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Original Research: Genetic and Developmental Disorders |

Differences in Disease Expression Between Primary Ciliary Dyskinesia and Cystic Fibrosis With and Without Pancreatic InsufficiencyDifferences in Disease Expression FREE TO VIEW

Malena Cohen-Cymberknoh, MD; Natalia Simanovsky, MD; Nurith Hiller, MD; Alex Gileles Hillel, MD; David Shoseyov, MD; Eitan Kerem, MD
Author and Funding Information

From the Department of Pediatrics (Drs Cohen-Cymberknoh, Gileles Hillel, and Shoseyov and Prof Kerem), the Cystic Fibrosis and Primary Ciliary Dyskinesia Center (Drs Cohen-Cymberknoh, and Shoseyov and Prof Kerem), and the Department of Radiology (Drs Simanovsky and Hiller), Hadassah Hebrew-University Medical Center, Mount Scopus, Jerusalem, Israel.

Correspondence to: Eitan Kerem, MD, Pediatric Division, Hadassah Hebrew-University Medical Center, POB 12000, 91120 Jerusalem, Israel; e-mail: kerem@hadassah.org.il


For editorial comment see page 674

Drs Cohen-Cymberknoh and Simanovsky contributed equally to this manuscript.

Funding/Support: This study was funded by departmental grants from Hadassah Hebrew University Hospital.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(4):738-744. doi:10.1378/chest.13-1162
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Background:  Impaired mucociliary clearance causes pulmonary disease in primary ciliary dyskinesia (PCD) and contributes to cystic fibrosis (CF) lung disease. Although the sinopulmonary disease is similar, morbidity and mortality are different. Both patients with PCD and patients with CF with pancreatic sufficiency (CF-PS) show no nutrient malabsorption and are diagnosed at a later age compared with patients with CF with pancreatic insufficiency (CF-PI).

Methods:  Clinical status, microbiology, FEV1, and high-resolution CT (HRCT) scans presented as total Brody score (CT-TBS) were compared for patients with PCD, CF-PI, and CF-PS, all treated at the same medical center, by the same team, and by a similar routine follow-up.

Results:  One hundred sixty-four patients, 34 with PCD, 88 with CF-PI, and 42 with CF-PS were enrolled. PCD was diagnosed at a similar age as CF-PS but significantly later than CF-PI. Mean FEV1 % predicted was similar for the three groups. The rate of FEV1 change with age in PCD was similar to CF-PS but significantly lower than in CF-PI. Severity of structural lung disease (CT-TBS) was similar for PCD and CF-PS and significantly higher in CF-PI. No correlation between TBS or Pseudomonas aeruginosa infection and FEV1 in PCD was seen, whereas a negative correlation with FEV1 was observed for both CF groups.

Conclusions:  Although in our study PCD was similar to CF-PS, the lack of correlation between FEV1 and age, CT-TBS, and P aeruginosa infection in PCD suggests that impaired mucociliary clearance is not the only cause for inducing pulmonary damage in these diseases. Furthermore, a comparison of disease characteristics for PCD and CF should distinguish between CF-PI and CF-PS as different entities.

Figures in this Article

Effective mucociliary clearance (MCC) in the respiratory system requires proper mucus production and a functioning airway surface fluid layer as well as competent and coordinated ciliary beating.1 The vital role of these mechanisms is best demonstrated for primary ciliary dyskinesia (PCD) and cystic fibrosis (CF), both characterized by impaired MCC leading to acute and chronic sinopulmonary infections. PCD is caused by defects in genes encoding the structure or function of the respiratory cilia.2,3 CF is caused by mutations in the CFTR gene causing an abnormal airway surface fluid layer, generating thickened and viscous mucus, which impairs MCC. In both diseases, recurrent and chronic respiratory infections and persistent inflammation cause progressive lung damage.46

