Changing Epidemiology of Pediatric Pulmonary Exacerbations in Cystic Fibrosis

Abstract

Rationale:

The introduction of elexacaftor/tezacaftor/ivacaftor (ETI), a highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, to younger ages and the COVID-19 pandemic have significantly reduced pulmonary exacerbations requiring hospitalization among children with CF.

Objective:

To assess demographic and clinical characteristics of children and young adults with CF hospitalized for pulmonary exacerbations before and after pediatric ETI approval.

Methods:

A retrospective chart review was conducted at five United States CF Foundation-accredited care centers. Hospitalization data from children and young adults with CF in 2018 and 2022 were analyzed.

Results:

Hospitalizations decreased from 471 cases (241 individuals) in 2018 to 163 cases (110 individuals) in 2022. The racial distribution shifted, with more hospitalized patients identifying as people of color in 2022 (28% vs. 14%; p = 0.018). A greater proportion of hospitalized children in 2022 had two non-F508del mutations compared with children hospitalized in 2018 (38% vs. 19%) and were less likely to be infected with methicillin-resistant Staphylococcus aureus (MRSA). Comparing 2022–2018, children on CFTR modulator therapy, including ETI (76%), showed reduced infections with Pseudomonas aeruginosa and Achromobacter xylosoxidans.

Conclusions:

The decline in hospitalizations for pulmonary exacerbations likely reflects the benefits of ETI therapy, as a higher proportion of children and young adults hospitalized in 2022 had two non-F508del mutations and were not eligible for ETI. A greater percentage of those hospitalized in 2022 identified as belonging to minority racial groups, highlighting ongoing health disparities in the ETI era. Additionally, there were notable changes in the microbiological characteristics between 2018 and 2022.

1 |. Introduction

Pulmonary exacerbations have been critical events in the lives of people with cystic fibrosis (pwCF), often resulting in hospitalizations and intravenous (IV) antibiotics. Historically, these exacerbations were associated with long-term declines in lung health, quality of life, and life expectancy among pwCF [1, 2]. Starting in 2020, a remarkable decrease in the number of pulmonary exacerbations was observed and has been sustained [3]. Three notable factors likely contributed to this decline in exacerbations. One was the coronavirus disease 2019 (COVID-19) pandemic with greater attention to preventive measures and associated decreased exposure to viruses [4]. Another was the approval and uptake of elexacaftor/tezacaftor/ivacaftor (ETI), a highly effective CF transmembrane conductance regulator (CFTR) modulator therapy, which has been shown to dramatically decrease the frequency of pulmonary exacerbations in those treated with this therapy [5–9]. Third, changes in CF care delivery post-COVID-19, including a shift from in-person to telehealth encounters, a decline in the average number of care encounters per individual, and a reduction in the frequency of lung function testing and respiratory cultures [3], may also partially explain exacerbation rate differences.

Most of what is known about the epidemiology of pulmonary exacerbations is based upon physician-diagnosed and treated events that are reported to registries in different countries including the United States CF Foundation Patient Registry (CFFPR). According to CFFPR data, 22% of children with CF less than 18 years of age were treated with IV antibiotics for pulmonary exacerbations in 2019 [3]. The major risk factors for a significant exacerbation treated with IV antibiotics included increasing age, lower lung function, infection with Pseudomonas aeruginosa, lower socioeconomic status, and a history of prior exacerbations [10–13]. Viral infections were also commonly involved as a trigger of pulmonary exacerbations in children [14].

Since the “protective” effect of the pandemic was theoretically the same for all pwCF, the effect of ETI therapy would affect only those who were started on the therapy. We hypothesized that the latter would be reflected by differences in the demographics and genetic make-up of the hospitalized patients between the two time periods. A better understanding of the factors that are associated with pediatric pulmonary exacerbations will hopefully lead to more targeted strategies to prevent exacerbations in those at increased risk. Some of the results of this study have been previously reported in the form of abstracts [15, 16].

2 |. Methods

2.1 |. Study Population and Design

Retrospective review of all children and young adults with CF (ages 0 to 25 years) who were hospitalized and treated with IV antibiotics for clinician-diagnosed pulmonary exacerbations over two 12-month time periods in 2018 and 2022 at five CFF-accredited pediatric CF Centers (Children’s Hospital Colorado, Children’s National Hospital, Rady Children’s Hospital, Children’s Hospital of Orange County, Seattle Children’s Hospital). Data collected from the CFFPR included demographics (age, sex, race, ethnicity, insurance, and CFTR genotype), home medications including use of CFTR modulator therapies, growth measurements, and lung function. The number of days of hospitalization, microbiology data (respiratory sample type, CF bacterial pathogens, viral testing), antibiotic treatment (IV, oral, and inhaled), and systemic steroid treatment were captured from chart reviews.

