Purpose: High dose interleukin-2 (IL-2) is known to be associated with cardiopulmonary toxicity, however there is a paucity of systematic in vivo data regarding the acute and chronic effects of IL-2 therapy on cardiopulmonary structure and function in humans.
Objectives: To evaluate the acute and chronic effects of high dose IL-2 therapy on cardiopulmonary structure and function.
Methods: Prospective comprehensive cardiopulmonary investigation, including combined cardiopulmonary magnetic resonance imaging (MRI), was performed in 7 patients in the acute period (2.7±1.5 days) following IL-2 therapy, and repeated in 4 patients in the chronic period (91±25 days) following IL-2 therapy. Comparison was made to data from 10 prospectively recruited matched healthy volunteers.
Results: IL-2 therapy was associated with myocardial and pulmonary capillary leak, tissue oedema and cardiomyocyte injury, which resulted in acute significant left ventricular (LV) dilatation, a reduction in LV ejection fraction (EF) (56% vs. 64%; p=0.013), an increase in LV mass (51±7g/m2 vs. 67±9g/m2; p=0.001) and a prolongation of QT interval. The acute effects occurred irrespective of symptoms. In the chronic period following IL-2 therapy many of the effects resolved, but LV hypertrophy ensued, driven by focal replacement and diffuse interstitial myocardial fibrosis (LV extracellular matrix mass; chronic IL-2: 38±8g vs. control: 26 ± 5g; p=0.005) and increased cardiomyocyte mass.
Conclusion: High dose IL-2 therapy is ubiquitously associated with acute cardiopulmonary inflammation, irrespective of symptoms, which leads to acute LV dilatation and dysfunction, increased LV mass and QT interval prolongation. Most of these effects are reversible, but IL-2 therapy is associated with chronic LV hypertrophy, driven by focal replacement and diffuse interstitial myocardial fibrosis and increased cardiomyocyte mass. The findings have important implications for the monitoring and long term impact of newer immunotherapies. Future studies are needed to improve risk stratification and develop cardiopulmonary-protective strategies.