Genetic aetiologies of bronchiectasis revisited: A new diagnosis of primary ciliary dyskinesia in adulthood

Highlights

• •Primary ciliary dyskinesia (PCD) is a disorder of ciliary structure and function that typically presents with a recurrent productive cough, sinus chronic rhinosinusitis and otitis media from the newborn period onwards. Additional features may include situs inversus and reduced fertility.
• •PCD should be remembered as a potential genetic aetiology of bronchiectasis.
• •Nasal nitric oxide is a useful initial investigation. A normal value should not exclude the diagnosis in patients in whom there is otherwise a high degree of clinical suspicion.
• •Further testing includes high-speed video microscopy analysis. The next line of investigation to confirm a diagnosis of PCD is with electron microscopy before proceeding to genetic testing.
• •Clinical management involves specialist care by a PCD multidisciplinary team and requires both effective airway and sinus clearance management, as well as prompt initiation of antibiotics when infections arise.

Abstract

Primary ciliary dyskinesia (PCD) is an inherited condition in which ciliary motility is defective. This may manifest clinically with chronic rhinosinusitis, otitis media and recurrent lower respiratory tract infections that lead to bronchiectasis. Additionally, fertility may be reduced and situs abnormalities can occur. We present a case of a patient in whom a diagnosis of PCD was initially excluded on the basis of two negative nasal nitric oxide tests. A high index of clinical suspicion was maintained and 23 years after his initial presentation to a specialist bronchiectasis service, additional investigations including nasal brushings and genetic testing culminated in a late diagnosis of PCD.

Background

Primary ciliary dyskinesia (PCD) is a rare inherited condition characterised by disordered motility of cilia throughout the body. It is generally inherited in an autosomal recessive fashion, though is known to be genetically heterogenous.¹ Rarely, autosomal recessive and X-linked inheritance patterns have been observed.² Cilia are hair-like organelles found lining the airways, middle ear, sinuses and reproductive tract, as well as in ependymal cells and some choroid plexus cells in the brain.³ Cilia are structurally composed of a cylindrical arrangement of nine microtubule doublets surrounding a central microtubule pair, referred to as the 9 + 2 arrangement. The motion of the cilia is created through dynein arms. These are structures on the surface of one of the microtubule pairs, which slide along the surface of the second pair, thus creating a bending motion within the cilium. Each airway cell contains approximately 200 cilia, which move in a synchronised beat at 8–20 Hz.³

In the airways, coordinated ciliary beating facilitates clearance of respiratory secretions and mucus.⁴ Defects in ciliary structure lead to impaired mucociliary clearance, giving rise to recurrent respiratory tract infections which may lead to bronchiectasis, rhinosinusitis and otitis media, as well as subfertility in women and infertility in men.^5,6 Between 40 and 50% of patients with PCD will have situs inversus. This is due to disturbed flow of extraembryonic fluid during early embryogenesis; flow is normally leftward; however, impaired ciliary function may result in a random direction of flow, with a 50% chance of flow being rightward, disrupting left/right symmetry and resulting in situs inversus.^7,8 Kartagener’s syndrome refers to a classical triad of chronic sinusitis, bronchiectasis and situs inversus.⁹ The prevalence of situs inversus varies among ethnic populations.

PCD should be suspected in patients with known situs inversus, neonatal respiratory pathology, lifelong productive cough, bronchiectasis and recurrent otitis media.¹⁰ Initial screening investigations often include nasal nitric oxide levels, which have been found to be low in PCD through unclear mechanisms.¹¹ High-speed video microscopy analysis (HSVMA) is used to directly visualise ciliary function. These are the two investigations which form the first recommended tests for PCD, as per current European Respiratory Society guidelines.¹² It is worth noting that the same guidelines recommend proceeding to further testing if the clinical history is convincing, but preliminary testing is normal. The next step in investigation is with electron microscopy to assess ciliary ultrastructure following nasal brushing. This enables direct visualisation of the structure and activity of the cilia.¹⁰ The final step typically involves genetic testing, with more than 50 genes identified that contribute to the condition.¹³ DNAH5 mutations are the underlying cause of 15–29% of PCD diagnoses and are associated with situs abnormalities.¹⁴ Approximately 20–30% of patients do not have any established pathogenic variant on genetic testing.¹⁴

Once PCD is diagnosed, meticulous respiratory physiotherapy is the mainstay of management.¹⁵ This includes optimisation of airway clearance, breathing pattern re-education and exercise programmes to improve cardiovascular fitness.¹ Long-term azithromycin prophylaxis has been shown to reduce pulmonary exacerbations.¹⁶ Finally, fast and aggressive management of chest infections with antibiotic therapy is required. This may entail cyclical intravenous antibiotic therapy if exacerbation frequency is high.^1,17

We present the case of a patient who was initially diagnosed with idiopathic bronchiectasis and in whom high clinical suspicion resulted in repeat testing for PCD and subsequent confirmation of the diagnosis.

Case presentation

A 58-year-old gentleman was reviewed in a bronchiectasis clinic. He reported chronic purulent sputum production and recurrent lower respiratory tract infections, associated with longstanding shortness of breath. His past medical history comprised asthma and allergic bronchopulmonary aspergillosis. He was born at term and had a history of neonatal atelectasis with an incubator requirement. During childhood, he had multiple chest infections and recurrent otitis media. He was found to have situs inversus with dextrocardia on a chest X-ray at the age of 6 years. Chest CT imaging showed bronchiectasis (Fig. 1). Previous PCD testing with nasal nitric oxide in 1999 and 2002 were both normal, with a value of 900 ppb on the latter test (PCD usually presents with a value <200¹⁸).

Fig. 1.

An axial section of a high-resolution chest CT scan showing dilated, ectatic bronchi and dextrocardia.

Investigations

During a routine bronchiectasis clinic follow-up appointment, the underlying aetiology was reconsidered. This was 23 years after the initial presentation to specialist services and was prompted due to an ongoing high index of suspicion of PCD on re-review of his full clinical history. Repeat nasal nitric oxide testing was normal at 500 ppb. HSVMA from nasal epithelial cells obtained by a brushing biopsy, however, showed a dyskinetic beat pattern of cilia, which were stiff at the bases, though with some normal areas. Beat frequency was at the lower end of normal at 9.8 Hz. Staining of DNAH5 protein by immunofluorescence was negative, with partial absence of the outer dynein arms. Genetic testing revealed two missense mutations in DNAH5 known to be associated with PCD.

Differential diagnosis

Bronchiectasis in general may have a broad aetiology. Potential different diagnoses included PCD (particularly in light of the known dextrocardia), cystic fibrosis and post-infective bronchiectasis (in view of the recurrent childhood respiratory tract infections).

Treatment

The patient was referred to the PCD specialist team, which is a multidisciplinary team (MDT) including specialist physiotherapists, clinical nurse specialists, ENT (ear, nose and throat) surgeons, clinical audiologists and respiratory consultants with a specialist interest in PCD. Additionally, he was referred to the genetic counselling team for further support regarding screening for family members.

Outcome and follow-up

Following diagnosis and referral to the PCD MDT, the patient remained clinically stable. He reported ongoing engagement with respiratory physiotherapy and a year free of any chest infections, which he had not experienced in a number of years. He remained on a fluticasone furoate/vilanterol combination inhaler for asthma, itraconazole for longstanding ABPA and nebulised saline to assist with airway clearance.¹⁹

Discussion

This patient experienced a late diagnosis of PCD, likely due to two previous normal screening nasal nitric oxide test results. A 2004 study reports nasal nitric oxide as having a specificity of 88% and sensitivity of 100% using a cut-off value of less than 105 ppb.²⁰ This level is far lower than the test results for our patient. Testing for nasal nitric oxide is recommended in British and European PCD diagnostic guidelines as a preliminary screening tool.¹¹ There are, however, a number of studies that have identified normal or raised nitric oxide levels in patients with confirmed PCD.^21,22 Therefore, in patients with a history strongly suggestive of PCD, a normal nasal nitric oxide level should not discount this diagnosis.

In this patient, there were a number of factors making the diagnosis of PCD likely. These include his history of neonatal atelectasis with an incubator requirement, recurrent chest infections, recurrent otitis media, bronchiectasis and dextrocardia. Despite the normal nasal nitric oxide at his initial presentation, it may have been prudent to investigate further with electron microscopy at an earlier point.¹⁰

Bronchiectasis may be encountered in a variety of medical specialties and it is important to note that a previous label of idiopathic bronchiectasis may need to be reconsidered if the clinical history is strongly suggestive of an underlying inherited aetiology. Correctly determining the aetiology of bronchiectasis is important for ensuring that patients receive optimised and tailored care. In cases where bronchiectasis is secondary to PCD, a correct diagnosis means that clinic follow-up by the appropriate specialist team can be offered, including rapid access to respiratory medicine, ENT and specialist respiratory physiotherapy services. It is therefore important for clinicians to maintain a high degree of clinical suspicion should the clinical narrative fit.

CRediT authorship contribution statement

Dylan Riley: Writing – original draft, Conceptualization. Kartik Kumar: Writing – review & editing, Conceptualization. Janet M. Stowell: Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Co-author is an associate editor and editorial board member of Clinical Medicine – K.K. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.