The Abbreviated Methacholine Challenge Test is Safe for Children.

OBJECTIVE: To evaluate the safety of an abbreviated methacholine challenge test (MCT) protocol in children. STUDY DESIGN: This prospective, observational study enrolled children aged 6 through 18 years referred for the MCT. The abbreviated protocol was initiated with a methacholine dose of 0.03 mg/ml and escalated in fourfold increments, unless the forced expiratory volume at 1 second decline exceeded 10%, at which point the next dose was only doubled. The safety of this abbreviated approach was assessed by monitoring adverse events, and specifically, decreases in forced expiratory volume at 1 second over 40%, hypoxemia, or uncontrollable cough. The number of methacholine doses and test duration were recorded and compared with estimated outcomes derived from the full-length MCT protocol. RESULTS: One hundred twelve participants, aged 13.7 years (±3.3), successfully completed the protocol. Fifty-seven (51%) presented a positive MCT response. No significant clinical adverse events were observed. Of all participants, 2.7% exhibited an exaggerated response, in line with previously reported findings for the full-length protocol. The abbreviated approach resulted in an estimated average time-savings of 18:19 minutes per participant, thus reducing test length by 22:47 minutes for a negative MCT and by 14:34 minutes for a positive outcome. CONCLUSIONS: This abbreviated MCT protocol is safe for children and effectively shortens the duration of the MCT.

Infant pulmonary function tests in individuals with Down syndrome.

BACKGROUND AND OBJECTIVE: Down syndrome is associated with significant respiratory morbidity. The available pulmonary function testing data in school aged children and adults with Down show evidence of restrictive lung disease. We aimed to evaluated infant pulmonary function tests (iPFTs) in individuals with Down. METHODS: An observational case-control study evaluating iPFTs results from a registry of patients assessed at the Hadassah Hebrew University Medical Center between 2008 and 2018. iPFTs results in Infants with Down were compared to a spirometry control group of infants with normal expiratory airflows, using the Mann-Whitney U and Fisher's exact tests. RESULTS: iPFT data from 66 infants (20 Down and 46 control) were evaluated in the study. Most infants with Down showed abnormalities of an obstructive lung disease with mildly increased lung volumes and significantly decreased expiratory flows, mostly unresponsive to bronchodilators. Airflow limitations were most prominent at low lung volumes (median (IQR); maximal expiratory flow at functional residual capacity, V˙max FRC = 48 (26-78) %predicted in Down Vs. V˙max FRC = 100 (93-114) %predicted in controls, p < 0.001). We further observed an alteration in breathing mechanics with significantly decreased respiratory system compliance and increased airway resistance associated with decreased tidal volumes but similar minute ventilation. CONCLUSION: Our study shows that infants with have a fixed airflow obstruction phenotype. These results add comprehensive data to allow better understanding of the lung disease present early in life of infants with Down syndrome. Further studies are required to improve management of respiratory disease in individuals with Down.

The Use of Infant Pulmonary Function Tests in the Diagnosis of Neuroendocrine Cell Hyperplasia of Infancy.

