Abstract
Background
Cystic fibrosis (CF) is a multi-organ disorder in which respiratory complications account for the majority of its cause of mortality. This study aimed to investigate the factors associated with pulmonary hypertension (PH) in pediatric patients with CF and acute pulmonary exacerbations (PEx).
Methods
This is a prospective cross-sectional study that enrolled children with CF who were hospitalized with PEx in a university hospital between 2020 and 2022. All patients underwent echocardiography, and their pulmonary artery pressure (PAP) was measured. They were then divided into two groups based on the presence or absence of PH. Clinical symptoms, spirometry, six-minute walk tests, laboratory findings, chest radiography, and other clinical parameters were compared in these two groups. The restricted cubic spline was plotted for variables with nonlinear associations with PH.
Result
A total of 107 pediatric patients were included in this study. The prevalence of PH in the studied population was 24.3%. Group 1 consisted of 81 patients with normal PAP values (PAP < 25 mmHg), and group 2 included 26 patients with increased levels of PAP (PAP ≥ 25 mmHg). Group 2 had significantly higher median age, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) levels, as well as a greater frequency of major chest X-ray abnormalities and NIV use compared to group 1. Univariate logistic regression demonstrated that older age (OR 1.191, 95% CI 1.052–1.348, p = 0.006), elevated CRP (OR 1.027, 95% CI 1.009–1.046, p = 0.004), ESR ≥ 21 mm/hr (OR: 3.567, 95% CI: 1.350–9.427, p = 0.010), lower lymphocyte counts (OR 0.972, 95% CI 0.946–0.999, p = 0.044), and NIV requirement (OR 3.055, 95% CI 1.230–7.586, p = 0.016) were significantly associated with an increased likelihood of PH. In multivariate analyses adjusted for confounders, older age (OR 1.176, 95% CI 1.035–1.337, p = 0.013), elevated CRP (OR 1.024, 95% CI 1.004–1.044, p = 0.020), ESR ≥ 21 mm/hr (OR: 1.149, 95% CI: 1.008–1.310, p = 0.037), and NIV requirement (OR 2.860, 95% CI 1.102–7.422, p = 0.031) remained independently associated with having PH.
Conclusion
In patients with CF and PEx, factors that suggest the possibility of concurrent PH include older age, infiltration or bronchiectasis on chest X-ray, NIV requirements, and elevated inflammatory markers.
Keywords: Cystic fibrosis, Pulmonary hypertension, Acute pulmonary exacerbation, Pulmonary artery pressure, Inflammation
Introduction
Cystic fibrosis (CF) is a multi-organ genetic disorder. Patients with CF may exhibit a range of symptoms, including bronchiectasis, nasal polyps, sinus inflammation, diabetes mellitus, and infertility [1]. Advancements in its treatment have significantly improved life expectancy for individuals with CF; however, pulmonary complications remain a major cause of morbidity and mortality [2]. Acute pulmonary exacerbations (PEx), marked by a worsening of respiratory symptoms and lung function, are common complications that can significantly impact a patient's quality of life and accelerate disease progression [3]. A less understood, potentially severe complication in this vulnerable population is the development of pulmonary hypertension (PH) [4]. Elevated pulmonary arterial pressure (PAP)levels as PH indicator were reported to be associated with decreased survival in a population with CF. Moreover, subclinical PH can negatively impact mortality rates, general quality of life, shortness of breath, and exercise capabilities [5].
The PH that develops in patients with CF is classified within Group 3 of the PH classification, which is PH due to lung disease/hypoxia [6]. The proposed pathophysiology for the development of PH in CF is as follows: Lung destruction leads to V/Q mismatch and right-to-left shunt, resulting in hypoxia. This hypoxia causes vasoconstriction [7]. Additionally, hypoxia leads to intimal proliferation and muscularization of the pulmonary arteries, consequently increasing PAP and causing PH [8]. Literature also indicates that pulmonary vascular abnormalities in CF may stem from dysfunctional CF-transmembrane regulator (CFTR) in the endothelium [9]. The prevalence of PH in CF varies across different studies. It depends on several factors, including patient age and the method used to measure PAP (echocardiography or right heart catheterization). Various studies have investigated the prevalence of PH and factors affecting its development in patients with severe pulmonary disease, often in adolescents and adults. PH was identified to be strongly associated with hypoxemia [10]. A decline in respiratory indicators during pulmonary function tests, along with chronic airway infections and microbial elements, was found to be linked to PH occurrence [11–13]. Inflammatory markers have also been described as correlates of pulmonary vascular remodeling in CF [14]. Chronic PH gradually arises due to ongoing structural lung damage, long-term hypoxemia, and pulmonary vascular remodeling and is usually persistent. However, acute PH can occur transiently during exacerbations as a result of acute worsening of hypoxia, systemic inflammation, and endothelial dysfunction associated with infection [15]. This form of PH can improve or even resolve completely following treatment for the exacerbation, indicating that not all PH conditions in CF represent permanent vascular disease. As a result, acute PH during flare-ups can be effectively managed if accurately diagnosed. According to the increased risk of mortality in pediatric patients with CF who experience acute respiratory failure due to PEx [16], exploring the factors associated with PH can serve as a hint for physicians to identify and manage at-risk patients. Therefore, this article was designed to investigate the prevalence and correlates of pulmonary hypertension in children with CF during hospitalization for PEx, shedding light on the intricate interplay of factors that drive this critical cardiovascular complication within the context of acute respiratory decline.
