Early immune response to the components of the type III system of Pseudomonas aeruginosa in children with cystic fibrosis.

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.

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 (FEV(1))/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. The best regression model for predicting changes in the WCXR included time to first positive culture and antibody titer for Pa elastase. Prior to Pa acquisition, WCXR worsened by 0.45 points/year (P > 0.25); after Pa acquisition, the rate of worsening increased significantly (P < 0.001) to 1.40 points/year. Each antibody titer level (log base 2) increased the score by 0.48 points (P < 0.001). The best regression model for predicting change in the FEV(1)/FVC included only time to first positive culture. Prior to Pa acquisition, the FEV(1)/FVC ratio declined by 1.29%/year; after Pa infection, the rate of decrease significantly accelerated to 1.81%/year (P = 0.001). Our data show that Pa acquisition is associated with declining pulmonary status in children with CF, and that this effect is probably gradual rather than precipitous. Because these patients were diagnosed and treated aggressively, our estimates of the effects of Pa acquisition may be conservative. We also conclude that the WCXR appears to be more sensitive than FEV(1)/FVC in detecting early changes in lung disease associated with CF.

Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Wisconsin Cystic Fibrosis Neonatal Screening Study Group.

OBJECTIVE: Despite its relative frequency among autosomal recessive diseases and the availability of the sweat test, cystic fibrosis (CF) has been difficult to diagnose in early childhood, and delays can lead to severe malnutrition, lung disease, or even death. The Wisconsin CF Neonatal Screening Project was designed as a randomized clinical trial to assess the benefits and risks of early diagnosis through screening. In addition, the incidence of CF was determined, and the validity of our randomization method assessed by comparing 16 demographic variables. METHODOLOGY: Immunoreactive trypsinogen analysis was applied to dried newborn blood specimens for recognition of CF risk from 1985 to 1991 and was coupled to DNA-based detection of the DeltaF508 mutation from 1991 to 1994. Randomization of 650 341 newborns occurred when their blood specimens reached the Wisconsin screening laboratory. This created 2 groups-an early diagnosis, screened cohort and a standard diagnosis or control group. To avoid selection bias, we devised a unique unblinding method with a surveillance program to completely identify the control subjects. Because sequential analysis of nutritional outcome measures revealed significantly better growth in screened patients during 1996, we accelerated the unblinding and completely identified the control group by April 1998. Having each member of this cohort enrolled and evaluated for at least 1 year and having completed a comprehensive surveillance program, we performed another statistical analysis of anthropometric evaluated indices that includes all CF patients without meconium ileus. RESULTS: The incidence of classical CF, ie, patients diagnosed in this trial with a sweat chloride of 60 mEq/L greater, was 1:4189. By incorporating other CF patients born during the randomization period, including 2 autopsy diagnosed patients and 8 probable patients, we calculate a maximum incidence of 1:3938 (95% confidence interval: 3402-4611). Although there were group differences in the proportion of patients with DeltaF508 genotypes and with pancreatic insufficiency, validity of the randomization plan was demonstrated by analyzing 16 demographic variables and finding no significant difference after adjustment for multiple comparisons. Focusing on patients without meconium ileus, we found a marked difference in the mean +/- standard deviation age of diagnosis for screened patients (13 +/- 37 weeks), compared with the standard diagnosis group (100 +/- 117). Anthropometric indices of nutritional status were significantly higher at diagnosis in the screened group, including length/height, weight, and head circumference. During 13 years of study, despite similar nutritional therapy and the inherently better pancreatic status of the control group, analysis of nutritional outcomes revealed significantly greater growth associated with early diagnosis. Most impressively, the screened group had a much lower proportion of patients with weight and height data below the 10th percentile throughout childhood. CONCLUSIONS: Although the screened group had a higher proportion of patients with pancreatic insufficiency, their growth indices were significantly better than those of the control group during the 13-year follow-up evaluation and, therefore, this randomized clinical trial of early CF diagnosis must be interpreted as unequivocally positive. Our conclusions did not change when the height and weight data before 4 years of age for the controls detected by unblinding were included in the analysis. Also, comparison of growth outcomes after 4 years of age in all subjects showed persistence of the significant differences. Therefore, selection bias has been eliminated as a potential explanation. In addition, the results show that severe malnutrition persists after delayed diagnosis of CF and that catch-up may not be possible. We conclude that early diagnosis of CF through neonatal screening combined with aggressive nutritional therapy can result

Wire stent for tracheomalacia in a five-year-old girl.

