Highlights
- Multimorbidity is near-ubiquitous in severe asthma, necessitating a shift from asthma-centric to patient-centric management models.
- The SHARP central database study identified three stable comorbidity clusters across Europe: steroid-induced (osteoporosis/weight gain), atopic (eczema/rhinitis), and sinonasal (sinusitis/nasal polyps).
- The ‘Steroid-associated Multimorbidity Phenotype’ (MMP ster) represents the most clinically burdened group, with the worst lung function, highest exacerbation rates, and highest BMI.
- Recognizing these multimorbidity phenotypes allows for targeted interventions and may mitigate the iatrogenic impact of long-term oral corticosteroid use.
Background
Severe asthma is rarely a solitary diagnosis. Instead, it frequently exists within a complex constellation of co-existing conditions, or multimorbidities, that significantly complicate clinical management and worsen patient outcomes. Historically, asthma research and guidelines have focused predominantly on the lower airway, treating comorbidities as secondary complications or ‘treatable traits’ in isolation. However, the phenotypic nature of how these comorbidities aggregate and their collective impact on the severe asthma disease course remain poorly understood.
The burden of severe asthma is substantial, characterized by persistent symptoms, frequent life-threatening exacerbations, and high healthcare resource utilization. Furthermore, the treatments often required to control severe asthma—specifically systemic corticosteroids—can contribute to a secondary layer of multimorbidity, creating a deleterious cycle of disease- and treatment-related morbidity. To address this, the European Respiratory Society (ERS) launched the Severe Heterogenous Asthma Research Collaboration: Patient Centred (SHARP) initiative. This study leverages the SHARP central database to delineate multimorbidity phenotypes (MMP) and their clinical characteristics across diverse European populations.
Key Content
Study Design and Methodological Framework
The study analyzed cross-sectional data from 2,690 severe asthma patients across 11 European countries, utilizing the SHARP Central database. To ensure geographical relevance, patients were categorized into four regions: North, South, East, and West. The researchers employed hierarchical clustering of the ten most prevalent comorbidities to identify stable co-aggregation patterns. This methodological approach allowed for the identification of ‘clusters’—groups of comorbidities that appear together more often than by chance—and ‘phenotypes’—groups of patients who share similar cluster alignments.
Identification of Replicable Comorbidity Clusters
One of the most significant findings was the identification of three core clusters that remained remarkably consistent across all four European regions, regardless of differing healthcare systems or environmental factors:
- Cluster 1: Steroid-Induced Impact: This cluster linked osteoporosis with steroid-induced weight gain. Its prevalence highlights the systemic toll of maintenance oral corticosteroids (m-OCS) and the high iatrogenic burden in this population.
- Cluster 2: Atopic/Allergic Diathesis: This cluster grouped eczema and rhinitis, reflecting a persistent Type 2 inflammatory state that manifests across different epithelial barriers.
- Cluster 3: Upper Airway/Sinonasal Disease: This cluster paired chronic sinusitis with nasal polyps. This reinforces the ‘unified airway’ concept, where upper and lower airway inflammation are intrinsically linked.
In contrast, other conditions such as obesity, bronchiectasis, gastro-oesophageal reflux disease (GORD), and psychological factors showed variable clustering across regions, suggesting that environmental, cultural, or local clinical practices may influence their manifestation in severe asthma.
Defining Multimorbidity Phenotypes (MMP)
Based on these clusters, the study identified four distinct Multimorbidity Phenotypes (MMPs) that provide a roadmap for clinical classification:
1. MMP sn (Sinonasal-associated)
The MMP sn phenotype is characterized by high rates of chronic rhinosinusitis and nasal polyps. This group often represents a specific inflammatory endotype (typically eosinophilic/T2-high). Patients in this group frequently require surgery for polyposis and may respond well to biologics targeting the IL-4/IL-13 or IL-5 pathways, which address both the upper and lower airway pathology.
2. MMP ster (Steroid-associated Multimorbidity)
This is arguably the most critical phenotype for clinicians to recognize. Patients in the MMP ster group exhibited the highest use of maintenance oral steroids and the highest BMI. Clinically, they suffered from the worst lung function (lowest FEV1), the poorest asthma control (highest ACQ scores), and the most frequent exacerbations. This group represents a high-risk cohort where the treatment (steroids) may be contributing to a metabolic and skeletal decline that further impairs asthma management.
