Download Ciliary dyskinesias: primary ciliary dyskinesia in adults

Chapter 9
Ciliary dyskinesias:
primary ciliary
dyskinesia in adults
L.J. Lobo*, M.A. Zariwala# and P.G. Noone*
PCD IN ADULTS
Summary
Primary ciliary dyskinesia (PCD) is a genetic disorder of cilia
structure and function, chronic infections of the respiratory
tract, fertility problems and disorders of organ laterality.
Establishing a definitive diagnosis can be challenging, requiring
a compatible phenotype and detection of ciliary functional and
ultra-structural defects, along with newer screening tools such
as nasal nitric oxide and genetics testing. 10 known PCDcausing mutations within two genes are now available in a
clinical panel, and in the future, comprehensive genetic testing
may serve to identify young infants with PCD to improve the
long-term outlook for patients with the disease. Therapy
includes regular pulmonary function testing and monitoring
of sputum flora to allow a targeted approach to treatment.
Referral to an academic centre with expertise in bronchiectasis
and/or PCD is prudent to ensure access to the most recent
diagnostic testing and therapies. With increased understanding
of the disease it is likely that we will expand the definitions of
classic and non-classic PCD, as well as its relationship to less
common ciliopathies.
Keywords: Bronchiectasis, cilia, dynein, mucociliary clearance,
nitric oxide, primary ciliary dyskinesia
C
*Division of Pulmonary Diseases, and
#
Dept of Pathology and Laboratory
Medicine, University of North
Carolina, Chapel Hill, NC, USA.
Correspondence: P.G. Noone, CB
7020, Pulmonary Division, University
of North Carolina School of
Medicine, Chapel Hill NC 275997020, USA, Email
[email protected]
Eur Respir Mon 2011. 52, 130–149.
Printed in UK – all rights reserved.
Copyright ERS 2011.
European Respiratory Monograph;
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10003910
130
iliary dyskinesia refers to a syndrome of oto-sino-pulmonary disease with other
accompanying phenotypic features. It is often referred to as primary ciliary dyskinesia
(PCD) and sometimes referred to as immotile cilia syndrome (ICS) or Kartagener syndrome, or
occasionally the motile ciliopathies [1–3]. PCD is currently the preferred term [4]. Although
secondary ciliary dyskinesia may be seen in diseases associated with acute and chronic airway
inflammation and infection, this chapter will focus primarily on the genetically transmitted form
of the disease, that is PCD, rather than nongenetic, generally secondary forms of the syndrome [5].
Since the hallmarks of the disease are chronic lung disease with bronchiectasis, a brief discussion of
the major respiratory features (bronchiectasis) is included, as well as a brief review of airway host
defence. This will allow a better understanding of the role of cilia in health and disease. This
chapter will focus on disease in adults, as an excellent review of PCD in children was recently
published [6].
The major clinical characteristics of PCD are chronic ear, sinus and lower airways symptoms and
signs from birth because of the failure of one of the major airway defence mechanisms, that of
MCC. By adulthood, bronchiectasis is invariable and is characterised by an abnormal and
permanent dilation of bronchi. It is the consequence of inflammation and destruction of the
structural components of the bronchial walls, usually in the walls of the medium-sized airways,
often at the level of segmental and sub-segmental bronchi. Most experts accept that a ‘‘vicious
cycle’’ of infection and inflammation is created by the basic defect in airway host defence. This
generates airway damage and further impairment of airway clearance, eventually with chronic
colonisation/infection with a variety of microorganisms, leading to further infection and
inflammation and eventually destruction of conducting airways and even alveolar surfaces. In its
most severe form, bronchiectasis may lead to respiratory failure and death. For the clinician faced
with a patient with bronchiectasis, the diagnostic algorithm involves sifting through the various
causes of the disease, with a predominant cause often elusive; thus, it may be labelled either as
idiopathic or, with an appropriate history, as post-infectious bronchiectasis [9]. However, a
careful clinical history, together with focused tests, may find an underlying cause such as CF or
PCD, which is almost always helpful from genetic, prognostic, therapeutic and healthcare system
standpoints.
L.J. LOBO ET AL.
PCD is a rare, usually autosomal recessive disease characterised by oto-sino-pulmonary disease,
including bronchiectasis, organ laterality defects and male infertility. First described early in the 20th
century, its disease origins as a defect in ciliary structure and function were described in Sweden in
the 1970s [7, 8]. The last decade or so has seen resurgence in interest in PCD, specifically a new focus
has emerged from several groups worldwide on more precisely defining the major aspects of the
disease phenotype, including elucidating the molecular basis for the ciliary abnormalities. Such data
will help clinicians establish a diagnosis of PCD (which can be difficult in many circumstances),
which in turn, will hopefully allow more targeted therapeutic approaches. Cystic fibrosis (CF) has
long been recognised as a prototype genetic disease associated with severe pulmonary disease and
bronchiectasis, with intense research activity devoted to CF pathogenesis and treatment over the last
several decades. PCD offers a similar disease model to CF, albeit with a different basic aetiology,
offering complementary insights into significant human disease associated with dysregulation of the
mucociliary clearance (MCC) apparatus in the respiratory tract.
Thus, structural and functional abnormalities of motile cilia and human flagellated cells (sperm)
explain the complex PCD phenotype involving various organ systems. The motile cilia in the
respiratory tract are vital components of the mucociliary apparatus used in airway clearance and
the flagellated structures are important in the male and female reproductive systems. Left–right
asymmetric organ defects may also be part of the phenotype, for example, situs inversus totalis,
commonly known as Kartagener syndrome [10].
Normal cilia structure and function
In addition to humoral, cellular and innate immune systems, the respiratory tract has developed
complex local physical defences to protect the airways from the myriad of inhaled pathogens,
allergens and other inhaled noxious particles. One such mechanism is the mucociliary escalator,
which mechanically eliminates bacteria and particulates that deposit on the epithelial surface of the
respiratory tract.
131
Cilia are hair-like attachments found on the epithelial surfaces (,200 per cell) of various organs
and are anchored on by a basal body to the apical cytoplasm and extend from the cell surface into
the extracellular space. Each cilium is composed of approximately 250 proteins organised into
longitudinal microtubules, which make up the basic axonemal structure [11]. Based on the
arrangement of the microtubules,
cilia are classified into motile cilia,
Inner dynein arm primary cilia and nodal cilia [12].
Motile cilia are the cilia found in
the apical surfaces of the upper and
Microtubule A
lower respiratory tract, the ependymal cells lining the ventricles of
the central nervous system, the
Microtubule B
oviducts of the female reproductive
tract and the flagellum of the male
Radial spoke
sperm. Motile cilia are organised
into nine microtubule pair doubCentral complex lets, surrounding a central pair
creating a distinctive 9+2 arrangement (fig. 1) [3]. The central pair
is linked to the surrounding pair
Figure 1. Diagram of a cross-section of the basic ciliary structure.
doublet through an array of radial
spoke proteins and the surrounding pair doublets are linked to one another via nexin linked proteins. Through ATP-containing
dynein arms on the peripheral microtubules, the microtubules slide by one another to produce
ciliary motion [13]. The protein links between the microtubules limit the degree of sliding and
allow the cilium to bend. Dyneins can be sub-divided into axonemal and cytoplasmic dyneins.
Axonemal dyneins move cilia and flagella, as described previously, while cytoplasmic dyneins are
involved in the organisation of spindle poles during mitosis [14]. Axonemal dyneins form two
structures, the inner and outer arms, and are attached to the microtubules of the nine outer
doublets throughout the length of the axoneme, thus they are central to the process of the bending
of the cilium or sperm tail. Through coordinated and synchronised bending, wave like movements
occur at ,16 Hz, which function to propel mucus and adherent particles/bacteria on the surface
of the airway. Integral to the normal function of cilia is normal airway periciliary fluid layer
composition and function. One of the main pathogenetic mechanisms in CF is thought to be
dysregulation of this fluid layer, which bathes cilia with a thin mucus layer on top [15]. It can be
readily seen, therefore, that two discrete abnormalities of MCC, one involving the cilia themselves,
the other involving the fluid that bathes the cilia, may result in a broadly similar airway phenotype
(bronchiectasis).
PCD IN ADULTS
Outer dynein arm
Finally, nodal cilia occur during embryonic development. In contrast to the 9+2 structure of
motile cilia, they have a 9+0 configuration. They have a very interesting rotational movement,
resulting in leftward flow of extracellular fluid, which is important for cell signalling during the
development of normal human left–right asymmetry (situs solitus) [12]. Defects in the nodal cilia
may cause errors with left–right body orientation; for example, dextrocardia, situs inversus totalis
and situs ambiguous [16–18]. This explains the association of organ laterality defects in PCD, as
well as other rare genetic diseases such as polycystic kidney disease, Senior–Loken syndrome,
Alstrom syndrome, Bardet–Biedl syndrome and retinitis pigmentosa [19].
Clinical manifestations
The clinical signs and symptoms of PCD are shown in table 1.
