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Pulmonary Radioaerosol Mucociliary Clearance in Diagnosis of Primary Ciliary Dyskinesia^*

^* From the Pediatric Pulmonary Service and Cystic Fibrosis Centre (Drs. Marthin, Pressler, and Nielsen), Department of Pediatrics, Clinic I, Juliane Marie Centre, and the Department of Clinical Physiology and Nuclear Medicine (Dr. Mortensen), Diagnostic Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Correspondence to: Kim Gjerum Nielsen, Dr Med Sci, Pediatric Pulmonary Service and Cystic Fibrosis Centre, Department of Pediatrics, Clinic I, Juliane Marie Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; e-mail: kgn{at}dadlnet.dk

Abstract

Background: Methods relying on nasal ciliary motility for the diagnosis of primary ciliary dyskinesia (PCD) are often hampered by secondary ciliary dyskinesia. A functional test for pulmonary mucociliary clearance, which is not influenced by secondary nasal ciliary defects, would be a valuable tool in a PCD workup.

Methods: The diagnostic validity and repeatability of a pulmonary radioaerosol mucociliary clearance (PRMC) test for the diagnosis of PCD was assessed in the following three sequentially performed substudies: (1) a preliminary cross-sectional study of PRMC in patients with known PCD; (2) a prospective blinded trial of patients referred for suspicion of PCD; and (3) an implementation study of PRMC as a routine method used in a PCD workup. PRMC was studied after ^99mTc-albumin colloid aerosol inhalation, and the results were compared to (1) the results of nasal ciliary motility studies, (2) ciliary ultrastructure, and (3) the final clinical diagnosis. The repeatability of PRMC was assessed in 14 patients.

Results: A total of 95 patients, 5 to 74 years of age, were included in the study (57 patients in whom PCD was diagnosed, 26 non-PCD patients, and 12 patients referred for PCD workup without a conclusive workup result). In substudy 1, 14 of 15 patients with known PCD showed impaired PRMC; the results were inconclusive in 1 patient. In substudy 2, among 59 patients referred for PCD workup PRMC test results, compared to nasal ciliary motility, showed a sensitivity of 88% and a specificity of 100%. In substudy 3, among 21 patients referred for PCD investigation who were included in a routine PCD workup after PRMC implementation, 71% of PRMC test results were in alignment with nasal ciliary motility. Repeatability of interpretation was seen in 13 of 14 cases. A conclusive PRMC after only one test was found in 81 of 95 patients (85%).

Conclusion: PRMC is a noninvasive functional test for total tracheobronchial mucociliary clearance with a high sensitivity and specificity for PCD, a high rate of conclusive results after only one test and a further ability to separate PCD from focal pulmonary mucociliary defects.

Key Words: mucociliary clearance • primary ciliary dyskinesia • secondary ciliary dyskinesia • ^99mTc-albumin colloid • tracheobronchial transport

A single test for the definitive diagnosis of primary ciliary dyskinesia (PCD) has yet to come. Until then, the workup of patients with PCD has relied on the combination of ciliary function analysis and electron microscopic (EM) examination of the ultrastructure, preferably after in vitro regeneration. Nasal nitric oxide measurement is a promising tool in PCD workup for screening and excluding PCD.¹ However, further investigations will still be needed when low nasal nitric oxide values indicate the presence of PCD in order to confirm or exclude PCD.

Hence, at present the diagnosis of PCD is complex and time consuming, yet not always exact, and the true incidence is most likely underreported.² The early diagnosis of PCD is important since early and aggressive management of lower airway infection is crucial in preventing bronchiectasis and reduced lung capacity.³

In patients with PCD, mucociliary transport is impaired as a result of abnormal ciliary motion. In this study, we applied a method based on clearance patterns after the inhalation of a radioaerosol tracer as a whole-lung functional test for pulmonary radioaerosol mucociliary clearance (PRMC) used as an adjunctive test in the workup of patients with proven and suspected PCD. PRMC is noninvasive and applicable to children older than approximately 5 years of age.

Aim

The aim of this three-part study was as follows: (1) to describe PRMC in a preliminary study by testing it on a population of patients with known PCD; (2) following that, to assess the diagnostic validity (ie, sensitivity, specificity, and positive and negative predictive values) in patients referred for a PCD workup in a blinded trial by testing PRMC against nasal ciliary motility studies; and (3) after acceptance of PRMC as a valid method based on the results of substudies 1 and 2, to implement PRMC in a routine PCD workup of a group of referred patients to evaluate the value of PRMC as a supplementary diagnostic test for PCD.

