Mark Splaingard

Nutritional Benefits of Neonatal Screening for Cystic Fibrosis

BACKGROUND Many patients with cystic fibrosis are malnourished at the time of diagnosis. Whether newborn screening and early treatment may prevent the development of a nutritional deficiency is not known. METHODS We compared the nutritional status of patients with cystic fibrosis identified by neonatal screening or by standard diagnostic methods. A total of 650,341 newborn infants were screened by measuring immunoreactive trypsinogen on dried blood spots (from April 1985 through June 1991) or by combining the trypsinogen test with DNA analysis (from July 1991 through June 1994). Of 325,171 infants assigned to an early-diagnosis group, cystic fibrosis was diagnosed in 74 infants, including 5 with negative screening tests. Excluding infants with meconium ileus, we evaluated nutritional status for up to 10 years by anthropometric and biochemical methods in 56 of the infants who received an early diagnosis and in 40 of the infants in whom the diagnosis was made by standard methods (the control group). Pancreatic insufficiency was managed with nutritional interventions that included high-calorie diets, pancreatic-enzyme therapy, and fat-soluble vitamin supplements. RESULTS The diagnosis of cystic fibrosis was confirmed by a positive sweat test at a younger age in the early-diagnosis group than in the control group (mean age, 12 vs. 72 weeks). At the time of diagnosis, the early-diagnosis group had significantly higher height and weight percentiles and a higher head-circumference percentile (52nd, vs. 32nd in the control group; P=0.003). The early-diagnosis group also had significantly higher anthropometric indexes during the follow-up period, especially the children with pancreatic insufficiency and those who were homozygous for the deltaF508 mutation. CONCLUSIONS Neonatal screening provides the opportunity to prevent malnutrition in infants with cystic fibrosis.

Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition

As part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV1)/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol‐determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height‐for age, and weight‐for‐age‐percentiles.

Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis

The objective of this study was to identify risk factors of significance for acquisition of Pseudomonas aeruginosa by children with cystic fibrosis (CF). Our working hypothesis is that exposure of infants and young children with CF to older, infected patients increases their risk for acquiring this organism. A special opportunity arose to study this question in detail, as we have been performing a randomized clinical trial of neonatal screening for CF throughout the state of Wisconsin during the period of 1985–1994. Patients were selected for this study based on either early identification through screening or diagnosis by standard methods. A longitudinal protocol employed at Wisconsins two CF Centers includes routine cultures of respiratory secretions and collection of clinical, demographic, and activity information on patients and their families. Previous observations in our trial revealed that one center at an old hospital in an urban location showed a significantly shorter time to acquisition of P. aeruginosafor CF patients followed there. To study the center effect further, we performed statistical analyses using survival curves and stepwise regression analysis of all life history covariates available. The results of these analyses showed that the statistically significant correlations involve the following risk factors: (1) center and old hospital (r = 0.42); (2) center and original physician (r = 0.61); (3) center and exposure to pseudomonas‐positive patients (r = 0.29); and (4) population density and urban location (r = 0.49). The final statistical model demonstrated that increased risk due to aerosol use (odds ratio = 3.45, P = 0.014) and a protective effect associated with education of the mother (odds ratio = 0.81, P = 0.024) were the most significant factors for acquisition of P. aeruginosa. The previously observed center effect was confined to the 1985–1990 interval at the old hospital (odds ratio = 4.43, P < 0.001). We conclude that multiple factors are involved in increasing the risk of young children with CF to acquire P. aeruginosa, and that the observed center effect can best be explained by a combination of factors. These results suggest that facilities and methods used to care for young children with CF can significantly influence their likelihood of acquiring pseudomonas in the respiratory tract. Pediatr Pulmonol. 1998; 26:81–88.

Survival and functional outcome of children requiring endotracheal intubation during therapy for severe traumatic brain injury.