132
The clinical phenotype that occurs with defective ciliary structure and function is fairly
predictable. Cells lining the nasopharanx, middle ear, paranasal sinuses, the lower respiratory tract
and the reproductive tract contain cilia and are generally affected in PCD when the disease is fully
expressed. In contrast to CF, pancreatic function is preserved, and hepatobiliary disease is usually
not a feature. In general, the clinical course of the disease is milder, with absence of the systemic
problems associated with CF such as nutritional issues and diabetes. Although there are few data
By system affected
By age of presentation
Middle ear
Chronic otitis media with tube placement
Conductive hearing loss
Nose and paranasal sinuses
Neonatal rhinosinusitis
Chronic nasal congestion and mucopurlent rhinitis
Chronic pansinusitis
Nasal polyposis
Lung
Neonatal respiratory distress
Chronic cough (lifelong)
Recurrent pneumonia
Bronchiectasis
Genitourinary tract
Male and female fertility problem or history of
in vitro fertilisation
Laterality defects
Situs inversus totalis
Heterotaxy (¡ congenital cardiovascular
abnormalities)
Central nervous system
Hydrocephalus (rare)
Eye
Retinitis pigmentosa
Family history
Communities or ethnicities with consanguinity
Close (usually first degree) relatives with clinical
symptoms
Antenatal
Heterotaxy on prenatal ultrasound
Newborn period
Continuous rhinorrhoea
Respiratory distress or neonatal pneumonia
Childhood
Chronic productive cough
Atypical asthma unresponsive to therapy
Idiopathic bronchiectasis
Chronic rhinosinusitis
Recurrent otitis media with effusion
Adolescence and adult life
Same as for childhood
Subfertility and ectopic pregnancies in females
Infertility in males with immotile sperm
Sputum colonisation with smooth/mucoid
pseudomonas, other Gram-negative organisms,
or nontuberculous mycobacteria
on life expectancy in PCD, it is believed from clinical experience, and some cross-sectional and
longitudinal studies, that PCD carries a more favourable prognosis than CF [20, 21]. Nonetheless,
the disease may be quite severe and some patients develop respiratory failure requiring
consideration for lung transplant [21].
As with CF, a clue to the diagnosis is a family history of PCD, particularly in populations with high
levels of consanguinity [22]. For example, there is a reported 1 in 2,200 prevalence of PCD in the
Asian population of Britain [23]. The prevalence of PCD in the general population is unknown,
although estimates based on mass radiology studies in differing countries (Scandinavia and Japan)
suggest a range of ,1:16,000 to 1:40,000 depending on the techniques and calculations involved,
and taking into account the likelihood that its prevalence is almost certainly underestimated, even
in these focused studies [6].
L.J. LOBO ET AL.
Table 1. Clinical signs and symptoms of primary ciliary dyskinesia
Oto-sino-pulmonary disease
133
At birth, newborns with PCD often present with a clinical syndrome of neonatal respiratory
distress, indicating the importance of ciliary function in clearing the fetal lung [24, 25]. It is useful
to consider PCD with this clinical history, whether in later childhood or adulthood (although
adult recall of neonatal events may not be reliable). Early childhood atelectasis, pneumonia,
hypoxaemia or respiratory failure can be seen [4, 26]. Frequently, these problems may be
attributed to other aetiologies (for example wet lung, aspiration or pneumonia), and PCD maybe
overlooked for some time. This is borne out by data showing the mean age at diagnosis in children
with PCD was .4 years even when persistent pulmonary symptoms occurred, such as chronic
cough and persistent rhinitis [27]. Children with wheezing may also be labelled as having
‘‘atypical’’ asthma that is unresponsive to appropriate therapy [28]. Frequently, infants and young
children have recurrent upper respiratory tract symptoms, including chronic rhinosinusitis and
chronic otitis media [27]. Nasal polyps and conductive hearing loss from the recurrent infections
and inflammation is common [29]. Most expert paediatricians discourage placement of drainage
tubes (‘‘grommets’’), as these frequently lead to otorrhoea, worsening of the tympanic scarring
and hearing loss over the long term [6, 25]. Although adult nutritional issues are generally not a
feature of PCD, infants with PCD may have significant issues with severe gastro-oesophageal
reflux, feeding and ability to obtain adequate nutrition and tend to be on the lower end of the
growth curve [30]. In later childhood and early adulthood, the impaired MCC in the lower
respiratory tract leads to recurrent episodes of bronchitis and pneumonias, which eventually leads
to bronchiectasis of the middle and lower lobes [31, 32]. In all age groups, chronic cough is a
predominant feature of the disease (often reported by family members), both in response to the
chronic inflammation and as a compensatory mechanism for defective ciliary function and MCC
[33]. Adults may develop clubbing as a marker of long standing pulmonary disease. By the time
patients present to adult clinics, many adults frequently have a history of lobectomy in early life,
prior to the diagnosis being established. Since this procedure cannot usually correct what is, after
all, a general problem in the lung, it can rarely be recommended [21]. Typically the disease
manifests itself as intermittent exacerbations of infectious symptoms, but always with a baseline
level of chronic symptoms (as is usual for most patients with bronchiectasis, whatever the cause)
[34]. At all stages of the disease the focus should be on minimising symptoms, improving quality
of life and slowing declines in lung function (see later). Another unusual, but recently reported
complication of chronic airway diseases in older patients with PCD is that of lithoptysis, that is,
expectoration of stone-like masses from the airways [35]. The hypothesis is that calcite stone
formation is a bio-mineralisation response to the chronic airway inflammation and retention of
infected airway secretions in some patients with PCD.
PCD IN ADULTS
Airway microbiology/imaging
It is not infrequent that adults present to bronchiectasis clinics having rarely had sputum cultures
[21]. However, monitoring of the flora of the airway is important, since older adults often harbour
problematic organisms that may require specific treatment [21]. Based on monitoring protocols
developed for CF and small studies in PCD, it is recommend that airway cultures be performed
every 3 to 6 months [20, 21]. Initially, cultures of airway secretions (sputum cultures) grow
Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus. Once bronchiectasis
is evident on chest imaging (high-resolution computed tomography (HRCT)), smooth and
mucoid Pseudomonas aeruginosa and other opportunistic pathogens such as nontuberculous
mycobacteria (NTM) may be present. In cross-sectional studies series, all adults .30 years of age
had evidence of bronchiectasis, with an increasing prevalence of these organisms [21, 36].
Pulmonary function testing
Most patients demonstrate progressive obstructive defects with advancing age. Although there are
few longitudinal data, cross-sectional studies suggest that the disease is milder than CF in terms of
the progression of loss of lung function [21, 36]. Nonetheless, it is important in order to guide
treatment, to obtain baseline and serial measures of lung function and assess disease severity and
progression, as some patients will develop severe or end-stage lung disease [21]. Ongoing studies,
involving larger numbers of patients in multiple centres, will better define longitudinal markers
and the natural history of the disease.
Radiology
134
With more abundant and specialised imaging, bronchiectasis is being observed more frequently in
general. Thus, PCD may be considered in patients with HRCT-proven bronchiectasis. The
computed tomography scan characteristics of bronchiectatic airways are well described [37].
However, HRCT features alone do not usually allow a confident distinction between cases of
idiopathic versus post-infectious bronchiectasis versus known causes or associations of
bronchiectasis, although there are certain patterns of disease distribution that support a diagnosis
of PCD, for example, a predilection for the middle and lower lobes has been reported in patients
with PCD, in contrast to the upper lobe distribution of cylindrical bronchiectasis in patients with
CF [38]. Some authors suggest that absence of bronchiectasis on a HRCT scan may have a role in
excluding the diagnosis of PCD, at least in adults [31].
Reproductive tract abnormalities
Infertility in both males and females is also a prominent feature. 98–99% of males with PCD have
impaired spermatozoa motility secondary to defective sperm flagella [39]. Data are scattered in
females, but a consistent feature is that of normal or delayed fertility in some, while other females
show impaired fertility with an increased risk of ectopic pregnancy, presumably because of
impaired ciliary function in the oviduct [40].
Organ laterality and other anatomic defects
Rare associations of PCD
PCD is occasionally seen with rare diseases linked to abnormalities in primary cilia or sensory cilia,
for example in the kidney, retina and embryonic node, which may lead to a wide spectrum of
clinical features. An example is PCD with retinitis pigmentosa. Mutations in the X-linked retinitis
pigmentosa GTPase regulator gene (RPGR) gene have been identified in a few cases of PCD cosegregating with retinitis pigmentosa [41, 42]. Ciliary dysfunction in both respiratory epithelium
and the photoreceptors of the retina seems to be the common factor [42]. Hydrocephalus may be
seen in mice with PCD, but its association in humans is less clear, the problem may be secondary
to the impaired cilia that line the ventricular ependymal cells of the central nervous system, which
helps cerebrospinal fluid flow through the sylvian aqueduct [43–45].
L.J. LOBO ET AL.
During the embryonic period, thoraco-abdominal orientation is determined via the unidirectional, rotating beat of nodal cilia. With abnormal nodal ciliary structure and function, thoracoabdominal organ orientation is random. This leads to situs inversus with reversal of the thoracic
and abdominal organs in ,50% of patients with PCD [16, 21]. Occasionally, laterality defects are
not ‘‘pure’’, that is, situs ambiguous/heterotaxy may be present. This is the phenomenon of left–
right asymmetry within specific organ systems, leading to either sole or randomly combined
anatomical deformities of the heart, liver and spleen. A recent series found that at least 6% of
patients with PCD have heterotaxy, including complex congenital heart defects [17]. Defects in the
outer dynein arm (ODA) may be a more common cilia abnormality in patients with laterality
defects than that of the inner dynein arm (IDA) or central apparatus [17].