A wire stent was used successfully to treat life-threatening tracheomalacia in a 5-year-old girl. Wire stents placed bronchoscopically are nonobstructing and have the potential for balloon expansion to accommodate growth.

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 children's 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.

Immune responses to Aspergillus fumigatus and Pseudomonas aeruginosa antigens in cystic fibrosis and allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) in Cystic Fibrosis (CF) is well documented. Aspergillus fumigatus is the causative agent of ABPA, and Pseudomonas aeruginosa particularly the mucoid variety has been frequently isolated from the sputum of patients with CF. This study investigates the cellular and humoral immune response to both A fumigatus and P aeruginosa antigens in patients with CF and ABPA (CF/ABPA), CF only, and healthy controls. The A fumigatus and P aeruginosa antigen specific IgE and IgG in sera and peripheral blood mononuclear cell culture supernatants (PBMC sups), lymphoproliferation to antigens, and leukotriene B4 (LTB4) were measured. Results indicate significant elevated levels of A fumigatus specific IgG (A fumigatus-IgG) and Paeruginosa-IgE in serum. Significant Paeruginosa-IgG was measured in PBMC sups. The concanavalin A nonbinding A fumigatus antigen, previously shown to induce specific T-cell responses in vitro in patients with ABPA, elicited significant lymphoproliferative response in a greater proportion of patients with CF/ABPA and not in CF or controls, underlining the importance of this antigen in the diagnosis of ABPA. In contrast, a greater proportion of the CF group responded to P aeruginosa antigens compared with the controls and CF/ABPA. Hence, the CF and CF/ABPA groups respond to both P aeruginosa and A fumigatus antigens with the former group responding strongly to P aeruginosa and the latter to A fumigatus antigens.

Brain abscess caused by Blastomyces dermatitidis in a child with cystic fibrosis.

An 8-year-old girl with moderately severe cystic fibrosis and right upper lobe bronchiectasis developed a cerebellar abscess caused by Blastomyces dermatitidis. To our knowledge, this is the youngest child with cystic fibrosis and a brain abscess, and the first documented case caused by a fungus.

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.

Survival and functional outcome of children with severe cerebral palsy following gastrostomy.

Survival, functional outcome, care setting, early and late complications, and caregiver satisfaction were determined in 61 children with severe cerebral palsy requiring gastrostomies during a six-year period. Fifty-three (87%) of the initial gastrostomies included a Nissen fundoplication. Early and late complications were 32.8% and 39.3%, respectively. Survival after initial surgery was 84.2% at one year, and 67.6% at four years. One child died within one month of surgery. Seventy percent of the children remained totally dependent in self-care, mobility, and communication; an additional 29% had significant limitations in function. Only 4 children (6.5%) ultimately became independent in feeding. Ninety-three percent of the children were cared for at home. Ninety-four percent of the parents/caregivers believed the gastrostomy was beneficial in management of the child. Survival was unexpectedly high compared to studies of adults and mentally retarded children requiring similar surgical procedures.

Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cbl-C type).

We report an infant with a bronchiolitis-like illness and rapid deterioration who developed a cor pulmonale-like picture with a dilated right ventricle. Urinary organic acid assays established a probable diagnosis of Cbl-C-type methylmalonic aciduria, later confirmed by complementation studies. Despite medical intervention and cyanocobalamin treatment the patient died on his tenth hospital day. Postmortem examination showed the presence of thromboemboli in the pulmonary circulation. We hypothesize that acute cor pulmonale developed in this infant secondary to thromboembolism of his pulmonary circulation. A review of the literature shows that thromboembolism may be a part of this disease process.

Social dimensions to functional gain in pediatric patients.

