To our knowledge, this is the first study of aspects related to the diagnosis and treatment of PCD in children and adolescents using Korean multicenter clinical data. The age of diagnosis for PCD ranged from 0.5 months to 25.5 years, with an average of 9.9 years. The most used diagnostic techniques were TEM and biopsy, and the most common abnormality in PCD was ODA defects (isolated or combined with IDA). It was also observed that majority of the patients are still being followed up due to inconsistent treatments or protocols.
The European Respiratory Society has recommended the use of the PICADAR score, which includes various predictive factors.3 The sensitivity and specificity of PICADAR score were reported to be 0.90 and 0.75, respectively, for a cut-off score of 5 points.3 However, only 42.9% of the patients met these criteria in this study. PICADAR scoring helps identify clinical features, but it is not an absolute diagnostic tool for PCD.
PCD diagnosis is known to be delayed, with a median age at diagnosis of 5.5 years in Europe and 2–22 years in the United States.19,20 The average age at diagnosis of PCD in our study was 9.9 years, suggesting that the diagnosis of PCD was delayed. This may be related to the fact that the most common complaint identified in our study was chronic nasal symptoms, which are very common even in healthy children and adolescents. Therefore, it is important to educate neonatologists, pediatricians, otolaryngologists, and primary care physicians about the clinical features of PCD. Primary symptoms of PCD include neonatal respiratory distress, even in term babies, chronic persistent lower respiratory tract symptoms, chronic persistent upper respiratory symptoms, and/or lateral defects. If two or more of these clinical manifestations are present, the patients should be strongly suspected for PCD.
Abnormal pulmonary function begins at an early age, and as a result, many children show abnormal airflow function.21,22 There is disagreement about the correlation between TEM results and lung function findings in patients with PCD.13,23 One study reported that PCD patients with specific phenotypes such as IDA defects, central pair defects, or microtubular disorganization showed severely impaired pulmonary function.13 In the present study, most patients showed decreased lung function, except those with isolated ODA defects, but statistical significance could not be achieved given the small number of patients analyzed. A longitudinal study reported that lung function can be preserved with aggressive treatment.24 National registry management and regular follow-up of lung function should thus be employed to monitor disease progression.16
The most widely used PCD diagnostic method is the detection of ciliary abnormalities in clinically suspected patients using TEM. It is known that approximately 70% of cases can be diagnosed by histological examination.9,10 However, this examination is dependent on adequate sample collection by skilled and experienced clinicians. In fact, in several centers across Korea, biopsy and pathology confirmation could not be performed due to the lack of experienced clinicians or neonatal patients. Moreover, 30% of patients did not exhibit ciliary defects and showed normal axonemal ultrastructure.20 Mutations in DNAH11 are known to have normal cilia and beat frequencies; our study results are in line with these findings.25
To overcome the limitations of pathological testing, genetic tests and nNO are being studied. The introduction of genetic testing has greatly improved diagnosis. The youngest patient in our study was a full-term child with situs inversus and respiratory difficulties diagnosed on the 3rd day after birth, in whom a mutation was found in a genetic test.15
PCD is a genetically heterogeneous disease that does not have a clear racial or sexual preference. Mutations in any protein involved in ciliary assembly, structure, or function can cause this condition. Gene discovery has relied on a combination of experimental models and targeted screening of candidate genes encoding proteins of the ciliome. However, whole-exome and massive parallel sequencing has led to the identification of new genes through international collaboration in Europe and North America.26–30 In the present study, one patient was diagnosed with PCD by TEM, but RPGR mutation was identified later through a genetic study. Since this mutation is known to be associated with retinitis pigmentosa, the patient underwent additional ophthalmologic examinations. Almost all genes associated with PCD are autosomal recessive, except for X-linked syndromic genes (RPGR and OFD1).16 Furthermore, genetic counselling in patients should also be planned following disease confirmation.
As it is difficult to diagnose PCD through a single test, the diagnostic methods should be selected according to the clinical characteristics of the patient. Ciliary biopsy with TEM, PCD genetic panels, functional ciliary movement with HSVA, nNO, and immunofluorescence testing are the different diagnostic tools available. Nasal fractional exhaled nitric oxide is not invasive and can be easily tested, but it is not commonly standardized, and the functional ciliary movement analysis with HSVA is only possible in centers that are highly experienced in this technology.