Abstract
Introduction
Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are respiratory conditions requiring regular chest radiography (CXR) surveillance to monitor pulmonary disease. However, CXR is insensitive for lung disease in CF and PCD. Lung ultrasound (LU) is a radiation‐free alternative showing good correlation with severity of lung disease in CF but has not been studied in PCD.
Method
Standardized, six‐zone LU studies and CXR were performed on a convenience sample of children with PCD or CF during a single visit when well. LU studies were graded using the LU scoring system, while CXR studies received a modified Chrispin‐Norman score. Scores were correlated with clinical outcomes.
Result
Data from 30 patients with PCD and 30 with CF (median age PCD 11.5 years, CF 9.1 years) with overall mild pulmonary disease (PCD median FEV1 90% predicted, CF FEV1 100%) were analyzed. LU abnormalities appear in 11/30 (36%) patients with PCD and 9/30 (30%) with CF. Sensitivity, specificity, positive predictive, and negative predictive values for abnormal LU compared to the gold standard of CXR are 42%, 61%, 42%, and 61% in PCD, and 44%, 81%, 50%, and 77% in CF, respectively. Correlation between LU and CXR scores are poor for both diseases (PCD r = −0.1288, p = 0.4977; CF r = 0.0343, p = 0.8571), and LU score does not correlate with clinical outcomes in PCD.
Conclusion
The correlation of LU findings with CXR surveillance studies is poor in patients with mild disease burdens from PCD or CF, and LU scores do not correlate with clinical outcomes in PCD.
Keywords: cystic fibrosis, lung ultrasound, primary ciliary dyskinesia
1. INTRODUCTION
Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are chronic suppurative respiratory diseases resulting in abnormal mucociliary clearance and progressive damage to the respiratory tract. Both are inherited as mainly recessive traits, with an overall prevalence of 1/7600–1/30,000 for PCD 1 and 1/2500 for CF. 2 In PCD and CF, progressive obstructive lung disease and bronchiectasis develop over time. For unknown reasons, greater structural lung damage occurs in the upper lobes in CF, while the middle and lower lobes are more often affected in PCD. 3 Management recommendations in both conditions include surveillance for structural pulmonary damage with chest radiography (CXR) every 2–4 years in stable children with PCD 4 and every 2 years in stable children with CF. 5 , 6 As a surveillance alternative in children with CF, computed tomography (CT) scans with the lowest reasonably achievable radiation dose may be considered every 2–3 years to replace CXR, 5 while CT surveillance in PCD can be considered at least once when children are able to comply without requiring sedation.
Both CXR and CT examinations result in exposure to ionizing radiation, and long‐term surveillance with these methods is of concern in pediatric patients who may require serial imaging over their lifetimes. 7 , 8 Lung ultrasound (LU) has emerged as a diagnostically accurate tool that may provide similar clinical information to CXR without radiation exposure. The diagnostic accuracy of LU in the acute care setting has been proven equivalent and sometimes superior to CXR for identifying pneumonia, pneumothorax, or other pulmonary conditions in children. 9 , 10 , 11 , 12 LU has been studied in pediatric patients with chronic lung diseases, including CF, where baseline LU findings have been described in stable patients and during respiratory exacerbations. 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 In CF, LU severity scores correlate well with CXR and CT severity scores in cross‐sectional analysis, 17 , 21 , 22 , 23 but similar studies have not been performed in patients with PCD, outside of isolated case reports. 24 We hypothesize that surveillance LU examination in children with PCD is a useful, radiation‐free diagnostic tool and results correlate with paired CXR findings and known patterns of disease in PCD, including middle and lower lobe predominance of pulmonary changes.
2. METHODS
This prospective, cross‐sectional study was conducted from February 2019 to March 2022 in the pediatric respiratory clinic of the McGill University Health Centre. Approval for this study was granted by the Institutional Research Ethics Board (Study 2019‐4615), and informed consent/assent was obtained from patients and/or guardians. Included patients were ≤18 years of age, with PCD diagnosed by two disease‐causing variants in a known PCD gene, and/or a classic ultrastructural ciliary defect on electron microscopy (EM), or repeated low nasal nitric oxide values (<77 nL/min by resistor technique) with a compatible PCD clinical phenotype, where testing for CF and classic immunodeficiency were negative. 25 As a comparator group, we included children <18 years of age with CF, who had sweat chloride values >60 mmol/L and/or two disease‐causing variants in CFTR. All patients were in their baseline state of health for at least 4 weeks before enrollment (no recent viral respiratory tract infection or respiratory exacerbation) and underwent a frontal view CXR (anteroposterior view in the supine position in younger children, and posteroanterior view in the standing position in older children), respiratory culture sampling (expectorated or deep pharyngeal swabs), and spirometry if able to perform correctly (generally those >6 years of age) during the visit. Spirometry results were calculated using race‐adjusted global lung initiative standards. 26 Further patient demographics, therapies, and clinical outcomes related to respiratory disease severity, including respiratory exacerbations in the past year, defined as need for oral antibiotics for respiratory infection or an acute drop in FEV1 of ≥10%, were extracted from patient records.
