IN PRACTICE

 

Primary ciliary dyskinesia: Meeting the challenges of diagnosis in South Africa

 

 

Z Dangor^{I, II}; M Birkhead^III; C Verwey^{I, II}; D M Gray^IV; A Vanker^IV; L Githinji^V; A Goga^{VI, VII}; R Masekela^{VIII, IX}; M Zampoli^IV

^IPhD; Vaccines and Infectious Diseases Analytics Research Unit, University of the Witwatersrand, Johannesburg, South Africa
^IIPhD; Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
^IIIPhD; Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases - a division of the National Health Laboratory Service, Johannesburg, South Africa
^IVPhD; Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Cape Town, South Africa
^VPhD; Department of Paediatrics, Faculty of Health Sciences, Nelson Mandela University, Gqeberha, South Africa
^VIPhD; HIV and other Infectious Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa
^VIIPhD; Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Pretoria, South Africa
^VIIIPhD; Department of Paediatrics and Child Health, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
^IXPhD; Africa Health Research Institute, Durban, South Africa

Correspondence

 

 

---

ABSTRACT

Primary ciliary dyskinesia (PCD) is an inherited ciliopathy that results in impaired mucous clearance and affects primarily the respiratory tract, causing upper airway disease, bronchial inflammation and bronchiectasis. The prevalence of PCD in low- and middle-income settings, including South Africa (SA), is unknown, largely owing to challenges with diagnosis, and identifying children or adults with PCD is challenging in a setting with a high prevalence of other infectious diseases, including lower respiratory tract infections and tuberculosis. No single test is diagnostic of PCD, and while some tests are costly, others are labour intensive and require highly specialised laboratory expertise. In the SA setting, awareness and opportunities for the diagnosis of PCD need to be created. In this commentary, we provide a pragmatic approach to identifying which children and adults require further investigations for PCD using a range of diagnostic tests or tools that are available. Furthermore, we recommend that designated centres of expertise for PCD diagnosis are created in SA. This would be an important step towards improving accessibility of diagnostic tests and developing local expertise to improving PCD diagnosis, especially in early childhood, to prevent long-term irreversible respiratory sequelae.

Keywords: ciliary dyskinesia, PCD

---

 

 

Ciliary dyskinesias are abnormalities in cilial function, and when present in the respiratory system can result in impaired mucous clearance from the respiratory tract, initiating a vicious cycle of bronchial inflammation, bacterial colonisation and bronchial wall damage that may result in bronchiectasis.^[1] Causes of ciliary dyskinesia can be primary or secondary, and result in transient or persistent ciliary impairment. The focus of this article will be primary ciliary dyskinesia (PCD), which is an inherited ciliopathy.^[2]

Columnar epithelial cells lining the respiratory tract typically bear 200 - 300 apical cilia. Cilia are motile, slender (0.3 μm in diameter), hair-like (6 - 7 μm in length) cell membrane projections enclosing a matrix with an axoneme (cytoskeletal microtubular core) (Fig. 1). The axoneme is composed of nine pairs of peripheral microtubules connected to two centrally positioned ensheathed central microtubular apparatus by radial spokes. Each pair of peripheral microtubules has molecular proteins arranged as hook-like outer and inner dynein arms attached to the α-microtubule. These cilia beat in the periciliary fluid layer and sweep the overlying mucus layer produced by epithelial goblet cells with their tips. This unidirectional movement of debris and mucus in a metachronal wave form (one after the other) ensures that mucus moves in a cephalad direction towards the laryngeal opening, where it is expelled out of the respiratory system (Fig. 2). Movement of mucus is therefore impeded by ciliary defects.^[3]

 

 

 

 

Axonemal structure and function are controlled by numerous mechano-regulatory components and proteins.^[4] Disruption or abnormal expression of any of these ciliary proteins involved in motile ciliogenesis, structure and/or function will lead to abnormal or absent ciliary beating and PCD disease. PCD is considered an uncommon disease caused by mutations in a PCD-causing gene, which typically are inherited in an autosomal recessive manner (biallelic autosomal), although heterozygous and X-linked gene mutations have been described. The estimated prevalence ranges from 1:2 300 in highly consanguineous cohorts to 1:15 000 in some European and East Asian cohorts.^[5,6] More than 50 PCD-associated pathogenic genes have been identified to date, and 70 - 75% of clinically suspected PCD cases can be confirmed by genetic sequencing.^[7] Biallelic mutations in DNAH5, DNAH11 and CCDC40 are most commonly reported in European ancestry, CCDC39 mutations in a North African (Tunisian) cohort, CCDC39, DNAH11 and DNAAF11 mutations in a Palestinian cohort and the DRC1 copy number variation the most important genetic identifier in the Japanese population.^[8-10] There is a paucity of data on the penetrance and most prevalent PCD gene mutations in sub-Saharan Africa. A recent publication on PCD in two South African (SA) families identified a homozygous variant in DNAAF3 and two pathogenic heterozygous variants in DNAAFJ neither of which were predicted among the top five African/Afro-American PCD-associated genes.^[8]