OBJECTIVE To determine the predictors of survival and functional outcome of pediatric patients with traumatic brain injury severe enough to require endotracheal intubation and mechanical ventilation. DESIGN Retrospective, observational cohort study. SETTING Pediatric intensive care unit (ICU) at a tertiary care childrens hospital. PATIENTS All children (n = 105) admitted over a 5-yr period with traumatic brain injury severe enough to require endotracheal intubation and mechanical ventilation. The median age was 43 months (range 1 month to 14 yrs). Of these children, 74% were male and 70% were white. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Variables studied included vital signs during the first 24 hrs of admission, Pediatric Risk of Mortality (PRISM) score, Glasgow Coma Score, duration of mechanical ventilation, and number of pediatric ICU and hospital days. Functional status was graded as normal, independent, partially dependent, or dependent in the areas of locomotion, self-care, and communication. This status was assessed at hospital discharge by chart review and at follow-up by telephone interview. The median Glasgow Coma Score was 6 (range 3 to 14) and the median PRISM score was 13 (range 1 to 51). There were 19 (18.1%) deaths, 17 in the pediatric ICU and two after hospital discharge. Of the patients who survived to hospital discharge, 39 (37.1%) patients were completely normal or independent, 42 (40%) patients were partially dependent, and seven (6.7%) patients were dependent in all three areas of function. Follow-up evaluations were available for 80 patients, with a median follow-up time of 24.5 months (range 8 to 70). Of the 78 patients who survived and were available for follow-up, the number who were functionally normal or independent increased to 69 (65.7%). At follow-up, there were eight (7.6%) patients remaining with partial dependency in at least one area of function while one (0.9%) patient continued to be dependent in all three areas of function. Mortality and dependent functional outcome were more likely in patients with younger age, lower Glasgow Coma Score, and higher PRISM score at hospital admission. Of the 27 patients with a Glasgow Coma Score of < or = 5, 11 (40.7%) survived with normal or independent functional status at follow-up. Of the 24 patients with PRISM scores of > 20, only five (20.8%) were functionally normal or independent at follow-up. The relative risk of a bad outcome for patients with a Glasgow Coma Score of < or = 5 and a PRISM score of > or = 20 was ten times higher than the group of patients with a Glasgow Coma Score of < or = 5 but a PRISM score of < 20. CONCLUSIONS Children with severe traumatic brain injury who survive to hospital discharge will continue to improve in their functional status over the next few years. Although low Glasgow Coma Score is strongly associated with death or poor functional outcome after therapy for traumatic brain injury, many patients with Glasgow Coma Score of < or = 5 can survive with good function. PRISM scores add to the power of Glasgow Coma Score to predict survival and functional outcome in tracheally intubated pediatric patients with Glasgow Coma Score of < or = 5.

Neonatal hypotonia and cardiomyopathy secondary to type IV glycogenosis

A neonate with deficiency of branching enzyme (glycogenosis type IV) presented symptoms of severe hypotonia pre- and postnatally, and dilated cardiomyopathy in early infancy. The classical clinical manifestation of liver cirrhosis was not present, although amylopectin-like inclusions were found in the hepatocytes. In contrast to a previous report, the neurons in the brain stem and spinal anterior horns contained PAS-positive, diastase-resistant deposits. The combined involvement of the muscles and motor neurones could account for the severity of hypotonia. The muscle biopsy, electromyogram and biochemical and enzyme assays were helpful in establishing the diagnosis.

Temporal Associations Among Energy Intake, Plasma Linoleic Acid, and Growth Improvement in Response to Treatment Initiation After Diagnosis of Cystic Fibrosis

