxis.


In Japan, in addition to the standard daily controller medication, four biologics are currently available for severe uncontrolled asthma: omalizumab (anti-immunoglobulin E (anti-IgE) monoclonal antibody), mepolizumab (anti-interleukin (anti-IL)-5 monoclonal antibody), benralizumab (anti-IL-5 receptor α (IL-5Rα) monoclonal antibody), and dupilumab (anti-IL-4 receptor α (IL-4Rα) monoclonal antibody). The use of these biologics or bronchial thermoplasty should be considered based on appropriate indications and availability to avoid frequent use of systemic corticosteroids. The use of corticosteroids is associated with complications, including osteoporosis, fractures, increased susceptibility to infections, stroke, hypertension, obesity, type 2 diabetes, cataracts, gastrointestinal ulcers, and thinning of the skin [1,2,3]. In patients with severe asthma, these complications increase significantly in a dose-dependent manner upon treatment with systemic corticosteroids [1].

Patients with severe asthma who have been treated for at least 6 months with a daily dose of 5 mg or more of prednisone have a significantly higher risk of developing corticosteroid-related complications than patients who have not received this treatment [1]. Moreover, exposure to four or more intermittent courses of systemic corticosteroids is associated with significantly higher odds of complications [3].

Where appropriate, the Global Asthma Initiative (GINA) guidelines for severe and difficult-to-treat asthma support the inclusion of an add-on type 2 targeted biologic for patients with exacerbations and eosinophilic and/or allergic biomarkers, despite their use of high-dose inhaled corticosteroids (ICS) and long-acting beta-agonist (LABA) therapy with or without systemic corticosteroids (daily oral corticosteroid (OCS)) [4]. Add-on omalizumab treatment can be considered for patients aged 6 years and older with moderate or severe allergic asthma that remains uncontrolled with GINA step 4 treatment. Add-on mepolizumab, benralizumab, or dupilumab treatment may also be considered for patients aged 12 years and older with severe eosinophilic or type 2 asthma that remains uncontrolled with GINA step 4 treatment [4,5,6,7,8,9,10]. As these biologics have a certain homology and affinity toward human tissues, they are generally well-tolerated in humans. Omalizumab was the first approved humanized antibody for the treatment of asthma in Japan. Although generally quite well-tolerated, there are many reports regarding potential adverse effects, including rare anaphylactic reactions [11,12,13,14,15,16,17]. However, anaphylactic reactions associated with mepolizumab or benralizumab treatment have rarely been reported [18,19,20]. To our knowledge, this is the first case of anaphylaxis following the administration of benralizumab, mepolizumab, and omalizumab, separately, in a patient with asthma.

Case presentation

A 35-year-old woman was initially diagnosed with asthma at the age of 16 years. The patient presented to our hospital 3 years ago with a 1-month history of an asthma exacerbation. The diagnosis of asthma was confirmed based on a clinical history of episodic symptoms with airflow limitation and variation in pulmonary function evaluated by forced expiratory volume in 1 s (FEV1), in accordance with the Asthma Prevention and Management Guideline 2015, Japan [21]. She required a daily dose of 1000 μg fluticasone propionate (ICS), 40 μg formoterol (LABA), 5 μg tiotropium (muscarinic antagonist), 10 mg montelukast (leukotriene receptor antagonist), 400 mg theophylline (methylxanthine), and 5 mg oral prednisolone to manage her severe persistent asthma. Despite the high dose of ICS-LABA with daily OCS, her asthma control test (ACT) score was less than 20, which is defined as uncontrolled asthma, and she needed an increase in systemic corticosteroids for a month. She met the criteria of the European Respiratory Society (ERS) and the American Thoracic Society (ATS) for the diagnosis of severe/refractory asthma [22]. Her peripheral blood eosinophil count was 117 cells/μL, total immunoglobulin E (IgE) level was 639 IU/mL, and specific IgE against house dust mites (Dermatophagoides farinae) was positive (chemiluminescence enzyme immunoassay class 4). Her repeated exacerbations of asthma, blood eosinophil count, and serum IgE level under maintenance treatment with daily OCS made us consider starting her on anti-IL-5 and anti-IgE treatment. To avoid the excessive use of systemic corticosteroids, she agreed to receive her first subcutaneous administration of 100 mg mepolizumab 2 years ago. She opted for mepolizumab treatment every 4 weeks over omalizumab treatment every 2 weeks, from the perspective of work convenience (benralizumab was not yet available at that point). Her FEV1 and ACT scores before treatment with mepolizumab were 1.99 L and 8 points, respectively, which increased to 2.61 L and 24 points, respectively, 3 months after treatment with mepolizumab. Her clinical symptoms of uncontrolled asthma disappeared; hence, the dose of oral corticosteroids was tapered off and discontinued completely after 9 months of treatment with mepolizumab. However, she occasionally experienced asthma exacerbations, which required systemic corticosteroid administration, although mepolizumab was partially effective in alleviating her symptoms for 1.5 years. To avoid the repeated exacerbations of asthma, she expressed an interest in trying a different therapy after the 19th administration of mepolizumab and agreed to receive 30 mg benralizumab subcutaneously. Within 10 min of administration, she developed a skin rash, throat discomfort, dyspnea, and wheezing without any gastrointestinal symptoms. Her blood pressure was 127/68 mmHg, pulse rate 65 beats/min, and oxygen saturation (SpO2) 98%. These symptoms resolved prior to the administration of any treatment, however, she was subsequently given intravenous antihistamines and corticosteroids as per our institute’s protocol. She did not develop a late-phase anaphylactic reaction.

