Primary ciliary dyskinesia diagnosis management in low-resource setting, a practical approach

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].

The first case is one of a 17-year-old girl previously diagnosed with epilepsy at age 3 (the last episode 2 years before current evaluation) situs inversus totalis (documented at age of 8 years) and asthma (suspected at age of 12 years). Personal history: first child of the couple, full term pregnancy, spontaneous vaginal delivery, with neonatal hypoxia that required monitoring and treatment in the Intensive Care Unit. Personal medical history included multiple episodes of acute upper respiratory tract infections, recurrent pneumonia, several episodes of otitis media. The patient presented herself to the emergency room of the hospital for nasal obstruction and productive cough, with onset more than 3 weeks before evaluation, without fever, with protracted evolution on prescribed treatment as outpatient. She was hospitalizedfor further investigations. The clinical examination detected underweight (with a body mass index of 17), important nasal obstruction, particular voice and anosmia, clear lung sounds except rare bronchial moist rales and slightly diminished in right basal area, prolonged exhalation, normal, right-sided heart sounds. An initial diagnosis of acute pneumonia and situs inversus in an underweight patient was established. Differentials ruled out were: exacerbation of asthma, cystic fibrosis and primary ciliary dyskinesia.

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 (Figure 1). Thoracoabdominal computed tomography was performed, confirming the situs inversus totalis and the presence of bronchiectasis (Figure 2). Further, questionnaires were carried out to assess the probability of PCD diagnosis: CI (6 points) - very high probability of PCD [19], PICADAR (11 points/14 points) - probability of PCD is >93% [17], NA- CDCF - very high probability of PCD [18] (Tables 1–3).

Figure 1.

Figure 2.

Testing of nasal nitric oxide (Figure 3) had a very low result (15 ppb) as in immotile/dysmotile ciliopathies and the diagnosis of PCD was presented to her family.

Figure 3.

The second case is a 4-year-old boy, the second born of a consanguineous family. At the age of 2 he was diagnosed incidentally with situs inversus totalis and horseshoe kidney. The patient had no other significant medical history, apart for an episode of otitis media treated with co-amoxiclav with favourable outcome. He came to the hospital with a 5-day history of high fever (with a maximum of 39,5 degrees Celsius), productive cough and right chest pain. The patient received symptomatic treatment at home with unfavourable outcome. During clinical examination the child was feverish, pale, lethargic, with nasal obstruction, productive cough, normal respiratory rate and oxygen-saturation, pectus excavatum, absent breath sounds and dullness on percussion in the lower half of the right hemithorax, no rales. He had diffuse abdominal pain and lower liver edge palpable at 2 cm below the left costal margin. Because the child came from a consanguineous family and presents situs inversus, the suspicion of primary ciliary dyskinesia with autosomal recessive familial transmission was raised.

In this patient, laboratory tests detected leucocytosis with neutrophilia and important inflammatory syndrome. Chest X-ray (Figure 4) documented right lower lobe consolidation and the presence of Damoiseau curve suggestive of parapneumonic pleural effusion. A thoracic ultrasound revealed transonic fluid in the right pleural space, supporting the diagnosis of pneumonia complicated with pleural effusion. The patient outcome was favourable with antibiotic treatment. Several tests were performed: negative TST (tuberculin skin test), ENT examination documeted chronic rhinitis and nasal polyps, cardiac ultrasound confirmed dextrocardia but no other anomalies, abdominal ultrasound that confirmed the situs inversus totalis, horseshoe kidney and accessory spleen. The patient’s family was counselled, and genetic testing was recommended.

Figure 4.

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 (Tables 1–3).

The third case, a 8-year-old boy, was referred to our hospital for a 2-week history of productive cough, chest pain and fever. He is the third child of the family, born full-term with normal weight, but often presented with wet cough episodes, starting from neonatal period, which led to multiple hospitalizations. One of his siblings, a 25-year- old male is known having situs inversus, chronic sinusitis, nasal polyposis, bronchiectasis, anaemia and anosmia, suggestive for Kartagener disease, though never diagnosed as PCD. Their grandfather had recurrent episodes of haemoptysis. The clinical examination revealed nasal obstruction, wet cough, prolonged exhalation, hyperresonant chest percussion, bilateral basal rhonchi, normal oxygen saturation and low body mass index (underweight). The presence of bronchiectasis on chest x-ray led to extensive evaluation.

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 (Figure 5). The patient had hypoplastic right frontal sinus and radiological signs of maxillary sinusitis matching history of recurrent headaches and nasal congestion. Sweat test was negative, so patient was considered to have non-CF bronchiectasis and underwent complementary testing: negative TST, normal alpha1 antitrypsin level, negative tests for inborn and acquired immunodeficiencies. PCD suspicion was raised and the scores were applied: he had a CI score [19] of 4 (high risk) and a PICADAR score [17] of 5 (Tables 1–3).

Figure 5.

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] (Tables 1–3).

PICADAR is a predictive score (Table 1), with seven simple questions, aiming to predict the likelihood of having PCD. After the total score is calculated the individual probability of having PCD diagnosis can be estimated from the probability curve. A score of 8 points means a 70% probability of PCD, and a score of 10 or more points equals to a PCD probability of more than 92,6% [17].

In Clinical Index (Table 2), the overall score and risk is: 0-1 point very low risk, 2 points low risk, 3 points medium risk, 4 points high risk, 5+ points very high risk [19].

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 Figure 6. For a school-age child with chronic wet cough, we should first rule out primary immunodeficiency disorders and Human Immunodeficiency Virus infection. Subsequently a high- resolution CT is advised. If bronchiectasis documented, cystic fibrosis will be ruled out, using specific diagnostic tests. Subsequently, the saccharin test will be performed. In case of a positive result, the nasal nitric oxide testing is recommended and in case of a negative result, genetic testing is recommended. The diagnostic management algorithm for PCD in school-age children, in low-resource settings is shown in Figure 7.

Figure 6.

Figure 7.

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.