Diagnostic approaches
Overview
135
Since the first reports of abnormal ciliary structure as the cause of PCD, the diagnosis of PCD has
usually been established by obtaining nasal samples of airway cilia for examination under light and
electron microscopy. With appropriate techniques, ciliary motion (absent or dyskinetic in PCD) may
be defined and ciliary ultra-structure examined for abnormalities, the classic being absent or short/
stubby dynein arms. However, these tests are quite dependent on technical factors and local expertise,
and thus it can sometimes be a challenge to definitively diagnose PCD. Recently, however, the
diagnostic work-up for PCD has evolved to encompass other methodologies, for example, measures
of nasal nitric oxide (NO), more sophisticated analyses of ciliary structure and function and genetic
testing (see later). Often, the resources needed to make a definitive diagnosis are only available in
specialised centres. Nonetheless, a history yielding the symptomatic clues above should prompt
consideration of the diagnosis and, if necessary, referral to the growing number of centres with an
interest and expertise in the diagnosis and treatment of PCD and related diseases. An algorithm of
currently available tests is presented to help the clinician work through the process (fig. 2). It goes
without saying that prior to consideration of the diagnosis of PCD, and embarking on a detailed
Clinical suspicion of PCD
CT chest scan with bronchiectasis
(middle/lower lobe predominantly
and/or heterotaxy)
No
PCD unlikely#
Rule out cystic fibrosis with a sweat chloride
test and/or CFTR gene mutation analysis
Yes
Other aetiologies of bronchiectasis
ruled out
No
Rule out primary immunodeficiencies
with Ig levels (IgG, IgA and IgM) and serum
electrophoresis and consider vaccine response
Rule out connective tissue disorders with
RF, ANA and ANCA
Yes
Nasal NO level reduced (usually 5–
20% of normal)
Consider ABPA, asthma, allergic rhinitis, gastrooesophageal reflux disease and α1-antitrypsin
deficiency
No
PCD unlikely#
PCD IN ADULTS
Yes
Cilia examination
via nasal biopsy
Yes
Ciliary beat frequency and pattern
Normal
PCD not ruled out¶
Abnormal
Electron microscopy with
ultra-structural defect in cilia
Normal
Normal beat frequency, pattern and
ultra-structure makes PCD unlikely,
but could be non-classic disease
Yes
PCD likely
Consider genetic testing for DNAI1 and
DNAH5 using clinical panel at select
institutions (accounts for ~40%) and there
are select genetic tests and gene analysis
available at specific academic centres
Figure 2. Diagnosis algorithm for primary ciliary dyskinesia (PCD) in adults. For clinical signs refer to table 1.
CT: computed tomography; NO: nitric oxide; CFTR: cystic fibrosis transmembrane conductance regulator;
Ig: immunoglobulin; RF: rheumatoid factor; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic
antibodies; ABPA: allergic bronchopulmonary aspergillosis. #: if clinical suspicion is still high for PCD other,
more specific tests may be undertaken; ": normal ciliary beat frequency and pattern does not completely rule
out PCD.
136
work-up, other diseases can be considered and ruled out as appropriate [9]. As there are wide
variations in PCD presentation and phenotype there may be overlap with CF, immunological
deficiencies, allergic bronchopulmonary aspergillosis (ABPA) and other causes of bronchiectasis.
Other chapters in this Monograph address these diseases in considerable detail.
Screening tests versus diagnostic tests
Tests of ciliary function can be divided into those that are indirect and may be used to screen
patients (e.g. the nasal saccharin test) and those that definitively assess function and structure
(ciliary beat frequency (CBF)/pattern tests and electron microscopy studies). Newer screening/
diagnostic tests currently undergoing study include nasal NO, which may reflect ciliary structure
function indirectly, immunofluorescent analysis of ciliary proteins, high-speed video-microscopy
to quantitate ciliary motion and clinically available panels of genetic tests known to be associated
with ciliary structural abnormalities.
MCC: the saccharin test
The saccharin test is cheap and can be readily performed in the clinical setting as a screening test.
However, it is subject to an array of technical factors that render it less reliable than other
methodologies. A 1–2 mm particle of saccharin is placed on the inferior nasal turbinate 1 cm from
the anterior end (if too far anterior cilia actually beat forwards from the nose). The difficult part is
that the patient must sit quietly with the head bent forward without sniffing, sneezing, coughing,
eating or drinking. The time it takes for the patient to taste the saccharin is a rough measure of
nasal MCC. Generally, tasting saccharin in ,30 minutes is normal. Patients with rhinosinusitis
commonly taste it within 60 minutes. If it is not tasted within 60 minutes, PCD can be considered.
The test is not suitable for small children who will not sit still for 60 minutes, patients with a poor
sense of taste and patients with a cold within the past 6 weeks [46].
NO is present in high concentrations in the upper respiratory tract and is produced by the
paranasal sinus epithelium [47]. NO is produced enzymatically from L-arginine by several
isoforms of NO synthase. NO appears to contribute to local host defence, modulate ciliary motility
and serve as an aerocrine mediator in helping to maintain adequate ventilation–perfusion
matching in the lung [48]. Abnormal values of nasal NO have been reported in various sinus and
lung diseases; for example, acute and chronic sinusitis, CF and nasal polyposis [48]. Quite
fortuitously, low nasal NO levels were first reported in PCD in the early 1990s by a Scandinavian
group researching exhaled NO in a variety of normal and diseased states [49]. The observation has
been replicated on several occasions and, although not fully understood at a mechanistic level, it
seems to be a robust index of classic PCD [21, 50]. In individuals with PCD, levels of exhaled NO
are extremely low (,10% of normal values) even when compared with patients with CF and other
sinus disorders, where nasal NO may be low, although not usually in the PCD range [51, 52].
Interestingly, in one study, carriers (nonsmoking parents of patients with PCD) had intermediate
levels of nasal NO [21]. Confirmation of the diagnosis of PCD requires further diagnostic tests.
Nevertheless, the highly reproducible nature of low nasal NO levels make it a valuable screening
tool [53].
L.J. LOBO ET AL.
NO levels
Ciliary function
137
Transnasal brushings or nasal scrape samples may be obtained fairly readily via direct visualisation
of the inferior turbinate, without local anaesthesia or sedation [54]. Ciliary beat patterns and
frequency can be seen under direct visualisation using a microscope, and classed as qualitatively
normal, dyskinetic or immotile [21, 55]. For more quantitative measures, CBF can be measured
and the ciliary waveform can be analysed using high-speed digital video imaging to differentiate
between abnormal beating cilia and the normal beat patterns [56]. A cilium can be viewed in slow
motion or frame by frame, with 40 to 50 frames per ciliary beat cycle [57]. Normal cilia beat
forward and backwards within the same plane, with no sideways recovery sweep. Recent advances
in computer image processing software may help standardise measures of waveform and direction
of multiple cilia, as a measure of the effectiveness of ciliary transport [58, 59]. This software may
also efficiently compute ciliary activity with accuracy and reproducibility. CBF and beat pattern
abnormalities have been associated with specific ultra-structural defects such as isolated outer arm
defects, isolated inner arm or radial defects or transposition defects [58]. If patients have both a
normal CBF and a normal beat pattern, then classic PCD can reasonably be excluded. However, if
one or the other is abnormal, further studies are necessary. As with any studies of cilia structure
and function, it is critical to exclude ongoing inflammation as a cause of secondary ciliary
dysfunction leading to false positives [5].
PCD IN ADULTS
Ciliary structure
In patients with an appropriate phenotype, suspicion for PCD for other reasons (for example,
respiratory symptoms and a sibling with disease) or positive screening tests (saccharin test, nasal
NO or CBF abnormalities), the axonemal structure of the respiratory cilia should be studied using
transmission electron microscopy (TEM) [8]. Inflammatory influences can be avoided by
sampling the patient in a stable state, post-antibiotics or, if in vitro testing, by culturing the
epithelial cells in an inflammation-free environment. The yield may be higher in patients with
sino-pulmonary symptoms rather than isolated upper or lower respiratory tract symptoms [60].
There are a number of structural phenotypes associated with PCD [61]. Most cases of PCD are due
to a lack of ODA, or a combined lack of both IDA and ODA [21]. Less common defects include
IDA defects alone or defects in combination with radial spoke defects, or central microtubule pair
defects such as transposition or central microtubular agenesis [62–64]. In a proportion of patients
with PCD, no structural defects were defined using existing TEM techniques [53, 60]. This, despite
a strong phenotype, defined ciliary functional abnormalities and demonstrated genetic defects,
underscoring the notion that the disease is almost certainly under-diagnosed, due to the hitherto
reliance on TEM as the ‘‘gold standard’’ for diagnosis of the disease. As seen later, advances in
molecular techniques will probably allow a broader definition of PCD (classic and non-classic
PCD, akin to the situation with CF), leading to more efficient diagnosis with subsequent beneficial
downstream effects for earlier diagnosis, treatment and improved long-term clinical outcomes.
Immunofluorescent stains
Immunofluorescent analysis using antibodies directed against the main axonemal components has
recently been used to facilitate identification of structural abnormalities of cilia, and is used in
diagnosis in some centres in Europe [65, 66]. PCD patients with ODA defects have absence of
DNAH5 staining from the entire axoneme and accumulation of DNAH5 at the microtubuleorganising centre as compared with normal individuals with normal DNAH5 staining along the
ciliary axoneme [66]. Recent work has also shown that antibody-based techniques can diagnose
not only ODA but also IDA abnormalities caused by KTU mutations in PCD [67]. In the future, it
may be possible to develop a panel of antibodies directed towards multiple ciliary proteins that
may enable the screening of respiratory epithelial samples.