BACKGROUND: Infant pulmonary function tests (iPFTs) in subjects with neuroendocrine cell hyperplasia of infancy (NEHI) have demonstrated substantial expiratory airflow obstruction and air trapping. RESEARCH QUESTION: Can indices from iPFTs be used in the diagnosis of NEHI? STUDY DESIGN AND METHODS: This is an observational case-control study evaluating iPFT results from a registry of patients assessed at the Hadassah Hebrew University Medical Center between 2008 and 2018. iPFTs results in infants with NEHI were compared to two disease control infant groups (infants evaluated for recurrent wheezing and infants evaluated due to prematurity) and a spirometry control group of infants with normal expiratory airflow, using the Kruskal-Wallis test. Receiver operating characteristic (ROC) curves were used to assess the diagnostic accuracy of iPFT indices. RESULTS: We evaluated iPFT data in 481 infants (15, NEHI; 292, wheezing; 128, premature; and 46, spirometry control group). Infants with NEHI had significantly increased trapped air volumes (median functional residual capacity measured with infant whole-body plethysmography [FRCpleth] was 199% predicted; median ratio of residual volume to total lung capacity was 59% predicted) when compared with results in all evaluated groups of infants (P < .001), including multiple pairwise comparisons. Airflow limitation was demonstrated in infants with NEHI when compared with the infants in the spirometry control group but was similar to the two disease control groups. FRCpleth had the best discriminatory ability for NEHI diagnosis, with an FRCpleth ≥ 150% predicted demonstrating a ROC of 0.91 (95% CI, 0.82-1.00), sensitivity of 86.7% (95% CI, 59.5%-98.3%), and specificity of 95.5% (95% CI, 93.2%-97.3%). INTERPRETATION: Findings on iPFTs of markedly increased air trapping, out of proportion to the degree of airflow limitation, are characteristic of infants with NEHI. iPFT results demonstrating an FRCpleth ≥ 150% predicted are highly specific for NEHI and may aid in early diagnosis. Further research is required to confirm these findings in a prospective cohort and to understand the pathophysiologic explanation for these findings.

Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia.

The diagnosis of primary ciliary dyskinesia (PCD) relies on clinical features and sophisticated studies. The detection of bi-allelic disease-causing variants confirms the diagnosis. However, a standardised genetic panel is not widely available and new disease-causing genes are continuously identified. To assess the accuracy of untargeted whole-exome sequencing (WES) as a diagnostic tool for PCD, patients with symptoms highly suggestive of PCD were consecutively included. Patients underwent measurement of nasal nitric oxide (nNO) levels, ciliary transmission electron microscopy analysis (TEM) and WES. A confirmed PCD diagnosis in symptomatic patients was defined as a recognised ciliary ultrastructural defect on TEM and/or two pathogenic variants in a known PCD-causing gene. Forty-eight patients (46% male) were enrolled, with a median age of 10.0 years (range 1.0-37 years). In 36 patients (75%) a diagnosis of PCD was confirmed, of which 14 (39%) patients had normal TEM. A standalone untargeted WES had a diagnostic yield of 94%, identifying bi-allelic variants in 11 known PCD-causing genes in 34 subjects. A nNO<77 nL·min was nonspecific when including patients younger than 5 years (area under the receiver operating characteristic curve (AUC) 0.75, 95% CI 0.60-0.90). Consecutive WES considerably improved the diagnostic accuracy of nNO in young children (AUC 0.97, 95% CI 0.93-1). Finally, WES established an alternative diagnosis in four patients. In patients with clinically suspected PCD and low nNO levels, WES is a simple, beneficial and accurate next step to confirm the diagnosis of PCD or suggest an alternative diagnosis, especially in preschool-aged children in whom nNO is less specific.

Giant lung cysts following necrotizing pneumonia: Resolution with conservative treatment.

RATIONALE: Necrotizing pneumonia is characterized by destruction and liquefaction of the lung tissue and loss of the normal pulmonary parenchymal architecture. During the course of resolution areas of hyperlucency are formed, sometimes with the development of giant lung cysts that can be a field with fluid resembling lung abscess. There is no consensus on the management of these abnormalities. OBJECTIVE: To assess the prevalence of giant lung cysts as a complication of necrotizing pneumonia and to report our experience with conservative treatment that achieved complete resolution. METHODS: Medical chart reviews of all children aged 0 to 18 years hospitalized with necrotizing pneumonia in a single tertiary center from 2015 to 2017, demographic data, and clinical course during and after hospitalization as well as serial chest imaging were collected. RESULTS: During the study period, 761 children were diagnosed with community-acquired pneumonia, 16 of 761 (2.3%) had necrotizing pneumonia and 6 of 16 (37.5%) with necrotizing pneumonia complicated by a giant lung cyst or lung abscess. All were closely observed and showed complete clinical and radiographic resolution with antibiotic treatment. CONCLUSIONS: Treatment of giant lung cyst formation following necrotizing pneumonia by a conservative approach with prolonged antibiotics results in complete recovery with no need for invasive procedures.