Method
This was a prospective cross-sectional study that consecutively enrolled all pediatric patients suffering from CF aged 6 to 17 who were hospitalized at Children's Medical Center, a university hospital, for PEx based on the specified criteria defined by Rosenfeld et al. [17] between 2020 and 2022. Patients with PH diagnosed on their most recent outpatient echocardiography, as well as those receiving chronic noninvasive ventilation (NIV), were excluded. Only patients who had undergone an echocardiogram within the preceding 12 months and demonstrated no evidence of PH were eligible for this study. Children who were unable to perform spirometry or the 6-min walk test (6MWT) and those whose parents or legal guardians did not provide informed consent were also excluded.
All eligible children with CF who experienced PEx during the study period were enrolled, yielding 107 participants. All patients included in the study were admitted to the hospital due to PEx, which, by definition, indicated a severity level of at least moderate-to-severe; none of the individuals experienced only mild exacerbations. Although CFTR modulator therapies were unavailable to these patients, other CF medications, such as inhaled hypertonic saline, dornase alfa, and inhaled tobramycin, were available and routinely used in the studied population. Using G*Power 3.1.9.2 (Universität Düsseldorf, Germany) with 'α' value of 0.05 and study power of 0.95 [18], the estimated total sample size was 112, which was aligned closely with the 107 patients enrolled in the study. The study was reviewed and approved by the Research Ethics Committee of Tehran University of Medical Sciences. All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki Declaration and its later amendments. Written informed consent to participate was obtained from the parents or legal guardians of all participants under the age of 16. For participants aged 16 years and older, written informed consent was obtained directly from each participant. No waiver of consent was applied.
Spirometry and 6MWT were performed according to the American Thoracic Society (ATS) guidelines [19, 20]. Spirometry was performed using a KOKO spirometer, and forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured as percent predicted values. The FEV1/FVC ratio was calculated as the measured FEV1 divided by the measured FVC, expressed as a proportion. FEV1 and FVC Z-scores, as well as Z-scores for the FEV1/FVC ratio, were calculated using the Global Lung Function Initiative (GLI) reference equations [21]. All spirometry testing was conducted under close supervision by trained personnel, in accordance with standard pediatric protocols. For the 6MWT, patients were asked to walk back and forth in a hallway for six minutes, and parameters such as oxygen saturation (SpO2) and heart rate (HR) were recorded before and after the walk, along with the total distance walked.
All enrolled patients underwent color Doppler echocardiography using a Philips E33 echocardiography machine to assess for congenital heart disease (CHD), left ventricular ejection fraction (EF), and PAP, according to the American Society of Echocardiography guidelines [22–25]. PAP was evaluated non-invasively by echocardiography through measurement of the tricuspid regurgitant jet velocity (TRV) with continuous-wave Doppler. Using the modified Bernoulli equation (ΔP = 4 × TRV2), the pressure gradient across the tricuspid valve was calculated, and the estimated Right Atrial Pressure (RAP) was incorporated based on the diameter and inspiratory collapsibility of the inferior vena cava (IVC). Hence, the formula applied to estimate systolic PAP was: 4 × (TRV)2 + RAP [26]. Patients with a mean PAP ≥25 mmHg were considered to have PH, and those with a PAP ≥ 35 mmHg were considered to have severe PH. Echocardiography was performed before initiating NIV in those who required it.
Patients were divided into two groups based on having PH. Those with normal PAP were classified as group 1 (patients without PH), and those with increased PAP, as noted above, were classified as group 2 (patients with PH). All clinical parameters and laboratory data were compared between the two groups.
Clinical findings, including age, cough, malaise, fever, decreased appetite, and increased sputum production, were recorded. Lab data, including white blood cell count (WBC), lymphocyte count, neutrophil count, hemoglobin level, platelet count, calcium level, phosphorus level, C-reactive protein (CRP) level, blood culture, sputum culture, and erythrocyte sedimentation rate (ESR), were also measured and recorded. All laboratory analyses were performed on the first blood sample collected at hospital admission. Since CT scans expose children to radiation, we performed chest X-rays (CXR) on all children. A board-certified pediatric radiologist evaluated chest X-rays. To minimize bias, the radiologist was blinded to the patients’ clinical status, including PH group assignment. Radiographic findings were systematically examined and classified based on predefined criteria, which included:
Bronchiectasis
Presence of dilated bronchi with or without wall thickening, visualizing as ring-like or tram-track opacities.