LU scans were performed by a single sonographer (NM), with extensive experience in LU techniques. The LU scans occurred on a single visit, using the zone ultra ultrasound and the L14‐3 linear transducer (Mindray, Zonare Medical System, Mahwah, NJ), with the patient sitting upright on the examination table or on a parent's lap. A six‐zone scanning protocol was performed, comparable to past LU studies. 9 Settings included a depth of 6–8 cm at a fundamental frequency (i.e., tissue harmonic imaging turned off) of 12 MHz. Ultrasound gel was layered on the probe and placed in a longitudinal manner scanning cephalo‐caudally over six zones (right and left anterior, midaxillary, and posterior chest zones). The zones were divided superior and inferior. Six‐second video clips were taken in each of the six zones. The images were later interpreted and scored by an expert sonographer (ASD) who was blinded to all participant clinical information.
The LU findings recorded the presence or absence of the following sonographic artifacts in each of the six lung zones, as defined by the 2012 international evidence‐based recommendations for LU 10 : 1) multiple or coalescent B‐lines (≥3 per intercostal space), 2) consolidation (defined as large if ≥1 cm or small if <1 cm, 3) pleural lung sliding, and 4) A‐lines. Per past LU studies in CF, the presence of Am‐lines were used as a surrogate for bronchiectasis. 17 The presence of multiple or coalescent B‐lines, Am‐lines, or consolidation in any lung zone was considered as a “positive LU” study. A “negative LU” was defined as the absence of any of these abnormal artifacts, with the presence of normal pleural sliding and a normal A‐line pattern in each zone. Quantitative analysis of LU images was performed with a modified version of the validated LU scoring system. 27 This scoring system grades artifacts on a scale of 0–3 in each of the six upper and lower lung zones with a score range of 0–36 and worse clinical scores being higher in value. The scores correspond to the four LU semiology patterns: a score of 0 indicates the presence of only A‐lines or up to 2 B‐lines in an intercostal space; 1 indicates at least three well‐spaced B lines or consolidation of <1 cm; 2 is given for crowded B‐lines (>50% of intercostal space or coalescent B lines), 3 indicates consolidation ≥1 cm (Appendix A).
Chest X‐ray images were scored for severity using the modified Chrispin‐Norman score, a validated CXR scoring system for images of patients with CF, and modified to assess only a frontal CXR view. 28 Chest X‐ray scoring was performed by a radiologist with 16 years of experience (KM). Higher modified Chrispin‐Norman scores equate with worse CXR changes and disease severity in populations with CF. Though this scoring system is not validated in PCD, it was employed in both disease groups to allow for comparisons between them.
2.1. Data analysis
Descriptive statistics were calculated for continuous and categorical variables as medians with interquartile ranges and frequencies, respectively. Ordinal and continuous variables were compared between groups using Fisher exact and Mann‐Whitney testing, respectively. Diagnostic accuracy was calculated with LU as the index test and CXR as the reference standard. Correlations between CF and PCD LU scores, Chrispin‐Norman scores, and clinical disease variables were calculated using Spearman coefficient. p‐values < 0.05 were considered significant. Data were analyzed with SPSS statistics (version 23; IBM, Armonk, NY).
3. RESULTS
Eighty‐one patients were enrolled, including 40 diagnosed with PCD and 41 diagnosed with CF. From these, nine patients were excluded for poor ultrasound image quality, and 11 patients were excluded for viral upper respiratory tract infection or pulmonary exacerbation in the past month. Final data analysis included 30 patients with PCD and 30 with CF. For the patients with PCD, the median age was 11.5 years (IQR 6.2,14.2), and the median FEV1 was 90.1% predicted, while 25 (83.3%) had diagnostic PCD genetics, two (6.6%) had a classic electron microscopic abnormality alone, and 3 (10%) had repeatedly low nNO values plus a compatible PCD phenotype, with normal EM and negative genetic testing. For patients with CF, median age was 9.1 years (IQR 6.9, 12.2), and the median FEV1 was 99.8% predicted, while 53% had homozygous F508del variants in CFTR, and 37% had a single F508del variant in compound heterozygous arrangement with another CFTR variant. Patient demographics for PCD and CF are shown in Table 1.
Table 1.