OBJECTIVE. It is unclear why some patients with cystic fibrosis (CF) succeed (“responders”) in recovering from malnutrition and growth faltering after treatment initiation whereas others fail to do so (“nonresponders”). We conducted a study to test the hypothesis that sustained high energy intake (↑EN) and normal plasma essential fatty acid status are critical determinants of treatment responsiveness within 2 years after diagnosis of CF. METHODS. A total of 71 CF children who had pancreatic insufficiency but not meconium ileus and were enrolled in the Wisconsin CF Neonatal Screening Project were studied. Responders were defined by having achieved adequate weight gain, as indicated by a recovery of weight z score (Wtz) comparable to Wtz at birth (WtzBR) within 2 years of diagnosis. ↑EN and sustained normal plasma linoleic acid level (↑pLA) were defined by achieving energy intake ≥120% of estimated requirement for ≥75% of the time and maintaining plasma LA ≥26% of total fatty acids for ≥75% of the time, respectively. RESULTS. Thirty-two (68%) screened patients and 13 (54%) patients whose CF was diagnosed conventionally recovered WtzBR within 2 years of diagnosis. Screened patients responded at significantly younger ages (mean/median: 6.3/4.3 months) than patients whose CF was diagnosed conventionally (mean/median: 15.8/11.8 months). Proportionately fewer screened patients (33%) achieved ↑EN compared with patients whose CF was diagnosed conventionally (73%). However, more screened patients responded to ↑EN and recovered WtzBR (91%) than patients whose CF was diagnosed conventionally (56%), although this difference was of borderline significance. Compared with having neither ↑EN nor ↑pLA, the likelihood of being a responder was greatest with combined ↑EN and ↑pLA, followed by ↑EN only. The positive associations between ↑EN and ↑pLA to treatment responsiveness remained significant after adjustment for neonatal screening status, baseline height and weight status, and indices of pulmonary disease severity. CONCLUSION. ↑EN and ↑pLA are critical in promoting adequate weight gain in children with newly diagnosed CF.

Survival and functional outcome of children requiring mechanical ventilation during therapy for acute bacterial meningitis.

OBJECTIVE To determine predictors of survival and functional outcome of pediatric patients requiring mechanical ventilation during therapy for acute bacterial meningitis. DESIGN Retrospective case series. SETTING Pediatric intensive care unit (ICU) at a midwestern tertiary care childrens hospital. PATIENTS Consecutive sample of 32 patients (median age 9.8 months; range 9 days to 12 yrs) from 1985 to 1990 with acute bacterial meningitis severe enough to require mechanical ventilation during therapy. Of these patients, 59% were female and 59% were white. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data were analyzed to identify predictors of survival and functional status after hospital discharge. Variables included were vital signs, Pediatric Risk of Mortality (PRISM) score within the first 24 hrs of hospitalization, Glasgow Coma Score, and course of illness. Functional status was assessed at hospital discharge and at follow-up (median follow-up: 41.5 months, range 7 to 77) in the areas of locomotion, self-care, and communication. There were ten inhospital deaths. The 22 survivors formed three groups. At hospital discharge, seven children showed no functional disability. Seven patients were dependent in all three areas of function at discharge, with six still dependent at follow-up evaluation. Eight patients showed mild to moderate impairment in at least one area of function at hospital discharge. At follow-up, four of these eight patients demonstrated no functional disability, one had improved status, two were unchanged, and one was lost to follow-up. The best predictor of death and functional status at follow-up was the admission PRISM score. Hypotension and tachycardia within the first 24 hrs after pediatric ICU admission were strongly associated with poor outcome. CONCLUSIONS After bacterial meningitis in children whose care included mechanical ventilation, half of the patients died or survived with severe functional deficits. Patients with mild or moderate functional deficits at hospital discharge improved with time.

Parent and child reports of sleep problems associated with early-onset bipolar spectrum disorders.

Despite sleep problems being part of the diagnostic criteria for mood disorders, research on sleep difficulties related to early-onset bipolar spectrum disorders (EBSDs) is sparse. The authors examined the parent and child agreement, frequency, and severity of EBSD-related manic, depressive, and comorbid sleep problems. A sample of one hundred thirty-three 8- to 11-year-olds with EBSDs was assessed with parental and self-report measures of EBSD-related sleep problems. Dimensional and categorical measures indicated low agreement and high discrepancy between parent and child reports of EBSD sleep problems. Subsequent combination of parent-child data revealed the majority (96.2%) of children had moderate-to-severe sleep problems related to manic, depressive, or comorbid symptoms, either currently or during their worst mood period. More depression-related sleep problems than mania-related sleep problems were reported, especially initial insomnia. Over half the sample had sleep problems associated with current comorbidity, particularly separation anxiety disorder. These findings, their implications, and study limitations are discussed.