3. MMP max (Maximal Multimorbidity)
Patients in the MMP max group showed a high prevalence across multiple variable clusters, including obesity, GORD, and bronchiectasis. These patients had the highest overall treatment needs, often requiring a combination of biologics and high-dose inhaled or oral therapies. Their management is the most complex, necessitating a multidisciplinary approach involving gastroenterology, nutrition, and potentially thoracic surgery or specialized physiotherapy.
4. MMP u (Unaligned)
While multimorbidity was ubiquitous, a subset of patients did not align strongly with one specific cluster. This ‘unaligned’ group serves as a reminder of the heterogeneity within severe asthma and the need for ongoing vigilance in screening for emerging comorbidities.
Expert Commentary: Clinical Implications and Mechanistic Insights
The findings from the SHARP registry underscore a paradigm shift in how we approach severe asthma. The consistency of the three primary clusters (steroid-induced, atopic, and sinonasal) across Europe suggests that these are not random associations but are driven by shared biological pathways or the predictable consequences of current therapeutic strategies.
The Iatrogenic Burden and the Biologic Era
The prominence of the MMP ster phenotype is a stark indictment of our historical reliance on oral corticosteroids. The association between osteoporosis and weight gain within this cluster highlights a metabolic-skeletal syndrome that is largely iatrogenic. In the modern era of biologics (anti-IgE, anti-IL5/5R, anti-IL4R, and anti-TSLP), the goal for any patient falling into the MMP ster category should be aggressive ‘steroid stewardship.’ By identifying these patients early, clinicians can prioritize the initiation of steroid-sparing biologics to prevent the irreversible complications of long-term OCS use.
The Unified Airway and T2 Inflammation
The stability of the sinonasal cluster (MMP sn) confirms that for a large portion of severe asthma patients, the disease is a systemic disorder of the respiratory mucosa. Mechanistically, this is often driven by Type 2 inflammation. Treating the lungs while ignoring the sinuses—or vice versa—is increasingly viewed as an incomplete clinical strategy. The use of monoclonal antibodies that address both asthma and nasal polyposis (e.g., Dupilumab, Mepolizumab, Omalizumab) is particularly warranted in this phenotype.
Addressing the ‘Whole Patient’
One of the limitations of current asthma guidelines is their vertical nature—focusing on escalating airway therapy without adequately addressing the horizontal impact of GORD, obesity, and psychological distress. The variable clustering of these traits suggests they are influenced by factors beyond simple Th2 inflammation. For example, obesity can lead to non-eosinophilic, mechanical airway changes, while GORD can trigger bronchospasm via micro-aspiration or vagal reflexes. A ‘maximal’ phenotype (MMP max) requires a ‘maximal’ care team, integrating mental health support, weight management, and gastrointestinal care.
Conclusion
The SHARP registry study provides a definitive look at the landscape of multimorbidity in European severe asthma patients. By identifying replicable phenotypes—specifically the sinonasal-associated and steroid-associated groups—the study provides clinicians with a framework for more precise risk stratification and treatment selection.
Future research must focus on longitudinal data to determine how these phenotypes evolve over time and how they respond to the introduction of next-generation biologics. Furthermore, clinical guidelines should be updated to move beyond the ‘Step 1-5’ pharmacological ladder, incorporating multimorbidity screening and phenotyping as a standard part of the severe asthma workup. Only by treating the ‘whole patient’ can we hope to improve the quality of life and long-term health outcomes for those living with the most severe forms of this disease.
References
- Freeman A, Rink S, Bansal AT, et al. Multimorbidity phenotypes and associated characteristics in severe asthma: an observational study of European severe asthma registries. Lancet Reg Health Eur. 2026 Feb 5;63:101600. doi: 10.1016/j.lanepe.2026.101600. PMID: 41694692.
- Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.
- Bousquet J, Farrell J, Crooks G, et al. Scaling up strategies of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Integrated Care). Lancet. 2016;388(10046):802-817.