Cystic Fibrosis and Primary Ciliary Dyskinesia Share Extensive Similarities: Is It Time to Place Them Under a Common Umbrella?

To the Editor,

Bronchiectasis is a chronic suppurative lung condition with high epidemiological, etiological, and clinical heterogeneity. As the common end‐stage sequela of a wide spectrum of underlying diseases, bronchiectasis is derived from the pathogenetic vicious vortex of airway structural damage, mucociliary clearance impairment, chronic respiratory infection, and immune dysregulation [1, 2]. Cystic fibrosis (CF) is a rare genetic disease, inherited in an autosomal recessive manner, which results from decreased production, altered stability, and/or impaired function of CF transmembrane conductance regulator (CFTR) due to mutations in the CFTR gene [3]. Primary ciliary dyskinesia (PCD) is an underrecognized rare genetic disease, usually inherited in an autosomal recessive manner, which derives from the structural and functional impairment of motile cilia due to pathogenetic mutations in more than 60 genes [4]. Both conditions impair different hydrodynamic components of mucociliary clearance [5], predispose to recurrent respiratory infections, and often lead to the development of bronchiectasis.

Non‐CF bronchiectasis has historically emerged as a practical inclusive term to differentiate CF from diverse other diseases that result to bronchiectasis, as the former is caused by a well‐described pathogenetic mechanism, has distinct epidemiological and clinical features, and requires specific diagnostic and therapeutic strategies [6]. Even though PCD shares more similarities than differences with CF, as opposed to other causes of bronchiectasis, it is usually included in the definition of non‐CF bronchiectasis and is collectively considered with other bronchiectatic conditions in the literature. Only rarely, the term “non‐CF, non‐PCD bronchiectasis” is used, mostly by authors with a clinical and research interest in PCD [7].

In this article, we highlight the similarities of CF and PCD, which differentiate them from all other causes of bronchiectasis, as they both inherently affect the mucociliary escalator in different aspects. We further suggest their consideration under the same umbrella as primary mucociliary diseases and their collective separation from bronchiectasis attributed to other causes.

The prevalence of bronchiectasis demonstrates significant geographical variability, estimated to be approximately 700 per 100,000 individuals in the United States, following an increasing trend over the last two decades, which probably does not reflect a true increase but rather an improved recognition of the condition [1, 8]. The introduction of prenatal screening has led to a reduction in the incidence of bronchiectasis in CF, which ranges from one per 1350 to one per 6000 individuals in countries with largely European ancestry, while the prevalence of the disease is steadily increasing due to a considerable improvement in the survival of patients [3]. The overall minimum global prevalence of PCD is estimated to be at least one in 7500 individuals, but diagnosed cases are significantly less than CF due to poor clinical recognition of the disease and the scarcity of specialized centers for its diagnosis [9].

Besides CF and PCD, bronchiectasis is caused by many other diverse etiologies, which are mostly acquired conditions and include prior pulmonary infections (viral or bacterial pneumonia, pulmonary tuberculosis, and allergic bronchopulmonary aspergillosis), other chronic airway diseases (asthma, chronic obstructive pulmonary disease, and α₁‐antitrypsin deficiency), airway obstruction (by foreign body or thoracic tumor), aspiration syndromes (gastroesophageal reflux disease, esophageal dysmotilities, and vocal cord dysfunction), immunodeficiencies (primary immunodeficiencies, acquired immunodeficiencies, and hematological malignancies), autoimmune diseases (connective tissue diseases and inflammatory bowel disease), and congenital tracheobronchial anomalies. More than one‐third of the cases are characterized as idiopathic, as no underlying cause can be found despite thorough investigation [1, 8].