Signs and symptoms of PCD are nonspecific and present variably depending on the genotype and age of the patient. Suggestive clinical presentation includes neonatal respiratory distress occurring 12 - 24 hours after birth (as opposed to present at birth seen in transient tachypnoea of the newborn or congenital pneumonia), pre-school chronic otitis media and/or recurrent lower respiratory tract infection, and a chronic wet cough or nasal polyps in older school-going children. Bronchiectasis, infertility (male or female) and/or chronic sinusitis may be presenting features in childhood, adolescence or adulthood.^[12- Disorders of lateralisation such as situs inversus totalis, dextrocardia and heterotaxy syndromes occur in ~50% of cases, and are therefore an important flag for underlying PCD diagnosis.

 

Making the diagnosis of PCD

Diagnosis of PCD, even in high-income settings, is challenging. There is no single diagnostic test, and confirming the diagnosis is often achieved through algorithms. Two main diagnostic algorithms have been described, and a third (PCD-UNiBe, University Children's Hospital, Inselspital Bern, Switzerland) was more recently described.^[13-15] All three have good agreement, but are established for high-income settings where capacity and expertise to diagnose PCD is more widely available.^[13] Certain signs and/or symptoms are entry points of the algorithm - the American Thoracic Society suggests that two of the following four signs and symptoms should prompt further investigation: (i) unexplained neonatal respiratory distress in a term infant; (ii) year-round daily cough beginning before 6 months of age; (iii) year-round daily nasal congestion beginning before 6 months of age; and (iv) organ laterality defects.^[14] The European Respiratory Society algorithm suggests that several of the following signs and symptoms should prompt further investigation:^[15] persistent wet cough, situs anomalies, congenital cardiac defects, persistent rhinitis, chronic middle-ear disease with or without hearing loss, neonatal upper/lower respiratory symptoms in a term neonate and neonatal intensive care admission.

Children and adults with suspected PCD should be referred to pulmonologists for specialised diagnostic investigations, as listed in Table 1, where available.^[2,11,15] All three algorithms start with nasal nitric oxide (nNO) measurements,^[13] followed by, and at the very minimum, genetic testing and transmission electron microscopy imaging of the ciliary structure. Although these algorithms cannot be currently applied to most centres in SA, a joint call to funders is urgently needed to improve accessibility to the diagnostic tests across various regions. Until such time, a pragmatic approach is warranted.

 

Pragmatic approach to diagnosing PCD in South Africa

In the SA setting, awareness and opportunities for the diagnosis of PCD need to be created. Importantly, guidance for identifying which children and adults require further investigations are needed. SA has a high infectious disease burden dominated by HIV and TB that results in respiratory sequelae; some of these presentations often overlap with the clinical features of PCD.

Deciding who to investigate with the limited diagnostic capacity is important to avoid overloading the health system. We therefore propose criteria and pathways for referral and investigation of PCD in children and adults in SA (Fig. 3). The special investigations are detailed in Table 1.

 

 

If no testing or referral facilities are available, we recommend that children or adults with a high PICADAR (Primary CiliARy DyskinesiA Rule) score (>10) be managed as PCD until testing becomes available. ^[241 The PICADAR score was developed and validated in Europe and serves as a useful screening tool in paediatric patients with a chronic wet cough. Seven signs and symptoms most associated with a diagnosis of PCD are scored.^[25] These include situs inversus, gestational age (full term), neonatal chest symptoms, neonatal unit admission, congenital cardiac defect, rhinitis and ear/hearing symptoms. Children with a score <5 have only a 10% probability of PCD (sensitivity and specificity of PICADAR in PCD diagnostics are 0.90 and 0.75, respectively), and therefore the negative predictive value is most useful.^[251 The PICADAR score provides a numerical number for the presence of the following clinical characteristics: (i) Was the patient born full term? (2 points); (ii) Did the patient experience chest symptoms in the neonatal period (e.g. tachypnoea, cough, pneumonia)? (2 points); (iii) Was the patient admitted to a neonatal unit? (2 points); (iv) Does the patient have a situs abnormality (situs inversus or heterotaxy)? (4 points); (v) Does the patient have a congenital heart defect? (2 points); (vi) Does the patient have persistent perennial rhinitis? (1 point); (vii) Does the patient experience chronic ear or hearing symptoms (e.g. glue ear, serous otitis media, hearing loss, ear perforation)? (1 point).

