Cystic fibrosis co-existing with trisomy 21.

Previous reports of children with co-existence of cystic fibrosis and full trisomy 21 suggest a very poor prognosis, with the majority of cases dying in infancy and the oldest reported survivor being 6 years of age. We report the case of a young man with genetically confirmed trisomy 21 and homozygous for the F508del cystic fibrosis mutation. Despite the diagnosis of cystic fibrosis being delayed until the age of 2 years he has transitioned to adult services and is now 25 years of age. Currently he has poor lung function and a continuous ambulatory oxygen requirement.

Serum tobramycin levels following delivery of tobramycin (Tobi) via eFlow advanced nebuliser in children with cystic fibrosis.

BACKGROUND: Safety and toxicity data for nebulised tobramycin are mainly derived from use of the Pari LC Plus nebuliser, yet many centres are now using advanced nebulisers, such as the eFlow. METHODS: Ten children (ages 2-16years) receiving 300mg TOBI via eFlow for clinical reasons participated. Serum tobramycin levels were obtained 1h post nebulisation. Nine provided samples for urinary NAG, and 10 underwent audiology. RESULTS: Tobramycin levels were >1mg/L in 3 children (maximum 3.8, 2 children aged 2years). Urine NAG/creatinine levels were raised (>0.94micromol/min/mmol) in 5 children, 1 of these had a tobramycin level of >1mg/L. One patient had high frequency hearing loss. CONCLUSION: Serum tobramycin levels over 1mg/L can occur 1h post 300mg TOBI delivered by eFlow. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.

Isolation of the fungus Geosmithia argillacea in sputum of people with cystic fibrosis.

We report the repeated isolation of the fungus Geosmithia argillacea from sputum samples of people with cystic fibrosis. Identification was based on morphology and DNA sequence analysis. Isolation of G. argillacea did not appear to be associated with clinical deterioration. The pathogenic potential of G. argillacea is discussed.

A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis.

Screening newborns for cystic fibrosis (CF) is considered to be an ethical undertaking in regions with a significant incidence of the condition. Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants. We have undertaken a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database. This consensus document will provide guidance to CF specialists with established screening programmes and those who are in the process of implementing newborn screening in their region.

Respiratory exacerbations in childhood associated with compound heterozygosity Phe508del/Arg117His-7T of the cystic fibrosis transmembrane regulator gene.

UNLABELLED: Debate continues regarding the clinical implications for compound heterozygotes identified with Phe508del and Arg117His-7T mutations of the cystic fibrosis transmembrane regulator (CFTR) gene. We report respiratory exacerbations and airway culture of Staphylococcus aureus and Pseudomonas aeruginosa in a child with this genotype. CONCLUSION: The compound heterozygote cystic fibrosis (CF) mutation Phe508del with Arg117His-7T should not necessarily be considered benign in childhood.

Low gammaglobulin subclass 2 levels in paediatric cystic fibrosis patients followed over a 2-year period.

The aim of this study was to relate serum immunoglobulin G2 subclass levels in a large paediatric population with cystic fibrosis, to clinical status and antibody levels to Haemophilus influenzae type b and Streptococcus pneumoniae and to observe any changes over a 2-year period. IgG subclasses were measured in 131 patients. Results were compared with levels from age-related normal population data. The following clinical data were collected at baseline and 2 years later; genotype: height, weight, and BMI z-scores: FEV1 (as percent predicted): Shwachman-Kulczcyki and Northern chest X-ray scores: Pseudomonas aeruginosa status. Antibody levels to H. influenzae type b and S. pneumoniae measured at baseline were related to IgG2 level. There was a reduction in the prevalence of low levels of IgG2 from 29% to 10% over the 2-year period. Low levels of IgG2 were not associated with any decline in clinical well-being. Low levels of IgG2 alone were associated with low antibody levels to S. pneumoniae. Low levels of IgG2 and low levels of antibody to H. influenzae and S. pneumoniae were not associated with any decline in clinical well-being. Children with high levels of IgG2 had worse lung function, worse Shwachman-Kulczcyki and Northern chest X-ray scores and higher levels of P. aeruginosa infection. Children with low IgG2 levels were not worse clinically compared to those with normal or high IgG2 levels. High IgG2 levels were associated with a worse clinical status.