Two weeks after this episode, she again developed marked symptoms of an exacerbation of severe asthma. Her symptoms did not improve despite the use of systemic corticosteroids. Owing to her persistent symptoms of asthma, a severe response to benralizumab, and a desire to avoid oral corticosteroid treatment, she requested the resumption of mepolizumab treatment. Although bronchial thermoplasty was suggested as the next treatment option, she preferentially chose treatment with biologics over bronchial thermoplasty, since hospitalization for the latter procedure would impair work life. It also came to light that she had a history of allergic contact dermatitis, which was possibly triggered by polysorbate, an excipient in a milky lotion that she had used. Since benralizumab and mepolizumab formulations contain polysorbate (Table 1), a skin-prick test (SPT) to evaluate her sensitivity to polysorbate 20 was performed. After her result was confirmed to be negative (Table 2A), she received her 20th subcutaneous administration of 100 mg mepolizumab. However, 2 h after administration, an anaphylactic reaction was observed; she developed skin rash, throat discomfort, dyspnea, and wheezing without gastrointestinal symptoms. Her blood pressure was 120/68 mmHg, pulse rate 55 beats/min, and SpO2 97%. These symptoms subsided without epinephrine injection, however she was again treated with intravenous antihistamines and corticosteroids per our protocol. She again did not develop a late-phase anaphylactic reaction.

Table 1 Components of each biologics
Table 2 The results of SPT and DLST

Although there was an improvement in the anaphylaxis induced by the mepolizumab injection, she required hospitalization for a month owing to the exacerbation of her asthma. To reduce the dose of administered systemic corticosteroids, she requested that her therapy be changed to omalizumab. Accordingly, she was administered a subcutaneous dose of 450 mg omalizumab, while the corticosteroid therapy was tapered (intravenous administration of 4 mg betamethasone). No anaphylactic reaction was observed. After the first administration of omalizumab, she was discharged without any indicative symptoms of asthma. Two weeks later, she was re-hospitalized for her second dose of omalizumab. However, the second dose caused anaphylaxis, and she experienced itchy skin, throat discomfort, dyspnea, wheezing, and transient loss of consciousness without gastrointestinal symptoms. Her vital signs within 30 min of this episode were as follows: a drop-in blood pressure to 86/54 mmHg, a pulse rate of 80 beats/min, and an SpO2 value of 88%. Oxygen was administered by nasal prongs at a rate of 3 L/min. Subsequent intramuscular epinephrine injection resulted in her regaining consciousness and an immediate improvement of hypotension. Her general condition improved within 50 min of receiving epinephrine. She was also treated with an intravenous drip of 40 mg methylprednisolone and chlorpheniramine maleate (histamine H1 receptor antagonist). Six hours after omalizumab administration, she experienced a late-phase anaphylaxis, which was not observed during therapy with mepolizumab and benralizumab. She experienced itchy skin, throat discomfort, dyspnea, and transient loss of consciousness without gastrointestinal symptoms. An intramuscular injection of epinephrine and an intravenous drip of 40 mg methylprednisolone were administered; her symptoms improved immediately.

