Measured Immunoglobulin E in Allergic Bronchopulmonary ...

Journal of Asthma, 47:942–945, 2010 Copyright © 2010 Informa Healthcare USA, Inc. ISSN: 0277-0903 print / 1532-4303 online DOI: 10.3109/02770903.2010.491144

CASE REPORT

Measured Immunoglobulin E in Allergic Bronchopulmonary Aspergillosis Treated With Omalizumab ROBERT Y. LIN, M.D.,1,2,* SONALI SETHI, M.D.,1,2 AND GEETA A. BHARGAVE, M.D.1 1

Department of Medicine, St Vincent’s Hospital–Manhattan–Saint Vincent’s Catholic Medical Centers, New York, New York, U.S.A. 2 Department of Medicine, New York Medical College, New York, New York, U.S.A. Background. The ability to assess adequate reductions in immunoglobulin E (IgE) in allergic bronchopulmonary aspergillosis (ABPA) has been a concern with regards to omalizumab treatment. Objective. To describe the clinical course and serial measured IgE levels in two adult patients with elevated IgE levels, hypersensitivity to Aspergillus fumigatus, and bilateral bronchiectasis who were treated with omalizumab. Clinical Descriptions. Patient 1 met commonly used critieria for ABPA and had a more than 3-fold increase (from 702 to 2462 IU/ml) in measured IgE 4 months after starting omalizumab. Two years after starting omalizumab, the IgE level decreased to baseline (473 IU/ml) even when corticosteroids were discontinued. Patient 2 had near normalization of elevated IgE levels when treated with corticosteroids but IgE levels subsequently rose again to over 10,000 IU/ml. After reducing the IgE level to 586 IU/ml with higher corticosteroid doses, omalizumab was initiated. Twenty months after starting omalizumab, the measured IgE was 510 IU/ml. Based on published omalizumab treatment–associated total/free IgE ratios, the estimated free IgE levels for both patients after more than a year of omalizumab treatment was less than their pre–omalizumab treatment IgE levels. Conclusions. These data suggest that omalizumab can be beneficial in treating ABPA and that measured IgE levels can still be useful in this context. Noting the pattern of IgE levels associated with ABPA exacerbations and with corticosteroid treatment may help both with achieving an IgE level appropriate for omalizumab treatment and with the interpretation of measured IgE changes associated with omalizumab treatment. Keyword: asthma; IgE; omalizumab; aspergillosis

INTRODUCTION

AND

BACKGROUND

disease, a left pneumothorax requiring operative intervention, eczema, and allergic rhinitis. He also had a history of keratoconus, which required corneal transplantation. Over the next 3 years, the patient had three more hospitalizations and two emergency room visits for asthma and respiratory infection, during which time frequent steroid bursts were prescribed. The tuberculin test was negative on numerous occasions. In 2005, there were at least five emergency room visits for asthma and respiratory infection, despite treatment with fluticasone/salmeterol, montelukast, and albuterol. An IgE determination in August 2005 measured 526 IU/ml using the Diagnostic Product Corp Immunlite® -2000 assay. In December 2005, the total eosinophil count was 922/mm3 (10.6%). By July 2006, the IgE level had risen to 702 IU/ml and continuous oral corticosteroids were prescribed at an average dose of 20 mg per day for the remainder of the year. A hypersensitivity pneumonitis screen revealed the presence of IgG antibody to Aspergillus fumigatus without reactivity to other pathogens (Micropolyspora faeni, Pigeon serum, Thermoactinomyces candidus, Thermoactinomyces vulgaris, and Saccharomonospora viridis). Partial identity with the aspergillus-positive control was observed in aspergillus precipitins testing. Immunocap® -determined allergen-specific IgE to Aspergillus fumigatus was 3.83 kU/L. Positive results were also observed to cat dander, tree and ragweed pollen, cockroach, and Dermatophagoides farinae. A computerized tomogram of the thorax revealed central bronchiectasis and bilateral apical fibrocavitary/granulomatous

