Primary Ciliary Dyskinesia Due to Microtubular Defects is Associated with Worse Lung Clearance Index.

PURPOSE: Primary ciliary dyskinesia (PCD) is characterised by repeated upper and lower respiratory tract infections, neutrophilic airway inflammation and obstructive airway disease. Different ultrastructural ciliary defects may affect lung function decline to different degrees. Lung clearance index (LCI) is a marker of ventilation inhomogeneity that is raised in some but not all patients with PCD. We hypothesised that PCD patients with microtubular defects would have worse (higher) LCI than other PCD patients. METHODS: Spirometry and LCI were measured in 69 stable patients with PCD. Age at testing, age at diagnosis, ethnicity, ciliary ultrastructure, genetic screening result and any growth of Pseudomonas aeruginosa was recorded. RESULTS: Lung clearance index was more abnormal in PCD patients with microtubular defects (median 10.24) than those with dynein arm defects (median 8.3, p = 0.004) or normal ultrastructure (median 7.63, p = 0.0004). Age is correlated with LCI, with older patients having worse LCI values (p = 0.03, r = 0.3). CONCLUSION: This study shows that cilia microtubular defects are associated with worse LCI in PCD than dynein arm defects or normal ultrastructure. The patient's age at testing is also associated with a higher LCI. Patients at greater risk of obstructive lung disease should be considered for more aggressive management. Differences between patient groups may potentially open avenues for novel treatments.

Lung Clearance Index (LCI) is Stable in Most Primary Ciliary Dyskinesia (PCD) Patients Managed in a Specialist Centre: a Pilot Study.

Primary ciliary dyskinesia is a condition in which abnormal cilia structure or function leads to reduced mucociliary clearance and obstructive lung disease. Twenty-nine patients had lung clearance index (LCI) measured in 2009 and we attempted to perform a 5-year follow-up. Only 12 patients could be re-recruited, but in this small group LCI was stable over the 5 years, which confirms previous data showing that spirometry is also stable in these patients over the medium term. The two patients with the highest LCI in 2009 had since died, despite one having relatively preserved spirometry at the time. These data may be used to inform sample size calculations of future studies.

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia

Impaired innate interferon induction in severe therapy resistant atopic asthmatic children.

Deficient type I interferon-ß and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-ß and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.

Twenty-year review of quantitative transmission electron microscopy for the diagnosis of primary ciliary dyskinesia.

BACKGROUND: The examination of ciliary ultrastructure in a nasal sample remains a definitive diagnostic test for primary ciliary dyskinesia (PCD). METHODS: The quantitative assessment of ciliary ultrastructure in the diagnosis of PCD over a 20-year period was reviewed. RESULTS: During this period, 1182 patients were referred for ciliary ultrastructural analysis, 242 (20%) of whom were confirmed as having the disease. The two main causes of PCD identified were a lack of outer dynein arms (43%) and a lack of both inner and outer dynein arms (24%). Other causes included transposition, radial spoke and inner dynein arm defects. No specific ultrastructural defects were detected in 33 patients (3%) diagnosed as having PCD on the basis of their clinical features and screening tests that included a low nasal nitric oxide concentration or slow saccharine clearance and abnormal ciliary beat frequency or pattern. CONCLUSIONS: Electron microscopy analysis can confirm but does not always exclude a diagnosis of PCD.

Elevated peripheral airway nitric oxide in bronchiectasis reflects disease severity.

BACKGROUND: Bronchiectasis is characterised by neutrophilic bronchial inflammation and patients are prone to recurrent or chronic bacterial airway infections. Direct measurement of lung inflammation would be useful in order to assess disease activity and guide need for antibiotic treatment and to monitor response. Current methods of monitoring inflammation are invasive, indirect or insensitive. Exhaled nitric oxide (FE(NO)) is a direct simple non-invasive test of inflammation used in other airway diseases. The aim of this study was to test whether peripheral airway nitric oxide (C(alv)) can provide a clinically useful direct measure of inflammation in the lungs of patients with bronchiectasis. METHODS: Fifty three patients with bronchiectasis were studied when clinically stable and a further 20 patients during an exacerbation of bronchiectasis. FE(NO) was measured by chemiluminescence using a NO analyser. Two models of pulmonary exchange dynamics were used to calculate proximal and peripheral contributions to final FE(NO) concentration. RESULTS: FE(NO) was elevated in bronchiectasis patients compared to 30 healthy controls (p < 0.05). Compartmental modelling reveals that this elevation is due to an increase in peripheral airway NO (bronchiectasis 3.6 ppb (2.1), controls 2.7 ppb (1.5) p < 0.05) whereas proximal airway NO levels are normal (bronchiectasis 777(751) pl/s, controls 582(579) pl/s ns). C(alv) relates to disease severity measured by lung function and HRCT scan and correlates with the quality of life score. There is no change in FE(NO) parameters at exacerbation and following treatment. CONCLUSIONS: Peripheral airway NO is elevated and reflects disease severity in bronchiectasis but does not provide information to inform acute treatment decisions.

Bronchial and peripheral airway nitric oxide in primary ciliary dyskinesia and bronchiectasis.