Patient demographics.
| N (%) or median (IQR) | PCD N = 30 | CF N = 30 |
|---|---|---|
| Median age at enrollment | 11.5 (6.2, 14.2) | 9.1 (6.9, 12.2) |
| Female | 15 (50%) | 17 (56%) |
| White | 24 (80%) | 29 (97%) |
| Median body mass index Z‐score | 0.1 (−0.83, 0.54) | −0.23 (−0.75, 0.34) |
| Genetic diagnosis | 25 (83%)# | 30 (100%) |
| EM defect alone | 2 (7%) | N/A |
| Low nNO + PCD phenotype## | 3 (10%) | N/A |
| Homozygous F508del | N/A | 16 (53%) |
| Compound heterozygous F508del | N/A | 11 (37%) |
| Past Pseudomonas aeruginosa on respiratory culture | 9 (30%) | 22 (73%) |
| Bronchiectasis on past CT* | 11 (37%) | 7 (23%) |
| Prophylactic azithromycin | 12 (40%) | 6 (20%) |
| Inhaled tobramycin | 0 (0%) | 4 (13%) |
| Inhaled Dnase | 0 (0%) | 16 (53%) |
| Inhaled hypertonic saline | 24 (80%) | 14 (46%) |
| CFTR modulators | N/A | 15 (50%) |
| Had a respiratory exacerbation in the past year | 12 (40%) | 14 (46%) |
| Median number of respiratory exacerbations in past year | 0.56 (0, 1) | 1 (0, 2) |
| Hospitalized for respiratory exacerbation in the past year | 3 (1%) | 6 (2%) |
| Median FEV1% predicted** | 90.1 (81.4, 104) | 99.8 (90.6, 105.8) |
| Median FVC% predicted** | 99 (87.9, 109.3) | 101.5 (94.6, 109.7) |
| Median FEV1/FVC** | 82 (76.7, 85.5) | 87 (80.7, 89.2) |
Abbreviations: CF, cystic fibrosis, FEV1, forced expiratory volume in 1 s, FVC, forced vital capacity; N/A, not applicable; nNO, nasal nitric oxide in nL/min, PCD, primary ciliary dyskinesia.
23 CF and 12 PCD patients did not have a previous CT scan.
4 CF and 6 PCD did not perform pulmonary function tests on the same day as their research visit, due to young age.
Numbers of patients with most common PCD genotypes: N = 6 HYDIN, N = 6 DNAH5, N = 3 CFAP221.
nNO < 77 nL/min by exhalation against resistance, with negative testing for CF and classic immunodeficiency.
Positive LUs were found in 11 (36%) patients with PCD and in nine (30%) patients with CF. Median ages for those with positive LU were 7.3 years (IQR 2.4–12.4) in PCD and 9.7 years (IQR 6.8–12.8) in CF (p = 0.596). None of the patients showed Am‐lines on LU, and thus, no cases of bronchiectasis were appreciated on LU. In the patients with positive LU studies, five (46%) patients with PCD had multiple or coalescent B‐lines versus 7seven (78%) with CF (p = 0.93), while nine (82%) patients with PCD had consolidations versus three (33%) with CF (p = 0.05). Small and large consolidations were seen in three (27%) and six (56%) patients with PCD versus two (22%, p = 0.79) and one (11%, p = 0.42) patients with CF, respectively. Some patients had more than one positive finding on LU. Overall, 11 patients (seven with PCD, four with CF) had a positive LU and negative CXR, while 12 patients (seven with PCD, five with CF) had a positive CXR and negative LU. Compared to CXR, positive LU in PCD and CF, had sensitivities of 42% versus 44%, specificities of 61% versus 81%, positive predictive values of 42% versus 50%, and negative predictive values of 61% versus 77%, respectively. The location of LU abnormalities across six lung zones is shown in Figure 1. There were no significant differences in pulmonary region of LU abnormalities by disease.
Figure 1.
The frequency of abnormal LU findings per specific lung zone in patients with primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). Anterior and lateral zones roughly correspond to the upper and middle lobes, while the posterior zone roughly corresponds to the lower lobes. Some patients had more than one lung zone affected on the same LU examination. Still, overall, there are no significant differences in affected lung zones between patients with PCD or CF. LU, Lung ultrasound.
Quantitative LU scores were similar in patients with PCD or CF (mean LU score in PCD 1.1 [IQR 0, 3]; mean LU score in CF 1.86 [IQR 0, 1], p = 0.463). Chrispin‐Norman CXR scores were significantly less severe in patients with PCD than in those with CF, (3.1 [IQR 1, 5] in PCD; 5.5 [IQR 2, 8.25] in CF, p = 0.02). The correlation between LU score and Chrispin‐Norman CXR score was poor for both diseases (r = −0.1288, p = 0.4977 for PCD; r = 0.0343, p = 0.857 for CF).
Analysis of correlation between clinical disease variables and LU score for both PCD and CF populations is shown in Table 2. There was moderate correlation between LU score and having a pulmonary exacerbation in the past year in patients with CF (r = 0.43, p = 0.02) but not in patients with PCD (r = −0.1354, p = 0.4757). There were no other significant positive correlations between LU score and clinical disease variables (respiratory exacerbations in the past year, pulmonary function, growth, and so on) in patients with PCD or CF.
Table 2.