Race and ethnicity were stratified by four self-reported racial groups and one ethnic group as defined by the US Census Bureau and entered by our CF Centers: non-Hispanic White, Black/African American, Asian, an “Other” category comprised of American Indian or Alaska Native, Native Hawaiian or Pacific Islander, and Other/Mixed Race, and Hispanic/Latino. We captured treatment with the CFTR modulators ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor among children hospitalized in 2018, and treatment with any of these modulators or with ETI among children hospitalized in 2022. Percent predicted forced expiratory volume in 1 s (ppFEV₁) values calculated using Global Lung Initiative equations [17] are reported from children who were able to perform spirometry. We captured the following lung function data: average in-clinic ppFEV₁ (up to 6 out of hospital visits) obtained in the 6 months before admission (baseline ppFEV₁), ppFEV₁ at the time of admission ±3 days (admission ppFEV₁), and the ppFEV₁ measurement nearest to or within 30 days of discharge (discharge ppFEV₁).

Clinical data from children with multiple admissions in 2018 or 2022 were recorded as individual events, but fixed demographic data were reported once per individual. Due to the retrospective nature of this study, treatments of pulmonary exacerbations including antibiotics were not standardized across participating sites. Data integrity was ensured by storing de-identified data in the Research Electronic Data Capture system (REDCap). Human ethics committees and local institutional review boards (IRB) at all five participating sites approved the study before data collection. This research was classified as exempt from IRB review by the Colorado Multiple IRB (COMIRB #22–2208) and other IRBs because it was deemed secondary research for which informed consent is not required. Data sharing agreements were executed between all participating institutions and Children’s Hospital Colorado.

2.2 |. Statistical Analyses

Cohort demographics and clinical characteristics were described using either counts and percentages for categorical variables and means and standard deviations (SD) or medians and interquartile ranges (IQR) for continuous variables. Pearson’s chi-squared tests or Fisher’s exact tests were used for comparisons of categorical data. Two-sample t-tests or Wilcoxon rank sum tests were used for comparisons of continuous variables. Distributions of all continuous variables were visually assessed for normality. Statistical significance was defined as a two-sided p ≤ 0.05 without correction for multiple comparisons. All analyses were performed with R version 4.4.2 (R Foundation for Statistical Computing) using the gtsummary package [18].

3 |. Results

3.1 |. Demographics and Clinical Characteristics

Across the five sites, the total number of hospitalizations for pulmonary exacerbations decreased from 471 in 2018 to 163 in 2022 (Figure 1). It is important to note that the number of children followed at our sites and reported to the CFFPR declined from 892 in 2018 to 799 in 2022, representing a 10% decrease. A greater proportion of children and young adults with CF had multiple (≥2) hospitalizations for pulmonary exacerbations within a single year in 2018 compared to 2022 (45.2% vs. 24.5%, p < 0.001) (Figure 1). The demographic and clinical characteristics of those hospitalized in 2018 and 2022 are summarized in Table 1. Children hospitalized in 2022 were younger compared to those hospitalized in 2018 (p = 0.004). The racial distributions of those hospitalized across the 2 years were significantly different (p = 0.018). Notably, a higher proportion of those hospitalized in 2022 identified as Black or as other races compared with those hospitalized in 2018 (28% vs. 14%). A similar proportion hospitalized in 2022 identified as Hispanic/Latino compared to those hospitalized in 2018 (41% vs. 30%, p = 0.093). Hospitalized children who were Black, Hispanic, or other race were less frequently treated with any CFTR modulator therapy in 2018 and 2022 compared to non-Hispanic Whites (p < 0.001 in 2018, p < 0.05 in 2022, Supporting Information S1: Table 1). There were no differences in the proportions of hospitalized children with CF using ETI by race in 2022 (p = 0.5, Supporting Information S1: Table 1). Children hospitalized in 2022 more frequently had two non-F508del CFTR mutations compared to those hospitalized in 2018 (38% vs. 19%, p < 0.001) (Table 1). The distributions of CFTR genotypes differed by race and ethnicity in 2018 (p < 0.001), with Black and Hispanic children with CF more frequently having two non-F508del mutations compared to non-Hispanic White children (Supporting Information S1: Table 2). Distributions of CFTR genotypes did not differ by race and ethnicity in 2022 (p = 0.2) (Supporting Information S1: Table 2). A similar proportion of hospitalized children in 2022 were on a CFTR modulator therapy, including 35% on ETI therapy, than in 2018 (46% vs. 38%, p = 0.071) (Table 1). There were no differences in the proportions of hospitalized children treated with chronic azithromycin and inhaled antibiotics in 2018 and 2022. The length of hospitalizations decreased from 2018 to 2022 (12 [IQR 8, 14] vs. 10 [8, 14] days, p = 0.041). The use of systemic corticosteroids during exacerbation treatment was similar between the 2 years.