Most patients with CF suffer from pancreatic insufficiency (CF with pancreatic insufficiency [CF-PI]), although up to 15% have sufficient pancreatic enzyme production to maintain normal fat absorption (CF with pancreatic sufficiency [CF-PS]). CF-PS is caused by CF transmembrane conductance regulator (CFTR) mutations of class IV and V, associated with a reduction in the number or activity of functional CFTR chloride channels over the apical membrane of respiratory epithelial cells.7 CF-PI is caused by CFTR mutations of class I, II, and III, resulting in severely reduced or absent CFTR function.810 Compared with CF-PI, patients with CF-PS are diagnosed at a later age, have better nutritional status, are less colonized by Pseudomonas aeruginosa, and generally live longer.11,12 Pulmonary function was shown to be highly variable in both patient groups.13 Additionally, we have recently shown that lung abnormalities on chest CT scans of patients with CF-PI and CF-PS show different patterns.14

Patients with PCD and CF-PS do not suffer from pancreatic insufficiency and, therefore, usually do not show nutritional deficiencies typically associated with more severe pulmonary disease in CF-PI. Additionally, PCD and CF-PS are often diagnosed at a later age, and patients have a longer survival compared with patients with CF-PI.13,15,16

In this study, we compared pulmonary disease expression between PCD, CF-PS, and CF-PI, as measured by pulmonary function, high-resolution CT (HRCT) scan scores, and sputum bacteriology, correlated with age and nutritional status. Previous studies between PCD and CF did not distinguish between CF-PS and CF-PI as separate groups.16,17

Patients with confirmed diagnosis of PCD or CF, who were treated at the Hadassah Medical Center from 2007 to 2011 and for whom spirometry, HRCT scan, sputum cultures, and pancreatic sufficiency test data were available, were included in the study. The study was approved by the Hadassah Medical Center Institutional Review Board, and written informed consent was waived (Committee on Research Involving Human Subjects of the Hebrew University—Hadassah Medical School, 0324-08-HMO).

The CF and PCD Centers at the Hadassah Medical Center maintain databases for their patients from the time of diagnosis. These patients present at the clinic routinely every 1 to 3 months and are seen by the same specialist staff. However, patients with PCD do not regularly consult with our nutritionist, in contrast to patients with CF. Besides this exception, a similar routine follow-up is performed for the three patient groups, namely, frequent visits, pulmonary function and sputum culture at each visit, and chest CT scans every 2 years. PCD is diagnosed according to typical clinical presentation together with low nasal nitric oxide and abnormal ciliary morphology on electron microscopy and/or abnormal ciliary beat pattern and/or two PCD known mutations15 (Table 1), whereas CF is diagnosed according to the consensus statement of the Cystic Fibrosis Foundation.18

Table Graphic Jump Location
Table 1 —Diagnostic Parameters of Patients With PCD

AOM = acute otitis media; DA = dynein arms; EM = electron microscopy; Feno = fractional exhaled nitric oxide; IDA = inner dynein arm; NO = nitric oxide; ODA = outer dynein arm; PCD = primary ciliary dyskinesia; ppb = parts per billion; TTN = transient tachypnea of the newborn.

Pancreatic function was defined in all patients based on 3-day stool fat collection, fecal elastase assessment, or both. Pancreatic insufficiency was defined as stool elastase < 100 μg/g stool or coefficient of fat absorption < 93%.

Pulmonary function tests were performed according to American Thoracic Society/European Respiratory Society guidelines.19 Patients able to complete spirometry tests, usually those > 5 years of age, were included. FEV1 was presented as a % predicted value according to Wang et al20 for children and Hankinson et al21 for adults.

Periodic HRCT scans were performed for all patients as part of the routine assessment, using dual-slice CT scanner (Twin Flash; Marconi Medical Systems), four-slice multidetector spiral CT scanner (Light Speed Plus; General Electric), or 16-slice scanner (Light Speed; General Electric). Images were acquired using standard scan parameters, including a maximum 120 kVp, auto-mA (maximal-350 mA), pitch-1, and 512 × 512 matrix. Slice width was 3.75 to 5 mm for conventional scans and 1 to 1.25 mm for high-resolution images, reconstructed with a bone algorithm. HRCT scans were obtained in a single breath-hold during suspended end-inspiration, in supine position, without contrast material injection. HRCT scan studies were jointly reevaluated on lung and mediastinal windows by an experienced pediatric radiologist (N. S.) and an experienced chest radiologist (N. H.), both blinded to the patient group, using the institutional PACS system (Centricity PACS; General Electric).

