Imágenes diagnósticas en el estudio del compromiso pulmonar de la discinesia ciliar primaria en niños / Chest imaging in study of primary ciliary dyskinesia in children

The diagnosis of primary ciliary dyskinesia (PCD) is complex and requires high clinical suspicion. The findings in the diagnostic images are nonspecific and can be seen in other conditions of the airway. In this review, we will describe the findings of PCD in chest radiography and computed tomography, with emphasis on some of the characteristics that differentiate it from cystic fibrosis and we will review the role of CT in the monitoring of changes of the PCD, since the CT findings correlate very well with the structural changes that occur in the course of PCD, especially bronchiectasis. However, using serial CTs should be decided on a case-by-case basis to avoid unnecessary radiation because they are pediatric patients.

El diagnóstico de la Discinesia ciliar primaria (DCP) es complejo y requiere alta sospecha clínica. Los hallazgos en la imágenes diagnósticas son inespecíficos y se pueden ver en otras afecciones de la vía aérea. En esta revisión describiremos los hallazgos de la DCP en Radiología simple y en Tomografía computada (TC), con énfasis en algunas de las características que permiten diferenciarla de la Fibrosis quística (FQ) y revisaremos el rol de la TC en la monitorización de la DCP ya que los hallazgos en la TC se correlacionan muy bien con los cambios estructurales que ocurren en el curso de la DCP, en especial las bronquiectasias. Sin embargo usar TC seriadas se debe decidir caso por caso para evitar la radiación innecesaria por ser pacientes pediátricos.

Clinical impact of Pseudomonas aeruginosa colonization in patients with Primary Ciliary Dyskinesia.

BACKGROUND: Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD. METHODS: Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized. These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters. RESULTS: Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV1) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results. CONCLUSIONS: Lung PA colonization in PCD is associated with more severe disease as shown by the FEV1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients.

Sinus bacteriology in patients with cystic fibrosis or primary ciliary dyskinesia: A systematic review.

BACKGROUND: A correlation exists between the microbial flora of the upper and lower airways in patients with cystic fibrosis (CF) or with primary ciliary dyskinesia (PCD). The sinuses can function as a bacterial reservoir where gram-negative bacteria adapt to the airways and repeatedly are aspirated to and colonize the lungs according to the theory of the united (unified) airways. Whereas the pattern of bacterial flora in the lower airways has been extensively studied, the upper airways have drawn limited attention. OBJECTIVE: Our aim was to review the literature that reported bacterial flora in the sinuses and nasal cavities of patients with CF or PCD. METHODS: A number of medical literature data bases were systematically searched between January 1960 and July 2016. We applied the following inclusion criteria: a minimum of one case of PCD (or Kartagener syndrome) or CF, and microbiology analyses from the nose or paranasal sinuses. RESULTS: We included 46 studies (1823 patients) from 16 countries. Staphylococcus aureus was found in 30% of the noses and sinuses of patients with CF. Other common bacteria found included Pseudomonas aeruginosa, coagulase negative staphylococci, and Haemophilus influenzae. In PCD, H. influenzae was the most common bacteria (28%), followed by Streptococcus pneumoniae and P. aeruginosa. If studies that included nonsurgical swab and blowing samples were excluded, then P. aeruginosa was the most common bacterium in patients with CF (34%) and in patients with PCD (50%), followed by S. aureus and H. influenza. CONCLUSION: S. aureus, P. aeruginosa, coagulase negative staphylococci, and H. influenzae dominated in the upper airways of patients with CF. In patients with PCD, H. influenzae, S. pneumoniae, and P. aeruginosa dominated. When studies that included swab and blowing samples were excluded, P. aeruginosa was the most common bacterium in both groups. Direct comparisons among the studies were restricted due to very heterogeneous methods, and a better standardization of procedures and outcomes is needed.

Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenzae biofilm formation.

Non-typeable Haemophilus influenzae (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesised that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonisation and biofilm development.We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using an air-liquid interface culture and then co-cultured with NTHi.NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells (p<0.05) and the distribution of NTHi on PCD epithelium showed more aggregated NTHi in biofilms (p<0.001). Apart from defective ciliary motility, PCD cells did not significantly differ from non-PCD epithelial cells in the degree of ciliation and epithelial integrity or in cytokine, LL-37 and NO production. Treatment of PCD epithelia using exogenous NO and antibiotic significantly reduced NTHi viability in biofilms compared with antibiotic treatment alone.Impaired ciliary function was the primary defect in PCD airway epithelium underlying susceptibility to NTHi biofilm development compared with non-PCD epithelium. Although NO responses were similar, use of targeted NO with antibiotics enhanced killing of NTHi in biofilms, suggesting a novel therapeutic approach.