FIGURE 1 |.

Total number of hospitalizations (a) and the proportion of children and young adults with CF with multiple (≥2) hospitalizations within a single year (b) in 2018 and 2022. [Color figure can be viewed at wileyonlinelibrary.com]

TABLE 1 |.

Demographic and clinical characteristics of children and young adults with CF who were hospitalized for treatment of pulmonary exacerbations in 2018 and 2022.

Characteristic		2018 (N = 471)	2022 (N = 163)
Sex, n (%)a	Female	131 (54%)	50 (45%)
Age distribution, n (%)	< 6 years	35 (7%)	32 (20%)
	≥ 6 to < 12 years	110 (24%)	34 (21%)
	≥ 12 to < 18 years	194 (41%)	66 (40%)
	≥ 18 years	131 (28%)	31 (19%)
Age, years	Mean (SD)	14.2 (5.1)	12.6 (6.3)
Race, n (%)a	White	207 (86%)	79 (72%)
	Black	11 (4.6%)	10 (8%)
	Asian	1 (0.4%)	2 (2%)
	Other	22 (9%)	19 (18%)
Ethnicity, n (%)a	Hispanic	72 (30%)	45 (41%)
Genotype, n (%)a	Homozygous F508del	110 (46%)	36 (33%)
	Heterozygous F508del	85 (35%)	32 (29%)
	No F508del	46 (19%)	42 (38%)
Insuranceb	Medicaid	233 (49%)	97 (60%)
	Medicare	24 (5%)	4 (2%)
	Private	154 (33%)	48 (29%)
	Tricare/Military	13 (3%)	1 (1%)
	Other/None	47 (10%)	13 (8%)
Chronic medications, n (%)	CFTR modulator	180 (38%)	75 (46%)
	Azithromycin	239 (51%)	70 (44%)
	Inhaled antibiotics	234 (50%)	80 (55%)
ppFEV1 mean (SD)c	Baseline	72 (22)	75 (21)
	Admission	67 (22)	68 (22)
	Discharge	79 (24)	82 (22)
Length of hospitalization	Median, [IQR]	12 [8, 14]	10 [8, 14]
Systemic corticosteroid use during hospitalization	n (%)	139 (30%)	43 (27%)

^aFor individuals with multiple admissions each year, fixed demographic data were only counted once in 2018 (n = 241) and 2022 (n = 110);

^bMedicaid category inclusive of other state-based programs (e.g., CHP+). Medicare category inclusive of other state-based programs (e.g., CHP+, Indian Health Service). Private insurance includes those with or without back-up federal or state-funded programs;

^cppFEV₁ was calculated using 2012 Global Lung Initiative equations.

3.2 |. Microbiologic Characteristics

There were no differences in the proportions of sample types obtained for respiratory cultures at the time of admission in 2018 and 2022 (Table 2). Spontaneously expectorated sputum was the most common sample type, representing over 60% of samples, in both years. Among the 57 children hospitalized in 2022 on ETI therapy, 35 (69%) provided a spontaneously expectorated sputum for respiratory culture at the time of admission. The most common bacteria identified were methicillin-susceptible Staphylococcus aureus (MSSA) and P. aeruginosa (Table 2). A lower proportion of children hospitalized in 2022 were infected with methicillin-resistant S. aureus (MRSA) compared to those hospitalized in 2018 (4.5% vs. 14%, p = 0.001). There were no statistical differences in the proportions of those hospitalized who were infected with any other CF bacterial pathogen in 2018 and 2022. A greater proportion of children hospitalized for pulmonary exacerbations did not have any CF bacterial pathogens cultured from respiratory samples in 2022 compared to those hospitalized in 2018 (34% vs. 23%, p = 0.015). Children with CF on CFTR modulator therapy in 2018 were more commonly infected with MRSA, Achromobacter xylosoxidans, and Burkholderia cepacia complex and less commonly infected with non-mucoid and mucoid P. aeruginosa compared to those not on modulator therapy (Supporting Information S1: Table 3). In 2022, children on CFTR modulator therapy (76% on ETI therapy) were less commonly infected with non-mucoid and mucoid P. aeruginosa and A. xylosoxidans compared to those not on modulator therapy (Supporting Information S1: Table 3). Detection of Aspergillus fumigatus, other fungal species, and nontuberculous mycobacterial species was similar in children with CF hospitalized in 2018 and 2022 (Table 2). Viral testing was performed more frequently in children hospitalized for pulmonary exacerbations in 2022 than in 2018 (75% vs. 38%), and a higher proportion tested positive for viruses in 2022 (50% vs. 38%, p = 0.043) (Table 2).