 

Leveraging on existing platforms

Delivering highly specialised care for rare orphan diseases in SA is complicated by the fragmented public and private healthcare sectors, and the high costs of some of these investigations (or equipment). Centres of expertise exist, but standards of care are highly variable and poorly co-ordinated. PCD, cystic fibrosis (CF) and bronchiectasis share similar clinical manifestations and require overlapping health needs and expertise. A successful model that partners with the CF community exists for CF care in SA, and could serve as a useful framework for building similar centres of excellence for PCD diagnosis and care in SA. A national CF registry covering the public and private health sector was established in 2018 and serves as a powerful research and advocacy tool for CF in SA (https://sacfa.org.za/). Similarly, prioritising a national bronchiectasis registry to serve as a research and advocacy tool for PCD in SA will help strengthen access to optimal diagnostics and care for those living with PCD. Creating designated centres of expertise for paediatric and adult PCD diagnosis and care would be an important step towards developing local expertise and improving PCD diagnosis, especially in early childhood, to ensure appropriate management and prevent long-term morbidity, in SA and this region of Africa.

 

Conclusion

PCD is likely underdiagnosed and under-recognised in SA due to limited diagnostic capacity. Greater awareness and collaboration between clinicians, geneticists and laboratory scientists is required to improve PCD diagnosis and care in SA. Establishing specialised PCD centres will improve access to the various modalities of diagnostic testing that are aligned with international standards.^[9,26]

Data availability. N/a.

Declaration. None.

Acknowledgements. None.

Author contributions. ZD wrote the first draft. All authors provided critical input and approved the final version.

Funding. None.

Conflicts of interest. None.

 

References

1. Verwey C, Gray DM, Dangor Z, et al. Bronchiectasis in African children: Challenges and barriers to care. Front Pediatr 2022;10:954608. https://doi.org/10.3389/fped.2022.954608        [ Links ]

2. Goutaki M, Shoemark A. Diagnosis of primary ciliary dyskinesia. Clin Chest Med 2022;43(1):127-140. https://doi.org/10.1016/j.ccm.2021.11.008        [ Links ]

3. Legendre M, Zaragosi LE, Mitchison HM. Motile cilia and airway disease. Semin Cell Dev Biol 2021;110:19-33. https://doi.org/10.1016/j.semcdb.2020.11.007        [ Links ]

4. Ghanaeian A, Majhi S, McCafferty CL, et al. Integrated modeling of the Nexin-dynein regulatory complex reveals its regulatory mechanism. Nat Commun 2023;14(1):5741. https://doi.org/10.1038/s41467-023-41480-7        [ Links ]

5. Fassad MR, Patel MP, Shoemark A, et al. Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. J Med Genet 2020;57(5):322-330. https://doi.org/10.1136/jmedgenet-2019-106501        [ Links ]

6. Lucas JS, Davis SD, Omran H, Shoemark A. Primary ciliary dyskinesia in the genomics age. Lancet Respir Med 2020;8(2):202-216. https://doi.org/10.1016/S2213-2600(19)30374-1        [ Links ]

7. Kim DY, Sub YJ, Kim HY, et al. LRRC6 regulates biogenesis of motile cilia by aiding FOXJ1 translocation into the nucleus. Cell Commun Signal 202331(1):142. https://doi.org/10.1186/s12964-023-01135-y        [ Links ]

8. Hannah WB, Seifert BA, Truty R, et al. The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: A genetic database analysis. Lancet Respir Med 2022;10(5):459-468. https://doi.org/10.1016/S2213-2600(21)00453-7        [ Links ]

9. Rumman N, Fassad MR, Driessens C, et al. The Palestinian primary ciliary dyskinesia population: First results of the diagnostic and genetic spectrum. ERJ Open Res 2023;9(2):00714-2022. https://doi.org/10.1183/23120541.00714-2022        [ Links ]

10. Pedersen ESL, Goutaki M, Schreck LD, Lucas JS, Kuehni CE, Eastvold T. Genotype-phenotype associations in primary ciliary dyskinesia. ERS International Congress: Euro Respir J 2023(62):PA2763. https://doi.org/10.1183/13993003.congress-2023.PA2763        [ Links ]