Primary ciliary dyskinesia (PCD) is a genetic condition resulting in bronchiectasis. Exhaled gas nitric oxide (FE(NO)) is reduced in PCD. A model of pulmonary NO exchange dynamics can be used to demonstrate relative contributions of bronchial (J'aw(NO)) and peripheral airway (Calv(NO)) NO to the final FE(NO) concentration. The aim of this study was to compare bronchial and peripheral airway contribution to FE(NO) in patients with PCD, non-PCD bronchiectasis and healthy controls in order to establish the source of present FE(NO) in these conditions and to compare these with severity of disease. NO was measured at 50, 100, and 200 ml/s using an NO analyser (NiOx Sweden). J'aw(NO) and Calv(NO) were calculated according to a model of pulmonary exchange dynamics. PCD patients had reduced levels of J'aw(NO) compared to healthy controls whereas patients with non-PCD bronchiectasis had elevated J'aw(NO) levels. There was no difference in Calv(NO) between the three groups. In the disease groups Calv(NO) correlated negatively with FEV(1). In conclusion patients with PCD had significantly reduced FE(NO) at all expiratory flow rates. This was due to a significantly low bronchial NO. In contrast, peripheral airway NO was increased with more severe disease.

Procalcitonin in stable and unstable patients with bronchiectasis.

Presently used markers of infection in bronchiectasis are inadequate to judge stability or make decisions about antibiotic treatment during bacterial exacerbations. Procalcitonin (PCT) is a new marker that has been used in community-acquired pneumonia and promises to allow much more specific and sensitive monitoring of patients with bacterial infections. This is the first study assessing its use in bronchiectasis. Thirty-eight consecutive inpatients and 63 consecutive outpatients were included in the study. All patients had PCT, other inflammatory markers, and a symptom score recorded. Inpatients had these values repeated at day 5 and 10 of their stay, while receiving intravenous antibiotics. Outpatients: PCT levels were generally low in the outpatient group. PCT was significantly correlated to C-reactive protein. Higher levels were associated with increased symptoms (P = 0.09) and an increased likelihood of antibiotic prescription (P = 0.007). Inpatients: As a group, inflammatory markers were significantly higher than in the outpatient group (P = 0.007). There was no correlation between the levels of PCT and the other inflammatory markers. PCT concentrations were generally low (as with other markers), which may reflect mucosal infection. Larger studies are needed, but PCT seems unlikely to be able to guide treatment of an exacerbation in bronchiectasis. PCT may offer more promise as a measure of stability.

Pseudomonas aeruginosa, cyanide accumulation and lung function in CF and non-CF bronchiectasis patients.

In patients with cystic fibrosis (CF) and non-CF bronchiectasis, Pseudomonas aeruginosa is the most important respiratory pathogen. It is able to synthesise hydrogen cyanide, a potent inhibitor of cellular respiration. The present study investigated whether cyanide is present in the sputum of CF and non-CF bronchiectasis patients infected with P. aeruginosa, and whether the detection of cyanide affected lung function. Cyanide was measured in sputum using a cyanide ion selective electrode. Cyanide was detected in sputum from 15 out of 25 CF and non-CF bronchiectasis patients with current P. aeruginosa infection; however, it was not detected in any of the 10 patients without this organism. Maximum levels were 130 microM (mean+/-SE 72+/-6.6 microM). Concurrent lung function data were available on all 21 P. aeruginosa-infected CF patients; the group with measurable sputum cyanide (n = 11) was not different from those without (n = 10) on the basis of age or sex. However, those with detectable cyanide had significantly poorer lung function than those without (forced expiratory volume in one second (% predicted) 26.8+/-3.8 versus 46.0+/-6.7%; forced vital capacity (% pred) 44.4+/-4.9 versus 60.1+/-7.7%). Cyanide is detectable in sputum from cystic fibrosis and non-cystic fibrosis bronchiectasis patients infected with Pseudomonas aeruginosa, and is also associated with impaired lung function.

Aetiology in adult patients with bronchiectasis.

BACKGROUND: Bronchiectasis has a number of causes. Their prevalence is not well documented. The aim of this study was to identify aetiology in a population of patients referred to a specialist clinic with symptoms suggestive of bronchiectasis, to determine the proportion of patients in whom knowing the aetiology altered management. In addition we wished to describe in detail those patients who remained idiopathic to facilitate future studies of this group; and establish the diagnosis in those without bronchiectasis. METHODS: A total of 240 consecutive patients referred to the Royal Brompton Hospital with a history of recurrent chest infections, chronic cough and regular sputum production underwent a 3 day program of investigation. RESULTS: A total of 165 patients had bronchiectasis on CT scan, an underlying cause was identified in 122 (74%) and this affected management in 61 (37%). The common aetiologies were: post-infection (52), primary ciliary dyskinesia (17), allergic bronchopulmonary aspergillosis (13), and immune deficiency (11). Fourty-three patients had idiopathic bronchiectasis. They had symmetrical predominant lower lobe disease with onset of chronic chest and sinus symptoms in middle age. CONCLUSION: Full investigation of problematic cases should occur in a specialist centre because results affect management in a third of cases.