Lung changes were assessed on high-resolution images in the lung window. For each lung lobe, including the lingula, counted as a separate lobe, the Brody score22 was calculated with a slight modification, namely, hyperaeration of the lungs was evaluated instead of air trapping, as expiratory images were not obtained in all patients. Such modification of the Brody score has been used previously.23 Briefly, subscores for the presence and severity of bronchiectasis, mucous plugging, bronchial wall thickening, parenchyma, and focal hyperaeration in each lobe were calculated. Parenchymal findings of ground glass, consolidation, and cysts or bullae were all considered in determining a single parenchyma subscore.22 The sum of subscores constituted lung total Brody scores (TBSs) for each patient.

For the current analysis, in patients who had more than one HRCT scan during the study period, the most recent study was considered and correlated with clinical parameters that were performed closest to the date of HRCT scan. BMI was calculated for all patients. For those < 20 years of age, BMI was presented as percentile for age, and for those ≥ 20 years, the corresponding BMI percentile was calculated, facilitating comparisons.24

Sputum cultures were obtained routinely at every clinic visit, using the same microbiologic culture methods for patients with PCD and CF. Chronic infection was defined when patients had at least three positive cultures within 1 year.

For this cross-sectional study, all parameters were calculated using descriptive statistics and percentile methods. Groups were compared using the Student t test, one-way analysis of variance, or nonparametric Pearson χ2 test. Correlations between continuous variables were evaluated with Pearson correlation, whereas correlations between nonparametric variables were evaluated with Spearman ρ correlation. Continuous data are expressed as mean ± SD unless otherwise specified. A two-tailed P < .05 was considered significant. All statistical analysis was performed with SPSS software (IBM).

A total of 164 patients, 34 with PCD and 130 with CF (88 with CF-PI [67.7% of patients with CF, 53.7% of the study population] and 42 with CF-PS [32.3% of CF and 25.6% of all patients]), were enrolled. Table 2 summarizes the clinical presentation of all patients. Patients with PCD and CF-PI were similar in age and younger than the CF-PS group (P = .074 and 0.014, respectively). Additionally, PCD was diagnosed at a significantly later age compared with the total CF group (P = .002) but at a similar age as CF-PS.

Table Graphic Jump Location
Table 2 —Parameters of Patients With PCD, CF-PI, and CF-PS

CF = cystic fibrosis; CF-PI = cystic fibrosis with pancreatic insufficiency; CF-PS = cystic fibrosis with pancreatic sufficiency. See Table 1 legend for expansion of other abbreviation.

a 

Comparison between the three groups.

Mean FEV1 was similar in the three groups (Table 2). As shown in Figure 1, there was a strong negative correlation between FEV1 and age in CF-PI and CF-PS (r = −0.348, P = .018, and r = −0.474, P = .022, respectively), whereas in PCD the correlation between age and FEV1 did not reach statistical significance (r = −0.358, P = .061). However, the rate of change in FEV1 with age was similar in PCD and CF-PS (B = −0.636, P = .061, and B = −0.683, P = .022, respectively) and significantly lower than in CF-PI (B = −1.082, P = .018), suggesting that in PCD, the decrease in lung function with age is similar to CF-PS and slower than in CF-PI.

