Persistent lobar atelectasis in an infant with cystic fibrosis: The role for flexible bronchoscopy and poractant alfa

To the Editor,

Lobar atelectasis is a well-documented complication of cystic fibrosis (CF) with reported rates of 4–11%¹. CF lung disease results from ineffective mucociliary clearance secondary to defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein in the respiratory epithelium with the subsequent accumulation of dehydrated and hyperconcentrated mucus. Conventional medical therapy consists of airway clearance therapy (ACT) with a combination of inhaled medications, including bronchodilators and mucolytics, and chest physical therapy in addition to antibiotic treatment. Some people with CF and lobar atelectasis do not respond to conventional medical therapy and may progress to develop localized, severe, irreversible bronchiectasis¹. In these instances, flexible bronchoscopy has been trialed to further facilitate airway clearance, often with the instillation of 0.9% normal saline or recombinant human DNase (rhDNase) in addition to therapeutic suctioning².

We present the case of a now one-year-old female of Ecuadorian ancestry with CF and persistent right upper lobe (RUL) atelectasis, first identified at three months of age, who underwent serial flexible bronchoscopies to improve aeration, ultimately responding to the instillation of poractant alfa with concomitant air insufflation with near total resolution of her RUL atelectasis by eleven months of age.

Our patient was diagnosed with CF following a positive CF New York State newborn screening with an elevated immunoreactive trypsinogen (119.6 ng/mL) and two detected CFTR variants (p.Trp496Arg, legacy name W496R, and a minimal function variant) and confirmatory sweat chloride testing (79 mmol/L and 85 mmol/L). Stool pancreatic elastase testing revealed pancreatic insufficiency (<50 mcg/g). She was started on ACT as well as table salt supplementation, a CF multivitamin, and pancreatic enzyme replacement therapy.

She was noted to have new RUL atelectasis on chest x-ray (CXR) (Figure 1A) during an acute viral illness at three months of age, and her ACT was escalated to thrice daily with nebulized albuterol, rhDNase, and 3% hypertonic saline. Following the resolution of her acute illness, she continued to have increased work of breathing with subcostal retractions as well as poor weight gain, dropping from the 45^th percentile to the 1^st percentile. With no significant change on serial CXRs, she underwent flexible bronchoscopy with the instillation of rhDNase and concomitant air insufflation at five months of age. No anatomic airway abnormalities were identified, and bronchoalveolar lavage microbiological studies revealed methicillin-sensitive Staphylococcus aureus and Acinetobacter baumannii complex, which were treated with a course of sulfamethoxazole and trimethoprim. With no significant change in physical exam or imaging findings (Figure 1B), she again underwent flexible bronchoscopy, now with the instillation of poractant alfa (Curosurf 240 mg/3 mL, Chiesi USA, Inc.; 0.5 mL per RUL segment for a total of 1.5 mL) and concomitant air insufflation (1 mL/kg x two aliquots), and was started on off-label ivacaftor (Kalydeco; Vertex Pharmaceuticals, Inc.) at six months of age. Her physical exam and imaging findings improved with only segmental RUL atelectasis evident (Figure 1C), confirmed to primarily involve the posterior segment on chest computerized tomography (CT) (Figure 2). She underwent an additional flexible bronchoscopy, again with the instillation of poractant alfa and concomitant air insufflation, at eleven months of age in an effort to improve the overall aeration of her RUL to good effect (Figure 1D). Repeat sweat chloride testing was largely unchanged (78 mmol/L), and a repeat chest CT was not obtained as she is clinically doing well with a normal physical exam and improved weight gain, now at the 47^th percentile.

Figure 1.

A) Initial CXR demonstrating RUL atelectasis during an acute viral illness at three months of age, B) follow-up CXR demonstrating persistent RUL atelectasis at five months of age following flexible bronchoscopy with the instillation of rhDNase and concomitant air insufflation, C) follow-up CXR demonstrating improved RUL atelectasis at eight months of age following flexible bronchoscopy with the instillation of poractant alpha and concomitant air insufflation and the initiation of ivacaftor, and D) follow-up CXR demonstrating nearly resolved RUL atelectasis at eleven months of age following flexible bronchoscopy with the instillation of poractant alpha and concomitant air insufflation.

Figure 2.

Chest CT demonstrating segmental RUL atelectasis, primarily involving the posterior segment, at nine months of age; axial images progress in the cranial (A) to caudal (D) direction.

Often attributed to either mucus plugging or severe parenchymal disease, lobar atelectasis is a well-documented complication of CF. Our patient had no visible mucus plug on serial flexible bronchoscopies and no significant precipitating lung disease, although she did have an initial precipitating viral illness. It is certainly possible that ineffective mucociliary clearance resulted in the accumulation of inflammatory debris with resulting airway obstruction and atelectasis from bronchial wall edema and smooth muscle constriction.

While case reports and series have documented the effectiveness of flexible bronchoscopy with the instillation of rhDNase for persistent lobar atelectasis refractory to conventional medical therapy in both children and adults with CF, we have had limited success with the aforementioned in our infant population^2–3. Flexible bronchoscopy with the instillation of poractant alfa has been reported in mechanically ventilated and recently extubated children with lobar atelectasis and a variety of underlying respiratory disorders, including CF⁴. Unlike rhDNase, which acts to reduce mucus viscosity by depolymerizing deoxyribonucleic acid from disintegrating neutrophils in CF mucus, poractant alfa may serve to reduce airway surface tension and improve mucus transport within obstructed airways as well as provide an additional anti-inflammatory effect⁴. Indeed, surfactant dysfunction and deficiency have been documented in CF as well as with atelectasis and may be more pronounced in the infant population due to a proportionally higher surfactant content at baseline⁴.

Our patient was additionally started on ivacaftor, a CFTR modulator therapy, prior to her first documented improvement in physical exam and imaging findings. Ivacaftor use is associated with reduced mucus viscosity and improved lung function as well as improved weight gain⁵. Indeed, there was visible improvement in mucus consistency from her pre- to post-ivacaftor flexible bronchoscopy with thinner, more readily suctionable mucus. Despite no significant change in her sweat chloride level, we believe that our patient derived clinical benefit, particularly with regard to weight gain, following the initiation of ivacaftor, but ivacaftor and ACT alone were not sufficient for the treatment of her persistent atelectasis, as the segmental RUL atelectasis persisted for months following the initiation of ivacaftor with near total resolution only after her last flexible bronchoscopy with the instillation of poractant alfa and concomitant air insufflation. We plan to transition our patient from ivacaftor to elexacaftor/tezacaftor/ivacaftor (Trikafta; Vertex Pharmaceuticals, Inc.) at two years of age given the recent United States Food and Drug Administration approval for her minimal function variant.

In our experience, flexible bronchoscopy with the instillation of poractant alfa and concomitant air insufflation is useful in the management of persistent lobar atelectasis in CF, particularly in the infant population where surfactant dysfunction and deficiency may be more pronounced.