Furthermore, a comparative study of high-resolution CT (HRCT) scanning and PRMC was performed in patients from substudies 2 and 3 in whom PRMC showed regional lung clearance defects in order to evaluate whether a regional abnormal PRMC could predict the localization of bronchiectasis that had been demonstrated on an HRCT scan. Finally, a study of the repeatability of PRMC interpretation for the diagnosis of PCD was performed.

Methods and Materials

Patients
We studied 95 patients, all of whom were referred to the National PCD Centre in Copenhagen for workup due to a clinical suspicion of PCD. Prior to study inclusion, cystic fibrosis was ruled out. Tests were performed at least 4 to 6 weeks after the occurrence of an acute upper or lower respiratory tract infection. In case of inconclusive tests, repeated testing was performed after treatment with antibiotics for 6 weeks. PRMC was allowed to be performed up to three times and a ciliary motility test was allowed to be performed up to five times in cases of inconclusive initial results. In cases of abnormal ciliary motility, the test would always be repeated at least once to exclude the possibility of secondary ciliary dysfunction, and only in cases of normal nasal ciliary motility would one test be considered acceptable. The study was designed as a three-part study:

Preliminary Cross-Sectional Study To Validate PRMC: In 1998, patients with known PCD were included for PRMC. PCD had been previously diagnosed in all patients as the result of an abnormal ciliary ultrastructural and an abnormal ciliary function test finding. The PCD diagnosis was known to the PRMC reader in this substudy.

Prospective Blinded Trial of Referred Patients With Suspected PCD: During a 3-year period (from 1999 to 2001), we consecutively included patients who had been referred and were suspected to have PCD and were > 5 years of age for evaluation by PRMC. All patients were additionally investigated routinely by nasal ciliary motility test for ciliary beat frequency and motion pattern analysis. Throughout this 3-year period, the PRMC reader was blinded to the results of nasal ciliary motility investigation, and the evaluation of PRMC results was not performed before all included patients were finally diagnosed. PRMC results were then compared to the results of (1) nasal ciliary motility, (2) EM ultrastructure, and (3) final clinical diagnosis.

A 1-Year Implementation Study of PRMC as a Routine Method in PCD Workup: In 2002, new patients who were > 5 years of age and had been referred for a PCD workup underwent PRMC as part of the investigation. The PRMC reader was blinded to the results of the nasal ciliary motility investigation. The results of a PRMC test were passed on to the pediatric department where the interpretation of those results was used equally to ciliary motility studies and EM studies when coming to a final clinical diagnosis of a referred patient.

Regional Lung Clearance Defects
Subjects from substudies 2 and 3 with a regional abnormal clearance pattern were further investigated by HRCT scan. The site for regional abnormal clearance on the PRMC test was then compared to the localization of structural defects on HRCT scans. The radiologists interpreting the HRCT scans were blinded to the PRMC test result. The PRMC reader was blinded to the HRCT scan in cases in which the HRCT scan was performed before the PRMC test.

Repeatability of PRMC Test Interpretation
From a randomly selected sample of subjects participating in substudies 1 and 2, an intraobserver repeatability test of interpretation was performed. The original raw data of radioaerosol measurements in 14 patients were deidentified, reanalyzed, and reread in a single-blinded manner by the same reader 11 months to 5 years after the first reading. The reader was blinded to the original PRMC result as well as to the results from ciliary function analysis, ultrastructure, and final diagnosis.