Figure Jump LinkFigure 1. The relationship between age and pulmonary function assessed by FEV1 in patients with PCD, CF-PI, and CF-PS. CF-PI = cystic fibrosis with pancreatic insufficiency; CF-PS = cystic fibrosis with pancreatic sufficiency; PCD = primary ciliary dyskinesia.Grahic Jump Location

Patients with PCD had less severe lung disease, measured by TBS, compared with CF (P = .019); however, different results were found when analyzing the CF subgroups separately (Table 3). The severity of TBS was similar for PCD and CF-PS (TBS of 30.8 for PCD vs 31.4 for CF-PS) and significantly higher in patients with CF-PI (TBS of 57.3, P < .001), again indicating a similar lung disease severity in PCD and CF-PS. For all groups, the level of lung disease was similar in both sides; however, the distribution of structural changes within the lung fields varied significantly: In PCD, 56% of TBS was assigned to the right middle lobe and lingula and 38% to the lower lobes, whereas only 6% was attributed to the upper lobes (P < .001). In contrast, in CF-PI, the upper lobes represented 39% of TBS (P = .005 for comparison between the upper, middle, and lower lobes in CF-PI). In CF-PS, no particular distribution of pathology was found in HRCT scan (P = .330).

Table Graphic Jump Location
Table 3 —Chest HRCT Scan TBS of Patients With PCD, CF-PI, and CF-PS

HRCT = high-resolution CT; TBS = total Brody score. See Table 1 and 2 legends for expansion of other abbreviations.

a 

Comparison between the three groups.

As shown in Figure 2, no correlation was seen between FEV1 and TBS in PCD (r = 0.08, P = .71), whereas there was a strong negative correlation between TBS and FEV1 for both CF subgroups (CF-PS: r = −0.564, P = .005; CF-PI: r = −0.583, P < .001). Patients with PCD had a significantly lower BMI compared with the CF group (P < .001) and with the CF-PI and CF-PS subgroups (P = .006 and P = .001, respectively). As expected, a strong positive correlation between BMI and FEV1 in CF-PI (r = 0.338, P = .007) and a trend toward a significant correlation for the PCD group (r = 0.438, P = .06) was observed. No correlation between BMI and FEV1 in CF-PS was found (r = −0.05, P = .77) (Fig 3).

Figure Jump LinkFigure 2. The relationship between pulmonary function assessed by FEV1 and TBS in high-resolution CT images of patients with PCD, CF-PI, and CF-PS. TBS = total Brody score. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. The relationship between FEV1 and BMI of patients with PCD, CF-PI, and CF-PS. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

The most common bacterial infection in PCD was Haemophilus influenzae, whereas for both CF subgroups P aeruginosa was predominant (Table 4). The rate of P aeruginosa infection in the PCD group was relatively high and similar to the CF-PS group. For both CF-PI and CF-PS groups, chronic infection with P aeruginosa was associated with reduced FEV1 (r = −0.382, P < .001) and with more severe TBS (r = 0.513, P < .001) (Fig 4); however, among patients with PCD, there was no correlation between P aeruginosa infection and FEV1 (r = 0.209, P = .29) or TBS (r = 0.234, P = .26).

Table Graphic Jump Location
Table 4 —Bacterial Sputum Cultures of Patients With PCD, CF-PI, and CF-PS

Data presented as % of patients. MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive Staphylococcus aureus. See Table 1 and 2 legends for expansion of other abbreviations.

Figure Jump LinkFigure 4. Correlation between P aeruginosa colonization and TBS. P. aeruginosa = Pseudomonas aeruginosa. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location

To our knowledge, this is the first study comparing disease expression between PCD and CF, analyzing separately CF-PI and CF-PS. Patients with PCD, like those with CF-PS, do not suffer from pancreatic insufficiency and are generally diagnosed at a later age compared with patients with CF-PI. In PCD, in contrast to results seen for both CF groups, no correlation between FEV1 and TBS or between FEV1 and age was found. For PCD, these data provide further support that FEV1 is not a strong predictor for lung disease severity.17,2527 Therefore, in the absence of strong markers, follow-up by chest HRCT scans should be considered. To compare lung structural abnormalities between the three groups, the Brody score system was used, as described previously for patients with PCD.17 The risk of radiation must be considered; therefore, a modification of the low-radiation protocol described by Loeve et al28 should be used for the follow-up. Although images are of lower quality, they suffice for monitoring progression of lung disease. The disparity in the distribution of lung structural changes between the three groups was not necessarily to be expected. It is unclear why structural damage of the lungs in PCD only scarcely involved the upper lobes; however, this could be due to gravitation augmenting mucus clearance. In CF, mechanical factors may possibly favor mucus stasis and progressive dilatation of bronchi and cysts in the upper lobes,29 or early or more severe gastroesophageal reflux in CF could lead to the observed damage. Differences in regional blood flow distribution for both diseases may be considered as well.

