Abstract
Background:
Hispanic subjects with cystic fibrosis (CF) have increased morbidity and mortality than non-Hispanic white subjects. The ethnic disparity in mortality varies by region. Factors influencing pulmonary function vary by both ethnicity and region.
Objective:
To determine if the ethnic difference in pulmonary function varies by region.
Methods:
This retrospective cohort study compared differences in longitudinal pulmonary function (percent predicted FVC, FEV1, FEF25–75, FEV1/FVC, FEV1 decline) between Hispanic and non-Hispanic white subjects with CF by Census region of the U.S. (West, South, Midwest, Northeast). Subjects were ages 6–25 years and in the CF Foundation Patient Registry from 2008 to 2013. We used linear mixed effects models with subject-specific slopes and intercepts, adjusting for 14 demographic and clinical variables.
Results.
Of 14,932 subjects, 1,433 (9.6%) were Hispanic and 13,499 (90.4%) were non-Hispanic white. Hispanic subjects’ FEV1 was 9.0% (8.3–9.8%) lower than non-Hispanic white subjects in the West, while Hispanic subjects’ FEV1 was only 4.0% (3.0–5.0%) lower in the Midwest, 4.4% (3.1–5.7%) lower in the Northeast, and 4.4% (3.2–5.5%) lower in the South. Similarly, FVC and FEF25–75 were lower among Hispanic subjects compared to non-Hispanic white subjects in all U.S. regions, with the biggest differences in the West. Only in the West was FEV1/FVC significantly lower in Hispanic subjects (−0.019; −0.022 to −0.015). FEV1 decline was not significantly different between ethnicities in any region.
Conclusions:
In CF, Hispanic subjects have lower pulmonary function than non- Hispanic white subjects in all geographic regions with the largest difference in occurring in the West.
Introduction:
Despite great advancements in care and outcomes, Hispanic patients with cystic fibrosis (CF) have worse outcomes compared to non- Hispanic white patients. Hispanic patients have a higher rate of mortality than do non-Hispanic white patients1,2 and Hispanic youth with CF have worse pulmonary function3. Our group has shown that Hispanic youth with CF have 5.8% lower percent predicted FEV1 compared with non-Hispanic white youth3. The ethnic disparity in CF mortality varies significantly between United States Census regions2. It is not known whether the ethnic disparity in pulmonary function also varies across geographic regions in the United States.
It is not yet understood what factors contribute to Hispanic patients having more severe pulmonary disease; there are numerous factors that determine pulmonary function in CF. For example, pulmonary function is strongly influenced by CFTR mutation severity4; however, Hispanic subjects have worse pulmonary function than non-Hispanic white subjects in all CFTR mutation severity classes3. In our prior analysis of pulmonary function3, Hispanic subjects still had worse pulmonary function3, even when controlling for measures of respiratory infections, environmental exposures, and socioeconomic status known to affect pulmonary function5–7. Many of these factors may not uniformly affect Hispanic patients across the United States. Exposure to factors that influence pulmonary function vary across geographic regions of the United States for all patients8–11. Persons of Hispanic ethnicity, also referred to as Latino or the gender neutral LatinX, are disproportionately exposed to some of these factors, such as air pollution, however, this exposure is not uniform across the country12. Healthcare factors, such as newborn screening and Medicaid qualifications, vary state by state and may disproportionately affect Hispanic patients13,14. Biological factors affecting pulmonary function may also differ between Hispanic patients. Persons of Hispanic ethnicity are a heterogeneous group and vary genetically across the United States due to different immigration patterns and countries of origin15,16. Hispanic people originating from Mexico are more likely to have immigrated to the West, while those from the Caribbean are more likely to have immigrated to the Northeast17. These different immigration patterns result in diverse genetic ancestry admixture among the Hispanic population between regions.
Given that Hispanic patients have higher mortality rates than non-Hispanic white patients which varied by geographic region2 and that factors influencing pulmonary function vary by both ethnicity and geographic region, we sought to examine if pulmonary function disparities between ethnicities also vary between U.S. geographic regions. We used the largest database of Hispanic and non-Hispanic white subjects with CF, the United States CF Foundation Patient Registry (CFFPR)18, to compare whether pulmonary function between ethnicities varies by geographic region of the United States.
