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1.  Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme 
Rationale: Children’s Interstitial and Diffuse Lung Disease (chILD) is a heterogeneous group of disorders that is challenging to categorize. In previous study, a classification scheme was successfully applied to children 0 to 2 years of age who underwent lung biopsies for chILD. This classification scheme has not been evaluated in children 2 to 18 years of age.
Objectives: This multicenter interdisciplinary study sought to describe the spectrum of biopsy-proven chILD in North America and to apply a previously reported classification scheme in children 2 to 18 years of age. Mortality and risk factors for mortality were also assessed.
Methods: Patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease from 12 North American institutions were included. Demographic and clinical data were collected and described. The lung biopsies were reviewed by pediatric lung pathologists with expertise in diffuse lung disease and were classified by the chILD classification scheme. Logistic regression was used to determine risk factors for mortality.
Measurements and Main Results: A total of 191 cases were included in the final analysis. Number of biopsies varied by center (5–49 biopsies; mean, 15.8) and by age (2–18 yr; mean, 10.6 yr). The most common classification category in this cohort was Disorders of the Immunocompromised Host (40.8%), and the least common was Disorders of Infancy (4.7%). Immunocompromised patients suffered the highest mortality (52.8%). Additional associations with mortality included mechanical ventilation, worse clinical status at time of biopsy, tachypnea, hemoptysis, and crackles. Pulmonary hypertension was found to be a risk factor for mortality but only in the immunocompetent patients.
Conclusions: In patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease, there were far fewer diagnoses prevalent in infancy and more overlap with adult diagnoses. Immunocompromised patients with diffuse lung disease who underwent lung biopsies had less than 50% survival at time of last follow-up.
PMCID: PMC4627419  PMID: 26291470
rare pediatric lung disease; interstitial lung disease; pathology
2.  Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review 
Pediatric Pulmonology  2015;51(2):115-132.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, rare lung disease resulting in chronic oto‐sino‐pulmonary disease in both children and adults. Many physicians incorrectly diagnose PCD or eliminate PCD from their differential diagnosis due to inexperience with diagnostic testing methods. Thus far, all therapies used for PCD are unproven through large clinical trials. This review article outlines consensus recommendations from PCD physicians in North America who have been engaged in a PCD centered research consortium for the last 10 years. These recommendations have been adopted by the governing board of the PCD Foundation to provide guidance for PCD clinical centers for diagnostic testing, monitoring, and appropriate short and long‐term therapeutics in PCD patients. Pediatr Pulmonol. 2016;51:115–132. © 2015 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.
PMCID: PMC4912005  PMID: 26418604
primary ciliary dyskinesia; PCD, kartagener; consensus statement; PCD Foundation
3.  A Parent-Child Dyad Approach to the Assessment of Health Status and Health-Related Quality of Life in Children with Asthma 
PharmacoEconomics  2012;30(8):697-712.
Assessment of health state and health-related quality of life (HR-QOL) are limited by a child’s age and cognitive ability. Parent-proxy reports are known to differ from children’s reports. Simultaneous assessment using a parent-child dyad is an alternative approach.
Our objective was to assess the validity, reliability and responsiveness of a parent-child dyad approach to utility and HR-QOL assessment of paediatric asthma health states.
The setting was specialist care in a hospital-based asthma clinic. Participants were 91 girls and boys with asthma aged 8 to 17 years and 91 parents. The intervention employed was parent-child dyad administration of the Health Utilities Index (HUI) 2 and 3, the Pediatric Quality of Life Inventory™ (PedsQL™) Core and Asthma modules, and the Pediatric Asthma Quality of Life Questionnaire (PAQLQ).
Questionnaires were administered by interview to children and parents separately and then together as a dyad to assess the child’s health state. The dyad interview was repeated at the next clinic visit. Dyad-child agreement was measured by intra-class correlation (ICC) coefficient; Spearman correlations were used to assess convergent validity. Test-retest reliability was assessed in 28 children who remained clinically stable between visits with a two-way ICC coefficient. Responsiveness to change from baseline was assessed with Spearman coefficients in 30 children who demonstrated clinical change between visits.
