the two groups (prednisolone 25/25, 100% and voriconazole 24/25, 96%). There was again no signifcant difference in timing to frst exacerbation or number of exacerbations between the groups, but higher rates of adverse events were noted in the prednisolone group. Given the results of these two trials, monotherapy with a mold-active azole with close monitoring for treatment failure may be an effective potential treatment option for acute ABPA, especially in patients in whom a glucocorticoid sparing agent is necessary.

Monoclonal Antibodies

Multiple case reports and small studies have reported on the use of monoclonal antibodies to treat refractory ABPA. Omalizumab is a humanized monoclonal IgG1 antibody that binds to free IgE. Approved for treatment of severe allergic asthma, dosing is based on the patient’s total IgE level and body weight up to a maximum of 750 mg monthly [101]. Given the high degree of total serum IgE elevation, patients with ABPA frequently exceed these dosing parameters. Despite the dosing limitations, there are reports of omalizumab used in the treatment of ABPA. A meta-analysis of 102 patients with ABPA treated with omalizumab found a 59% average decline in total serum IgE levels with an improvement in clinical symptoms and a decrease in the exacerbation rate [102]. There were no reported adverse events including no reported episodes of anaphylaxis. In a partially industry-sup- ported, open-label, placebo-controlled randomized trial in Australia of 13 asthmatic patients with chronic ABPA, there was a signifcant decrease in the rate of exacerbations with omalizumab use compared to placebo [103]. Furthermore, each patient who had an exacerbation in the placebo phase experienced fewer exacerbations in the omalizumab crossover phase. In a retrospective study of 18 pediatric patients with ABPA complicating CF in France, treatment with omalizumab was associated with stabilization of lung function and a decrease in the average daily corticosteroid dose without any adverse events noted [104]. In contrast, an industry-sponsored, double-blind randomized controlled trial evaluating the safety and effcacy of omalizumab for treatment of ABPA complicating CF noted higher rates of adverse events, with 6/9 (67%) patients in the omalizumab group experiencing one or more serious side effects [105]. In that trial, an omalizumab dose of 600 mg subcutaneous injection daily for 6 months was higher than those in other studies and there was signifcant drop out of participants. The study was terminated early due to insuffcient enrollment.

Mepolizumab is a monoclonal antibody against IL-5. Approved for treatment of severe eosinophilic asthma, it

has also been utilized for the treatment of ABPA complicating asthma. In two patients in Japan with ABPA complicating asthma who declined treatment with systemic corticosteroids, initiation of mepolizumab for treatment of severe asthma led to improved symptoms with a decrease in peripheral blood eosinophil count and improved FEV1 but no change in total serum IgE levels [106]. The two patients were treated with mepolizumab for more than 20 months without any adverse events. There is also a case report of mepolizumab used in combination with omalizumab successfully treating a patient with ABPA complicating asthma that remained refractory to treatment despite initiation of omalizumab [107]. Further studies including randomized controlled trials are necessary prior to formally recommending treatment of ABPA with omalizumab or mepolizumab.

Monitoring for Treatment Response

Patients should be closely monitored when initiating treatment for ABPA with serial total serum IgE levels, lung function testing, and chest radiograph every 6–8 weeks until remission is achieved, as discussed above. Treatment can be considered successful if there is symptomatic improvement, a decrease in total serum IgE levels, and clearing of opacities on chest imaging. Since, in most patients, ABPA is a chronic process, in our clinical practice, we follow patients regularly in outpatient pulmonary clinics after remission is achieved with continued periodic monitoring of serum IgE levels and lung function testing as well as intermittent chest imaging.

Conclusions

Signifcant progress has been made in the awareness of ABPA as an important disease entity in patients with asthma and CF, with recent proposed expert panel guidelines increasing the ease of diagnosis in patients with asthma. Nonetheless, recognition of ABPA still requires thoughtful clinical assessment, with annual screening serum IgE levels recommended in CF. An improved understanding of the pathophysiology of ABPA has led to an expansion of treatment options, which, in addition to systemic corticosteroids, now includes antifungal azole agents, and, in some circumstances, anti-IgE and anti-IL-5 asthma therapies. It is imperative to induce clinical remission with long-term surveillance monitoring once remission has been achieved. The role of prevention of disease by limiting exposure to Aspergillus in at-risk patients requires further study.

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