[ Diffuse Lung Disease CHEST Pulmonary Reviews ]

Primary Ciliary Dyskinesia

Michael Glenn O’Connor, MD; Ricardo Mosquera, MD; Hilda Metjian, MD; Meghan Marmor, MD;
Kenneth N. Olivier, MD, MPH; and Adam J. Shapiro, MD

Primary ciliary dyskinesia (PCD) is a rare but underdiagnosed disorder that affects motile cilia
function throughout the body. With increasing prevalence through ongoing genetic discovery,
PCD underlies the disease process in a significant number of patients with chronic suppurative
lung disease and bronchiectasis when properly investigated using current diagnostic standards.
Classic PCD symptoms include chronic rhinosinusitis and otitis, organ laterality defects, infer-
tility, year-round productive cough, and recurrent pneumonias with bronchiectasis. Clinical
symptoms of PCD manifest very early in life (often at birth), although diagnosis frequently is
delayed because of poor phenotypic recognition and limited access to specialized diagnostic
testing. In the past decade, PCD research networks have established specific PCD phenotypes
to increase clinical recognition, and the availability of PCD genetic panels in various commercial
laboratories has expanded access to an accurate PCD diagnosis greatly. Clinical practice
guidelines also were created to guide diagnosis and management of this rare but increasingly
recognized suppurative respiratory disease. PCD is more common than previously thought and
can be recognized through specific clinical phenotypes in both children and adults. Diagnostic
PCD testing outside of highly specialized centers can be difficult, but increased availability of
nasal nitric oxide measurement and commercial genetic panels now allows for noninvasive
screening and definitive diagnosis regardless of center expertise. Identification of patients with
accurately diagnosed PCD is needed worldwide to populate future clinical trials and to develop
disease-specific therapies for PCD. CHEST Pulmonary 2023; 1(1):100004

KEY WORDS: bronchiectasis; Kartagener; laterality; primary ciliary dyskinesia; sinusitis

Primary ciliary dyskinesia (PCD) is a rare infections leading to bronchiectasis,

genetic disease affecting motile cilia
throughout the body. The resulting ciliary
dysfunction causes the common PCD
symptoms of persistent rhinosinusitis and
otitis, neonatal respiratory distress, chronic
wet cough, recurrent lower respiratory tract
infertility, and organ laterality defects.1 Over
the past 2 decades, advances in genetic
sequencing have expanded the
understanding of the origins of PCD.
Implementation of multigene panels by
numerous commercial genetic testing

ABBREVIATIONS: nNO = nasal nitric oxide; NO = nitric oxide; PCD =
primary ciliary dyskinesia; TEM = transmission electron microscopy
AFFILIATIONS: From the Division of Pulmonary Medicine (M. G. O.),
Department of Pediatrics, Vanderbilt University Medical Center,
Nashville, TN; the Division Pulmonary Medicine (R. M.),
Department of Pediatrics, McGovern Medical School at The
University of Texas Health Science Center at Houston and Chil-
dren’s Memorial Hermann Hospital, Houston, TX; the Division of
Pulmonary, Critical Care and Sleep Medicine (H. M.), National
Jewish Health, Denver, CO; the Division of Pulmonary, Allergy
and Critical Care Medicine (M. M.), Stanford University School of
Medicine, Stanford, CA; the Division of Pulmonary Diseases and
Critical Care Medicine (K. N. O.), University of North Carolina at
Chapel Hill, Chapel Hill, NC; and the Division of Pediatric Res-
piratory Medicine (A. J. S.), McGill University Health Centre
Research Institute, Montreal, QC, Canada.
CORRESPONDENCE TO: Adam J. Shapiro, MD; email: Adam.shapiro@
muhc.mcgill.ca
Copyright Ó 2023 The Authors. Published by Elsevier Inc under
license from the American College of Chest Physicians. This is an open
access article under the CC BY license (http://creativecommons.org/
licenses/by/4.0/).
DOI: https://doi.org/10.1016/j.chpulm.2023.100004