TABLE 2 |.

Microbiologic characteristics of respiratory samples collected during hospitalizations from children and young adults with CF in 2018 and 2022.

Characteristic	2018 (N =471)	2022 (N =163)	p value
Number of respiratory cultures for CF pathogens performed at admission	460	154
Sample collected for respiratory culture, n (%)
Oropharyngeal swab	122 (27%)	51 (33%)	0.2
Expectorated sputum	312 (67%)	94 (61%)
Induced sputum	3 (1%)	3 (2%)
Bronchoalveolar lavage	23 (5%)	6 (4%)
CF respiratory culture results at admission, n (%)
No CF bacterial pathogens detected	108 (23%)	53 (34%)	0.015
Methicillin sensitive Staphylococcus aureus	192 (42%)	69 (45%)	0.7
Methicillin resistant S. aureus	64 (14%)	7 (4.5%)	0.001
Non-mucoid Pseudomonas aeruginosa	116 (25%)	35 (23%)	0.4
Mucoid P. aeruginosa	101 (22%)	46 (30%)	0.077
Stenotrophomonas maltophilia	47 (10%)	17 (11%)	0.9
Achromobacter xylosoxidans	39 (8.5%)	9 (6%)	0.3
Haemophilus influenzae	18 (4%)	6 (4%)	> 0.9
Burkholderia cepacia complex	22 (5%)	3 (2%)	0.11
Aspergillus fumigatusa	55 (21%)	17 (23%)	0.8
Any fungal speciesa	161 (62%)	47 (63%)	> 0.9
Nontuberculous mycobacteriab	15 (10%)	4 (8.5%)	> 0.9
Viral testing performed, Yes, n (%)	178 (38%)	122 (75%)
Positive viral results, n (%)	68 (38%)	61 (50%)	0.043
Influenza A or B	14 (8%)	7 (6%)	0.5
Respiratory Syncytial Virus	5 (3%)	4 (3%)	> 0.9
SARS CoV-2	N/A	16 (13%)	N/A
Rhinovirus/enterovirus	41 (23%)	21 (17%)	0.2

^aIn 2018, 259 samples were submitted for fungal testing. In 2022, 75 samples were submitted for fungal testing;

^bInclusive of Mycobacterium abscessus species, M. avium complex species, and other mycobacteria species. In 2018, 145 samples were submitted for mycobacteria testing. In 2022, 47 samples were submitted for mycobacteria testing.

3.3 |. Change in Lung Function With Inpatient Treatment

The results of pulmonary function testing are displayed in Table 1 and Figure 2. There were no differences in baseline, admission, and discharge ppFEV₁ between those hospitalized in 2018 and 2022. Mean improvement in ppFEV₁ during inpatient treatment did not differ between 2018 (13 ± 12) and 2022 (15 ± 14, p = 0.2). There were no differences in the proportions of individuals whose discharge ppFEV₁ returned to ≥ 90% and ≥ 100% baseline ppFEV₁ in 2018 and 2022 (Supporting Information S1: Figure 1). Among those hospitalized in 2022, mean improvement in ppFEV₁ did not differ between those on ETI therapy (17 ± 16) compared to those not on ETI (13 ± 12, p = 0.2).

FIGURE 2 |.

Box-plots showing median and interquartile range of FEV1 percent predicted at baseline, admission, and discharge among children and young adults with CF hospitalized for pulmonary exacerbations who performed spirometry in 2018 and 2022. [Color figure can be viewed at wileyonlinelibrary.com]

4 |. Discussion

Our multicenter study reveals changing demographic and clinical profiles among children and young adults with CF in the United States who are being hospitalized for pulmonary exacerbations. Recognizing that the number of individuals followed at our five pediatric CF Centers and reported to the CFFPR declined by 10% from 2018 to 2022, we observed a 65% decrease in the number of hospitalizations from 2018 to 2022 and the proportion of children experiencing multiple exacerbations requiring hospitalization in the same year decreased from almost one-half to approximately one-fourth. This change mirrors the decline in pulmonary exacerbations seen across the US CF Care Center network following the widespread availability of ETI therapy and the COVID-19 pandemic [3].