Matrix metalloproteinases and airway remodeling and function in primary ciliary dyskinesia.

BACKGROUND: The balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is important in the regulation of airway damage. OBJECTIVE: To evaluate whether they are important in the pathophysiology of primary and secondary ciliary dyskinesia (PCD, SCD). METHODS: We measured sputum bacteriology, lung CT changes, MMPs, TIMPs and lung function in 86 patients (51 PCD, 35 SCD) in a cross-sectional study; the 10 controls studied did not have HRCT or sputum cultures. MMPs, TIMPs and lung function were evaluated longitudinally for up to one year in 38 PCD patients. RESULTS: At baseline, there were no differences in MMPs, TIMPs and MMPs/TIMPs, between PCD and SCD but lower levels were found in controls. There was an association between poorer lung function with increasing levels of MMPs in PCD, while in SCD only MMP-9/TIMP-1 values correlated with FRC z-scores. Levels of MMPs and TIMPs significantly correlated with severity HRCT changes. Longitudinally, there were significant correlations between slope of changes in spirometric parameters and slope of change in sputum MMPs in PCD patients. CONCLUSIONS: In conclusion, we report for the first time that increased MMPs are associated with worse airway damage in PCD and SCD, and thus are potential therapeutic targets.

Sinus surgery can improve quality of life, lung infections, and lung function in patients with primary ciliary dyskinesia.

BACKGROUND: Chronic rhinosinusitis (CRS) and bacterial sinusitis are ubiquitous in patients with primary ciliary dyskinesia (PCD). From the sinuses, Pseudomonas aeruginosa can infect the lungs. METHODS: We studied the effect of endoscopic sinus surgery (ESS) on symptoms of CRS and lower airway infections in PCD patients in a prospective single-arm intervention study of ESS with adjuvant therapy using nasal irrigation with saline, topical nasal steroids, and 2 weeks of systemic antibiotics. Additional treatment with local colistin for 6 months was instigated when P. aeruginosa was cultured at ESS. RESULTS: Twenty-four PCD patients underwent ESS to search for an infectious focus (n = 10), due to severe symptoms of CRS (n = 8), or both (n = 6). Bacteria were cultured from sinus samples in 21 patients (88%), and simultaneous sinus and lung colonization with identical pathogens were observed in 13 patients (62%). Four patients with preoperative P. aeruginosa lung colonization (25%) had no regrowth during follow-up; 2 of these had P. aeruginosa sinusitis. Sinonasal symptoms were improved 12 months after ESS and we observed a trend toward better lung function after ESS. CONCLUSION: We demonstrated an improvement in CRS-related symptoms after ESS and adjuvant therapy. In selected PCD patients, the suggested regimen may postpone chronic lung infection with P. aeruginosa and stabilize lung function.

A novel method for investigating Burkholderia cenocepacia infections in patients with cystic fibrosis and other chronic diseases of the airways.

BACKGROUND: Burkholderia cenocepacia is a Gram-negative, opportunistic pathogen that is a cause of morbidity and mortality in patients with cystic fibrosis (CF). Research efforts over the past few decades contributed to our understanding of these infections by identifying virulence factors. However, little is known about how this pathogen adapts to the harsh environment found inside the CF airways, which is characterized by a unique mucus containing high concentrations of inflammatory markers. The current study developed a novel model to further investigate this phenomenon. RESULTS: Monolayers of human A549 lung carcinoma cells (HLCCs) were exposed to a mixture of artificial CF sputum medium (ASMDM) in tissue culture growth medium, and subsequently infected with B. cenocepacia K56-2 for 24 h. The data showed that this model supported B. cenocepacia growth. In addition, consistent with similar studies using current models such as CF airway tissue samples, HLCC viability was reduced by more than 70 % when grown in 60 % ASMDM and infected with B. cenocepacia compared to mock-infected controls and medium alone. Furthermore, the amount of B. cenocepacia cells associated with the HLCC monolayer was more than 10 times greater in 60 % ASMDM when compared to medium controls. CONCLUSIONS: These findings suggest that HLCC monolayers in 60 % ASMDM serve as a valid alternative to study B. cenocepacia infections in patients with CF, and possibly other chronic diseases of the airways. Furthermore, the results obtained in this study suggest an important role for CF sputum in B. cenocepacia pathogenesis.

