Report Describes Consequences of Airway Remodeling in Pediatric Nonresponders to Omalizumab

A recent case report described how bronchial wall thickness was linked to a poor response to omalizumab in severe pediatric asthma.

Writing in Journal of International Medical Research, the authors note that there is a subgroup of patients who do not achieve asthma control with omalizumab. However, pediatric studies that may predict poor response, such as through the examination of blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum periostin, are lacking. The hypothesis of the current study was that, for pediatric nonresponders, airway remodeling has already progressed and created irreversible airflow obstruction, leading to treatment resistance.

The researchers, working in Japan, retrospectively assessed 3 children who did not respond to the biologic with a 3-dimensional (3D) bronchial wall analysis with CT. They were then compared with 6 pediatric patients who did respond to omalizumab. Notably, all of the nonresponders had asthma that had been inadequately managed since early childhood.

All of the patients were treated at the Department of Pediatrics at the Matsuyama Red Cross Hospital between April 2015 and March 2019.

The first case was an 11-year-old boy who suffered from monthly asthma exacerbations accompanied by hospitalizations several times a year since the age of 1. Although he received a diagnosis of moderate to severe asthma, he was prescribed only montelukast without an inhaled corticosteroid (ICS) for 10 years, which does not align with asthma care guidelines. He was referred to the authors by his family doctor.

Upon examination, he was found to have allergic rhinitis, a family history of bronchial asthma, and an asthma control test (ACT) score of 13, indicating poor asthma control. Blood tests showed eosinophilia (758/μL), a high serum nonspecific immunoglobulin E (IgE) concentration (876 IU/L), and an allergy to dust mites.

His serum periostin concentration was 53.1 ng/mL, and the FeNO concentration was 39 ppb. Spirometry results were also poor, showing a decrease in predicted forced expiratory flow in 1 second (57.0%), predicted peak expiratory flow (%PEF; 49.8%), and predicted maximal midexpiratory flow (63.8%).

Physicians added a medium dose of salmeterol/fluticasone inhalation, but asthma symptoms continued. A change to inhalation of high-dose salmeterol/fluticasone and the combined use of oral sustained-release theophylline and oral prednisolone was added, but exacerbations continued.

At the time that omalizumab was started, chest CT was performed and showed marked thickening of the bronchial wall. A little more than 1 year of omalizumab treatment showed no improvement in any of the boy’s respiratory functions and treatment was stopped.

The second case was a 14-year-old boy with a similar history; he was not prescribed any controller medications and had only been prescribed inhaled β2-agonists for use during asthma attacks. Since the age of 12, he was hospitalized several times a year. His doctor then prescribed montelukast and a moderate dose of inhaled fluticasone; he was then switched to a medium-dose salmeterol/fluticasone inhalation and an oral theophylline sustained-release preparation. Ultimately, he was referred to the authors.

He, too, had allergic rhinitis but there was no family asthma history. He also had a poor ACT score and high IgE, as well as dust mite and cat allergies. He had no eosinophilia. Serum periostin concentration was 39.9 ng/mL, and his FeNO concentration was 6 ppb. Spirometry showed a decrease in the %PEF (71.2%). After the hospital visit, high-dose salmeterol/fluticasone inhalation was started but there was no improvement. A CT scan showed the same thickening of the bronchial wall, and as with the first boy, a year of omalizumab therapy did not provide any improvement.

The third case was a 13-year-old boy with frequent exacerbations and hospitalizations who, when he was younger, was prescribed daily montelukast, but he only took it when his asthma symptoms were flaring. He started to become hospitalized 2 to 3 times a year and was treated with inhaled β2-agonists only during the attacks. His doctor added moderate-dose fluticasone inhalation in addition to montelukast and then referred him to the authors, who switched him to high-dose fluticasone inhalation with oral montelukast and low-dose oral prednisolone.

The boy was unable to take certain other therapies because of adverse effects, and he was started on omalizumab after he did not improve. His chest CT also showed a thickening of the bronchial wall. His hospitalizations for asthma did not improve, and the biologic treatment ended after 12 months.

The researchers observed differences between the 2 groups of patients. Spirometry test results were improved in responders compared with nonresponders. Compared with patients who had a good response to the biologic, a 3D-CT bronchial wall analysis showed that the percentage of wall thickness and the percentage of the bronchial wall area in nonresponders were higher. In addition, values of the bronchial inner luminal area adjusted by the body surface area in the nonresponders were lower, indicating narrowing, compared with those who responded to omalizumab.

The 3D-CT scans of the airway structure in these children suggest that the damage done by uncontrolled asthma had progressed to the point that they would have a poor response to omalizumab, the authors wrote.

“We consider that earlier treatment with omalizumab in children with severe asthma before progression of airway wall remodeling may prevent subsequent deterioration of respiratory function and quality of life,” the researchers said.

The study was limited by a small sample size and that only patients with severe asthma who had undergone chest CT were included.

Further studies with a larger group of pediatric patients, taking into account the risks and benefits of such a trial due to the radiation exposure from CT scans, would need to be designed, they said.

Reference

Tsuge M, Ikeda M, Kondo Y, Tsukahar H. Severe pediatric asthma with a poor response to omalizumab: a report of three cases and three-dimensional bronchial wall analysis. J Int Med Res. Published online January 7, 2022. doi:10.1177/03000605211070492