Incidence of cystic fibrosis in ethnic Italians and Greeks and in Australians of predominantly British origin

The incidence of cystic fibrosis among the Australian born children of parents born in Italy was 1:3 625 live births and among Australian born children of parents born in Greece 1:3 726. These incidences were significantly lower than the incidence for cystic fibrosis of 1:2 021 in children born to Australian born parents, about 90% of whom have ancestors born in the British Isles. The figures suggest there are significant variations in the incidence of cystic fibrosis in different European populations.     

Influence of five years of antenatal screening on the paediatric cystic fibrosis population in one region

BACKGROUND: Antenatal screening for cystic fibrosis has been endorsed by the US National Institutes of Health. Edinburgh is the only city in the UK with an established routine antenatal screening programme for cystic fibrosis. AIMS: To report the change in numbers of infants diagnosed with cystic fibrosis born in Edinburgh after the introduction of antenatal screening for the disease. POPULATION: Infants diagnosed as having cystic fibrosis (by sweat test or genotyping, or both) in the seven years before antenatal testing (1984-90) and the first five years of antenatal testing (1991-95). Children born in this region who had moved before diagnosis were identified from the UK cystic fibrosis survey database. RESULTS: The incidence of cystic fibrosis decreased from an average of 4.6 to 1.6 children each year with antenatal screening. The reduction in the incidence (65%) was greater than that accounted for by prenatal diagnosis and termination (36%). Of the eight children born with cystic fibrosis during the period of antenatal screening, five had been subject to antenatal screening: three had only one mutation identified, one was missed due to a laboratory error, and one was identified as a one in four risk, but prenatal diagnosis was not performed. CONCLUSIONS: Antenatal testing for cystic fibrosis has successfully reduced the incidence of cystic fibrosis in this region. Although the numbers are small, it is possible that the reduction in numbers may have been greater than might be expected from antenatal screening alone.     

Influence of five years of antenatal screening on the paediatric cystic fibrosis population in one region

BACKGROUND—Antenatal screening for cystic fibrosis has been endorsed by the US National Institutes of Health. Edinburgh is the only city in the UK with an established routine antenatal screening programme for cystic fibrosis.
AIMS—To report the change in numbers of infants diagnosed with cystic fibrosis born in Edinburgh after the introduction of antenatal screening for the disease.
POPULATION—Infants diagnosed as having cystic fibrosis (by sweat test or genotyping, or both) in the seven years before antenatal testing (1984-90) and the first five years of antenatal testing (1991-95). Children born in this region who had moved before diagnosis were identified from the UK cystic fibrosis survey database.
RESULTS—The incidence of cystic fibrosis decreased from an average of 4.6 to 1.6 children each year with antenatal screening. The reduction in the incidence (65%) was greater than that accounted for by prenatal diagnosis and termination (36%). Of the eight children born with cystic fibrosis during the period of antenatal screening, five had been subject to antenatal screening: three had only one mutation identified, one was missed due to a laboratory error, and one was identified as a one in four risk, but prenatal diagnosis was not performed.
CONCLUSIONS—Antenatal testing for cystic fibrosis has successfully reduced the incidence of cystic fibrosis in this region. Although the numbers are small, it is possible that the reduction in numbers may have been greater than might be expected from antenatal screening alone.

     

Australian Paediatric Surveillance Unit study of haemoglobinopathies in Australian children

Aim: The aims of this study were to determine the incidence and types of haemoglobinopathies in Australian children and their distribution among ethnic groups, and to collect information on timing of diagnosis of haemoglobinopathies in Australia. Methods: Between January 2004 and March 2006, the Australian Paediatric Surveillance Unit asked paediatricians to report all children under 15 years of age with a newly diagnosed haemoglobinopathy. A questionnaire requesting further information was forwarded to those clinicians. Carrier states such as thalassaemia minor were excluded. Results: Eighty‐four notifications of haemoglobinopathy were received by the Australian Paediatric Surveillance Unit, with 59 confirmed cases giving a national incidence of 0.74 per 100 000 children < 15 years of age per annum. Of 59 cases, 42 (71%) were Australian born. Twenty‐nine (35.6%) children had sickle cell disease, 17 (28.8%) had Hb H disease, six (10.2%) had beta‐thalassaemia major and 15 (25.4%) had compound heterozygous conditions. One child died from sickle cell disease. Of Australian born children, at least 10 mothers (23.8%) and 11 fathers (26.2%) were unaware of their carrier status pre‐partum (information unavailable for 13 mothers and 17 fathers). Only 11 parents (18.6%) had risks of haemoglobinopathy discussed with them antenatally and only three cases (5.1%) were diagnosed antenatally. Conclusions: We found that a small but significant number of children with haemoglobinopathies are being born in Australia despite existing programmes of testing at‐risk groups and neonatal screening. Haemoglobinopathies were also diagnosed in recent immigrants. Greater awareness of these conditions and enhancements of screening and detection programmes may be needed as the genetic diversity of the Australian population continues to develop.     