We hypothesized that patients with PCD would have a nutritional status and respiratory disease similar to that of patients with CF-PS, as both groups do not show pancreatic insufficiency. Unexpectedly, we found that patients with PCD had a worse nutritional status than patients with CF-PI. Maintaining good nutrition is a fundamental component of medical management for patients with CF. However, in PCD, the focus on nutrition is not part of the standard of care.30 The direct correlation between BMI and FEV1 in our patients with PCD emphasizes the need to include routine nutritional assessment as part of the routine PCD management. Assessment and correction of nutritional deficiencies may prevent or slow disease progression in PCD, as it does in CF.

Rates of bacterial infection detected by sputum cultures differed between the three groups. The most common bacterium observed in patients with PCD was H influenzae, which was significantly less common in patients with CF. In patients with CF as a group, as in both subgroups as well, chronic infection with P aeruginosa was associated with more severe lung disease, and reduced FEV1 (Fig 4). However, no correlation between P aeruginosa infection and FEV1 or TBS was observed in PCD, suggesting a different role for this microorganism in the pathogenesis of pulmonary disease.

Although both PCD and CF are associated with impaired MCC, the type of impairment and its relative contribution to lung damage is different for the two diseases. It was shown that in CF, MCC is preserved in young patients and those with mild lung disease,31 whereas patients with PCD have no MCC from birth, which may explain their neonatal respiratory distress and middle ear problems rarely seen in CF. Cough clearance is well preserved in PCD, whereas in CF it is dramatically decreased (by tenacity), again arguing for immune dysregulation as being most important for the pathogenesis and progress of CF.32,33 The principal problem in CF is probably a hyperinflammatory response.34,35 CF sputum has been shown to be nonviscous, but rather tenacious. This is a surface property that is influenced by polymeric DNA and actin. Bush et al16 compared mucus properties in both diseases, showing that inflammation, measured by IL-8 concentration, was greater in PCD sputa. No significant differences in the sputum biophysical or transport properties were seen; however, survival in patients with PCD was generally better. Another study, by Santamaria et al,17 compared pulmonary HRCT scan scores for patients with PCD and a group of age- and sex-matched patients with CF. They showed that patients with PCD had significantly less structural lung damage than patients with CF. In our study, patients with CF-PI had worse FEV1 and TBS compared with patients with PCD, suggesting that other causes, in addition to impaired MCC, are responsible for the higher pulmonary morbidity in CF. Epithelial cell dysregulation, excessive airway inflammation, and innate immune deficiency in CF were recently described.4,34,35 It is important to note that, in general, patients with PCD receive less intensive therapy,30 and in our experience, many do not adhere to the scheduled visits and to the routine treatments, although there is also published evidence of suboptimal treatment adherence for patients with CF. Standard care for patients with PCD in our center consists of treatment with rotating oral antibiotics, daily inhalations with hypertonic saline, physiotherapy, and monthly follow-up. Many of these modalities are used in CF, although no evidence for their efficacy was demonstrated in PCD.36 Nevertheless, the results of this study show that adults with PCD do have better pulmonary functions, reaffirming that disease progression in most patients is slower than in CF.

PCD and CF are both characterized by impaired MCC and respiratory infections; nevertheless, patients with PCD have different disease expression compared with patients with CF-PS and CF-PI, as assessed by FEV1, HRCT scan, BMI, and bacterial infection detected by sputum cultures. Mean FEV1 was comparable for the three groups. In PCD, FEV1 was close to normal even for patients with severe structural lung damage with no substantial change with age. This may suggest more involvement of the large airways in PCD, whereas in CF small airways are more affected. Furthermore, P aeruginosa infection was less common in PCD than in both CF groups and was not associated with worse lung disease.

