Measuring total IgE is useful in detecting exacerbations in patients with allergic bronchopulmonary aspergillosis receiving omalizumab

Abstract

The pathogenesis of allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity reaction to Aspergillus fumigatus antigens, is complex and not yet fully clarified.Moreover, the diagnosis might sometimes represent a challenge because there is no universal consensus on the diagnostic criteria originally proposed by Rosenberg et al. Nonetheless, IgE plays a key pathogenic role in the disease, and is currently accepted as a marker of both initial diagnosis and disease activity. Systemic corticosteroids are required to suppress the immunological response, but ABPA is a chronic and progressive disease, associated with repeated exacerbations after successful treatment with steroids and/or antifungal agents. The well-known adverse effects of steroids have prompted clinicians to look for other therapeutic options. Hence, omalizumab, an mAb that binds to circulating IgE, has been repeatedly reported to successfully control ABPA within the initial months of treatment, both in retrospective case series and in a recent placebo-controlled registered clinical trial, but no long-term information is currently available. Another problem is that the ability to assess adequate reductions in total IgE levels afterward, or even to detect further exacerbations, on the basis of indicator and predictor value of serum IgE in ABPA, represents a concern in all patients receiving omalizumab. This occurs given that measuring the total IgE level through commercially available methods is considered not quite reliable in patients receiving omalizumab, and measuring free IgE is both controversial and, above all, not available for most clinicians. The aim of this communication was to describe the long-term clinical follow-up and serial measured total and specific IgE levels in 3 adult patients with ABPA while receiving treatment with omalizumab. All 3 patients have severe asthma according to the European Respiratory Society/American Thoracic Society criteria, and central bilateral bronchiectasis on chest computed tomography. The main clinical, laboratory, and spirometric parameters of the 3 patients are summarized in Table I. The pattern of total IgE levels over time is shown in Figure 1. Patient 1 (male, 44 years old) met commonly used criteria for ABPA since 1999, with multiple severe exacerbations requiring systemic corticosteroids and itraconazole (on average 3/year), a mean baseline total IgE level of 1000 KU/L (ImmunoCAP Phadia, Uppsala, Sweden), rising up to 4000 KU/L during exacerbations, and lung function impairment (mean baseline FEV1 70% of predicted, decreasing down to 43% during exacerbations). In 2010, he was started on omalizumab, with clinical and lung function improvement and a decrease in the total IgE level to 315 KU/L within the first year, being stable afterward and without ABPA exacerbations for almost 2 years. Still on omalizumab, in 2013 he had an ABPA relapse consisting of clinical and spirometrical decline, blood eosinophilia up to 1393/mm, increase in specific IgE and IgG levels to Aspergillus fumigatus, and also an almost 10-fold increase (from 400 to 3788 IU/mL) in measured total IgE level, which decreased progressively after initiating treatment with oral corticosteroids and itraconazole, coinciding with clinical improvement and progressive steroid step-down. Patient 2 (female, 50 years old) has aspirin-exacerbated respiratory disease (chronic rhinosinusitis with recurrent nasal polyps, difficult-to-control asthma, and aspirin hypersensitivity) since 1983; therefore, off-label treatment with omalizumab was started in 2008, achieving clinical and spirometrical stability (mean FEV1, 70%-75% of predicted) and no further need of sinus surgery. Every now and then she presented blood eosinophilia up to 900/mm, but the total IgE level was always around 400 KU/L, specific IgE and IgG for Aspergillus spp had always been negative, and Churg-Strauss and other autoimmune vasculitis had also been excluded. Almost 6 years after starting omalizumab, the patient experienced progressively worsening asthma symptoms and FEV1 decline down to 54% predicted. Chest X-ray was normal. The skin prick test performed to A fumigatus was positive (6 8 mm), and blood work revealed a total IgE level of 2402 KU/L, specificAspergillus IgG of 66mgA/L, and r Asp f 4 of 212 KU/L. The total IgE level decreased after starting oral steroids and itraconazole in July 2014, with progressive clinical and spirometric improvement up to previous values (FEV1 79% predicted). One year later (July 2015), she maintains asthma control (Asthma Control Test: 24 points), with no further exacerbations and having suspended oral steroids. Patient 3 (male, 34 years old) has early-onset allergic bronchial asthma. At age 20 years, he was diagnosed with ABPA, experiencing frequent and severe exacerbations, some of them requiring hospital admission. In 2008, he was started on omalizumab with consequent clinical improvement and stability for almost 3 years. In 2011, he was referred for a moderate clinical worsening (Asthma Control Test value decreased from 25 to 19 points). The total IgE level increased from 1132 kU/L to 2425 KU/L. One month after starting oral steroids, the total IgE level decreased to 964 KU/L, and clinical and lung function