Clinical manifestations of bronchiectasis almost entirely affect the lower respiratory system. The cardinal symptom is chronic productive cough, which characterizes both CF and PCD. Other respiratory symptoms include sputum production, dyspnea, fatigue, and occasionally hemoptysis [1, 2]. Due to the widespread localization of CFTR and motile cilia in other organs and systems, both CF and PCD typically demonstrate variable extrapulmonary involvement [3, 4, 10]. Rhinosinusitis, nasal polyposis, and chronic otitis media are common presentations of upper airway involvement in both diseases [3, 4, 10]. CF usually affects the gastrointestinal system causing obstructive phenomena in the biliary and pancreatic ductal systems and the small intestine, which arise from the increased viscosity of bile, pancreatic fluid, and intestinal content, respectively. The related clinical manifestations may variably include exocrine pancreatic insufficiency, malabsorption, acute and chronic pancreatitis, diabetes mellitus, biliary cirrhosis, liver failure, and distal intestinal obstruction syndrome, as well as meconium ileus in newborns [3]. Dehydration and electrolyte disturbances due to increased salt losses through the sweat glands are also commonly encountered, particularly during the summer season [3]. On the other hand, PCD may additionally present with body laterality defects, such as situs inversus, because of the malfunction of the embryonic nodal cilium and the impaired left‐right symmetry establishment early in embryonic life [4]. Rarely, hydrocephalus may also be present due to defective ependymal ciliary beating and resultant compromised circulation of the cerebrospinal fluid in the cerebral ventricular system [4]. Male and female subfertility may be observed in both CF and PCD, although for different reasons [3, 4, 10]. Congenital bilateral absence of the vas deferens and obstructive azoospermia in males and viscous cervical mucus and irregular ovulation in females are commonly encountered in CF [3, 10]. On the other hand, dysmotility of the spermatozoa flagellum in males and impaired ciliary beating in the fallopian tubes in females affect the transport of the sperm and egg at the fertilization site, as well as the transport of the early embryo to the uterus in PCD [4, 10]. Multisystemic involvement is only rarely observed in other causes of bronchiectasis. Particularly, this occurs in systemic diseases, such as immunodeficiencies and autoimmune diseases [11, 12]. Wide phenotypic heterogeneity characterizes CF and PCD, as reflected in multiple described endotypes with variable severity of manifestations across different organs and systems, arising from different CFTR mutations in CF and different involved genes and mutations in PCD, as well as from modifier genes [13, 14].

In both CF and PCD, genetic mutations contribute through different mechanisms to an inherent impairment of the mucociliary escalator, which represents the point of entry into the pathogenetic vicious vortex that eventually leads to the development of bronchiectasis. From the hydrodynamic perspective, the effectiveness of the mucociliary escalator, as reflected by the velocity of the airway surface fluid, depends on (i) the airway epithelial ciliary density, (ii) the airway epithelial ciliary forcing, and (iii) the friction coefficient influenced by the viscosity and thickness of the periciliary fluid [5, 15]. In PCD, variants in a set of > 60 genes identified so far, encoding proteins that either constitute structural components of motile cilia or take part in their assembly process [16], lead to altered ciliary structure, with detrimental effects on ciliary motility and/or sparse ciliation in the airway epithelium [17]. These defects impair the first two hydrodynamic factors of the airway surface fluid velocity and compromise the effectiveness of mucociliary escalator (Figure 1). On the other hand, variants in the CFTR gene, encoding a transmembrane protein present in the cell membrane of airway epithelial cells, primarily ionocytes, which serves as a chloride anion channel [18], result in decreased chloride excretion to the airway lumen and hyperabsorption of sodium and water towards the cytoplasm, thus dehydrating the airway surface and depleting the periciliary fluid layer [19]. This defect affects the third hydrodynamic factor of the airway surface fluid velocity and restricts the effectiveness of the mucociliary escalator (Figure 1). Recent data suggest that in PCD the absence of ciliary motility‐dependent sensing of mucus limits the release of local autocrine/paracrine hydrating mediators, thus producing a dehydrated airway surface and mucus hyperconcentration [20].

FIGURE 1.