In conclusion, comparison of disease characteristics for PCD and CF should distinguish between CF-PI and CF-PS as different entities. Further studies are needed to understand the implications of these results and the correlation between CT scan findings and outcome in PCD.

Author contributions: Prof Kerem is guarantor of the manuscript, taking responsibility for the integrity of the data and accuracy of the data analysis.

Dr Cohen-Cymberknoh: contributed to conception and design of the study, acquisition of data, analysis of the results, and revision of the manuscript and provided final approval of the version to be published.

Dr Simanovsky: contributed to performing the CT scans, analysis, calculations of TBS, and revision of the manuscript and provided final approval of the version to be published.

Dr Hiller: contributed to performing the CT scans, analysis, calculations of TBS, and revision of the manuscript and provided final approval of the version to be published.

Dr Gileles Hillel: contributed to acquisition of data, analysis of the results, and revision of the manuscript and provided final approval of the version to be published.

Dr Shoseyov: contributed to acquisition of data, analysis of the results, and revision of the manuscript and provided final approval of the version to be published.

Prof Kerem: contributed to conception and design of the study, acquisition of data, analysis of the results, and revision of the manuscript and provided final approval of the version to be published.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

CF

cystic fibrosis

CF-PI

cystic fibrosis with pancreatic insufficiency

CF-PS

cystic fibrosis with pancreatic sufficiency

CFTR

cystic fibrosis transmembrane conductance regulator

HRCT

high-resolution CT

MCC

mucociliary clearance

PCD

primary ciliary dyskinesia

TBS

total Brody score

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Figures

Figure Jump LinkFigure 1. The relationship between age and pulmonary function assessed by FEV1 in patients with PCD, CF-PI, and CF-PS. CF-PI = cystic fibrosis with pancreatic insufficiency; CF-PS = cystic fibrosis with pancreatic sufficiency; PCD = primary ciliary dyskinesia.Grahic Jump Location
Figure Jump LinkFigure 2. The relationship between pulmonary function assessed by FEV1 and TBS in high-resolution CT images of patients with PCD, CF-PI, and CF-PS. TBS = total Brody score. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. The relationship between FEV1 and BMI of patients with PCD, CF-PI, and CF-PS. See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Correlation between P aeruginosa colonization and TBS. P. aeruginosa = Pseudomonas aeruginosa. See Figure 1 and 2 legends for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Diagnostic Parameters of Patients With PCD

AOM = acute otitis media; DA = dynein arms; EM = electron microscopy; Feno = fractional exhaled nitric oxide; IDA = inner dynein arm; NO = nitric oxide; ODA = outer dynein arm; PCD = primary ciliary dyskinesia; ppb = parts per billion; TTN = transient tachypnea of the newborn.

Table Graphic Jump Location
Table 2 —Parameters of Patients With PCD, CF-PI, and CF-PS

CF = cystic fibrosis; CF-PI = cystic fibrosis with pancreatic insufficiency; CF-PS = cystic fibrosis with pancreatic sufficiency. See Table 1 legend for expansion of other abbreviation.

a 

Comparison between the three groups.

Table Graphic Jump Location
Table 3 —Chest HRCT Scan TBS of Patients With PCD, CF-PI, and CF-PS

HRCT = high-resolution CT; TBS = total Brody score. See Table 1 and 2 legends for expansion of other abbreviations.

a 

Comparison between the three groups.

Table Graphic Jump Location
Table 4 —Bacterial Sputum Cultures of Patients With PCD, CF-PI, and CF-PS

Data presented as % of patients. MRSA = methicillin-resistant Staphylococcus aureus; MSSA = methicillin-sensitive Staphylococcus aureus. See Table 1 and 2 legends for expansion of other abbreviations.

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