Lung Function in Patients with Primary Ciliary Dyskinesia A Cross-Sectional and 3-Decade Longitudinal Study

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1 Lung Function in Patients with Primary Ciliary Dyskinesia A Cross-Sectional an 3-Decae Longituinal Stuy June K. Marthin 1, Naia Petersen 1, Lene T. Skovgaar 2, an Kim G. Nielsen 1 1 Copenhagen University Hospital, Rigshospitalet, Danish PCD Center, Peiatric Pulmonary Service, Copenhagen, Denmark; an 2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark Rationale: Early iagnosis an treatment is consiere important to prevent lung amage in primary ciliary yskinesia (PCD). Objectives: Few stuies have aresse long-term evolution of lung function after PCD iagnosis. We investigate whether long-term lung function was epenent on age or level of lung function at PCD iagnosis. Methos: An observational, single-center, cross-sectional, an threeecae longituinal stuy of FEV 1 an FVC relate to age at iagnosis until current age was performe. Linear regression was use to escribe the relation between first measure lung function values an age at iagnosis across the cohort. Courses of lung function after iagnosis an the accoring slopes were use to group patients into increasing, stable, or ecreasing courses. Aitionally, slopes from courses of 10 years of follow-up were relate to age at iagnosis an initial level of lung function, respectively, using linear regression. Measurements an Main Results: Seventy-four chilren an aults with PCD were observe for meian 9.5 (range, ) years uring which 2,937 lung function measurements were performe. First measure FEV 1 was less than 80% of preicte in one-thir of preschool-iagnose chilren. During observation, 34% of patients lost more than 10 percentage points, 57% were stable, an 10% improve more than 10 percentage points in FEV 1. Courses of lung function after iagnosis were relate to neither age at iagnosis nor initial level. Conclusions: Our stuy strongly suggests that PCD is a isease of serious threat to lung function alreay at preschool age, an with a high egree of variation in courses of lung function after iagnosis that was not linke to either age or level of lung function at iagnosis. Early iagnosis i not protect against ecline in lung function. Keywors: ciliary motility isorers/physiopathology; longituinal stuies; respiratory function tests Primary ciliary yskinesia (PCD) is rare inherite isorer characterize by abnormalities in ciliary function an structure, although structure may be normal (1). Irreversible lung amage, ecrease quality of life, an in rare cases en-stage lung isease requiring lung transplantation are likely cause by frequent, recurrent, or chronic airway infections, precipitate by impaire airway mucociliary clearance. Although early iagnosis of PCD is generally consiere an important factor in preventing eterioration of lung function (2, 3), few stuies have aresse long-term evolution of lung (Receive in original form November 16, 2009; accepte in final form February 17, 2010) Corresponence an requests for reprints shoul be aresse to Kim G. Nielsen, Dr. Me. Sci.; Copenhagen University Hospital, Rigshospitalet, Danish PCD Center, Peiatric Pulmonary Service, Blegamsvej 9, DK-2100 Copenhagen, Denmark. kgn@alnet.k This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Me Vol 181. pp , 2010 Originally Publishe in Press as DOI: /rccm OC on February 18, 2010 Internet aress: AT A GLANCE COMMENTARY Scientific Knowlege on the Subject Previous longituinal stuies of lung function in primary ciliary yskinesia (PCD) inclue only a few patients. These stuies mainly showe stabilization of lung function after PCD iagnosis an initiate treatment, whereas ecrease in lung function after iagnosis has been reporte very rarely. What This Stuy As to the Fiel This stuy is the largest longituinal stuy reporte so far on evolution of lung function in PCD. Seventy-four patients were inclue. Follow-up range over 30 years an with a total of 2,937 spirometries performe. We foun a high egree of variation in the course of lung function after iagnosis. This variation was not linke to either age at iagnosis or level of lung function when iagnose. Thus, early iagnosis was not shown to protect against ecline in lung function espite treatment, pointing to the fact that much has yet to be learne about this isease. function in relation to age at iagnosis. Previous reports from Corkey an coworkers (4), Hellinckx an coworkers (5), an Ellerman an Bisgaar (6) have inicate that lung function can be stabilize after establishe PCD iagnosis an initiate treatment, even in patients with late iagnosis an poor lung function. In Denmark, patients with PCD were followe at the National Danish PCD Center in Copenhagen. This cohort was first initiate in the late 1970s (7) an inclues both chilren an aults with PCD. Bronchopulmonary symptoms in 27 patients from the present cohort have been previously reporte in 1983 (8). Later, Ellerman an Bisgaar (6) reporte longituinal lung function in 24 patients with iagnosis before an after the age of 18 years. They observe poorer lung function in patients with iagnosis in aulthoo, but i not fin eterioration of lung function in either groups once the iagnosis was establishe an routine care initiate, thereby suggesting that aggressive treatment coul prevent further lung amage once the iagnosis was establishe even if iagnosis was elaye (6). Our impression from aily clinical practice is that the preventive treatment effect on lung function ecline is unsatisfactory in patients with PCD an late iagnosis an more favorable in patients with early iagnosis espite similar treatment, as oppose to the finings of publishe stuies (4 6). We therefore hypothesize that evolution of long-term lung function after initiation of treatment is linke to age at PCD iagnosis an aime to investigate if pattern of long-term lung function iffere between patients with early an late PCD iagnosis. Some of the results of this stuy have been previously reporte in the form of an abstract (9).