Correlations between lung ultrasound score and clinical variables.
| PCD (%) N = 30 | CF (%) N = 30 | |||||
|---|---|---|---|---|---|---|
| Value | Correlation | p‐Value | Value | Correlation | p‐Value | |
| Median age at diagnosis (years) | 5 | −0.0779 | 0.6824 | 0.5 | −0.1856 | 0.3263 |
| Median age at study entry (years) | 11.5 | ‐0.0060 | 0.9749 | 9.1 | −0.0831 | 0.6626 |
| Median BMI Z‐scorea | 0.1 | −0.2545 | 0.1828 | −0.23 | −0.2087 | 0.2684 |
| Median FEV1 Z‐scorea | −0.56 | −0.2233 | 0.2944 | 0.069 | −0.1201 | 0.5589 |
| Median FVC Z‐scorea | −0.061 | −0.2343 | 0.2596 | 0.178 | −0.0419 | 0.8423 |
| Median FEV1/FVC% predicteda | 93 | 0.0114 | 0.9568 | 87 | −0.1180 | 0.5658 |
| FEF25/75% Z‐scorea | −1.322 | −0.1648 | 0.4311 | −0.089 | −0.1179 | 0.5745 |
| Respiratory exacerbation in past year | 12 (40) | 0.1354 | 0.4757 | 14 (46) | 0.4341 | 0.0165 |
| Past pseudomonas respiratory culture | 9 (30) | 0.1231 | 0.5170 | 22 (73) | −0.0432 | 0.8208 |
| Inhaled Dnase | 0 | −0.1605 | 0.3970 | 16 (53) | 0.1913 | 0.3112 |
| Prophylactic azithromycin | 12 (40) | 0.2897 | 0.1205 | 6 (20) | 0.3579 | 0.0522 |
| Inhaled tobramycin | 0 | N/A | N/A | 4 (13) | 0.1965 | 0.2980 |
| Bronchiectasisb | 11 (36) | 0.4056 | 0.0949 | 7 (23) | −0.1315 | 0.5498 |
Note: Ordinal and continuous variables were compared between groups using Fisher exact and Mann–Whitney testing, respectively. Abbreviations: BMI, body mass index; CF, cystic fibrosis; FEF27/75, forced expiratory flows at 25% and 75% of FVC; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity, PCD, primary ciliary dyskinesia.
25 PCD and 26 CF performed spirometry on the day of the visit.
18 PCD and seven CF had previous CT scans.
For CXR score results, Table 3 shows correlation was low between median age of diagnosis and the Chrispin‐Norman score (r = 0.36, p = 0.04) in patients with CF. Patients with CF or PCD showed positive correlation between the Chrispin‐Norman score and number of pulmonary exacerbations in the past year (low correlation in PCD, r = 0.3613, p = 0.0498; moderate correlation in CF, r = 0.5421, p = 0.002). Bronchiectasis on past chest CT scan was present in 11 (37%) and 7 (23%) patients with PCD or CF, respectively, but only two patients had visible bronchiectasis on CXR (one patient with PCD and one patient with CF) (Figure 2).
Table 3.
Correlations between Chrispin‐Norman score and clinical variables.
| PCD (%) N = 30 | CF (%) N = 30 | |||||
|---|---|---|---|---|---|---|
| Value | Correlation | p‐Value | Value | Correlation | p‐Value | |
| Median age at diagnosis (years) | 5 | 0.0553 | 0.7717 | 0.5 | 0.3658 | 0.0468 |
| Median age at study entry (years) | 11.5 | −0.0461 | 0.8087 | 9.1 | 0.3172 | 0.0877 |
| Median BMI Z‐score | 0.1 | −0.1129 | 0.5598 | −0.23 | −0.2384 | 0.2047 |
| Median FEV1 Z‐scorea | −0.565 | −0.0114 | 0.9579 | 0.069 | ‐0.2171 | 0.2971 |
| Median FVC Z‐scorea | −0.061 | 0.0210 | 0.9206 | 0.178 | ‐0.2140 | 0.3043 |
| Median FEV1/FVC% predicteda | 93.1 | −0.0244 | 0.9080 | 87 | ‐0.2966 | 0.1412 |
| FEF25/75% Z‐scorea | −1.322 | −0.0403 | 0.8482 | −0.089 | −0.2140 | 0.3043 |
| Respiratory exacerbation in past year | 12 (40) | 0.3613 | 0.0498 | 14 (46) | 0.5421 | 0.0020 |
| Past pseudomonas respiratory culture | 9 (30) | 0.1766 | 0.3507 | 22 (73) | ‐0.1446 | 0.4457 |
| Inhaled Dnase | 0 | 0.0366 | 0.8480 | 16 (53) | −0.2244 | 0.2333 |
| Prophylactic azithromycin | 12 (40) | −0.0744 | 0.6959 | 6 (20) | 0.2199 | 0.2431 |
| Inhaled tobramycin | 0 | 0.2193 | 0.2443 | 4 (13) | −0.0470 | 0.8050 |
| Bronchiectasisb | 11 (36) | −0.0944 | 0.6840 | 7 (23) | 0.2630 | 0.2254 |
Abbreviations: BMI, body mass index; CF, cystic fibrosis; FEF27/75, forced expiratory flows at 25% and 75% of FVC; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; PCD, primary ciliary dyskinesia. Ordinal and continuous variables were compared between groups using Fisher exact and Mann–Whitney testing, respectively.
