Introduction
A genetically and clinically diverse condition known as primary ciliary dyskinesia (PCD) is characterized by defective motile ciliary activity. It has a predominately autosomal recessive inheritance pattern. Epithelial cilia in the lungs, paranasal sinuses, reproductive system, and Eustachian tubes exhibit aberrant function and ultrastructure due to gene mutations that encode or assemble ciliary proteins.
An essential defense mechanism in the airways against germs and particle debris is provided by mucociliary clearance. As a result, patients with PCD experience chronic and recurring infections of the upper and lower airways and hearing loss due to conductive hearing loss. After birth, airway symptoms frequently appear within a few hours. Immotile sperm results in infertility in many males, although not necessarily all of them.
Data is sparse, but immotile cilia in the Fallopian tubes likely contribute to subfertility in some women. In about half of the cases, dysfunction of the embryonic node's motile cilia results in situs abnormalities, such as situs inversus or situs ambiguity, which can be linked to congenital heart disease.
Primary ciliary dyskinesia (PCD) may sometimes be associated with renal disease, retinitis pigmentosa, deafness, or hydrocephalus. These conditions arise from the dysfunction of nonmotile primary cilia, which serve as photoreceptors in the eyes, stereocilia in the inner ear, and mechanoreceptors in renal tubules.
PCD is known to result from mutations in more than 35 genes, although more are still to be found. A disease with a very diverse ciliary morphology and function is caused by many PCD genes and an even more significant number of disease-causing mutations. For instance, the DNAH5 gene encodes a protein that is found in the outer dynein arm, which is a structure that provides the force necessary for cilia to move. Patients with biallelic mutations in DNAH5, missing external dynein arm structures under transmission electron microscopy (TEM) examination. Individuals with these mutations have cilia that are essentially static. Dynein regulatory and inner dynein arm complex assembly requires the proteins encoded by CCDC39 and CCDC40.
Is Primary Ciliary Dyskinesia Underdiagnosed?
The estimated prevalence of primary ciliary dyskinesia (PCD) is approximately one in 10,000 individuals. However, the actual majority remains uncertain, and a significant number of patients remain undiagnosed. In populations with a higher prevalence of consanguineous marriages, such as British Asians, the prevalence can be substantially higher, reaching up to one in 2,000 individuals, comparable to most cystic fibrosis (CF).
According to a European survey, only a tiny percentage of PCD patients had been diagnosed in most nations, especially among adults, with significant regional variation. A variety of factors cause underdiagnosis. Since they don't see many cases, general practitioners, pediatricians, and even pulmonary doctors have little knowledge.
According to a global study of PCD patients, 37 % of individuals had >40 visits to doctors because of symptoms before being recommended for testing. Due to the broad nature of PCD symptoms, it is unsurprising that patients with situs inversus—a disorder uncommon in the general population—are identified earlier in life. As the test's availability differs across Europe, the need for highly specialized diagnostic tests that are frequently only accessible at a great distance from the patients' residences adds to underdiagnosis. While it is anticipated that most patients will live into later adulthood, the situation is worse for adults as a disproportionately high percentage of patients in the International PCD Cohort are under 20.
How Should Patients Be Referred for Primary Ciliary Dyskinesia Diagnosis?
A specialist, such as a pulmonologist or ENT doctor, may serve a 20,000-person area. On average, they can anticipate seeing two PCD patients in their practice and make a new diagnosis every 40 to 50 years. As a result, specialists in pulmonary or ENT medicine and primary care physicians have a limited understanding of PCD. Primary care physicians, specialists, and PCD centers must work together to improve the diagnosis of PCD (and other rare disorders). General pediatricians and primary care doctors (GPs) should triage. They must recognize the numerous individuals with respiratory symptoms who should be sent to a specialist (a pulmonologist or an ENT doctor) due to a severe or unusual illness.
An ENT should:
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Choose the people with severe or unusual diseases most likely to have PCD.
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Rule out more prevalent conditions, including CF and immunological deficiencies, that cause chronic upper and lower respiratory morbidity.
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After that, send the patients to a PCD diagnostic facility for additional testing.
Centers for PCD diagnostics facilities must be equipped with the most up-to-date tools and knowledge to establish a precise diagnosis and decide whether a patient has "definite PCD," whether PCD is "very likely" or "extremely unlikely," or whether test results are still ambiguous.
Which Tests Are Used for Primary Ciliary Dyskinesia Diagnosis?
There is no single "gold standard" diagnostic test for PCD; hence multiple technically challenging and sophisticated examinations are necessary for diagnosis. To convey the experience of the spectrum of normality and abnormality associated with PCD in contrast to respiratory patients without PCD, the Task Force advises conducting testing only in specialized centers with a high volume of referrals. The Task Force looked at the data supporting the five PCD tests, which include genotyping, high-speed video-microscopy analysis of ciliary beat frequency and pattern, TEM, and immunofluorescence labeling of ciliary proteins. Nasal nitric oxide is a typical PCD test. The guidelines allow for considerable flexibility in the tests that should be employed because the combination and availability of these tests differ between nations.
Nasal Nitric Oxide (nNo): nNO has historically only been recommended as a PCD screening test. With its outstanding sensitivity (90 percent to 100 percent) and strong specificity (75 percent to 97 percent), the Task Force suggested that nNO should be included in the battery of confirmatory diagnostic tests in addition to screening. Also, it is inexpensive, noninvasive, and reasonably simple to perform. A chemiluminescence analyzer with a velum closure approach should best be used for measurements in school-aged children and adults. There is some proof that younger kids who are unable to do the breath-hold method can still have their nNO measured during tidal breathing, but the differentiation between PCD and non-PCD may be less accurate, especially in infants whose nNO is lower than that of healthy kids.
High-Speed Video-Microscopy Analysis: If nNO and HSVA are normal, further testing is typically unnecessary. HSVA is a significant component of the diagnostic toolkit but is insufficient to rule PCD in or out. Individuals with PCD have aberrant ciliary function, and it might be beneficial to examine the respiratory epithelium from the nose or bronchi to determine the frequency and pattern of ciliary beats. Nasal sampling is a short yet painful process for patients. Many PCD patients have ciliary function problems that are readily apparent (such as static cilia or revolving cilia), but some have more subtle flaws, like an incomplete sweep. Hence, analyses should only be performed by trained observers and always include both ciliary beat frequency and pattern.
Transmission Electron Microscopy (TEM): TEM is an expensive and time-consuming investigation to detect anomalies in the ciliary ultrastructure, such as missing dynein arms and microtubular disarrangement. The ERS Task Committee suggested using TEM as a critical component of the diagnostic process since it is highly specific (>99 percent) and can confirm a diagnosis. However, TEM cannot be used alone to rule out a diagnosis because it is normal in 15 percent to 20 percent of PCD patients.
Conclusion
The condition known as primary ciliary dyskinesia (PCD) is uncommon and diverse. In 70 percent of cases, genetic abnormalities lead to aberrant ciliary ultrastructure and inappropriate ciliary function. Due to the disease's rarity and the lack of further understanding of its clinical features, PCD in children is underdiagnosed and diagnosed too late, especially in relatively small centers with little to no expertise in treating PCD patients.