chestpulmonary.org 1
companies has advanced genetic analysis to the forefront
of clinical PCD diagnostics, allowing for definitive PCD
diagnosis at any center, regardless of PCD expertise.
This review focuses on clinical recognition, accurate
diagnosis, and standard therapies that can be used by
clinicians who may encounter this rare but increasingly
recognized disease.
Literature Search
For this review, two authors (M. G. O., A. J. S.) queried
the PubMed database for articles relating to the search
terms primary ciliary dyskinesia or Kartagener,
considering only publications after 2001, when the first
gene causing PCD was discovered and the genomic era
of PCD investigation began. Results were filtered to
exclude cases in nonhumans and case reports, resulting
in 562 publications for which abstracts were reviewed.
Reviewers next selected publications with clinical impact
for full-text evaluation. Additional references were
supplemented from authors’ pre-existing literature
collections, as warranted.
Evidence Review
Epidemiologic Characteristics
The prevalence of PCD is estimated at 1:7,500 to
1:15,000 individuals and occurs across all races and
ethnicities.2,3 With these estimates, 25,000 to 50,000
people in North America should be affected with PCD,
yet the PCD Foundation (the primary PCD patient
advocacy group in North America) has estimated that
only 1,000 individuals in North America have received
an accurate diagnosis. This low prevalence stems from
poor clinical recognition of PCD phenotypes and a lack
of easily accessible PCD diagnostic tools outside of
highly specialized centers. As a result, the average age at
diagnosis is approximately 5 years in some cohorts, but
PCD frequently is diagnosed later in childhood or in
adulthood.4 Unfortunately, a delayed PCD diagnosis is
associated with poor respiratory outcomes.5 Significant
numbers of patients with PCD also are found in adult
bronchiectasis cohorts through exome sequencing,
revealing that up to 12.5% of these patients have
genetically confirmed PCD.6
Pathophysiologic Characteristics
The central biologic pathology in PCD is a lack of
effective ciliary movement at the upper and lower airway
surfaces. This leads to loss of normal mucociliary
clearance with mucostasis and subsequent infection with
chronic inflammation.7 Abnormal ciliary movement in
2 CHEST Pulmonary Reviews
the paranasal sinuses causes chronic rhinitis and acute
on chronic sinusitis, whereas stasis in the lower airways
results in chronic wet cough, recurrent pneumonia or
bronchitis, and eventual development of bronchiectasis.8
Ciliary function also is essential for middle-ear fluid
egression, and when abnormal, contributes to frequent
otitis media, persistent middle-ear effusions, and hearing
loss.9 Dysfunction of motile, ependymal cilia in the CNS
may result in hydrocephalus, although only a small
portion of patients with PCD with specific genetic
defects actually demonstrate this.10,11 Finally, ciliary
movement directs the embryonic nodal system
responsible for proper organ laterality placement in
utero and for propulsive structures in sperm tails and
fallopian fimbriae of the reproductive system.12,13
Disease Phenotypes
Chronic cough and rhinorrhea are common symptoms
in outpatient pulmonary clinics. Although PCD is rarely
the underlying cause of these symptoms, recognizing the
PCD-specific clinical aspects of these affords clinicians
the proper index of suspicion to detect PCD cases.
Research from the Genetic Disorders of Mucociliary
Clearance Consortium and International PCD cohorts
has defined the key clinical features of PCD in children,
including: (1) year-round wet or productive cough that
begins in early infancy, (2) year-round rhinitis that also
begins in early infancy, (3) unexplained neonatal
respiratory distress despite term birth, and (4) presence
of an organ laterality defect (ie, situs inversus totalis or
situs ambiguus).14 Adult PCD cohorts from the Genetic
Disorders of Mucociliary Clearance Consortium also
have shown high prevalence of these key clinical
symptoms in patients who receive a diagnosis after 18
years of age,15 with the evolution of chronic rhinitis to
chronic sinusitis (Table 1).
Approximately 80% of children with PCD have a history
of neonatal respiratory distress at term birth,14,16 but
this prevalence decreases for those who receive a
diagnosis in adulthood, likely because of recall bias. In
PCD, the onset of neonatal respiratory distress often is
delayed for 12 to 24 h, as opposed to other causes of
neonatal respiratory distress (ie, neonatal pneumonia,
meconium aspiration, and transient tachypnea of the
newborn), which appear immediately after birth.16 The
respiratory distress in infants with PCD often is
prolonged, requiring an average of 2 weeks of
respiratory support or supplemental oxygen, and often is
accompanied by persistent upper lobe or shifting lobar
atelectasis on neonatal chest radiography.16,17
[ 1#1 CHEST Pulmonary JUNE 2023 ]
TABLE 1 ] Key Clinical Symptoms of PCD in Adults and
Children
When to Suspect PCD in Pediatric and Adult Patients
Symptoms highly suggestive of PCD in children

At least two of four key clinical symptoms14
◦ Year-round wet cough with onset before 6 mo of age
or
◦ Year-round nasal congestion with onset before 6 mo
of age or
◦ Neonatal respiratory distress at term birth requiring
supplemental oxygen or positive pressure support
for at least 24 h or
◦ An organ laterality defect

Unexplained bronchiectasisa with chronic
oto-sino-pulmonary disease
Symptoms highly suggestive of PCD in adults:

At least two of four key clinical symptoms above14 or

Unexplained bronchiectasisa with chronic rhinosinusitis
or

Unexplained bronchiectasisa with ongoing otitis in
adulthood or

Unexplained bronchiectasisa with an organ laterality
defect or

Unexplained bronchiectasisa with male or female
infertility or

Unexplained bronchiectasisa with chronic respiratory
symptoms since early childhood
PCD ¼ primary ciliary dyskinesia.
a
Bronchiectasis in PCD shows a predominance for middle- and lower-lobe
involvement.
The chronic cough in PCD is almost always wet, and
even infants are sometimes able to expectorate
sputum, which is rare in other pediatric respiratory
conditions. The characteristic wet cough never
resolves completely, even after prolonged antibiotic
therapy. The chronic rhinitis of PCD is similarly
fastidious, never completely resolving even with
aggressive antibiotic and topical nasal therapy. In
classic PCD, both the wet cough and nasal
congestion appear before 6 months of age (often
immediately after birth); later onset of these
symptoms (ie, during adolescence or adulthood) is
not characteristic of PCD and should push clinicians
toward other possible diagnoses.
Most patients with PCD also have recurrent otitis media
and persistent middle-ear effusions in childhood. For
many, these are accompanied by hearing deficits and
language delay.9,18 Repeat myringotomy tube placement
features prominently in patient histories. A complete
lack of recurrent otitis or ear effusions is exceedingly
rare in PCD. For unknown reasons, ear disease greatly
improves in many adolescent patients with PCD, yet
some adults with PCD continue to experience otitis
media and hearing deficits.19
chestpulmonary.org
Recurrent lower respiratory tract infections are also a
major clinical finding in PCD, and the persistent,
suppurative lung inflammation behind these infections
eventually leads to development of bronchiectasis.
Approximately 50% of children demonstrate
bronchiectasis by 8 years of age, and nearly 100% of
adults with PCD display bronchiectasis, often with a
predilection for middle- and lower-lobe
involvement.20,21
Other common PCD features found mainly in
adulthood include chronic sinusitis and infertility. Most
adult patients with PCD require endoscopic sinus
surgery for chronic sinus disease and may have
hypoplastic or absent frontal and sphenoid sinuses,
although their burden of nasal polyposis seems relatively
low compared with that of other suppurative diseases,
like cystic fibrosis.22-24 Most men with PCD reportedly
are infertile because of sperm immotility (because sperm
tail propulsion relies on the same motile ciliary
apparatus as respiratory cilia), and intracytoplasmic
sperm injection is required for successful conception.13
Women with PCD can show reduced fertility secondary
to dysfunction of oviductal fimbriae motion, yet a
proportion can still bear children without fertility
assistance.25 The prevalence of ectopic (tubal) pregnancy
also may be increased in women with PCD.26
Because of dysfunction of nodal cilia in developing
embryos, organ laterality defects frequently occur in
PCD, with slightly < 50% of patients displaying mirror-
image inversion of all internal organs (situs inversus
totalis). However, closer inspection of cardiac, thoracic,
and abdominal organs sometimes reveals other laterality
abnormalities in 12% to 20% of patients, known as situs
ambiguus. In situs ambiguus, defects may arise as
grouped patterns (isomerism) or in isolation along a
spectrum between normal organ placement and situs
inversus totalis. Cardiac defects may include isolated
dextrocardia, simple septal defects, or complex
congenital heart disease (heterotaxy), whereas thoracic
defects can include bilateral bilobed or trilobed lungs
and abdominal defects may comprise dextrogastria,
polysplenia or asplenia, interrupted inferior vena cava,
or other alterations (Table 2).27 Thus, the presence of
any organ laterality defect, in isolation or throughout the
body, should greatly increase the suspicion of PCD in
patients with chronic respiratory disease. Notably, a lack
of organ laterality defects does not rule out PCD because
these occur randomly, even within related patients
affected by identical PCD gene variants. People with
disease-causing variants in genes encoding radial spoke
3
TABLE 2 ] Examples of Possible Organ Laterality Defects With Situs Ambiguus in PCD
Cardiac defects Vascular defects

Isolated dextrocardia
Right aortic arch

Simple congenital heart defects (ASD, VSD, and so
Bilateral or left superior vena cava
forth)
Interrupted inferior vena cava

Complex congenital heart defects (heterotaxy)
Levotransposition or dextrotransposition of the great vessels

Atrial isomerism
Anomalous pulmonary venous return

Common atrium
Others

Atrioventricular discordance

Ventriculoarterial discordance

Others
Abdominal defects Pulmonary defects

Situs inversus abdominalis
Left pulmonary isomerism (bilateral bilobed lungs or hyparterial

Midline liver bronchi)

Dextrogastria
Right pulmonary isomerism (bilateral trilobed lungs or eparterial

Polysplenia or asplenia (right or left sided) bronchi)

Intestinal malrotation
Pulmonary situs inversus

Horseshoe kidney

Annular pancreas

Duodenal atresia

Fused adrenal glands

Extrahepatic biliary atresia

Others

Any defect may occur in isolation or in combination with other defects across the cardiac, vascular, pulmonary, or abdominal compartments. Specific
patterns of left or right isomerism are possible with primary ciliary dyskinesia, but identification of an isolated lesion also should raise suspicion greatly of
primary ciliary dyskinesia in a patient with chronic respiratory, sinonasal, or ear disease.28 ASD ¼ atrial septal defect; VSD ¼ ventricular septal defect.

