Severe asthma concomitant with allergic bronchopulmonary ...

Allergology International xxx (2018) 1e3

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Letter to the Editor

Severe asthma concomitant with allergic bronchopulmonary aspergillosis successfully treated with mepolizumab Dear Editor, Allergic bronchopulmonary aspergillosis (ABPA) is characterized by systemic and airway eosinophilia, elevated serum IgE levels, lung infiltration, bronchiectasis, and mucoid impaction of the central bronchi attributable to a complex hypersensitivity reaction to Aspergillus fumigatus (A. fumigatus).1 We report the case of a 33-year-old male diagnosed with severe eosinophilic asthma concomitant with ABPA, successfully treated with mepolizumab. The patient was referred to our hospital because of poorly controlled severe asthma. He was diagnosed with bronchial asthma at the age of 24 years. One year later, he was suspected to have ABPA because of peripheral blood eosinophilia, an elevated IgE level (1505 IU/mL), mucoid impaction and lung infiltration evident on chest computed tomography (CT), and a brownish mucous plug apparent on bronchoscopy. He was treated with itraconazole and oral prednisolone for 8 months. Thereafter, he was treated with high-dose ICS, LABA, a leukotriene receptor antagonist, theophylline, and oral prednisolone (5 mg/day); however, he experienced repeated asthma exacerbation and lung infiltration requiring increased levels of systemic corticosteroids, which finally rendered him unable to work. At the time of his first visit to our hospital, he presented with a cough, yellow-brown sputum, wheezing, and chronic rhinosinusitis with nasal polyps (CRSwNP). The peripheral blood eosinophil count, the FeNO level, and the serum IgE concentration were 6370/mL, 230 ppb, and 182 IU/mL, respectively. The C-anti-neutrophil cytoplasmic antibody (ANCA) and P-ANCA tests were negative. A lung function test revealed an obstructive disorder; the FEV1 and FEV1/forced vital capacity (FVC) ratio were 2.36 L and 59.1%. Chest CT revealed central bronchiectasis, mucoid impaction, and lung infiltration (Fig. 1A). Immediate cutaneous hypersensitivity and Arthus's reaction to A. fumigatus antigen was evident. Therefore, he was diagnosed with severe asthma concomitant with ABPA. A. fumigatus was not detected in cultured sputum similar to some reported ABPA cases.1 We initiated mepolizumab (100 mg every 4 weeks). Eight weeks later, the peripheral blood eosinophil and FeNO levels decreased to 64/mL and 105 ppb. His Asthma Health Questionnaire-Japan score improved from 51 to 21 and his Asthma Control Test score improved from 5 to 25 points. Twenty-four weeks later, the FEV1 and the FEV1/FVC ratio improved to 3.16 L and 71.0%. At 32 weeks, chest CT revealed that the mucoid impaction and lung infiltration were attenuated (Fig. 1B), and precipitating antibody for

A. fumigatus, which exhibited weak reaction 12 weeks after mepolizumab initiation, decreased to be negative. The peripheral eosinophil counts remained low, and he has not exacerbated in the 8 months since mepolizumab was initiated. The asthma is well controlled, and the oral prednisolone dose has been decreased to 2.5 mg/day. However, the CRSwNP did not improve and he required endoscopic sinus surgery (Fig. 2). The pathophysiology of ABPA reflects changes in both innate and adaptive immunity, including Th2 responses in susceptible hosts who cannot efficiently clear inhaled fungal spores from the respiratory epithelium.2 Th2 cells produce cytokines such as IL-4 (that induces class-switching of IgE-secreting B cells) and IL-5 (that triggers eosinophil mobilization). Oral corticosteroids are the mainstay of management, attenuating the Th2 responses triggered by A. fumigatus. Antifungal treatment complements the oral corticosteroids, and can reduce the steroid dose and duration by reducing the burden of fungal colonization. Recently, several reports have described the efficacy of omalizumab (a humanized anti-IgE mAb) in the context of ABPA. Although only case reports have appeared, omalizumab may be effective against IgE-mediated ABPA.3 Mepolizumab is a humanized antiIL-5 mAb approved for treatment of severe eosinophilic asthma.4 As clinical trials of mepolizumab excluded ABPA patients, the efficacy of mepolizumab as an ABPA treatment remains unknown. In our case, the serum IgE level became suppressed after long-term oral corticosteroid treatment, but the peripheral blood eosinophil numbers remained markedly elevated. We considered that eosinophilic inflammation induced by IL-5 was not suppressed by oral corticosteroids, and decided to initiate mepolizumab. Interestingly, mepolizumab treatment not only improved the asthmatic symptoms but also contributed to remarkable attenuation of ABPAassociated mucoid impaction and lung infiltration, and allowed sparing of oral corticosteroids. A case of ABPA treated with a combination of omalizumab and mepolizumab has recently been reported.5 In that case, omalizumab exerted some effect, but mepolizumab and omalizumab were suggested to act synergistically. In our case, eosinophils appeared to play the central role in both the severe asthma and ABPA, and mepolizumab was helpful. To the best of our knowledge, this is the first report to demonstrate the efficacy of mepolizumab alone (thus, without omalizumab) as a treatment for ABPA. Mepolizumab suppresses both systemic and sputum eosinophilia in severely eosinophilic asthma patients.6 ABPA mucus plugs

