Inhaled alpha1-antitrypsin administered to treat pneumatocele in autosomal dominant hyperimmunoglobulin E syndrome.

Members of the serine protease, matrix metalloproteinase, and cysteinyl protease families have been found to be associated with lung in ammation and airway extracellular matrix [1]. The serine protease neutrophil elastase induces protease and tissue destruction in the lung [1]. Protease-antiprotease imbalance in humans has been described in chronic destructive lung diseases such as cystic fibrosis and -1 antitrypsin de ciency [2,3]. Aerosolized -1 antitrypsin therapy has been administered to restore the protease-antiprotease imbalance and inhibit destructive lung in ammation [4,5]. Autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES) causes significant lung destruction and pneumatoceles owing to aberrant in ammatory responses without the classic ndings of in ammation (warmth, redness, and fever) [6]. Pneumatocele is a common and particularly problematic complication of AD-HIES. However, the only effective approach for the management of progressive lung destruction involves antibiotic prophylaxis and therapy. While susceptibility to recurrent infections due in part to decreased subtype 17 helper T-cell formation [7] contributes to lung tissue damage, intrinsic susceptibility to exaggerated in ammation and tissue destruction may also be at work. The signal transducer and activator of transcription 3 gene (STAT3) is the target of the heterozygous loss of function mutation in this disorder and has been shown to protect against different forms of lung injury, including hyperoxia, in part by suppressing expression of metalloproteases [8]. Therefore, we hypothesized that STAT3 de ciency leads to dysregulated protease expression, which may in turn contribute to pneumatocele formation. Here, we report our experience with inhaled -1 antitrypsin applied to treat a girl with AD-HIES and progressive formation of bilateral pneumatoceles despite appropriate administration of antibiotic prophylaxis, intravenous immunoglobulin, and subcutaneous interferon gamma. A 9-year-old Turkish girl presented with recurrent pneumonia that had begun at 9 months of age. As a newborn, she developed erythroderma and skin abscesses. Physical examination revealed eczema, high palate, coarse facial features, double-row teeth, and scoliosis. Her National Institute of Health score was 78, which is highly suggestive of AD-HIES (>40) [6]. The initial laboratory evaluation revealed mild eosinophilia (550/mm) and anemia. Immunological analyses disclosed normal serum immunoglobulin (Ig) levels (IgA, 44.3 mg/dL; IgG, 1912 mg/dL; IgM, 150 mg/dL), except for increased IgE (14 000 IU/mL), and normal values for CD3, CD4, CD8 T cells and CD19 and CD20 B cells. Computed tomography of the lung revealed 2 large pneumatoceles (longest diameter, 53 mm in the right lung and 43 mm in left lung) (Figure). Sequencing studies con rmed the presence of a heterozygous missense mutation (g.58854G>A; c.1145g>A, R382Q) in the DNA-binding domain of the STAT3 gene, thus con rming the diagnosis of AD-HIES. Treatment included inhaled corticosteroids ( uticasone propionate 2×500 g/d since age 6 years), intravenous immunoglobulin (1 dose of 0.8 g/kg every 3 weeks for 1 year followed by 1 dose of 1 g/kg every 2 weeks for the last 2 years of follow-up) and