Genetic testing
Overview
138
As the molecular underpinnings and the genetics of PCD become more defined, genetic testing
may overcome some of the drawbacks of the currently available diagnostic tests. Given the
complexity of ciliary structure and the genetic heterogeneity of PCD, finding gene mutations
causative for PCD has been challenging. Fortunately, non-human models have helped in the
process of discovery. Since the basic structure of cilia is highly conserved across species, an
example being a simple green alga, Chlamydomonas reinhardtii, extensive information has been
gleaned regarding the structure, function and genetics of human cilia, specifically identifying
candidate proteins and genes from mutant Chlamydomonas that are critical for normal ciliary function
(e.g. slow swimmers with ODA defects and mutant c-heavy chain dynein) [68]. Initial mutations
Table 2. Primary ciliary dyskinesia-causing genes in humans showing extensive locus heterogeneity
Human gene
DNAI1
DNAI2
DNAH5
DNAH11
TXNDC3
KTU/PF13
LRRC50
CCDC39
CCDC40
RSPH4A
RSPH9
Chromosomal
location
Axonemal
component
Ultra-structure of
patients with mutations
[Ref.]
9p13.3
7q25
5p15.2
7p21
7p15.2
14q21.3
16q24.1
3q26.33
17q25.3
6q22.1
6p21.1
ODA IC
ODA IC
ODA HC
ODA HC
ODA IC/LC
Cytoplasmic#
Cytoplasmic#
Ciliary Axoneme
Ciliary axoneme
RS
RS
ODA defects
ODA defects
ODA defects
Normal ultra-structure
ODA defects
ODA+IDA defects
ODA+IDA defects
Axonemal disorganisation
Axonemal disorganisation
Transposition defect
CP defects and normal
ultra-structure
[69–73]
[74, 75]
[76–78]
[79–83]
[84]
[67]
[85, 86]
[87, 88]
[87, 89]
[90]
[90]
found using the candidate gene approach include mutations in DNAI1, homologous to the
Chlamydomomas genes IC78. This was discovered in PCD patients with ODA defects and
functional ciliary abnormalities [69, 70]. Since then, there have been several more PCD-causing
gene mutations published, using a variety of approaches (table 2). Homozygosity mapping in large
families that may or may not be consanguineous, but have multiple affected and unaffected siblings
can be successfully used to identify disease-causing genes. This method utilises the marker analysis
to look for the shared region of the genome from affected and unaffected individuals, to identify the
chromosomal locus/loci shared between the affected siblings. Genes within the shared locus/loci are
candidates, which can be further aided by the candidate gene approach to prioritise the genes to be
tested from the shared locus. OMRAN et al. [91] successfully used this method to localise the shared
locus in affected individuals from a large consanguineous family and identified mutations in the
DNAH5 gene. Genome-wide linkage analysis, another approach to find disease-causing mutations,
using 31 multiplex families with PCD failed to identify disease-causing genes [92]. The main
limitation of genome-wide linkage analysis is the extensive genetic and ultra-structural
heterogeneity in PCD that limits the comparison of data across the families to get meaningful
log of odds (LOD) genetic linkage scores that helps indicate the possible disease-causing loci. Other
methodologies include the comparative computational analysis approach, which identifies
candidate genes using the DNA information collected from various sequencing projects from
various distinct species. It assumes that higher-level organisms independently lost certain genetic
information during evolution once the information coding for the specific processes was obsolete.
Using subtraction analysis it is possible to find candidate genes necessary for cilia formation and
function by comparing the genome of a ciliated eukaryote with eukaryotes not dependent on cilia
[93, 94]. A comprehensive discussion of the molecular basis of PCD is beyond the scope of this
chapter; the reader is referred to KNOWLES et al. [4].
L.J. LOBO ET AL.
DNAI1: dynein, axonemal, intermediate chain 1 gene; DNAI2 : dynein, axonemal, intermediate chain 2 gene;
DNAH5: dynein, axonemal, heavy chain 5 gene; DNAH11: dynein, axonemal, heavy chain 11 gene; TXNDC3 :
thioredoxin domain containing 3 (spermatozoa) gene; KTU/PF13 : Kintoun; LRRC50 : leucine-rich repeat
containing 50; CCDC: coiled-coil domain containing; RSPH4A: radial spoke head 4 homologue A gene;
RSPH9 : radial spoke head 9 homologue; ODA: outer dynein arm; IC: intermediate chain; HC: heavy chain; LC:
light chain; RS: radial spokes; IDA: inner dynein arm; CP: central pair. #: cytoplasmic protein required for the
dynein arms assembly.
DNAI1 and DNAH5 are associated with ODA defects in PCD
139
Mutations in DNAI1 and DNAH5 [69, 70, 71–73, 76–78] that encode dynein axonemal
intermediate chain 1 and heavy chain 5, respectively, have been well documented in several studies
as causative for PCD. DNAI1 accounts for ,2–10% of patients with PCD, although if one
‘‘selected’’ the phenotype to include patients with ODA defects alone, this increases to ,4–14%.
The commonest mutation (founder mutation) in DNAI1 is IVS+2_3insT, accounting for .50% of
mutations. DNAH5 is a heavy chain dynein and mutations in the gene were initially found in a
large inbred family of Arab descent. Subsequent studies show mutations in DNAH5 to be present
in ,15–28% of patients with PCD. Together therefore, DNAI1 and DNAH5 account for ,20–40%
of patients with classic disease with ODA defects. Despite extensive allelic heterogeneity, four
exons in DNAI1 and five exons in DNAH5 represent mutation clusters, which became the basis of
development of the clinical genetic testing for PCD.
PCD IN ADULTS
Miscellaneous other mutations associated with PCD
Mutations have been identified in other genes in patients with PCD, specifically, DNAH11, DNAI2,
KTU, RSPH9, RSPH4A, TXNDC3 and LRRC50, CCDC39 and CCDC40 (table 2) [26, 67, 74, 79–81,
84, 85, 88–90]. Some genotype–phenotype associations have been defined amidst the plethora of
mutations found, primarily at the ultra-structural level (rather than at the clinical level). Mutations
in DNAH5, DNAI1 and DNAI2 are exclusively seen in patients with ODA defects, whereas
mutations in KTU and LRRC50 are exclusively seen in patients with combined ODA+IDA defects
[4]. The genetics of the DNAH11 (which encodes dynein axonemal heavy chain 11) mutation are
quite interesting as it was found in a patient with proven CF and situs inversus. It was not clear if this
patient had PCD/Kartagener syndrome, or isolated situs inversus, as there is an obvious phenotypic
overlap between the CF and PCD. However, the patient had abnormal ciliary beat pattern as seen in
PCD, normal ciliary ultra-structure, but with a mutation in the DNAH11 gene that was assumed to
be linked to the situs inversus [95, 96]. Subsequently, mutations in DNAH11 were unequivocally
shown to be PCD causing in a large German kindred and more recently two patients with PCD were
found to harbour mutations in DNAH11 [80, 81]. All of the patients with DNAH11 mutations
presented with normal dynein arms. This phenotype highlights the difficulty in diagnosis in those
patients with a strong clinical phenotype, but with normal cilia on TEM analysis. Mutations in
DNAI2 that encode for a dynein axonemal intermediate chain 2 have been identified in 4% of PCD
patients with ODA defects [79]. In contrast to the above proteins and genes, which encode for
dynein proteins, KTU is a cytoplasmic protein, required for the assembly of the dynein complex
[67]. First noted to be mutated in Mekada fish with laterality defects, and subsequently
Chlamydomonas, it was then found to be mutated in PCD patients with both IDA and ODA defects
(logical since it is required for normal ODA and IDA assembly and transportation). Mutations in
KTU are seen in ,12% of PCD patients with combined ODA and IDA defects. RSPH9, which
encodes for the radial spoke head protein 9, was identified as being a PCD-causing gene using
homozygosity mapping in two Arab Bedouin families. Subsequently, an identical homozygous 3-bp
inframe deletion mutation was identified in both families. Interestingly, the ultra-structure analysis
of patients from one family depicted 9+2 or 9+0 microtubular configuration, and from the other
family normal ciliary ultra-structure was seen [90]. Using homozygosity mapping in three inbred
Pakistani families, RSPH4A was identified as a PCD-causing gene that encode another radial spoke
head protein 4A. Ultra-structural analysis showed transposition defects with the absence of a central
pair and 9+0 or 8+1 configuration. TXNDC3 (encoding thioreduxin domain-containing protein 3)
is a component of the sperm flagella ODA, and a nonsense mutation on one allele and a splice
mutation on the other allele were found in one PCD patient [84]. Large genomic deletions, as well
as point mutations involving LRRC50 (leucine-rich repeat containing 50), are responsible for a
distinct PCD variant that is characterised by a combined defect involving assembly of the ODA and
IDA. Functional analyses shows that LRRC50 deficiency disrupts assembly of distally and
proximally DNAH5 and DNAI2 containing ODA complexes, as well as DNALI1-containing IDA
complexes, resulting in immotile cilia [85]. Multiple other candidate genes have been tested in
patients and families with PCD, and were found to be negative.
Other genetic associations
140
X-linked retinitis pigmentosa, sensory hearing deficits and PCD have been associated via
mutations in the RPGR, essential for photoreceptor maintenance and viability [41]. In addition, a
single family was reported with a novel syndrome that is caused by oral-facial-digital type 1 gene
(OFD1) mutations, and characterised by X-linked recessive mental retardation, macrocephaly and
PCD [45].