Immunoglobulin and IgG subclass levels in a regional pediatric cystic fibrosis clinic.

The aim of this study was to report serum immunoglobulin (Ig) and IgG subclass levels in a large pediatric population with cystic fibrosis, and relate these to measures of disease severity. Total immunoglobulin levels were measured in 154 patients, and IgG subclass levels were measured in 136 patients and compared to age-related normal population data and to levels reported in previously published studies of children with cystic fibrosis. Clinical data were also collected: genotype; height, weight, and BMI standard deviation scores; FEV(1) (as percent predicted); Shwachmann-Kulczycki (S-K) and Northern chest X-ray scores; and Pseudomonas aeruginosa infection status. The clinical well-being of patients with hypo- or hyper-gammaglobulinemia was compared with age- and sex-matched control patients who had normal levels of gammaglobulin. IgG subclass levels were measured, and the results were compared with previous studies. Eleven patients had hypergammaglobulinemia (7.8% compared with 0-69% in the published literature). Patients with hypergammaglobulinemia had lower FEV(1) percent-predicted values, and worse S-K and Northern chest X-ray scores than controls. Three patients had hypogammaglobulinemia (1.9% compared with 0-10.8% in the published literature). There was no difference in any clinical parameter between controls and those with hypogammaglobulinemia. Nineteen patients (14%) had low levels of IgG1, and 40 patients (29%) had low levels of IgG2. The low percentage of patients with abnormally high immunoglobulin levels probably reflects the improved respiratory status of today's children with CF. The low percentage of those with low IgG probably reflects better nutritional status. The finding of worse lung function and clinical scores in patients with hypergammaglobulinemia agrees with the published literature. The high percentage of patients with low IgG2 was unexpected and was not previously reported. The clinical significance of this in patients with CF is unknown.

Clinical value of obtaining sputum and cough swab samples following inhaled hypertonic saline in children with cystic fibrosis.

Prompt detection and treatment of lower respiratory tract infection are essential in the management of patients with cystic fibrosis (CF), who often have signs or symptoms of respiratory infection without any pathogens being isolated from sputum or cough swab specimens. The aims of this study were to assess the efficacy and clinical value of obtaining sputum and oropharyngeal cough swab samples following induction with hypertonic saline (HS) in this group of patients. Forty-three outpatients with CF, mean age 7.2 years (range, 1.8-12.9 years), were recruited over a 2-year period. Nebulized salbutamol was administered, followed by 6% HS. Sputum was preferentially obtained before and after HS induction if possible. If the patient was not able to expectorate, oropharyngeal cough swabs were taken instead. Four patients were able to expectorate sputum before and 19 after HS induction. The procedure was tolerated in 41 of 43 patients. Pathogens were isolated from 13 patients' HS-induced samples, but not from their corresponding preinduced specimens, and 4 patients' preinduced specimens cultured organisms which were not identified from their HS-induced samples. Significant changes were made in the management of 13 (30.2%) patients directly resulting from the positive culture of pathogens only from HS-induced samples. Cultures from oropharyngeal cough swab or expectorated sputum specimens following inhalation of HS provide additional microbiological information which is of clinical value and may lead to changes in patient management.

Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis.

