Dr Vikas Goyal

Children with bronchiectasis who cough up phlegm every day may have more extensive lung disease and a higher risk of hospitalisation, Australian researchers have found.

Dr Vikas Goyal, a paediatric respiratory and sleep physician at Queensland Children’s Hospital, and colleagues identified the first clinical phenotypes in paediatric bronchiectasis, according to a study published in Thorax [link here].

The researchers analysed data from 356 children enrolled in two multicentre bronchiectasis trials. They identified the phenotypes in a cohort of 158 children, then validated the findings in an independent cohort of 198 children.

Three distinct phenotypes emerged:

• Baseline-Well — children with relatively mild symptoms and little cough
• Wheeze-Dyspnoea Predominant — children with a substantial burden of wheeze and breathlessness
• Daily Wet-Cough Predominant — children with persistent cough and a cluster of features linked to more severe disease

Children in the Daily Wet-Cough Predominant group had the highest rates of daily cough, spontaneous wet cough, abnormal chest examination findings, digital clubbing, haemoptysis and primary ciliary dyskinesia. They were also more likely to have been exposed to household smoke.

Compared with the Baseline-Well group, children with the Daily Wet-Cough Predominant phenotype had:

• a 4.3-fold higher rate of previous bronchiectasis-related hospitalisation in the development cohort
• a near-threefold higher rate of previous hospitalisation in the validation cohort
• around three times higher odds of bronchiectasis affecting three to six lung lobes in the validation cohort
• higher rates of bronchiectasis-related hospitalisation in the two years after enrolment

Across both cohorts, outcomes worsened in a stepwise pattern, from Baseline-Well through Wheeze-Dyspnoea Predominant to Daily Wet-Cough Predominant.

Speaking to the limbic Dr Goyal said children with the Daily Wet-Cough Predominant phenotype should prompt closer attention in practice, particularly around early treatment of exacerbations.

“If you think your patient has this type of symptom profile … then I would be more aggressive in treatment,” he said.

“We know they are going to end up needing more hospitalisations, so treating their exacerbations more aggressively and, importantly, treating them immediately rather than letting them go on.”

He said clinicians should also look for microbiological reasons why a child had persistent wet cough, while future trials should test therapies that improve mucus clearance or airway clearance in this subgroup.

“If I were thinking about using a mucolytic in children with bronchiectasis, I would rather use it in patients who are wet at baseline,” he said.

“Those patients are more likely to benefit from a mucolytic than children who only produce sputum during an exacerbation.”

A treatment subgroup?

The Wheeze-Dyspnoea Predominant phenotype also stood out, the researchers said. Current paediatric bronchiectasis guidelines do not recommend routine use of asthma-type therapies, but the authors suggested this group could be a target for future trials testing whether such treatments help some children with bronchiectasis.

Dr Goyal said the phenotype may represent children with bronchiectasis who also had overlapping asthma-type symptoms, or a distinct phenotype in its own right.

However, he noted the phenotype was based on parental reports of wheeze rather than spirometry-confirmed asthma and said further studies would need to include spirometry and atopic testing.

“Going forward, we’re hoping to do another study where we identify this subgroup of children with bronchiectasis who have this Wheeze-Dyspnoea phenotype and see whether targeting their atopic symptoms and asthma phenotype more aggressively is beneficial, rather than using empirical bronchiectasis treatment for everyone,” he said.

“I think this tells us there is a need for a more personalised medicine approach to paediatric bronchiectasis rather than using empirical guidelines for everyone.”

Towards precision medicine

Phenotyping has reshaped understanding of complex airway diseases such as asthma and COPD by revealing subgroups with different risks, trajectories and treatment needs, the researchers said. Comparable phenotypes linked to clinical outcomes had been missing in paediatric bronchiectasis until now, they said.

Dr Goyal said the clinical groupings may reflect both disease severity and underlying biology.

“Both are possible,” he said.

He noted the more severe cohort had a higher likelihood of primary ciliary dyskinesia, suggesting some children may have an underlying genetic predisposition or more severe disease process.

But he said the phenotypes should not necessarily be viewed as permanent categories.

Some children may have an underlying biological predisposition to more severe disease, while others could move along the spectrum depending on how well their symptoms are managed.

“If the patient is managed more aggressively or optimally, the more severe phenotype might improve over a period of time,” he said.

The researchers cautioned that phenotype-guided management had not yet been shown to improve outcomes, and the findings should not change clinical practice. However, they said the phenotypes provided a framework for future precision medicine approaches and could help with participant selection for intervention studies.

The authors suggested phenotyping might eventually help identify children likely to benefit from earlier intervention, rather than waiting for disease progression to meet existing treatment thresholds. For example, they said phenotyping could help identify children who might benefit from earlier macrolide treatment, rather than waiting until they met current guideline thresholds of more than one hospitalised exacerbation, or more than three non-hospitalised exacerbations, a year.

Dr Goyal said the next step was to test more trait-based approaches in paediatric bronchiectasis trials, while also exploring pheno-endotypes using blood and molecular biomarkers.