Researchers have identified distinct multimorbidity “phenotypes” in severe asthma, with some clusters of chronic illness linked to substantially worse outcomes despite modern biologic therapies.

The findings add to growing evidence that the chronic illnesses accumulating around severe asthma may play a major role in shaping disease burden, treatment response and long-term outcomes, investigators say.

Dr Ramesh Kurukulaaratchy

Publishing data from the Severe Heterogenous Asthma Research Collaboration: Patient Centred (SHARP) [link here], Professor Ramesh Kurukulaaratchy of the University of Southampton and colleagues argued that, for some patients, the major drivers of poor outcomes may lie as much in multimorbidity as persistent airway inflammation itself.

The authors said the work builds on the recently developed Multimorbidity in Difficult Asthma Score (MiDAS), which linked rising comorbidity burden to worsening asthma and general health outcomes, but did not distinguish whether recognisable multimorbidity patterns existed within severe asthma itself.

“We have demonstrated that most patients with severe asthma experience multimorbidity and that there are distinct multimorbidity phenotypes in severe asthma with different adverse outcome risks,” the investigators wrote.

The analysis included 2690 severe asthma patients from 11 European countries. Nearly four in five patients were receiving biologic therapies, yet 30% still required maintenance oral corticosteroids. 

Patients had a median of three chronic conditions in addition to asthma, while in some participating countries virtually every patient had at least one additional comorbidity.

Researchers identified three recurring clusters of disease that repeatedly travelled together across Europe:

• osteoporosis and steroid-related weight gain;
• eczema and rhinitis; and
• chronic sinusitis and nasal polyps.

Other conditions – including obesity, reflux disease, bronchiectasis and psychological comorbidity – shifted between groups depending on the broader phenotype.

Several distinct severe asthma subtypes then emerged:

• Steroid-associated phenotype – highest maintenance oral corticosteroid exposure, poorest lung function, worst asthma control and greatest exacerbation burden despite extensive biologic use, reinforcing the importance of earlier steroid-sparing strategies and biologic consideration.
• Maximal multimorbidity phenotype – carried comorbidities from all three major clusters, with persistent type-2 inflammatory activity, substantial steroid-related morbidity and poor disease control.
• Sinonasal-associated phenotype – characterised by chronic sinusitis and nasal polyps, with stronger type-2 inflammatory markers, better lung function and comparatively better asthma control.
• “Unclustered” phenotype – lacked the major anchor comorbidity patterns but still demonstrated poor outcomes, obesity, smoking exposure and bronchiectasis, suggesting some patients may require broader multidisciplinary assessment beyond airway-focused escalation alone.

The steroid-associated phenotype – comprising about 8% of patients – emerged as one of the clearest signals of risk in the study.

These patients carried a heavy additional disease burden, including high rates of obesity, smoking exposure and systemic comorbidity despite widespread biologic use.

Collectively, the phenotype suggested a group trapped in a cycle of persistent disease, escalating steroid exposure and accumulating morbidity despite modern therapy.

“MMP ster might be regarded as a potentially iatrogenic steroid-associated multimorbidity group,” the investigators wrote.

The authors suggested some of the phenotype’s characteristics may reflect delayed transition to biologic therapies and cumulative harms associated with prolonged oral corticosteroid exposure.

“This overall phenotype, and its associated morbidity, might be prevented by avoidance of OCS over-reliance in future clinical management,” they wrote.

By contrast, patients with chronic sinusitis and nasal polyps appeared to represent a more airway-centric form of disease, with better lung function and comparatively better asthma control – findings the researchers said aligned with emerging evidence that these patients may derive stronger responses from biologic therapies targeting type-2 inflammation.

Meanwhile, the “unclustered” phenotype raised the possibility that some patients sit outside conventional inflammatory severe asthma frameworks altogether – a “symptom high, biomarker low” state potentially less responsive to airway-focused biologic strategies and more dependent on multidisciplinary management of systemic disease, lifestyle factors and non-airway morbidity.

The investigators said identification of the higher-risk multimorbidity phenotypes reinforced the importance of managing multimorbidity burden alongside type-2 inflammation rather than treating severe asthma as an isolated airway disorder.

They said the phenotypes may also provide clinicians with a more practical framework for recognising multimorbidity patterns in severe asthma clinics, particularly in patients with persistent symptoms despite biologic therapy. 

They also noted that chronic oral corticosteroid exposure may suppress type-2 biomarkers in some patients, while others may require broader assessment of obesity, reflux disease, bronchiectasis, smoking or psychological comorbidity rather than further escalation of airway-directed therapy alone.

“The fact that some of the more severe MMPs were steroid-associated emphasises the need to eradicate oral steroid dependency in severe asthma management,” the authors wrote.

They said the findings supported earlier consideration of biologic therapy where appropriate, while also highlighting “the need for a considered approach to understand more complex symptom presentations where factors beyond airway pathophysiology are likely to be relevant”.

“Recognition of these phenotypes can guide better care of the ‘whole patient’ with severe asthma,” they concluded.