2 Marthin, Petersen, Skovgaar, et al.: Long-term Lung Function in PCD 1263 METHODS Design The stuy was partly cross-sectional an partly esigne as an uncontrolle, observational, single-group, single-center, longituinal, an retrospective stuy of prospectively collecte lung function measurements in a PCD cohort. Subjects, Diagnosis, an Clinical Features Patients with PCD are followe lifelong at the National Danish PCD Center an were all eligible for the stuy. Because of the changing stanars of PCD work-up over the 30-year stuy perio, patients in this cohort were not uniformly iagnose. However, all patients ha a verifie abnormal function analysis of ciliary beat pattern an ciliary beat frequency in combination with a consistent history of symptoms of PCD an continuing clinical signs of PCD throughout follow-up. Aitionally, electron microscopy (EM) of ciliary ultrastructure, pulmonary raioaerosol mucociliary clearance (10), an nasal nitric oxie measurements was performe in most patients. Nasal nitric oxie was measure using NIOX (Nitric Oxie Monitoring System, Aerocrine, Solna, Sween) equipment with sampling of nasal nitric oxie uring breathhol to ensure soft palate closure in alignment with American Thoracic Society an European Respiratory Society recommenations (11). Our own reference values for nasal nitric oxie levels were use with a cut off value of 175 ppb (unpublishe ata). Inclusion Criteria Patients iagnose with PCD, as iscusse previously, an at least 1.5 years of follow-up with acceptable spirometries were eligible for the stuy. Exclusion Criteria Patients with uncertain iagnosis, poor cooperation to spirometry, or nonvali lung function measurements, an patients followe less than 1.5 years were all exclue. PCD Management at the National Danish PCD Centre The intentional treatment strategy for Danish patients with PCD is erive from cystic fibrosis (CF) care at our center (12), although patients with PCD are followe less closely (3-month versus monthly clinic visits) an consists of the following: Twice aily: Chest physiotherapy using a positive-expiratory pressure mask. Monthly: All patients are aske to sen sputum samples once every month. Enolaryngeal suction (using a nasal suction catheter) is performe whenever a patient (chil or ault) is unable to prouce a sputum sample. Every 3 months: Clinical examination for all patients an lung function measurements by spirometry (from approximately 5 years of age). Yearly: Chest x-ray; visit to ear-nose-throat epartment. Immeiate antibiotic treatment is initiate whenever a sputum or enolaryngeal suction sample is positive, even with only minor or absent clinical symptoms. Haemophilus influenzae an Moraxella catarrhalis are treate with 14 ays of amoxicillin with or without clavulanic aci an in some cases alternately macrolie for 14 ays (M. catarrhalis) to 3 months (H. influenzae). Pseuomonas aeruginosa is treate with colistin inhalation an oral ciprofloxacin for 30 ays whenever P. aeruginosa is culture positive in patients without chronic P. aeruginosa infection. When chronic infection exists, elective intravenous treatment is given for 14 ays every thir month. Data Collection Age, sex, clinical, an iagnostic parameters, combine with longituinal ata on height, FEV 1 (liter), an FVC (liter) were extracte from the PCD cohort atabase an from patient files. All PCD patients entere the PCD cohort at the time of their iagnosis an were then followe prospectively. Data were collecte post hoc. Spirometry Spirometry was performe as soon as the chil coul cooperate consistently, usually from 5 to 6 years of age, an continuously performe approximately every thir month hereafter. For each chil every flow volume curve was evaluate an exclue if technique was insufficient to minimize bias because of spirometry training. FEV 1 an FVC measurements were as per American Thoracic Society stanars (13). Values of both z score an percent preicte for both FEV 1 an FVC were calculate (14). Statistics Cross-sectional