Alveolar consolidation
Homogeneous opacities with loss of lung volume, suggesting alveolar filling processes.
Hyperinflation
Elevated lung volumes with flattened diaphragms, indicative of air trapping.
Atelectasis
Partial or complete collapse of lung segments or lobes, leading to volume loss.
Lobar collapse
Complete collapse of a lobe, often correlated with bronchial obstruction.
Pneumothorax
Presence of air in the pleural space, considered as a lucent area without lung markings.
Ground-glass opacity
Hazy elevated lung opacity with preserved bronchovascular markings, suggesting partial filling of air spaces.
Interstitial or reticular changes
Fine linear or net-like opacities, reflecting interstitial lung disease.
These findings were recorded for each patient. The need for NIV, intensive care unit (ICU) admission, and intubation during hospitalization was documented. All patients underwent follow-up echocardiography after recovery from PEx.
Statistical analysis
Descriptive statistics, including means and standard deviations (SD) or medians and quartiles (Q1, Q3), were calculated for continuous variables. Categorical variables were summarized as frequencies and percentages. Patients were divided into two groups based on their PAP levels. Group 1 had normal PAP levels (PAP < 25 mmHg), and group 2 had elevated PAP levels (PAP ≥ 25 mmHg). Comparisons between patients in these two groups were conducted using appropriate statistical tests. The normality of continuous variables was assessed using the Shapiro–Wilk test and graphical methods (e.g., Q–Q plots and histograms). For variables that met the normality assumption, parametric tests, such as independent-samples t-tests, were used to compare means between two groups. For variables that did not meet the normality assumption, the non-parametric equivalent, the Mann–Whitney U test, was applied. For categorical variables, chi-square tests or Fisher’s exact tests were used to evaluate differences in proportions between groups. Paired sample t-tests were utilized to assess changes in SpO2 and heart rate before and after 6MWT within each group. Additionally, the mean differences in these changes between the two groups were compared using independent-samples t-tests or their nonparametric equivalents, where appropriate. ESR and CRP were categorized based on the population median levels (21 mm/hr and 12 mg/dL, respectively) into two groups. Univariate logistic regression analyses were performed to investigate the association between having elevated PAP levels and potential factors, including age (years), sex (reference: male), WBC (× 103/μL), lymphocytes (%), neutrophils (%), hemoglobin (g/dL), platelets (× 103/μL), ESR (mm/hr), CRP (mg/dL), FEV1 (% predicted) and Z-score, FVC (% predicted) and Z-score, FEV1/FVC ratio (% predicted) and Z-score, ICU admission (reference: no ICU requirement), intubation performed (reference: no intubation requirement), and NIV usage (reference: no NIV requirement). Multivariable logistic regression analyses were performed, adjusting for age, sex, and FEV1. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. For variables in the multivariate logistic model, the 95% CI was represented as a horizontal line, with the OR shown as a colored dot on the line in Fig. 1. The ORs were plotted on a logarithmic scale, with an OR = 1 reference line. To explore nonlinear associations between continuous variables and PH, a restricted cubic spline (RCS) was plotted. RCS was constructed with three knots, and the median value of each variable was used as the reference. Nonlinearity was assessed using a likelihood ratio test comparing the spline model to a linear model. Figures were created using Python 3.11 with the following libraries: pandas, numpy, patsy, statsmodels, matplotlib, and scipy. A p-value < 0.05 was considered statistically significant. All analyses were conducted using Python 3.11 and Stata v18.0. A two-sided p-value of < 0.05 was considered statistically significant.
Fig. 1.