25 PCD and 26 CF performed spirometry on the day of the visit.
18 PCD and 7 CF had previous CT scans.
Figure 2.
Images from a 14 year‐old male with primary ciliary dyskinesia from biallelic variants in CCDC40, which is known to result in severe respiratory disease. The patient has an FEV1 of 65% predicted and history of Pseudomonas aeruginosa in sputum cultures. Lung ultrasound shows multiple B lines in the right anterior zone (A) and consolidation (B) with adjacent multiple coalescent B lines (C and D) in the left lateral zone, with an overall LU score of 8/36. Chest radiography shows bronchial wall thickening and possible bronchiectasis at the bilateral lung bases in the pericardiac region (E), with a Chrispin‐Norman score of 7/38. Previous CT scan shows bronchiectasis in the right middle lobe and in the lingula. FEV1, forced expiratory volume in 1 s; LU, lung ultrasound.
4. DISCUSSION
Primary ciliary dyskinesia and CF are diseases of mucociliary clearance requiring long‐term surveillance of pulmonary changes through repeat radiology exams exposing patients to ionizing radiation. This cumulative radiation doses may prove significant over a lifetime, and thus, LU provides an alternative mode of imaging for surveillance in these diseases. However, this study shows that the diagnostic accuracy of a positive LU study is poor compared to CXR as a surveillance tool in patients with PCD or CF.
In PCD cases with a positive LU, 82% have consolidations as opposed to 33% of CF cases. With magnetic resonance imaging of the chest, similar increases in pulmonary consolidation have been reported for children with PCD compared to those with CF. 29 The artifact interpreted as consolidation on LU is defined as a hypoechoic lesion below the pleural line, which can occur with the loss of aeration of lung tissue, such as in atelectasis. 10 Our finding of increased consolidation in PCD compared to CF could possibly be from the ability of PCD patients to mobilize mucus more proximally through intact cough clearance, resulting in regionalized mucus plugging and atelectasis of larger airway segments in PCD. 30 , 31 Patients with CF had increased zones with multiple B‐lines as their most common LU abnormality in our cohort (85% of abnormal LU in CF, compared to 45% in PCD). B‐lines are vertical artifacts hypothesized to be from acoustic traps along the lung surface. These traps can form in connection with a large variety of pathologies and are due to the replacement of lung volumes originally occupied by air with media (water, blood, or scar tissue) that are acoustically similar to intercostal tissue. 32 This media allows sound waves to pass in between air‐filled alveoli and produce LU artifacts. These B‐line artifacts may arise from mucus plugging, atelectasis, or chronic inflammation with fibrosis causing scar tissue formation. As PCD and CF result in suppurative lung disease with neutrophilic inflammation and bronchiectasis, the regular presence of B‐lines in both diseases is not surprising.
LU scores correlate with respiratory exacerbation in the past year for patients with CF, but not for patients with PCD. CXR severity with the modified Chrispin‐Norman score did correlate with pulmonary exacerbations over the past year in patients with PCD or CF, but CXR severity did not correlate with other clinical outcomes in either disease. The lack of a reliable CXR scoring tool in PCD makes quantitative analysis of disease progression difficult through CXR imaging alone. The Chrispin‐Norman score is validated for CXR disease monitoring in patients with CF, and Chrispin‐Norman scores were significantly worse in patients with CF than in those with PCD. This difference may result from the lack of validation for this scoring system in patients with PCD.