There was no significant agreement between parent and child for the HUI2 or HUI3 whereas agreement between dyad and child was 0.55 (95% confidence interval [CI] 0.36, 0.69) for the HUI2 and 0.74 (95% CI 0.61, 0.82) for the HUI3 overall. With respect to dyad performance characteristics, both HUI2 and HUI3 overall scores demonstrated moderate convergent validity with the generic PedsQL™ Core domains (range r = 0.30–0.52; p < 0.01). Dyad HUI2 attributes demonstrated moderate convergent validity with the generic PedsQL™ Core domains of similar constructs (range r = 0.35–0.43; p < 0.001) and weaker convergent validity with disease-specific domains (range r = 0.13–0.32). Dyad HUI3 attributes demonstrated weaker convergent validity compared with the HUI2. For the assessment of test-retest reliability, significant agreement between baseline and follow-up was observed for dyad HUI2 total (r = 0.53), dyad PedsQL™ Core summary (r = 0.70) and select dyad disease-specific domains. Significant responsiveness (r > 0.4; p < 0.05) was observed for dyad HUI2 total score change over time as correlated with dyad HUI3, dyad PedsQL™ Core summary and select disease-specific domains.
The parent-child dyad approach demonstrated moderate to strong performance characteristics in generic and disease-specific questionnaires suggesting it may be a valuable alternative to relying on parent proxies for assessing children’s utility and HR-QOL. Future research in additional paediatric populations, younger children and a population-based sample would be useful.
PMCID: PMC4931918  PMID: 22788260 CAMSID: cams5783
4.  Diagnosis and management of asthma in preschoolers: A Canadian Thoracic Society and Canadian Paediatric Society position paper 
Paediatrics & Child Health  2015;20(7):353-361.
Asthma often starts before six years of age. However, there remains uncertainty as to when and how a preschool-age child with symptoms suggestive of asthma can be diagnosed with this condition. This delays treatment and contributes to both short- and long-term morbidity. Members of the Canadian Thoracic Society Asthma Clinical Assembly partnered with the Canadian Paediatric Society to develop a joint working group with the mandate to develop a position paper on the diagnosis and management of asthma in preschoolers.
In the absence of lung function tests, the diagnosis of asthma should be considered in children one to five years of age with frequent (≥8 days/month) asthma-like symptoms or recurrent (≥2) exacerbations (episodes with asthma-like signs). The diagnosis requires the objective document of signs or convincing parent-reported symptoms of airflow obstruction (improvement in these signs or symptoms with asthma therapy), and no clinical suspicion of an alternative diagnosis. The characteristic feature of airflow obstruction is wheezing, commonly accompanied by difficulty breathing and cough. Reversibility with asthma medications is defined as direct observation of improvement with short-acting ß2-agonists (SABA) (with or without oral corticosteroids) by a trained health care practitioner during an acute exacerbation (preferred method). However, in children with no wheezing (or other signs of airflow obstruction) on presentation, reversibility may be determined by convincing parental report of a symptomatic response to a three-month therapeutic trial of a medium dose of inhaled corticosteroids with as-needed SABA (alternative method), or as-needed SABA alone (weaker alternative method). The authors provide key messages regarding in whom to consider the diagnosis, terms to be abandoned, when to refer to an asthma specialist and the initial management strategy. Finally, dissemination plans and priority areas for research are identified.
PMCID: PMC4614088  PMID: 26526095
Asthma; Child; Criteria; Diagnosis; Disease management; Preschool; Therapeutic trial
6.  Clinical Features of Childhood Primary Ciliary Dyskinesia by Genotype and Ultrastructural Phenotype 
Rationale: The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined.
Objectives: To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype.
Methods: A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping.
Measurements and Main Results: Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA + IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n = 40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations.
Conclusions: Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.
PMCID: PMC4351577  PMID: 25493340
Kartagener syndrome; cilia; respiratory function tests; X-ray computed tomography scanners; ultrastructure
7.  Pulmonary Alveolar Microlithiasis 
Canadian Respiratory Journal  2016;2016:4938632.
Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive condition that is often asymptomatic despite significant changes in chest imaging. Diagnosis is often made when patients become symptomatic in adulthood. There are still no proven treatments, but earlier diagnosis may allow for evaluation of preventative strategies that could improve outcome. It is an important diagnosis to consider in children who have marked radiographic findings with no or very mild symptoms or physical findings. Diagnosis can be made with imaging alone but may necessitate lung biopsy for definitive diagnosis.
PMCID: PMC4904551  PMID: 27445543
8.  Primary Ciliary Dyskinesia and Neonatal Respiratory Distress 
Pediatrics  2014;134(6):1160-1166.
Primary ciliary dyskinesia (PCD) is a rare inherited disease affecting motile cilia lining the respiratory tract. Despite neonatal respiratory distress as an early feature, diagnosis is typically delayed until late childhood. Our objective was to identify characteristics that differentiate PCD from common causes of term neonatal respiratory distress.
This was a case-control study. Patients with PCD born after 1994 attending a regional PCD clinic who had a history of neonatal respiratory distress (n = 46) were included. Controls (n = 46), term neonates with respiratory distress requiring a chest radiograph, were randomly selected from hospital birth records and matched on gender, birth month/year, and mode of delivery. Multiple logistic regression was used to determine the association between neonatal characteristics and PCD diagnosis. The diagnostic performance of the best predictive variables was estimated by calculating sensitivity and specificity.
PCD cases required more oxygen therapy (39 cases, 29 controls, P = .01), longer duration of oxygen therapy (PCD mean = 15.2 days, control mean = 0.80 days, P < .01), had later onset of neonatal respiratory distress (PCD median = 12 hours, control median = 1 hour, P < .001), and higher frequency of lobar collapse and situs inversus (PCD = 70% and 48% respectively, control = 0% for both, P < .001). Situs inversus, lobar collapse, or oxygen need for >2 days had 87% (95% confidence interval: 74–94) sensitivity and 96% (95% confidence interval: 85–99) specificity for PCD.
When encountering term neonates with unexplained respiratory distress, clinicians should consider PCD in those with lobar collapse, situs inversus, and/or prolonged oxygen therapy (>2 days).
PMCID: PMC4243067  PMID: 25422025
ciliary motility disorders; Kartagener syndrome; PCD; pulmonary atelectasis; respiratory distress syndrome; infant
9.  COPA mutations impair ER-Golgi transport causing hereditary autoimmune-mediated lung disease and arthritis 
Nature genetics  2015;47(6):654-660.
Advances in genomics have allowed unbiased genetic studies of human disease with unexpected insights into the molecular mechanisms of cellular immunity and autoimmunity1. We performed whole exome sequencing (WES) and targeted sequencing in patients with an apparent Mendelian syndrome of autoimmune disease characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease (ILD). In five families, we identified four unique deleterious variants in the Coatomer subunit alpha (COPA) gene all located within the same functional domain. We hypothesized that mutant COPA leads to a defect in intracellular transport mediated by coat protein complex I (COPI)2–4. We show that COPA variants impair binding of proteins targeted for retrograde Golgi to ER transport and demonstrate that expression of mutant COPA leads to ER stress and the upregulation of Th17 priming cytokines. Consistent with this pattern of cytokine expression, patients demonstrated a significant skewing of CD4+ T cells toward a T helper 17 (Th17) phenotype, an effector T cell population implicated in autoimmunity5,6. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease. These findings provide a unique opportunity to understand how alterations in cellular homeostasis caused by a defect in the intracellular trafficking pathway leads to the generation of human autoimmune disease.
PMCID: PMC4513663  PMID: 25894502
10.  Parents and adolescents preferences for asthma control: a best-worst scaling choice experiment using an orthogonal main effects design 
BMC Pulmonary Medicine  2015;15:146.