She required systemic corticosteroids (oral prednisolone 5 mg/day) for severe persistent asthma and an intermittent high dose of corticosteroids for repeated severe exacerbation of asthma for 6 months after the anaphylaxis following omalizumab administration. She was also treated with bronchial thermoplasty, and no adverse events were experienced. After the third bronchial thermoplasty, she is currently being treated without systemic corticosteroids and her condition has been stable for 4 months. Moreover, her FEV1 and ACT scores have increased to 2.79 L and 25 points, respectively.

Discussion and conclusions

In this paper, we present the first reported case of anaphylaxis induced by three humanized antibodies (benralizumab, mepolizumab, and omalizumab), which are generally considered safe and indicated for use in severe asthma. Anaphylaxis is a rapid, systemic, and a potentially life-threatening immune reaction that requires immediate pharmacological intervention. Epinephrine is universally recommended as the first-line therapy for anaphylaxis to prevent a potentially fatal outcome and works best when administered at the onset of the reaction [23,24,25,26]. In addition, non-administration or delayed administration of epinephrine increases the risk of death [27, 28]. Thus, epinephrine should be administered to all patients who experience anaphylaxis. However, it has been reported that only 1 in 4 patients with severe anaphylaxis are administered epinephrine, and these statistics have remain unchanged over the past decade [29]. A possible reluctance to use epinephrine as the first-line therapy in anaphylaxis owing to unfounded fear of the drug itself may be a factor deterring its use [30]. The significant discrepancy between the recommended and actual practice suggests that there is a need to educate and advocate the use of epinephrine at the onset of clinical anaphylaxis. In the present case, the patient was neither hypotensive nor desaturated during her two episodes of anaphylaxis following treatment with benralizumab and mepolizumab. However, considering the patient’s history of acute respiratory disorder with unstable asthma, it would have been more appropriate to administer epinephrine immediately, rather than delay or not administer epinephrine, even if her symptoms improved spontaneously in those two episodes. Furthermore, her symptoms improved spontaneously without epinephrine injection, suggesting that she may not have experienced anaphylaxis. However, this should not be the reason to refrain from epinephrine therapy, and in hindsight, our patient should have been administered epinephrine immediately once anaphylaxis was suspected. In addition, there is a lack of evidence to support the efficacy of glucocorticoids and antihistamines, including H1- and H2-antihistamines, in the management of anaphylaxis [30, 31]. Therefore, given that these therapies could delay the timely administration of epinephrine, it should be emphasized to administer epinephrine as first-line therapy [30,31,32].

Furthermore, omalizumab, but not benralizumab and mepolizumab, induced a late-phase anaphylactic reaction, 6 h after administration. Late-phase anaphylactic reactions to allergens have been studied mainly in cutaneous models, leukocytes (eosinophils and smaller numbers of neutrophils and basophils), and monocytes recruited during late-phase reactions in the human skin [33]. Benralizumab and mepolizumab can suppress eosinophils and consequently inhibit the late-phase anaphylactic reaction. However, this hypothesis needs further investigation.

Biologics should be used cautiously, and clinicians should be aware of the possibility of anaphylactic reactions to different/multiple agents if a patient develops anaphylactic reactions to one of the biologics in use. After the first episode of anaphylaxis induced by benralizumab, bronchial thermoplasty was considered for the next treatment option. Our present patient experienced an improved quality of life, increased respiratory functionality, and fewer exacerbations of asthma after successful bronchial thermoplasty. Bronchial thermoplasty might thus be an option for asthmatic patients who do not respond well to pharmacological treatment; however, the long-term safety of bronchial thermoplasty treatment is still unclear [34, 35]. Moreover, owing to severe uncontrolled asthma in our patient despite the use of high dose of corticosteroids, we were unable to decide if bronchial thermoplasty during the initial treatment was a viable option.