A systematic review of the reporting of Data Monitoring Committees' roles, interim analysis and early termination in pediatric clinical trials

Background  

This paper reports the findings of a South Australian qualitative, exploratory study of children and young people living with a chronic disease, and their perceptions and experiences of physical activity. The perceptions and experiences of their parents were also explored. The chronic diseases were type 1 diabetes, asthma and cystic fibrosis.     

Cystic fibrosis identified by neonatal screening: incidence, genotype, and early natural history

The incidence of cystic fibrosis over the last 10 years in East Anglia (a region of the United Kingdom with a population of 2.1 million) has halved. This has happened during the establishment of a neonatal screening programme, which has enabled early diagnosis, genetic counselling, and lately the option of prenatal diagnosis in subsequent pregnancies. One hundred and seven children were born with cystic fibrosis between 1981 and 1990, eight of whom were siblings. The Guthrie blood spots of 82 infants detected by neonatal immunoreactive trypsin screening between 1981 and 1990 were examined for the presence of the most common cystic fibrosis gene mutation (delta F508). It was present in 135 (82%) of the 164 cystic fibrosis genes analysed with 54 (66%) cases being homozygous and 27 (33%) heterozygous. Sixty nine per cent of infants were symptomatic at the time of diagnosis regardless of genotype. No association was found between the early clinical or biochemical features of the disease and homozygosity or heterozygosity for this mutation. Screening for cystic fibrosis using the blood immunoreactive trypsin assay alone remains an effective method of identifying infants with the disease soon after birth, thereby allowing early therapeutic intervention. Genetic counselling and prenatal diagnosis have contributed to a reduction in the number of children born with cystic fibrosis, but may not entirely explain the decreasing incidence of the disease.     

Screening for cystic fibrosis: a four year regional experience.

A four year regional screening programme to detect cystic fibrosis using measurement of immunoreactive trypsinogen is described. During this period 60 infants were diagnosed; 34 by screening, 12 born with meconium ileus, and 14 not identified by the screening assay but who presented with clinical symptoms at a later age, giving an incidence of cyst fibrosis in the region during this time of 1/1807. Screening has resulted in earlier detection of cystic fibrosis in many infants, thus allowing treatment to be instituted at an early age, and genetic counseling offered to the parents. There were a number of false positives and false negatives with the immunoreactive trypsinogen screening assay. In addition, eight infants who were sweat tested at an early age had a sweat sodium concentration of less than 70 mmol/l, although they were subsequently shown to have cystic fibrosis. These results confirm other published data showing that sweat sodium results may be low in very young infants with cystic fibrosis. At the time of diagnosis seven (20%) of the infants identified by screening were totally asymptomatic and several additional children had symptoms of such a type that the diagnosis of cystic fibrosis had not been considered at the time of screening. Despite the problems experienced it has been decided to continue screening.     

Cystic fibrosis identified by neonatal screening: incidence, genotype, and early natural history.