Since most children experiencing pulmonary exacerbations are treated on an outpatient basis with oral antibiotics [19], we acknowledge that we are reporting on a minority of exacerbations diagnosed and treated at our pediatric CF Centers. We also recognize that some of the differences in event rates between 2018 and 2022 may have resulted from shifts in care standards for exacerbation treatment from inpatient to outpatient management and that reductions in the number of hospitalizations may not equate to a reduction in the number of diagnosed exacerbations.

Compared to children hospitalized in 2018, those hospitalized in 2022 more frequently identified as people of color, or as Hispanic/Latino and more frequently had two non-F508del CFTR mutations. It is not surprising that children with CF hospitalized for pulmonary exacerbations more frequently have two non-F508del CFTR mutations. These individuals are less likely to qualify for ETI therapy, which has been shown to significantly reduce pulmonary exacerbations [5–9]. Our finding that hospitalized children with CF who identify as Black, Other race, or Hispanic were less frequently treated with any CFTR modulator therapy in 2018 and 2022 is consistent with previous studies demonstrating that pwCF from minoritized groups are less likely to be eligible for CFTR modulators including ETI [20], and are less likely to be prescribed ETI compared to non-Hispanic White pwCF [21]. The shifting racial distributions in which a higher proportion of those hospitalized in 2022 identified as Black or as other races represents another health disparity among minoritized populations with CF in the era of ETI therapy. Also, there may be racial/ethnic disparities increasing the risk of acquiring viral upper respiratory tract infections [22]. Because viral respiratory infections are triggers for pulmonary exacerbations in CF, this may further contribute to racial and ethnic disparities in pulmonary exacerbations in children with CF. The shift in demographics among hospitalized children may also reflect the increasing diversity of the US CF population [3], as over 17% percent of pwCF identified as either Hispanic, Black, multiracial, Asian or as other than White in 2023. Our analysis did not account for probable changing demographics (e.g., shifts in racial and ethnic distributions) among the children followed at our sites between 2018 and 2022.

A lower proportion of hospitalized children in 2022 were infected with MRSA than in 2018. The decreased MRSA rates in our hospitalized children are concurrent with decreased rates of MRSA hospital-acquired and community-associated infections nationally in the general population [23]. Other explanations for the decrease in MRSA infections include the implementation of comprehensive infection control and prevention measures during the COVID-19 pandemic [24], and a decline in the number of in-person visits to CF clinics during the pandemic [25]. This observation is also consistent with results from a single center study reporting reductions in MRSA culture-positivity after starting ETI [26], even though many of the hospitalized children in our study did not qualify for ETI therapy.

In 2022, children with CF hospitalized for pulmonary exacerbations being treated with CFTR modulator therapy, most of whom were on ETI therapy, were less commonly infected with non-mucoid and mucoid P. aeruginosa and A. xylosoxidans compared to those not on modulator therapy. This finding is consistent with recent observations that ETI use in adolescents and adults with CF led to decreased P. aeruginosa and S. maltophilia prevalence during the first month of ETI which remained relatively stable through 3.5 years of therapy [27, 28]. Reductions in mean sputum densities of S. aureus, P. aeruginosa, S. maltophilia, and Burkholderia spp. were also observed over 3.5 years of ETI therapy in individuals with sputum cultures positive for these pathogens pre-ETI therapy [27, 28]. While ETI therapy has led to decreased sputum expectoration in pwCF [29], spontaneously expectorated sputum remained the most common sample type collected from children with CF hospitalized for pulmonary exacerbations in 2022, and was collected at a frequency similar to 2018 when ETI was not available for clinical use. Granted, we are not able to ascertain the quality of sputum samples submitted for respiratory culture in these hospitalized individuals and cannot be certain that a decline in the quality of sputum samples in 2022 might have contributed to observed differences in infection rates between 2018 and 2022. Regardless, our findings suggest that sputum may continue to be available as a respiratory sample to potentially identify pathogens during severe pulmonary exacerbations, especially in children with CF not being treated with ETI therapy.