Polysorbate, an additive used to increase the solubility of poorly water-soluble drugs, is one of the excipients in these three biologics responsible for hypersensitivity reactions [11,12,13,14,15,16,17, 36,37,38]. There are four types of polysorbates used as excipients: polysorbates 20, 40, 60, and 80, of which, polysorbates 20 and 80 are more common [37]. Benralizumab and omalizumab used in our clinical setting contained polysorbate 20 as an emulsion stabilizer, whereas mepolizumab contained polysorbate 80 (Table 1). The anaphylactic reaction following the first administration of benralizumab may have been due to the presence of polysorbate 20. Our patient presented with a history of allergic rhinitis, pollinosis, skin rash after a meal of raw shrimps as well as allergic contact dermatitis caused by a milky lotion, which may have contained polysorbate as an excipient. However, as shown in Table 2, her SPT results for reactions due to polysorbate 20, mepolizumab, and omalizumab were negative. Additionally, she tested negative for the drug-induced lymphocyte stimulation test (DLST) for mepolizumab and omalizumab (Table 2). However, she tested positive for the SPT and DLST for benralizumab (Table 2). These tests are commonly used for the auxiliary diagnosis of drug allergies [39,40,41,42,43,44,45,46]. However, the results of the SPT for drug allergies are drug-dependent and not always reliable, for many drugs the sensitivity and specificity have not been established [39]. Similarly, the DLST can produce false-positive or false-negative results, and the drug-allergy results greatly depend on the drug of interest [40, 41]. Therefore, there is a possibility that the biologics used in this study displayed false-positive or false-negative results in SPTs and DLSTs. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood by density-gradient centrifugation and used for the DLST. Since benralizumab interacts directly with PBMC through the IL-5 receptor α unit, interpreting these DLST results could be challenging. Further studies are required to investigate why all three biologics induced anaphylaxis in the patient, although she showed positive results for the SPT and DLST only for benralizumab.

Mast cell activation syndrome (MCAS) and mastocytosis are also possible causes of repeated episodes of anaphylaxis [47,48,49,50,51]. Hypotension is an important diagnostic parameter commonly manifesting in mast cell activation (MCA) and MCAS. Moreover, the diagnosis of MCAS is strongly supported by acute serum tryptase levels higher than plus 20% of the baseline [47,48,49,50,51]. In the present case, the lack of hypotension during anaphylaxis following benralizumab and mepolizumab administration did not make us aware of the possibility of MCA and MCAS. The patient’s baseline serum tryptase levels were 3.1, 2.5, and 2.9 μg/L, before treatment with mepolizumab, benralizumab, and bronchial thermoplasty, respectively; her acute serum tryptase levels were not measured after the anaphylactic reaction. When anaphylactic reactions are severe and recurrent, the diagnoses of MCA and MCAS must be considered [47,48,49,50,51]. Therefore, the lack of this data is a limitation of our case presentation.

In conclusion, to the best of our knowledge, this is the first report of an asthmatic patient developing anaphylaxis following the administration of three commonly used biologics to treat asthma—benralizumab, mepolizumab, and omalizumab. Since the reasons for the anaphylaxis are unclear, these biologics should be administered carefully in clinical settings.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.



Asthma control test


Bronchial thermoplasty


Drug-induced lymphocyte stimulation test

FEV1 :

Forced expiratory volume in 1 s


Global Asthma Initiative


Inhaled corticosteroid


Immunoglobulin E




Long-acting beta-agonist


Mast cell activation


Mast cell activation syndrome


Oral corticosteroid


Peripheral blood mononuclear cells

SpO2 :

Oxygen saturation


Skin-prick test


  1. Dalal AA, Duh MS, Gozalo L, Robitaille MN, Albers F, Yancey S, et al. Dose-response relationship between long-term systemic corticosteroid use and related complications in patients with severe asthma. J Manag Care Spec Pharm. 2016;22(7):833–47.

    PubMed  Google Scholar 

  2. Sarnes E, Crofford L, Watson M, Dennis G, Kan H, Bass D. Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review. Clin Ther. 2011;33(10):1413–32.

    Article  PubMed  Google Scholar 

  3. Sullivan PW, Ghushchyan VH, Globe G, Schatz M. Oral corticosteroid exposure and adverse effects in asthmatic patients. J Allergy Clin Immunol. 2018;141(1):110–6.

    Article  CAS  PubMed  Google Scholar 

  4. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and prevention. Available from: 2019.

  5. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;1:003559.

    Google Scholar 

  6. Rodrigo GJ, Neffen H. Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents. Pediatr Allergy Immunol. 2015;26(6):551–6.

    Article  PubMed  Google Scholar 

  7. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9.

    Article  CAS  PubMed  Google Scholar 

  9. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017;376(25):2448–58.

    Article  CAS  PubMed  Google Scholar 

  10. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–96.

