C. Centrilobular nodules associated with some bronchiectasis in the basal segment of the lower left lobe
Discussion
Sinus and chest CT scans of our patient revealed the “presence of
pansinusitis; some nuanced centrolobular nodules associated with some
bronchiectasis in the basal segment of the lower left lobe; concomitant
thickening of the bronchial walls. Our patient then underwent nasal
nitric oxide (nNO) testing, which was low (left: 131 ppb; right: 137
ppb). In order to evaluate ciliary motility and ultrastructure, an
epithelial sample was obtained from the upper airways. Ciliary movement
analysis documented poor ciliary activity with an average beat frequency
of 1.7 Hz (range 0.5 - 3.5 Hz). Signs of inflammation were observed in
28% of fields and immobile cilia in 92% of fields. Ciliary
ultrastructure revealed 100% pathological cilia analyzed due to an
absence of internal and external dynein arms. No known genetic mutations
were found, but the patient was diagnosed with Primary Ciliary
Dyskinesia (PCD) based on the clinical and diagnostic features.
PCD is a clinical and genetic heterogeneous group of respiratory
ciliopathies, with reduced mucociliary clearance of the airways. The
prevalence is approximately 1 per 10,000 births. Although PCD is a rare
disease, its main presenting symptoms are common in the pediatric
population. Clinical manifestations include respiratory distress in at
least 80% of full-term newborns. Patients also present with chronic
upper and lower airway disease (year-round daily nasal congestion,
chronic cough, otitis media with effusion and recurrent lower
respiratory infections), left-right laterality defects and infertility. A
persistent, year-round, daily wet cough and nasal congestion from early
infancy are documented in nearly 100% of PCD patients. Respiratory
symptoms do not completely resolve with antibiotic therapy or seasonal
changes. By preschool age, up to 80% of PCD patients have recurrent
lower respiratory tract infections, but frequent treatments with
antibiotics for rhinorrhea or otitis media may mask this. Fifty percent
of children will have bronchiectasis by 8 years of age. Situs inversus
is present in approximately 50% of patients and heterotaxy defects are
attributed to the loss of function of nodal cilia during embryogenesis.
American Thoracic Society (ATS) guidelines suggest that diagnostic
testing is mandatory in patients with at least two of four key features:
1) year-round, daily, wet cough; 2) year-round, daily, nonseasonal
rhinosinusitis; 3) neonatal respiratory distress syndrome in term
newborns; 4) laterality defects in the absence of a single definitive
test for PCD, the ATS recommends that a combination of nasal nitric
oxide (nNO), transmission electron microscopy (TEM) and genetic testing
are required for a definitive diagnosis. Diagnostic criteria differ in
Europe, where diagnosis is currently based on a combination of high
speed videomicroscopy analysis (HVMA), TEM, genetic test results and
abnormally low nNO. Screening for PCD by measuring nNO during a velum
closure maneuver is accurate with good sensitivity and specificity and
it is relatively easy to perform in non-cooperative children. TEM can
show most defects associated with pathological cilia immobility, but up
to 30% of patients have a normal ciliary ultrastructure; therefore,
normal ciliary TEM cannot rule out a PCD diagnosis. Furthermore,
inflammation and infections can alter the normal 9+2 cilia
ultrastructural arrangement. Therefore, it can be difficult to
differentiate acquired defects from PCD. Several studies have suggested
that genetic testing identifies the gene in ~65% of cases.
ATS PCD guidelines suggest:
- Using an extended genetic panel (testing > 12 genes) as a
diagnostic test over the reference standard of TEM and/or standard
genetic panel (≤12 genes) testing;
- Using nasal nitric oxide testing in patients over the age of five,
who have tested negative for cystic fibrosis (one-third of CF patients
can have nNO values below PCD diagnostic cutoffs);
- Not using ciliary beat frequency analysis by digital high-speed
videomicroscopy as a replacement diagnostic test over the reference
standard.
To date, there are no evidence-based treatment guidelines informed by
randomized clinical trials in patients with PCD. Thus, physicians
treating PCD adapt therapeutic approaches used for other chronic
respiratory diseases, such as cystic fibrosis and non-CF bronchiectasis.
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