Methods:
This is a longitudinal study of Hispanic and non-Hispanic white subjects in the CFFPR, a retrospective observational study of patients from accredited CF centers which includes approximately 81–84% of patients with CF in the United States18. We included subjects with CF, ages 6 to 25 years, enrolled between 2008 to 2013, with pulmonary function measured at least once. Each subject contributed between 1 and 19 years of pulmonary function measurements, with an average of 8.1 years. We analyzed all data from time of entry in CFFPR until December 31, 2013 or age ≥26 years. The study was approved by the University of California, San Francisco Institutional Review Board (15–17491) and the CF Foundation Registry/ Comparative Effectiveness Research Committee.
The primary outcome was longitudinal forced expiratory volume in one second (FEV1) percent predicted. We also analyzed longitudinal forced vital capacity (FVC) percent predicted, forced expiratory flow at 25%−75% of FVC (FEF25–75%) percent predicted, FEV1/FVC, and FEV1 decline as secondary outcomes. Annual pulmonary function was the average of the 4 highest quarterly values during a calendar year based on Global Lung Initiative (GLI) equations19. We did not include data obtained after lung transplantation. FEV1 decline was not analyzed in the 445 subjects with only 1 measurement of FEV1 percent predicted.
The predictors were domicile location in the United States, defined as the West, Midwest, Northeast, or South according to the United States Census20, and self-identified race and ethnicity, defined as Hispanic or non-Hispanic white.
All analyses were adjusted a priori based on previous medical literature for the following covariates: age, sex, pancreatic enzyme replacement therapy (PERT) use (yes/no), body mass index (BMI) (underweight = BMI <10th percentile if age <20 years or BMI <18.5 kg/m2 if age ≥20 years21), sweat chloride concentration, methicillin-resistant Staphylococcus aureus (MRSA) (any positive cultures yearly), Pseudomonas aeruginosa (any positive cultures yearly), tobacco exposure (no tobacco, secondhand tobacco exposure, vs. active smoker), age at diagnosis, CF-related diabetes, CFTR mutation class (CFTR class I-III, CFTR class IV-V, or unclassified4), insurance status (Medicaid regardless of secondary insurance listed, no Medicaid, or no insurance), maternal education (high school or less compared with some college or more), rural urban commuting area codes (rural or urban). Rural Urban Commuting Area Codes (RUCA) are a Census tract-based classification scheme using subject’s zip codes from the United States Department of Agriculture to categorize zip codes into rural or urban22. Covariates were recorded annually.
Statistical Analysis:
We fit linear mixed effects regression models to the longitudinal pulmonary function data with subject-specific random intercepts and random slopes to compare longitudinal pulmonary function between Hispanic and non-Hispanic white subjects for each United States geographic region. Models included ethnicity, geographic region, and their interaction as well potential confounding variables as predictors. The ethnicity by geographic region interaction terms measured the difference across geographic regions in the ethnic difference in pulmonary function. The following covariates were entered as time-dependent variables: age, PERT use, BMI, sweat chloride concentration, MRSA, Pseudomonas aeruginosa, tobacco exposure, CFRD, insurance status, maternal education, and RUCA. MRSA and Pseudomonas aeruginosa infections were recorded as any positive cultures yearly. Some patients had multiple sweat chloride concentrations recorded over years so was entered as a time-dependent variable. If no sweat chloride concentration was done in a year, the last previously sweat chloride concentration value was used. Missing data in covariates was assessed as plausible to be missing at random since not all CF centers collect complete datasets, so we performed multiple imputations by chained equations (10 data sets were imputed and analyzed). Ethnic differences in clinical characteristics and demographics at time of study entry were compared between each geographic region using Chi square tests for categorical variables and Student t tests for continuous variables. A 2-sided P-value <0.05 was considered statistically significant. Statistical analysis was performed with Stata 14.1 (Stata Corporation, College Station, Texas).