The preferences of parents and children with asthma influence their ability to manage a child’s asthma and achieve good control. Potential differences between parents and adolescents with respect to specific parameters of asthma control are not considered in clinical asthma guidelines. The objective was to measure and compare the preferences of parents and adolescents with asthma with regard to asthma control parameters using best worst scaling (BWS).
Fifty-two parents of children with asthma and 44 adolescents with asthma participated in a BWS study to quantify preferences regarding night-time symptoms, wheezing/chest tightening, changes in asthma medications, emergency visits and physical activity limitations. Conditional logit regression was used to determine each group’s utility for each level of each asthma control parameter.
Parents displayed the strongest positive preference for the absence of night-time symptoms (β = 2.09, p < 0.00001) and the strongest negative preference for 10 emergency room visits per year (β = −2.15, p < 0.00001). Adolescents displayed the strongest positive preference for the absence of physical activity limitations (β = 2.17, p < 0.00001) and the strongest negative preference for ten physical activity limitations per month (β = −1.97). Both groups were least concerned with changes to medications.
Parents and adolescents placed different weights on the importance of asthma control parameters and each group displayed unique preferences. Understanding the relative importance placed on each parameter by parents and adolescents is essential for designing effective patient-focused disease management plans.
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-015-0141-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4650923  PMID: 26577906
Adolescents; Asthma control; Best-worst scaling; Child health; Preferences
11.  Association among fraction of exhaled nitrous oxide, bronchodilator response and inhaled corticosteroid type 
Airway inflammation is a hallmark of asthma, a condition affecting up to 15% of children in Canada. Spirometry is usually used to confirm the diagnosis and to monitor asthma control, and fraction of exhaled nitrous oxide – a key, albeit nonspecific, spirometric marker of airway inflammation – has been the subject of recent investigation of asthma control in children. Conducted at a regional pediatric asthma centre among 183 children <18 years of age, this retrospective study investigated the relationship between fraction of exhaled nitrous oxide and several spirometric parameters and inhaled corticosteroid type.
Fraction of exhaled nitrous oxide (FeNO) is a known marker of airway inflammation and a topic of recent investigation for asthma control in children.
To investigate the relationship among FeNO and bronchodilator response measured by spirometry and types of inhaled corticosteroids (ICS).
A one-year review of children tested with spirometry and FeNO in a regional pediatric asthma centre was conducted.
A total of 183 children were included (mean [± SD] age 12.8±2.8 years). Fluticasone was used most commonly (n=66 [36.1%]), followed by ciclesonide (n=50 [27.3%]). Most children (n=73 [39.9%]) had moderate persistent asthma. Increased FeNO was associated with percent change in forced expiratory volume in 1 s (FEV1) after bronchodilator adjusted for allergic rhinitis, parental smoking and ICS type (B=0.08 [95% CI 0.04 to 0.12]; P<0.001). Similarly, FeNO was associated with percent change in forced expiratory flow at 25% to 75% of the pulmonary volume (FEF25–75) after bronchodilator adjusted for parental smoking and ICS type (B=0.13 [95% CI 0.01 to 0.24]; P=0.03). FeNO accounted for only 16% and 9% of the variability in FEV1 and FEF25–75, respectively. Mean-adjusted FeNO was lowest in fluticasone users compared with no ICS (mean difference 18.6 parts per billion [ppb] [95% CI 1.0 to 36.2]) and there was no difference in adjusted FeNO level between ciclesonide and no ICS (5.9 ppb [95% CI −9.0 to 20.8]).
FeNO levels correlated with bronchodilator response in a regional pediatric asthma centre. However, FeNO accounted for only 16% and 9% of the variability in FEV1 and FEF25–75, respectively. Mean adjusted FeNO varied according to ICS type, suggesting a difference in relative efficacy between ICS beyond their dose equivalents.