or central apparatus components do not manifest organ
laterality defects because these structures are not
necessary for proper function of embryonic nodal cilia
and normal organ placement.
According to American Thoracic Society clinical
practice guidelines, the presence of at least two key
clinical symptoms in a patient should prompt further
PCD diagnostic testing.28 Moreover, a diagnosis of PCD
should be pursued in adults with bronchiectasis
accompanied by chronic sinonasal disease, infertility, an
organ laterality defect, or the onset of chronic
respiratory symptoms in early childhood (Table 3).
Diagnosis
After establishing an appropriate PCD clinical
phenotype, diagnostic testing can be performed with a
myriad of tests. No single test is 100% sensitive or
specific for a PCD diagnosis, and each test has
limitations related to availability and feasibility outside
of highly specialized centers. In North America, PCD
diagnosis rests on screening nasal nitric oxide (nNO)
measurement and confirmatory genetic panel testing,
followed by ciliary transmission electron microscopy
(TEM) as needed for inconclusive genetic results.28
Some highly experienced European centers complement
this approach with high-speed videomicroscopy analysis
of ciliary beat pattern and ciliary protein
immunofluorescence, neither of which are available
routinely in North America.36 For individuals 5 years of
age and older, American Thoracic Society guidelines
recommend nNO measurement as the first-line
diagnostic test when available.28 However, nNO testing
needs to be performed in an accredited PCD Foundation
center with a chemiluminescence nitric oxide analyzer
using an approved measurement protocol.29 In patients
younger than 5 years or without access to nNO
chemiluminescence testing, the recommended first-line
test is PCD genetic panel analysis.
nNO testing has high diagnostic accuracy for PCD
diagnosed by genetics or TEM.37 The test is noninvasive,
can be performed quickly, and is inexpensive, and
results are available immediately.29,37 The biologic
mechanism affecting nNO levels in PCD is not
understood fully, and investigations have shown that
low nNO values do not result from decreased nitric
oxide (NO) production, NO synthase deficits, increased
NO breakdown, mucus obstruction of sinonasal
passages, or colonization of nasal secretions with
denitrifying bacteria.38 It is possible that expression or
activity of a NO metabolic protein downstream of NO
synthase is regulated abnormally in association with
ciliary dysfunction, but this remains unproven.39
It has been observed robustly that 90% to 95% of
patients with PCD will show repeatedly low nNO values

4 CHEST Pulmonary Reviews [ 1#1 CHEST Pulmonary JUNE 2023 ]

TABLE 3 ] Summary of Available PCD Diagnostic Testing
Testing Population and Specific
Testing Considerations
nNO measurement
Cystic fibrosis must be ruled
out

Must be $ 5 y of age and
able to exhale against a
resistora

In North America, only
available in accredited PCD
Foundation centers with
chemiluminescence ana-
lyzers and approved
protocols29

Must be in baseline state of
health for at least 2 wk
Genetic testing
Perform at any age and
anytime

Highly feasible in most
clinical care centers

Most commercial multigene
panels evaluate $ 40
known PCD genes through
NGS, including deletion and
duplication analysis

Whole exome sequencing
will increase sensitivity, but
is not covered by most
insurance
TEM of respiratory
Perform at any age
cilia
Must be in baseline state of
health for at least 2 wk

Requires a pathology labo-
ratory with extensive expe-
rience in ciliary TEM
processing and analysis to
avoid insufficient sampling
High-speed video
Perform at any age
microscopy with
Must be in baseline state of
beat pattern health for at least 2 wk
analysis
Limited resources and
expertise for this in North
America

Requires repeat analysis on
three separate visits or af-
ter air-liquid cellular
regrowth to avoid
secondary causes of
dyskinesia36
Immunofluorescence
Perform at any age
testing of ciliary
Must be in baseline state of
proteins health for at least 2 wk
chestpulmonary.org
Positive Results
< 77 nL/min by exhalation
against resistor maneuver
on at least two separate
occasions29
Two pathogenic or likely
pathogenic variants within
one autosomal recessive
PCD-causing gene31,b
Class 1 ultrastructural
defects: (1) outer dynein
arm defect, (2) outer and
inner dynein arm defect, (3)
absent inner dynein arm
with microtubule
disorganization34
Abnormal ciliary beat pattern
Absent fluorescence of ciliary
proteins in specific
axonemal components
Comments

Increasing false-negative
results with specific PCD
genotypes (RSPH1,
CCDC103, and so
forth)30,31

False-positive results are
possible (eg, acute viral
illness, cystic fibrosis,
epistaxis, rare forms of
immunodeficiency)32,33

Repeat testing is required

Testing is nondiagnostic in
20-30% of cases

Single variants in different
PCD genes are non-
diagnostic, because both
variants must occur within
the same gene to cause
PCD

Frequently results in VUS,
which are nondiagnostic

Different PCD genes
included in various com-
mercial panels will affect
overall sensitivity

Known intronic variants in
DNAH11 and CCDC39 will
not be detected on NGS
panels31

30% of the patients with
PCD harbor normal or non-
diagnostic ciliary
ultrastructure35

Changes aside from class 1
defects are nondiagnostic34

Not applicable to certain
ciliary production defects
caused by specific genes
(CCNO, MCIDAS)31

Normal cilia waveform
analysis does not rule out a
PCD diagnosis, because
some mutations may result
in normal or near-normal
movement

Beat-pattern interpretation
is nonstandardized and may
differ between reviewers
and laboratories36

Abnormal ciliary beat
pattern also may result
from a secondary cause,
like acute respiratory illness

False-negative results in
specific genetic forms of
PCD, including cases
(Continued)
5
TABLE 3 ] (Continued)
Testing Population and Specific
Testing Considerations