The incidence of cystic fibrosis over the last 10 years in East Anglia (a region of the United Kingdom with a population of 2.1 million) has halved. This has happened during the establishment of a neonatal screening programme, which has enabled early diagnosis, genetic counselling, and lately the option of prenatal diagnosis in subsequent pregnancies. One hundred and seven children were born with cystic fibrosis between 1981 and 1990, eight of whom were siblings. The Guthrie blood spots of 82 infants detected by neonatal immunoreactive trypsin screening between 1981 and 1990 were examined for the presence of the most common cystic fibrosis gene mutation (delta F508). It was present in 135 (82%) of the 164 cystic fibrosis genes analysed with 54 (66%) cases being homozygous and 27 (33%) heterozygous. Sixty nine per cent of infants were symptomatic at the time of diagnosis regardless of genotype. No association was found between the early clinical or biochemical features of the disease and homozygosity or heterozygosity for this mutation. Screening for cystic fibrosis using the blood immunoreactive trypsin assay alone remains an effective method of identifying infants with the disease soon after birth, thereby allowing early therapeutic intervention. Genetic counselling and prenatal diagnosis have contributed to a reduction in the number of children born with cystic fibrosis, but may not entirely explain the decreasing incidence of the disease.     

Cystic fibrosis mutations in Romania

We have investigated the genotype in 32 children with cystic fibrosis from Romania. The diagnosis of cystic fibrosis was made on the basis of typical clinical findings and sweat electrolyte levels using the pilocarpine iontophoresis method. Conclusion Genetic analysis of 32 children with cystic fibrosis from Romania showed a 25% incidence of DeltaF508 mutation and a 64.5% incidence of unknown mutations, 5 other known mutations and 1 new mutation 1717–2(A > G). Received: 26 December 1995 and in revised form: 14 May 1996 / Accepted: 24 May 1996     

Quality-of-life in children and adolescents with cystic fibrosis managed in both regional outreach and cystic fibrosis center settings in Queensland

OBJECTIVES: To assess the health-related quality-of-life (HRQOL) of children/adolescents with cystic fibrosis (CF) and compare HRQOL in children managed by cystic fibrosis outreach service (CFOS) with those treated in a cystic fibrosis center (CFC). To compare HRQOL of children with CF in Queensland with previously published HRQOL data from the United States and examine the relationship between HRQOL scores and pulmonary function. STUDY DESIGN: Participants were children/adolescents with CF and their parents managed by the Royal Children's Hospital Queensland at a CFC or CFOS. Two HRQOL surveys were used: PedsQL and Cystic Fibrosis Questionnaire (CFQ). RESULTS: There were 91 CFC and 71 CFOS participants with similar demographics. PedsQL total summary score was statistically higher in CFOS, P=.05. There was no significant difference in CFQ scores between groups. Queensland parents reported lower HRQOL for their children compared with US parents (P<.01) despite similar pulmonary function. Declining pulmonary function correlated with worse CFQ scores in adolescents, P<.05. CONCLUSIONS: Children living in regional Queensland reported as good as or slightly better HRQOL compared with children attending a CFC. Parent proxy HRQOL scores were generally low suggesting a reduced perception of HRQOL by parents for their children.     

Cystic fibrosis and family stress: effects of age and severity of illness

Stress and adjustment in mothers of children with cystic fibrosis was compared with that in a control group of mothers of healthy children. Mothers of children in four age groups were included: preschool, middle childhood, early adolescence, and late adolescence. Mothers of children with cystic fibrosis did not report significantly higher levels of stress than did the control group mothers; nor did they report greater feelings of inadequacy as parents. However, mothers of children with cystic fibrosis in two age groups, preschool and early adolescence, scored higher on a measure of depression than did mothers of healthy children in the same age groups. The relationship of illness severity to maternal stress and adjustment was examined in the cystic fibrosis group. The mother's subjective rating of the child's illness severity was a better indicator of her reported stress than was the Schwachman clinical rating. It appears that many mothers are able to adapt to the presence of cystic fibrosis in the family, although certain periods in the child's life and perceived increases in illness severity are associated with increased maternal distress.     

Clinical outcomes of newborn screening for cystic fibrosis.