Early Immune Response to the Components of the Type III System of Pseudomonas aeruginosa in Children with Cystic Fibrosis

ABSTRACT The lungs of patients with cystic fibrosis (CF) are colonized initially by Pseudomonas aeruginosa, which is associated with progressive lung destruction and increased mortality. The pathogenicity of P. aeruginosa is caused by a number of virulence factors, including exotoxin A (ETA) and the type III cytotoxins (ExoS, ExoT, ExoU, and ExoY). P. aeruginosa contacts the plasma membrane to deliver type III cytotoxins through a channel formed by PopB, PopD, and PcrV; ETA enters mammalian cells via receptor-mediated endocytosis. The Wisconsin CF Neonatal Screening Project is a longitudinal investigation to assess the potential benefits and risks of newborn screening for CF; the project was the source of serum samples used in this study. Past studies evaluated the longitudinal appearance of antibodies to ETA and elastase and P. aeruginosa infections in patients with CF. The current study characterized the longitudinal appearance of antibodies to components of the type III system in children with CF. Western blot analyses showed that serum antibodies to PopB, PcrV, and ExoS were common. Longitudinal enzyme-linked immunosorbent assays determined that the first detection of antibodies to pooled ExoS/PopB occurred at a time similar to those of detection of antibodies to a P. aeruginosa cell lysate and the identification of oropharyngeal cultures positive for P. aeruginosa. This indicates that children with CF are colonized early with P. aeruginosa expressing the type III system, implicating it in early pathogenesis, and implies that surveillance of clinical symptoms, oropharyngeal cultures, and seroconversion to type III antigens may facilitate early detection of P. aeruginosa infections.

Esophageal sensation in premature human neonates: temporal relationships and implications of aerodigestive reflexes and electrocortical arousals

Electrocortical arousal (ECA) as an effect of visceral provocation or of its temporal relationships with aerodigestive reflexes in premature neonates is not known. We tested the hypothesis that esophageal provocation results in both esophageal reflex responses and ECAs during sleep and that ECAs are dependent on the frequency characteristics of esophageal neuromotor responses. We defined the spatiotemporal relationship of ECAs in relation to 1) spontaneous pharyngoesophageal swallow sequences and gastroesophageal reflux (GER) events and 2) sensory-motor characteristics of esophageal reflexes. Sixteen healthy premature neonates born at 27.9 ± 3.4 wk were tested at 36.8 ± 1.9 wk postmenstrual age. Ninety-five midesophageal and 31 sham stimuli were given in sleep during concurrent manometry and videopolysomnography. With stimulus onset as reference point, we scored the response latency, frequency occurrence and duration of arousals, peristaltic reflex, and upper esophageal sphincter contractile reflex (UESCR). Changes in polysomnography-respiratory patterns and esophageal sensory-motor parameters were scored by blinded observers. Significantly (for each characteristic listed, P < 0.05), swallow sequences were associated with arousals and sleep state changes, and arousals were associated with incomplete peristalsis, response delays to lower esophageal sphincter relaxation, and prolonged esophageal clearance. GER events (73.5%) provoked arousals, and arousals were associated with response delays to peristaltic reflexes or clearance, sleep state modification, and prolonged respiratory arousal. Midesophageal stimuli (54%) provoked arousals and were associated with increased frequency, prolonged latency, prolonged response duration of peristaltic reflexes and UESCR, and increased frequency of sleep state changes and respiratory arousals. In human neonates, ECAs are provoked upon esophageal stimulation; the sensory-motor characteristics of esophageal reflexes are distinct when accompanied by arousals. Aerodigestive homeostasis is defended by multiple tiers of aerodigestive safety mechanisms, and when esophageal reflexes are delayed, cortical hypervigilance (ECAs) occurs.