Results:
Of the 14,932 subjects in our retrospective cohort study, 1,433 were Hispanic (9.6%) and 13,499 were non-Hispanic white (90.4%). Hispanic subjects were asymmetrically distributed across the United States with 36.1% in the West, 29.2% in the Midwest, 15.1% in the Northeast, and 19.5% in the South. Hispanic subjects made up varying proportions of the study cohort by region. In the West, 19.2% of the study cohort was Hispanic compared with 7.9% Hispanic in the Midwest, 6.6% Hispanic in the Northeast, and 7.7% Hispanic in the South.
The cohort’s clinical characteristics and ethnic make-up showed great variation across geographic regions of the United States (Table 1). In the West, more Hispanic subjects had MRSA than non-Hispanic white subjects (+1.1%), while in other geographic regions fewer Hispanic subjects had MRSA than non- Hispanic white subjects (−0.9% to −5.9%). There were higher rates of Pseudomonas aeruginosa in Hispanic subjects in the West than in non-Hispanic white subjects (+11.1%) compared to other regions (1.1%−5.9%). The West had the largest difference in Pseudomonas aeruginosa between ethnicities due to the highest Pseudomonas aeruginosa rate (42.7%) of any group occurring in Hispanic subjects and the lowest rate (31.6%) occurring in non-Hispanic white subjects. More Hispanic subjects had government insurance than non-Hispanic white subjects in the West (+22.5%) compared to the other regions (15.2%−21.0%). In the West, fewer Hispanic mothers had completed education beyond high school than non-Hispanic white mothers (−18.7%) compared to other regions (−5.4% to −11.8%). More Hispanic subjects had Class IV-V (+2.5%) or unclassified (+22.0%) CFTR mutations than non-Hispanic white subjects in the West. There was no pattern in differences between ethnicities in CFTR classes in the other regions.
Table 1:
Study Population Characteristics at Cohort Entry
| United States | West | Midwest | Northeast | South | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Hispanic | Non-Hispanic White | Hispanic | Non-Hispanic White | Hispanic | Non-Hispanic White | Hispanic | Non-Hispanic White | Hispanic | Non-Hispanic White | |
| Number (%) | 1,433 | 13,499 | 518 | 2,183 | 419 | 4,878 | 217 | 3,071 | 279 | 3,367 |
| (9.6%) | (90.4%) | (19.2%) | (80.8%) | (7.9%) | (92.1%) | (6.6%) | (93.4%) | (7.7%) | (92.4%) | |
| Age* | 10.3 | 10.6 | 10.4 | 10.6 | 9.6 | 10.5 | 10.7 | 10.8 | 10.4 | 10.7 |
| (7.8–13.9) | (8.0–14.4) | 7.8–14.1 | 8.0–14.1 | 7.6–13.2 | 7.9–14.3 | 8.2–14.7 | 8.1–14.8 | 7.9–13.8 | 7.9–14.3 | |
| Sex, male | 52.6% | 50.9% | 52.9% | 49.0% | 55.4% | 50.9% | 48.2% | 52.0% | 50.9% | 51.2% |
| +1.7% | +3.9% | +4.5% | −3.8% | −0.3% | ||||||
| Age at Diagnosis, mths* | 6.2 | 4.4 | 6.0 | 4.9 | 5.8 | 4.5 | 7.1 | 3.0 | 7.0 | 5.1 |
| +1.8 (+0.7 to +12.4) | +1.1 (+0.5 to +11.5) | +1.3 (−0.4 to +10.9) | +4.1 (+0.8 to +15.5) | +1.9 (+0.8 to +10.1) | ||||||
| PERT use | 87.3% | 90.7% | 91.9% | 91.8% | 88.3% | 91.5% | 81.6% | 87.7% | 85.0% | 91.8% |
| -3.4% | +0.1% | −3.2% | −6.1% | −6.8% | ||||||
| Sweat Chloride Concentration | 95.5 | 97.6 | 96.1 | 97.7 | 97.4 | 98.2 | 91.5 | 96.5 | 95.0 | 97.5 |
| −2.0 (−0.89 to −3.2) | −1.6 (−3.7 to +0.5) | −0.8 (−2.9 to +1.3) | −5.0 (−8.1 to −1.9) | −2.5 (−5.0 to −0.7) | ||||||