Radioaerosol Inhalation and Imaging
The radioaerosol technique has been described earlier.⁴⁵ In brief, the patients inhaled ultrasonically (model 35 B; Devilbiss; Somerset, PA) nebulized ^99mTc-albumin colloid (Venticoll; GI PHARMA; Saluggia, Italy). The mass median aerodynamic particle diameter was 3.4 µm (geometrical SD, 1.9 µm [as measured by Cascade Impactor; Intox; Albuquerque, NM]) during tidal breathing by 20 slow inspirations and forced expirations. Inhalation volume was not measured. The radioaerosol was administered during the whole inspiration phase. The patients exhaled forcefully immediately after inspiration without a breathhold. Immediately following the radioaerosol inhalation, the patients rinsed their mouth by gargling three times. Then, the subjects were placed in the supine position against a posteriorly positioned gamma camera for detecting lung radioactivity. If a target rate of 1,000 counts per second (equivalent to approximately 0.5 mSv) was not obtained, a number of extra inspirations were performed. Measurements of pulmonary radioactivity were performed for 2 h as dynamic acquisitions in the first hour and as static acquisitions at 0, 30, 60, 90, and 120 min. A 15-min static measurement after 24 h served as an index of the deposition onto nonciliated airways (called alveolar deposition). Mucociliary clearance was calculated over both lungs as the whole-lung retention after 1 h (LR1) and 2 h (LR2) corrected for background and physical decay. Regional ventilation distribution was visualized by a ^81mKr-gas scintigram. The initial ^99mTc aerosol distribution was compared to the ^81mKr ventilation distribution to indicate how far the radioaerosol had penetrated into the airways and lungs (ie, reflecting the length of the path that the ^99mTc aerosol had to move before being cleared from the airways). This penetration index (PI) was used to calculate each subject’s predicted values for LR1 and LR2 from our previously published reference equations.⁵ In this study, although based on incomplete data, a comparison of the initial aerosol delivery was performed between patients with normal 24-h picture findings (ie, non-PCD patients) and patients with abnormal 24-h picture findings (ie, PCD and regional abnormal PRMC results in non-PCD patients) to assess whether these two groups differed in mean PI.

A lung retention value of the expected + 1.67 SD represented the calculated upper limit for lung retention in an individual. The difference between measured lung retention and predicted lung retention was given by the term residual SD (RSD) for LR1 and LR2, respectively.

An example of the calculation of normal range and RSD in an individual is demonstrated in the ^Appendix. In addition to the static acquisitions, two 20-min dynamic acquisitions (films) were obtained in the first hour on the first day. This dynamic part of the investigation was used to assess large airway mucus transport. When bolus transport occurred, distinctive radiomucous boli were formed in the tracheobronchial area and were seen to ascend the mainstem bronchi and the trachea (Fig 1 ; Fig 1A, online material). This transport rate was visually assessed as normal, abnormal (ie, slow/absent/retrograde), or inconclusive.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. A series of 9 x 2 min dynamic acquisitions of tracheobronchial bolus transport in a healthy individual. Top left, 1: initial dynamic picture. In this series of pictures, every picture represents 2 min of clearance. Boluses of mucus are seen to ascend upward from the main bronchi to the trachea (top left, 1, to middle center, 5) ascending further up the trachea (middle right, 6, to bottom center, 8) to be fully cleared from the trachea at the last acquisition (bottom right, 9). The swallowed radioaerosol is seen to pass from the stomach further to the duodenum and jejunum.

All of these three parameters need to be in concordance for the test to be conclusive. The PRMC test results can then be interpreted as normal, abnormal, or regional abnormal (Fig 2 ). An inconclusive PRMC test result usually results from one of the following causes: cough; initial very peripheral radioaerosol deposition; or inconsistency among LR1 and LR2 values, tracheobronchial bolus transport, and 24-h retention. Cough during the 2 h of static acquisitions can result in an inconclusive test result as the measured clearance may be a result of cough clearance instead of clearance due to ciliary function. Otherwise, a patient with a true abnormal clearance pattern can mistakenly be interpreted as having normal clearance due to cough clearance (ie, a false-negative result). Yet, the occurrence of an abnormal mucociliary clearance despite coughing is still reliable (ie, a true-positive result). Cough and throat clearing were therefore monitored during the 2 h of static acquisitions by a staff member, who registered the number and time of the coughs. In case of cough or extensive throat clearing and an apparently normal clearance, the test result would be interpreted as inconclusive. Initial peripheral deposition may also result in an inconclusive test result, as the LR1 + LR2 values would be falsely high due to the increased length of the pathway, although the breathing pattern of slow inspirations followed by forced expirations serves to promote the preferential deposition of the radioaerosol in the central airways.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Three examples of static acquisitions showing initial aerosol deposition, the remaining aerosol deposition after 2 h and after 24 h in an abnormal, a normal, and a regionally abnormal PRMC test. Top row: abnormal PRMC test result. The radioaerosol is seen initially centrally deposited, and still very little is cleared after 2 h. The remaining foci are present after 24 h. Two 57Co markers seen over the cervical and lumbar spine were placed initially to help positioning the subjects. Bolus transport was very slow (not shown). The LR2 was 92% (expected, 65%; upper normal limit, 80%), corresponding to + 2.8 RSDs (ie, 2.8 SDs above the expected retention; PI, 0.123). Abdominal situs inversus is seen in this patient. Center row: normal PRMC (LR2, 54%; expected, 73%; upper normal limit, 88%), corresponding to –2.0 RSDs (ie, 2.0 SDs below the expected retention; PI, 0.436). Bottom row: regional abnormal PRMC (LR2, 75%; expected, 68%; upper normal limit, 83%), corresponding to + 0.8 RSD but within the normal range (PI, 0.140).