part of the stuy. Lung function (in percent of preicte values) at the first spirometry following iagnosis was relate to age using linear regression. Because a fraction of patients less than 10 years of age ha their first spirometry performe months to years after iagnosis, we groupe chilren less than 10 years of age after whether their first spirometry was time to age at iagnosis or performe more than 6 months after iagnosis. An unpaire t test was use to evaluate if levels of first measure FEV 1 iffere between these two groups. Longituinal part of the stuy. Longituinal lung function measurements in each subject following iagnosis were analyze using linear regression on time since iagnosis, for each subject separately, yieling subject-specific estimates of slope. From these slopes, each patient was groupe accoring to whether the course of lung function increase overall more than 10 percentage points, stabilize (change within 610 percentage points), or ecrease more than 10 percentage points in preicte values. To illustrate further the variation in courses of lung function, the cross-sectional regression line was overlai with meian an interquartile ranges of the iniviual slopes for the time course of follow-up spirometries of which the starting point was chosen arbitrarily an somewhat equiistant across the age span. Because the uration of follow-up varie among subjects, the uncertainties of these slopes were likewise ifferent. To circumvent this, we also calculate slopes from spirometries in a subgroup of patients followe for at least 5 years. These slopes were calculate over a maximum 10 years of follow-up since the first spirometry, to make the ata set uniform. The slopes were subsequently relate to age at iagnosis using linear regression. We also investigate the relation between follow-up slopes an initial level of lung function, although this is ifficult because by efinition these are negatively correlate as a result of the estimation proceure. However, by recalculating slopes, leaving out the first observation for each subject, we coul eliminate most of this technical correlation. Still, a minor positive serial correlation between successive measurements must be expecte. RESULTS Demographics an Duration of Observation We inclue 74 patients with PCD (39 males, 35 females) from the National Danish PCD cohort. The perios of follow-up range over three ecaes, with variable lengths of follow-up for each patient since PCD iagnosis (Figure 1). During the 3-ecae follow-up, a total of 2,937 lung function measurements were performe. Meian (range) age at iagnosis was 8.1 (0 43.7) years with a skewe istribution towar preschool age (Figure 2). Meian (range) uration of follow-up after iagnosis was 9.5 ( ) years (Figure 1). The meian (range) age of the cohort increase uring the 30 years between the first spirometry (1979) an the last spirometry (2009) from 9 ( ) years to 19.3 (6 70) years. The cohort consiste mostly of chilren an young aults, as shown by the accumulate number of patient years (PY) an associate recorings of lung function that fell into each age intervals as follows: 0 10 years, 136 PY; years, 410 PY; years, 250 PY; years, 102 PY; years, 76 PY; an more than 51 years,

3 1264 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 1. Lexis iagram of follow-up perios in each of the 74 inclue PCD patients from iagnosis (left-han time point) to last spirometry (right-han time point). Open circles 5 year of iagnosis; ashe lines before circles 5 perio of time after iagnosis with no spirometries; full lines 5 time since first acceptable spirometry. 