Recurrent Pneumonia due to Fibrosing Mediastinitis in a Teenage Girl: A Case Report with Long-Term Follow-Up.

A teenage girl was evaluated for recurrent right pneumonia. The evaluation revealed a calcified mediastinal mass that compressed the right intermediate and middle lobar bronchi, as well as the right pulmonary artery and veins. The clinical picture together with imaging studies and borderline positive serology testing suggested a diagnosis of fibrosing mediastinitis associated with histoplasmosis. This rare condition is characterized by the local proliferation of invasive fibrous tissue within the mediastinum due to a hyperimmune reaction to Histoplasma capsulatum. Antifungal and anti-inflammatory therapies are usually ineffective, and surgical intervention contains a high morbidity risk. Palliative surgery and stenting of the compressed airway have been suggested. In the past, the prognosis was thought to be poor, but recent studies demonstrate a more positive outcome. Our patient had been radiologically and functionally stable under follow-up for over thirteen years and has married and delivered two healthy children, both following an uneventful pregnancy.

Use of tidal breathing curves for evaluating expiratory airway obstruction in infants.

OBJECTIVE: To evaluate tidal breathing (TB) flow-volume and flow-time curves for identification of expiratory airway obstruction in infants. METHODS: Pulmonary function tests were analyzed retrospectively in 156 infants aged 3-24 months with persistent or recurrent respiratory complaints. Parameters derived from TB curves were compared to maximal expiratory flow at functional residual capacity ( V˙ maxFRC) measured by rapid thoracoabdominal compression technique. Analyzed parameters were: inspiratory time (tI), expiratory time (tE), tidal volume, peak tidal expiratory flow (PTEF), time to peak tidal expiratory flow (tPTEF), expiratory flow when 50% and 25% of tidal volume remains in the lungs (FEF50, FEF25, respectively), and the ratios tPTEF/tE, tI/tE, FEF50/PTEF, and FEF25/PTEF. Statistical comparisons between flow indices and TB parameters were performed using mean squared error and Pearson's sample correlation coefficient. The study population was also divided into two groups based on severity of expiratory obstruction (above or below z-score for V˙ maxFRC of -2) to generate receiver operating characteristic (ROC) curves and calculate discriminatory values between the groups. RESULTS: TB parameters that were best correlated to V˙ maxFRC were: tPTEF/tE, FEF50/PTEF, and FEF25/PTEF, with r = 0.61, 0.67, 0.65, respectively (p < 0.0001 for all). ROC curves for FEF50/PTEF, FEF25/PTEF and tPTEF/tE showed areas under the curve of 0.813, 0.797, and 0.796, respectively. Cutoff value z-scores of -0.35, -0.34, and -0.43 for these three parameters, respectively, showed an 86% negative predictive value for severe airway obstructions. CONCLUSION: TB curves can assist in ruling out severe expiratory airway obstruction in infants.

Primary ciliary dyskinesia in Israel: Prevalence, clinical features, current diagnosis and management practices.