Omalizumab is a humanized monoclonal antiimmunoglobulin E (IgE) that reduces free IgE and IgE receptor density (1), when given in therapeutic doses. Although IgE normally has a serum half-life of 3 days, omalizumab-bound IgE has a much longer half-life (2). Currently available IgE assays measure total IgE (both bound and free) (3). As a result, measured IgE levels in patients receiving omalizumab are elevated compared to baseline (4, 5). In patients with allergic bronchopulmonary aspergillosis (ABPA), decreases in IgE are one gauge of successful treatment (6). Omalizumab has been reported to be useful in treating cystic fibrosis children with ABPA (7–12), but experience in adults has not been reported in detail (13, 14). In addition, it is not known how to interpret measured IgE responses in ABPA patients treated with omalizumab. CASE REPORTS Patient 1 A 39-year-old Hispanic American homeless male was hospitalized in September 2001 for asthma and dermatitis. A nonsmoking native of New York City, he had a history of adult onset asthma, apical granulomatous ∗ Corresponding author: Robert Y. Lin, M.D., New York Downtown Hospital, 83 Gold Street, New York, NY 10038, U.S.A.; E-mail: robert. [email protected]

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IgE IN ABPA TREATED WITH OMALIZUMAB changes. In September 2006, the forced expiratory volume in one second (FEV1 ) was 1.76 L (56% predicted) and the forced vital capacity (FVC) was 3.06 L (80% predicted). In October 2006, the patient, by then domiciled, weighed 59 kg, and omalizumab 375 mg subcutaneous administration every 2 weeks was started. Immunotherapy was also initiated using extracts of mixed molds, tree/ragweed pollen, and cockroach. In January 2007, a 4-month course of itraconazole was prescribed. The prednisone dose was increased to 25 mg/day. In February 2007, while on omalizumab, the IgE level was 2462 IU/ml. Another IgE determination in April 2007 measured 1407 IU/ml. The patient had two hospitalizations and three emergency room visits during 2007 for asthma and respiratory infection and remained on at least 20 mg/day of prednisone. In 2008, the patient had no hospitalizations or emergency room visits for asthma or respiratory infection. The prednisone dose was decreased to 5 mg/day. In 2009, the patient had two hospitalizations and two emergency room visits for asthma with respiratory infection and was treated with 10 mg/day prednisone for the first half of the year. During the latter part of 2009, no oral corticosteroids were administered. In October 2009, the IgE level was 473 IU/ml using the Diagnostic Product Corp Immunlite® -2000 assay. Using the Immunocap® assay, IgE level in December 2009 was found to be 789 IU/ml. He was hospitalized for a respiratory infection and asthma in March 2010. In April 2010, while not on oral corticosteroids, office spirometry was performed. The FEV1 was 1.72 L (56% predicted) and the FVC was 3.09 L (83% predicted). Patient 2 A 51-year-old Hispanic American male was hospitalized in March 2004 for shortness of breath and wheezing. A native of New York City, he had a history of mental retardation and required long-term custodial care. On a chest computerized tomogram taken in 1999, there was right upper lobe fibrocavitary disease with pleural thickening, and there was a history of prior tuberculous treatment. However, New York City Department of Health records reported that sputum cultures and smears were consistently negative for acid-fast bacteria/Mycobacterium tuberculosis for this patient. Radiographs also showed bilateral bronchiectasis and air trapping, which was felt to be consistent with obstructive lung disease. In 2002, there was a prolonged hospitalization where an esophageal web repair via a right thoracotomy was complicated by ventilator-associated pneumonia with pleuropericardial infection, requiring drainage and prolonged mechanical ventilation by tracheostomy. During the 2004 admission, the physical examination revealed right lung rales and expiratory wheezing on the left lung fields. There was also digital clubbing, tracheostomy and substernal scars, and a right thoracotomy scar. The IgE level was 9541 IU/ml using the Diagnostic Product Corp Immunlite® 2000 assay. Aspergillus precipitins were not detected. He was rehospitalized for 18 days in April 2004 for asthma, at

