Respiratory phenotypes in amyotrophic lateral sclerosis: heterogeneity, disease spread, and survival in a population-based cohort

BACKGROUND AND AIMS Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous neurodegenerative disease characterized by progressive motor neuron degeneration and variable clinical presentations. Although respiratory dysfunction is a major determinant of disease progression and survival, a subset of patients presents predominant respiratory involvement from the earliest stages of the disease, defining a distinct respiratory phenotype whose clinical characteristics and prognostic implications remain incompletely understood. The aim of this study was to characterize respiratory phenotype ALS and compare it with other ALS phenotypes in a large population-based cohort. METHODS ALS patients prospectively recorded in the Emilia-Romagna ALS Registry (ERRALS) between January 2009 and December 2025 were included. Patients fulfilling criteria for respiratory phenotype ALS were identified through predefined clinical criteria and detailed chart review. Demographic, clinical, respiratory, and prognostic characteristics were compared with those of non-respiratory ALS patients. Survival was assessed using Kaplan–Meier and Cox proportional hazards analyses, while longitudinal functional decline was evaluated through linear mixed-effects models based on repeated ALS Functional Rating Scale-Revised (ALSFRS-R) assessments. RESULTS Among 2,065 ALS patients included in the registry, 54 (2.6%) fulfilled criteria for respiratory phenotype ALS. Compared with other ALS phenotypes, respiratory phenotype patients were more frequently male (81.5% vs 56.0%, p<0.0001), older at symptom onset (71.6 vs 66.3 years, p=0.0008), and exhibited greater weight loss at diagnosis (9.6 vs 4.2 kg, p<0.0001). They showed lower baseline ALSFRS-R scores (32.2 vs 38.2, p<0.0001) and markedly reduced forced vital capacity (60.8% vs 85.9%, p<0.0001). Respiratory phenotype ALS was also associated with a higher prevalence of respiratory, cardiovascular, metabolic, and autoimmune comorbidities, more frequent use of non-invasive ventilation (88.9% vs 40.9%, p<0.0001), and earlier ventilatory support initiation. Survival analyses demonstrated a significantly poorer prognosis for respiratory phenotype patients compared with other ALS phenotypes (HR 1.67, 95% CI 1.17–2.38; p=0.005). Within the respiratory phenotype subgroup, longer diagnostic delay (HR 0.89, 95% CI 0.84–0.94; p<0.0001) and higher baseline ALSFRS-R scores (HR 0.86, 95% CI 0.81–0.91; p<0.0001) independently predicted longer survival. Longitudinal analyses showed significantly lower ALSFRS-R scores throughout follow-up in respiratory phenotype patients; however, the subsequent rate of functional decline did not differ significantly from that observed in the remaining ALS population. CONCLUSIONS Respiratory phenotype ALS represents a rare but clinically distinct presentation within the ALS spectrum, characterized by older age at onset, male predominance, greater respiratory impairment, increased comorbidity burden, and reduced survival. Despite its overall poorer prognosis, substantial heterogeneity exists within this subgroup, including patients with prolonged survival, higher BMI, lower weight loss at diagnosis, and longer diagnostic delay. The finding that respiratory phenotype patients present with a more severe functional status at diagnosis, without a significantly faster subsequent decline, suggests that their unfavorable prognosis may largely reflect a greater disease burden at presentation rather than a more aggressive disease course. Early recognition of respiratory involvement and systematic assessment of respiratory and nutritional status may improve prognostic stratification and support more personalized multidisciplinary management strategies.