Bacterial evolution in PCD and CF patients follows the same mutational steps.

Infections with Pseudomonas aeruginosa increase morbidity in primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) patients. Both diseases are associated with a defect of the mucociliary clearance; in PCD caused by non-functional cilia, in CF by changed mucus. Whole genome sequencing of P. aeruginosa isolates from CF patients has shown that persistence of clonal lineages in the airways is facilitated by genetic adaptation. It is unknown whether this also applies to P. aeruginosa airway infections in PCD. We compared within-host evolution of P. aeruginosa in PCD and CF patients. P. aeruginosa isolates from 12 PCD patients were whole genome sequenced and phenotypically characterised. Ten out of 12 PCD patients were infected with persisting clone types. We identified convergent evolution in eight genes, which are also important for persistent infections in CF airways: genes related to antibiotic resistance, quorum sensing, motility, type III secretion and mucoidity. We document phenotypic and genotypic parallelism in the evolution of P. aeruginosa across infected patients with different genetic disorders. The parallel changes and convergent adaptation and evolution may be caused by similar selective forces such as the intensive antibiotic treatment and the inflammatory response, which drive the evolutionary processes.

Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia.

Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation.We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment.In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (p<0.05), but absolute neutrophil counts were higher in PCD patients (p=0.02). While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD (p<0.05) but not CF patients.PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment.

A longitudinal study of lung bacterial pathogens in patients with primary ciliary dyskinesia.

In patients with primary ciliary dyskinesia (PCD), impaired mucociliary clearance leads to an accumulation of secretions in the airways and susceptibility to repeated bacterial infections. The primary aim of this study was to investigate the bacterial flora in non-chronic and chronic infections in the lower airways of patients with PCD. We retrospectively reviewed the presence of bacteria from patients with PCD during an 11-year period and genotyped 35 Pseudomonas aeruginosa isolates from 12 patients with chronic infection using pulsed-field gel electrophoresis. We identified 5450 evaluable cultures from 107 patients with PCD (median age 17 years, range 0-74 years) (median age at diagnosis 7.8 years, range 0-63 years). Haemophilus influenzae was the most frequent microorganism. Other common pathogens were P. aeruginosa, Streptococcus pneumoniae, Moraxella catarrhalis and Staphylococcus aureus. The number of patients colonized with P. aeruginosa at least once varied from 11 to 44 patients (15-47%) annually, and 42 patients (39%) met the criteria for chronic infection at least once. Pseudomonas aeruginosa was more frequently isolated in teenagers and adults than children (p 0.02) and the prevalence was significantly lower in patients with preschool (<6 years) PCD diagnosis (p 0.04). Ten out of 12 patients (83%) were chronically infected with a unique clone-type of P. aeruginosa. No sharing of clone-types or patient-to-patient transmission was observed. In conclusion, PCD patients were infected by a unique set of bacteria acquired in an age-dependent sequence. Pseudomonas aeruginosa frequently colonizes the lower respiratory tract and the incidence of chronic infection was higher than previously reported.

Simultaneous sinus and lung infections in patients with primary ciliary dyskinesia.

CONCLUSION: The sinuses should be considered as a bacterial reservoir and a target for surgery and antibiotic treatment in patients with primary ciliary dyskinesia (PCD). The observed decrease in serum precipitating antibodies (precipitins) against Pseudomonas aeruginosa may indicate a beneficial effect of combined endoscopic sinus surgery (ESS) and concomitant medical treatment. OBJECTIVES: The purpose of this research, which is the first study addressing bacteriology in the sinuses of patients with PCD, was to examine the association between sinus and lung infections. METHODS: We reviewed findings of bacterial pathogens from the sinuses obtained during ESS and the lung infection status in eight PCD patients over a 6 year period. Precipitins against P. aeruginosa were used as a marker of severity of chronic infection and effect of treatment. RESULTS: Preoperatively, seven of the eight patients (88%) exhibited intermittent or chronic pulmonary infection with P. aeruginosa. Sinus cultures were obtained during ESS in seven patients. The sinuses were colonized with P. aeruginosa in four of seven patients (57%). Bacterial sinusitis was found in five of seven patients (71%) and the same bacterium was found in the sinuses and lungs in all cases. Decreasing precipitins against P. aeruginosa were observed postoperatively in three of four evaluable patients.

Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia.

BACKGROUND: Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis. METHODS: Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves. RESULTS: CF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%). CONCLUSION: Exhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile.