| CFTR Class I-III | 53.2% | 75.5% | 53.5% | 78.0% | 52.5% | 75.1% | 47.9% | 71.1% | 57.7% | 78.3% |
| −22.3% | −24.5% | −22.6% | −23.2% | −20.6% | ||||||
| CFTR Class IV-V | 8.9% | 7.1% | 8.3% | 5.8% | 8.8% | 7.3% | 9.2% | 9.8% | 9.7% | 5.3% |
| +1.8% | +2.5% | +1.5% | −0.6% | +4.4% | ||||||
| CFTR Unclassified | 37.9% | 17.4% | 38.2% | 16.2% | 38.7% | 17.6% | 42.9% | 19.1% | 32.6% | 16.4% |
| +20.5% | +22.0% | +21.1% | +23.8% | +16.2% | ||||||
| BMI, percentile | 53.8 | 50.4 | 51.5 | 48.7 | 55.6 | 50.4 | 56.3 | 52.7 | 53.1 | 49.5 |
| +3.4 (1.7 to 4.9) | +2.8 (1.3 to 4.2) | +5.2 (3.1 to 7.3) | +3.4 (0.7 to 6.7) | +3.6 (1.0 to 6.2) | ||||||
| CF-Related Diabetes | 4.8% | 4.8% | 4.8% | 4.2% | 5.7% | 5.2% | 1.8% | 4.1% | 5.4% | 5.4% |
| +0% | +0.6% | +0.5% | −2.3% | +0% | ||||||
| MRSA | 13.5% | 16.3% | 11.0% | 9.9% | 15.8% | 16.7% | 12.0% | 14.2% | 15.8% | 21.7% |
| −2.8% | +1.1% | −0.9% | −2.2% | −5.9% | ||||||
| Pseudomonas | 39.9% | 33.8% | 42.7% | 31.6% | 38.7% | 32.8% | 34.1% | 33.0% | 40.9% | 37.6% |
| +6.1% | +11.1% | +5.9% | +1.1% | +3.3% | ||||||
| NTM | 2.4% | 1.2% | 1.7% | 1.7% | 1.9% | 1.0% | 2.8% | 0.8% | 3.9% | 1.7% |
| +1.2% | +0% | +0.9% | +2.0% | +2.2% | ||||||
| Tobacco Exposure | 6.1% | 9.7% | 3.5% | 5.5% | 8.6% | 10.7% | 8.3% | 9.6% | 5.4% | 11.0% |
| −3.6% | −2.0% | −2.1% | −1.3% | −5.6% | ||||||
| Government Insurance | 58.8% | 41.5% | 53.7% | 31.2% | 62.8% | 44.3% | 59.9% | 38.9% | 61.7% | 46.5% |
| +17.3% | +22.5% | +18.5% | +21.0% | +15.2% | ||||||
| Mat. Ed, College | 15.4% | 27.4% | 8.3% | 27.0% | 21.5% | 26.1% | 17.5% | 29.3% | 17.9% | 27.7% |
| −12.0% | −18.7% | −5.4% | −11.8% | −9.8% | ||||||
| RUCA, rural | 7.4% | 13.9% | 6.0% | 11.9% | 9.8% | 17.5% | 4.2% | 10.3% | 9.0% | 13.0% |
| −6.5% | −5.9% | −7.7% | −6.1% | −4.0% | ||||||
There were wide variations between ethnicities in percent predicted pulmonary function between geographic regions (Figure 1, Table 2). In the West, Hispanic subjects’ percent predicted FEV1 was 9.0 percentage points (8.3–9.8%) lower than non-Hispanic white subjects, while Hispanic subjects’ percent predicted FEV1 was only 4.0 percentage points (3.0–5.0%) lower in the Midwest, 4.4 percentage points (3.1–5.7%) lower in the Northeast, and 4.4 percentage points (3.2–5.5%) lower in the South. In the West, Hispanic subjects had the overall lowest percent predicted FEV1 (78.1%) while non-Hispanic white subjects had close to the highest (87.1%) of any group. Hispanic subjects’ percent predicted FVC was 7.7 percentage points (7.0–8.3%) lower than non-Hispanic white subjects in the West, while Hispanic subjects’ percent predicted FVC was only 4.4 percentage points (3.5–5.3%) lower in the Midwest, 4.1 percentage points (3.0–5.2%) lower in the Northeast, and 4.0 percentage points (2.9–5.0%) lower in the South. Only in the West did Hispanic subjects have lower FEV1/FVC than non-Hispanic white subjects. In the West, Hispanic subjects’ percent predicted FEF25–75 was 6.5 percentage points (5.2–7.7%) lower than non-Hispanic white subjects, while Hispanic subjects’ percent predicted FEF25–75% was only 2.4 percentage points (2.0–4.1%) lower in the Midwest, 4.4 percentage points (2.0–6.7%) lower in the Northeast, and 2.7 percentage points (0.5–5.0%) lower in the South. There was no difference by ethnicity in the rate of percent predicted FEV1 decline in any geographic region.