The odds ratios (ORs) and 95% confidence intervals (CIs) of variables in the multivariate logistic regression model adjusted for age, sex, and FEV1 (% predicted). After adjusting for confounding variables in multivariate analysis, older age (OR: 1.176, 95% CI: 1.035–1.337, p = 0.013), elevated CRP levels (OR: 1.024, 95% CI: 1.004–1.044, p = 0.020), CRP ≥ 12 mg/dL (OR 3.65, 95% CI: 1.26–10.52, p = 0.017), ESR ≥ 21 mm/hr (OR: 1.149, 95% CI: 1.008–1.310, p = 0.037), and NIV requirement (OR: 2.860, 95% CI: 1.102–7.422, p = 0.031) remained significantly associated with PH. CI: Confidence interval, OR: Odds ratio, CRP: C-reactive protein, NIV: Non-invasive ventilation, ESR: Erythrocyte sedimentation rate, FEV1: Forced expiratory volume in one second
Results
Characteristics of participants
There were 107 pediatric patients in this study. The median age of the patients was 9 years (Q1-Q3: 7.0,14.0). Sixty-one patients (57.0%) were female, and 46 patients (43.0%) were male. Eighty-one patients (75.7%) had normal PAP levels (PAP < 25 mmHg) and were labeled as group 1. Twenty-six patients (24.3%), marked as group 2, had high PAP as defined in the method section (mean PAP of 25 mmHg or higher). Of these patients, only one had severe PH (mean PAP > 35 mmHg). No patient had pulmonary hypertension on follow-up echocardiography after recovery from the acute PEx. A total of 53.1% of group 1 and 69.2% of group 2 were female. The gender distribution was not statistically significant between the two groups (p = 0.148). The median age of group 2 was 14 years, which was significantly higher than that of group 1, which was 9 years (p = 0.023). The median CRP value in group 2 was 26.5 mg/dL, which was significantly higher (p = 0.002) than in group 1 (7 mg/dL). The median ESR level was also significantly higher in group 2 (26 mm/hr) compared to group 1 (11 mm/hr) (p = 0.045). The lymphocyte percentage was 30% in group 2, which was lower compared to group 1 with 38% of lymphocyte percentage; although the difference was not significant (p = 0.076). Other quantitative laboratory markers, including WBC count, neutrophil percentage, hemoglobin level, platelet count, pH, HCO3- (bicarbonate), and partial pressure of carbon dioxide (pCO2), as well as pulmonary function test (FEV1(% predicted) and Z-score, FVC (% predicted) and Z-score, FEV1/FVC ratio (% predicted) and Z-score) and 6MWT parameters (distance, Spo2 and heart rate before and after test) did not show statistically significant differences between two groups (p > 0.05) (Table 1).
Table 1.
The characteristics of the studied population
| Total (n = 107) | Pulmonary artery pressure | p-value | |||
|---|---|---|---|---|---|
| Group 1 (PAP < 25 mmHg) (n = 81) | Group 2 (PAP ≥ 25 mmHg) (n = 26) | ||||
| Age (year) | 9.0 (7.0, 14.0) | 9.0 (7.0, 12.0) | 14.0 (7.0, 14.25) | 0.023 | |
| Female n (%) | 61 (57.0%) | 43 (53.1%) | 18 (69.2%) | 0.148 | |
| Laboratory findings | |||||
| WBC (× 103/μL) | 11.5 (8.98,16.47) | 11.3 (9.07,16.35) | 13.28 (7.98, 16.51) | 0.586 | |
| Lymphocytes (%) | 36.4 (20.0,47.2) | 38.0 (20.8,50.8) | 30.0 (19.32,39.77) | 0.076 | |
| Neutrophils (%) | 52.9 ± 18.60 | 52.4 ± 19.12 | 54.6 ± 17.12 | 0.616 | |
| Hemoglobin (g/dL) | 11.9 (10.4,13.0) | 11.8 (9.95, 13.15) | 12.1 (10.95,12.92) | 0.780 | |
| Platelets (× 103/μL) | 335.0 (247,456) | 334.0 (251.0,465.0) | 340.0 (225.2,433.0) | 0.603 | |
| ESR (mm/hr) | 21.0 (5.0,35.0) | 11.0 (5.0,34.0) | 26.0 (11.5,46.75) | 0.045 | |
| CRP (mg/dL) | 12.0 (2.0,37.0) | 7.0 (2.0,29.0) | 26.5 (11.75,55.75) | 0.004 | |
| Blood acidosis (pH) | 7.38 (7.30,7.40) | 7.38 (7.30, 7.40) | 7.38 (7.30,7.40) | 0.877 | |
| pCO2 (mmHg) | 40.3 (34.1,45.4) | 40.2 (33.6, 45.8) | 40.7 (35.2,46.2) | 0.343 | |
| HCO3- (mmol/L) | 23.0 (20.9,27.0) | 23.2 (20.4,26.8) | 22.9 (21.1,28.1) | 0.856 | |
| Spirometry parameters | |||||
| FEV1 | % predicted | 76.8 ± 22.30 | 77.2 ± 23.20 | 75.9 ± 19.60 | 0.797 |
| Z-score# | −1.64 (−2.71, −0.41) | −1.64 (−2.71, −0.35) | −1.64 (−2.91, −0.82) | 0.589 | |
| FVC | % predicted | 73.6 ± 18.86 | 73.6 ± 19.97 | 73.5 ± 15.33 | 0.986 |
| Z-score | −2.13 (−3.00, −1.19) | −2.10 (−3.08, −1.11) | −2.13 (−3.00, −1.15) | 0.863 | |
| FEV1/FVC | % predicted | 80.61 ± 12.879 | 80.89 ± 13.64 | 79.71 ± 9.91 | 0.685 |
| Z-score | 0.75 (−0.50, 1.81) | 0.82 (−0.57, 1.82) | 0.61 (−0.52, 1.04) | 0.447 | |
| 6-min walk test | |||||