Another noteworthy finding is that viral testing was performed in three-quarters of admissions in 2022 compared with approximately one-third of admissions in 2018. This is likely because of the widespread availability of SARS-CoV-2 and multiplex viral PCR testing, coupled with aggressive infection control measures and enhanced use of personal protective equipment in those with positive viral test results. The results that a higher proportion of children had more frequent positive viral test results in 2022 compared to those hospitalized in 2018 could be due to more frequent testing among our five sites. The differences appear driven by positive results for SARS CoV-2 since the proportions of non-SARS CoV-2 viral infections were similar in 2018 and 2022. Published data from the STOP2 trial in adults with CF, performed before the COVID-19 pandemic, examined the role that viruses play in pulmonary exacerbations in adults with CF, noting that the rate of virus identification was higher in those receiving CFTR modulators [30]. It is possible that viral-induced airway inflammation, even with improvement from CFTR modulator therapy, could lead to more severe symptoms including sputum production that drive hospitalization decisions.

The length of hospitalizations decreased by 2 days from 2018 to 2022. The shorter duration may have been influenced by recent data from a multicenter, randomized controlled trial in adults (not children) with CF demonstrating that among early treatment responders, 10 days of IV antibiotics is not inferior to 14 days [31]. Despite the shorter duration of inpatient treatment of pulmonary exacerbations in 2022, lung function improvement in children with CF was comparable in both years as evidenced by similar proportions of individuals with discharge ppFEV₁ who returned to ≥90% and ≥100% baseline ppFEV₁ in 2018 and 2022. Interestingly, the proportion of patients with CF hospitalized for pulmonary exacerbations who returned to ≥90% and ≥100% baseline ppFEV₁ among our five sites was similar to or higher than those previously reported [32, 33]. The rate of systemic corticosteroid use during hospitalizations was similar across both years, though recent studies questioning the utility of corticosteroids in the management of pulmonary exacerbations in children and adults with CF may alter this practice in the future [34–36].

An important implication of healthier children with CF being hospitalized less frequently is that trainees at all levels (medical students, pediatric residents, pediatric fellows, junior faculty) will have less exposure to and less experience taking care of children with CF in the hospital. This has the potential to contribute to an educational gap, rendering future pediatric professionals less knowledgeable about managing acute pulmonary exacerbations and CF-related complications. Taking care of children with CF in the hospital historically fostered interest in careers in pediatric pulmonary medicine. Pediatric CF programs will need to adapt training models to ensure that trainees are being exposed to CF in the outpatient setting.

Our study has limitations. The main one being access to data from a limited number of centers and not from the entire US CF Care Center network. Another one is the lack of standardized management approaches across and within our sites. The purpose of this study was to determine the changing demographic and clinical profiles of children with CF being hospitalized for exacerbations in the era of ETI therapy, not to examine specific treatment practices associated with better treatment responses and clinical outcomes. We know that there is substantial variability in inpatient CF pulmonary exacerbation treatment and monitoring practices across CF centers [37]. We also did not assess medication adherence in these children. Poor medication adherence has been associated with more CF-related hospitalizations [38] and could contribute to the need for hospitalization in some children with CF. Through this retrospective chart review, we could not assess measures of mental and social health which may be associated with changing rates of hospitalization. Furthermore, we do not know whether public health interventions (e.g., remote learning, social distancing) in the regions of our five sites played a role in differences in hospitalizations between the 2 years. Lastly, these data were collected from children and young adults with CF, and may not be generalizable to the older adult CF population.

The main strength of our study is capturing hospitalization data from five accredited CF care centers from different geographic regions in the United States which allows for improved accuracy and generalizability in describing the pediatric CF population. Additionally, the availability of comprehensive demographic, clinical, and microbiologic data from rigorous on-site chart review coupled with CFFPR data capture allows for a broad description of key factors associated with current hospitalizations for pulmonary exacerbations in children with CF.

This study reveals the changing demographic and clinical profiles of children with CF hospitalized for pulmonary exacerbations in the era of ETI therapy. Most notably, children with CF from minoritized groups, who are less likely to be eligible for and treated with CFTR modulators including ETI, compose a greater proportion of children with CF hospitalized for IV antibiotic treatment of pulmonary exacerbations as fewer White children with CF are being hospitalized. We hope these results will prompt targeted efforts to monitor these at-risk children more closely on an outpatient basis and encourage development of novel treatment strategies to reduce severe pulmonary exacerbations and improve outcomes in children with CF who continue to be hospitalized despite advances in CFTR modulator therapy.

Data Availability Statement

The authors have nothing to report.