Animal models for PCD have been reported to occur in nature, although they have rarely been
studied in depth [97]. Similarly animals with a PCD phenotype have been constructed using
molecular techniques, mainly in mice [4]. Other than the Mdnah5 deficient mouse and the Dpcd/
poll knock out mouse, the causative gene in the other models are unknown. The Mdnah5 deficient
mice were created via transgenic insertional mutagenesis that leads to a frame shift mutation. The
mice have the classic PCD phenotype and the ultra-structural analysis reveals absent ODA [98,
99]. The Dpcd/poll knock out mice present a phenotype of sinusitis, situs inversus, hydrocephalus,
male infertility and ciliary IDA defects [43]. Recently, a murine mutation of the evolutionarily
conserved adenylate kinase 7 (Ak7) gene resulted in animals presenting with pathologic signs
characteristic of PCD, including ultra-structural ciliary defects and decreased CBF in respiratory
epithelium [100]. The mutation is associated with hydrocephalus, abnormal spermatogenesis,
mucus accumulation in paranasal passages and a dramatic respiratory pathology upon allergen
challenge. Ak7 appears to be a marker for cilia with 9+2 microtubular organisation. Mutations of
the human equivalent may underlie a subset of genetically uncharacterised PCD, although no
human mutations have been identified as yet. Finally, a novel method of developing a mouse
model with a PCD phenotype was recently published [101]. A transgenic mouse lacking an ODA
was developed by deleting Dnaic1, a mouse intermediate chain dynein. Importantly, the mice did
not develop many of the problems that usually result in an early death for the animals, such as
hydrocephalus or other severe developmental defects. Thus, the survival of the animals allowed the
investigators to show that the animals did experience problems consistent with defective MCC, at
least in the upper airway (severe rhinosinusitis). Objective measures of MCC were also consistent
with defective ciliary function in the nasal passage, though interestingly not in the lower airway,
possibly reflecting differing turnover of ciliated epithelium in various regions of the respiratory
tract (upper versus lower). This animal model may allow studies that attempt to dissect out the
relative importance of the various components of the MCC apparatus in different airway regions.
L.J. LOBO ET AL.
Future directions
Summary: an algorithm for testing
As there is no easy, single diagnostic test to diagnose PCD, it is recommended that the diagnosis be
based on multiple contributing pieces of data (fig. 2). A typical clinical presentation to suggest
additional testing for PCD includes recurrent respiratory tract infections (either upper or lower, or
both), neonatal respiratory distress, childhood ear infections, adult bronchiectasis in the absence
of a diagnosis and male/female fertility problems. Additional features to provoke further tests
include organ laterality defects, and complex congenital heart or other organ defects and retinitis
pigmentosa. Ciliary dyskinesia, sperm immotility or identification of specific defects of axonemal
structures on electron microscopy are also suggestive of the diagnosis. The reader should bear in
mind that patients with PCD with atypical histories may have no demonstrable ciliary ultrastructural defects on standard TEM. Nasal NO, if available, helps exclude the disease if normal or
very high and, if very low, strongly suggests the diagnosis. Recently, clinically available genetic
testing, a rapidly evolving field, may assist in an increasing number of patients with PCD.
Therapeutic approaches
Overview
141
The goal for the management of PCD is to prevent exacerbations and complications as much as
possible, and to slow the progression of disease. As the disease is generally not as severe as CF, and
PCD IN ADULTS
the diagnosis may be delayed, adults with the disease may not fully appreciate or understand the
nature and/or severity of the disease. Thus, education as to the diagnosis, prognosis and
therapeutic avenues need to be discussed thoroughly with the patients once the diagnosis is secure
(usually on several occasions). Although there are few literature-based studies in PCD, there are
enough studies in CF and non-CF bronchiectasis to allow significant extrapolation (although not
total, see later) into patients with PCD, to at least frame a plan of treatment depending on disease
severity, sputum microbiology and patient circumstances. Medical therapy has been shown to slow
the deterioration in lung function [20, 102]. ELLERMAN and BISGAARD [20] reported longitudinal
lung function in 24 patients diagnosed before and after the age of 18 years. They observed worse
lung function in patients diagnosed in adulthood, but did not find further deterioration in lung
function in either group once the diagnosis was established and routine care initiated. This
suggests that aggressive treatment could prevent further lung damage. It should be noted, however,
that other larger patient cohorts followed for a longer time period suggest that PCD may be a
serious threat to lung function as early as pre-school, with a high degree of variation in the loss of
lung function once diagnosed [103]. There was no link to either age or level of lung function at
diagnosis and early detection did not slow the rate of decline in lung function. These data support
the genetic and phenotypic heterogeneity of PCD. Despite this, regular clinical surveillance is
strongly recommended to establish trends of disease progression, and to detect exacerbations early
to attempt to prevent irreversible lung damage. This should include at least lung function testing,
sputum or throat cultures to assess airway microbiology and annual chest radiographs [104].
Pulmonary function in PCD patients appears to decline slower compared with patients with CF
and the majority of patients with PCD seem to have a normal to near normal life span [21].
However, there are patients that develop progressive bronchiectasis, leading to severe lung disease
and respiratory failure.
Specific therapies
There are no therapies to date that have been shown to correct ciliary dysfunction in PCD
patients. Some pilot or single case reports suggest benefit for some of the underlying
pathogenetic pathways in PCD, but none are yet available on a general basis, or proven in
randomised controlled studies (although patients will often inquire as to their availability)
[33, 105, 106]. Thus, therapies to enhance airway clearance, as well as to suppress or kill bacteria
are the cornerstones to PCD care.
Airway clearance
As with CF, routine airway clearance with cardiovascular exercise, percussion vests, chest physical
therapy and various valve/positive expiratory pressure devices should be performed on a daily
basis. The aims of respiratory physiotherapy include mobilising and aiding expectoration of
broncho-pulmonary secretions, improving efficiency of ventilation, maintaining or improving
exercise tolerance, improving knowledge and understanding and reducing breathlessness and chest
pain. There are no data in either CF or PCD to support any one method of airway clearance over
another, and in adults a good practice is to facilitate a consultation with a chest physiotherapist for
an education ‘‘class’’, and to determine what modality of airway clearance and what devices the
patient prefers. As with any chronic lung disease, exercise is highly recommended for
cardiovascular fitness and specifically for airway clearance. Even though a chronic cough is a
major complaint, it should not be suppressed as it is a compensatory mechanism for mucus
clearance with dysfunctional cilia [33].
Antibiotics
142
Antibiotics are the mainstay of treatment for bacterial infections of the airways associated with
PCD. The microbiological flora of the airways is broadly similar to that of CF, although with a
delayed appearance of P. aeruginosa. Antibiotic therapy should be based on regular sampling of
Modulation of airway secretions
In the CF population, nebulised hypertonic saline (7% hypertonic saline) is beneficial by
modulating the liquid content of the periciliary fluid layer, thereby thinning thick secretions
and triggering a cough reflex [109, 110]. However, in PCD, its utility is less clear as it
stimulates cough to help clear secretions but its role in thinning secretions is not known [111].
A small study of 24 patients with non-CF bronchiectasis showed that hypertonic saline resulted
in greater expectorated sputum weight and a greater reduction in sputum viscosity compared
with the active cycle of breathing technique alone [112]. Thus, it may be considered in the
PCD population as it can augment mucus clearance with little to no risk, other than time.
Other aerosolised hypertonic agents such as dry powder mannitol are currently being
investigated and may be promising in the future [113]. Deoxyribonuclease (dornase alfa), an
enzyme that hydrolyses eukaryotic DNA released from decaying neutrophils to diminish
mucus viscosity and enhances clearance, is beneficial in CF patients, but its use by
extrapolation into PCD patients remains unproven and may even be detrimental to lung
function [114, 115].
L.J. LOBO ET AL.
airway secretions for Gram-positive, Gram-negative and acid fast pathogens to build a pattern of
the main pathogens in any given patient’s airways [21, 107]. In adults, sputum is usually easy to
acquire and bronchoscopy is not usually necessary to gather specimens. When PCD patients have
symptoms of a respiratory tract infection, they require treatment with antibiotics based on airway
cultures and sensitivities. H. influenzae, S. aureus, and S. pneumoniae are commonly isolated from
the airways of PCD patients. There are no randomised placebo-controlled studies evaluating the
efficacy of antibiotics in exacerbations in adults or children although numerous studies indicate
that antibiotics can improve symptoms and hasten recovery. Antibiotics are recommended for
exacerbations that present with an acute deterioration (usually over several days) with worsening
local symptoms (cough, increased sputum volume or change of viscosity, increased sputum
purulence with or without increased wheeze, breathlessness and haemoptysis) and/or a decrease in
lung function based on lung function testing. Expert consensus is that 2 weeks of therapy is
reasonable. The choice of antibiotics may be initially empirical, based on the likely microbial agent
or guided via previous sputum cultures in an individual (hence the recommendation to gather
serial samples). The recommended route of antibiotics needs further study to address the optimal
regimen, but most clinicians use oral antibiotics for milder exacerbations and combined antipseudomonal intravenous drugs for more significant deteriorations. Previous studies suggest that
the combination of intravenous and inhaled antibiotics might have greater efficacy than
intravenous therapy alone [34]. In patients chronically colonised with P. aeruginosa, the addition
of nebulised tobramycin to high-dose oral ciprofloxacin for 14 days led to a greater reduction in
microbial load at day 14 although there was no clinical benefit [108]. Attempts at early eradication
of newly acquired bacteria are recommended as in CF, although there are no data that show that
such an approach prevents the progression of lung disease. Long-term antibiotics or nebulised
antibiotics (tobramycin, colomycin or aztreonam) may be used in patients with chronic or
frequent exacerbations. Some patient do well on ‘‘rotating’’ cycles of oral antibiotics, although
there are no data to support such an approach and there is a general concern about inciting
microbial resistance.