Respiratory tract infection with eventual respiratory failure is the major cause of morbidity and mortality in cystic fibrosis (CF). Infective exacerbations need to be treated promptly and effectively to minimize potentially accelerated attrition of lung function. The choice of antibiotic depends on in vitro sensitivity patterns. However, physicians treating patients with CF are increasingly faced with infection with multidrug-resistant isolates of Pseudomonas aeruginosa. In addition, innately resistant organisms such as Burkholderia cepacia complex, Stenotrophomonas maltophilia and Achromobacter (Alcaligenes) xylosoxidans are becoming more prevalent. Infection with methicillin-resistant Staphylococcus aureus (MRSA) is also a problem. These changing patterns probably result from greater patient longevity and increased antibiotic use for acute exacerbations and maintenance care. Multidrug-resistant P. aeruginosa infection may be treated successfully by using two antibiotics with different mechanisms of action. In practice antibiotic choices have usually been made on a best-guess basis, but recent research suggests that more directed therapy can be achieved through the application of multiple-combination bactericidal testing (MCBT). Aerosol delivery of tobramycin for inhalation solution achieves high endobronchial concentrations that may overcome bacterial resistance as defined by standard laboratory protocols. Resistance to colistin is rare and this antibiotic should be seen as a valuable second-line drug to be reserved for multidrug-resistant P. aeruginosa. The efficacy of new antibiotic groups such as the macrolides needs to be evaluated.CF units should adopt strict segregation policies to interrupt person-to-person spread of B. cepacia complex. Treatment of panresistant strains is difficult and often arbitrary. Combination antibiotic therapy is recommended, usually tobramycin and high-dose meropenem and/or ceftazidime, but the choice of treatment regimen should always be guided by the clinical response.The clinical significance of S. maltophilia, A. xylosoxidans and MRSA infection in CF lung disease remains uncertain. If patients show clinical decline and are chronically colonized/infected with either of the former two pathogens, treatment is recommended but efficacy data are lacking. There are defined microbiological reasons for attempting eradication of MRSA but there are no proven deleterious effects of this infection on lung function in patients with CF. Various treatment protocols exist but none has been subject to a randomized, controlled trial. Multidrug-resistant microorganisms are an important and growing issue in the care of patients with CF. Each patient infected with such strains should be assessed individually and antibiotic treatment planned according to in vitro sensitivity, patient drug tolerance, and results of in vitro studies which may direct the physician to antibiotic combinations most likely to succeed.

Peripherally inserted central catheters in children with cystic fibrosis. Eight cases of difficult removal.

Peripherally inserted central catheters (PICCs) are widely used in the management of cystic fibrosis (CF) in children and adults. The authors present a collection of eight case reports of patients with CF in whom removal of PICCs was difficult, including two PICCs that required surgical removal. The cases were observed in a regional pediatric CF unit in the United Kingdom. Possible etiology and strategies that can be used to achieve catheter removal are discussed.

Methicillin resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis.

BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) infection is increasingly found in patients with cystic fibrosis (CF). AIMS: To determine whether MRSA infection has a deleterious effect on the clinical status of children with CF. METHODS: Children with MRSA in respiratory cultures during a seven year period were identified and compared with controls matched for age, sex, and respiratory function. Respiratory function tests, anthropometric data, Shwachman-Kulczycki score, Northern chest x ray score, intravenous and nebulised antibiotic therapy, and steroid therapy were compared one year before and one year after MRSA infection. RESULTS: From a clinic population of 300, 10 children had positive sputum or cough swab cultures for MRSA. Prevalence rose from 0 in 1992-1994 to 7 in 1998. Eighteen controls were identified. Children with MRSA showed significant worsening of height standard deviation scores and required twice as many courses of intravenous antibiotics as controls after one year. They had significantly worse chest x ray scores at the time of the first MRSA isolate and one year later, but showed no increase in the rate of decline in chest x ray appearance. There was a trend towards lower FEV(1) and FEF(25-75) in children with MRSA. There were no significant differences between the two groups with respect to change in weight, body mass index, or Shwachman score. There was no significant difference in prior use of steroids or nebulised antibiotics. CONCLUSION: MRSA infection in children with CF does not significantly affect respiratory function, but may have an adverse effect on growth. Children with MRSA require significantly more courses of intravenous antibiotics and have a worse chest x ray appearance than controls.

Evaluation of fecal pancreatic elastase-1 as a measure of pancreatic exocrine function in children with cystic fibrosis.