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which time mechanical ventilation was required and high dose corticosteroids were administered. On the fourth hospital day, IgE level was found to be 640 IU/ml. He was rehospitalized for asthma in May and then August 2004 despite treatment with daily prednisone doses ranging between 15 and 30 mg/day plus fluticasone/salmeterol, montelukast, and albuterol. In June 2004, the IgE level was 516 IU/ml. ImmunocapTM -determined allergenspecific IgE were positive for Aspergillus fumigatus (.83 kU/L) and white ash (.59 kU/L). In February 2005, the patient was taking 15 mg prednisone daily. The IgE level at that time was 189 IU/ml. By June 2005 prednisone was discontinued. At that time, Immunocap® -determined allergen-specific IgE was positive to A. fumigatus 5.75 kU/L. Positive allergen-specific IgE was also found for Candida albicans (2.78 kU/L), Fusarium moniliforme (5.74 kU/L), Helminthosporium halode (2.45 kU/L), Mucor racemosus (0.83 kU/L), and Penicillium notatum (0.64 kU/L). In October 2005, while still not taking prednisone, the IgE level was 5811 IU/ml and the total eosinophil count was 363/mm3 (7.4%). While still off systemic corticosteroids, a hypersensitivity pneumonitis screen showed no antibody to aspergillus or other pathogens. By the Fall of 2006, the patient required oral cortisteroids again and was rehospitalized for asthma. Voriconazole 200 mg/day was initiated because of the possibility of allergic bronchopulmonary fungal disease. In October 2006, the IgE level was 10200 IU/ml. In 2007, the patient was hospitalized once for asthma and was on daily prednisone doses between 10 and 20 mg/day. Although the patient could not cooperate for full pulmonary function testing, an office spirometry-determined FEV1 was 1.2 L (40% predicted). Continuous nasal oxygen therapy was administered for exertional hypoxemia. The IgE level in August 2007 was 1758 IU/ml. Voriconazole was discontinued in September 2007. The patient was hospitalized for pneumonia in January 2008. In February 2008, the IgE level was 586 IU/ml. At a weight of 61 kg, the patient was started on omalizumab 375 mg subcutaneously every 2 weeks in March 2008. By the beginning of 2009, the patient was able to discontinue prednisone and home oxygen. The tuberculin test was negative in September 2009 and had been negative on repeated occasions previously. In February 2009, the IgE level was 688 kU/L. In November 2009, the IgE level was 510 IU/ml using the Diagnostic Product Corp Immunlite® -2000 assay. Using the Immunocap® assay, IgE level in December 2009 was found to be 877 IU/ml. Throughout 2009 through the Spring of 2010, there were no hospitalizations or emergency department visits. DISCUSSION The diagnosis of ABPA involves clinical, serological, and radiological features (15). Both patients herein described had obstructive lung disease with central bronchiectasis, specific IgE against Aspergillus fumigatus, and elevated total IgE levels. Whereas the first patient also had IgG to