Other airway treatments
143
Bronchodilators are not particularly effective in PCD or CF unless a coexisting asthmatic
component exists [116]. PCD patients may be initially misdiagnosed as asthmatics unresponsive to
conventional therapy, including b-agonists and inhaled corticosteroids. b-Adrenoceptor agonists
have been shown to augment CBF in functional cilia but there is little data in the dyskinetic cilia
seen in the PCD population [117]. Anti-inflammatory strategies such as alternate-day
prednisolone have not been shown to be effective in CF; there are no studies in PCD [118].
Inhaled steroids may or may not be of benefit in individual patients with PCD; a recent Cochrane
review concluded no benefit in non-CF bronchiectasis overall [119]. As with other inflammatory
diseases of the lung, the macrolide antibiotics may exert long-term benefits for the modulation of
airway inflammation and thus disease expression [106, 120].
Miscellaneous lung treatments
PCD IN ADULTS
L-Arginine
might hypothetically have a therapeutic role in PCD patients, in augmenting the
production of airway NO, theoretically enhancing CBF (although the exact role of NO in this
process is unknown). However, in the small studies performed, L-arginine did not normalise nasal
NO levels and no improvement in lung function was observed [121]. Uridine-5-triphosphate
(UTP), or its analogues, is also a potential therapy for CF and similar diseases [122]. UTP
stimulates chloride ion secretion and mucin release in goblet cells, therefore increasing airway fluid
hydration and enhancing cough clearance in healthy individuals. A small acute clinical trial of
nebulised UTP in PCD demonstrated enhanced airway clearance during cough, but no long-term
benefits in pulmonary function have been shown [33]. Localised surgery may be considered in
situations that resemble that of CF or idiopathic bronchiectasis, where occasionally very localised
lung disease is considered to be problematic in causing severe systemic symptoms, frequent
exacerbations and/or life threatening haemoptysis [123, 124]. Patients with such localised disease,
haemoptysis or refractory pulmonary infections, have undergone surgical resection of the
bronchiectatic lung but the long-term effects are unknown [124]. If PCD does progress to endstage lung disease, lung transplantation must be considered. PCD patients have undergone
successful heart-lung, double lung or living donor lobar lung transplant [125]. In patients with
situs inversus, the anatomic disorientation adds an extra challenge when considering the
anastomotic sites but is not a contraindication. The long-term survival appears similar to other
lung transplant recipients.
Treatment of extrapulmonary disease in adults
As PCD affects other aspects of the respiratory tract other than the lungs, treatment of those areas
must be considered. Chronic rhinitis and sinusitis may cause significant morbidity in patients with
PCD. As of now, no treatments have been shown to be unequivocally effective, although most
patients are treated with intranasal corticosteroids, sinus lavage procedures and antibiotics.
Antibiotics should be used sparingly for sinus symptoms as resistance occurs quickly and
antibiotics should be reserved for more pressing pulmonary symptoms. If sinus symptoms persist
despite aggressive medical management or are severe, endoscopic sinus surgery can be used to
promote drainage and better delivery of topical medications [126]. Male infertility due to sperm
immotility can be overcome by assisted fertilisation techniques such as intracytoplasmic sperm
injections [127]. Females, who are infertile secondary to fallopian tube dysfunction, can have
direct ovum harvesting from the ovaries and can get in vitro fertilisation.
Statement of interest
P.G. Noone is principal investigator on an industry sponsored study (multicentre) looking at the
effects of inhaled mannitol in non-cystic fibrosis bronchiectasis (Pharmaxis). He is also principal
investigator on an industry sponsored study (multicentre) looking at the effects of inhaled
aztreonam in non-cystic fibrosis bronchiectasis (Gilead).
References
144
1.
2.
3.
Kartagener M, Stucki P. Bronchiectasis with situs inversus. Arch Pediatr 1962; 79: 193–207.
Afzelius BA. A human syndrome caused by immotile cilia. Science 1976; 193: 317–319.
Noone PG, Zariwala M, Knowles MR. Primary ciliary dyskinesia. In: Runge M, Patterson C, eds. Principles of
Molecular Medicine. Totowa, Humana Press, 2006; pp. 239–250.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
L.J. LOBO ET AL.
5.
Knowles MR, Metjian H, Leigh MW, et al. Primary ciliary dyskinesia. In: McCormack FX, Panos RJ, Trapnell BC,
eds. Molecular Basis of Pulmonary Diseases. Totowa, Humana Press, 2010; pp. 293–323.
Carson JL, Collier AM, Hu SS. Acquired ciliary defects in nasal epithelium of children with acute viral upper
respiratory infections. N Engl J Med 1985; 312: 463–468.
Barbato A, Frischer T, Kuehni CE, et al. Primary ciliary dyskinesia: a consensus statement on diagnostic and
treatment approaches in children. Eur Respir J 2009; 34: 1264–1276.
Kartagener M. Zur pathogenese der bronkiectasien: bronkiectasien bei situs viscerum inversus. Beitr Klin Tuberk
1933; 82: 489–501.
Camner P, Mossberg B, Afzelius BA. Evidence for congenitally nonfunctioning cilia in the tracheobronchial tract
in two subjects. Am Rev Respir Dis 1975; 112: 807–809.
Pasteur MC, Helliwell SM, Houghton SJ, et al. An investigation into causative factors in patients with
bronchiectasis. Am J Respir Crit Care Med 2000; 162: 1277–1284.
Afzelius BA. Inheritance of randomness. Med Hypotheses 1996; 47: 23–26.
Ibanez-Tallon I, Heintz N, Omran H. To beat or not to beat: roles of cilia in development and disease. Hum Mol
Genet 2003; 12: Suppl. 1, R27–R35.
Wheatley DN, Wang AM, Strugnell GE. Expression of primary cilia in mammalian cells. Cell Biol Int 1996; 20:
73–81.
Fliegauf M, Benzing T, Omran H. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 2007; 8:
880–893.
Vallee RB, Gee MA. Make room for dynein. Trends Cell Biol 1998; 8: 490–494.
Boucher RC. Bronchiectasis: a continuum of ion transport dysfunction or multiple hits? Am J Respir Crit Care
Med 2010; 181: 1017–1019.
Noone PG, Bali D, Carson JL, et al. Discordant organ laterality in monozygotic twins with primary ciliary
dyskinesia. Am J Med Genet 1999; 82: 155–160.
Kennedy MP, Omran H, Leigh MW, et al. Congenital heart disease and other heterotaxic defects in a large cohort
of patients with primary ciliary dyskinesia. Circulation 2007; 115: 2814–2821.
Nonaka S, Tanaka Y, Okada Y, et al. Randomization of left-right asymmetry due to loss of nodal cilia generating
leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 1998; 95: 829–837.
Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging class of human genetic disorders. Annu Rev
Genomics Hum Genet 2006; 7: 125–148.
Ellerman A, Bisgaard H. Longitudinal study of lung function in a cohort of primary ciliary dyskinesia. Eur Respir
J 1997; 10: 2376–2379.
Noone PG, Leigh MW, Sannuti A, et al. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J
Respir Crit Care Med 2004; 169: 459–467.
Lie H, Zariwala MA, Helms C, et al. Primary ciliary dyskinesia in Amish communities. J Pediatr 2010; 156: 1023–1025.
O’Callaghan C, Chetcuti P, Moya E. High prevalence of primary ciliary dyskinesia in a British Asian population.
Arch Dis Child 2010; 95: 51–52.
Holzmann D, Felix H. Neonatal respiratory distress syndrome – a sign of primary ciliary dyskinesia? Eur J Pediatr
2000; 159: 857–860.
Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur Respir J 1998; 12:
982–988.
Leigh MW, Pittman JE, Carson JL, et al. Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener
syndrome. Genet Med 2009; 11: 473–487.
Coren ME, Meeks M, Morrison I, et al. Primary ciliary dyskinesia: age at diagnosis and symptom history. Acta
Paediatr 2002; 91: 667–669.
Eastham KM, Fall AJ, Mitchell L, et al. The need to redefine non-cystic fibrosis bronchiectasis in childhood.
Thorax 2004; 59: 324–327.
Greenstone M, Rutman A, Dewar A, et al. Primary ciliary dyskinesia: cytological and clinical features. Q J Med
1988; 67: 405–430.
Morini F, Cozzi DA, Conforti A, et al. An infant with respiratory distress and failure to thrive. Eur Respir J 2002;
20: 500–503.
Kennedy MP, Noone PG, Leigh MW, et al. High-resolution CT of patients with primary ciliary dyskinesia. AJR
Am J Roentgenol 2007; 188: 1232–1238.
Jain K, Padley SP, Goldstraw EJ, et al. Primary ciliary dyskinesia in the paediatric population: range and severity
of radiological findings in a cohort of patients receiving tertiary care. Clin Radiol 2007; 62: 986–993.