PMCID: PMC4470548  PMID: 25874734
Asthma; Children; Exhaled airway markers; Fraction of exhaled nitrous oxide (FeNO); Inhaled corticosteroid (ICS)
12.  Diagnosis and management of asthma in preschoolers: A Canadian Thoracic Society and Canadian Paediatric Society position paper 
The early onset of asthma and difficulty of performing spirometry in children <6 years of age contribute to the lack of standardized terminology to describe the condition in preschool-age children. Presumptive diagnoses in this young age group currently rely on suggestive symptomatology and exclusion of alternative diagnoses. Early diagnosis, however, is vital to avoid treatment delay and to reduce morbidity. Given the the lack of clarity in this area, the aim of the proposed operational criteria and recommendations presented in this position paper is to standardize the diagnosis of asthma in the absence of lung function tests in this particular patient population.
Asthma often starts before six years of age. However, there remains uncertainty as to when and how a preschool-age child with symptoms suggestive of asthma can be diagnosed with this condition. This delays treatment and contributes to both short- and long-term morbidity. Members of the Canadian Thoracic Society Asthma Clinical Assembly partnered with the Canadian Paediatric Society to develop a joint working group with the mandate to develop a position paper on the diagnosis and management of asthma in preschoolers.
In the absence of lung function tests, the diagnosis of asthma should be considered in children one to five years of age with frequent (≥8 days/month) asthma-like symptoms or recurrent (≥2) exacerbations (episodes with asthma-like signs). The diagnosis requires the objective document of signs or convincing parent-reported symptoms of airflow obstruction (improvement in these signs or symptoms with asthma therapy), and no clinical suspicion of an alternative diagnosis. The characteristic feature of airflow obstruction is wheezing, commonly accompanied by difficulty breathing and cough. Reversibility with asthma medications is defined as direct observation of improvement with short-acting ß2-agonists (SABA) (with or without oral corticosteroids) by a trained health care practitioner during an acute exacerbation (preferred method). However, in children with no wheezing (or other signs of airflow obstruction) on presentation, reversibility may be determined by convincing parental report of a symptomatic response to a three-month therapeutic trial of a medium dose of inhaled corticosteroids with as-needed SABA (alternative method), or as-needed SABA alone (weaker alternative method). The authors provide key messages regarding in whom to consider the diagnosis, terms to be abandoned, when to refer to an asthma specialist and the initial management strategy. Finally, dissemination plans and priority areas for research are identified.
PMCID: PMC4470545  PMID: 25893310
Asthma; Child; Criteria; Diagnosis; Disease management; Preschool; Therapeutic trial
13.  Health risk of air pollution on people living with major chronic diseases: a Canadian population-based study 
BMJ Open  2015;5(9):e009075.
The objective of this study was to use health administrative and environmental data to quantify the effects of ambient air pollution on health service use among those with chronic diseases. We hypothesised that health service use would be higher among those with more exposure to air pollution as measured by the Air Quality Health Index (AQHI).
Health administrative data was used to quantify health service use at the primary (physician office visits) and secondary (emergency department visits, hospitalisations) level of care in Ontario, Canada.
We included individuals who resided in Ontario, Canada, from 2003 to 2010, who were ever diagnosed with one of 11 major chronic diseases.
Outcome measures
Rate ratios (RR) from Poisson regression models were used to estimate the short-term impact of incremental unit increases in AQHI, nitrogen dioxide (NO2; 10 ppb), fine particulate matter (PM2.5; 10 µg/m3) and ozone (O3; 10 ppb) on health services use among individuals with each disease. We adjusted for age, sex, day of the week, temperature, season, year, socioeconomic status and region of residence.
Increases in outpatient visits ranged from 1% to 5% for every unit increase in the 10-point AQHI scale, corresponding to an increase of about 15 000 outpatient visits on a day with poor versus good air quality. The greatest increases in outpatient visits were for individuals with non-lung cancers (AQHI:RR=1.05; NO2:RR=1.14; p<0.0001) and COPD (AQHI:RR=1.05; NO2:RR=1.12; p<0.0001) and in hospitalisations, for individuals with diabetes (AQHI:RR=1.04; NO2:RR=1.07; p<0.0001) and COPD (AQHI:RR=1.03; NO2:RR=1.09; p<1.001). The impact remained 2 days after peak AQHI levels.