BACKGROUND: Primary Ciliary Dyskinesia (PCD) is rare and its features in Israel have not been described. AIMS: to assess prevalence utilizing state-of-the-art diagnostic techniques, and describe clinical features, diagnostic and management practices in Israel. METHODS: A national multicenter study from 2012 to 2013 recruited patients diagnosed or suspected of having PCD. Diagnosis was verified using: nasal Nitric Oxide (nNO); High-speed Video Microscope Analysis (HVMA); Transmission Electron Microscopy (TEM) of cilia; Immuno-fluorescence staining (IF) for ciliary proteins, and genetic analysis. RESULTS: Of the 203 patients recruited from 14 pediatric centers, 150 had a PCD diagnosis verified. Median age was 15.05y, with range 0.15-60.5y. PCD prevalence was 1:54,000 for the general population and 1:25,000 in children (5-14 y). For the non-Jewish (mainly Druze and Arab Moslem) compared to Jewish populations, prevalence was 1:16,500 and 1:139,000 respectively (p < 0.0001) and parental consanguinity was 85.4% and 21.9% respectively (p < 0.0001). Clinical features included bronchiectasis (88%), rhinitis (81%), recurrent pneumonia (78%), recurrent otitis (62%), neonatal pneumonia (60%) and situs inversus (42%). Prior diagnostic practices varied widely between centers with TEM assessed in 55% and abnormal in 61% of these. Management included antibiotics and airway clearance. Diagnostic verification revealed for 150 PCD patients: 81% nNO<233 ppb, 62% abnormal HVMA, 51% diagnostic TEM, 58% diagnostic IF and, 57% genetic diagnosis. CONCLUSIONS: PCD in Israel is rare, with comprehensive diagnostic tests showing prevalence in children similar to Europe. Prevalence was higher in non-Jews, associated with parental consanguinity. Diagnostic and management practices vary. Referral centers providing comprehensive diagnostic and care capabilities should be established.

Collecting clinical data in primary ciliary dyskinesia- challenges and opportunities.

Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.

Bronchodilator responsiveness in wheezy infants predicts continued early childhood respiratory morbidity.

OBJECTIVE: Spirometry including bronchodilator responsiveness is considered routine in the workup of asthma in older children. However, in wheezy infants the existence of bronchodilator responsiveness and its prognostic significance remain unclear. METHODS: Infants (< 2 years) with chronic or recurrent wheezing or coughing were evaluated by infant pulmonary function testing (PFT). Maximal expiratory flow at the point of functional residual capacity (V̇maxFRC) was measured before and 20 minutes after salbutamol administration. Only infants with an obstructive profile (V̇maxFRC < 80% predicted) were included. The infants were divided into two groups with regard to whether or not a response to salbutamol was observed on PFT. A response was defined as a mean V̇maxFRC after salbutamol administration exceeding the upper confidence interval limit of individual pre-bronchodilator V̇maxFRC measurements. Follow-up data was gathered after a mean of 2 years. MEASUREMENTS AND MAIN RESULTS: Sixty infants were included in the study of which 32 (53%) demonstrated responsiveness to bronchodilators. The infants in the responsive group had a significantly higher frequency of physician visits for wheezing than the non-responders (3.0 mean visits/yr vs. 1.5 respectively, P = 0.03), and had a higher likelihood of having received asthma medication in the last year of the follow-up period (84% vs. 50% respectively, RR: 1.68[1.10-2.56]). At the end of the follow-up period, more parents in the responsive group reported continued respiratory disease (71% vs. 22%, RR:3.21[1.30-7.95]). CONCLUSIONS: Bronchodilator responsiveness can be demonstrated by infant PFT in infants with recurrent wheezing and can predict increased respiratory morbidity until 3 years of age.

Infant pulmonary function testing in chronic pneumonitis of infancy due to surfactant protein C mutation.

Pulmonary function testing is a vital tool in evaluation and management of adult ILD patients and is rarely overlooked during workup. However, there is paucity of data regarding its usefulness in management of infants with suspected interstitial lung disease. In this paper, we present the contribution of infant pulmonary function testing (iPFT) to the management of two infants with biopsy confirmed chronic pneumonitis of infancy due to surfactant protein C mutation. We have productively and safely used serial iPFT for decision making both during diagnosis and follow-up of these infants.

MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.

Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder. Affected persons suffer from recurrent infections of upper and lower airways because of highly reduced numbers of multiple motile respiratory cilia. Here we report recessive loss-of-function and missense mutations in MCIDAS-encoding Multicilin, which was shown to promote the early steps of multiciliated cell differentiation in Xenopus. MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia. Consistent with this finding, FOXJ1-regulating axonemal motor protein expression is absent in respiratory cells of MCIDAS mutant individuals. CCNO, when mutated known to cause RGMC, is also absent in MCIDAS mutant respiratory cells, consistent with its downstream activity. Thus, our findings identify Multicilin as a key regulator of CCNO/FOXJ1 for human multiciliated cell differentiation, and highlight the 5q11 region containing CCNO and MCIDAS as a locus underlying RGMC.

Natural history of five children with surfactant protein C mutations and interstitial lung disease.

Interstitial lung diseases in infants and children are uncommon and may be caused by specific inborn errors of surfactant metabolism. Five children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for surfactant protein gene mutations. Four of the children were originally diagnosed as desquamative interstitial pneumonitis and one as chronic interstitial pneumonitis. All had good response to chloroquine or hydroxychloroquine treatment for periods of 7-38 months. Lung function tests, incremental exercise tests, and rentgenological studies were performed in the children. Surfactant protein gene mutations were searched in all the patients and in part of their families. Three of the patients, aged now 32, 29, and 37 years, feel well and have normal lung function, while two of the patients, both females, aged 28 and 37 years, conduct normal activities of daily living, have healthy children but have clinical, physiological and rentgenological evidence of restrictive lung disease. All five patients were found to have surfactant protein C gene (SFTPC) mutations, three of them with the most common mutation (p.I73T) and the other two with new mutations of surfactant protein C gene (p.I38F and p.V39L). We conclude that detection of surfactant protein mutations should be attempted in all children presenting with interstitial lung disease. Furthermore, treatment with hydroxychloroquine should be considered in children with SFTPC mutations. Prospective evaluation of hydroxychloroquine therapy in a greater number of patients is needed.

Predictive value of adenosine 5'-monophosphate challenge in preschool children for the diagnosis of asthma 5 years later.

We evaluated the predictive values of preschool bronchial challenge with nebulized adenosine 5'-monophosphate (AMP) using the auscultation method for having asthma 5 years later. Preschool AMP challenge had a high negative (90%) and a moderate positive (67%) predictive value for asthma 5 years later. Positive predictive value increased with the age at which the challenge was performed. The degree of preschool response to AMP was associated with the severity of asthma at school age.

Relation between partial and raised volume forced expiratory flows in sick infants.

RATIONALE: The maximal expiratory flow-volume (MEFV) and the partial expiratory flow-volume (PEFV) maneuvers are interchangeably performed when testing infant lung function. In recent years, the MEFV has gained popularity over the PEFV as it offers the investigator various forced expiratory flow and volume variables in addition to the sole, maximal flow at functional residual capacity (Vmax FRC) available from the PEFV maneuver. Both types of measure are considered to provide information on airway function. OBJECTIVES: To compare Vmax FRC values by PEFV to flows at low lung volumes by MEFV in infants suffering from a variety of illnesses. METHODS: Retrospective analysis of records of 175 infants attending a tertiary out-patient clinic (age range 2-234 weeks). Comparisons between parameters derived from the PEFV and MEFV curves were made by linear regression and by Bland-Altman plots. MEASUREMENTS AND MAIN RESULTS: Vmax FRC highly correlated with forced expiratory flows at 85% of forced vital capacity (FEF85; r = 0.87, P < 0.0001) with a mean bias of 20 ml/sec, and at 75% (FEF75; r = 0.83, P < 0.0001) with a greater mean bias of -72 ml/sec, but less with forced expired volume in 0.5 sec (FEV0.5; r = 0.66, P < 0.0001) showing a much wider scatter especially in infants with more severe obstruction. Same agreement between Vmax FRC and FEF85 or FEF75 was seen when presented as z-scores (r = 0.77 and 0.76; respectively). CONCLUSIONS: Regardless of the maneuver performed, PEFV or MEFV, Vmax FRC and FEF85, and FEF75 show high agreement in sick infants. As they both describe small airways function, both maneuvers may be interchangeable.