LU scores correlate poorly with CXR scores and with most clinical outcomes in our patients with PCD or CF, albeit the majority had mild pulmonary disease. This seems contrary to recent findings in other cohorts with CF. Curatola and colleagues enrolled 29 patients with CF who were >10 years of age, and demonstrated LU scores correlate well with spirometry values. 33 Despite using the identical LU scoring system, our median patient age at enrollment was much younger (9 years) as compared to the more advanced median age (27 years) in Curatola and colleagues, and this may account differences in LU correlations. Jaworska and colleagues examined 131 patients with CF and showed strong correlation seen between LU scores and CXR scores, as well as LU and pulmonary function. 17 Their work differed from ours in several ways, including larger patient number, worse CF disease severity, and an alternate LU scanning technique. In our study, 96% of patients with CF had FEV1 values > 70% predicted, and 81% had FEV1 > 90% predicted (median FEV1 99.8%), while Jaworska and colleagues included patients with much lower FEV1 values, including 10% with FEV1 value <70% predicted (the median FEV1 is not reported for the entire cohort). One‐half of our patients with CF were also taking CFTR modulator therapies, which were not reported by Jaworska and colleagues, but may have affected findings on both CXR and LU exams. CFTR modulator therapies significantly reduce mucus plugging and bronchial wall thickening on magnetic resonance imaging of patients with CF, and these types of improvements may have resulted in fewer detected LU abnormalities in our cohort. 34
Our LU image acquisition procedure was also different from past LU studies. We performed LU in six different zones, scanned in a line cranio‐caudally with longitudinally held probe on the patient's chest, as opposed to the procedure by Jaworska and colleagues, which scanned the entire lung surface (all intercostal spaces) with a transversely‐held probe. The six‐zone LU technique we employed has been conceived and clinically validated in numerous other LU studies examining asthma, COPD, pneumothorax, and pneumonia, including the seminal LU paper by Lichtenstein and Mezière. 35 This six‐zone technique allows visualization of more rib spaces with each view and a more rapid scanning process, while possibly sacrificing some of the sensitivity that a more extensive scan of each intercostal space may achieve. This may have also decreased our detection of anomalies compared to Jaworska and colleagues. Additionally, Jaworska and colleagues used both linear and convex probes for their LU protocol, while we used only a linear probe, which employs a high frequency to allow for greater resolution with a lower depth of imaging. 20 In patients with larger amounts of soft tissue (i.e., obesity), use of only a linear probe may affect image results. However, in our study, the median patient body mass index Z‐scores (0.1 for PCD [range −1.13–2.17]; −0.23 for CF [range –1.55–1.58]) were in the normal range, suggesting that subcutaneous tissue and obesity did not impede LU imaging.
Patients with PCD or CF have different pathophysiology leading to differences in location of pulmonary disease on radiology imaging. However, the reasons for these differences are unknown. PCD is more likely to affect the middle and lower lobes with increased consolidation, atelectasis, and bronchiectasis in these dependant regions as compared to CF, 36 , 37 which often presents with more disease effects in the upper lobes. While our data show more PCD cases with findings in the lateral and posterior LU zones (corresponding to mostly the middle and lower lobes) as compared to CF, this was not significant. Thus, our LU scans did not demonstrate the recognized regional differences in lung pathology in patients with PCD versus those with CF.
There are several limitations to this study. First, the majority of patients had mild respiratory disease, which may have influenced our findings. Expanding LU studies to PCD populations with more severe pulmonary disease may affect the diagnostic accuracy and correlation of LU with CXR studies. There was also a small number of participants in our study, which may be underpowered to detect smaller LU score changes and subtle correlations in PCD. However, in a rare disease like PCD, a larger number will be difficult to attain without multi‐center protocols. The LU and CXR images were both read by experts blinded to the CF or PCD diagnosis, but with situs inversus totalis evident on CXR images from a number of patients with PCD, this blinding may have been incomplete. Lastly, as mentioned above, the Chrispin‐Norman score has not been validated in patients with PCD.
5. CONCLUSION
This study shows one‐third of patients with PCD or CF have LU anomalies when not acutely ill, with poor correlation between LU severity and CXR severity scores. Overall, the LU score does not correlate with CXR scores or with clinical outcomes in patients with PCD. This lack of LU correlation may result from milder respiratory disease in our young patient cohort with PCD. Older patients with PCD and more advanced respiratory disease may show LU correlations. Compared to CXR, LU does detect more pulmonary consolidations in patients with PCD, but the clinical significance of this requires further, longitudinal analysis to know if this finding correlates with other disease outcomes over time.
AUTHOR CONTRIBUTIONS
Noah Marzook: Conceptualization; writing—review and editing; writing—original draft; methodology; investigation; formal analysis; visualization; project administration; data curation. Alexander S. Dubrovsky: Conceptualization; writing—review and editing; investigation; methodology; formal analysis. Karl Muchantef: Writing—review and editing; conceptualization; investigation; methodology; formal analysis. David Zielinski: Writing—review and editing; methodology; conceptualization; formal analysis; investigation. Larry C. Lands: Methodology; writing—review and editing; conceptualization; formal analysis; investigation. Adam J. Shapiro: Supervision; conceptualization; methodology; validation; visualization; project administration; writing—review and editing; data curation; investigation; formal analysis; writing—original draft.
CONFLICT OF INTEREST STATEMENT
Adam J. Shapiro receives salary support from the Primary Ciliary Dyskinesia Foundation. He is a consultant for parion sciences, recode therapeutics, and Ethris GmbH.
ACKNOWLEDGMENTS
Funding for the research assistant was provided by an innovation grant from the Department of Pediatrics of the Montreal Children's Hospital—McGill University Health Center.