20 PY. The low number of accumulate PY at age 0 10 years is cause by the fact that spirometry is only performe from approximately 5 6 years of age. Diagnostic Characteristics Clinical an iagnostic features of the patients in the cohort are shown in Table 1. All 74 patients ha a typical clinical phenotype suggestive of PCD an a ciliary function analysis showing abnormal ciliary beat pattern or ciliary beat frequency. Abnormal ciliary ultrastructure was emonstrate in all patients in whom EM was performe an conclusive (n 5 45; 60.8%). Nasal nitric oxie, sample uring breathhol in 19 (meian age [range]: 18 [7 71] yr) of the 29 patients without EM was below our cut off of 175 ppb (unpublishe ata), thus further supporting the PCD iagnosis. In 5 of the remaining 10 cases, pulmonary raioaerosol mucociliary clearance was performe in aition to ciliary function analysis an emonstrate abnormal mucociliary clearance. In the last 5 cases abnormal ciliary function serve as the only criterion for iagnosis. Situs inversus was seen in 9 (31%) of 29 of the patients without EM result, which was not significantly ifferent from the ratio of situs inversus among patients with verifie EM efects (17 [z38%] of 45 ). No patients with synromic PCD variants were inclue in the stuy. Lung Function: Cross-Sectional Analysis A cross-sectional analysis of the first recore lung function measurement versus age is shown in Figure 2. The first measure FEV 1 in patients with preschool iagnosis (,6 yrof age; n 5 28) varie wiely between normal an subnormal (i.e.,,80% preicte), but with a substantial number (n 5 10; 36%) emonstrating subnormal values (59 79% preicte). Yet, another complementary an overlapping subgroup of 30 (41%) chilren younger than 10 years of age ha their first spirometry performe more than 6 months, meian (range) 4 Figure 2. Linear regression of the first recore lung function by spirometry after iagnosis versus age in 74 patients. (A) FEV 1 % preicte. (B) FVC % preicte. Asterisks 5 patients with first spirometry performe less than 6 months after iagnosis; open circles 5 patients with first spirometry performe more than 6 months after iagnosis; ashe lines before open circles 5 perio of time after iagnosis with no spirometries. ( ) years, after iagnosis an initiate treatment because of unacceptable performances with spirometry. Still, this group i not exhibit better FEV 1 % preicte (P 5 0.5) or FVC % preicte (P 5 0.8) compare with chilren less than 10 years of age with spirometry performe within 6 months from iagnosis. Lung function, expresse as the percentage of preicte, was consierably lower in patients with later iagnosis, an the mean annual ecline across the cohort was 0.8% per year (P, ; 95% confience interval, 1.2 to 20.4). However, there was a tenency to eviate from linearity at oler ages, where the relation seeme to become less steep. Most patients with late iagnosis exhibite subnormal values, even as low as 35 to 50% of preicte in FEV 1. Lung Function: Longituinal Analysis A total of 2,937 lung function measurements were performe in the longituinal stuy of the 74 patients uring the 30-year observation perio. Time courses of lung function following iagnosis, escribe as slopes over 10 subsequent years for subjects with at least 5 years of follow-up varie greatly between iniviuals but with no significant association to age at iagnosis (n 5 58; P ) (see Figure EA in the online supplement). Furthermore, no significant association between the slopes, recalculate by omitting the first spirometry for each subject an initial measurement, was foun (n 5 58; P ). However, we i observe a tenency to a negative association as expecte from the positive correlation between observations of lung function close in time (see Figure EB). Linear regressions of full-length follow-up for all 74 patients are shown in Figure 3A (FEV 1 % preicte) an Figure 3B (FVC % preicte) an as z-scores in Figure EC (FEV 1 ) an Figure ED (FVC). The regression lines are ashe accoring to the behavior seen in the full-length follow-up perio (i.e., increasing [n 5 7; 10%] FEV 1 % preicte more than 10 percentage points, stable [n 5 42; 57%] with change within 610 percentage points, an ecreasing [n 5 25; 34%] more than 10 percentage points). Altogether, the change in lung function range from 237 to 142 percentage points in FEV 1 an 228 to 128 percentage points in FVC, across the cohort.

