RESULTS
A total of 9,793 children born between 2010-2020 contributed data to the CFFPR. We excluded 1,028 children missing sweat chloride or genotype data. Of the remaining 8,765 children, 7,591 had a CF diagnosis and 1,174 a CRMS diagnosis reported by a CF care team (Figure 1), leading to a CF:CRMS ratio of 6.5:1. Of those with a clinical diagnosis of CRMS, 65 had a guidelines-based diagnosis of CF and were excluded from comparison of summary statistics, leaving a total of 8,700 children. Only 42 infants who were initially diagnosed with CRMS had their diagnosis changed to CF in the CFFPR. Figure 1 illustrates how children were categorized based on CFF diagnosis guidelines. The agreement between CF care team-reported and CFF guidelines-based diagnosis was similar between children with CF (93%) and children with CRMS (94%). However, similar to our earlier analysis, a substantial number of infants (N=504) who met guideline criteria for CRMS were classified as CF by their CF Care Center (32% of all CRMSg). The distribution of sweat chloride data and number of CF causing variants for the entire study cohort is presented in Table S1 (available online). Among the children who met guideline criteria for CRMS, the proportion of children reported as having CFc by their care team (by birth cohort) has generally declined over time, with 38%-41% of children born in 2010-2012 to 18%-23% of children born 2018-2020 (Table S2).
Loss-to-follow-up among the CFc/CFg cohort was minimal, with only 4.2% of the overall CFc/CFg group not reporting data in 2021 compared to 17.3% of CFc/CFg and 43% of CRMSc/CRMSg children (p-value <0.0001). Figure 2 illustrates the proportion of each birth cohort that contributed data through 2021 and shows participation in the CFFPR is differential by age and diagnosis category. Participation rates by subgroup and birth year are presented in Tables S3-S5 and show much higher participation among the CFc/CFg group compared to children classified as CRMS by either a care team or CFF guidelines. Children classified as CRMSc/CRMSg born in 2010 had the lowest participation rates, as only 36.6% contributed data through 2021. A total of 41 deaths were reported in the entire cohort, with <5 deaths in the CFc/CRMSg or CRMSc/CRMSg subgroups.
We found differences in patient characteristics comparing CFc/CFg to the other two groups during the first year of life (Table 1). The proportion of Hispanic patients was higher in the CFc/CRMSg (20.0%) and CRMSc/CRMSg (16.8%) cohorts compared to CFc/CFg (13.9%) (p-value <0.0001). We found 35.2% of CFc/CFg reported any Medicaid/Medicare during the first year of life compared to 23.8% CFc/CRMSg and 15.0% CRMSc/CRMSg (p-value < 0.0001).
Differences in health care utilization and treatment were present between all three groups, with CFc/CRMSg and CRMSc/CRMSg children reporting fewer mean visits and few cultures in the first year of life. Very few CFc/CRMSg and CRMSc/CRMSg reported fecal elastase data (12.2% and 1.4%, respectively) but most children in those categories did report at least one throat culture (74.6% and 62.0%, respectively). CFc/CFg patients had a lower mean weight-for-age percentile (32.8th percentile) compared to CFc/CRMSg (44.1st percentile) or CRMSc/CRMSg (48.0th percentile) (p-value < 0.0001). Height percentile and weight-for-length percentiles were also higher among CFc/CRMSg and CRMSc/CRMSg children compared to CFc/CFg. The prevalence of airway microorganisms was highest in CFc/CFg children and lowest among CRMSc/CRMsg children. The prevalence of Pa among CFc/CRMSg children was 18% compared to 22% among CFc/CFg children; methicillin sensitive Staphylococcus aureus (MSSA) prevalence was also similar among those two groups. Infants with CFc/CFg were more likely to be prescribed CF therapies such as dornase alfa or bronchodilators. Pancreatic enzyme replacement therapy (PERT) was only reported in 24.0% of CFc/CRMSg and 3.8% of CRMSc/CRMSg children.
We next assessed the prevalence of airway bacteria among each diagnosis group at older ages among children for whom data are available (Table 2). The prevalence of positive Pa respiratory cultures in the first year of life in was higher in CF patients (22.8%) compared to CFc/CRMSg (18.1%) or CRMSc/CRMSg (7.0%) patients. A similar pattern was observed for Stenotrophomonas maltophilia , Staphylococcus aureus , and Hemophilus influenzae . Prevalence of Pa and other bacteria was higher in the CFc/CRMSg cohort compared to the CRMSc/CRMSg cohort. In CFc/CFg patients, the annual prevalence of Pa was relatively unchanged by age (range 24%-28%)(Figure 3). However, in the CFc/CRMSg and CRMSc/CRMSg populations, the greatest prevalence of Pa occurred in infancy and was lower at age 2 and older (Figure 3).
Among children old enough for pulmonary function testing (>6 years of age), we compared the mean percent predicted forced expiratory volume in 1 second (ppFEV1) between groups (Table 3) at integer ages. The mean ppFEV1 in CFc/CFg children was lower compared to the other two groups from age six through age 10 years, with CRMSc/CRMSg children having the highest lung function at all ages. We also compared mean height and weight percentiles between groups (Table S4 and Table S5) at integer ages. Similar to ppFEV1 results, mean height and weight percentiles in CFc/CFg children were lower compared to the other two groups from age 0 through age 10 years, with CRMSg/CRMSg children having the highest percentiles through age 1, then CFc/CRMSg having higher clinical measures.