    Article  CAS  PubMed  Google Scholar 

  11. Baker DL, Nakamura GR, Lowman HB, Fischer SK. Evaluation of ige antibodies to omalizumab (Xolair(r)) and their potential correlation to anaphylaxis. AAPS J. 2016;18(1):115–23.

    Article  CAS  PubMed  Google Scholar 

  12. Kim HL, Leigh R, Becker A. Omalizumab: practical considerations regarding the risk of anaphylaxis. Allergy Asthma Clin Immunol. 2010;6(1):32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lieberman PL, Jones I, Rajwanshi R, Rosen K, Umetsu DT. Anaphylaxis associated with omalizumab administration: Risk factors and patient characteristics. J Allergy Clin Immunol. 2017;140(6):1734–6.

    Article  PubMed  Google Scholar 

  14. Lieberman PL, Umetsu DT, Carrigan GJ, Rahmaoui A. Anaphylactic reactions associated with omalizumab administration: Analysis of a case-control study. J Allergy Clin Immunol. 2016;138(3):913–5.

    Article  CAS  PubMed  Google Scholar 

  15. 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(6):1378–81.

    Article  CAS  PubMed  Google Scholar 

  16. Pichler WJ. Adverse side-effects to biological agents. Allergy. 2006;61(8):912–20.

    Article  CAS  PubMed  Google Scholar 

  17. Price KS, Hamilton RG. Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy. Allergy Asthma Proc. 2007;28(3):313–9.

    Article  CAS  PubMed  Google Scholar 

  18. Khatri S, Moore W, Gibson PG, Leigh R, Bourdin A, Maspero J, et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J Allergy Clin Immunol. 2019;143(5):1742–51.

    Article  CAS  PubMed  Google Scholar 

  19. Lugogo N, Domingo C, Chanez P, Leigh R, Gilson MJ, Price RG, et al. long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, phase IIIb study. Clin Ther. 2016;38(9):2058–70.

    Article  CAS  PubMed  Google Scholar 

  20. Benralizumab (Fasenra) for Severe Eosinophilic Asthma. JAMA. 2018;319(14):1501-2.

  21. Asthma prevention and management guidelines 2015, Japan. 2015.

  22. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–73.

    Article  CAS  PubMed  Google Scholar 

  23. Bautista E, Simons FE, Simons KJ, Becker AB, Duke K, Tillett M, et al. Epinephrine fails to hasten hemodynamic recovery in fully developed canine anaphylactic shock. Int Arch Allergy Immunol. 2002;128(2):151–64.

    Article  CAS  PubMed  Google Scholar 

  24. Soar J, Pumphrey R, Cant A, Clarke S, Corbett A, Dawson P, et al. Emergency treatment of anaphylactic reactions–guidelines for healthcare providers. Resuscitation. 2008;77(2):157–69.

    Article  PubMed  Google Scholar 

  25. Fineman SM. Optimal treatment of anaphylaxis: antihistamines versus epinephrine. Postgrad Med. 2014;126(4):73–81.

    Article  PubMed  Google Scholar 

  26. Simons FE, Ardusso LR, Bilo MB, El-Gamal YM, Ledford DK, Ring J, et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J. 2011;4(2):13–37.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol. 2007;119(4):1016–8.

    Article  PubMed  Google Scholar 

  28. Gallagher M, Worth A, Cunningham-Burley S, Sheikh A. Epinephrine auto-injector use in adolescents at risk of anaphylaxis: a qualitative study in Scotland. UK Clin Exp Allergy. 2011;41(6):869–77.

    Article  CAS  PubMed  Google Scholar 

  29. Grabenhenrich LB, Dolle S, Rueff F, Renaudin JM, Scherer K, Pfohler C, et al. Epinephrine in severe allergic reactions: the european anaphylaxis register. J Allergy Clin Immunol Pract. 2018;6(6):1898–906.

    Article  PubMed  Google Scholar 

  30. Campbell DE. Anaphylaxis management: time to re-evaluate the role of corticosteroids. J Allergy Clin Immunol Pract. 2019;7(7):2239–40.

    Article  PubMed  Google Scholar 

  31. Turner PJ, Campbell DE, Motosue MS, Campbell RL. Global trends in anaphylaxis epidemiology and clinical implications. J Allergy Clin Immunol Pract. 2019;8:1169–76.