Limited resources and
expertise for this in North
America
NGS ¼ next generation sequencing; nNO ¼ nasal nitric oxide; PCD ¼ primary ciliary dyskinesia; TEM ¼ transmission electron microscopy; VUS ¼ variant of
uncertain significance.
a
Nasal nitric oxide measurement can be performed down to 2 years of age using a tidal breathing technique, but diagnostic cutoff values are not well
defined for this group.
b
Variants should be proven biallelic with phase testing of other family members as possible. In RPGR, OFD1, PIH1D3 (X-linked), and FOXJ1 (autosomal
dominant), only one pathogenic or likely pathogenic variant is required for a PCD diagnosis.
when using a sensitive and specific cutoff value of < 77
nL/min.40 Rare, but increasing, cases that often are
associated with specific PCD genotypes (eg, RSPH1,
CCDC103, and CFAP221) sometimes result in nNO
values of more than the 77-nL/min cutoff.27,30,41,42
These cases represent a minority, but important,
proportion of currently recognized PCD cases, and the
use of a higher cutoff value (108 nL/min) for PCD
screening has been suggested.41 Consequently, when the
clinical suspicion for PCD is high, nNO values of > 77
nL/min should not rule out PCD, and additional testing
with genetics and TEM is still warranted. Most
individuals with PCD maintain reduced nNO levels for
life, and normalization of nNO levels should alert
clinicians to an alternative diagnosis.
Limitations of nNO testing include false-positive results
in patients with cystic fibrosis or with recent viral illness,
epistaxis, or sinonasal instrumentation (Table 3).41,43 In
addition, evidence is increasing that patients with rare
immunodeficiencies can have repeatedly low nNO
values.32,44 Specific evidence exists for repeatedly low
nNO values with RAG1 and PIK3CD genetic variants,
but it is possible that other immunodeficiencies with low
nNO values have yet to be described.32,33 When
immunodeficiencies are misdiagnosed as PCD based on
nNO test results alone, patients risk significant
morbidity and even mortality secondary to untreated
immune issues.30 For these reasons, updated American
Thoracic Society guidelines recommend all cases of PCD
be verified through genetic or TEM analysis, and when
these tests are inconclusive, consultation with an
immunology specialist is necessary (Fig 1).45
Genetic panel testing with next generation sequencing is
rapidly becoming the de facto first-line test for PCD
across North America because of the high feasibility of
this testing method regardless of expertise in PCD.
6 CHEST Pulmonary Reviews
Positive Results Comments
caused by DNAH11 and
HYDIN variants

Not applicable to certain
ciliary production defects
caused by specific genes
(CCNO, MCIDAS)31
Commercially available genetic panel tests require only a
sample of blood or buccal cells, which can be collected in
medical resource-poor locations. However, the
intricacies of PCD genetics often pose issues for
clinicians interpreting these results. More than 50 PCD
genes have been described, and most follow an
autosomal recessive pattern of inheritance.8,31
Importantly, no reports exist of digenic variants causing
PCD, and thus a genetic diagnosis of PCD is made by
the presence of two pathogenic or likely pathogenic
variants (per American College of Genetics and
Genomics pathogenicity classification) within the same
gene (Table 3).1,46 Single variants in different PCD-
causing genes are not diagnostic of PCD. Furthermore, a
diagnosis cannot be confirmed when one variant is
pathogenic but the other is a variant of uncertain
significance, even when the variants have been
confirmed to be on opposite chromosomes. Current next
generation sequencing genetic panel testing does not
provide a confirmatory diagnosis in 20% to 30% of
patients with PCD, but additional PCD-causing genes
are being identified continually, and new genes
frequently are being added to existing commercial
panels.31 As clinical exome sequencing becomes more
widely available, one can expect the proportion of
genetically diagnosed cases of PCD to increase further,
as has been shown in research protocols.47 Consultation
with a clinical geneticist often is required to interpret
PCD genetic testing results correctly.
TEM analysis of respiratory cilia is now a second-line
PCD diagnostic test because numerous technical
challenges prevent successful TEM studies outside of
highly experienced pathology laboratories. These include
difficulty obtaining an adequate biopsy sample and
appropriately processing the sample to obtain a
minimum of 50 unique ciliary cross sections for
[ 1#1 CHEST Pulmonary JUNE 2023 ]
 At least 2 of the 4 major clinical features for PCD:
Unexplained neonatal respiratory distress in term infant
Year-round daily cough beginning before 6 months of age No PCD Unlikely
Year-round daily nasal congestion beginning before 6 months of age
Organ laterally defect

Yes

Access to nNO testing (with chemiluminescence device and standardized protocol) at

specialty center and cooperative patient ≥ 5 years old, capable of performing nNO testing maneuver

Yes to both
(preferred pathway when No to either
≥ 5 years old)

Nasal nitric oxide measurement Extended genetic testing panela

Biallellic pathogenic Single pathogenic No pathogenic

Consistently low nNO level
Normal nNO level variants in PCD- variant in PCD- variants in PCD-
on repeated measures
associated gene associated genec,d associated genesc