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Aspergillus fumigatus, the second patient did not. The second patient, however, had marked decreases in IgE levels when treated with corticosteroids that is typical for treated ABPA. As there is variability in the criteria applied to ABPA patients reported in the literature (13, 16, 17), we believe that it was reasonable to consider patient 2 as having at least a disorder with many features consistent with advanced ABPA at the time of the index hospitalization. Proposed major criteria for ABPA include asthma, fleeting pulmonary opacities, type I reaction to aspergillus, eosinophilia, precipitating antibodies, elevated IgE levels, central bronchiectasis, and elevated IgG and IgE to aspergillus (17, 18). Both patients had fibrocavitary disease involving the upper lobes suggestive of some degree of parenchymal disease. According to the classification schema of Patterson et al. (17), fibrotic disease represents the most advanced form of ABPA, which is felt to be unlikely to respond to treatment. In our patients, the fibrosis was more localized to the upper lobes, raising the possibility of tuberculous infection, which was excluded on the basis negative tuberculin tests. It was plausible that there was potential to preserve areas significant nonfibrosed lung, prompting the therapeutic approaches described. In patient 2, the historical ability to normalize total IgE levels with corticosteroid treatment in this patient and in ABPA in general raised the possibility of using omalizumab as a stepped therapeutic approach. Whereas corticosteroids could be used to reduce the bronchial allergic inflammatory cellular response, it could also bring the total IgE levels down to a value at which optimal omalizumab complexing would be likely. Omalizumab treatment then could block the allergen-specific IgE, which is presumably central to the cascade of events in ABPA. What was not known is whether the tendency of total IgE levels to increase with recurrences of ABPA would overwhelm the binding capacity of already maximal omalizumab dosing used. In this patient after 18 months of omalizumab treatment (the last 12 of which were in the absence of corticosteroid treatment), the measured IgE levels were less than a tenth of the maximum total IgE levels that the patient had 18 months prior to starting omalizumab. Although both patients appeared to have a good clinical response to omalizumab, the patients also had adjunctive treatment with antifungal treatment. In patient 2, a broader antifungal agent was utilized because of the presence of specific IgE to several fungal species. The primary clinical benefit of antifungal treatment in ABPA relates to decreasing systemic corticosteroid dosing/duration, but antifungal treatment courses are usually administered for a limited period of time. In the two patients herein described, the benefit of antifungal treatment was not marked. Of interest is the much lower Aspergillus fumigatus–specific IgE value observed when the total IgE level of patient 2 was normalized 4 years prior to starting omalizumab. The reactivity towards several fungal species provided another rationale for using omalizumab, which would presumably bind all specific IgE, since an

antifungal approach might not have activity against the appropriate pathogenic agent. In patient 1, the use of omalizumab was felt to provide a safer clinical context for employing allergen immunotherapy (19), which is typically avoided in more severe asthma because of the difficulty in distinguishing systemic reactions from acute asthma exacerbations and because of their increased risk of systemic allergic reactions (20). The elevation of measured IgE levels in patients treated with omalizumab relates to the multiple IgE molecules that are bound to a single more slowly cleared omalizumab molecule (2). Modeling of the IgE omalizumab pharmacokinetics suggest that appropriate omalizumab dosing can reduce free IgE to less than 20.8 IU/ml (21). This estimate was confirmed by the observations of Hamilton et al. (4) who showed that the free IgE levels of 12 patients treated with 3 months of omalizumab had a mean of 19.4 IU/ml. The ratio of free to total measured IgE in those samples ranged from .009 to .148, with a mean of .047. If these ratios were applied to the Immunocap® -determined levels of IgE of the two patients herein described, the maximum free IgE would be 130 IU/ml and a mean estimate would be about 40 IU/ml, which would in either case be significantly lower than the IgE levels prior to omalizumab administration. The Immunocap® assay of total IgE is not associated with omalizumab interference compared to the Diagnostic Product Corp Immunlite® 2000 assays, which has been reported to underestimate total IgE levels by about 40% (3). The last two measured IgE levels in both patients showed a higher IgE level with Immunocap® assay compared to the Diagnostic Product Corp Immunlite® 2000 assay, consistent with this magnitude of underestimation (3). It is also interesting to note that IgE levels measured by the same assay in patient 1 were initially over 2000 IU/ml when measured 3 months after starting omalizumab, but decreased to below 500 IU/ml after 3 years of treatment. This suggests that even in the absence of commercially available free IgE assays, serial measurements of measured IgE levels can be interpreted in a relativistic manner. These data taken together also suggest that free IgE levels for both patients were significantly reduced during the period of omalizumab administration. Free IgE assay methodology has been described in the literature (4), and is based on capture by monoclonal anti-IgE Fc antibody followed by detection using labeled FcεR1α. Reports on the use of omalizumab in pediatric ABPA (7–12) with cystic fibrosis have not discussed the interpretation of measured IgE levels in terms of estimated changes in free IgE, which would be an important response parameter. In this report, we provide observations including serial measured IgE levels that suggest a clinical approach and potential role for omalizumab in treating adults with ABPA. Although clinical stability and decreased oral corticosteroid use was observed for the herein described patients, the risks and cost-benefit ratio need to be further examined in utilizing this treatment for ABPA patients.

IgE IN ABPA TREATED WITH OMALIZUMAB DECLARATION

OF I NTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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