Final Clinical Diagnosis
The clinical workup included spirometry (ie, FEV₁ and FVC or plethysmographic specific airway resistance if the patient was unable to perform spirometry), chest radiograph, HRCT scan, and ear, nose, and throat evaluation in the ear-nose-throat department. The final clinical diagnosis was based on the combination of the following three factors: (1) nasal biopsy studies of function and ultrastructure; (2) history and symptoms; and (3) results of the clinical workup.

Statistical Analysis
Sensitivity, specificity, and positive and negative predictive values were calculated when comparing PRMC results with ciliary motility results, EM analysis, and the final stated clinical diagnosis, respectively. Confidence intervals (CIs) for sensitivity and specificity were calculated. statistics was applied in the intraobserver repeatability-test of interpretation as a measure for the strength of agreement.

Median and range were given for PI values. A two-sample t test for means was used for the comparison of PI between patients with normal and abnormal 24-h retention study results. A 5% level was considered to be significant.

Ethics
The study was approved by the local ethics committee of Copenhagen, and the study was performed in concordance with the Declaration of Helsinki II. Informed consent was obtained from all participating patients.

Results

A total of 95 patients (age range, 5 to 74 years) were included in this three-part study. Among the 95 patients, the 15 patients from substudy 1 were already known to have PCD, in substudy 2 PCD was diagnosed in an additional 36 patients, and in substudy 3 PCD was diagnosed in an additional 6 patients. PCD was ruled out in 26 patients in substudies 2 and 3. Hence, the study population consisted of 57 patients with a confirmed diagnosis of PCD, 26 non-PCD patients, and 12 patients who had been referred for a PCD workup without a conclusive workup result.

Preliminary Cross-Sectional Study To Validate PRMC
LR1 and LR2 were compared to expected normal values based on previously published reference material comprising 62 healthy nonsmokers.⁵ In 14 of 15 patients (93%) with known PCD (median time since diagnosis, 12 years; range, 4 to 17 years), PRMC test results were abnormal, which is in alignment with their diagnosis.

In one case, the PRMC test was inconclusive due to severe coughing during static acquisitions, and lung retention values were within the normal range due to cough clearance (Table 1 ). In another case, the predicted value could not be calculated since PI calculations could not be performed due to failed missing delivery of krypton gas from the producer. However, as this patient had 99% of the radioaerosol left after both 1 h and 2 h, the mucociliary clearance was still interpreted as being abnormal (Table 1). The median PI for patients in this substudy was 0.345 (range, 0.168 to 0.708; 7 of 15 patients) [values are shown in Table 1].

In all three cases of discrepancy (7%), PRMC was normal, whereas ciliary motility was abnormal, suggesting the presence of PCD. However, in the end PCD was ruled out in all three patients on the basis of the final diagnosis (Table 3 ). In this substudy, median PI was 0.367 (range, 0.110 to 0.768; 33 of 59 patients).

PRMC gave conclusive results after a single test in 81 cases (85%). In the remaining 14 cases, 11 patients underwent PRMC twice and 3 patients underwent PRMC more than twice (three times for 2 patients and four times for 1 patient). In comparison, the mean (± 2 SDs) number of ciliary motility investigations performed per patient was 3.1 ± 2.0.

Regional Lung Clearance Defects
HRCT scanning was performed in nine non-PCD patients with regional abnormal PRMC results. HRCT scans showed concordance between the localization of bronchiectasis seen on HRCT scans and focal PRMC retention in five of seven cases (71%). One patient had signs of atelectasis at the site of regional clearance defect. One patient with normal HRCT scan findings and two patients with bronchiectasis seen on HRCT scans demonstrated isolated clearance defects in the trachea (Table 5 ). In the latter of these two patients, repeated PRMC study results were normal (LR1, –3.0 RSD; LR2, – 4.0 RSD; normal bolus transport; normal 24-h picture), which could indicate that the abnormal clearance pattern that was initially seen was caused by a temporary tracheitis. HRCT scans were repeated but unfortunately were inconclusive in this patient due to artifacts. In the end, this patient became symptom free and was finally discharged from the hospital 3 years after referral for suspicion of PCD and undergoing the initial HRCT scan. Median PI was 0.394 (range, 0.163 to 0.632; five of nine patients).

