Jack F. Price

Clinical Characterization of Left Ventricular Noncompaction in Children A Relatively Common Form of Cardiomyopathy

Background—Left ventricular noncompaction (LVNC) is a reportedly uncommon genetic disorder of endocardial morphogenesis with a reportedly high mortality rate. The purpose of this study was to identify the clinical characteristics of children with LVNC. Methods and Results—We retrospectively reviewed 36 children with LVNC evaluated at Texas Children’s Hospital (TCH) from January 1997 to December 2002. Five children had associated cardiac lesions. There were 16 girls and 20 boys. The median age at presentation was 90 days (range, 1 day to 17 years). The median duration of follow-up was 3.2 years (range, 0.5 to 12 years). Twenty-seven patients (75%) had ECG abnormalities, most commonly biventricular hypertrophy (10 patients, 28%). Both ventricles were involved in 8 patients (22%) and only the left ventricle in 28 patients (78%). Left ventricular systolic function was depressed in 30 patients (83%), with a median ejection fraction of 30% (range, 15% to 66%) at diagnosis. Nine patients presenting in the first year of life with depressed left ventricular contractility had a transient recovery of function; however, ejection fraction deteriorated later in life, at a median interval of 6.3years (range, 3 to 12 years). Two patients had an “undulating” phenotype from dilated to hypertrophic cardiomyopathy. Two patients (6%) were identified with an underlying G4.5 gene mutation. Five patients (14%) died during the study. Conclusions—LVNC does not have an invariably fatal course when diagnosed in the neonatal period. A significant number of patients have transient recovery of function followed by later deterioration, which may account for many patients presenting as adults, some manifesting an “undulating” phenotype.

Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests

Background: Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple-breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. Objectives: To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco–abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. Methods: Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. Results: Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV0.5 and FEF25–75 ) than boys (mean (95% CI girls–boys): –1.2 (–2.1 to −0.3) for FEV0.5 Z score; FEF25–75: –1.2 (–2.2 to −0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. Conclusions: These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.

Characterization of Left Ventricular Diastolic Function by Tissue Doppler Imaging and Clinical Status in Children With Hypertrophic Cardiomyopathy

Background—Conventional transmitral Doppler indices are unreliable in assessing clinical status in patients with hypertrophic cardiomyopathy (HCM) because they are affected by loading conditions. This study sought to determine whether tissue Doppler velocities are predictive of adverse clinical outcomes including death, cardiac arrest, ventricular tachycardia (VT), significant cardiac symptoms, and exercise capacity in children with HCM. Methods and Results—We studied 80 consecutive children (median age 12 years, median follow-up 26 months) evaluated at 1 hospital from January 1999 to August 2003 compared with 80 age- and gender-matched controls. Patients underwent echocardiography, ambulatory Holter monitoring, and upright exercise testing. Children with HCM had significantly decreased early diastolic tissue Doppler velocities at the lateral mitral (13.2 versus 19.3 cm/s), tricuspid (13.3 versus 16.3 cm/s), and septal (9.4 versus 13.5 cm/s) annuli compared with controls (P <0.001 for each comparison). By forward stepwise regression analysis, early transmitral left ventricular filling velocity (E)/septal Ea ratio predicted death, cardiac arrest, or VT (r =0.610, R2 =0.37, P <0.001). Peak oxygen consumption (&OV0312;O2) was most predictive of children who developed symptoms (r =0.427, R2 =0.182, P <0.001). Peak &OV0312;O2 correlated inversely with E/Ea septal ratio (r =−0.740, P <0.01). Conclusions—Transmitral E/septal Ea ratio predicts children with HCM who are at risk of adverse clinical outcomes including death, cardiac arrest, VT, and significant cardiac symptoms. Peak &OV0312;O2 correlated with peak exercise capacity in HCM patients.

Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis.