Noone PG, Bennett WD, Regnis JA, et al. Effect of aerosolized uridine-59-triphosphate on airway clearance with
cough in patients with primary ciliary dyskinesia. Am J Respir Crit Care Med 1999; 160: 144–149.
Pasteur MC, Bilton D, Hill AT. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010; 65:
Suppl. 1, i1–i58.
Kennedy MP, Noone PG, Carson J, et al. Calcium stone lithoptysis in primary ciliary dyskinesia. Respir Med 2007;
101: 76–83.
Brown DE, Pittman JE, Leigh MW, et al. Early lung disease in young children with primary ciliary dyskinesia.
Pediatr Pulmonol 2008; 43: 514–516.
145
4.
PCD IN ADULTS
146
37. Naidich DP, McCauley DI, Khouri NF, et al. Computed tomography of bronchiectasis. J Comput Assist Tomogr
1982; 6: 437–444.
38. Nadel HR, Stringer DA, Levison H, et al. The immotile cilia syndrome: radiological manifestations. Radiology
1985; 154: 651–655.
39. Munro NC, Currie DC, Lindsay KS, et al. Fertility in men with primary ciliary dyskinesia presenting with
respiratory infection. Thorax 1994; 49: 684–687.
40. Halbert SA, Patton DL, Zarutskie PW, et al. Function and structure of cilia in the fallopian tube of an infertile
woman with Kartagener’s syndrome. Hum Reprod 1997; 12: 55–58.
41. Moore A, Escudier E, Roger G, et al. RPGR is mutated in patients with a complex X linked phenotype combining
primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet 2006; 43: 326–333.
42. Zito I, Downes SM, Patel RJ, et al. RPGR mutation associated with retinitis pigmentosa, impaired hearing, and
sinorespiratory infections. J Med Genet 2003; 40: 609–615.
43. Kobayashi Y, Watanabe M, Okada Y, et al. Hydrocephalus, situs inversus, chronic sinusitis, and male infertility in
DNA polymerase l-deficient mice: possible implication for the pathogenesis of immotile cilia syndrome. Mol Cell
Biol 2002; 22: 2769–2776.
44. Ibanez-Tallon I, Pagenstecher A, Fliegauf M, et al. Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits
ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet 2004; 13:
2133–2141.
45. Budny B, Chen W, Omran H, et al. A novel X-linked recessive mental retardation syndrome comprising
macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet 2006; 120:
171–178.
46. Canciani M, Barlocco EG, Mastella G, et al. The saccharin method for testing mucociliary function in patients
suspected of having primary ciliary dyskinesia. Pediatr Pulmonol 1988; 5: 210–214.
47. Lundberg JO, Farkas-Szallasi T, Weitzberg E, et al. High nitric oxide production in human paranasal sinuses. Nat
Med 1995; 1: 370–373.
48. Barnes PJ, Dweik RA, Gelb AF, et al. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest
2010; 138: 682–692.
49. Lundberg JO, Weitzberg E, Nordvall SL, et al. Primarily nasal origin of exhaled nitric oxide and absence in
Kartagener’s syndrome. Eur Respir J 1994; 7: 1501–1504.
50. Karadag B, James AJ, Gultekin E, et al. Nasal and lower airway level of nitric oxide in children with primary
ciliary dyskinesia. Eur Respir J 1999; 13: 1402–1405.
51. Corbelli R, Bringolf-Isler B, Amacher A, et al. Nasal nitric oxide measurements to screen children for primary
ciliary dyskinesia. Chest 2004; 126: 1054–1059.
52. Deja M, Busch T, Bachman S, et al. Reduced nitric oxide in sinus epithelium of patients with radiologic maxillary
sinusitis and sepsis. Am J Respir Crit Care Med 2003; 168: 281–286.
53. Leigh MW, Zariwala MA, Knowles MR. Primary ciliary dyskinesia: improving the diagnostic approach. Curr
Opin Pediatr 2009; 21: 320–325.
54. Carson JL, Hu SS, Collier AM. Computer-assisted analysis of radial symmetry in human airway epithelial cilia:
assessment of congenital ciliary defects in primary ciliary dyskinesia. Ultrastruct Pathol 2000; 24: 169–174.
55. van der Baan S, Veerman AJ, Wulffraat N, et al. Primary ciliary dyskinesia: ciliary activity. Acta Otolaryngol 1986;
102: 274–281.
56. Bush A, Chodhari R, Collins N, et al. Primary ciliary dyskinesia: current state of the art. Arch Dis Child 2007; 92:
1136–1140.
57. Stannard WA, Chilvers MA, Rutman AR, et al. Diagnostic testing of patients suspected of primary ciliary
dyskinesia. Am J Respir Crit Care Med 2010; 181: 307–314.
58. Chilvers MA, Rutman A, O’Callaghan C. Ciliary beat pattern is associated with specific ultrastructural defects in
primary ciliary dyskinesia. J Allergy Clin Immunol 2003; 112: 518–524.
59. Escudier E, Couprie M, Duriez B, et al. Computer-assisted analysis helps detect inner dynein arm abnormalities.
Am J Respir Crit Care Med 2002; 166: 1257–1262.
60. Papon JF, Coste A, Roudot-Thoraval F, et al. A 20-year experience of electron microscopy in the diagnosis of
primary ciliary dyskinesia. Eur Respir J 2010; 35: 1057–1063.
61. de Iongh RU, Rutland J. Ciliary defects in healthy subjects, bronchiectasis, and primary ciliary dyskinesia. Am J
Respir Crit Care Med 1995; 151: 1559–1567.
62. Sturgess JM, Chao J, Turner JAP. Transposition of ciliary microtubules. Another cause of impaired motility.
N Engl J Med 1980; 303: 318–322.
63. Sturgess JM, Chao J, Wong J, et al. Cilia with defective radial spokes. A cause of human respiratory disease.
N Engl J Med 1979; 300: 53–56.
64. Stannard W, Rutman A, Walne A, et al. Central microtubular agenesis causing primary ciliary dyskinesia. Am J
Respir Crit Care Med 2004; 169: 634–637.
65. Fliegauf M, Olbrich H, Horvath J, et al. Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients
with primary ciliary dyskinesia. Am J Respir Crit Care Med 2005; 171: 1343–1349.
66. Olbrich H, Horvath J, Fekete A, et al. Axonemal localization of the dynein component DNAH5 is not altered in
secondary ciliary dyskinesia. Pediatr Res 2006; 59: 418–422.
L.J. LOBO ET AL.
147
67. Omran H, Kobayashi D, Olbrich H, et al. Ktu/PF13 is required for cytoplasmic pre-assembly of axonemal
dyneins. Nature 2008; 456: 611–616.
68. Geremek M, Witt M. Primary ciliary dyskinesia: genes, candidate genes and chromosomal regions. J Appl Genet
2004; 45: 347–361.
69. Zariwala M, Noone PG, Sannuti A, et al. Germline mutations in an intermediate chain dynein cause primary
ciliary dyskinesia. Am J Respir Cell Mol Biol 2001; 25: 577–583.
70. Pennarun G, Escudier E, Chapelin C, et al. Loss-of-function mutations in a human gene related to
Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. Am J Hum Genet 1999; 65:
1508–1519.
71. Guichard C, Harricane MC, Lafitte JJ, et al. Axonemal dynein intermediate-chain gene (DNAI1) mutations result
in situs inversus and primary ciliary dyskinesia (Kartagener syndrome). Am J Hum Genet 2001; 68: 1030–1035.
72. Failly M, Saitta A, Munoz A, et al. DNAI1 mutations explain only 2% of primary ciliary dykinesia. Respiration
2008; 76: 198–204.
73. Zariwala MA, Leigh MW, Ceppa F, et al. Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder
effect in a common mutation. Am J Respir Crit Care Med 2006; 174: 858–866.
74. Pennarun G, Chapelin C, Escudier E, et al. The human dynein intermediate chain 2 gene (DNAI2): cloning
mapping expression pattern and evaluation as a candidate for primary ciliary dyskinesia. Hum Genet 2000; 107:
642–649.
75. Loges NT, Olbrich H, Fenske L, et al. DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer
dynein arm. Am J Hum Genet 2008; 83: 547–558.
76. Olbrich H, Haffner K, Kispert A, et al. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization
of left/right asymmetry. Nat Genet 2002; 30: 143–144.
77. Failly M, Bartoloni L, Letourneau A, et al. Mutations in DNAH5 account for only 15% of a non-preselected
cohort of patients with primary ciliary dyskinesia. J Med Genet 2009; 46: 281–286.
78. Hornef N, Olbrich H, Horvath J, et al. DNAH5 mutations are a common cause of primary ciliary dyskinesia with
outer dynein arm defects. Am J Respir Crit Care Med 2006; 174: 120–126.
79. Bartoloni L, Blouin JL, Pan Y, et al. Mutations in the DNAH11 (axonemal heavy chain type dynein type 11) gene
cause one form of situs inversus and most likely primary ciliary dyskinesia. Proc Natl Acad Sci USA 2002; 99:
10282–10286.
80. Pifferi M, Michelucci A, Conidi ME, et al. New DNAH11 mutations in primary ciliary dyskinesia with normal
axonemal ultrastructure. Eur Respir J 2010; 35: 1413–1416.
81. Schwabe GC, Hoffmann K, Loges NT, et al. Primary ciliary dyskinesia associated with normal axoneme
ultrastructure is caused by DNAH11 mutations. Hum Mutat 2008; 29: 289–298.