Discussion

This is the first study of PRMC comprising a larger population of PCD patients and also the first study in which PRMC has been applied in a routine clinical setting for diagnosing PCD. Our study of PRMC studies applied to known PCD patients confirmed PRMC to be a highly valid functional test for detecting impaired tracheobronchial clearance in patients in whom PCD had previously been diagnosed by the presence of abnormal nasal ciliary motility and ultrastructure.

In the prospective blinded trial on referrals for PCD workup, PRMC showed high sensitivity and specificity when compared to the standard routine PCD investigation. In the 1-year follow-up after the implementation of PRMC in our routine PCD workup, PRMC results highly supported the results of our usual workup and clinical diagnoses.

At present, diagnosing PCD requires ciliary beat frequency and motion pattern analysis together with EM studies of the ciliary ultrastructure. However, secondary ciliary defects due to viral and bacterial infection are well known.⁶⁷ Secondary ciliary defects frequently lead to inconclusive ciliary motion pattern analysis with the need for subsequent repeated investigations and/or in vitro regeneration of the cilia.⁸⁹ A study from Jorissen et al⁸ reported a finding of uncoordinated ciliary activity in 20% of non-PCD biopsy specimens before in vitro regeneration. Ultimately, an EM study of the ciliary ultrastructure is the "gold standard" that should be used to confirm the diagnosis, although PCD with normal ultrastructure has been described.^8101112 Overall, an estimate of 10 to 25% of misdiagnoses even by the combination of ciliary function analysis and EM ultrastructure analysis has been presented in a large study⁸ of > 700 biopsy specimens that were evaluated for the presence of PCD and secondary ciliary defects. Repeated investigations are expensive and time consuming, and they postpone the final diagnosis. In our study, PRMC studies showed a favorable high rate of conclusive results after the first test compared to the results of the ciliary motility test.

The usual applied tests for measuring mucociliary clearance are the saccharin test or Tc-labeled albumin droplet test.¹³¹⁴¹⁵ A study¹⁶ of nasal mucociliary transport using nasally deposited ^99mTc-albumin colloid droplets demonstrated this test to be a potentially reliable tool in the exclusion of PCD, even in infants. However, these methods only assess the regional nasal mucociliary clearance. We believe PRMC to be superior to these tests as this is a functional test for the mucociliary clearance in all ciliated parts of the lower airways and is not influenced by local nasal secondary mucociliary defects.

Reported studies of PRMC in PCD are sparse and are restricted to a very limited number of PCD patients.¹⁷¹⁸¹⁹ In a study of 28 patients, Camner and colleagues¹⁷ showed all the patients who fulfilled the diagnostic criteria of having PCD to also have extremely low tracheobronchial clearance, whereas patients who did not have the criteria had some clearance, indicating that the measurement of tracheobronchial clearance was valuable not only to diagnose PCD, but was also valuable in excluding the disease. Pavia et al¹⁸ found a markedly reduced tracheobronchial clearance in one patient with Kartagener syndrome compared to nine healthy nonsmoking control subjects. Zwas and colleagues¹⁹ applied the measurement of tracheobronchial clearance to 13 patients with chronic lung disease, one of whom had PCD and bronchiectasis (the PCD patient showed a similar particle deposition pattern but a lower clearance rate compared to bronchiectatic non-PCD patients). In comparison to these studies, our study contains a very large population of PCD patients and is also the first study in which PRMC has been applied in a routine investigation setting for PCD workup. Our results, showing low tracheobronchial clearance in patients with PCD, are in alignment with those of these previous studies.

In cases of regional abnormal clearance, evaluation by HRCT scan was performed to compare the site of focal radioaerosol retention with the localization of bronchiectasis. We found an association between HRCT scan findings and PRMC study results (71%) for detecting regional mucociliary clearance defects, which is supported by a previous study,²⁰ suggesting the ability of this method to examine regional mucociliary clearance. In three cases, the regional abnormality was restricted to the trachea. The reason behind this was unclear, but one possible explanation could be mechanical disturbance due to frequent coughing that was caused by a recent infection. In one such case, a video bronchoscopy study was performed, but no abnormalities were demonstrated. All nine patients were finally determined to be non-PCD. This should be expected, since a PCD patient with bronchiectasis has a universally abnormal clearance pattern instead of a focal regional clearance defect.

