Type 2 inflammation in COPD – is it important?

20th July 2024, A/Prof Chee L Khoo

Chronic obstructive pulmonary disease (COPD) is not just a disease of obstructed airways. In a significant proportion of COPD sufferers, there is an inflammatory component to the disease. This not only affects the aetiology of the disease and its exacerbations but also its management. We are used to using all sorts of bronchodilators to keep the obstructed airways opened and inhaled corticosteroids (ICS) to tackle the inflammatory component. What if triple therapy is not enough? Ongoing unchecked inflammation will contribute significantly to ongoing lung damage as well as quality of life.

It used to be thought that the Inflammation in COPD was driven solely by type 1 immune responses which involved cluster of differentiation 4 cells (CD4+), T-helper cell type 1 cells, CD8+ cytotoxic T cells, macrophages, and neutrophils (7). On the other hand, the inflammation in patients with asthma is driven by type 2 inflammation involving CD4+ T-helper cell type 2 (Th2) cells, type 2 innate lymphoid cells (ILC2s), eosinophils, and alternatively activated macrophages.

20–40% of patients with COPD exhibit type 2 inflammation (1-4). Type 2 inflammation has been associated with higher future exacerbation risk in patients with histories of exacerbation (2-6). We are aware that some patients have both asthma and COPD but type 2 inflammation can be present in patients with COPD without asthma (7,8).

Type 2 inflammation is meant to be provide protection against helminths (worms) and parasites but its role of type 2 in allergic and inflammatory conditions when dysregulated is widely studied. In response to epithelial-derived alarmins, TH2 and ILC2 cells secrete IL-4, IL-5 and IL-13. IL-4 and IL-13 promote the activation and trafficking of inflammatory cells including eosinophils to the lungs. They have also been shown to impair the IFN-γ response to rhinovirus infection leading to increased rhinovirus replication.

Blood eosinophil counts, a commonly used biomarker in asthma, are both a prognostic and a predictive biomarker in COPD (5, 9, 10). In the subgroup of patients with COPD with elevated plasma eosinophile count, there is an enhanced response to oral and inhaled corticosteroids. Thus, the mainstay of pharmacological intervention is combination therapy with long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), sometimes combined with inhaled corticosteroids (ICSs). However, substantial proportion of patients with moderate to very severe COPD continue to have exacerbations despite receiving this standard-of-care therapies.

As IL-4, IL-5 and IL-13 are the key drivers of Type 2 inflammation, it makes sense to target these pathways in patients with are on maximal therapy and still suffer frequent exacerbations. Therapies targeting eosinophils via the IL-5 pathway (mepolizumab and benralizumab) have not been shown to be very efficacious (11-13).

Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, key and central drivers of type 2 inflammation, thus inhibiting their signalling. Dupilumab has been shown to be efficacious and safe in two Phase 3 randomised controlled trial.

In the first RCT (2023), 939 patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks (14). There was a 30% reduction in moderate to severe exacerbations over a period of 12 months. There was improvement in FEVas well as quality of life scores.

In the second RCT (2024), 935 patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher were randomised to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks (15). There was a 34% reduction in moderate to severe exacerbations over a 12-month period. There was a significant improvement in pre-bronchodilator FEV1 both at week 12 and week 52. There were no improvements in quality scores.

In summary, there is a subgroup of patients with COPD who, despite triple puffer therapy (LABA + LAMA + ICS), continue to suffer frequent exacerbations. If their eosinophil count is elevated > 300 cells/ml, biological therapy has been shown to significantly reduce exacerbations of their COPD. This can reduce further pulmonary function decline and improve quality of life in our patients. It is easy to accept that in patients with moderate to severe COPD who are already on maximal therapy, there isn’t much we can do for them. Perhaps, a referral to a respiratory physician or immunologist might be useful.

References:

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