RATIONALE The markedly improved life expectancy of children with cystic fibrosis (CF) has created a new challenge, as traditional markers of lung disease are frequently normal in young children. This prevents identification of individuals who may benefit from more aggressive therapy and also obliges large study numbers and prolonged duration for intervention studies. There is an urgent need for alternative surrogates that detect early lung disease and track through early childhood. OBJECTIVES This study aimed to determine whether multiple-breath washout (MBW) results at preschool age can predict subsequent abnormal lung function. METHODS Preschool children (3-5 yr) with CF and healthy control subjects underwent spirometry and MBW with testing repeated during early school age (6-10 yr). Primary outcomes were FEV1 from spirometry and lung clearance index (LCI) from MBW. MEASUREMENTS AND MAIN RESULTS Forty-eight children with CF and 45 healthy children completed testing. Thirty-five (73%) children with CF had abnormal LCI at preschool age, whereas only five had abnormal FEV1. The positive predictive value of preschool LCI for predicting any abnormal school-age result was 94%, with a negative predictive value of 62%. Only one child with abnormal FEV1 at school age had had a normal preschool LCI. In contrast, for preschool FEV1 the positive predictive value was 100%, but negative predictive value was only 25%. CONCLUSIONS This study demonstrates that an abnormal preschool LCI predicts subsequent lung function abnormalities, whereas a normal preschool LCI usually remains normal. MBW has potential as a clinical and research outcome in young children with CF.

Higher risk of infantile atopic dermatitis from maternal atopy than from paternal atopy

The risk of infantile atopic dermatitis (AD) posed by maternal atopy and paternal atopy, respectively, were compared in the infants from a birth cohort in whom one of the parents had been designated atopic by skin prick testing. Nineteen with atopic mothers were compared with 20 with atopic fathers. AD, other atopic manifestations and potentially influential factors such as breast‐feeding were documented prospectively during the first year in all infants. At 3, 6 and 12 month assessments skin prick sensitivity and total serum IgE concentration were determined. Nine of 19 infants with atopic mothers and two of 20 with atopic fathers had AD (P= 0.023) giving a relative risk of 4.7 (95% confidence interval 2.5 to 9.0). Seven of 19 with atopic mothers and none with atopic fathers had AD with onset before 6 months (P= 0.007). When all types of disease evidence (AD, recurrent wheeze and food reactions) were analysed together no significant difference was apparent between the groups. The two groups were found to be well matched with regard to breast‐feeding, time of starting cows milk, solids and egg, sex, month of birth, parental AD and smoking, race, household pets and neonatal IgE concentration. IgE concentrations at each age and the prevalence of skin prick positivity were similar between the groups. Maternal atopy poses a higher risk for infantile AD and paternal atopy. Whether this may be due to genetic or congenital factors or both is uncertain, but clearly the finding is of relevance in the prediction of allergy in childhood.

B-Type Natriuretic Peptide Predicts Adverse Cardiovascular Events in Pediatric Outpatients With Chronic Left Ventricular Systolic Dysfunction

Background— Plasma B-type natriuretic peptide (BNP) levels are elevated in adults with heart failure and correlate with functional classification and prognosis. The range and predictive power of BNP concentrations in children with chronic heart failure, however, are not known. Methods and Results— Whole blood BNP concentrations were measured in 53 consecutive patients with chronic left ventricular (LV) systolic dysfunction (biventricular hearts, ejection fraction <50%, >3 months since diagnosis). Children who had been hospitalized within 3 months before potential enrollment and those <2 months or >21 years of age were excluded. BNP concentrations were measured with the Triage assay (Biosite Diagnostics, Inc, San Diego, Calif). Echocardiographers and clinicians were blinded to BNP levels. An adverse cardiovascular event was defined as cardiac death, cardiac-related hospitalization, or listing for cardiac transplantation. The median age of patients with LV dysfunction was 9.3 years (interquartile range [IQR], 2.7 to 15.1 years). BNP levels were elevated in children with LV dysfunction compared with healthy controls (median, 78 pg/mL [IQR, 22 to 551 pg/mL] versus median, 7 pg/mL [IQR, 5 to 11 pg/mL]; P<0.0001). Whole blood BNP concentrations were increased in patients who had a 90-day adverse cardiovascular event compared with those who did not (median, 735 pg/mL [IQR, 685 to 1510 pg/mL] versus median, 37 pg/mL [IQR, 14 to 92 pg/mL]; P<0.001). Patients with a BNP concentration ≥300 pg/mL were at increased risk of death, hospitalization, or listing for cardiac transplantation (adjusted hazard ratio, 63.6; P<0.0001). Conclusions— BNP concentrations are elevated in children with chronic LV systolic dysfunction and predict the 90-day composite end point of death, hospitalization, or listing for cardiac transplantation.

Lung function from infancy to the preschool years after clinical diagnosis of cystic fibrosis.

