Philip M. Farrell

Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report

Newborn screening (NBS) for cystic fibrosis (CF) is increasingly being implemented and is soon likely to be in use throughout the United States, because early detection permits access to specialized medical care and improves outcomes. The diagnosis of CF is not always straightforward, however. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a clear answer. Genotype analysis also does not always provide clarity; more than 1500 mutations have been identified in the CF transmembrane conductance regulator (CFTR) gene, not all of which result in CF. Harmful mutations in the gene can present as a spectrum of pathology ranging from sinusitis in adulthood to severe lung, pancreatic, or liver disease in infancy. Thus, CF identified postnatally must remain a clinical diagnosis. To provide guidance for the diagnosis of both infants with positive NBS results and older patients presenting with an indistinct clinical picture, the Cystic Fibrosis Foundation convened a meeting of experts in the field of CF diagnosis. Their recommendations, presented herein, involve a combination of clinical presentation, laboratory testing, and genetics to confirm a diagnosis of CF.

Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus.

Neurotoxic effects of prenatal administration of dexamethasone were examined in the fetal rhesus monkey brain at 135 and 162 days of gestation (term is 165 days). In an experimental design mimicking human clinical trials, dexamethasone was given intramuscularly to pregnant monkeys on day 132 (single injection with doses of 0.5, 5, or 10 mg/kg maternal body weight) or on days 132 and 133 (multiple injections at 12-h intervals with 0.125 x 4, 1.25 x 4, or 2.5 mg/kg x 4). The fetuses were delivered by caesarean section on day 135 or day 162 and hippocampal slices were prepared for evaluation. Light and electron microscopic observation revealed decreased numbers of pyramidal neurons in the hippocampal CA regions and of granular neurons in the dentate gyrus associated with degeneration of neuronal perikarya and dendrites. Axodendritic synaptic terminals of the mossy fibers in the CA3 hippocampal region showed pronounced degeneration. Degeneration was dose-dependent and multiple injections induced more severe damage than single injections of the same total dose. Even the lowest dose (0.5 mg/kg, which is similar to the dose used in human clinical trials) produced these changes. Degenerative changes induced by dexamethasone treatment (5 mg/kg) on days 132 and 133 were also clearly evident in fetuses studied at 162 days. Therefore, caution is recommended in the use of prenatal corticosteroids in premature deliveries.

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice

It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.

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.

Assessing personal qualities in medical school admissions.

The authors analyze the challenges to using academic measures (MCAT scores and GPAs) as thresholds for admissions and, for applicants exceeding the threshold, using personal qualities for admission decisions; review the literature on using the medical school interview and other admission data to assess personal qualities of applicants; identify challenges of developing better methods of assessing personal qualities; and propose a unified system for assessment. The authors discuss three challenges to using the threshold approach: institutional self-interest, inertia, and philosophical and historical factors. Institutional self-interest arises from the potential for admitting students with lower academic credentials, which could negatively influence indicators used to rank medical schools. Inertia can make introducing a new system complex. Philosophical and historical factors are those that tend to value maximizing academic measures. The literature identifies up to 87 different personal qualities relevant to the practice of medicine, and selecting the most salient of these that can be practically measured is a challenging task. The challenges to developing better personal quality measures include selecting and operationally defining the most important qualities, measuring the qualities in a cost-effective manner, and overcoming “cunning” adversaries who, with the incentive and resourcefulness, can potentially invalidate such measures. The authors discuss potential methods of measuring personal qualities and propose a unified system of assessment that would pool resources from certification and recertification efforts to develop competencies across the continuum with a dynamic, integrated approach to assessment.

Cystic Fibrosis Foundation Evidence-Based Guidelines for Management of Infants with Cystic Fibrosis

Newborn screening for cystic fibrosis (CF) offers the opportunity for early medical and nutritional intervention that can lead to improved outcomes. Management of the asymptomatic infant diagnosed with CF through newborn screening, prenatal diagnosis, or sibling screening is different from treatment of the symptomatically diagnosed individual. The focus of management is on maintaining health by preventing nutritional and respiratory complications. The CF Foundation convened a committee to develop recommendations based on a systematic review of the evidence and expert opinion. These guidelines encompass monitoring and treatment recommendations for infants diagnosed with CF and are intended to help guide families, primary care providers, and specialty care centers in the care of infants with CF.

The Occurrence and Effects of Human Vitamin E Deficiency: A STUDY IN PATIENTS WITH CYSTIC FIBROSIS

The role of vitamin E in human nutrition was studied by investigation of patients with cystic fibrosis (CF) and associated pancreatic insufficiency. Vitamin E status was assessed by measurement of the plasma concentration of the principal circulating isomer, alpha-tocopherol. Results of such determinations in 52 CF patients with pancreatogenic steatorrhea revealed that all were deficient in the vitamin. The extent of decreased plasma tocopherol varied markedly but correlated with indices of intestinal malabsorption, such as the serum carotene concentration and percentage of dietary fat absorbed. Supplementation with 5-10 times the recommended daily allowance of vitamin E in a water-miscible form increased the plasma alpha-tocopherol concentrations to normal in all 19 CF patients so evaluated. Studies on the effects of vitamin E deficiency focused on possible hematologic alterations. An improved technique was developed to measure erythrocyte hemolysis in vitro in the presence of hydrogen peroxide. While erythrocyte suspensions from control subjects demonstrated resistance to hemolysis during a 3-h incubation, all samples from tocopherol-deficient CF patients showed abnormal oxidant susceptibility, evidenced by greater than 5% hemoglobin release. The degree of peroxide-induced hemolysis was related to the plasma alpha-tocopherol concentration in an inverse, sigmoidal manner. The possibility of in vivo hemolysis was assessed by measuring the survival of (51)Cr-labeled erythrocytes in 19 vitamin-E deficient patients. A moderate but statistically significant decrease in the mean (51)Cr erythrocyte half-life value was found in this group. Measurement of erythrocyte survival before and after supplementation of 6 patients with vitamin E demonstrated that the shortened erythrocyte lifespan could be corrected to normal with this treatment. Other hematologic indices in deficient subjects, however, were normal and did not change upon supplementation with vitamin E. It is concluded that CF is invariably associated with vitamin E deficiency, provided that the patient in question has pancreatic achylia and is not taking supplementary doses of tocopherol. Concomitant hematologic effects consistent with mild hemolysis, but not anemia, occur and may be reversed with vitamin E therapy. Patients with CF should be given daily doses of a water-miscible form of vitamin E to correct the deficiency.

The prevalence of cystic fibrosis in the European Union

This study combined a variety of methods to determine the prevalence of cystic fibrosis in the European Union. The results of literature reviews, surveys, and registry analyses revealed a mean prevalence of 0.737/10,000 in the 27 EU countries, which is similar to the value of 0.797 in the United States, and only one outlier, namely the Republic of Ireland at 2.98.

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.