1.
| Score | RT Ant Sup | RT Ant Inf | RT Lat Sup | Rt Lat Inf | RT Post Sup | RT Post Inf | LT Ant Sup | LT Ant Inf | LT Lat Sup | LT Lat Inf | LT Post Sup | LT Post Inf |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0 | ||||||||||||
| 1 | ||||||||||||
| 2 | ||||||||||||
| 3 |
Calculation of lung ultrasound (LU) scores. Each lung was divided into three zones (RT = Right, LT = Left, Ant = Anterior, Lat = Lateral, and Post = Posterior), then further divided into Superior (Sup) and Inferior (Inf) zones. For each zone, a 0–3 score was assigned. A maximum score of 36 was attainable. The score values correspond to the four LU semiology patterns. 0 indicates the presence of only A‐lines or up to 2 B‐lines in an intercostal space; 1 indicates at least three well‐spaced B lines or consolidation of <1 cm; a score of 2 is given for crowded B‐lines (>50% of intercostal space or coalescent B lines), 3 indicates consolidation >1 cm.
Marzook N, Dubrovsky AS, Muchantef K, Zielinski D, Lands LC, Shapiro AJ. Lung ultrasound in children with primary ciliary dyskinesia or cystic fibrosis. Pediatr Pulmonol. 2024;59:3391‐3399. 10.1002/ppul.27215
Meeting: This study was presented at the 2021 Pediatric Emergency Research Canada annual meeting (January 2021, Mont Tremblant, Quebec, Canada). It was also presented as a poster of the abstract at the American Thoracic Society Conference in May 2022.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
REFERENCES
- 1. Hannah WB, Seifert BA, Truty R, et al. The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis. Lancet Respir Med. 2022;10(5):459‐468. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Hamosh A, FitzSimmons SC, Macek Jr., M , Knowles MR, Rosenstein BJ, Cutting GR. Comparison of the clinical manifestations of cystic fibrosis in black and white patients. J Pediatr. 1998;132(2):255‐259. [DOI] [PubMed] [Google Scholar]
- 3. Cohen‐Cymberknoh M, Simanovsky N, Hiller N, Hillel AG, Shoseyov D, Kerem E. Differences in disease expression between primary ciliary dyskinesia and cystic fibrosis with and without pancreatic insufficiency. Chest. 2014;145(4):738‐744. [DOI] [PubMed] [Google Scholar]
- 4. Shapiro AJ, Zariwala MA, Ferkol T, et al. Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: pcd foundation consensus recommendations based on state of the art review. Pediatr Pulmonol. 2016;51(2):115‐132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Lahiri T, Hempstead SE, Brady C, et al. Clinical practice guidelines from the cystic fibrosis foundation for preschoolers with cystic fibrosis. Pediatrics. 2016;137(4):e20151784. 10.1542/peds.2015-1784 [DOI] [PubMed] [Google Scholar]
- 6. Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic fibrosis foundation evidence‐based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155(6):S73‐S93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Brody AS. Thoracic CT technique in children. J Thorac Imaging. 2001;16(4):259‐268. [DOI] [PubMed] [Google Scholar]
- 8. Brenner DJ, Hall EJ. Computed tomography—An increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277‐2284. [DOI] [PubMed] [Google Scholar]
- 9. Copetti R, Cattarossi L. Ultrasound diagnosis of pneumonia in children. Radiol Med (Torino). 2008;113(2):190‐198. [DOI] [PubMed] [Google Scholar]
- 10. Volpicelli G, Elbarbary M, Blaivas M, et al. International evidence‐based recommendations for point‐of‐care lung ultrasound. Intensive Care Med. 2012;38:577‐591. [DOI] [PubMed] [Google Scholar]
- 11. Balk DS, Lee C, Schafer J, et al. Lung ultrasound compared to chest x‐ray for diagnosis of pediatric pneumonia: a meta‐analysis. Pediatr Pulmonol. 2018;53(8):1130‐1139. [DOI] [PubMed] [Google Scholar]
- 12. Lichtenstein D. Lung ultrasound in acute respiratory failure an introduction to the blue‐protocol. Minerva Anestesiol. 2009;75(5):313‐317. [PubMed] [Google Scholar]
- 13. Marzook N, Gagnon F, Deragon A, et al. Lung ultrasound findings in asymptomatic healthy children with asthma. Pediatr Pulmonol. 2022;57(10):2474‐2480. [DOI] [PubMed] [Google Scholar]
- 14. Gagnon F, Marzook N, Deragon A, et al. Characterizing pediatric lung ultrasound findings during a chemically induced bronchospasm. Pediatr Pulmonol. 2022;57(6):1475‐1482. [DOI] [PubMed] [Google Scholar]
- 15. Hassanzad M, Kiani A, Abedini A, et al. Lung ultrasound for the diagnosis of cystic fibrosis pulmonary exacerbation. BMC Pulm Med. 2021;21(1):353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Dankoff S, Li P, Shapiro AJ, Varshney T, Dubrovsky AS. Point of care lung ultrasound of children with acute asthma exacerbations in the pediatric ed. Am J Emerg Med. 2017;35(4):615‐622. [DOI] [PubMed] [Google Scholar]