| HR before* (beats/min) | 93.8 ± 12.55 | 93.7 ± 13.30 | 94.0 ± 10.16 | 0.907 | |
| HR after* (beats/min) | 115.6 ± 14.98 | 116.2 ± 15.96 | 113.6 ± 11.43 | 0.370 | |
| Spo2 before* (%) | 93.7 ± 2.18 | 93.7 ± 2.33 | 93.6 ± 1.65 | 0.920 | |
| Spo2 after* (%) | 88.8 ± 4.24 | 88.6 ± 4.48 | 89.4 ± 3.41 | 0.440 | |
| Distance (m) | 440.0 (400.0,490.0) | 460.0 (400.0,490.0) | 430.0 (375.0,500.0) | 0.541 | |
Data are presented as mean ± SD or median (Q1, Q3) or (%)
PAP Pulmonary artery pressure, ESR Erythrocyte sedimentation rate, WBC White blood cell, CRP C-reactive protein, PCO2 Partial pressure of carbon dioxide, HCO3 Bicarbonate, FEV1 Forced expiratory volume in one second, FVC Forced vital capacity, HR Heart rate
*before and after 6-min walk test
#calculated according to the Global Lung Function Initiative (GLI)
In all patients, the SpO2 values decreased significantly by 4.9% at the end of the 6MWT compared to before the 6MWT (p < 0.001). The mean decrease was statistically significant in both groups (group 1: 5.1%and group 2: 4.2%, p < 0.001). However, the difference in the SpO2 values before and after the 6MWT between the two groups was not statistically significant (p > 0.05). The mean heart rate significantly increased by 21.8 beats per minute after the 6-MWT compared to before walking in the 6-MWT (p < 0.001). The mean increase was statistically significant in both groups (group 1: 22.5 b/min; group 2: 20 b/min; p < 0.001). However, the difference in the heart rate increase between the two groups was not statistically significant (p > 0.05).
Clinical parameters of participants
Among all patients, 19.6% were admitted to the ICU, and 5.6% had a positive blood culture; however, these variables did not differ significantly between the two groups (p > 0.05). Cough (81.3%) and malaise (26.2%) were the most and least common symptoms, respectively, among patients, and the frequency of any symptom did not differ significantly between the two groups (p > 0.05). Only one patient in group 1 (normal PAP) had reduced EF. While 37.4% of all patients received NIV during hospitalization, this percentage was significantly higher among group 2 compared to group 1 (57.7% vs. 30.9%, p = 0.014). 13 non-PH patients (16%) and three PH patients (11.5%) had a history of congenital heart disease, with no significant difference between the groups (Table 2).
Table 2.
The frequency (%) of clinical parameters in the two groups defined by pulmonary artery pressure levels
| Total (n = 107) | Pulmonary artery pressure | p-value | ||
|---|---|---|---|---|
| Group 1 (PAP < 25 mmHg) (n = 81) | Group 2 (PAP ≥ 25 mmHg) (n = 26) | |||
| ICU admission n (%) | 21 (19.6) | 14 (17.3) | 7 (26.9) | 0.282 |
| Positive blood culture n (%) | 6 (5.6) | 4 (4.9) | 2 (7.7) | 0.631 |
| Positive symptom | ||||
| Cough n (%) | 87 (81.3) | 63 (77.8) | 24 (92.3) | 0.148 |
| Sputum n (%) | 64 (59.8) | 46 (56.8) | 18 (69.2) | 0.260 |
| Malaise n (%) | 28 (26.2) | 23 (28.4) | 5 (19.2) | 0.355 |
| Fever n (%) | 47 (43.9) | 33 (40.7) | 14 (53.8) | 0.241 |
| Loss of appetite n (%) | 34 (31.8) | 29 (35.8) | 5 (19.2) | 0.114 |
| NIV usage n (%) | 40 (37.4) | 25 (30.9) | 15 (57.7) | 0.014 |
| Intubation n (%) | 8 (7.5) | 7 (8.6) | 1 (3.8) | 0.676 |
| Congenital heart disease n (%) | 16 (15.0) | 13 (16.0) | 3 (11.5) | 0.756 |
| Positive sputum culture n (%) | 71 (66.4) | 51 (63.0) | 20 (76.9) | 0.190 |
| Major abnormalities in chest X-ray n (%) | 92 (86.0) | 66 (81.5) | 26 (100.0) | 0.020 |
ICU Intensive Care Unit, NIV Non-Invasive Ventilation, PAP Pulmonary artery pressure
In the analysis of sputum cultures, Staphylococcus aureus was isolated in 26 patients (23.9%), Pseudomonas aeruginosa in 20 patients (18.6%), Haemophilus influenzae in 13 patients (12.1%), Escherichia coli in 3 patients (2.8%), and Burkholderia cepacia in 1 patient (0.9%). In addition, Staphylococcus aureus and Pseudomonas aeruginosa were co-isolated in 3 patients (2.8%), H. influenzae and Pseudomonas in 2 patients (1.8%), E. coli and Pseudomonas in 1 patient (0.9%), Pseudomonas and Stenotrophomonas in 1 patient, Klebsiella and Pseudomonas in 1 patient, and finally, a mixed growth of Pseudomonas, E. coli, and Staphylococcus aureus in 1 patient. Overall, sputum cultures were positive for pathogenic bacteria in 71 patients, of whom 51 were in group 2. No significant differences in the distribution of microorganisms were observed between the two groups.