Among individuals with chronic diseases, health service use increased with higher levels of exposure to air pollution, as measured by the AQHI. Future research would do well to measure the utility of targeted air quality advisories based on the AQHI to reduce associated health service use.
PMCID: PMC4563262  PMID: 26338689
14.  Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia 
G3: Genes|Genomes|Genetics  2015;5(8):1775-1781.
Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder resulting from loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus, and infertility. Clinical features may be subtle and highly variable, making the diagnosis of PCD challenging. The diagnosis can be confirmed with ciliary ultrastructure analysis and/or molecular genetic testing of 32 PCD-associated genes. However, because of this genetic heterogeneity, comprehensive molecular genetic testing is not considered the standard of care, and the most efficient molecular approach has yet to be elucidated. Here, we propose a cost-effective and time-efficient molecular genetic algorithm to solve cases of PCD. We conducted targeted copy number variation (CNV) analysis and/or whole-exome sequencing on 20 families (22 patients) from a subset of 45 families (52 patients) with a clinical diagnosis of PCD who did not have a molecular genetic diagnosis after Sanger sequencing of 12 PCD-associated genes. This combined molecular genetic approach led to the identification of 4 of 20 (20%) families with clinically significant CNVs and 7 of 20 (35%) families with biallelic pathogenic mutations in recently identified PCD genes, resulting in an increased molecular genetic diagnostic rate of 55% (11/20). In patients with a clinical diagnosis of PCD, whole-exome sequencing followed by targeted CNV analysis results in an overall molecular genetic yield of 76% (34/45).
PMCID: PMC4528333  PMID: 26139845
primary ciliary dyskinesia; whole-exome sequencing; copy number variation; diagnostic testing
15.  Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with a Unique Clinical and Ciliary Phenotype 
Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.
Objectives: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.
Methods: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis.
Measurements and Main Results: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 ± Hz at 25°C), but an abnormal, circular beat pattern.
Conclusions: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.
PMCID: PMC3983840  PMID: 24568568
cilia; Kartagener syndrome; ciliopathy; exome sequencing; RSPH1
16.  The Role of Molecular Genetic Analysis in the Diagnosis of Primary Ciliary Dyskinesia 
Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disorder of motile cilia. The diagnosis of PCD has previously relied on ciliary analysis with transmission electron microscopy or video microscopy. However, patients with PCD may have normal ultrastructural appearance, and ciliary analysis has limited accessibility. Alternatively, PCD can be diagnosed by demonstrating biallelic mutations in known PCD genes. Genetic testing is emerging as a diagnostic tool to complement ciliary analysis where interpretation and access may delay diagnosis.
Objectives: To determine the diagnostic yield of genetic testing of patients with a confirmed or suspected diagnosis of PCD in a multiethnic urban center.
Methods: Twenty-eight individuals with confirmed PCD on transmission electron microscopy of ciliary ultrastructure and 24 individuals with a probable diagnosis of PCD based on a classical PCD phenotype and low nasal nitric oxide had molecular analysis of 12 genes associated with PCD.
Results: Of 49 subjects who underwent ciliary biopsy, 28 (57%) were diagnosed with PCD through an ultrastructural defect. Of the 52 individuals who underwent molecular genetic analysis, 22 (42%) individuals had two mutations in known PCD genes. Twenty-four previously unreported mutations in known PCD genes were observed. Combining both diagnostic modalities of biopsy and molecular genetics, the diagnostic yield increased to 69% compared with 57% based on biopsy alone.
Conclusions: The diagnosis of PCD is challenging and has traditionally relied on ciliary biopsy, which is unreliable as the sole criterion for a definitive diagnosis. Molecular genetic analysis can be used as a complementary test to increase the diagnostic yield.
PMCID: PMC4028737  PMID: 24498942
primary ciliary dyskinesia; genetic analysis; diagnostic testing
17.  Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia 
Rationale: Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized.
Objectives: To use a standard protocol for measuring nNO to establish a disease-specific cutoff value at one site, and then validate at six other sites.
Methods: At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD.
