Primary ciliary dyskinesia (PCD) is a congenital disorder with genetic determinism, characterized by chronic infections of the upper and lower respiratory tract (sinuses, nose, ears, bronchi, lungs), produced by slow mucociliary clearance generated by ciliary dysmotility or immobility [1–5]. PCD is usually inherited in an autosomal recessive manner [6]. However, more recently, X-chromosomal and autosomal dominant modes of inheritance were described [7]. It has been associated with defects in more than 40 mutations of genes that are responsible for cilia structure [3]. In populations with significant consanguineous families, a much higher prevalence of PCD has been reported [8,9]. The triad of situs inversus, chronic sinusitis and bronchiectasis is labelled as Kartagener Syndrome [10].
Depending on the population, PCD appears in 1 in 10,000 - 20,000 live births, but due to underdiagnosis, the actual incidence could be higher [11, 28]. The signs and symptoms of PCD are caused by the malfunction of the cilia with or without structural defects. Abnormal cilia movement leads to defective mucociliary clearance resulting in chronic cough, nasal congestion, recurrent otitis and sinusitis and, in longterm, non-cystic fibrosis bronchiectasis [2,4,10,12].
PCD does not have a gold standard diagnostic test and requires multiple complementary tests. The European Respiratory Society guidelines suggest using nasal nitric oxide (nNO) measurement, high-speed video-microscopy analysis (HSVA), transmission electron microscopy (TEM) and genetic testing [2]. If TEM is not available, immunofluorescence labelling of ciliary proteins can suggest a likely diagnosis. [3] Overall, ciliary ultrastructural and beat pattern correlated well with the genotype, but 26% of documented PCD patients (via genetics, nNO and TEM) don’t have ultrastructural abnormalities [5,13,14].
The diagnosis of PCD is complex and requires the existence of a suggestive clinical examination, a relevant medical history and specific diagnostic tests [15]. Other chronic respiratory conditions you should consider when suspecting PCD are: cystic fibrosis, immunodeficiency, severe asthma, pulmonary aspiration, allergic rhinitis, protracted bacterial bronchitis, congenital airway malformations and other rare structural abnormalities of collagen that facilitate bronchiectasis occurrence [16].
Given the personal history and the clinical findings, the diagnosis of PCD was very likely. ENT examination was performed and a diagnosis of chronic rhino-sinusitis was diagnosed. Spirometry was within normal limits and no bronchodilator reversibility was documented. Due to recurrent pneumonia and low BMI, there was a suspicion of cystic fibrosis, but sweat testing came back normal.
Sinus X-ray showed bilateral maxillary sinus lower third opacities consistent with sinusitis (
Sinus X-ray is documenting partially opacified maxillary sinuses.
The high-resolution computer tomography images demonstrate situs inversus totalis (left) and the presence of bronchiectasis (right), with the “tree-in-bud” pattern at the level of the lateral segment of the middle lobe.
PICADAR score, reproduced after “PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia” [17]
Does the patient have a daily wet cough that started in early childhood? | Yes - complete PICADAR No - STOP. PICADAR is not designed for patients without a wet cough | |
---|---|---|
1. Was the patient born pre-term or full term? | Term | 2 |
2. Did the patient experience chest symptoms in the neonatal period (e.g., tachypnoea, cough, pneumonia)? | Yes | 2 |
3. Was the patient admitted to a neonatal unit? | Yes | 2 |
4. Does the patient have a situs abnormality (situs inversus or heterotaxy)? | Yes | 4 |
5. Does the patient have a congenital heart defect? | Yes | 2 |
6. Does the patient have persistent perennial rhinitis? | Yes | 1 |
7. Does the patient experience chronic ear or hearing symptoms (e.g., glue year, serous otitis media, hearing loss, ear perforation)? | Yes | 1 |
Clinical Index, a seven-item questionnaire, reproduced after “Evaluation of a Clinical Index as a Predictive Tool for Primary Ciliary Dyskinesia”[l9]
Did the child manifest with significant respiratory difficulties with breathing after birth? | Yes=1 point |
Did the child have rhinitis or excessive mucus production in the first 2 months of life? | Yes=1 point |
Did the child suffer from pneumonia? | Yes=1 point |
Did the child present with 3 or more episodes of bronchitis? | Yes=1 point |
Was the child treated for chronic secretory otitis or suffered from >3 episodes of acute otitis? | Yes=1 point |
Does the child have a year-round nasal discharge or nasal obstruction? | Yes=1 point |
Was the child treated with antibiotics for acute upper respiratory tract infection >3 times? | Yes=1 point |
NA-CDCF schematic diagram, reproduced after “Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents”. Early onset is defined as onset before 6 months of age; year-round is defined as occurring in all 12 months of the year; wet cough is defined as sounds productive even if unable to expectorate sputum [18].