Clinical significance of respiratory isolates for Mycobacterium abscessus complex from pediatric patients.

Mycobacterium abscessus complex is the most virulent of rapidly growing mycobacteria causing invasive lung disease. To better delineate clinical pediatric experience and outcomes with M. abscessus complex, we retrospectively gathered 5-year data on M. abscessus complex infection and outcomes in a large, hospital-based pediatric pulmonary center. Patients were selected from the database of the microbiology department at Miller Children's Hospital in Long Beach, CA. Patients had at least one positive pulmonary isolate for M. abscessus complex from February 2006 to May 2011. Treatment modality data were collected and successful therapy of disease was determined as clearance of M. abscessus complex infection after antibiotics proven by culture negative respiratory isolate within at least 12 months of therapy initiation. Two cystic fibrosis patients with M. abscessus complex were identified, one with failed therapy and the other with stable pulmonary status despite persistent isolation. One primary ciliary dyskinesia patient had successful clearance of M. abscessus complex, however is now growing M. avium intracellulare. A patient with no prior medical history was successfully treated with antimycobacterial therapy. Eleven patients with neuromuscular disorders had tracheal aspirates positive for M. abscessus complex. None were treated due to stable lung status and all but two had spontaneous clearance of the mycobacteria. The two remaining persist with sporadic isolation of M. abscessus complex without clinical significance. We concluded that patients with tracheostomy associated M. abscessus complex infections do not appear to require treatment and often have spontaneous resolution. Cystic fibrosis or primary ciliary dyskinesia patients may have clinical disease warranting treatment, but current antimycobacterial therapy has not proven to be completely successful. As M. abscessus complex gains prevalence, standardized guidelines for diagnosis and therapy are needed in the pediatric population. Multicenter cohort analysis is necessary to achieve such guidelines.

Innate immune functions of the airway epithelium.

The epithelium of the respiratory tract forms a large surface area that maintains intimate contact with the environment. Through the act of breathing, this mucosal surface encounters an array of pathogens and toxic particulates. In response to these challenges many strategies have evolved to protect the host. These include the barrier functions of the epithelium, cough, mucociliary clearance, resident professional phagocytes, and the secretion of a number of proteins and peptides with host defense functions. Thus, the surface and submucosal gland epithelium of the conducting airways is a constitutive primary participant in innate immunity. In addition, this tissue may serve the function of a secondary amplifier of innate immune responses following neurohumoral input, stimulation with cytokines from cells such as alveolar macrophages, or engagement of pattern recognition receptors. Here, we provide an overview of the airway epithelium's role in pulmonary innate immunity, especially in the context of bacterial and viral infections, emphasizing findings from human cells and selected animal models. We also provide examples of human disease states caused by impaired epithelial defenses in the lung.

Calcium stone lithoptysis in primary ciliary dyskinesia.

BACKGROUND: An association between lithoptysis and primary ciliary dyskinesia (PCD) has not been previously reported. However, reports of lithoptysis from 2 older patients (>60 yr) prompted a study of this association. METHODS: We performed a prospective study of all PCD patients presenting to our institution between August 2003 and March 2006, seeking the symptom of lithoptysis or calcium deposition on radiology. A retrospective analysis of all PCD patients presenting prior to August 2003 was also performed. Patients age > or = 40 previously reviewed were recontacted. If a history of lithoptysis or calcium deposition was present, we further reviewed radiographic, microbiologic, and biochemical data, including serum calcium and phosphate. Broncholiths were analyzed by light and electron microscopy- and electron-dispersive X-ray analysis. RESULTS: In total, 142 patients (n=28 age > or = 40) were included, 41 in the prospective and 91 in the retrospective study. Lithoptysis was reported in 5 patients (all age > or = 40). Chest CT scans identified calcification (4/5), involving bronchiectatic airways in 3 patients and focal nodular calcification in 1 patient. Two other patients (age 46, 59) were identified with airway calcification without lithoptysis. Available broncholiths from 2 of these patients were composed of calcite, whereas a broncholith from 1 patient with focal nodular calcification contained calcium phosphate. Sputum was positive for Pseudomonas aeruginosa in all 7 patients, but negative for mycobacterial and fungal cultures. CONCLUSION: There is an association between lithoptysis and PCD in patients age > or = 40. We hypothesize that calcite stone formation is a biomineralization response to chronic airway inflammation and retention of infected airway secretions in PCD in a subset of PCD patients.