A 44-year-old woman of Turkish origin presented to the emergency department with severe dyspnea and inspiratory pleural chest pain that had developed over the previous few days. She had delivered healthy twins 6 weeks prior to presentation and had been diagnosed with a pulmonary embolism 3 months previously. She had never smoked. Her past medical history revealed a diagnosis of COPD that had been made 9 years earlier during her pregnancy with her first child, at which time she became symptomatic for the first time. There was no family history of respiratory or liver disease. She had no history of childhood asthma or allergies. Her current medication consisted of subcutaneous tinzaparin, a low molecular weight heparin, for pulmonary embolism, and inhaled tiotropium, formoterol, and budesonide.
Initial laboratory workup showed a leukocytosis of 12.6 g/L (normal range 6-11 g/L), mildly elevated C-reactive protein of 2.6 (normal range <0.5) and thrombocytosis of 485 g/L (normal range 150-400 g/L). Differential white blood cells showed an eosinophilia of 7% (normal <4%). Blood gas analysis showed severe respiratory insufficiency (paO2 54 mmHg, paCO2 38 mmHg).
A chest computed tomography scan revealed very severe bronchiectasis with large cysts and mucus plugging, predominantly in the lower lung segments, suggestive of cystic fibrosis (Figure 1). Additionally, ground glass opacities were noted in the upper lung segments and infiltrates in the right middle lobe. Marked emphysema was not present, and no residual thrombi were seen in the pulmonary arteries. Upon echocardiography, right and left heart function were normal and her brain natriuretic peptide level was normal.
Lung function analysis showed severe obstruction (forced expiratory volume in 1 second [FEV1] 1,06 L/43%, FEV1/vital capacity 47%) and moderate relative hyperinflation (residual volume 2.2 L/140%, total lung capacity 4.37 L/99%). Sputum analysis revealed mucoid Pseudomonas aeruginosa and Aspergillus fumigatus. Mycobacterial infection was excluded by repeated sputum analysis, including polymerase chain reaction. An interferon-gamma release assay for tuberculosis antigen-specific T-cell response was negative. Bronchiectasis workup, including immunoglobulin (Ig)A, IgM, IgG, and subclasses, was normal. Total IgE levels were increased to 584 IU/mL (normal <100 IU/mL) and specific IgG and IgE were high for A. fumigatus (IgG 106 mgA/I; low range <14 mgA/I, intermediate range 14-39 mgA/I; high range >39 mgA/I; IgE 46 IU/mL, FEIA class 4), indicative of possible allergic bronchopulmonary aspergillosis (ABPA). Prick testing against common environmental antigens, such as pollen, house dust mite, and animal hair, was negative. An antinuclear antibody titer of 1:100 was noted, but extractable nuclear antigen screening (RNP/Sm, Sm, SS-A, SS-B, Scl70, CentB, Ho-1, Rib-P) was unremarkable. Antineutrophil cytoplasmic antibody (ANCA) testing was negative. A thrombophilia screen, including factor V Leiden, prothrombin gene mutation, antithrombin 3, proteins C and S, and lupus anticoagulant had been performed at the time of diagnosis and had revealed no abnormalities.
Sweat chloride testing was normal (<25 mM) and no CFTR gene mutation was found. Capillary zone electrophoresis indicated a marked decrease in alpha-1 globin band 0.18 g/dL, 2.6% (Figure 2). The AAT level in serum was below 25 mg/dL (measured by the Cobas C702 nephelometry kit, Roche, Basel, Switzerland; quantification range 25-600 mg/dL, detection limit 10 mg/dL).
Upon genetic testing, no S or Z mutations were found in the sequencing of exon 3 or exon 5 of the SERPINA-1 gene. Further sequencing analysis of all exons of the SERPINA-1 gene revealed a homozygous CA insertion in exon 2, leading to a frame shift starting at codon 73. This mutation probably leads to a dysfunctional truncated protein lacking the reactive center loop (Figure 3). There was no suggestion of liver disease on sonography and liver enzymes (alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase) were normal. There was no apparent skin disease.
The patient was treated with oxygen therapy, oral ciprofloxacin, and inhaled colistin twice daily for P. aeruginosa infection. Later, itraconazole and prednisolone were added for treatment of probable ABPA.