Figure 1.
Difference In Pulmonary Function Between Hispanic and Non-Hispanic Subjects
Table 2:
Ethnic Differences In Pulmonary Function Vary By Geographic Region
| Hispanic FVC | Non-Hispanic Whites FVC | Difference in FVC % | 95% CI | p-value | |
|---|---|---|---|---|---|
| West | 86.7% | 94.4% | −7.7% | −8.3% to −7.0% | Ref. |
| Midwest | 88.5% | 92.9% | −4.4% | −5.3% to −3.5% | <0.001 |
| Northeast | 89.8% | 93.9% | −4.1% | −5.2% to −3.0% | <0.001 |
| South | 87.8% | 91.8% | −4.0% | −5.0% to −2.9% | <0.001 |
| Hispanic FEV1 | Non-Hispanic Whites FEV1 | Difference in FEV1% | 95% CI | p-value | |
| West | 78.1% | 87.1% | −9.0% | −9.8% to −8.3% | Ref. |
| Midwest | 81.4% | 85.4% | −4.0% | −5.0% to −3.0% | <0.001 |
| Northeast | 82.9% | 87.3% | −4.4% | −5.7% to −3.1% | <0.001 |
| South | 79.6% | 84.0% | −4.4% | −5.5% to −3.2% | <0.001 |
| Hispanic FEV1/FVC | Non-Hispanic Whites FEV1/FVC | Difference in FEV1/FVC | 95% CI | p-value | |
| West | 0.793 | 0.812 | −0.019 | −0.022 to −0.015 | Ref. |
| Midwest | 0.814 | 0.811 | 0.003 | −0.001 to 0.008 | <0.001 |
| Northeast | 0.816 | 0.820 | −0.004 | −0.009 to 0.002 | 0.005 |
| South | 0.803 | 0.806 | −0.003 | −0.008 to 0.003 | 0.002 |
| Hispanic FEF25–75 | Non-Hispanic Whites FEF25–75 | Difference in FEF25–75 | 95% CI | p-value | |
| West | 65.1% | 71.6% | −6.5% | −7.7% to −5.2% | Ref. |
| Midwest | 68.5% | 70.9% | −2.4% | −4.1% to −2.0% | 0.015 |
| Northeast | 67.7% | 72.1% | −4.4% | −6.7% to −2.0% | 0.3 |
| South | 66.8% | 69.5% | −2.7% | −5.0% to −0.5% | 0.055 |
-West region is the reference group
-Model adjusted for age, sex, pancreatic enzyme replacement use, body mass index, sweat chloride concentration, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, maternal education level, insurance type, tobacco exposure, age at diagnosis, CF-related diabetes, Rural Urban Commuting Area Codes (RUCA), CFTR mutation class.
Discussion:
In the largest database of Hispanic patients with CF, we found that pulmonary function disparities between Hispanic and non-Hispanic white subjects vary between geographic regions, even with adjustment for factors known to influence pulmonary function. In all geographic regions, the difference in percent predicted FEV1 between Hispanic and non-Hispanic white subjects varied from the overall ethnic disparity of 5.8% in percent predicted FEV1 that we had found in our previous work3. The ethnic gap in pulmonary function was significantly wider in the West than in the other geographic regions for all measures (percent predicted FVC, FEV1, FEV1/FVC, FEF25–75%). The Midwest, Northeast, and South regions had similar ethnic gaps in pulmonary function. Non-Hispanic white subjects residing in the West had the highest pulmonary function values of any region, while Hispanic subjects residing in the West had the lowest pulmonary function values of any region. Despite Hispanic subjects having lower pulmonary function that non-Hispanic white subjects, there was no difference in the rate of decline in percent predicted FEV1 by ethnicity in any geographic region. This is consistent with our prior findings on overall rate of percent predicted FEV1 decline and pulmonary function differences by ethnicity3.