Pathophysiology of CF‐ and PCD‐related bronchiectasis. CF and PCD are diseases that inherently impair the mucociliary escalator, either passively or actively, respectively, by affecting different hydrodynamic aspects of airway surface fluid velocity. The pathogenetic cascades in both diseases converge to the pathogenetic vicious vortex that leads to the development of bronchiectasis. Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; Created with, BioRender.com. [Color figure can be viewed at wileyonlinelibrary.com]

Evidently, CF and PCD are the only causes of bronchiectasis that inherently affect the mucociliary escalator, as all other etiologies impair mucociliary clearance at a secondary level (Figure 2). In both, the pathogenetic vicious vortex process in the airway initiates at the time of birth [21, 22], whereas in most other causes of bronchiectasis the detrimental effects on the lungs begin later in life. Despite these pathophysiological differences, the onset of clinical manifestations of bronchiectasis in all underlying etiologies varies. CF and PCD usually become evident during childhood, although their recognition and diagnosis may take place at a later stage.

FIGURE 2.

Etiological categorization of bronchiectasis. Bronchiectasis can be etiologically categorized in three major groups, that is, idiopathic bronchiectasis of unknown cause despite thorough investigation, bronchiectasis attributed to diseases primarily impairing the mucociliary escalator (CF and PCD), and bronchiectasis attributed to diseases secondarily impairing the mucociliary escalator. Occasionally, primary and secondary mucociliary escalator diseases may coexist in the presence (**) or absence (*) of bronchiectasis. Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; PMD, primary mucociliary disease; SMD, secondary mucociliary disease. Created with, BioRender.com. [Color figure can be viewed at wileyonlinelibrary.com]

The high genotypic and phenotypic heterogeneity of CF and PCD is associated with complexities in their diagnosis. Genetic testing has emerged as the most reliable diagnostic approach for both diseases, although there are numerous CFTR mutations whose disease‐causing capacity remains equivocal and probably several yet undiscovered PCD‐causing genes, as the currently known genes are responsible for approximately only 70%–80% of the cases [3, 4]. Further, next generation sequencing, which is far more sensitive than Sanger sequencing and multiplex ligation‐dependent probe amplification, is not always accessible. Nongenetic tests are thus very helpful in both diseases. The detection of high sweat chloride levels has traditionally been diagnostic for CF. Modern approaches include the ex vivo measurement of the intestinal current in rectal biopsy and the in vivo measurement of the potential difference across the nasal epithelium [23, 24, 25]. On the other hand, the detection of low nasal nitric oxide levels is highly suggestive of PCD. Further, high‐speed video microscopy allows the assessment of ciliary beating pattern and frequency in real‐time, immunofluorescence reveals the absence of specific ciliary components, and transmission electron microscopy depicts the ultrastructural ciliary defects in airway epithelial biopsy, thus establishing the diagnosis of PCD in a multimodal approach [26, 27]. In contrast, the diagnosis of other underlying etiologies of bronchiectasis is more straightforward, for example, by means of medical history, spirometry, and immunological profile assessments.

Although pathogens are commonly isolated in respiratory secretions of bronchiectasis patients [8, 28], the airway microbiological profile in CF and PCD follows similar specific patterns across different age groups. More specifically, Pseudomonas aeruginosa remains the cardinal pathogen in both diseases, demonstrating a steadily increasing isolation rate with ascending age, and is associated with higher morbidity and mortality [29, 30], whereas the isolation rate of other pathogens (Staphylococcus aureus and Haemophilus influenzae) rises from birth to adolescence and early adulthood and then follows a declining trend. A particular distinction between the two diseases is the infection by Burkholderia cepacia, which is occasionally observed in a minority of patients with CF but not in PCD [31, 32].

Conventional treatment in PCD generally follows the experience from the management of CF and non‐CF bronchiectasis and mainly focuses on airway clearance and antimicrobial therapy guided by the findings of airway microbiological surveillance. Although evidence is limited, certain airway clearance therapeutic modalities, which are adequately effective, safe, and tolerated in CF but not in non‐CF bronchiectasis, such as nebulized dornase alpha, a human recombinant DNase, and hypertonic saline, are probably beneficial in PCD as well [33]. Further, novel dipeptidyl peptidase 1 inhibitors, such as the recently approved brensocatib, have been demonstrated to dampen the detrimental effects of neutrophilic airway inflammation in non‐CF bronchiectasis [34]. It is important though to highlight the necessity for the investigation of their clinical benefit in CF and PCD separately from non‐CF bronchiectasis due to their distinct pathophysiology.

