Clinical and Lung Function Outcomes in a Cohort of Children With Severe Asthma

Patricia de Gouveia Belinelo; Aleisha Nielsen; Bernadette Goddard; Lauren Platt; Carla Rebeca Da Silva Sena; Paul D. Robinson; Bruce Whitehead; Jodi Hilton; Tanya Gulliver; Laurence Roddick; Kasey Pearce; Vanessa E. Murphy; Peter G. Gibson; Adam Collison; Joerg Mattes


BMC Pulm Med. 2020;20(66) 

In This Article


This retrospective analysis describes clinical audit data exploring outcomes in children with uncontrolled SA managed in a nurse-led SAC, which included lung function parameters and lung ventilation inhomogeneities. Our SAC was largely implemented in accordance with the Royal Brompton Hospital London SAC model[25] with changes made to best suit local resources and clinical needs. For instance, we accepted referrals of children younger than 6 years and tested for true steroid-resistant asthma using oral steroids only in exceptional circumstances. Interestingly, prior to their first SAC visit, all children had been managed by paediatric respiratory specialists who were all part of the multidisciplinary SAC team and case discussions. Despite this, it seems likely that some children had difficult-to-treat rather than therapy-refractory asthma. Those difficult to treat asthmatic children were identified by a nurse-led assessment, including a home visit and evidence-based tools, and have responded to nurse-led interventions such as improvement of inhaler technique, compliance, and medication availability at home and in school, and control of environmental symptom triggers. A proportion of them was not further followed-up in the SAC. It could be hypothesised that the nurse-led assessment was an effective means to identify treatment difficulties more effectively. Indeed the "simple" steps of checking for adherence to therapy concurrent with asthma education can markedly improve asthma control and promote a better quality of life for some patients.[8,26,27] Our analysis was not appropriately controlled to provide high-level evidence for a beneficial effect of a nurse-led SAC on outcomes. Specifically, we did not have a cohort of children with SA not managed in a nurse-led SAC in our Department. This would be critical as Ross and co-workers have recently shown in a cohort of children with uncontrolled SA that half of those children no longer had severe asthma after 3 years.[28] Therefore future studies elucidating the efficacy of interventions in children with SA require appropriate control groups.

Independent of what intervention was pursued after the first SAC visit, the majority of children referred to our SAC demonstrated a significant disease burden evidenced by asthma onset in early childhood, a history of numerous past hospital admissions for asthma attacks, and clinically significant reductions in ACT, ACQ and PAOLQ scores. 61% of children with SA had a parental history of asthma. Increased asthma severity in this cohort was supported by reduced lung function parameters, including a higher prevalence of lung ventilation inhomogeneities when compared to a cohort of children with doctor-diagnosed asthma and children without asthma. Children with SA also had a high prevalence of "trapped air" when measuring lung volumes. Previously abnormal spirometry has not been observed as highly discriminatory for different severities of asthma in children[25,29] and our results support this by showing that an abnormal LCI appears more discriminatory (e.g., Table 3: 79% abnormal LCI versus 48% abnormal FEV1% in SAC children). The novel finding of highly abnormal LCI values in children with SA is consistent with recent specialised imaging studies that have described the presence of significant ventilation inhomogeneities with hyperpolarized gas MRI imaging, with the degree of abnormality associated with asthma severity and due to subsegmental narrowing or complete obstruction of small airways.[30,31]

Improvements were observed in ACT and lung function parameters before and after BD inhalation, and a reduction in "trapped air" was apparent. Stratifying the analysis of the SA cohort by treatment with biologic agents resulted in small case numbers per group. It is possible that this may have resulted in a lack of power to show that either group had greater improvements over the other. However, following a protocol with a standard set of investigations may have allowed for a more personalised management approach and could explain the significant improvements in asthma control and lung function of most children independent of what that intervention was.

Our results suggest that LCI may have improved, although not significantly, at the follow-up SAC visit. However, for the majority of patients, LCI remained in the abnormal range (83%) even after a personalised asthma intervention. Abnormal LCI measurements have been demonstrated in children with normal spirometry.[32] More studies are required to elucidate the precise mechanisms underpinning the occurrence of lung ventilation inhomogeneities in SA and the clinical relevance of its persistence. Possibly, an optimal treatment modality for some children with severe therapy-refractory asthma has yet to be identified, and monitoring changes in LCI may be a sensitive marker for the persistence of small airway disease. A number of biologics have been trialled, mostly in adults, to treat severe asthma with a type (T)2-high inflammatory response, including mAb directed against IgE (omalizumab), IL-5 (mepolizumab), IL-5 receptor alpha (benralizumab), IL-13 (lebrikizumab and tralokinumab) and the IL-4 receptor alpha chain (dupilumab).[33,34] In children with severe asthma, however, increased submucosal expression of IL-33, an epithelial-derived alarmin, and IL-33 positive non-residential cells are found in the airway wall. IL-33 levels were correlated with reticular basement membrane (RBM) thickness, which is considered the result of subepithelial fibrosis.[35] Investigating the efficacy of a combination of dupilumab and SAR440340, an antibody directed against IL-33, may shed light on the role of IL-33 in severe childhood asthma.[36] Subsegmental narrowing or complete obstruction of small airways observed in SA may adversely affect the deposition of inhalant anti-inflammatory and bronchodilating drugs. It could then be speculated that the severity of lung ventilation inhomogeneities may be associated with asthma that is more refractory to inhalant therapies.