Presumed diagnosis of PCD PCD diagnosis less likely,

Diagnosis of PCD Electron microscopy of ciliary ultrastructure
if CF excluded consider further testing
for PCD, if strong clinical
features, or for primary
immunodeficiency

Confirm with corroborative PCD testing, Recognized ciliary Inadequate sample

Normal ciliary
including extended genetic panel testing ultrastructural or indeterminate
ultrastructure
(first line) and TEM of ciliary ultrastructure defectb analysis

Normal or non- No or single pathogenic Unknown.

diagnostic ciliary variants in PCD-associated Diagnosis of PCD Possible PCD diagnosis.
Consider repeat
ultrastructure genesc,d Consider referral to
TEM, referral to PCD
PCD specialty center or
specialty center, or
testing for primary
testing for primary
immunodeficiency
immunodeficiency
Recommend testing for
primary immunodeficiency

Figure 1 – American Thoracic Society clinical practice guideline algorithm for diagnosing PCD. aGenetic panels testing for mutations in > 12 diseases
associated with PCD genes, including deletion and duplication analysis. bKnown disease-associated TEM-identified ultrastructural defects include outer
dynein arm defects, outer dynein arm plus inner dynein arm defects, and inner dynein arm defects with microtubular disorganization. cIn genes
associated with autosomal recessive trait. dOr presence of variants of unknown significance. CF ¼ cystic fibrosis; nNO ¼ nasal nitric oxide; PCD ¼
primary ciliary dyskinesia; TEM ¼ transmission electron microscopy. (Reprinted with permission of the American Thoracic Society. Copyright Ó 2023
American Thoracic Society. All rights reserved.28,45)

interpretation.48 Although ciliated cells can be obtained
nasally in nonsedated, cooperative patients,
inexperienced operators may collect samples when
patients are not at a baseline state of health or may fail to
probe deep enough under the inferior turbinate, making
cellular yields too low for reliable TEM analysis. These
challenges lead to sample failure in 12% to 40% of
patients who undergo TEM,49,48 even at experienced
centers. Even when these critical steps are achieved
successfully, approximately 30% of individuals with
PCD will show normal ciliary ultrastructure on
TEM.35,50,51 According to European Respiratory Society
consensus, only class 1 defects (absent outer dynein
arms, absent outer and inner dynein arms, or absent
inner dynein arms with microtubule disorganization)
are diagnostic of PCD, whereas the remainder of TEM
changes often are secondary to processing artifact or
inflammation and are only suggestive, rather than
diagnostic, of a possible ultrastructural defect.34
Clinical Monitoring
Making a diagnosis early in life is an essential step to
prescribing effective therapies for individuals with
PCD.4,52 When a diagnosis of PCD is confirmed later in
life or after serious lung damage has occurred already,
treatment effectiveness may be impaired. Long-term
outcomes in PCD are becoming more apparent as
cohorts with a proper diagnosis are followed up through

chestpulmonary.org 7
childhood and into adulthood. Severe pulmonary
function impairment, supplemental oxygen dependence,
or need for lung transplantation are reported in 38% to
51% of adults with PCD.21,53 Overall mortality and life
expectancy and outcomes after lung transplantation
have been explored poorly in patients with PCD.54 With
> 50 distinct genes causing PCD, clinical outcomes are
highly variable, but diagnosis of specific PCD genotypes
leads to better understanding of clinical variability and
disease progression. As an example, individuals with
PCD resulting from absent inner dynein arms with
microtubule disorganization (or corresponding variants
in the CCDC39 or CCDC40 genes) experience worse
respiratory and nutritional outcomes,55 whereas milder
respiratory outcomes have been seen with the RSPH1
genotype.27 Continued observation and evidence are
needed to understand new genotype-phenotype
relationships and to evaluate if prior observations
remain true.
The PCD Foundation created a consensus statement for
disease monitoring and therapies1 and suggests that at
the time of PCD diagnosis, evaluation for organ
laterality abnormalities be considered. Approximately
one-half of individuals with PCD have an organ
laterality abnormality,27 which may include the absence
of a functioning spleen compromising the immune
system.56 Verification of normal splenic function is
especially important because it can predispose patients
to life-threatening infections and may necessitate
accelerated vaccinations and antibiotic prophylaxis.57
Approximately 10% of individuals with PCD also have
congenital heart disease, and thus screening with
echocardiography is suggested at the time of PCD
diagnosis.58
Patients with a diagnosis of PCD should be seen two to
four times annually by a pulmonologist experienced in
the management of chronic suppurative lung disease or
at an accredited PCD Foundation center.1 During these
visits, lung function testing and bacterial respiratory
culture analyses are recommended. Respiratory culture
analyses for nontuberculous mycobacteria also are
recommended at least every 2 years, although this may
be performed more frequently in patients receiving
chronic azithromycin therapy. In contrast to individuals
with cystic fibrosis, where Pseudomonas aeruginosa and
Staphylococcus aureus are the most common bacterial
respiratory pathogens, Haemophilus influenzae is the
most commonly isolated respiratory pathogen in
children and adolescents with PCD, whereas P
aeruginosa appears in 20% to 40% of pediatric
8 CHEST Pulmonary Reviews
respiratory cultures. The prevalence of P aeruginosa
increases in adults with PCD, becoming even more
prevalent after 30 years of age. Mucoid P aeruginosa in
patients with PCD is comparatively less prevalent than
in patients with cystic fibrosis, but also increases in older
adults.59 Allergic bronchopulmonary aspergillosis has
been reported in pediatric and adult patients with PCD,
but this entity overall seems less common than in
patients with cystic fibrosis.60,61
Current guidelines recommend obtaining chest CT scan
imaging for evaluation of bronchiectasis, after the
diagnosis of PCD has been confirmed.1 Visualization of
the lung parenchyma with careful attention to the
development and progression of bronchiectasis is an
important part of PCD disease monitoring; the
appropriate interval for repeat CT scan imaging is not
known.
Although clinical variability of ear and sinus
manifestations exists in individuals with PCD, initial
consultation and establishing care with an
otolaryngology expert is an important part of
comprehensive care in this population.62 From an otic
perspective, routine hearing monitoring early in life can
improve hearing loss, can prevent delay in speech
development, and can improve school performance.63
Treatment of hearing loss also is an important quality of
life issue for both adult and pediatric patients with
PCD.19 Sinus involvement with or without polyposis can
be quite cumbersome in PCD, and this significantly
affects quality of life, often worsening as patients age.62
However, the ideal time for medical vs surgical
intervention is unique to each patient and involves
continued monitoring by rhinology specialists in
otolaryngology clinics.
Therapeutics
Treatment primarily consists of regular airway clearance
routines, management of airway inflammation, and
treatment of acute pulmonary infections.1 Randomized
controlled trials in PCD patient populations are limited;
however, some initial studies support available
treatments (Table 4).1,56
The mainstay of PCD care is to restore effective airway
clearance. Because the mucus in patients with PCD is
much less dehydrated with lower percent solids than in
cystic fibrosis,70 cough clearance is relatively preserved
and, when stimulated, can clear lower airway secretions.
This can be accomplished through regular use of
handheld positive expiratory pressure devices,
[ 1#1 CHEST Pulmonary JUNE 2023 ]
TABLE 4 ] Clinical Monitoring and Therapies for PCD
Method Description
Recommended clinical Pulmonary
monitoring1
Outpatient visits 2-4 times/y with spirometry testing

