Maria Di Cicco

Evaluation of pulmonary disease using static lung volumes in primary ciliary dyskinesia

Background In primary ciliary dyskinesia (PCD) lung damage is usually evaluated by high-resolution CT (HRCT). Objective To evaluate whether HRCT abnormalities and Pseudomonas aeruginosa infection were better predicted by spirometry or plethysmography. Methods A cross-sectional study performed in consecutive patients with PCD who underwent sputum culture, spirometry, plethysmography and HRCT within 48 h. Principal component analysis and soft computing were used for data evaluation. Results Fifty patients (26 children) were studied. P aeruginosa infection was found in 40% of the patients and bronchiectasis in 88%. There was a correlation between infection with P aeruginosa and extent of bronchiectasis (p=0.009; r =0.367) and air-trapping (p=0.03; r =0.315). Moreover, there was an association between infection with P aeruginosa and residual volume (RV) values >150% (p=0.04) and RV/total lung capacity (TLC) ratio >140% (p=0.001), but not between infection with P aeruginosa and forced expiratory volume in 1 s (FEV1)<80%, or forced expiratory flow between 25% and 75% of forced vital capacity (FVC) (FEF25–75%)<70% or FEV1/FVC<70% (<80% in children). Severity of the total lung impairment on chest HRCT directly correlated with RV when expressed as per cent predicted (p=0.003; r =0.423), and RV/TLC (p<0.001; r =0.513) or when expressed as z scores (p=0.002, r =0.451 and p<0.001, r =0.536 respectively). Principal component analysis on plethysmographic but not on spirometry data allowed recognition of different severities of focal air trapping, atelectasis and extent of bronchiectasis. Conclusions Plethysmography better predicts HRCT abnormalities than spirometry. Whether it might be a useful test to define populations of patients with PCD who should or should not have HRCT scans requires further longitudinal studies.

Rapid diagnosis of primary ciliary dyskinesia: cell culture and soft computing analysis

Diagnosis of primary ciliary dyskinesia (PCD) sometimes requires repeated nasal brushing to exclude secondary ciliary alterations. Our aim was to evaluate whether the use of a new method of nasal epithelial cell culture can speed PCD diagnosis in doubtful cases and to identify which are the most informative parameters by means of a multilayer artificial neural network (ANN). A cross-sectional study was performed in patients with suspected PCD. All patients underwent nasal brushing for ciliary motion analysis, ultrastructural assessment and evaluation of ciliary function after ciliogenesis in culture by ANN. 151 subjects were studied. A diagnostic suspension cell culture was obtained in 117 nasal brushings. A diagnosis of PCD was made in 36 subjects (29 of whom were children). In nine out of the 36 patients the diagnosis was made only after a second brushing, because of equivocal results of both tests at first examination. In each of these subjects diagnosis of PCD was confirmed by cell culture results. Cell culture in suspension evaluated by means of ANN allows the separation of PCD from secondary ciliary dyskinesia patients after only 5 days of culture and allows diagnosis to be reached in doubtful cases, thus avoiding the necessity of a second sample.

Gene editing of DNAH11 restores normal cilia motility in primary ciliary dyskinesia

Background Primary ciliary dyskinesia (PCD) is a rare autosomal recessive genetic disorder characterised by dysfunction of motile cilia. Ciliary dysmotility causes poor mucociliary clearance and leads to impairment of pulmonary function and severe respiratory infections. PCD has no specific therapy. With the aim to permanently restore gene function and normalise ciliary motility, we used gene editing to replace mutated with wild-type sequence in defective cells. Methods The target gene was dynein heavy chain 11 (DNAH11), an essential component of ciliary structure. Airway ciliated cells were collected from two patients with PCD with DNAH11 nonsense mutations and altered ciliary beating and pattern. Repair of the genetic defect was performed ex vivo by site-specific recombination using transcription activator-like effector nucleases (TALENs). Results In an epithelial cell line engineered to contain the DNAH11 target site, TALENs cleaved over 80% of the mutated DNAH11 sequence and replaced the mutated sequence with wild-type sequence in about 50% of cells. In airway ciliated cells of patients with PCD, site-specific recombination and normalisation of ciliary beating and pattern occurred in 33% and 29% of cells, respectively. Conclusion This study demonstrates that gene editing can rescue ciliary beating ex vivo, opening up new avenues for treating PCD.

Uncommon Pulmonary Presentation of IgG4-Related Disease in a 15-Year-Old Boy

IgG4-related disease was first described in adults with autoimmune pancreatitis but is now known to affect multiple organs. Lung involvement has never been described in children to our knowledge. Here, we report an adolescent presenting with recurrent dry cough and hemoptysis who was found to have venous ectasia in the left upper lobe, and diffuse bronchiectasis. Sustained high levels of IgG4 (1,090 mg/dL) were found, and the endobronchial biopsy revealed a marked infiltration of plasma cells producing IgG4 (ratio of IgG4 plasma cells to IgG plasma cells >50%). This unique case highlights the occurrence of IgG4-related disease in a child and underscores the importance of careful scrutiny of all investigations in complex pediatric respiratory cases.