Measurements and Main Results: At the lead site, nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5–207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5–867.0 nl/min), asthma (267.8 ± 103.2; 125.0–589.7 nl/min), or chronic obstructive pulmonary disease (223.7 ± 87.1; 109.7–449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6–386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD.
Conclusions: Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.
PMCID: PMC3960971  PMID: 24024753
primary ciliary dyskinesia; Kartagener syndrome; ciliopathy; axoneme
18.  Founder mutation in RSPH4A identified in patients of Hispanic descent with Primary Ciliary Dyskinesia 
Human mutation  2013;34(10):1352-1356.
Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6delAAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent.
PMCID: PMC3906677  PMID: 23798057
Cilia; Kartagener syndrome; sequencing; RSPH4A
19.  An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy 
Background: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults.
Methods: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient’s or family’s quality of life, and death.
Results: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having “childhood ILD syndrome”; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research.
Conclusions: After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential.
PMCID: PMC3778735  PMID: 23905526
diffuse lung disease; lung growth abnormalities; surfactant proteins; neuroendocrine cells
Pediatric pulmonology  2011;46(5):483-488.
Examination of ciliary ultrastructure remains the cornerstone diagnostic test for primary ciliary dyskinesia (PCD), a disease of abnormal ciliary structure and/or function. Obtaining a biopsy with sufficient interpretable cilia and producing quality transmission electron micrographs (TEM) is challenging. Methods for processing tissues for optimal preservation of axonemal structures are not standardized. This study describes our experience using a standard operating procedure (SOP) for collecting nasal scrape biopsies and processing TEMs in a centralized laboratory. We enrolled patients with suspected PCD at research sites of the Genetic Disorders of Mucociliary Clearance Consortium. Biopsies were performed according to a SOP whereby curettes were used to scrape the inferior surface of the inferior turbinate, with samples placed in fixative. Specimens were shipped to a central laboratory where TEMs were prepared and blindly reviewed. 448 specimens were obtained from 107 young children (0–5 years), 189 older children (5–18 years), and 152 adults (> 18 years), and 88% were adequate for formal interpretation. The proportion of adequate specimens was higher in adults than in children. 50% of the adequate TEMs showed normal ciliary ultrastructure, 39% showed hallmark ultrastructural changes of PCD, and 11% had indeterminate findings. Among specimens without clearly normal ultrastructure, 72% had defects of the outer and/or inner dynein arms, while 7% had central apparatus defects with or without inner dynein arm defects. In summary, nasal scrape biopsies can be performed in the outpatient setting and yield interpretable samples, when performed by individuals with adequate training and experience according to an SOP.
PMCID: PMC3875629  PMID: 21284095
cilia; nasal biopsy; primary ciliary dyskinesia
22.  Mutations of DNAH11 in Primary Ciliary Dyskinesia Patients with Normal Ciliary Ultrastructure 
Thorax  2011;67(5):433-441.
Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterized by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognized to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in DNAH11.
In order to test further for mutant DNAH11 as a cause of PCD, we sequenced DNAH11 in patients with a PCD clinical phenotype, but no known genetic etiology.
We sequenced 82 exons and intron/exon junctions in DNAH11 in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer ± inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, we sequenced DNAH11 in 13 patients with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.
Of the 58 unrelated PCD patients with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; plus, 2 PCD patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or Ioss-of-function splice-site mutations.
Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.