Rehabilitation hospitals recognize the need for holistic patient care and employ professionals who are concerned with the social dimensions of functional independence. However, there have been few empirical studies of the relationship between social variables and functional gain. Functional assessment data for 66 pediatric patients admitted to an inpatient rehabilitation program were analyzed. Regressing residual gain scores on social variables from the Patient Evaluation and Conference System (a patient tracking data base) showed significance (p less than .01) in pediatric functional gain. Patients whose families were less able to support their independent living before admission made the greatest functional gains. Family support for disabled pediatric patients affected functional gain, affirming the importance of rehabilitation professionals' involvement with the patient's social needs throughout the rehabilitation process.

Brain injury: functional outcome in children with tracheostomies and gastrostomies.

Survival, functional outcome, placement, and need for appliances at six and 24 months after either anoxic metabolic encephalopathies (AME) or traumatic head injuries (TI) were determined in 36 children with both tracheostomies and gastrostomies who were discharged from acute care hospitals. Five deaths occurred in totally dependent children with both tracheostomies and gastrostomies in place. Ten of 22 children with TI (48% of survivors) achieved independence in three functional areas by two years, whereas none of 14 with AME achieved functional independence in any area at two years (p = 0.001). Only one of the 18 who were dependent in all three areas at six months achieved partial independence in any area on reevaluation at two years. Institutionalization at two years was strongly predicted by six-month functional status (p less than 0.01). Four of 18 children dependent at six months returned to home care by two years, whereas all 16 children who achieved partial independence within six months of insult were cared for at home at two years (p less than 0.001), regardless of age or injury type. The need for tracheostomy at two years correlated with functional status at six months (p less than 0.01). Two-year survival was unexpectedly high for this group of children when compared to studies in adults. Functional status at six months is a strong predictor of dependency and institutionalization at two years.

Aspiration in rehabilitation patients: videofluoroscopy vs bedside clinical assessment.

This paper reports the results of a blinded study comparing videofluoroscopy with bedside clinical evaluations by speech/language pathologists in the diagnosis of aspiration. One hundred and seven inpatients from a general rehabilitation hospital were evaluated over a four-month period. Of the total patient population, 43 (40%) aspirated at least one consistency of food during videofluoroscopy. Bedside evaluation identified only 18 (42%) of these patients. The positive predictive value of bedside assessment was 0.75; negative predictive value was 0.70. Aspirators on videofluoroscopy were more likely to have brainstem or multilobe central nervous system involvement than nonaspirators. However, there was no statistically significant difference in lesion sites between clinically detected and "silent" aspirators. While the significance of aspiration noted on videofluoroscopy is debatable, it is clear that bedside evaluation alone underestimates the frequency of aspiration in patients with neurologic dysfunction.

Survival after chloroquine ingestion in a child.

We report the case of a 17 month old, 14 kg male who ingested 4 grams of chloroquine phosphate. He developed ventricular fibrillation and cardiovascular collapse 1 hour after the ingestion. After resuscitation he was treated with diazepam 2 mg/kg acutely, and 0.25 mg/kg/hour for 4 days with no further cardiac electrophysiologic abnormalities. Gallium-67 scan showed increased radionuclide uptake in heart and renal cortex, but there was no clinical evidence of myocardial or renal dysfunction at the time of the scan. He survived with severe neurologic sequelae from the cardiovascular collapse. He had dynamic peripheral neuropathy and progressive loss of retinal function, as evidence of ongoing chloroquine neurotoxicity.

Central venous catheters in older children.

This report discusses the safety of 89 cuffed, Silastic (Dow Corning, Midland, MI) catheters placed in children between the ages of 1 and 18, a group that may be considered high risk on the basis of age. The overall complication rate was once every 288 days, three times more often than in published results in adults, but less often than in other pediatric series. The sepsis rate of once each 1236 days was almost twice the adult rate. Thirty (35%) of the catheters were used at home, accounting for 85 per cent of the total catheter use. Among this group, the overall complication rate was only once every 815 days, three times less frequent than in comparable adult series. The complication rate due to sepsis was once each 2444 days, the same as noted in adults. Whereas these catheters may be more hazardous overall in this age group, home usage appears to be safer than expected. These catheters are well accepted by this age group and their use, particularly among outpatients, should not be restricted for fear of an unacceptably high complication rate.