- 17. Jaworska J, Buda N, Kwaśniewicz P, Komorowska‐Piotrowska A, Sands D. Lung ultrasound in the evaluation of lung disease severity in children with clinically stable cystic fibrosis: a prospective cross‐sectional study. J Clin Med. 2023;12(9):3086. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Strzelczuk–Judka L, Wojsyk–Banaszak I, Zakrzewska A, Jończyk–Potoczna K. Diagnostic value of chest ultrasound in children with cystic fibrosis—Pilot study. PLoS One. 2019;14(7):e0215786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Crispino AA, Musolino AM, Buonsenso D, Caloiero M, Concolino D. Point of care lung ultrasound in preschool children with cystic fibrosis: a case‐controlled, prospective, pilot study. J Ultrasound. 2024;27:303‐314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Mojoli F, Bouhemad B, Mongodi S, Lichtenstein D. Lung ultrasound for critically ill patients. Am J Respir Crit Care Med. 2019;199(6):701‐714. [DOI] [PubMed] [Google Scholar]
- 21. Ciuca I, Pop L, Marc M, Oancea C. How useful is the lung ultrasound in cystic fibrosis? Eur Respiratory Soc. 2016;48:PA1261. 10.1513/annalsats.202305-453oc [DOI] [Google Scholar]
- 22. Ciuca IM, Pop LL. 145 lung ultrasound in CF children's exacerbation—one center experience. J Cystic Fibrosis. 2015;14:S95. [Google Scholar]
- 23. Ciuca IM, Pop LL, Dediu M, et al. Lung ultrasound in children with cystic fibrosis in comparison with chest computed tomography: a feasibility study. Diagnostics. 2022;12(2):376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Guitart C, Del Rey Hurtado de Mendoza B, Camprubi Camprubi M, Rodriguez‐Fanjul J. Lung ultrasound in the follow‐up of primary ciliary dyskinesia. J Matern‐Fetal Neonatal Med. 2021;34(8):1344‐1346. [DOI] [PubMed] [Google Scholar]
- 25. Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. an official American thoracic society clinical practice guideline. Am J Respir Crit Care Med. 2018;197(12):e24‐e39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi‐ethnic reference values for spirometry for the 3–95‐yr age range: the global lung function 2012 equations. Eur Respiratory Soc. 2012;40:1324‐1343. 10.1183/09031936.00080312 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Mongodi S, De Luca D, Colombo A, et al. Quantitative lung ultrasound: technical aspects and clinical applications. Anesthesiology. 2021;134(6):949‐965. [DOI] [PubMed] [Google Scholar]
- 28. Benden C. The Chrispin–Norman score in cystic fibrosis: doing away with the lateral view. Eur Respir J. 2005;26(5):894‐897. [DOI] [PubMed] [Google Scholar]
- 29. Wucherpfennig L, Wuennemann F, Eichinger M, et al. MRI of pulmonary and paranasal sinus abnormalities in children with primary ciliary dyskinesia compared to children with cystic fibrosis. Ann Am Thorac Soc. 2024;21(3):438‐448. 10.1513/annalsats.202305-453oc [DOI] [PubMed] [Google Scholar]
- 30. Itani OA, Chen J‐H, Karp PH, et al. Human cystic fibrosis airway epithelia have reduced cl—Conductance but not increased na+ conductance. Proc Natl Acad Sci. 2011;108(25):10260‐10265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Livraghi A, Randell SH. Cystic fibrosis and other respiratory diseases of impaired mucus clearance. Toxicol Pathol. 2007;35(1):116‐129. [DOI] [PubMed] [Google Scholar]
- 32. Demi L, Wolfram F, Klersy C, et al. New international guidelines and consensus on the use of lung ultrasound. J Ultrasound Med. 2023;42(2):309‐344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Curatola A, Corona F, Squillaci D, et al. Lung ultrasound evaluation in people with cystic fibrosis: a new approach in the pulmonology outpatient clinic. Pediatr Pulmonol. 2023;59(3):592‐599. [DOI] [PubMed] [Google Scholar]
- 34. Graeber SY, Renz DM, Stahl M, et al. Effects of elexacaftor/tezacaftor/ivacaftor therapy on lung clearance index and magnetic resonance imaging in patients with cystic fibrosis and one or two f508del alleles. Am J Respir Crit Care Med. 2022;206(3):311‐320. [DOI] [PubMed] [Google Scholar]
- 35. Lichtenstein DA, Mezière GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure*: the blue protocol. Chest. 2008;134(1):117‐125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Maglione M, Montella S, Mollica C, et al. Lung structure and function similarities between primary ciliary dyskinesia and mild cystic fibrosis: a pilot study. Ital J Pediatr. 2017;43:34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Primary ciliary dyskinesia. Seminars in Respiratory and Critical Care Medicine; 2015: Thieme Medical Publishers. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.