Unexplained neonatal respiratory distress (sensitivity 81%, specificity 68%) | Term gestation, Supplemental O2 requirement ≥ 1day and no meconium aspiration (sensitivity 57%, specificity 89%) |
Chronic cough (sensitivity 97%, specificity 17%) | Year-round wet cough with early onset ≤ 6 months of age (sensitivity 62%, specificity 74%) |
Chronic nasal congestion (sensitivity 97%, specificity 19%) | Year-round with early onset ≤ 6 months of age (sensitivity 74%, specificity 60%) |
Situs inversus totalis (sensitivity 46%, specificity 92%) | Other laterality defects (sensitivity 53%, specificity 85%) |
Testing of nasal nitric oxide (
Nasal nitric oxide had a very low result (15 ppb), value found in immotile/dysmotile ciliopathies.
In this patient, laboratory tests detected leucocytosis with neutrophilia and important inflammatory syndrome. Chest X-ray (
Chest X-ray posteroanterior view(left) and lateral view (right), documenting right pleural effusion with consolidation of the lower right lobe and dextrocardia.
Considering history data (consanguinity, chronic sinusitis, nasal polyposis), clinical, paraclinical and imaging data (showing situs inversus totalis) the suspicion of PCD was raised. The CI score [19] showed medium risk (3 points) for PCD and PICADAR [17] also detected a medium risk (7 points) for PCD (
Laboratory tests revealed mild leucocytosis with immature neutrophils, thrombocytosis but normal inflammation markers. Chest X-ray documented dense consolidation in the right lower hemithorax suggestive for pneumonia with associated pleural effusion. A CT lung scan was performed (
CT scan of the lung showing cylindrical bronchiectasis located in middle lobe and left anterior basal segment.
The saccharin test was performed and the transit time exceeded 1 hour (prolonged), supporting the existence of an abnormal mucociliary clearance [20,21].
All three cases were a diagnostic challenge and required a multidisciplinary approach. Interdisciplinary collaboration and accessible and modern diagnostic tests are necessary to establish the diagnosis of PCD. Nasal NO is scarcely available, genetic testing expensive and HSVA and TEM require ultra-specialized personnel. A genetic cause can be identified in approximately 70% of patients known to have primary ciliary dyskinesia [6].
The use of diagnostic questionnaires was useful as a predictive tool for the first and third patient, but it was not decisive for the second one. As particular aspects of the first case, we can mention the very late diagnosis of PCD and the coexistence of epilepsy. The second case represents a diagnostic uncertainty due to the lack of additional diagnostic tests, especially since not all situs inversus patients have PCD [22]. In the third case the positive saccharin test supported the presumed diagnosis. These three case reports aim to highlight the diagnostic difficulties of a genetic syndrome involving lung damage.
The second objective consisted in outlining the importance of using diagnostic algorithms that take into account the available diagnostic methods. From the paediatric pulmonologist’s perspective, the diagnosis of PCD is the first step towards establishing a correct therapeutic management and should rely on clinical scoring systems like PICADAR, CI and NA- CDCF [17–19] (
PICADAR is a predictive score (
In Clinical Index (
Nasal mucociliary clearance time can be measured with the saccharine clearance test which is an inexpensive and easy method [23,24]. The saccharin test, although a rather historical method in PCD diagnosis that has been replaced by better performing tests, is still used to document mucociliary clearance anomalies in adults and may be useful for low-income countries in order to select patients with non-CF bronchiectasis that are candidates for nasal nitric oxide testing [20,21,23]. The saccharin test is also still used in ENT department for estimation of the mucociliary function in patients with nasal septal deviation [25]. Recent studies have shown a good reproducibility of the saccharin transit time test, both in the short- and long-term and good tolerability [26].
We propose a diagnostic management algorithm for PCD, in low-resource settings. For an infant with chronic wet cough, the PICADAR questionnaire will be performed. In case of a result of at least 5 points, genetic testing will be performed if no other reasonable diagnosis is obvious after GP evaluation and treatment for common scenarios, as shown in
Proposed algorithm for diagnosis of PCD in infants, in low-resource settings.
Proposed algorithm for diagnosis of PCD in school-age children, in low-resource settings. HIV, Human Immunodeficiency Virus; PID, Primary immunodeficiency disorders; HRCT, High-resolution computed tomography; CF, cystic fibrosis; NO, nitric oxide.
So far, the restoration of ciliary function has not been possible in patients and treatment has been focused on improving mucociliary clearance (physiotherapy, mucolytics) and the early treatment of respiratory tract infections, so, a high index of suspicion about potential PCD case should be present in any non-cystic fibrosis bronchiectasis patient [27].
PCD in a real-life approach of a pulmonologist from a low-resource country can be a challenge. Because not all PCD cases have known genetic mutations and some don’t have ultrastructural abnormalities we should rely on the old saccharin test in order to select patients that are candidates for nasal NO. A high index of suspicion of PCD should be present in any non-cystic fibrosis bronchiectasis patient.
PCD remains a rare and underdiagnosed genetic syndrome in real-life paediatric setting in countries with limited neonatal screening programs. Increasing awareness of the condition and potential diagnostic tool are desirable in order to find patients with high-likelihood of PCD and to refer selected patients to specialized centres.