AIM: To determine how early diagnosis of cystic fibrosis, using neonatal screening, affects long term clinical outcome. METHODS: Fifty seven children with cystic fibrosis born before neonatal screening was introduced (1978 to mid 1981) and a further 60 children born during the first three years of the programme (mid 1981 to 1984), were followed up to the age of 10. The cohorts were compared on measures of clinical outcome, including height, weight, lung function tests, chest x-ray picture and Shwachman score. RESULTS: Age and sex adjusted standard deviation scores (SDS) for height and weight were consistently higher in children screened for cystic fibrosis than in those born before screening. At 10 years of age, average differences in SDS between groups were 0.4 (95% CI -0.1, 0.8) for weight and 0.3 (95% CI -0.1, 0.7) for height. This translates to an average difference of about 2.7 cm in height and 1.7 kg in weight. Mean FEV1 and FVC (as percentage predicted) were significantly higher in the screened cohort at 5 and 10 years of age, with an average difference of 9.4% FEV1 (95% CI 0.8, 17.9) and 8.4% FVC (95% CI 1.8, 15.0) at 10 years. Chest x-ray scores were not different between the groups at any age, but by 10 years screened patients scored an average 5.3 (95% CI 1.2, 9.4) points higher on the Shwachman score. CONCLUSION: Although not a randomised trial, this long term observational study indicates that early treatment made possible by neonatal screening may be important in determining subsequent clinical outcomes for children with cystic fibrosis. For countries contemplating the introduction of neonatal screening for cystic fibrosis, its introduction to some areas in a cluster randomised design will permit validation of studies performed to date.     

Malnutrition in cystic fibrosis: Psychosocial functioning of patients and their families

The relationship between nutritional status and psychosocial functioning was examined in 35 children with cystic fibrosis, aged 7-16 years. Twelve malnourished children and their families were compared with 23 well nourished children and their families. Established measures of adjustment and coping in the children, parents and families were used. Few statistically significant differences between the two groups emerged, and all comparisons of psychosocial functioning were not significant. The results of the study suggest that there is no relationship between the nutritional status of the child with cystic fibrosis and the current psychosocial adjustment and coping of child, parents and family.     

Newer therapies for cystic fibrosis

Cystic fibrosis is the most common lethal inherited disease in Caucasians in the UK, with an incidence of approximately one in 2500 live births. It is a heterogeneous disease which reflects different mutations in the cystic fibrosis transmembrane conductance regulator gene, modifier genes and environmental influences. The median life expectancy of children with cystic fibrosis born in the UK is approximately 30 years. Longer survival is the result of improvements in basic therapies including airway clearance, aggressive use of antibiotics and optimizing nutrition. Care given in a specialist centre has also been shown to improve survival. Despite this progress, pulmonary disease still accounts for most of the morbidity and is the cause of death in over 90% of patients with cystic fibrosis. This review will focus on newer therapies aimed at pulmonary disease which are now being used in the clinical setting, and other novel therapies which are still at the research stage.     

Clinical and genetic comparisons of patients with cystic fibrosis, with or without meconium ileus

We set out to determine if the clinical course or genetic profiles of patients with cystic fibrosis who had meconium ileus differed from those of other patients with cystic fibrosis. Since 1950 we have followed 158 patients with meconium ileus among 1175 patients with cystic fibrosis (13.4%). Patients with meconium ileus had lower birth weight (3026 +/- 610 gm) than patients with no meconium ileus (3169 +/- 534 gm; p less than 0.008); the deficit was especially evident in female patients. Survival in the first year of life increased from 55% in those born between 1958 and 1972 to 96% in those born between 1973 and 1987. Since 1973 the median survival of male and female patients with meconium ileus was similar to that in female patients with no meconium ileus (21 years), whereas 78% of males with no meconium ileus survived to this age (p less than 0.0001). Patients with meconium ileus born before 1972 had lower weight and height percentiles at age 13 years compared with patients with no meconium ileus, but this difference was not as apparent in patients born after 1973. There were no differences between the two groups in forced vital capacity, forced expiratory volume in 1 second, or forced expiratory flow in the middle half of forced vital capacity. Patients with meconium ileus acquired Pseudomonas aeruginosa at a younger age than did patients with no meconium ileus (4.20 +/- 4.67 vs 7.18 +/- 5.19 years), but there was no difference in age of acquisition of P. cepacia. In families in which the first child had meconium ileus, 29% of subsequent siblings with cystic fibrosis had meconium ileus, compared with 6% of siblings born to families in which the first child did not have meconium ileus. Allelic frequencies and haplotypic variants for cystic fibrosis chromosomes with respect to DNA markers closely linked to the cystic fibrosis locus were similar in families with cystic fibrosis with meconium ileus and those with no meconium ileus. These findings suggest that patients with cystic fibrosis and those without meconium ileus do not have major intrinsic differences and that the previously poor outlook in patients with meconium ileus has improved greatly.     