11. Surdut SP, van der Merwe E, Goussard P, Urban MF. Which side are they on? Diagnosing primary ciliary dyskinesias in low- or middle-income countries: A review and case series. Afr J Thorac Crit Care Med 2023;29(3):e425. https://doi.org/10.7196/AJTCCM.2023.v29i3.425        [ Links ]

12. O'Connor MG, Horani A, Shapiro AJ. Progress in diagnosing primary ciliary dyskinesia: The North American perspective. Diagnostics (Basel) 2021;11(7):1278. https://doi.org/10.3390/diagnostics11071278        [ Links ]

13. Nussbaumer M, Kieninger E, Tschanz SA, et al. Diagnosis of primary ciliary dyskinesia: Discrepancy according to different algorithms. ERJ Open Res 2021;7(4):00353-2021. https://doi.org/10.1183/23120541.00353-2021        [ Links ]

14. Shapiro AJ, Davis SD, Polineni D, et al. Diagnosis of primary ciliary dyskinesia. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2018;197(12):e24-e39. https://doi.org/10.1164/rccm.201805-0819ST        [ Links ]

15. Shoemark A, Dell S, Shapiro A, Lucas JS. ERS and ATS diagnostic guidelines for primary ciliary dyskinesia: Similarities and differences in approach to diagnosis. Eur Respir J 2019;54(3):190-1066. https://doi.org/10.1183/13993003.01066-2019        [ Links ]

16. Shapiro AJ, Dell SD, Gaston B, et al. Nasal nitric oxide measurement in primary ciliary dyskinesia. A technical paper on standardised testing protocols. Ann Am Thorac Soc 2020;17(2):e1-e12. https://doi.org/10.1513/AnnalsATS.201904-347OT        [ Links ]

17. Beydon N, Kouis P, Marthin JK, et al. Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesia: European Respiratory Society technical standard. Eur Respir J 2023;61(4):2202031. https://doi.org/10.1183/13993003.02031-2022        [ Links ]

18. Raidt J, Krenz H, Tebbe J, et al. Limitations of nasal nitric oxide measurement for diagnosis of primary ciliary dyskinesia with normal ultrastructure. Ann Am Thorac Soc 2022;19(8):1275-1284. https://doi.org/10.1513/AnnalsATS.202106-728OC        [ Links ]

19. Horani A, Brody SL. One person can make a difference: Identification of people with a rare genetic lung disease. ERJ Open Res 2023;9(2):00122-2023. https://doi.org/10.1183/23120541.00122-2023        [ Links ]

20. Raidt J, Wallmeier J, Hjeij R,et al. Ciliary beat pattern and frequency in genetic variants of primary ciliary dyskinesia. Eur Respir J 2014;44(6):1579-1588. https://doi.org/10.1183/09031936.00052014        [ Links ]

21. Shoemark A, Boon M, Brochhausen C, et al. International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria). Eur Respir J 2020;55(4):1900725. https://doi.org/10.1183/13993003.00725-2019        [ Links ]

22. Castillo M, Freire E, Romero VI. Primary ciliary dyskinesia diagnosis and management and its implications in America: A mini review. Front Pediatr 2023;11:1091173. https://doi.org/10.3389/fped.2023.1091173        [ Links ]

23. Austero RM, Gelera JE. Evaluation of nasal mucociliary clearance using saccharin test versus charcoal test among Filipinos in a tertiary government hospital. Cureus 2022;14(2):e22065. https://doi.org/10.7759/cureus.22065        [ Links ]

24. Rademacher J, Buck A, Schwerk N, et al. Nasal nitric oxide measurement and a modified PICADAR score for the screening of primary ciliary dyskinesia in adults with bronchiectasis. Pneumologie 2017;71(8):543-548. https://doi.org/10.1055/s-0043-111909        [ Links ]

25. Behan L, Dimitrov BD, Kuehni CE, et al. PICADAR: A diagnostic predictive tool for primary ciliary dyskinesia. Eur Respir J 2016:47(4):1103-1112. https://doi.org/10.1183/13993003.01551-2015        [ Links ]

26. De Jesús-Rojas W, Reyes-Peña L, Muñiz-Hernández J, et al. Bronchiectasis assessment in primary ciliary dyskinesia: A non-invasive approach using forced oscillation technique. Diagnostics (Basel) 2023;13(13):2287. https://doi.org/10.3390/diagnostics13132287        [ Links ]

 

 

Correspondence:
Z Dangor
ziyaad.dangor@wits.ac.za

Received 29 March 2024
Accepted 2 June 2024