In the evaluation of chest radiographs, the following findings were observed among the patients: 15 patients (14%) had no major abnormalities in radiographs; 33 patients (30.8%) showed bronchiectasis; 20 patients (18.6%) had bronchiectasis with consolidation; 10 patients (9.3%) demonstrated alveolar consolidation; 6 patients (5.6%) had bronchiectasis with hyperaeration;5 patients(4.6%) had hyperaeration;4 patients(3.7%) had bronchiectasis and atelectasis; 3 patients (2.8%) had bronchiectasis with pneumothorax; 3 patients (2.8%) presented with lobar collapse; 3 (2.8%) patient demonstrated consolidation with hyperaeration; two patient(1.8%) showed reticular and interstitial consolidation; one patient (0.9%) had bronchiectasis with hyperaeration and collapse; one patient had bronchiectasis with ground-glass opacity and one patient showed consolidation with atelectasis. Sixty-six patients (81.5%) in group 1 and twenty-six patients (100%) in group 2 exhibited major abnormalities on chest X-rays, indicating a statistically significant difference between the two groups (Table 2).
Univariate logistic regression
The results of the univariable logistic regression model demonstrated a significant association between elevated PAP and older age, higher CRP and ESR levels, NIV use, and lower lymphocyte counts. With each additional year of age, the odds of having PH increased by 1.19 (95% CI: 1.052–1.348). Patients requiring NIV are associated with a 3.055-fold higher likelihood of having PH compared to those not requiring NIV. Similarly, higher CRP values were associated with an increased likelihood of PH (OR 1.027, 95% CI 1.009–1.046, p = 0.004). CRP levels above 12 mg/dL were associated with increased odds of PH compared with CRP levels below 12 mg/dL (OR 4.608, 95% CI 1.673–12.695, p = 0.003). ESR ≥ 21 mm/hr was associated with higher odds of PH compared with ESR < 21 mm/hr (OR 3.567, 95% CI 1.350–9.427, p = 0.010). Furthermore, higher lymphocyte counts were significantly associated with a lower likelihood of PH (OR = 0.972, 0.946–0.999, p = 0.044) (Table 3).
Table 3.
The results of univariate logistic regression for having pulmonary hypertension (defined as PAP ≥ 25 mmHg)
| OR | 95% CI | p-value | ||
|---|---|---|---|---|
| Age (year) | 1.191 | 1.052—1.348 | 0.006 | |
| Sex (reference: male) | 1.988 | 0.777–5.091 | 0.152 | |
| WBC (× 103/μL) | 1.005 | 0.936–1.080 | 0.883 | |
| Lymphocytes (%) | 0.972 | 0.946—0.999 | 0.044 | |
| Neutrophils (%) | 1.006 | 0.982–1.031 | 0.613 | |
| Hemoglobin (g/dL) | 0.987 | 0.925–1.053 | 0.688 | |
| Platelets (× 103/μL) | 0.999 | 0.996–1.001 | 0.384 | |
| ESR (mm/hr) | 1.017 | 0.998—1.037 | 0.079 | |
| ESR categorized (reference: ESR < 21 mm/hr) | 3.567 | 1.350–9.427 | 0.010 | |
| CRP (mg/dL) | 1.027 | 1.009—1.046 | 0.004 | |
| CRP categorized (reference: CRP < 12 mg/dL) | 4.608 | 1.673–12.695 | 0.003 | |
| FEV1 | % predicted | 0.997 | 0.978–1.017 | 0.795 |
| Z -score # | 0.971 | 0.765–1.234 | 0.811 | |
| FVC | % predicted | 1.000 | 0.977–1.024 | 0.986 |
| Z -score | 0.997 | 0.749–1.328 | 0.986 | |
| FEV1/FVC | % predicted | 0.993 | 0.958–1.028 | 0.682 |
| Z -score | 0.916 | 0.708–1.185 | 0.503 | |
| ICU admission (reference: no ICU requirement) | 1.763 | 0.623–4.991 | 0.285 | |
| Intubation performed (reference: no intubation requirement) | 0.423 | 0.050–3.608 | 0.431 | |
| NIV usage (reference: no NIV requirement) | 3.055 | 1.230—7.586 | 0.016 | |
CI Confidence interval, OR Odds ratio, CRP C-reactive protein, NIV: Non-invasive ventilation, ESR Erythrocyte sedimentation rate, PAP Pulmonary artery pressure, WBC White blood cell, FEV1 Forced expiratory volume in one second, FVC Forced vital capacity, ICU Intensive Care Unit
#calculated according to the Global Lung Function Initiative (GLI)
Multivariate logistic regression
