Between 5% and 10% of children worldwide suffer from asthma (1). The familial nature of asthma is well known; the risk for a first cousin of an asthmatic patient is multiplied by 2.5–3 compared with the general population (2). Studies of twins have confirmed this genetic component finding higher concordance of asthma among monozygotic (58.97%) than dizygotic twins (23.64%) (3). We report an exceptional clinical situation of monozygotic twin sisters with severe allergic asthma where one was treated with a monoclonal anti-IgE antibody (omalizumab), and the other with a placebo in a randomized, double-blind, placebo-controlled study (4).
Premature monozygotic twin sisters developed bronchopulmonary dysplasia secondary to hyaline membrane disease. Afterwards, the two sisters had similar respiratory history; first, asthma with exacerbations related to viral infections in infancy, then at the age of 6, developing respiratory allergies to various aeroallergens with symptoms of seasonal rhinitis and persistent atopic dermatitis. Despite treatment with high doses of inhaled corticosteroids in combination with long-acting β2-mimetics and delayed-release theophylline, their asthma remained poorly controlled. Repeated severe exacerbations (>10 hospitalizations between 4 and 8) led to several stays in the mountains for climatic treatment. In 1998 at the age of 12, the twins were enrolled in a 32-week randomized, double-blind, placebo-controlled study (4). One received omalizumab and the other a placebo. The twin receiving omalizumab was able to reduce her long-term treatment with fluticasone to 500 μg/day, while the other required treatment with fluticasone at a dose of 1250 μg/day and regular courses of oral corticosteroids due to persistent exacerbations. They were both then treated with omalizumab during a 6-year extension phase. During this time, there was clinical improvement with the absence of hospitalizations for severe attacks, disappearance of pollen-induced rhinitis and improved respiratory function (Fig. 1) under reduced long-term treatment with fluticasone 500 μg/day and occasional administration of oral corticosteroids. The adult height of the twin who first received omalizumab was 159 cm compared with 156 cm for the other.
The effectiveness of omalizumab in adolescents has previously been demonstrated in a pooled analysis showing that the relative risk of an adolescent aged between 12 and <18 presenting an asthma exacerbation when treated with omalizumab was 0.470 compared with the control group (95% CI: 0.318–0.695; P = 0.0002) (5). Our observation of monozygotic twins one treated with omalizumab and the other with a placebo for 32 weeks, then both with omalizumab for 6 years, and living in the same environment, supports these findings and suggests the effectiveness of omalizumab on a specific phenotype of severe asthma.
Moreover, treatment with omalizumab produced progressive improvement in respiratory function in these twins which was not significantly demonstrated in the core study. The improvement in respiratory function in these complex cases of obstructive bronchopathy, in part linked to a history of severe neonatal respiratory disease, could be explained by: (i) a strong allergic phenotype associated with severe allergic asthma, pollen-induced rhinitis and atopic dermatitis and (ii) the particularly prolonged duration of treatment with omalizumab.
The second distinctive feature of these observations was the possibility of reducing doses of inhaled corticosteroids earlier, particularly in the twin who received omalizumab from the start, at puberty, a crucial age for growth. It has been recognized, moreover, that the high-dose corticosteroid therapy required to control severe asthma can cause growth retardation (6).
These observations suggest the beneficial effects of treatment with omalizumab in severe allergic asthma (i) on respiratory function when there is a strong allergic phenotype and treatment is continued over a long period and (ii) on maintaining the height/weight growth curve compared with prolonged treatment with high doses of inhaled corticosteroids, particularly during puberty.