There was a high repeatability of the interpretation of PRMC as agreeable diagnoses were seen in 93% of patients. In no case was the conclusion altered from normal to abnormal or vice versa. In our previous study⁴ of the repeatability of the same PRMC method, the intraobserver and interobserver variations were evaluated to distinguish between bronchiectatic patients and healthy control subjects; the observed agreement was then 0.96 and 0.92, respectively, for intraobserver and interobserver variations.

There are some limitations to PRMC measurement. (1) Children < 5 years of age cannot cooperate with a PRMC study. (2) There is exposure to radiation, although this is rather low (< 1 mSv) and compares favorably to the yearly background radiation (3 to 5 mSv in Denmark). (3) An inconclusive result due to coughing during the investigation is a most important factor. However, the rate of conclusive results after only one test was in favor of PRMC testing (85%) compared to nasal ciliary motility testing. Additionally, (4), the investigation is time consuming for the patient, who also has to attend the following day for a short (15-min) 24-h acquisition. Our reference material is based on healthy adult volunteers, for ethical reasons, because no normal reference material for children has been made available.⁵ It is however, our impression that children showing normal clearance have faster clearance rate than adults. If this is the case, a borderline normal clearance rate (when compared to the adult reference material) in a child then probably should be interpreted as being abnormal. A possible explanation for this apparently faster clearance in children could simply be that children have shorter airways and hence a shorter clearance path length, or it could be due to faster ciliary beating in children, as has been described.²¹ Finally, faster clearance in children could be the result of a more proximal deposition of the inhaled radioaerosol. Still, as we calculate PI as a measure of path length when interpreting the PRMC results, we take into account the interpersonal variance of aerosol deposition in any individual, adult, or child.

Our comparison of initial aerosol delivery in subjects with normal vs abnormal 24-h retention given by the calculated PI, showing no significant difference in PI values, was based on incomplete data. Still, the majority of the data was available, and we therefore consider the results for patients with abnormal 24-h retention not to be biased with a more peripheral initial aerosol deposition compared to the results in the normal 24-h retention group.

We stress that the use of PRMC as a diagnostic tool in PCD workups should be performed in a selected group of patients in whom PCD is suspected. Other patient groups with impaired mucociliary clearance (eg, cystic fibrosis patients) may show an overlap in clearance patterns; therefore, PRMC should not be used as a primary test for PCD.

Conclusion

In this study, we have evaluated PRMC as a functional test for mucociliary clearance in patients suspected of having PCD. PRMC is at present the only method for testing the mucociliary function in ciliated parts of the lower airways of an individual and is not influenced by local nasal secondary mucociliary defects.

We conclude from this study, that PRMC (1) has a high diagnostic validity and repeatability of interpretation in the diagnosis and exclusion of PCD in a selected group of patients who were referred for a PCD workup, (2) has a high rate of conclusive results after only one test compared to the nasal ciliary motility test, and (3) has the ability to detect regional clearance defects, which is useful for differential diagnoses. PRMC is proposed as a supplemental noninvasive method that is to be included in the armamentarium of PCD workup in patients > 5 years of age.

Appendix

The procedure for the calculation of reference values for PRMC and RSDs based on a multiple regression model⁵ is as follows:

Example
The predicted LR2 calculated for a 43-year-old woman (sex = 2; PI, 0.70) is as follows:

The normal range for the LR2 of this woman (comprising 95% of the population) is as follows:

or more correctly since abnormal mucociliary clearance can only be too slow:

In this patient with PCD, the measured lung retention after 2 h was 100% (ie, nothing cleared within 2 h).

Calculation of RSD for LR2 in This Patient

Thus, the measured 2-h retention lies 2.3 RSDs above the predicted value, which is abnormal (ie, all RSDs> 1.67 are abnormal).

Acknowledgements

We thank the bioanalytical technologists (especially Ulla Kernchen and Lene Højby) in the Department of Clinical Physiology and Nuclear Medicine for their help in performing the radioaerosol clearance studies; and bioanalytical technologist Marianne Moller Andersen in the Department of Pediatrics for performing the ciliary function analysis.

Footnotes

Abbreviations: CI = confidence interval; EM = electron microscopy; HRCT = high-resolution CT; LR1 = lung retention after 1 h; LR2 = lung retention after 2 h; PCD = primary ciliary dyskinesia; PI = penetration index; PRMC = pulmonary radioaerosol mucociliary clearance; RSD = residual SD

Dr. Marthin was supported during this work by a grant from SanCop Foundation.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication December 7, 2006. Accepted for publication May 18, 2007.

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