After adjusting for age, sex, and FEV1, multivariable logistic regression analysis revealed that older age, elevated CRP levels, and the NIV requirement remained significantly associated with an increased likelihood of having PH. Specifically, each additional year of age was associated with a 1.176-fold higher odds of PH (95% CI: 1.035–1.337, p = 0.013). Elevated CRP levels were linked to a 1.024-fold increased likelihood of PH (95% CI: 1.004–1.044, p = 0.020). Patients with CRP levels above 12 mg/dL had a significantly higher odds of PH compared with those with CRP levels below 12 mg/dL (OR 3.65, 95% CI: 1.26–10.52, p = 0.017). Patients requiring NIV had a 2.860-fold higher likelihood of PH compared to those not requiring NIV (95% CI: 1.102–7.422, p = 0.031). The lymphocyte percentage was no longer significant in the adjusted model. (Fig. 1 and Table 4).
Table 4.
Multivariate logistic regression for having pulmonary hypertension (defined as PAP ≥ 25 mmHg) adjusted for age, sex (reference: male), and FEV1 (% predicted)
| OR | 95%CI | p-value | |
|---|---|---|---|
| Age (year) | 1.176 | 1.035–1.337 | 0.013 |
| Lymphocytes (%) | 0.984 | 0.954–1.014 | 0.289 |
| ESR (mm/hr) | 1.013 | 0.992–1.034 | 0.223 |
| ESR categorized (reference: ESR < 21 mm/hr) | 1.149 | 1.008–1.310 | 0.037 |
| CRP (mg/dL) | 1.024 | 1.004–1.044 | 0.020 |
| CRP categorized (reference: CRP < 12 mg/dL) | 3.647 | 1.264–10.522 | 0.017 |
| NIV usage (reference: no NIV requirement) | 2.860 | 1.102–7.422 | 0.031 |
CI Confidence interval, OR Odds ratio, CRP C-reactive protein, NIV Non-invasive ventilation, ESR Erythrocyte sedimentation rate, PAP Pulmonary artery pressure, FEV1 Forced expiratory volume in one second
Restricted Cubic Spline of age and PH
Figure 2 illustrates the RCS plot evaluating the association between age and PH. The median age of 9 years was selected as the reference value, with the OR set at 1. The RCS model demonstrated a nonlinear relationship between age and the likelihood of PH among pediatric patients with CF and PEx. ORs and corresponding 95% CIs were estimated using the RCS model with three knots, positioned at the specified percentiles of the age distribution.
Fig. 2.
The restricted cubic spline (RCS) of the association between age and pulmonary hypertension (PH) in pediatrics with cystic fibrosis (CF) and acute pulmonary exacerbations (PEx). The restricted cubic spline (RCS) shows the odds ratio (OR) of having pulmonary hypertension relative to the median value of age (reference point, OR = 1). The RCS function used three knots based on the age distribution. A significant nonlinear association between age and pulmonary hypertension in pediatric patients with CF and PEx was demonstrated (p-nonlinearity = 0.039)
Discussion
In this study, pediatric patients with CF and PEx were classified as group 1 (PAP < 25 mmHg) and group 2 (PAP ≥ 25 mmHg) based on PH presence. The prevalence of PH in the studied population was 24.3%. The median values of age, ESR, and CRP, as well as the prevalence of major CXR abnormalities and NIV requirements, were significantly higher in group 2 than in group 1. The univariate logistic regression showed that older age, elevated CRP and ESR levels, and NIV requirement were significantly associated with an increased likelihood of PH. However, higher lymphocyte counts were associated with a reduced likelihood of having PH. After adjusting for confounding variables, older age (OR: 1.176, 95% CI: 1.035–1.337, p = 0.013), elevated CRP levels (OR: 1.024, 95% CI: 1.004–1.044, p = 0.020), ESR ≥ 21 mm/hr (OR: 1.149, 95% CI: 1.008–1.310, p = 0.037), and NIV requirement (OR: 2.860, 95% CI: 1.102–7.422, p = 0.031) remained significantly associated with having PH.
The prevalence of PH in the current study among children with CF and PEx who were aged 6 to 17 years was 24.3%. Similarly, studies examining the prevalence of PH in adults have estimated it to be between 20 and 65% [7, 8], with a higher prevalence observed in those with end-stage lung disease.