Our study findings suggest there are geographical differences in disease severity among Hispanic patients with CF. Our findings are consistent with prior findings by J. Rho, who found there are significant geographical variations in CF mortality between ethnicities2. However, the difference in mortality between ethnicities was the widest in the Midwest, while our study found that the widest differences in pulmonary function occurred in the West. This incongruity in findings may be due to age differences between the two study populations; our study included subjects 25 years old and younger, while the mortality study included older subjects. This incongruity in findings may also be due to differences in the factors influencing mortality compared to those influencing pulmonary function in CF.
Our findings have the greatest implications for the CF population residing in the West, where the largest disparity in pulmonary function occurred. Not only does the West have the largest number of Hispanic CF subjects of all four regions, but also in the West, Hispanic patients make up the highest proportion of the regional CF population compared to the other regions.
There is a paucity of research examining factors that contribute to CF disease severity in Hispanic subjects. Focusing on factors that differentially impact Hispanic subjects residing in the West, may provide insight into the observed ethnic disparities in pulmonary function between geographic regions. In this study, we have identified several factors known to be associated with reduced pulmonary function in CF that vary by ethnicity and geographic region.
Respiratory infections, which negatively affect pulmonary function, are known to vary by ethnicity2,23 and by geographic region8,24,25 outside of CF. We found that Hispanic subjects were more likely to have Pseudomonas aeruginosa than non-Hispanic white subjects in CF. Furthermore, we found significant geographic variations in the difference in the rate of Pseudomonas aeruginosa between ethnicities with the greatest difference occurring in the West. Consistent with our pulmonary function findings, we found that Hispanic subjects in the West had the highest rate of Pseudomonas aeruginosa of any group while non-Hispanic white subjects in the West had the lowest rate of any group. Interestingly, Hispanic subjects had a lower rate of MRSA than non-Hispanic white subjects except in the West where Hispanic subjects had a higher rate of MRSA. The significant geographic and ethnic differences in Pseudomonas aeruginosa and MRSA infections may contribute to the largest ethnic gap in pulmonary function occurring in the West. The ethnic gap in pulmonary function persisted despite adjustment for Pseudomonas aeruginosa and MRSA for a few possible reasons. Respiratory infections may differentially impact pulmonary function by ethnicity, such that Pseudomonas aeruginosa may cause a greater drop in pulmonary function in Hispanic subjects than in non-Hispanic white subjects. There may be differences between ethnicities in the treatment of respiratory infections. There may also be differences in timing of infection acquisition or conversion of non-mucoid to mucoid Pseudomonas aeruginosa between ethnicities. Further investigation into the pattern of respiratory infections in Hispanic subjects is needed.
CFTR mutations and genes other than CFTR have been shown to influence pulmonary function severity in CF4,26. Hispanic subjects in all geographic regions were more likely to have unclassified CFTR mutations and less likely to have CFTR class I-III. We have previously shown that there were no significant differences in the ethnic gap in pulmonary function between CFTR mutation severity classes3. The Hispanic ethnicity is heterogeneous with genetically diverse heritages that vary across the United States regions due to distinct migration patterns. Hispanic people residing in the West are more likely to originate from Mexico or Central America, while those in the Northeast are more likely to originate from the Caribbean17. Gene modifiers that influence pulmonary function may vary between Hispanic populations by region. It would be important to identify gene modifiers in future studies to guide care and reduce the ethnic gaps between geographic regions.