Pancreatic elastase-1 (EL-1) is a specific human protease synthesised by the acinar cells. It is stable, unaffected by exogenous pancreatic enzyme treatment, and correlates well with stimulated pancreatic function tests. We report our experience of EL-1 measurements in 142 patients from a large cystic fibrosis (CF) clinic. The median patient age was 7.7 years (range, 0.1-20.8 years), 93 were homozygous and 38 heterozygous for DeltaF508, and 11 had other or unidentified mutations. There were 85 non-CF control subjects. Seven were pancreatic sufficient (PS). The median (quartile 1-quartile 3) fecal EL-1 of the 135 pancreatic insufficient (PI) patients was 10 microg/g stool (2.5-33); of the 7 PS patients, 698 microg/g stool (400.5-824.5), and of the non-CF controls, 615 microg/g stool (420-773). Using the Mann-Whitney U test, there was a statistically significant difference for fecal EL-1 activity between the PS and PI patients (P = 0.0001) and the PI and control group (P < 0.0001), but not between the control and PS groups (P = 0.63). Median (quartile 1-quartile 3) fecal EL-1 in the pancreatic insufficient DeltaF508 homozygotes was 10 microg/g stool (2-33), and in the heterozygotes 12 microg/g stool (4-39) (not significant, P = 0.62). We now use fecal EL-1 as evidence of PI in screened CF infants (reliable over the age of 2 weeks); in older CF patients at diagnosis; for confirming the need for pancreatic enzymes in patients referred to the clinic already taking enzymes; for annual monitoring of PS patients to detect the onset of PI; and as supporting evidence when excluding the diagnosis of CF in patients attending the pediatric gastroenterology clinic. The low values in the first 2 weeks in some normal and premature infants, and the persisting normal values in PS infants, make the fecal EL-1 test unsuitable for neonatal CF screening.

Randomised placebo controlled trial of nebulised corticosteroids in acute respiratory syncytial viral bronchiolitis.

OBJECTIVE: To evaluate short and long term effects of giving nebulised budesonide early in respiratory syncytial viral (RSV) bronchiolitis. DESIGN: A multicentre randomised double blind placebo controlled trial. SUBJECTS: Infants admitted to hospital with their first episode of RSV positive bronchiolitis. INTERVENTION: Randomisation to receive either 1 mg of nebulised budesonide (Bud) or placebo (Pla) twice daily from admission until 2 weeks after discharge. Follow up was for 12 months. MAIN OUTCOME MEASURES: Duration of hospital admission, time taken to become symptom free, re-admission rates, general practitioner consultation rates, and use of anti-wheeze medication during follow up. RESULTS: 161 infants were studied. Both arms were similar with respect to initial clinical severity, age, sex, socioeconomic class, and tobacco exposure. Median time from first nebulisation to discharge: Bud and Pla, 2 days. Median number of days for 50% of infants to be symptom free for 48 hours: Bud, 10 days; Pla, 12 days. Respiratory re-admission rates in the 12 month follow up: Bud, 16%; Pla, 18%; median difference (95% confidence interval (CI)), -2 (-14 to 10). Median respiratory related general practitioner attendances: Bud, 4.0; Pla, 4.5; median difference (95% CI), -1 (-2 to 0). Percentage of infants receiving at least one prescription for anti-wheeze medication during follow up, corticosteroids: Bud, 50%; Pla, 60%; difference (95% CI), -10 (-26 to 6); bronchodilators: Bud, 60%; Pla, 67%; difference (95% CI), -7 (-22 to 8). CONCLUSIONS: There are no short or long term clinical benefits from the administration of nebulised corticosteroids in the acute phase of RSV bronchiolitis.

Plasma creatinine rises dramatically in the first 48 hours of life in preterm infants.