CRP and ESR levels were significantly higher in patients with elevated PAP than in the normal group. These findings are consistent with other studies [27, 28], indicating that inflammatory mediators play a crucial role as vasoconstrictors in the pathophysiology of PH. In addition to vasoconstriction, vascular remodeling resulting from endothelial dysfunction contributes to increased vascular resistance and the development of PH. The correlation between elevated CRP levels and PH suggests that an inflammatory stimulus can lead to vascular stiffness [29]. The results of the current study suggest that higher CRP and ESR levels are associated with an increased likelihood of having PH during pulmonary exacerbations in pediatric patients with CF. However, these associations may be confounded by the exacerbation itself. Therefore, further longitudinal studies are required to clarify whether CRP and ESR can serve as correlates of PH independent of exacerbation status, and to determine whether anti-inflammatory therapies may have a prophylactic role in the management of CF.
Chronic airway infection and inflammation induce a fragile pulmonary vasculature, characterized by hypoxic injury, endothelial dysfunction, and early structural remodeling. During an acute pulmonary exacerbation accompanied by respiratory distress, severe hypoxemia, and hypercapnia, pulmonary vasoconstriction is intensified. At the same time, the inflammatory cascade suppresses nitric oxide–mediated vasodilation, augments vasoconstrictor activity, and triggers microvascular thrombosis. Together, these mechanisms substantially increase pulmonary vascular resistance, predisposing patients to acute pulmonary hypertension and right ventricular overload [30–32]. As shown in this study, individuals with CF and PEx requiring NIV can have an increased likelihood of developing PH. Furthermore, CXRs of the studied patients revealed multiple structural issues, such as consolidation, lobar collapse, atelectasis, hyperinflation, bronchiectasis, and ground-glass opacity. Although pre-exacerbation radiographs were not available, children who developed PH during PEx more frequently demonstrated these parenchymal abnormalities. These findings suggest that the presence or extent of radiographic abnormalities during an acute exacerbation may be associated with concurrent PH.
The current findings also demonstrated that older ages were associated with having increased PAP among pediatrics with CF and PEx. This may suggest that aging in CF is associated with cumulative parenchymal injury and systemic inflammatory stress, which may predispose to alterations in the pulmonary vasculature [33].
This study has several limitations that need to be addressed. Initially, the sample size was relatively small in comparison to larger multicenter studies. Second, data on pancreatic insufficiency, colonization status, CFTR gene mutation, the number of PEx patients experienced in the preceding year, and baseline pulmonary function, PAP, CRP values, and radiological findings were unavailable. In addition, the cross-sectional nature of the study precludes establishing causality between the variables under study and PH. Moreover, the PAP assessment was performed noninvasively using echocardiography rather than traditional right heart catheterization, as echocardiography is frequently used in pediatric medicine due to its safety and practicality. Although all patients underwent standardized echocardiography as part of the study protocol, this procedure is not routinely performed in all children with PEx at our center. This study only involved children experiencing moderate-to-severe exacerbations that required hospitalization; those with mild pulmonary exacerbations managed in outpatient care were excluded. Finally, the evaluation of PH was limited to the acute pulmonary exacerbation phase. Long-term studies are needed to determine if patients who experience PH during PEx face a higher risk of progressing to chronic PH in comparison to the general CF population.
Conclusion
This study showed that approximately one in four children with CF who were not receiving CFTR modulator therapy developed PH while hospitalized for moderate-to-severe PEx. The main factors associated with PH included older age, abnormal chest X-ray findings, the need for NIV, and elevated inflammatory markers, such as CRP and ESR. At follow-up, PH was no longer present in patients. These findings suggest that transient PH during PEx may reflect the reversible pulmonary vascular changes secondary to inflammation and hypoxia, rather than chronic pulmonary vascular remodeling. Further studies are required to inform policy on monitoring strategies and resource allocation in the management of pediatric CF with PEx.
Acknowledgements
Not applicable.
Authors’ contributions
Rohola Shirzadi and Zahra Roshanzamir designed the study. Rohola Shirzadi performed the experiments and collected the data. Fatemeh Mohammadi assisted with data re-analysis and contributed to rewriting sections of the manuscript in response to reviewer comments. Zahra Roshanzamir discussed the results and strategy. Rohola Shirzadi supervised, directed, and managed the study. All authors (Rohola Shirzadi, Zahra Roshanzamir, and Fatemeh Mohammadi) reviewed, edited, and approved the final version of the manuscript for publication.
Funding
No funds, grants, or other support were received.
Data availability
The datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study was approved by the Research Ethics Committee of the School of Medicine, Tehran University of Medical Sciences. The specific code is IR.TUMS.MEDICINE.REC.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.