4 Marthin, Petersen, Skovgaar, et al.: Long-term Lung Function in PCD 1265 TABLE 1. ELECTRON MICROSCOPIC AND CLINICAL FEATURES IN THE 74 PATIENTS ACCORDING TO THEIR CILIARY FUNCTION ANALYSIS RESULT Immotility Asynchrony, CBF,8 Hz Asynchrony, CBF 8 11 Hz Slow Synchrony, CBF,8 Hz Hypermotility Total % Number of patients EM efects ODA efect IDA efect Combine ODA an IDA efect Peripheral microtubule efect in one-thir of cross sections Raial spoke efect Transposition efect Abnormal * EM not one Total EM results Clinical features PCD relative 8/23 8/35 4/13 0/1 0/2 20/ Situs inversus 10/23 12/35 2/13 1/1 1/2 26/ Newborn respiratory istress 9/23 12/35 5/13 1/1 0/2 27/ Chronic cough 23/23 32/35 11/13 1/1 2/2 69/ Newborn nasal secretion 13/23 15/35 7/13 0/1 0/2 35/ Otitis meia 15/23 24/35 10/13 0/1 1/2 50/ Chronic sinusitis 6/23 17/35 5/13 0/1 1/2 29/ Congenital heart isease 0/23 2/35 1/13 0/1 0/2 3/ Bronchiectasis verifie by 8/23 10/35 5/13 0/1 0/2 23/ high-resolution CT scan Chest X-ray with chronic abnormalities 19/23 27/35 12/13 1/1 1/2 60/ Definition of abbreviations: CBF 5 ciliary beat frequency; EM 5 electron microscopic; IDA 5 inner ynein arm; ODA 5 outer ynein arm; PCD 5 primary ciliary yskinesia. * Missing EM result sheet. EM note as abnormal in patient file. Normal range for ciliary beat frequency was 8 11 beats per secon (Hz) at room temperature (our own normal reference ata, not shown). Figure 4 shows the cross-sectional relation from Figure 2 now with an overlay showing the meian an interquartile range of the iniviual slopes for the time course of follow-up spirometries. It illustrates that although the meian slope after iagnosis is somewhat less steep than the cross-sectional line, there is also a large fraction of subjects exhibiting an even larger ecrease with age. The meian follow-up slope was , the corresponing average was very close at , an a 95% confience interval was to (i.e., not significantly ifferent from 0 [P ], but just about significantly ifferent from the general ecline accoring to the cross-sectional regression line [P ]). DISCUSSION This stuy of 74 patients with PCD contains the largest number of longituinal spirometry ata on the largest reporte cohort of patients with PCD followe since iagnosis an also with the longest perio of time to follow-up. Cross-Sectional Part of the Stuy The stuy suggests PCD to be a serious threat to evolution of lung function even early in life: lung function was shown to ecline very rapily with age, starting alreay among preschool chilren. Aitionally, lung function measure at iagnosis (or as soon as possible hereafter) was below 80% of preicte in more than one-thir of chilren with preschool iagnosis espite initiate stanar monitoring an control. This is inee worrying, although selection bias towar early iagnosis of chilren with more severe symptoms may contribute to some extent to such a large fraction. Still, little is known to ate of the progression of lung isease in early chilhoo PCD. A concern is that even the youngest patients alreay have irreversible lung amage. A recent case report to support this concern showe two out of three chilren with PCD less than 3 years of age to have bronchiectasis verifie by high-resolution CT scan an three of three to have ecrease lung function by infant pulmonary lung function testing espite the very early age at iagnosis (15). Thirty chilren (41%) less than 10 years of age were too young to have spirometry performe when iagnose, an therefore ha their first spirometry postpone for more than 6 months (meian, 3.2 yr) after iagnosis. This group i not show significantly ifferent first FEV 1 or FVC compare with chilren less than 10 years (n 5 13) with spirometry performe when newly iagnose (,6 mo). Again, our ata i not support the existence of a possible short-term effect of initial treatment. First measure lung function ecline with age. Because this ecline was expresse by percent of preicte values (FEV 1 )in which formula the natural ecline with age is alreay inclue, the emonstrate loss of lung function probably results from elay of iagnosis. We foun an annual ecline of 0.8% in FEV 1 % preicte relate to age at first measure spirometry after PCD iagnosis. This is completely comparable with another large cross-sectional stuy of spirometry ata on patients with PCD in which Noone an colleagues (16) foun an overall ecrease of 0.8% in FEV 1 per year across their cohort. Longituinal Part of the Stuy Course of lung function varie greatly in the stuy. The course of lung function after iagnosis was relate neither to age at iagnosis nor to level of lung function at first measurement after iagnosis. This is new knowlege an in contraiction with previous stuies suggesting that lung function can be hel stable after iagnosis an initiate treatment (4 6). As escribe later, our results inicate a great variation in course of lung function after iagnosis, because course of lung function coul present with three ifferent patterns that were all

