K.G. Brownlee

European best practice guidelines for cystic fibrosis neonatal screening

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.

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.

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.

Methicillin resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis

BACKGROUND Methicillin resistantStaphylococcus 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 xray appearance. There was a trend towards lower FEV1 and FEF25–75 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.

Vitamin k status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover

Objective. The aim of this study was to assess vitamin K status in an unselected population of children with cystic fibrosis (CF) and to investigate any vitamin K effect on bone turnover and bone mineral status. Methods. Children ≥5 years of age who were attending the CF unit were invited to enter the study. Fasting blood samples were analyzed for levels of vitamin K1 and prothrombin produced in vitamin K absence; total, undercarboxylated, and carboxylated osteocalcin (OC); and bone-specific alkaline phosphatase and procollagen I carboxy-terminal propeptide (bone formation markers). Levels of N-telopeptide and free pyridinoline and deoxypyridinoline (bone breakdown products) were measured in urine samples. Bone mineral density and bone mineral content were measured at the lumbar spine and for the total body with a GE Lunar Prodigy densitometer. Statistical analyses were performed with Minitab version 9.1. Results. One hundred six children entered the study. Sixty-five of 93 children (70%) from whom blood samples were obtained showed suboptimal vitamin K status, on the basis of low serum vitamin K1 levels, increased prothrombin produced in vitamin K absence levels, or both abnormalities. Vitamin K1 levels showed a significant negative correlation with undercarboxylated OC levels but showed no significant correlation with any marker of bone turnover or measurement of bone mineral status. Undercarboxylated OC levels were correlated significantly with bone turnover markers, which themselves showed a significant negative correlation with measurements of bone mineral density and content. There were no significant correlations between carboxylated or undercarboxylated OC levels and bone density measurements. Conclusions. Vitamin K1 deficiency is common among children with CF, and routine supplements should be considered. Through its role in the carboxylation of OC, vitamin K deficiency may be associated with an uncoupling of the balance between bone resorption and bone formation. A cause-effect relationship between vitamin K deficiency and low bone mass has not been proved.

Catabolic effect of dexamethasone in the preterm baby.

Most babies treated with dexamethasone for bronchopulmonary dysplasia exhibit an appreciable rise in the blood urea concentration, from a mean of 2.3 mmol/l before steroid to a mean of 7.1 mmol/l after. In order to discover whether this was primarily the result of increased protein catabolism, nitrogen balance studies before and after the start of dexamethasone were performed and a mean deficit in nitrogen retention of 158 mg/kg/24 hours was found. Similarly the urinary 3-methylhistidine (3MH):creatinine ratio before and after the commencement of dexamethasone treatment in a group of preterm babies was measured. It was found that there was a substantial increase in 3MH excretion after dexamethasone: from a mean 3MH:creatinine ratio of 46 in the week before steroids to a mean ratio of 77 in the week after. As 3MH emanates almost exclusively from the breakdown of actin in skeletal muscle cell, this finding implies the loss of muscle tissue. It was also found that the babies were in less positive nitrogen balance after dexamethasone, to a degree which is significant relative to their protein reserves. The long term consequences of a period of increased catabolism are not yet known but the authors suggest caution in the use of dexamethasone, at least in babies with milder degrees of bronchopulmonary dysplasia in whom the ratio of benefit to risk may be less favourable.

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 ΔF508, and 11 had other or unidentified mutations. There were 85 non‐CF control subjects.

Isolation of the Fungus Geosmithia argillacea in Sputum of People with Cystic Fibrosis

ABSTRACT 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.

Serologic diagnosis of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis through the detection of immunoglobulin G to Aspergillus fumigatus

Allergic bronchopulmonary aspergillosis (ABPA) is seen in approximately 10% of patients with cystic fibrosis (CF) and can be difficult to diagnose. Consensus criteria require the presence of multiple elevated immunologic markers such as total immunoglobulin E (IgE), Aspergillus IgE and Aspergillus IgG, or precipitins for a robust diagnosis. There is some degree of standardization of total IgE and Aspergillus IgE levels, but there is no standardization in the measurement of IgG antibodies or precipitins to Aspergillus. The interpretation of results may, therefore, be confusing. Eighty-seven patients with CF were categorized as having ABPA or as controls, using the consensus criteria and an in-house enzyme immunoassay to measure IgG levels to Aspergillus. All sera from patients were then analyzed by commercial fluorescent immunoassay (FEIA) for the quantitative detection of anti-Aspergillus IgG. FEIA results were analyzed against the consensus conference minimum diagnostic criteria to ascertain a cutoff point, which could predict a diagnosis of ABPA in CF. Eighty patients with CF and with no or incomplete evidence of ABPA had a mean FEIA score of 51.1 mg/L, whereas 7 CF patients with ABPA had a mean FEIA score of 132.5 mg/L. Using receiver operator characteristic curve analysis of the ImmunoCAP (Phadia) IgG score on ABPA versus all other patients gave an area under the curve of 0.933 (estimated SE, 0.027). This analysis provisionally suggested that a score of 90 mg/L may be used as a cutoff point, which would give a sensitivity of 91% and specificity of 88.0% for the diagnosis of ABPA, though this requires further validation. This quantitative approach to Aspergillus IgG measurement in patients with CF along with the results of other tests will hopefully provide a more accurate approach to the diagnosis of ABPA.

The effect of intravenous ranitidine on the intragastric pH of preterm infants receiving dexamethasone

Gastric perforation is a catastrophic, albeit uncommon, side effect of steroid treatment for premature infants with bronchopulmonary dysplasia (BPD). A reduction of intragastric acidity may protect against peptic ulceration. The effect of different doses of ranitidine, given as intravenous infusions, on intragastric acidity in premature neonates was therefore examined. Ten consecutive, enterally starved, infants receiving dexamethasone (0.6 mg/kg) for BPD were enrolled. Intragastric pH was continuously monitored on the day before steroid treatment and on the four following days, initially without H2 blockade and then using a continuous intravenous infusion of ranitidine at 0.031, 0.0625, and 0.125 mg/kg/hour. An infusion of 0.0625 mg/kg/hour of ranitidine was sufficient to increase and maintain gastric pH above 4; the authors therefore use this infusion during dexamethasone administration as possible prevention of gastric perforation.