Markers of lower socioeconomic status, including government insurance and maternal education, are associated with poor outcomes in CF, including lower pulmonary function7,27. Consistent with our findings of differences in pulmonary function between Hispanic and non-Hispanic subjects, Hispanic subjects were more likely to have government insurance in every region compared to non-Hispanic white subjects with the largest difference occurring in the West. In all regions, Hispanic subjects had the lowest rate of maternal education beyond high school again with the largest difference between ethnicities occurring in the West. Socioeconomic factors, such as poor health literacy, discrimination, acculturation level, English proficiency, and language spoke at home28–30 are more likely to affect Hispanic than non-Hispanic white subjects and may contribute to our findings of ethnic and geographic variations in pulmonary function. Unfortunately, these socioeconomic markers are not collected by the CFFPR and could not be examined in this study. Further studies are needed to examine the influence of these other socioeconomic factors on our findings, including the socioeconomic factors that specifically affect Hispanic subjects.
We found that there was no significant difference in age of diagnosis between Hispanic and non-Hispanic white subjects except for in the West where Hispanic subjects were diagnosed at an older age. Newborn screening leads to earlier diagnosis and initiation of treatment which is associated with higher pulmonary function in CF31. Hispanic infants are less likely to be diagnosed via newborn screening than non-Hispanic white infants, however, this varies state by state32 due to differences in newborn screening protocols. For example, in the California newborn screening, Hispanic babies were more likely than non-Hispanic white babies to be diagnosed with CFTR-related metabolic syndrome (CRMS)33. CRMS is a positive newborn screening for CF but does not meet diagnostic criteria for CF with either an indeterminate sweat chloride concentration or less than 2 disease-causing CFTR genes. Many babies with CRMS go on to have a delayed diagnosis of CF34. Delay in diagnosis in Hispanic subjects in the West may explain the larger ethnic disparity in pulmonary function occurring in the West.
We could not account for environmental exposures in this study as they are not collected by the CFFPR, but air pollution and pesticide exposure may be contributing to the observed geographic differences in pulmonary function between ethnicities. Early life exposure to air pollution and pesticides negatively impact pulmonary function35–37. Hispanic children are more likely than non-Hispanic white children to be exposed to air pollution12 and to pesticides38. Furthermore, air pollution and pesticide exposure are not uniform across all areas of the United States39.
We recognize several limitations of our study. First, subjects could have been misclassified as Hispanic or non-Hispanic white, which would underestimate the association of ethnicity with pulmonary function. This is unlikely to have been a significant factor given that in the CFFPR, less than 2% of race and ethnicity have been found to be inaccurate40. Second, dividing the U.S. into Census regions is a crude measure that doesn’t fully account for differences in Hispanic patients with CF by genetic background or environmental exposures. It is interesting that despite using a crude measure, significant differences between geographic regions were found. Although we were not able to demonstrate causality, factors known to be associated with more severe pulmonary function, such as Pseudomonas aeruginosa and government insurance, were also higher in Hispanic subjects, especially in the West.
In conclusion, we found that Hispanic subjects have lower pulmonary function than non-Hispanic white subjects in all geographic regions. However, the most striking difference in pulmonary function between ethnicities occurred in the West. Factors influencing pulmonary function vary by both ethnicity and geographic region with the greatest differences occurring in the West, similar to the differences in pulmonary function. There is an urgent need to identify modifiable factors contributing to severe disease in Hispanic subjects with CF to guide CF treatment and reduce ethnicity gaps in CF mortality.
Acknowledgements
MEM takes responsibility for the content of the manuscript, including the data and analysis.
Financial disclosures: MEM is supported by the NHLBI (1K23HL133437–01A1) and Cystic Fibrosis Foundation Therapeutics (MCGARR16A0). JMN is supported by the NIH (KL2 TR001870). DWN is supported by the NIDDK (P30 DK072517). NPL is supported by Vertex Pharmaceuticals (VX-7029098), Cystic Fibrosis Foundation (LY18Y0, CC029–18), NHLBI (UG1HL139106, U10HL109146 – 01), National Science Foundation (IIP-1622950).
The authors would like to thank the Cystic Fibrosis Foundation for the use of the CF Foundation Patient Registry data to conduct this study. Additionally, we would like to thank the patients, care providers, and care coordinators at CF centers throughout the United States for their contributions to the CF Foundation Patient Registry.
Footnotes
No conflicts of interest for MEM, JMN, DWN, and NPL.
Data previously presented at the North American Cystic Fibrosis Conference in November 2017 in Indianapolis, Indiana.
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