5 1266 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 3. Linear regressions on full-length follow-up (years) on courses of lung function in 74 patients with PCD from their first measure lung function. Each regression line represents one patient. Lines are ivie into three categories accoring to whether the patients followe an increasing (.10% percentage points), stable (change over time within 6 10 percentage points), or ecreasing (.10 percentage points) course of lung function. (A) FEV 1 % preicte. (B) FVC % preicte. unrelate to age at iagnosis an unrelate to level of lung function at iagnosis: (1) a eclining course of lung function after iagnosis, (2) increasing lung function after iagnosis, an (3) a course of stabilize function. Hence, in our stuy, lung function was not maintaine in all patients espite their being enrolle to follow the stanar PCD treatment regimen at our Center. These ata emphasize that treatment, preominantly with antibiotics, an monitoring alone are not sufficient to maintain lung function in a newly iagnose patient with PCD at all times. However, meian ecline in 5 to 10 years of follow-up was less steep than the cross-sectional regression, inicating that there was some effect of treatment. Still, a large fraction of subjects exhibite an even larger ecrease with age, as is shown by the interquartile ranges given in Figure 4, unerlining the consistent variation in course of lung function after iagnosis for patients with early an late PCD iagnosis. Previous publishe ata on part of this cohort (6) have shown that patients with early iagnosis ha better lung function at age at iagnosis compare with patients with late iagnosis. This is in alignment with our present stuy. However, in contrast to these previous finings (6), our stuy i not support that lung function is stabilize because of iagnosis an initiate treatment. On the contrary, our stuy suggests that the further course of lung function after iagnosis can ecrease, stabilize, or even increase regarless of age at iagnosis an regarless of level of lung function when iagnose. Our stuy inclues more patients, an overall longer perio of follow-up after iagnosis, an full ata sets of spirometry as oppose to mean values per year. Also, the present applie statistical analysis of ata allows each age at a PCD iagnosis to be inclue in our calculations instea of grouping accoring to fixe age groups. Only a few other stuies on lung function in patients with PCD have been reporte an two of these inclue only a small number of patients: Hellinckx an colleagues (5) inclue 10 patients with PCD for longituinal follow-up 3 to 20 years after iagnosis an foun stabilize lung function in 8 out of 10 of these patients. As oppose to these results, Corkey an colleagues (4) inclue seven 12- to 25-year-ol patients with PCD who all remaine stable in lung function in the observe perios of 4 to 14 years, regarless of the level of lung function, when the patients entere the cohort. Our stuy brings new knowlege to the fiel in two ways: previous longituinal stuies have only shown capability to stabilize lung function (4 6), whereas capability to improve lung function, as shown in a minority in the present stuy, has not previously been reporte; an from the previous stuies (4 6) ecrease in lung function after iagnosis an initiate treatment was only very rarely observe. We foun approximately onethir of the patients to have a ecrease in lung function of more than 10 percentage points in preicte values over time, some even as much as 237 percentage points in FEV 1. We suggest that the implications of these new finings are that any patient with PCD, regarless of age at iagnosis an level of lung function when iagnose, coul harbor the potential to improve, stabilize, or eteriorate in lung function, that it is highly unpreictable which route each patient will follow, an that early iagnosis in itself shoul not be consiere a guarantee for a goo prognosis. We foun the course of lung function after iagnosis to be inepenent of both age at iagnosis an level of lung function at iagnosis. Thus, we were unable to preict from these two parameters alone if a patient woul have a beneficial increasing course of lung function or a further eterioration after entering the cohort an after initiating treatment. Possibly, these latter patients coul have benefite from a more iniviualize an perhaps intensifie treatment regimen, because the given treatment has not been satisfactory. However, the remaining an problematic future task will efinitely be how to pinpoint these patients at an early stage to intervene. This complicates the strategies in PCD care for preventing lung function ecline. Of similar importance, however, is that our finings also suggest a challenge in pinpointing patients that can actually improve lung function after iagnosis. Therefore,