82. Zariwala M, Leigh M, Carson J, et al. Mutations in DNAH11 are exclusively seen in primary ciliary dyskinesia
patients with normal ciliary ultrastructure: deciphering the effect of splice mutations on the transcript. Abstract
375. American Society of Human Genetics, 59th Annual Meeting. October, 2009, Honolulu, Hawaii. www.ashg.
org/cgi-bin/2009/ashg09s
83. Zariwala M, Leigh M, Carson J, et al. DNAH11 mutations are a common cause of primary ciliary dyskinesia
(PCD) in patients with normal ciliary dynein arms. Am J Respir Crit Care Med 2009; 179: A1213.
84. Duriez B, Duquesnoy P, Escudier E, et al. A common variant in combination with a nonsense mutation in a
member of the thioredoxin family causes primary ciliary dyskinesia. Proc Natl Acad Sci USA 2007; 104: 3336–3341.
85. Loges NT, Olbrich H, Becker-Heck A, et al. Deletions and point mutations of LRRC50 cause primary ciliary
dyskinesia due to dynein arm defects. Am J Hum Genet 2009; 85: 883–889.
86. Duquesnoy P, Escudier E, Vincensini L, et al. Loss-of-function mutations in the human ortholog of
Chlamydomonas reinhardtii ODA7 disrupt dynein arm assembly and cause primary ciliary dyskinesia. Am J Hum
Genet 2009; 85: 890–896.
87. Davis EE, Merveille A-C, Becker-Heck A, et al. A bobtail ties CCDC39 to human ciliary defects and the assembly
of inner dynein arms and dynein regulatory complexes. Abstract 168. American Society of Human Genetics, 60th
Annual Meeting. November, 2010, Washington DC, USA. www.ashg.org/cgi-bin/2010/ashg10s
88. Merveille AC, Davis EE, Becker-Heck A, et al. CCDC39 is required for assembly of inner dynein arms and the
dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet 2011; 43: 72–78.
89. Becker-Heck A, Zohn IE, Okabe N, et al. The coiled-coil domain containing protein CCDC40 is essential for
motile cilia function and left-right axis formation. Nat Genet 2011; 43: 79–84.
90. Castleman VH, Romio L, Chodhari R, et al. Mutations in radial spoke head protein genes RSPH9 and RSPH4A
cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. Am J Hum Genet 2009; 84:
197–209.
91. Omran H, Haffner K, Volkel A, et al. Homozygosity mapping of a gene locus for primary ciliary dyskinesia on
chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene. Am J Respir Cell Mol
Biol 2000; 23: 696–702.
92. Blouin JL, Meeks M, Radhakrishna U, et al. Primary ciliary dyskinesia: a genome-wide linkage analysis reveals
extensive locus heterogeneity. Eur J Hum Genet 2000; 8: 109–118.
93. Avidor-Reiss T, Maer AM, Koundakjian E, et al. Decoding cilia function: defining specialized genes required for
compartmentalized cilia biogenesis. Cell 2004; 117: 527–539.
PCD IN ADULTS
148
94. Fliegauf M, Omran H. Novel tools to unravel molecular mechanisms in cilia-related disorders. Trends Genet
2006; 22: 241–245.
95. Supp DM, Witte DP, Potter SS, et al. Mutation of an axonemal dynein affects left-right asymmetry in inversus
viscerum mice. Nature 1997; 389: 963–966.
96. Supp DM, Brueckner M, Potter SS. Handed asymmetry in the mouse: understanding how things go right (or left)
by studying how they go wrong. Sem Cell Develop Biol 1998; 9: 77–87.
97. Cavrenne R, De Busscher V, Bolen G, et al. Primary ciliary dyskinesia and situs inversus in a young dog. Vet Rec
2008; 163: 54–55.
98. Ibanez-Tallon I, Gorokhave S, Heintz N. Loss of function of axonemal dynein Mdnah5 causes primary ciliary
dyskinesia and hydrocephalus. Hum Mol Genet 2002; 11: 715–721.
99. Tan SY, Rosenthal J, Zhao XQ, et al. Heterotaxy and complex structural heart defects in a mutant mouse model
of primary ciliary dyskinesia. J Clin Invest 2007; 117: 3742–3752.
100. Fernandez-Gonzalez A, Kourembanas S, Wyatt TA, et al. Mutation of murine adenylate kinase 7 underlies a
primary ciliary dyskinesia phenotype. Am J Respir Cell Mol Biol 2009; 40: 305–313.
101. Ostrowski LE, Yin W, Rogers TD, et al. Conditional deletion of dnaic1 in a murine model of primary ciliary
dyskinesia causes chronic rhinosinusitis. Am J Respir Cell Mol Biol 2010; 43: 55–63.
102. Hellinckx J, Demedts M, de Boeck K. Primary ciliary dyskinesia: evolution of pulmonary function. Eur J Pediatr
1998; 157: 422–426.
103. Marthin JK, Petersen N, Skovgaard LT, et al. Lung function in patients with primary ciliary dyskinesia: a crosssectional and 3-decade longitudinal study. Am J Respir Crit Care Med 2010; 181: 1262–1268.
104. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis.
Am J Respir Crit Care Med 2003; 168: 918–951.
105. Loukides S, Kharitonov S, Wodehouse T, et al. Effect of arginine on mucociliary function in primary ciliary
dyskinesia. Lancet 1998; 352: 371–372.
106. Yoshioka D, Sakamoto N, Ishimatsu Y, et al. Primary ciliary dyskinesia that responded to long-term, low-dose
clarithromycin. Intern Med 2010; 49: 1437–1440.
107. Cystic Fibrosis Foundation. Patient Registry. Annual Report to the Center Directors. Cystic Fibrosis Foundation
Annual, Bethesda, MD, USA. www.cff.org/UploadedFiles/research/ClinicalResearch/Patient-Registry-Report2009.pdf
108. el Din MA, Palmer LB, el Tayeb MN, et al. Nebulizer therapy with antibiotics in chronic suppurative lung disease.
J Aerosol Med 1994; 7: 345–350.
109. Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with
hypertonic saline. N Engl J Med 2006; 354: 241–250.
110. Robinson M, Regnis JA, Bailey DL, et al. Effect of hypertonic saline, amiloride, and cough on mucociliary
clearance in patients with cystic fibrosis. Am J Respir Crit Care Med 1996; 153: 1503–1509.
111. Bennett WD, Olivier KN, Zeman KL, et al. Effect of uridine 5-triphosphate plus amiloride on mucociliary
clearance in adult cystic fibrosis. Am J Respir Crit Care Med 1996; 153: 1796–1801.
112. Kellett F, Redfern J, Niven RM. Evaluation of nebulised hypertonic saline (7%) as an adjunct to physiotherapy in
patients with stable bronchiectasis. Respir Med 2005; 99: 27–31.
113. Wills P, Greenstone M. Inhaled hyperosmolar agents for bronchiectasis. Cochrane Database Syst Rev 2006; 2:
CD002996.
114. Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on
exacerbations on respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med
1994; 331: 637–642.
115. Donnell AE, Barker AE, Ilowite JS, et al. Treatment of idiopathic bronchiectasis with aerosolized recombinant
human DNase. Chest 1998; 113: 1329–1334.
116. Phillips GE, Thomas S, Heather S, et al. Airway response of children with primary ciliary dyskinesia to exercise
and b2-agonist challenge. Eur Respir J 1998; 11: 1389–1391.
117. Bennett WD. Effect of b-adrenergic agonists on mucociliary clearance. J Allergy Clin Immunol 2002; 110: Suppl. 6,
S291–S297.
118. Balfour-Lynn IM, Lees B, Hall P, et al. Multicenter randomized controlled trial of withdrawal of inhaled
corticosteroids in cystic fibrosis. Am J Respir Crit Care Med 2006; 173: 1356–1362.
119. Kapur N, Bell S, Kolbe J, et al. Inhaled steroids for bronchiectasis. Cochrane Database Syst Rev 2009; 1:
CD000996.
120. Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis
chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290:
1749–1756.
121. Grasemann H, Gartig SS, Wiesemann HG, et al. Effect of L-arginine infusion on airway NO in cystic fibrosis and
primary ciliary dyskinesia syndrome. Eur Respir J 1999; 13: 114–118.
122. Deterding RR, Lavange LM, Engels JM, et al. Phase 2 randomized safety and efficacy trial of nebulized denufosol
tetrasodium in cystic fibrosis. Am J Respir Crit Care Med 2007; 176: 362–369.
123. Balkanli K, Genc O, Dakak M, et al. Surgical management of bronchiectasis: analysis and short-term results in
238 patients. Eur J Cardiothorac Surg 2003; 24: 699–702.
149
L.J. LOBO ET AL.
124. Smit HJ, Schreurs AJ, Van den Bosch JM, et al. Is resection of bronchiectasis beneficial in patients with primary
ciliary dyskinesia? Chest 1996; 109: 1541–1544.
125. Rabago G, Copeland JG III, Rosapepe F, et al. Heart-lung transplantation in situs inversus. Ann Thorac Surg 1996;
62: 296–298.
126. Parsons DS, Greene BA. A treatment for primary ciliary dyskinesia: efficacy of functional endoscopic sinus
surgery. Laryngoscope 1993; 103: 1269–1272.
127. Gerber PA, Kruse R, Hirchenhain J, et al. Pregnancy after laser-assisted selection of viable spermatozoa
before intracytoplasmatic sperm injection in a couple with male primary cilia dyskinesia. Fertil Steril 2008; 89:
9–12.