    Article  PubMed  Google Scholar 

  32. Turner PJ, Jerschow E, Umasunthar T, Lin R, Campbell DE, Boyle RJ. Fatal anaphylaxis: mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5(5):1169–78.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008;454(7203):445–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hashimoto S, Bel EH. Current treatment of severe asthma. Clin Exp Allergy. 2012;42(5):693–705.

    Article  CAS  PubMed  Google Scholar 

  35. Wechsler ME, Laviolette M, Rubin AS, Fiterman J, Lapa e Silva JR, Shah PL, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132(6):1295–302.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV, 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(6):1373–7.

    Article  CAS  PubMed  Google Scholar 

  37. Hoffmann C, Blume A, Miller I, Garidel P. Insights into protein-polysorbate interactions analysed by means of isothermal titration and differential scanning calorimetry. Eur Biophys J. 2009;38(5):557–68.

    Article  CAS  PubMed  Google Scholar 

  38. Steele RH, Limaye S, Cleland B, Chow J, Suranyi MG. Hypersensitivity reactions to the polysorbate contained in recombinant erythropoietin and darbepoietin. Nephrology. 2005;10(3):317–20.

    Article  PubMed  Google Scholar 

  39. Heinzerling L, Mari A, Bergmann KC, Bresciani M, Burbach G, Darsow U, et al. The skin prick test—European standards. Clin Transl Allergy. 2013;3(1):3.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Nyfeler B, Pichler WJ. The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity. Clin Exp Allergy. 1997;27(2):175–81.

    Article  CAS  PubMed  Google Scholar 

  41. Saito D, Hayashida M, Sato T, Minowa S, Ikezaki O, Mitsui T, et al. Evaluation of the drug-induced lymphocyte stimulation test for diagnosing mesalazine allergy. Intest Res. 2018;16(2):273–81.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tokuwaka J, Takahashi S, Tanaka M. Anaphylaxis after sugammadex administration. Can J Anaesth. 2013;60(7):733–4.

    Article  PubMed  Google Scholar 

  43. Fujisaki A, Kondo Y, Goto K, Morita T. Life-threatening anaphylaxis to leuprorelin acetate depot: case report and review of the literature. Int J Urol. 2012;19(1):81–4.

    Article  CAS  PubMed  Google Scholar 

  44. Mochitomi Y, Inoue A, Kawabata H, Ishida S, Kanzaki T. Stevens-Johnson syndrome caused by a health drink (Eberu) containing ophiopogonis tuber. J Dermatol. 1998;25(10):662–5.

    Article  CAS  PubMed  Google Scholar 

  45. Arima M, Kanoh T, Yamasaki A, Matsuda S, Kasuya H, Sunayama S, et al. Eosinophilic myocarditis associated with toxicodermia caused by phenobarbital. Jpn Circ J. 1998;62(2):132–5.

    Article  CAS  PubMed  Google Scholar 

  46. Yoshimura T, Kurita C, Hayata M, Nagai H. Diagnosis of drug allergy by the lymphocyte stimulation test with the MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. Biol Pharm Bull. 1993;16(7):686–9.

    Article  CAS  PubMed  Google Scholar 

  47. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010;126(6):1099–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26(3):451–63.

    Article  PubMed  Google Scholar 

  49. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. 2008;63(2):226–32.

    Article  CAS  PubMed  Google Scholar 

  50. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol. 2009;123(3):680–6.

    Article  CAS  PubMed  Google Scholar 

  51. Valent P, Akin C, Bonadonna P, Hartmann K, Brockow K, Niedoszytko M, et al. Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome. J Allergy Clin Immunol Pract. 2019;7(4):1125–33.

    Article  PubMed  PubMed Central  Google Scholar 

Download references


We would like to thank Editage ( for English language editing.


Not applicable.

Author information

Authors and Affiliations



KJ, NH, JI, and KT participated in the design of the study and drafted the manuscript. NH, TN, MT, TY, TA, HT, TT and JI participated in patient care. KT aided with the diagnosis and provided treatment-related advice. NH and JI performed the SPT and interpretation of the results. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Norihiro Harada.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Consent for publication was obtained from the patient.

Competing interests

The authors declare no conflicts of interest in association with the present study.

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 The Creative Commons Public Domain Dedication waiver ( 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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jingo, K., Harada, N., Nishioki, T. et al. Anaphylaxis to three humanized antibodies for severe asthma: a case study. Allergy Asthma Clin Immunol 16, 46 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: