Cystic fibrosis (CF) is an autosomal recessive disorder, with an estimated incidence of 1 per 2,500 live births in Caucasian populations. It is caused by mutations in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene which is located on chromosome 7 and encodes for the CFTR chloride channel on cell membranes. Mutations affect CFTR function by a variety of routes including complete loss of the protein, rapid breakdown of CFTR and surface expression of a dysfunctional protein. The most common mutation is ΔF508; a deletion of three nucleotides which results in loss of phenylalanine at the 508th position on the protein causing abnormal tertiary structure and rapid degradation with no apical membrane expression. A very large number of mutations (>500) have been identified in the CFTR gene, but a select group are more commonly associated with disease (e.g. G542X, G551D, N1303K). The prevalence of mutations differs between ethnic populations.

Abnormalities in CFTR cause abnormal ion transport regulation across the cell membrane. In the lungs this results in abnormal airway fluid. Dehydrated mucus is characteristically highly viscoelastic, and adheres to the cilia and airway cells, causing airway plugging. The reduced-volume periciliary fluid layer does not adequately support and lubricate the cilia, and results in defects of ciliary function (Fig. 4.1). Adherent mucus and impaired ciliary function both contribute to reduced airway clearance, chronic infection and biofilm formation. Eventually the chronic infection and inflammation lead to bronchiectasis, which can develop very early in life [23]. Bronchiectasis in CF predominantly affects the upper lobes initially, spreading to all lobes over time. The reasons for upper lobe predominance have been suggested to include aspiration, poor clearance by cough and poor lymphatic clearance to this region, although the disparity with PCD which tends to have worse disease in the middle lobe is difficult to explain.

Although respiratory disease accounts for the vast majority of morbidity and mortality [24]. CF is a multisystem disorder, with manifestations including meconium ileus, pancreatic insufficiency, steatorrhea, failure to thrive, liver disease, diabetes, nasal polyposis and sinusitis. Most cases present before the age of 2 years although later presentation, including in adulthood, is not unheard of particularly in individuals carrying mutations other than ΔF508 who are more likely to be pancreatic sufficient and less likely to have diabetes or pseudomonas colonisation [25]. Diagnosis of classical cases of CF is based on an abnormal sweat test (sweat chloride > 60 mmol/L). Supplementary investigations include CFTR mutations and abnormal transepithelial potential difference.

The majority of patients with CF are easy to diagnose early as they have classical lung disease ± pancreatic insufficiency associated with two CF associated CFTR mutations and an abnormal sweat test result (>60 mmol/l). A further group of patients with mild lung disease and pancreatic sufficiency is confidently diagnosed, often in adulthood, on the basis of a diagnostic sweat test and two disease causing mutations. The group that cause particular difficulty are those with clinically milder phenotypes associated with a variety of equivocal outcomes from genotype and functional investigations (sweat test and nasal potential difference). This is a difficult and controversial area for clinicians and recently international consensus guidelines have been proposed to help in the diagnosis of patients with “CFTR dysfunction that does not fulfil diagnostic criteria for CF” [26]. These single organ disease states are becoming recognised as a spectrum of CFTR related disorders. Very many mutations have been identified in CFTR, but not all are associated with disease and it has been suggested that some only cause disease when interacting with certain environmental factors or other genes. Some patients present with two known disease-causing mutations, but an equivocal sweat test result. These patients generally have more severe lung disease than those with an equivocal sweat test and normal genotype, but they have milder disease than a patient with the same genotype and sweat chloride concentration >60 mmol/l. This highlights different phenotypes associated with a spectrum of test results, indicating the need to perform functional tests even in the presence of two mutations. It is probably appropriate to consider patients with mild CF-like disease associated with two mutations and a normal sweat test as an atypical CF variant. Another group that cause diagnostic uncertainty are those with only one CFTR mutation. These patients may have atypical CF. However the diagnosis of mild or atypical CF with equivocal CF results should only be made after all other causes of bronchiectasis have been excluded. It is prudent to keep the diagnosis under review as our understanding of CFTR related disorders evolves.

After CF, primary ciliary dyskinesia (PCD) is the most prevalent (1:10–40,000) genetically determined cause of impaired mucociliary clearance. PCD is inherited in an autosomal recessive pattern, and is characterised by chronic infection of the upper and lower airway [21, 27]. The impaired mucociliary clearance is a consequence of abnormal ciliary beat function which is usually [27], but not always [28, 29], associated with abnormal ciliary ultrastructure seen by transmission electron microscopy (Fig. 4.2a–d). Motile cilia are important in organ systems besides the respiratory tract, such as the embryonic node, sperm flagella (Fig. 4.2e), the female reproductive tract, and ependyma of the brain and spinal cord. PCD patients therefore often have extra-pulmonary symptoms caused by dysmotile cilia such as serous otitis media, infertility and rarely hydrocephalus. The cilia of the embryonic node, responsible for left-right asymmetry, are similar in structure to respiratory cilia. Embryonic node dysfunction in PCD causes situs inversus (termed Kartagener’s syndrome) in 50 % of cases (Fig. 4.3a, b) and is associated with congenital heart disease in approximately 6 % of cases [30]. Neonates typically present with respiratory distress of unknown cause and rhinitis. As infants, patients have a persistent wet cough, recurrent respiratory tract infections, rhinitis, and frequently glue ear associated with conductive hearing difficulty. Patients frequently develop sinusitis (Fig. 4.3c). These symptoms may not always be recognised as indicative of PCD and although the mean age of diagnosis is approximately 4 years [31], the range is considerable and reflects local expertise and clinical suspicion. Respiratory symptoms continue into later childhood and adulthood, with many patients developing bronchiectasis, commonly affecting the middle and lower, rather than upper lobes as in CF.

The diagnosis of PCD requires specialist investigation, and a number of different tests should be available, since no one investigation can be considered confirmatory [27, 32].

Extremely low levels of nasal nitric oxide are supportive of the diagnosis of PCD [33]. However, some patients with PCD have been described with normal nitric oxide levels, and levels can be low in other conditions including CF. Nasal nitric oxide measurement should therefore only be used as a screening test, and if clinical suspicion is high, further diagnostic investigation should be conducted even if the levels are normal [21].

Patients should have their respiratory epithelial cells visualised by high speed video microscopy for evidence of ciliary dysfunction (e.g. static, dyskinetic, or vibratory cilia). Subtle abnormalities may be significant, but difficult to recognise; facilities should therefore be based at centres with expertise and a high throughput of PCD diagnostic patients. Following abnormal high speed video microscopy analysis, confirmation of diagnosis by an additional method is required because ciliary dysfunction can be secondary, for example to infection. Most, patients with PCD have diagnostic abnormalities of ciliary ultrastructure on transmission electron microscopy and this used to be considered the ‘gold standard’ investigation for PCD (Fig. 4.2). However, it is now recognised that at least 15 % of patients with PCD have normal ciliary ultrastructure and this investigation should not be used in isolation. Transmission electron microscopy analysis requires expert interpretation.

Air liquid interface cell culture techniques are particularly helpful where secondary ciliary defects are suspected, for example due to chronic infection. Re-differentiation of basal epithelial cells to ciliated cells is achieved by culturing the cells, allowing a repeat HSV analysis and electron microscopy having reduced environmental factors that compromise ciliary function for example pollution, infection. However, air liquid interface culture is technically demanding and time consuming; it is routinely available in a small number of specialist centres.

Immunofluorescence microscopy analysis, is a promising technique to help in the clinical diagnosis; it is based on the ability to detect and localise intra-ciliary proteins e.g. DNAH5 by immunofluorescence. However, this method is only routinely available at one centre which is based in Germany.

Genetic testing is currently only able to identify perhaps 50 % of PCD cases, but it is an active area of international research with potential for significant advances. Whilst CF is caused by mutations in one gene, PCD is polygenic with over 200 proteins involved in the formation of cilia. Additionally the disease-causing genes are large, making genetic diagnosis of PCD a challenge. Mutations in 24 genes have been associated with PCD to date, mainly encoding for dynein arm components (reviewed in [32, 34], and summarised in Table 4.2). The two commonest mutations, dynein, axonemal, heavy chain 5 (DNAH5) mutation [37] and dynein arm intermediate chain 1 (DNAI1) mutation [35], have a combined prevalence of 17–35 % in patients with PCD and are associated with static cilia on light microscopy, and dynein arm deficiencies on electron microscopy. Other known mutations are all rare. Mutations in the kintoun gene (KTU) [43], which is required for cytoplasmic pre-assembly of axonemal dyneins results in a similar ciliary phenotype to DNAH5. Mutations in the radial spoke head genes RSPH9 and RSPH4A have been reported in PCD patients with abnormalities of the central microtubular pair causing an abnormal rotating movement of the cilia [56]. Patients with mutations in the dynein axonemal heavy chain 11 (DNAH11) have hyperkinetic vibratory cilia, but apparently normal ultrastructure on electron microscopy [39]. There are therefore a variety of ciliary phenotypes seen on microscopy depending on the responsible mutations, but all result in a severe mucociliary clearance impairment, and clinical phenotype is indistinguishable.

In extremely rare cases, PCD has been genetically linked to other ciliopathies. X-linked recessive retinitis pigmentosa, sensory hearing deficits, and PCD have been associated with mutations in the Retinitis Pigmentosa guanosine triphosphatase regulator (RPGR) [63]. A single family has been reported with a novel syndrome that is caused by Oral-facial-digital type 1 syndrome (OFD1) gene mutations characterized by X-linked recessive mental retardation, macrocephaly, and PCD [62].

Young’s syndrome, or Barry-Perkins-Young syndrome, is a clinical entity characterised by bronchiectasis, chronic sinusitis and impaired fertility. The diagnosis is considered most commonly in middle aged men presenting with infertility. Although Young’s syndrome has been reported in identical twins prompting suggestions of a genetic aetiology, there is some evidence that this syndrome has declined following the removal of mercury from teething powders and worm medicines in the 1950s [64]. Moreover, whilst Young’s syndrome and other disorders of mucociliary clearance have partially overlapping symptomatology, a common causative link has not been identified. Indeed the mechanism of reduced fertility in Young’s appears to be due to functional obstruction of sperm transport down the epididymal tract rather than due to absence of the vas deferens which is seen in CF or to dysmotility seen in PCD. There are reports that mucociliary clearance is impaired in Young’s syndrome [65] but ciliary ultrastructure is largely normal [66]. Similarly, patients with Young’s are not frequently carriers of common CF mutations [67], although possibly there may be an association with atypical CF mutations [68]. Some authors have even questioned whether Young’s syndrome exists as a recognised clinical entity at all [69], and it is quite possible that as diagnoses of rare variants of CF are established, Young’s syndrome will disappear as a diagnosis.

Non-motile or ‘primary’ cilia are found on the surface of many cells in the body. An increasing number of diseases are attributed to abnormal motile or primary ciliary function, collectively known as ciliopathies (http://​www.​ciliopathyallian​ce.​org). For example, in the eye and kidney ciliopathies can cause retinitis pigmentosa, autosomal dominant polycystic kidney disease (ADPKD) or nephronophthisis. Primary cilia are similar in structure to the respiratory epithelial cilia (9 + 2), but in cross section, there is no central pair of microtubules (9 + 0). There are several case reports of patients with PCD-like disease in association with retinitis pigmentosa [70, 71]. In some patients it may be that both primary and motile cilia are impaired. In others it may be that the problem is purely of primary cilia, with abnormalities of primary pulmonary cilia causing lung disease. This needs further evaluation.

Autosomal dominant polycystic kidney disease (ADPKD) is an example of renal ciliopathy associated with bronchiectasis. It affects between 1 in 400 and 1 in 1,000 people [72]. The disease most commonly manifests in adulthood and is caused by defective ciliary function in renal epithelial cells. Two genes, PKD1 and PKD2 coding for proteins known as polycystins have been implicated in the pathogenesis of ADPKD. In ADPKD, impaired primary cilial sensing results in abnormal intracellular signalling, cell hyperproliferation, and cyst formation [73]. A predisposition to bronchiectasis is recognised, although the mechanism for this is not fully understood [74].

An association between alpha-1 antitrypsin (AAT) deficiency and emphysema is well-known but there are also reported cases of an association with severe PiZ genotypes and bronchiectasis, this is largely seen in adulthood. A study of 74 patients with severe AAT deficiency found high resolution CT scan evidence of bronchiectasis in 70 subjects and judged this to be clinically significant in 20 [75]. AAT deficiency alleles are over represented in patients with bronchiectasis and asthma combined, suggesting that bronchiectasis may occur as a consequence of airway obstruction, in turn reducing airway clearance [76].

Common variable immunodeficiency (CVID) has an estimated prevalence of 1 per 25,000 population and is the commonest immunodeficiency. Presentation is usually in young adulthood but diagnosis may be delayed [80]. Patients affected by CVID display a defective antibody response to protein and polysaccharide antigens and low IgG, IgM and IgA levels. This places affected individuals at risk of recurrent bacterial infection as well as autoimmune disease and malignancy [81]. Clinical features vary in CVID, perhaps reflecting heterogeneity of the molecular defects underlying the disease. Susceptibility loci for CVID have been identified within the MHC class II alleles [82], and polymorphisms in the tumour necrosis factor gene have been also been reported in association with CVID [83]. Mutations associated with CVID have been identified within the inducible costimulator (a molecule expressed by T cells) [84], CD19 (a T cell marker important in B cell development, activation and proliferation) [85], and in transmembrane activator and CAML interactor (a receptor believed to be important in antibody responses to type II T-independent antigens) [86].

In individuals with CVID at least one episode of pneumonia has usually occurred before diagnosis of CVID is made [81]. Possibly as a consequence of delayed diagnosis, the risk of bronchiectasis is greater in patients with CVID than in those with X-linked agammaglobulinemia or other immunodeficiency diseases and may approach 70 % [87]. Bronchiectasis tends to be more common in the lingual, middle and lower lobes. The threshold for HRCT imaging should be low in cases of known or suspected immunodeficiency, particularly if there are signs of persisting lung disease [78].

X-linked agammaglobuinemia (XLA) is characterised by almost complete absence of circulating B lymphocytes and of all immunoglobulin [88]. Mutations of the Bruton’s tyrosine kinase gene cause an incomplete block of B cell development at the pre-B cell stage [89]. This leaves affected patients susceptible to infection by encapsulated bacteria and mycoplasma [90]. More recently autosomal recessive forms of agammaglobulinemia have been identified that are caused by mutations in genes that encode for other components of the pre-B cell receptor and its signalling pathway [91]. Pulmonary infections can occur shortly after birth but generally become noticeable beyond 6 months of age following the disappearance of maternal IgG. The most common age for diagnosis is under a year but presentation as late as 5 years has been known [92]. Although a recent survey has found less than a third of adults with XLA to be severely affected by bronchiectasis [93], there is evidence to suggest that the risk of developing significant lung disease increases over time and can be reduced by early detection and treatment [94]. Chronic lung disease, including bronchiectasis, has also been observed in children with IgA deficiency, particularly when associated with IgG2 deficiency [95].

Chronic granulomatous disease (CGD) results from impaired function of NADPH oxidase. This enzyme is required for effective functioning of the phagocytic respiratory burst and for superoxide production. Impaired NADPH oxidase is generally transmitted by X-linked inheritance but autosomal recessive variants are also recognised [96]. Mean age at presentation in autosomal recessive disease is 10 years, slightly later than X-linked disease where the mean is 5 years suggestive of a more severe phenotype [97]. Sufferers are vulnerable to recurrent and severe bacterial and fungal infections, frequently Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia and Aspergillus spp.

A similar pattern of recurrent pneumonia and lung aspergillosis may also be observed in patients with severe congenital neutropenia [98]. Most commonly this disorder occurs as a consequence of mutations in the gene encoding for neutrophil elastase [99] but can also be attributable to mutations affecting a mitochondrial protein thought to be involved in protecting myeloid cells from apoptosis [100] or an endosomal protein involved in intracellular signalling [101]. The characteristic feature of this disease is low levels of circulating neutrophils and hence vulnerability to bacterial and fungal pathogens.

Bronchiectasis, alongside severe pneumonias, empyemas and pneumatoceles, is common in children with hyper-IgE or Job’s syndrome, in which neutrophil defects occur in combination with a wide variety of lymphocyte and humoral function defects as well as very high levels of serum IgE [102]. Job’s syndrome is inherited in an autosomal dominant pattern. Mutation of the signal transducer and activator of transcription 3 or STAT3 gene is known to cause Job’s syndrome [103], although in some cases the responsible mutation is unknown. STAT3 is a transcription factor which influences the expression of a variety of genes and plays a key role in many cellular processes such as growth and apoptosis. An autosomal recessive form of Job’s syndrome is recognised, this is less common than the autosomal dominant form and less likely to have respiratory complications. Bronchiectasis is also seen in association with Shwachman-Bodian-Diamond syndrome, a rare autosomal recessive disorder characterised by exocrine pancreatic insufficiency, bone marrow dysfunction, leukemia predisposition, and skeletal abnormalities. In most cases, Shwachman-Bodian-Diamond syndrome is associated with mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene located on chromosome 7 [104]. Bone marrow dysfunction results in neutropenia in the majority of patients and may be accompanied by defects in neutrophil mobility, migration, and chemotaxis.

It is currently difficult to identify many causes of innate immunodeficiency, and it is likely that as new defects are discovered, many cases currently labelled as suffering from ‘idiopathic bronchiectasis’ will have an underlying cause. Rare instances of bronchiectasis in association with deficiency of C2, or mannose binding lectin, have been reported and an association between deficiency of l-ficolin and bronchiectasis has been reported in adult patients [105]. Complement deficiency is also known to affect the severity of bronchiectatic disease in CVID [106] and in CF [107].

Ataxia telangiectasia is an autosomal recessive multisystem disorder resulting from mutation of the Ataxia telangiectasia mutated (ATM) gene, characterised by the development of telangiectasia and cerebellar ataxia. It is the most common of the DNA repair disorders and is associated with chromosomal instability and cellular radiosensitivity rendering sufferers susceptible to cancer and to infection. The ATM gene is involved in antibody class switch recombination and defects in this process may underlie the increased susceptibility of ataxia telangiectasia patients to bacterial infections [108]. The most common humoral immunological defects are diminished or absent serum IgA and IgG2, and impaired antibody responses to vaccines [109]. Ataxia telangiectasia leads to thymic hypoplasia and variable T cell deficiency. It is likely that recurrent aspiration due to swallowing impairment also contributes to respiratory disease [110]. Fifty percent of patients die in adolescence from overwhelming bronchopulmonary disease [109].

Marfan syndrome is a rare hereditary disorder characterised by skeletal, cardiovascular and ocular abnormalities. Pulmonary abnormalities occur in approximately 10 % of patients, the commonest being spontaneous pneumothorax and emphysema [111]. Although rare, cases of bronchiectasis in adults [112] and children [113] who have Marfan syndrome have been described. Marfan syndrome is autosomal dominantly inherited with variable expression; features of the condition arise as a consequence of a defect in Type 1 collagen. The defect in collagen may be responsible for the reduced tensile strength of the connective tissue leading to bronchiectasis and increased susceptibility to infection.

In the 1960s Williams and Campbell first described a series of children with bronchiectasis who had a bronchial cartilage deficiency from the third division with normal trachea and central bronchi [114]. It is hypothesised that the compliant bronchi collapse during coughing, leading to poor airway drainage [115]. The familial pattern and the early onset of symptoms support the possibility that this is a rare congenital syndrome [116]. Williams-Campbell syndrome has most frequently been described in children although adult cases have been reported. CT imaging demonstrates bilateral bronchiectasis affecting segmental and subsegmental bronchi [117]. Cartilage deficiency is not evident outside of the bronchi and the cause of the deficiency is not well understood. It has been hypothesised that children who are born with a bronchial cartilaginous defect develop pathology after suffering a viral respiratory infection in infancy. As a precise genetic defect has not been identified and solitary cases have been reported with greater frequency than familial, the genetic basis of Williams-Campbell syndrome is debateable, indeed secondary cartilaginous damage due to infection and inflammatory change cannot be completely excluded.

A contrasting condition characterised by dilated trachea and large bronchi was first described by Mounier-Kuhn in 1932 [118]. This idiopathic tracheobronchomegaly is associated with varying degrees of bronchiectasis varies in age and severity at presentation but usually presents in mid-adulthood. Males are more frequently affected than females, and a racial predominance has been proposed [119]. The trachea may have a ridged appearance with multiple diverticula. Dynamic collapse of the enlarged airways in expiration, particularly posteriorly, is also likely [120] and pooling of secretions may predispose to lower respiratory tract infections [118]. The aetiology of Mounier-Kuhn syndrome remains uncertain, although histological data suggest that tracheal and bronchial dilatation occur as a consequence of abnormal development of airway connective tissue, with a deficiency of elastic and muscular fibres [121]. Tracheobronchomegaly occurs in association with other congenital connective tissue disorders, including Ehlers Danlos syndrome [122] and cutis laxa [123]. Together with reports of the disorder occurring in siblings [119] this makes an unidentified genetic cause possible, at least in some cases. Generally, there is no curative treatment for the syndrome, although the use of tracheobronchial prostheses may improve symptoms in adults [124].