Airway microbiology culture 2-4 times/y

NonTB mycobacteria culture every 2 y and with unexpected lung function decline (and
more frequently if receiving azithromycin therapy)

Chest radiography every 2-4 y or with illness

Chest CT scan imaging at least once at or after diagnosis

Allergic bronchopulmonary aspergillosis testing with unexpected lung function decline
Otolaryngology

Outpatient visits 1-2 times/y in children, as needed in adults

Audiology evaluation at diagnosis and as needed
Organ laterality

Echocardiography at diagnosis56

Abdominal imaging at diagnosis (usually with ultrasound, but can be visualized on CT
scan; confirmation of spleen presence and consider testing for splenic function when
splenic anomalies present)56
Recommended therapies in all Pulmonary
patients1
Airway clearance at least daily (more frequent with respiratory illness)

Cardiovascular exercise at least daily

Azithromycin thrice weekly when frequent respiratory exacerbations occur64

Inhaled antibiotics for eradication of new P aeruginosa respiratory culture

14-21 d of oral or parenteral antibiotics for acute respiratory exacerbations

Standard vaccinations, including annual influenza vaccine, extended serotype pneu-
mococcal vaccine
Otolaryngology

Nasal sinus lavage: daily when appropriate
Treatments used on a case-
Inhaled 3%-7% hypertonic saline at least daily (more frequent with respiratory
by-case basis1 illness)65-67

Inhaled DNase (dornase alfa): long-term use may worsen pulmonary function and
increase exacerbations in bronchiectasis67,68

Chronic inhaled antibiotics for P aeruginosa sputum colonization
Treatments not routinely
Inhaled corticosteroids (outside of asthma diagnosis)
recommended1
IV immunoglobulin (outside of diagnosed immunodeficiency)

Regular bronchodilators (outside of asthma or premedication for inhaled agents)

Lobectomy69

PCD ¼ primary ciliary dyskinesia.

intrapulmonary percussive ventilation devices, of 3% to 7% nebulized hypertonic saline.1 Although the

oscillating chest wall vests, or various breathing
techniques.71 A short-term comparison of chest
percussion and postural drainage with high-frequency
chest wall oscillation therapy in patients with PCD
found no difference in pulmonary function test results,
with both groups showing significantly improved
pulmonary function.72 Aerobic exercise also is an
important part of PCD clinical treatment. In some
centers, clearance of airway mucus in patients with PCD
is performed with dedicated aerobic exercise of $
30 min coupled with huff coughing.73 To be an effective
means of airway clearance, aerobic exercise needs to be
performed consistently.
In addition to standard airway clearance, a commonly
used regimen for patients with PCD is daily inhalation
use of inhaled hypertonic saline has not been well
studied in PCD, its ability to induce a cough reflex has
led to its clinical adoption by many PCD caregivers.66
One underpowered study examining the efficacy of
inhaled hypertonic saline found no significant
differences in respiratory exacerbations, lung function,
or quality of life on the St. George’s Respiratory
Questionnaire score when compared with inhaled
isotonic saline. However, the health perception score on
the Quality of Life Questionnaire-Bronchiectasis
instrument did improve significantly with inhaled
hypertonic saline.65
In 2020, results from the first randomized, placebo-
controlled clinical trial in patients with PCD
demonstrated clinical efficacy for maintenance dosing of