Peer review under responsibility of Japanese Society of Allergology. https://doi.org/10.1016/j.alit.2018.03.004 1323-8930/Copyright © 2018, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Please cite this article in press as: Oda N, et al., Severe asthma concomitant with allergic bronchopulmonary aspergillosis successfully treated with mepolizumab, Allergology International (2018), https://doi.org/10.1016/j.alit.2018.03.004

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Letter to the Editor / Allergology International xxx (2018) 1e3

Fig. 1. Chest computed tomography performed prior to mepolizumab administration (A) showing central bronchiectasis and mucoid impaction in the left lower lobe, and lung infiltration in the right middle lobe. Patchy lung infiltration and grand grass opacity suggesting eosinophilic pneumonia or centrilobular grand grass nodules indicating eosinophilic bronchiolitis were not shown. Chest computed tomography performed 32 weeks after mepolizumab administration showing improvements in these findings (B).

Fig. 2. The clinical course. After mepolizumab administration, the peripheral blood eosinophil counts decreased and the FEV1 value increased. Eo, peripheral blood eosinophil counts; PSL, prednisolone.


Letter to the Editor / Allergology International xxx (2018) 1e3

contain many eosinophils; thus, mepolizumab contributes to plug clearance. ILC2s produce large amounts of IL-5, and are present in severely asthmatic patients.7 Both ILC2s and Th2 cells produce substantial amounts of IL-5, inducing increases in eosinophil numbers; therefore, mepolizumab may be useful to treat severe eosinophilic asthma associated with ABPA. In our case, the CRSwNP did not improve despite reductions in eosinophilia. CRSwNP is a form of refractory chronic rhinosinusitis characterized by nasal polyps containing abundant eosinophils, often associated with severe asthma. Such pathophysiology suggests that mepolizumab should counter CRSwNP8 and, indeed, modest effects were reported in a small-scale clinical trial (750 mg mepolizumab every 4 weeks).9 Mepolizumab at 100 mg every 4 weeks of our case might not adequately address the CRSwNP; it might depend on the difference in the threshold of the expression effect, as mepolizumab exerts its effects systemically rather than locally. In the present case, Aspergillus-specific IgE antibodies were negative (data not shown), and total IgE levels and Aspergillus-specific precipitating antibody titers were relatively low. This case was considered to be in the “corticosteroid dependent asthma” stage, which might have affected these titers.10 In conclusion, we report a case of severe asthma with ABPA successfully treated with mepolizumab. The drug not only improved the asthma symptoms but also remarkably attenuated ABPAcaused mucoid impaction and lung infiltration. Further work is warranted to confirm the efficacy of mepolizumab used to treat ABPA. Conflict of interest The authors have no conflict of interest to declare.

Naohiro Oda a, Nobuaki Miyahara a,b, Satoru Senoo a, Junko Itano c, Akihiko Taniguchi a, Daisuke Morichika a, Utako Fujii a, Yoshinobu Maeda a, Katsuyuki Kiura c, Arihiko Kanehiro a,d,* a

Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

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b Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan c Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan d Department of Allergy and Respiratory Medicine, Okayama Rosai Hospital, Okayama, Japan

* Corresponding author. Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. E-mail address: [email protected] (A. Kanehiro).

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