Adam J. Shapiro

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.

Laterality Defects Other Than Situs Inversus Totalis in Primary Ciliary Dyskinesia: Insights Into Situs Ambiguus and Heterotaxy

BACKGROUND Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied. METHODS In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD. RESULTS Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P < .001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P < .001). CONCLUSIONS At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov.

Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review.

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.

Point-of-care lung ultrasound in young children with respiratory tract infections and wheeze

Objective Characterise lung ultrasound (LUS) findings, diagnostic accuracy and agreement between novice and expert interpretations in young children with respiratory tract infections and wheeze. Methods Prospective cross-sectional study in a paediatric ED. Patients ≤2 years with a respiratory tract infection and wheeze at triage were recruited unless in severe respiratory distress. Prior to clinical management, a novice sonologist performed the LUS using a six-zone scanning protocol. The treating physician remained blinded to ultrasound findings; final diagnoses were extracted from the medical record. An expert sonologist, blinded to all clinical information, assessed the ultrasound video clips at study completion. Positive LUS was defined as the presence of ≥1 of the following findings: ≥3 B-lines per intercostal space, consolidation and/or pleural abnormalities. Results Ninety-four patients were enrolled (median age 11.1 months). LUS was positive in 42% (39/94) of patients (multiple B-lines in 80%, consolidation in 64%, pleural abnormalities in 23%). The proportion of positive LUS, along with their diagnostic accuracy (sensitivity (95% CI), specificity (95% CI)), were as follows for children with bronchiolitis, asthma, pneumonia and asthma/pneumonia: 46% (45.8% (34.0% to 58.0%), 72.7% (49.8% to 89.3%)), 0% (0% (0.0% to 23.3%), 51.3% (39.8% to 62.6%)), 100% (100% (39.8% to 100.0%), 61.1% (50.3% to 71.2%)), 50% (50% (6.8% to 93.2%), 58.9% (48.0% to 69.2%)), respectively. There was good agreement between the novice and expert sonographers for a positive LUS (kappa 0.68 (95% CI 0.54 to 0.82)). Conclusions Among children with respiratory tract infections and wheeze, a positive LUS seems to distinguish between clinical syndromes by ruling in pneumonia and ruling out asthma. If confirmed in future studies, LUS may emerge as a point-of-care tool to guide diagnosis and disposition in young children with wheeze.

The prevalence of clinical features associated with primary ciliary dyskinesia in a heterotaxy population: results of a web-based survey

Primary ciliary dyskinesia and heterotaxy are rare but not mutually exclusive disorders, which result from cilia dysfunction. Heterotaxy occurs in at least 12.1% of primary ciliary dyskinesia patients, but the prevalence of primary ciliary dyskinesia within the heterotaxy population is unknown. We designed and distributed a web-based survey to members of an international heterotaxy organisation to determine the prevalence of respiratory features that are common in primary ciliary dyskinesia and that might suggest the possibility of primary ciliary dyskinesia. A total of 49 members (25%) responded, and 37% of the respondents have features suggesting the possibility of primary ciliary dyskinesia, defined as (1) the presence of at least two chronic respiratory symptoms, or (2) bronchiectasis or history of respiratory pathogens suggesting primary ciliary dyskinesia. Of the respondents, four completed comprehensive, in-person evaluations, with definitive primary ciliary dyskinesia confirmed in one individual, and probable primary ciliary dyskinesia identified in two others. The high prevalence of respiratory features compatible with primary ciliary dyskinesia in this heterotaxy population suggests that a subset of heterotaxy patients have dysfunction of respiratory, as well as embryonic nodal cilia. To better assess the possibility of primary ciliary dyskinesia, heterotaxy patients with chronic oto-sino-respiratory symptoms should be referred for a primary ciliary dyskinesia evaluation.

Use of an endoscopic urology basket to remove bronchial foreign body in the pediatric population

Foreign body (FB) aspiration is a common problem in the pediatric population. Rigid bronchoscopy is considered the treatment of choice for removal of tracheobronchial FB. This is a report of two cases of tracheobronchial foreign body aspiration that were managed using an endoscopic urology basket through a flexible bronchoscope. This reports main purpose is to inform physicians on the benefit of flexible bronchoscopy and of the potential use of the endoscopic urology basket for tracheobronchial FB retrieval. We hope that the flexible bronchoscopy and the endoscopic basket will become a standard tool in FB retrieval kits for pediatric otolaryngologists who deal with this issue on a routine basis.

Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis.

Rationale: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown. Objectives: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. Data Sources: Ten databases were searched for reference sources from database inception through July 29, 2016. Data Extraction: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. Synthesis: Meta‐analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies‐2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7‐99.2) and specificity was 96.0% (87.9‐98.7), with a positive likelihood ratio of 24.3 (7.6‐76.9), a negative likelihood ratio of 0.03 (0.01‐0.08), and a diagnostic odds ratio of 956.8 (141.2‐6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7‐98.9) and specificity of 96.4% (85.1‐99.2), with a positive likelihood ratio of 26.5 (5.9‐119.1), a negative likelihood ratio of 0.04 (0.01‐0.12), and a diagnostic odds ratio of 699.3 (67.4‐7256.0). Certainty of the evidence was graded as moderate. Conclusions: nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta‐analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.

Vaccine induced Hepatitis A and B protection in children at risk for cystic fibrosis associated liver disease

OBJECTIVES Hepatitis A (HAV) and Hepatitis B (HBV) infections can cause serious morbidity in patients with liver disease, including cystic fibrosis associated liver disease (CFALD). HAV and HBV vaccinations are recommended in CFALD, and maintenance of detectable antibody levels is also recommended with chronic liver disease. A better understanding of factors predicting low HAV and HBV antibodies may help physicians improve protection from these viruses in CFALD patients. METHODS We examined HAV and HBV vaccine protection in children at risk for CFALD. Clinical and vaccine histories were reviewed, and HAV and HBV antibody titers measured. Those with no vaccination history or low HAV or HBV titers received primary or booster vaccinations, and responses were measured. RESULTS Thirty-four of 308 children were at risk for CFALD per project criteria. Ten had previous HAV vaccination, of which 90% had positive anti-HAV antibodies. Thirty-three of 34 had previously received primary HBV vaccination (most in infancy), but only 12 (35%) had adequate anti-HBs levels (≥10mIU/mL). Children with adequate anti-HBs levels were older at first HBV vaccine (median 2.3 vs. 0.1 years, p<0.01), and at final HBV vaccine (median 4.0 vs. 0.8 years, p=0.01). Fourteen of 19 (74%) responded to HBV boosters. Z-scores for BMI at HBV booster were significantly lower in booster non-responders (p=0.04). CONCLUSIONS Children at increased risk of CFALD have inadequate HAV and HBV antibody levels, and HBV antibody protection can be enhanced through vaccine boosters. HBV antibody titers should be assessed in CFALD patients with a history of vaccination, particularly in those who received HBV vaccines in infancy or who are malnourished.

Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline

Background: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD). Target Audience: Clinicians investigating adult and pediatric patients for possible PCD. Methods: Systematic reviews and, when appropriate, meta‐analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by a multidisciplinary panel with expertise in PCD. Predetermined conflict‐of‐interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript. Results: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD. Conclusions: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.

Nasal Nitric Oxide and Ciliary Videomicroscopy: Tests Used for Diagnosing Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare disease affecting approximately 1/15,000 to 1/30,000 persons. In this disease, respiratory cilia are dysmotile and mucociliary clearance is decreased; thereby, leading to chronic respiratory tract infections. Primary ciliary dyskinesia is difficult to diagnose, and there is no gold standard test that will detect all cases of PCD. Screening with nasal nitric oxide measurement is a rapid, sensitive, and noninvasive method that allows physicians to make proper referrals for further PCD investigations. High speed digital videomicroscopy is a powerful tool which allows for detailed assessment of ciliary beat pattern and can detect novel forms of PCD which may be missed on electron microscopy. With the rapidly expanding knowledge of genetic mutations causing PCD, both nasal nitric oxide and ciliary videomicroscopy testing will require future correlation and validation with genetic mutations in PCD patients.