PhD defence G.E. (Elizabeth) Benz Inalaf

Below is a brief summary of the dissertation: 

Chronic airway diseases such as COPD and asthma, are chronic pulmonary inflammatory diseases that cause significant global morbidity and mortality. COPD and asthma encompass several phenotypes and share extra-pulmonary manifestations. Sarcopenia is a main clinical and functional musculoskeletal disorder linked to COPD and (severe) asthma. This thesis aimed to determine the prevalence, clinical characteristics, and risk of all-cause mortality in older adults with COPD or asthma and sarcopenia. In addition, we focused on identifying inflammatory and cardiometabolic markers of sarcopenia in the general population as well as in persons with chronic airway diseases. We used data from the population-based Rotterdam study. All participants had a pre-bronchodilator spirometry and distinguished participants with normal spirometry values (FEV1/FCV≥70% and FEV1 ≥80%) and participants with COPD (FEV1/FVC<70%). Asthma diagnosis was based on physician-diagnosis. Moreover, all participants underwent sarcopenia assessment according to the revised European Working Group on sarcopenia. Within this assessment, repeated measurements of muscle mass (by using dual-energy X ray absorptiometry: DXA) and muscle strength (by using a hydraulic dynamometer) were used.

In Chapter 2, we showed that 21.6% [95% CI 14.6-30.9%] of persons with COPD present sarcopenia. Furthermore, we demonstrated that 12% and 3% of participants with chronic airway diseases had probable or confirmed sarcopenia, respectively, when we applied the updated definition and cut-off values of sarcopenia (EWGSOP2) in the Rotterdam Study. Moreover, we showed that among participants with chronic airway diseases, those with FEV1 % pred <80% had lower handgrip strength (=-1.03 [95% CI-1.75; -0.31]) and lower appendicular skeletal muscle index (ASMI) (=-0.25[95% CI: -0.36; -0.15]), than those with FEV1 % pred ≥80%.
When taking age and severity of airway disease, into account, sarcopenia is most prevalent in older persons with severe COPD and asthma, affirming the representativeness of the results presented in this thesis.
In Chapter 3 we investigated the changes in two important body composition indices over time: Appendicular skeletal muscle index (ASMI) which is a key component in confirming sarcopenia-, and fat-mass to fat-free mass (FM/FFM) which is part of the sarcopenic obesity phenotype. Our results showed that participants with COPD had a lower ASMI and an accelerated decline in ASMI compared with participants without COPD or asthma. Moreover, participants with COPD had a higher FM/FFM at baseline. Furthermore, similar FM/FFM change over time were found in participants with COPD and participants without COPD or asthma. Among participants with COPD, changes in these two body composition indices were driven by smoking status. Moreover, participants with COPD who had a low ASMI at baseline had an increased risk of all-cause mortality. Additionally, we found similar ASMI and FM/FFM changes over time in older participants with asthma and participants without COPD or asthma. 
To increase our understanding of how sarcopenia may affect persons with chronic airway diseases, we explored the associations of sarcopenia and its phenotypic components (including low muscle strength and muscle mass) and with potential determinants. More specifically, we investigated the association of sarcopenia with (1) oral corticosteroids (OCS) use, (2) the systemic immune-inflammatory index, and (3) circulating blood proteomics. 
In Chapter 4.1 we studied the association of use, dose, and duration of oral corticosteroids (OCS) with sarcopenia-phenotypic components in the total general population as well as within participants with chronic airway disease. We found that OCS users had lower muscle function (low handgrip strength) compared to never-OCS users, and this association was dependent on the cumulative dose of OCS. Furthermore, this association of OCS use with low handgrip strength was more pronounced in participants with mild to moderate COPD. Importantly, persons with COPD who were ever users of OCS and who were free of any sarcopenia-phenotypic component at baseline, had a significant decline in muscle strength after 5.6 years of follow-up, but no in lean mass. This association was dependent on OCS dose and duration of use (i.e., cumulative OCS dose).

In Chapter 4.2, we investigated the association between systemic inflammation (i.e., systemic immune-inflammation index, SII), sarcopenia, chronic airway diseases, and all-cause mortality. A common mechanism underlying both COPD and sarcopenia is chronic inflammation, and we demonstrated that a high level of systemic inflammation was independently associated with a higher risk of mortality in all participants. The results presented in Chapter 4.2 confirm findings from previous studies showing an increased risk of mortality in participants with COPD and asthma, especially in participants who also have sarcopenia and high levels of systemic inflammation. 
Moreover, in Chapter 4.3 we investigated the associations of proteins in plasma with both appendicular skeletal muscle index and handgrip strength in the Rotterdam Study. We showed that 21 out of 171 proteins are associated with sarcopenia traits (handgrip strength and/or ASMI) after adjustment for age, sex, cell counts, body fat percentage, and height. A gain in muscle strength was associated with cartilage oligometric matrix protein (COMP) and thrombospondin-4 over 5.5 years follow-up. Loss of muscle mass (ASMI) was associated with higher levels of leukemia inhibitory factor receptor (LIF.R) and carboxylesterase 1 (CES1). Tumor necrosis factor, which is a classical biomarker of sarcopenia had a borderline significant association with lower muscle strength.

The general discussion in Chapter 5 is focused on the main strengths and limitations of the work described in this thesis and on how this work can contribute to answering questions related to the pathogenesis, epidemiology role and impact of sarcopenia in chronic airway diseases.