6 Marthin, Petersen, Skovgaar, et al.: Long-term Lung Function in PCD 1267 Because ata were collecte post hoc, compliance with treatment was not recore in our stuy. Obviously, lacking compliance may influence outcome of lung function. However, we believe that through close monitoring of patients, asking for monthly sputum samples or enolaryngeal suction, an seeing them at 3-month clinical visits permanently after iagnosis, we ha the opportunity to keep a high level of compliance. Being a genetic isease (17), various genetic efects may well cause ifferent lung function outcomes. Unfortunately, we were not able to inclue ata on genetic PCD variants in this stuy. Situs inversus was foun in only 35.1% of patients, which was surprisingly few. Also, an unexpecte high incience of combine outer ynein arm an inner ynein arm efect was foun (18.9%). Most of these outer ynein arm inner ynein arm efect results are from early in the stuy perio where the EM pictures were of poorer quality compare with the present time; some of these may be outer ynein arm efects misinterprete as outer ynein arm inner ynein arm efects because of ifficulty in ientifying the inner ynein arms. Figure 4. Linear regression line (full line) of the first recore FEV 1 % preicte after iagnosis versus age in 74 patients with an overlay of ashe lines showing the meian an interquartile range of the iniviual slopes for the time course of follow-up spirometries with origins at ifferent ages an lung function levels. PCD care shoul not just aim for stabilizing lung function in a patient. Chronic infection with Pseuomonas aeruginosa has been reporte to be expecte in ault patients with PCD (16), which was also an observation from our cohort (ata not reporte). However, the potential impact of P. aeruginosa infection on lung function in patients with PCD remains to be investigate. Limitations of the Stuy There has likely been an improvement in overall population health uring the stuy perio. Also, antibiotic treatment has change over time, especially the more aggressive anti-p. aeruginosa treatment that has been rawn from stuies in CF. The introuction of elective intravenous antibiotics for 14 ays every thir month in patients with CF an chronic P. aeruginosa in 1976 was followe by introuction of inhale colistin an a hoc oral ciprofloxacin between elective intravenous therapy. This resulte in a marke increase in survival rate in Danish patients with CF (12). Later, the immeiate treatment with inhale colistin an oral ciprofloxacin, whenever P. aeruginosa was culture from sputum in patients with noncolonize CF, was implemente in This is still the main strategy toay for postponing chronic P. aeruginosa in patients with CF an PCD. These changes are potential confouners that may have biase our ata towar a poorer outcome in patients iagnose early in the stuy perio compare with those enrolle in the cohort in more recent years an have not been aresse in this stuy. However, most patients were iagnose after 1990 (as illustrate in Figure 1) where treatment strategies an general is comparable to a large extent with present stanars. Diagnostic tools an stanars have also change over 30 years, an hence, some of our patients receive the iagnosis with less work-up than the present stanar with the risk of incluing patients in the cohort that i not have PCD. However, because these patients are also the ones followe for the longest time with continuous clinical symptoms of PCD, their iagnoses seem likely to be correct. Future Perspectives With increasing focus on PCD across the Unite States an Europe, a growing population of ault patients with PCD may be expecte. The establishe European Respiratory Society PCD Task Force in 2008 is a welcome initiative with the opportunity to collect an compare ata from many PCD centers in Europe (1, 18, 19). Hopefully, with such initiatives, stanars will follow for evience-base treatment protocols, for how often patients with PCD shoul be monitore an how aggressive they shoul be treate with antibiotics an physiotherapy if lung function starts to ecline, for how to hanle P. aeruginosa infections, an for the impact on prognosis of these infections. This stuy emonstrate PCD to be of serious threat to lung function alreay in early chilhoo, because one-thir of preschool chilren ha a first measure FEV 1 below 80% of preicte. Across the entire cohort, one-thir of the patients lost more than 10 percentage points of FEV 1 uring follow-up, espite treatment. Surprisingly, early iagnosis was not foun to be protective against further ecline in lung function, an the initial level of lung function i not preict the further course of lung function. Finally, no short-term effect of initial treatment on first FEV 1 or FVC coul be emonstrate in chilren less than 10 years of age when comparing those that receive treatment months to years before first lung function measurements with those less than 10 years of age who were newly iagnose at their first lung function. This efinitely raises the concern of a more pessimistic perspective on the