PMCID: PMC3739700  PMID: 22184204
Cilia; Dynein; Kartagener syndrome; Dextrocardia; Heterotaxy
23.  Clinical and Genetic Aspects of Primary Ciliary Dyskinesia / Kartagener Syndrome 
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder of motile cilia. Most of the disease-causing mutations identified to date involve the heavy (DNAH5) or intermediate (DNAI1) chain dynein genes in ciliary outer dynein arms, although a few mutations have been noted in other genes. Clinical molecular genetic testing for PCD is available for the most common mutations. The respiratory manifestations of PCD (chronic bronchitis leading to bronchiectasis, chronic rhino-sinusitis and chronic otitis media) reflect impaired mucociliary clearance owing to defective axonemal structure. Ciliary ultrastructural analysis in most patients (>80%) reveals defective dynein arms, although defects in other axonemal components have also been observed. Approximately 50% of PCD patients have laterality defects (including situs inversus totalis and, less commonly, heterotaxy and congenital heart disease), reflecting dysfunction of embryological nodal cilia. Male infertility is common and reflects defects in sperm tail axonemes. Most PCD patients have a history of neonatal respiratory distress, suggesting that motile cilia play a role in fluid clearance during the transition from a fetal to neonatal lung. Ciliopathies involving sensory cilia, including autosomal dominant or recessive polycystic kidney disease, Bardet-Biedl syndrome, and Alstrom syndrome, may have chronic respiratory symptoms and even bronchiectasis suggesting clinical overlap with PCD.
PMCID: PMC3739704  PMID: 19606528
Primary ciliary dyskinesia; PCD; Kartagener syndrome; situs inversus; dynein
24.  A new exposure metric for traffic-related air pollution? An analysis of determinants of hopanes in settled indoor house dust 
Environmental Health  2013;12:48.
Exposure to traffic-related air pollution (TRAP) can adversely impact health but epidemiologic studies are limited in their abilities to assess long-term exposures and incorporate variability in indoor pollutant infiltration.
In order to examine settled house dust levels of hopanes, engine lubricating oil byproducts found in vehicle exhaust, as a novel TRAP exposure measure, dust samples were collected from 171 homes in five Canadian cities and analyzed by gas chromatography–mass spectrometry. To evaluate source contributions, the relative abundance of the highest concentration hopane monomer in house dust was compared to that in outdoor air. Geographic variables related to TRAP emissions and outdoor NO2 concentrations from city-specific TRAP land use regression (LUR) models were calculated at each georeferenced residence location and assessed as predictors of variability in dust hopanes.
Hopanes relative abundance in house dust and ambient air were significantly correlated (Pearson’s r=0.48, p<0.05), suggesting that dust hopanes likely result from traffic emissions. The proportion of variance in dust hopanes concentrations explained by LUR NO2 was less than 10% in Vancouver, Winnipeg and Toronto while the correlations in Edmonton and Windsor explained 20 to 40% of the variance. Modeling with household factors such as air conditioning and shoe removal along with geographic predictors related to TRAP generally increased the proportion of explained variability (10-80%) in measured indoor hopanes dust levels.
Hopanes can consistently be detected in house dust and may be a useful tracer of TRAP exposure if determinants of their spatiotemporal variability are well-characterized, and when home-specific factors are considered.
PMCID: PMC3711892  PMID: 23782977
Air pollution; Dust; Exposure assessment; Hopanes; Land use regression; Traffic
25.  Canadian Thoracic Society 2012 guideline update: Diagnosis and management of asthma in preschoolers, children and adults: Executive summary 
In 2010, the Canadian Thoracic Society (CTS) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older, and adults, including an updated Asthma Management Continuum. The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline update process, focusing, in this first iteration, on topics of controversy and/or gaps in the previous guidelines.
Four clinical questions were identified as a focus for the updated guideline: the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy; the initiation of adjunct therapy to inhaled corticosteroids (ICS) for uncontrolled asthma; the role of a single inhaler of an ICS/long-acting beta2-agonist combination as a reliever, and as a reliever and a controller; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan. The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics. In addition, literature searches were performed to identify relevant systematic reviews and randomized controlled trials. The panel formally assessed and graded the evidence, and made 34 recommendations.
The updated guideline recommendations outline a role for inclusion of assessment of sputum eosinophils, in addition to standard measures of asthma control, to guide adjustment of controller therapy in adults with moderate to severe asthma. Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations. New recommendations for the adjustment of controller medication within written action plans are provided. Finally, priority areas for future research were identified.
The present document is an executive summary of the first update of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee’s new guideline development process. Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide updates reflecting new evidence.
PMCID: PMC4527232  PMID: 23248807
Asthma; Clinical practice guideline; Management

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