OBJECTIVE: Published data show that plasma creatinine falls steadily during the first 28 days of life and that creatinine levels in the neonatal period are higher in more premature infants. However, the best reference data commence on day 2 of life. The objective of this study was to document how plasma creatinine changes in the first 48 hours of life and to examine the reason for the apparently high levels of creatinine in preterm infants, compared with maternal levels. DESIGN: A prospective observational study on a regional neonatal intensive care unit. PATIENTS: A total of 42 preterm infants, mean gestational age of 29.4 weeks (range: 23-35), mean birth weight of 1.42 kg (.55-2.77), divided into 4 gestation groups: 23 to 26 weeks (n = 9), 27 to 29 weeks (n = 13), 30 to 32 weeks (n = 12), and 33 to 35 weeks (n = 8). INTERVENTIONS: Measurement of plasma creatinine and urea concentration in cord blood and in serial samples taken for routine arterial blood gas analysis. OUTCOME MEASUREMENTS: Changes in creatinine concentration with time and relationship to gestational age, birth weight, and illness severity. RESULTS: Mean creatinine at birth was 73 micromol/L (95% confidence interval [CI]: 68-79 micromol/L). Plasma creatinine rose significantly over the first 48 hours. Mean peak creatinine in the most preterm infants (23-26 weeks) was 221 micromol/L (CI: 195-247 micromol/L). Peak plasma creatinine was inversely related to gestation (Spearman's coefficient: -.73) and birth weight (Spearman's coefficient: -.76). Significant differences in creatinine concentration were seen among different gestational groups at 24 and 48 hours of life. Peak creatinine correlated with a high Clinical Risk Index for Babies score (Spearman's coefficient:. 64). The fall in creatinine began later in more premature infants. All 38 surviving infants had normal renal function; their mean plasma creatinine at discharge was 52 micromol/L (CI: 46-58 micromol/L). CONCLUSIONS: Rather than falling steadily from birth, creatinine rises dramatically in the first 48 hours of life, especially in infants of <30 weeks' gestation. Even large rises in creatinine in the first 48 hours may be expected and should not be used in isolation to diagnose renal failure.

Acute bronchopulmonary infection due to Streptococcus milleri in a child with cystic fibrosis.

An 8 year old girl with cystic fibrosis had severe respiratory disease associated with chronic Pseudomonas aeruginosa bronchopulmonary infection. Despite regular courses of intravenous antipseudomonal antibiotics, she continued to deteriorate over 18 months with persistent productive cough, worsening respiratory function, and increasing oxygen dependence. During her 11th admission Streptococcus milleri was isolated from sputum cultures in addition to P aeruginosa. She failed to respond to antipseudomonal antibiotics but improved dramatically with the addition of intravenous benzylpenicillin. Although S milleri is considered a normal mouth commensal and its isolation from sputum of cystic fibrosis patients is of uncertain significance, it was associated with clinically significant infection in this child. S milleri was eradicated with antibiotic treatment and clinical improvement has been maintained.

Role of epidermal growth factor and transforming growth factor alpha in the developing stomach.

AIMS: To determine whether epidermal growth factor (EGF) or the related transforming growth factor alpha (TGF alpha) may have a role in the developing human stomach; to substantiate the presence of EGF in human liquor in the non-stressed infant and whether EGF in amniotic fluid is maternally or fetally derived. METHODS: The temporal expression and localisation of EGF, TGF alpha, and their receptors during fetal and neonatal life were examined in 20 fetal and five infant stomachs. Simultaneously, samples of amniotic fluid and fetal urine from 10 newborn infants were collected and assayed for EGF by radioimmunoassay. RESULTS: EGF immunoreactivity was not noted in any of the specimens examined. In contrast, TGF alpha immunoreactivity was shown in mucous cells from 18 weeks of gestation onwards. EGF receptor immunoreactivity was seen on superficial mucous cells in gastric mucosa from 18 weeks of gestation onwards. The median concentration of EGF was 30 and 8.5 pg/ml in amniotic fluid and fetal urine, respectively, suggesting that EGF is not produced by the fetus. CONCLUSIONS: This study adds weight to the hypothesis that swallowed EGF, probably produced by the amniotic membranes, and locally produced TGF alpha, may have a role in the growth and maturation of the human stomach.

An expert system to assist neonatal intensive care.

An expert system for neonatal intensive care (ESNIC) for the management of mechanically ventilated neonates on intermittent positive pressure ventilation (IPPV) has been developed. The system uses the rule based expert system shell XiPlus (Inference Inc.) and runs on an IBM-compatible PC. The rules have been derived from the knowledge of two consultant paediatricians. The inputs to the system are the current ventilator settings, blood gas tensions and pH. The output of the system is a set of suggested new ventilator settings. The aim of the system is to provide ventilator settings which will maintain the arterial blood gas tensions within an acceptable range, reducing pressures whenever feasible and increasing pressures only as a last resort. In addition, ESNIC provides data archiving, graphical displays of all parameters, ventilation and discharge summaries. With the 63 patients in the study ESNIC was consulted for 76% of all ventilator adjustments and the advice given was accepted on 83% of these occasions.