Monitoring Asthma Control in Children With Allergies by Soft Computing of Lung Function and Exhaled Nitric Oxide

BACKGROUND Asthma control is emphasized by new guidelines but remains poor in many children. Evaluation of control relies on subjective patient recall and may be overestimated by health-care professionals. This study assessed the value of spirometry and fractional exhaled nitric oxide (FeNO) measurements, used alone or in combination, in models developed by a machine learning approach in the objective classification of asthma control according to Global Initiative for Asthma guidelines and tested the model in a second group of children with asthma. METHODS Fifty-three children with persistent atopic asthma underwent two to six evaluations of asthma control, including spirometry and FeNO. Soft computing evaluation was performed by means of artificial neural networks and principal component analysis. The model was then tested in a cross-sectional study in an additional 77 children with allergic asthma. RESULTS The machine learning method was not able to distinguish different levels of control using either spirometry or FeNO values alone. However, their use in combination modeled by soft computing was able to discriminate levels of asthma control. In particular, the model is able to recognize all children with uncontrolled asthma and correctly identify 99.0% of children with totally controlled asthma. In the cross-sectional study, the model prospectively identified correctly all the uncontrolled children and 79.6% of the controlled children. CONCLUSIONS Soft computing analysis of spirometry and FeNO allows objective categorization of asthma control status.

Mannose-binding lectin 2 gene polymorphism and lung damage in primary ciliary dyskinesia.

Mannose‐binding lectin (MBL) plays an important role in innate immunity and has been reported to be associated with the age‐related decline in lung function in cystic fibrosis.

Up to date on primary ciliary dyskinesia in children.

Primary ciliary dyskinesia (PCD) is a congenital, clinically and ultrastructurally heterogeneous disease due to abnormal structure and/or function of cilia, with impaired mucociliary transport leading to several respiratory disorders. PCD can be diagnosed by the combination of thorough clinical examination with functional and ultrastructural analysis of the cilia. This paper shows progresses in PCD diagnosis obtained by ciliogenesis in culture evaluation of ciliated respiratory cells and by genetic analysis of mutations in candidate genes. Moreover, since to date no specific treatments are available to correct the ciliary dysfunction, the paper shows the proper therapeutical approach by the use of respiratory physiotherapy and regular exercise to favour airways clearance, by antibiotics administration to control acute airway infections. Macrolides administration as antiinflammatory option is suggested.

Is the sensitivity of primary ciliary dyskinesia detection by ciliary function analysis 100

From the authors : We wish to thank M. Boon and co-workers for their careful reading of our manuscript and to apologise to them and the readers for our mistake in the preparation of table 2 of our original article [ …

Olfactory dysfunction is worse in primary ciliary dyskinesia compared with other causes of chronic sinusitis in children

Cilia have multiple functions including olfaction. We hypothesised that olfactory function could be impaired in primary ciliary dyskinesia (PCD). Olfaction, nasal nitric oxide (nNO) and sinus CT were assessed in patients with PCD and non-PCD sinus disease, and healthy controls (no CT scan). PCD and non-PCD patients had similar severity of sinus disease. Despite this, defective olfaction was more common in patients with PCD (P<0.0001) and more severe in patients with PCD with major Transmission Electron Microscopy (TEM) abnormalities. Only in classical PCD did olfaction inversely correlate with sinusitis and nNO. We speculate that defective olfaction in PCD is primary in nature.

How Much Asthma Is Atopic in Children

Asthma is the most common chronic childhood disease worldwide and poses a significant health and socioeconomic burden. The prevalence of this disease differs geographically and seems on the rise in many parts of the world. (1). Cross-sectional and longitudinal studies have identified several indicators associated with high risk of asthma (2). Personal history of atopy in early life seems to be one of the key factors of an individual’s risk of persistent asthma. Indeed, numerous studies have demonstrated that early and multiple allergic sensitization (AS) specific to aeroallergens and some food antigens places a strong risk for the development of asthma in children (2–6). Atopic asthma represents the most common form of asthma in the pediatric age and is characterized by eosinophilic airway inflammation associated with specific immunoglobulin E (IgE) antibodies sensitization to various allergens, as evidenced by serology or skin prick test (7). According to a large population survey, including data from people aged 6–59 years (the Third National Health and Nutrition Examination Survey), 56.3% of asthma cases in the United States were attributable to atopy (8). Similarly, the 14-year follow-up analysis of an Australian community-based birth cohort showed that the proportion of asthma associated with atopy was 52% overall (9). The results of a recent cohort study, which followed a large group of newborns over various periods, indicated that the prevalence of asthma from 4 to 16 years is markedly higher among ever-allergic sensitized children compared to never-sensitized ones (10). At a population level, a recently published longitudinal study that prospectively collected data over the first four decades of life showed that the occurrence of asthma before the age of 13 years was more strongly associated with atopy and greater airflow obstruction than later onset asthma (11). Nevertheless, there is still controversy about the causal relationship between atopy and asthma, as other non-allergenic factors may trigger the specific IgE pathway and influence the occurrence of this disease (12). Over the last 20 years, accumulating evidence has shown that the interrelation between AS and subsequent development of asthma is more complex than a linear dose–response relationship, with gene–environment interactions and epigenetic modifications playing crucial pathophysiological roles (13). One impediment to understand the relationship between atopy and asthma is the common use of atopy as a binary variable (i.e., sensitized or non-sensitized). Another major impediment is that asthma is a heterogeneous condition, which comprises several different disease endotypes sharing similar symptoms. Recent data indicate that atopy may also encompass distinct endotypes characterized by different patterns of association with asthma (13). This opinion article outlines the most recent and debated findings about the interrelation between atopy and pediatric asthma.