chestpulmonary.org 9
azithromycin.64 It was found to be well tolerated and to
reduce pulmonary exacerbations by nearly one-half
without increasing antibiotic resistance of sputum
organisms.
Inhaled DNase (dornase alfa) has not been studied
specifically in individuals with PCD, but its use in
patients with bronchiectasis without cystic fibrosis
showed no clinical benefits and even worsened outcomes
(lung function and respiratory exacerbations) in some
patients.1,67,68 Thus, DNase is used on a case-by-case
basis in patients with PCD,1 but providers must be
aware of its potentially harmful effects. Bronchodilators
frequently are used as part of an airway clearance
routine and as pretreatment before inhaled hypertonic
saline, but no evidence exists of long-term benefit from
routine use of bronchodilators.74 In addition, no
evidence exists for the routine use of inhaled
corticosteroids outside of those patients with PCD with a
concurrent asthma diagnosis.75 It is rare for a patient
with PCD to have a concurrent immunodeficiency, and
thus routine treatment with immunoglobulin
replacement is not recommended.76 Lobectomy
similarly is not recommended in PCD because it is
associated with poor outcomes and will not halt disease
progression (Table 4).69
Broad spectrum oral antibiotics should be used for mild,
acute respiratory exacerbations, which most often
present with increased cough, sputum, work of
breathing, and sinonasal congestion (above the baseline
state) for at least 5 to 7 days in patients with PCD.
Antibiotics should target recent organisms isolated from
surveillance sputum cultures. Moderate or severe
exacerbations should be treated with parenteral
antibiotics. As in other suppurative respiratory diseases,
longer therapeutic courses (14-21 days) are used
commonly, although no evidence supports this. Acutely
increasing the frequency of airway clearance sessions
and inhaled mucolytics (hypertonic saline and airway
clearance up to qid) also may be performed during acute
exacerbations. Inhaled antibiotics have not been studied
in patients with PCD, and their use largely has been
reserved for eradication or maintenance therapy in
patients with sputum cultures showing positive results
for P aeruginosa.
Closing Section
Although the next decade of PCD research will continue
to expand genetic discovery and genotype-phenotype
correlations, a notable shift in therapeutic studies is
10 CHEST Pulmonary Reviews
expected. These should include multiple randomized
clinical trials assessing efficacy of repurposed therapies
from suppurative respiratory disease as well as novel,
disease-specific treatments for PCD. A phase 2 trial
assessing mucus hydration therapies in PCD recently
completed enrollment, and various entities are
evaluating inhaled messenger RNA therapies for
protein-specific defect correction in PCD.77 Multicenter
observational protocols also are enrolling patients for
cross-sectional assessment of upper airway disease in
PCD,78,79 while other studies are investigating
parameters of natural disease progression in adult
populations with PCD.80 Ongoing patient registries
through the PCD Foundation in North America and the
International PCD Cohort in Europe are vital resources
to support these efforts, which ultimately will result in
effective therapies and improved patient outcomes in
this rare but increasingly recognized respiratory disease.
Summary
PCD is underdiagnosed worldwide, but knowledge of
specific clinical phenotypes, coupled with new and
accessible diagnostic testing, is allowing increased
detection of this chronic respiratory disease. Although
much of the monitoring and therapy remains unproven
in PCD, regular clinical follow-up, daily airway
clearance, reduction of chronic airway inflammation,
and aggressive treatment of upper and lower respiratory
tract infections are the cornerstones of care for patients
with PCD. Accurate PCD diagnosis to grow patient
cohorts is the best way to increase public awareness for
this rare disease and to populate future clinical trials.
Funding/Support
Funding support for research was provided to K. N. O.
and A. J. S. by the National Heart, Lung, and Blood
Institute (NHLBI), National Institutes of Health [Grant
U54HL096458]. The Genetic Disorders of Mucociliary
Clearance Consortium [Grant U54HL096458] is part of
the National Center for Advancing Translational
Sciences (NCATS) Rare Diseases Clinical Research
Network (RDCRN) and supported by the RDCRN Data
Management and Coordinating Center [Grant
U2CTR002818]. RDCRN is an initiative of the Office of
Rare Diseases Research funded through a collaboration
between NCATS and NHLBI.
Financial/Nonfinancial Disclosures
None declared.
[ 1#1 CHEST Pulmonary JUNE 2023 ]
Acknowledgments
Author contributions: All authors participated in the writing and
editing of this review manuscript.
Role of sponsors: The sponsor had no role in the design of the study,
the collection and analysis of the data, or the preparation of the
manuscript.
Disclaimer: The contents are solely the responsibility of the authors
and do not necessarily represent the official views of the National
Institute of Health.
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