In‐depth understanding of the underlying pathogenetic mechanisms in CF and PCD has enabled the development of targeted therapies, some of which are currently in clinical trials or clinical use in combination with conventional nonspecific treatment. The introduction of CFTR modulators, targeting the posttranslational stage of CFTR synthesis, has drastically changed the natural history of CF during the last decade [35]. In parallel, clinical trials based on mRNA molecules, targeting the posttranscriptional stage of gene expression, are in progress aiming to enhance ciliary growth or restore ciliary motility in PCD [33]. Finally, advances in genetic engineering and gene editing have opened the way for the development of gene therapies for CF and PCD, by directly repairing the DNA lesions that drive their pathogenesis, pointing towards the possibility of their permanent cure in the future [33, 35]. In other etiologies of bronchiectasis, no targeted therapies exist, either at the genome, transcriptome, or proteome level, to directly restore mucociliary clearance.

The inherent impairment of the mucociliary escalator in CF and PCD raises the question of their distinction from all other bronchiectatic diseases. We believe that the extensive similarities in their clinical, diagnostic, and therapeutic features, as summarized in Table 1, are sufficient to place them under a common umbrella and differentiate them from bronchiectasis attributed to other causes. We propose the term “non‐CF, non‐PCD bronchiectasis” or “non‐primary mucociliary disease bronchiectasis” to be used in the literature and the design of clinical and translational research, to clearly separate PCD in the same way as CF is separated from all other bronchiectatic diseases. This distinction will eventually enhance the personalized management of both PCD and the “non‐CF, non‐PCD” bronchiectasis patients in clinical practice.

TABLE 1.

Comparison between CF, PCD, and other causes of bronchiectasis with regard to their pathophysiology, clinical features, investigation, and management.

Disease features	Cystic fibrosis	Primary ciliary dyskinesia	Other causes of bronchiectasis
Origin	Genetic	Genetic	Usually acquired
Age at onset of clinical symptoms	Usually in childhood	Usually in childhood	Variable
Age at onset of disease process (trigger of the pathogenetic vicious vortex)	Birth	Birth	Later in life
Inherent impairment of airway mucociliary clearance	Yes, attributable to increased friction coefficient in airway surface fluid velocity	Yes, attributable to decreased ciliary density and/or ciliary forcing in airway surface fluid velocity	No
Distinct endotypes and phenotypes	Many, attributable to different CFTR mutations	Many, attributable to different involved genes and mutations	None to few
Specific airway microbiological patterns	Yes	Yes	No
Involvement of other organs and systems beyond lungs	Common	Common	Uncommon
Diagnostic strategy	Complex, involving genetic testing, sweat chloride testing, NPD, and ICM	Complex, involving genetic testing, nNO measurement, HSVM, TEM, and IF	Usually simple
Targeted therapies	Yes, including CFTR modulators and transcript/read‐through therapy (currently under development)	Yes, including transcript/read‐through therapy (currently under development)	No
Curability (excluding lung transplantation)	Possibly in the future by means of gene therapy	Possibly in the future by means of gene therapy	No

Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; HSVM, high‐speed video microscopy; ICM, intestinal current measurement; IF, immunofluorescence; nNO, nasal nitric oxide; NPD, nasal potential difference; TEM, transmission electron microscopy.

Author Contributions

Andreas M. Matthaiou: conceptualization, visualization, writing – original draft, writing – review and editing. Panayiotis Kouis: writing – review and editing. Pinelopi Anagnostopoulou: writing – review and editing. Panayiotis K. Yiallouros: conceptualization, supervision, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Matthaiou AM et al. 2025 Pediatr Pulmonol Supplement.

Matthaiou A. M., Kouis P., Anagnostopoulou P., and Yiallouros P. K., “Cystic Fibrosis and Primary Ciliary Dyskinesia Share Extensive Similarities: Is It Time to Place Them Under a Common Umbrella?,” Pediatric Pulmonology 60 (2025): 1‐6, 10.1002/ppul.71368.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.