RATIONALE After recent standardization of forced expiratory maneuvers for both infants and preschool children, longitudinal measurements are now possible from birth. OBJECTIVES The aim of this study was to investigate the evolution of lung function during the first 6 years of life after a clinical diagnosis of cystic fibrosis (CF) in infancy in children with CF and in healthy control subjects. METHODS The raised volume technique was used during infancy and incentive spirometry during the preschool years. MEASUREMENTS AND MAIN RESULTS Forty-eight children with CF and 33 healthy control subjects had up to seven (median, 3) measurements. Over these early years, the diagnosis of CF itself accounted for a significant mean reduction of 7.5% (95% confidence interval, 0.9 - 13.6%) in FEV(0.75) and 15.1% (95% confidence interval, 3.6 - 25.3%) in FEF(25-75). Wheeze on auscultation, recent cough, and Pseudomonas aeruginosa (PsA) infection (even if apparently effectively treated) were all independently associated with further reductions in lung function. Premorbid lung function did not predict infection with PsA. CONCLUSIONS This is the first study to describe physiologic measurements from infancy through the preschool years in subjects with CF and healthy control subjects, the understanding of which is critical for future intervention trials. Airflow obstruction in uncomplicated CF persists through the preschool years despite treatment, with PsA acquisition being associated with further deterioration in lung function, even when apparently eradicated. This suggests that new therapies are needed to treat the airflow obstruction of uncomplicated CF, and rigorous strategies to prevent PsA acquisition.

Airway function in infants newly diagnosed with cystic fibrosis.

The lung function of infants with cystic fibrosis is often reduced shortly after diagnosis. We measured the airway function of newly diagnosed infants to test whether this reduction is independent of clinically recognised lower respiratory illness. We compared the airway function of 33 infants with cystic fibrosis and 87 healthy controls after adjustment for sex, age, bodyweight and length, and exposure to maternal smoking. Airway function was significantly reduced in children with cystic fibrosis, even in those without clinically recognised previous lower respiratory illness. Our findings raise important questions about the onset and natural history of impaired airway function in infants with cystic fibrosis.

Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children

Background—Some patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy also present with skeletal myopathy and Wolff-Parkinson-White (WPW) syndrome; mutations in the gene encoding the lysosome-associated protein-2 (LAMP-2) have been identified in these patients, suggesting that some of these patients have Danon disease. In this study we investigated the frequency of LAMP2 mutations in an unselected pediatric HCM population. Methods and Results—LAMP2 was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing. In 2 of the 50 probands (4%), nonsense mutations were identified. In 1 family the proband initially presented with HCM as a teenager, which progressed to dilated cardiomyopathy (DCM) and heart failure. Skeletal myopathy and WPW were also noted. The teenage sister of the proband is a carrier of the same LAMP2 mutation and has HCM without skeletal myopathy or WPW. The other proband presented with HCM, WPW, and skeletal myopathy as a teenager, whereas his carrier mother developed DCM during her 40s. Skeletal and cardiac muscle sections revealed the absence of LAMP-2 on immunohistochemical staining. Conclusions—LAMP2 mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community.

Persistent increase in plasma and urinary leukotrienes after acute asthma.

Leukotrienes may mediate bronchoconstriction in asthma. Cysteinyl leukotriene production rises in vivo after allergen challenge, but few reports describe leukotriene concentrations in clinical asthma or in children. Using high performance liquid chromatography/radioimmunoassay, plasma and urinary leukotrienes in asthmatic children (aged 5-10 years) were measured during an acute exacerbation (peak expiratory flow (PEF) < 65%, n = 10) and one month later (PEF 74-169%, n = 9), and in non-atopic normal children (aged 1.3-13.2 years). In the asthmatics, geometric mean (95% confidence interval) plasma leukotriene B4 (LTB4) was 746 pg/ml (398 to 1403) acutely and 1026 pg/ml (662 to 1593) in remission, compared with 369 pg/ml (167 to 728) in the normal children (n = 14). Plasma cysteinyl leukotrienes were low or undetectable, but urinary leukotriene E4 (LTE4) was higher in the asthmatics during an acute episode (210 pmol/mmol creatinine, 101 to 454) and at follow up (179 pmol/mmol, 110 to 293), compared with the normal children (98 pmol/mmol, 81 to 118, n = 41). This persistent increase in plasma LTB4 and urinary LTE4 concentrations one month after a severe asthmatic episode suggests leukotriene production is related to chronic inflammation rather than to acute bronchoconstriction.