Natural history of respiratory function in DMD
A major measure of lung function is absolute vital capacity (VC), which rises from age 7 and usually peaks between 12 and 14 years and then declines due to progressive muscle weakness. While absolute VC continues to rise, the percentage of ideal or predicted VC (VC%pred) declines in a linear fashion reaching about 80% predicted at age 1013. Hence, gradually falling VC%pred values include absolute values which occur before, at and following peak VC. Some investigators suggest that the identification of absolute values before, at and following peak VC may be best to assess the effect of interventions 14. In a large cohort study the VC of untreated individuals peaked at 1.85 liters at age 12 to 13 yrs and began to decline when VC%pred fell to 60-70% 15. Rates of decline of VC%pred per year have varied in the literature between as little as 5% (ages 5 to 24 yrs) 16 to as much as 10.7% (ages 12 to 15 yrs) 17. Following peak VC, absolute decline in ml/yr varies between 118 14and 180 mls/yr 18 with subsequently both FVC and VC%pred reaching an asymptotic floor after 20 years of age14-16,19,20. Without ventilatory support, a more favorable prognosis is associated with a higher, later peak and a more gradual decline in VC 21. Consensus guidelines recommend lung volume recruitment strategies at VC 60%pred, mechanically assisted coughing at 50%pred and NIV below 50%pred22. A VC of less than 1 liter has been associated with a 5 year survival of only 8% without respiratory supports18. At VCs below a liter (680cc) up to 24 hour respiratory support, preferably noninvasively, may be required. As such, disease modifying therapies have the goal of increasing and delaying the peak VC and reducing the post-plateau rate of decline. The more or less linear decline of VC%pred as an outcome measure may not be as sensitive to change as a result of interventions, as absolute VC13.
Phenotypic differences in pulmonary function and therefore clinical outcomes have been recognized for years. Phillips identified a longer surviving population who experienced peak VC at a median of 2 years later, 13 vs. 15 years and a slower yearly decline in VC%pred, 6% vs, 7.8% 18 and other investigators have divided DMD populations in to cohorts with different outcomes and survival related to the number of mutations upstream to exon 30 23. Even within the same genotype heterogeneity exists and needs to be considered in the evaluation of emerging therapies 23.