Low concentrations of sodium and magnesium in erythrocytes from cystic fibrosis heterozygotes

The concentrations of electrolytes and trace elements in erythrocytes were determined in eight children with cystic fibrosis (CF) and the parents of four of the children and compared with age- and sex-matched healthy controls. The children with CF had significantly lower median erythrocyte concentrations of sodium, magnesium and zinc and a higher median concentration of calcium than both the healthy control children and the parents of the CF children. Although the sodium and magnesium median values were higher in CF parents than in CF children they were nevertheless significantly lower than in adult controls. These data indicate a system for heterozygote detection.     

Cough sensitivity in children with asthma, recurrent cough, and cystic fibrosis

In adults, cough sensitivity is influenced by gender and is heightened in those with non-productive cough. This study examined if cough sensitivity is (i) altered in children with asthma, recurrent cough, and cystic fibrosis and (ii) influenced by age, gender, or forced expiratory volume in one second (FEV1). Cough sensitivity to capsaicin and spirometry were performed on 209 children grouped by the diagnosis of asthma, recurrent dry cough, cystic fibrosis, and controls. Cough sensitivity was increased in children with recurrent cough, and lower in children with cystic fibrosis when compared with children with asthma and controls. Age influenced cough sensitivity in the controls. In the asthmatics, FEV1 (% predicted) correlated to cough sensitivity measures. There was no gender difference in cough sensitivity. It is concluded that cough sensitivity is different among children with recurrent dry cough, asthma, and cystic fibrosis. In children, age, but not gender, influences cough sensitivity measures and when cough sensitivity is used in comparative studies, children should be matched for age and FEV1.     

13C and H2 breath tests to study extent and site of starch digestion in children with cystic fibrosis.

BACKGROUND: Starch is an important source of energy for children with cystic fibrosis, but little is known about their capacity to digest it. METHODS: A 13C breath test was used to measure starch digestion and oxidation in 16 children with cystic fibrosis (median [range] age, 7.9 [4-15] years; 7 girls, 9 boys) and 5 normal healthy control subjects (median age, 8.3 [7-13] years; 3 girls, 2 boys). A test meal of 13C flour and lactulose was consumed and breath samples were obtained half-hourly thereafter for 6 hours to measure 13C enrichment by isotope ratio mass spectrometry and H2 by electrochemistry. The test was repeated on 10 children with cystic fibrosis when they were taking pancreatic supplements. RESULTS: The median (range) cumulative percentage 13C dose recovery (cPDR), was 35% (18-52%) in control subjects, 18% (9-33%) in children with cystic fibrosis without enzymes, and 29% (22-51%) in those with pancreatic supplements. cPDR differed significantly between healthy control subjects and children with cystic fibrosis without enzymes (p = 0.01) and between children with cystic fibrosis with and without enzymes (p < 0.0001), but there was no difference between control subjects and children with cystic fibrosis taking enzymes (p = 0.5). Eight children with cystic fibrosis had a cPDR within control range, and in six there was a second peak in 13CO2 enrichment coincident with an increase in H2. CONCLUSIONS: Starch digestion and oxidation are diminished in children with cystic fibrosis, but pancreatic enzymes restored them to near normal levels. A second peak in 13CO2 enrichment, suggestive of colonic starch fermentation was absent in healthy children, but present in some children with cystic fibrosis and abolished by pancreatic enzymes.     

Low Concentrations of Sodium and Magnesium in Erythrocytes from Cystic Fibrosis Heterozygotes

ABSTRACT. The concentrations of electrolytes and trace elements in erythrocytes were determined in eight children with cystic fibrosis (CF) and the parents of four of the children and compared with age- and sex-matched healthy controls. The children with CF had significantly lower median erythrocyte concentrations of sodium, magnesium and zinc and a higher median concentration of calcium than both the healthy control children and the parents of the CF children. Although the sodium and magnesium median values were higher in CF parents than in CF children they were nevertheless significantly lower than in adult controls. These data indicate a system for heterozygote detection.