prognosis of lung function in PCD, compare with previous knowlege (6). However, PCD is a heterogeneous isease, an the implications of this in terms of prognosis are still largely unexplore. Moreover, treatment guielines for PCD are mainly erive from CF care an so far lack evience of the neee intensity of care. Hence, one may speculate whether closer monitoring or aitional therapeutics, such as anti-inflammatory rugs, coul have a place in this isease, because our strategy primarily base on antibiotics is unsatisfactory in preventing eterioration. Moreover, the exact lung pathology of this isease has yet to be clearly establishe, an illumination of probable genotypephenotype relations may be warrante. Given the large fraction of young chilren with ecrease lung function an the highly unpreictable variability in further course of lung function, we believe this stuy emphasizes that prognosis of lung function in PCD is inee very complex, espite management in a single national center. We therefore foun our stuy to stress that PCD is a isease that nees close

7 1268 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL attention in every patient an at any age, incluing patients with early iagnosis, because neither age nor initial level of lung function at iagnosis were etermining factors on the course of lung function. Conclusions Our stuy suggests that PCD is a isease of serious threat to lung function alreay at preschool age an with a high egree of variation in the course of lung function after iagnosis. This variation was not linke to either age at iagnosis or level of lung function when iagnose, an early iagnosis was not shown to protect against ecline in lung function. This stuy emphasizes that prognosis of lung function in PCD is inee complex in aults as well as in young chilren. There is still a lot to learn about this rare isease. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. References 1. Barbato A, Frischer T, Kuehni CE, Snijers D, Azeveo I, Baktai G, Bartoloni L, Eber E, Escribano A, Haarman E, et al. Primary ciliary yskinesia: a consensus statement on iagnostic an treatment approaches in chilren. Eur Respir J 2009;34: Bush A, Chohari R, Collins N, Copelan F, Hall P, Harcourt J, Hariri M, Hogg C, Lucas J, Mitchison HM, et al. Primary ciliary yskinesia: current state of the art. Arch Dis Chil 2007;92: Bush A, Cole P, Hariri M, Mackay I, Phillips G, O Callaghan C, Wilson R, Warner JO. Primary ciliary yskinesia: iagnosis an stanars of care. Eur Respir J 1998;12: Corkey CW, Levison H, Turner JA. The immotile cilia synrome. A longituinal survey. Am Rev Respir Dis 1981;124: Hellinckx J, Demets M, De BK. Primary ciliary yskinesia: evolution of pulmonary function. Eur J Peiatr 1998;157: Ellerman A, Bisgaar H. Longituinal stuy of lung function in a cohort of primary ciliary yskinesia. Eur Respir J 1997;10: Peersen H, Mygin N. Absence of axonemal arms in nasal mucosa cilia in Kartagener s synrome. Nature 1976;262: Peersen M, Stafanger G. Bronchopulmonary symptoms in primary ciliary yskinesia. A clinical stuy of 27 patients. Eur J Respir Dis Suppl 1983;127: Marthin JK, Pressler T, Nielsen KG. Long term course of lung function in PCD. Room for Improvement [abstract]? Am J Respir Crit Care Me 2008;177:A Marthin JK, Mortensen J, Pressler T, Nielsen KG. Pulmonary raioaerosol mucociliary clearance in iagnosis of primary ciliary yskinesia. Chest 2007;132: ATS/ERS recommenations for stanarize proceures for the online an offline measurement of exhale lower respiratory nitric oxie an nasal nitric oxie, Am J Respir Crit Care Me 2005;171: Freeriksen B, Lanng S, Koch C, Hoiby N. Improve survival in the Danish center-treate cystic fibrosis patients: results of aggressive treatment. Peiatr Pulmonol 1996;21: Stanarization of spirometry, 1994 upate. American Thoracic Society. Am J Respir Crit Care Me 1995;152: Stanojevic S, Wae A, Stocks J, Hankinson J, Coates AL, Pan H, Rosenthal M, Corey M, Lebecque P, Cole TJ. Reference ranges for spirometry across all ages: a new approach. Am J Respir Crit Care Me 2008;177: Brown DE, Pittman JE, Leigh MW, Forham L, Davis SD. Early lung isease in young chilren with primary ciliary yskinesia. Peiatr Pulmonol 2008;43: Noone PG, Leigh MW, Sannuti A, Minnix SL, Carson JL, Hazucha M, Zariwala MA, Knowles MR. Primary ciliary yskinesia: iagnostic an phenotypic features. Am J Respir Crit Care Me 2004;169: Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, Knowles MR, Zariwala MA. Clinical an genetic aspects of primary ciliary yskinesia/kartagener synrome. Genet Me 2009;11: Maurer E, Barbato A, Frischer T, Strippoli M, Kuehni C, ERS Taskforce on PCD in Chilren. Treatments for primary ciliary yskinesia (PCD) in chilren across Europe. Eur Respir J 2008; 32(Suppl. 52):P Strippoli M, Frischer T, Barbato A, Maurer E, Kuehni C, ERS Taskforce on PCD in Chilren. Age at iagnosis in chilren with primary ciliary yskinesia (PCD) across Europe. Eur Respir J 2008; 32(Suppl. 52): P4022.