John Massie

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.

Infection, Inflammation, and Lung Function Decline in Infants with Cystic Fibrosis

RATIONALE Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies. OBJECTIVES To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation. METHODS Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV(0.5)), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing. MEASUREMENTS AND MAIN RESULTS Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were -0.8 (1.0), -0.9 (1.1), and -1.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV(0.5) were -1.4 (1.2), -2.4 (1.1), and -4.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P=0.003), and FEV(0.5) z-scores 0.96 lower (P=0.001), respectively. Significantly greater decline in FEV(0.5) z-scores occurred in those infected with Staphylococcus aureus (P=0.018) or Pseudomonas aeruginosa (P=0.021). CONCLUSIONS In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

National study of infants hospitalized with pertussis in the acellular vaccine era.

Background. In Australia in 1999 acellular pertussis vaccine (DTPa) replaced locally manufactured whole cell vaccine given at 2, 4 and 6 months of age with coverage of about 95% by 12 months of age. Few data are available on pertussis hospitalizations or sources of infection in countries exclusively using DTPa. Methods. In 2001 national active monthly surveillance of infant hospitalizations for pertussis was conducted through the Australian Pediatric Surveillance Unit, which surveys all child health specialists monthly. A standard questionnaire was completed for notified cases. Results. There were 140 infants reported (median age at diagnosis, 8 weeks). The rate of hospitalization in indigenous infants was significantly higher than in nonindigenous infants (P < 0.01). Of 97 (69%) infants who had not been vaccinated for pertussis, 63 (65%) were <8 weeks old (before the first scheduled dose of DTPa vaccine). Of 76 infants age ≥8 weeks, only 28 (37%) were appropriately immunized for age. Of 68 coughing contacts whose ages were known, 46 (68%) were adults, usually one of the infant’s parents. Of 32 child contacts 16 (50%) were siblings. Four infants <6 weeks old died. Conclusion. Despite universal vaccination with DTPa in Australia, pertussis remains an important cause of hospitalization, morbidity and death in infants, most of whom were too young to be vaccinated or had missed vaccinations. The most common source of infection was a parent. Strategies to improve pertussis control in countries with high DTPa coverage could include adult-formulated booster pertussis vaccines for adolescents and recent parents and/or accelerated pertussis vaccine schedules for infants.

Chylothorax: Diagnosis and Management in Children

Chylothorax is the accumulation of chyle in the pleural space, as a result of damage to the thoracic duct. Chyle is milky fluid enriched with fat secreted from the intestinal cells and lymphatic fluid. Chylothorax in children, is most commonly seen as a complication of cardiothoracic surgery but may occur in newborns or conditions associated with abnormal lymphatics. The diagnosis is based on biochemical analysis of the pleural fluid, which contains chylomicrons, high levels of triglycerides and lymphocytes. Investigations to outline the lymphatic channels can prove helpful in some cases. Initial treatment consists of drainage, dietary modifications, total parenteral nutrition and time for the thoracic duct to heal. Somatostatin and its analogue octreotide may be useful in some cases. Surgery should be considered for patients who fail these initial steps, or in whom complications such as electrolyte and fluid imbalance, malnutrition or immunodeficiency persist. Surgical intervention may be attempted thoracoscopically with repair or ligation of the thoracic duct.

Changing Their Minds With Time: A Comparison of Hypothetical and Actual Reproductive Behaviors in Parents of Children With Cystic Fibrosis

OBJECTIVE. Newborn screening for cystic fibrosis, with appropriate counseling, enables carrier parents to be informed early about future reproductive choices. Previous studies have assessed attitudes toward reproductive decisions in a hypothetical pregnancy or have measured reproductive behaviors. We aimed to measure parent attitudes to reproductive technologies and to compare prospectively these attitudes with later reproductive behaviors. METHODS. Parents of children who had cystic fibrosis and were aged 2 to 7 years were surveyed at baseline using a written questionnaire that explored attitudes to prenatal testing and termination of pregnancy in a hypothetical pregnancy. Parent knowledge and access to genetic counseling services also were assessed. Five years later, we compared attitudes with actual reproductive behaviors. RESULTS. Fifty-six mothers participated at baseline, and 43 were resurveyed 5 years later. Parent knowledge of cystic fibrosis and genetics was very good. A total of 93% had met a genetic counselor at the time of diagnosis, and more than half had on at least 1 subsequent occasion. At baseline, 82% reported that they would be likely to have prenatal diagnosis in a subsequent pregnancy, and 56% reported that they would be likely to terminate an affected pregnancy. Twenty-seven mothers since had been pregnant, with prenatal diagnosis used in 33 of the 55 pregnancies. In 67%, the hypothetically reported behavior regarding use of prenatal testing was the same as their actual behavior. Five of the 33 tested pregnancies were affected; all ended in termination. Reproductive choices in relationship to the number of children wanted, together with attitudes toward prenatal diagnosis and termination of pregnancy, were dynamic over time, with decisions having changed in both directions. CONCLUSIONS. This cohort of parents has actively used reproductive technologies since the birth of a child who has cystic fibrosis that was diagnosed by newborn screening. The dynamic aspect of reproductive choices highlights the importance of ongoing access to genetic counseling beyond the initial period of diagnosis and education, regardless of whether parents report that they expect to use reproductive technologies.

Parental attitudes to the identification of their infants as carriers of cystic fibrosis by newborn screening

Aim:  To investigate parental attitudes to cystic fibrosis (CF) carrier detection of their infant by newborn screening (NBS).

Diagnosis of cystic fibrosis by sweat testing: age-specific reference intervals.

OBJECTIVE To develop reference intervals (RIs) for sweat chloride and sodium in healthy children, adolescents, and adults. STUDY DESIGN Healthy, unrelated subjects aged from 5 to >50 years and subjects who were pancreatic insufficient with cystic fibrosis (CF) were recruited. Sweat collection was performed on all subjects with the Wescor Macroduct system. Sweat electrolytes were analyzed with direct ion selective electrodes. DeltaF508 mutation analysis was performed on the healthy subjects >/=15 years old. RESULTS A total of 282 healthy and 40 subjects with CF were included for analysis. There was no overlap of sweat chloride between the group with CF and the group without CF, but there was some overlap of sweat sodium. Sweat chloride increased with age, with the rate of increase slowing progressively to zero after the age of 19 years. The estimated median (95% RI) for sweat chloride were: 5 to 9 years, 13 mmol/L (1-39 mmol/L); 10 to 14 years, 18mmol/L (3-47 mmol/L); 15 to 19 years, 20 mmol/L (3-51mmol/L); and 20+ years 23 mmol/L (5-56mmol/L). CONCLUSIONS We have successfully developed the age-related RI for sweat electrolytes, which will be useful for clinicians interpreting sweat test results from children, adolescents, and adults.

Understanding the Costs of Care for Cystic Fibrosis: an Analysis by Age and Health State

OBJECTIVES Cystic fibrosis (CF) is an inherited disease that requires more intensive treatments as the disease progresses. Recent medical advancements have improved survival but have also increased costs. Our lack of understanding on the relationship between disease severity and lifetime health care costs is a major impediment to the timely economic assessment of new treatments. METHODS Using data from three waves of the Australian Cystic Fibrosis Australia Data Registry, we estimate the annual costs of CF care by age and health state. We define health states on the basis of annual lung-function scores and patients organ transplant status. We exploit the longitudinal nature of the data to model disease progression, and we use this to estimate lifetime health care costs. RESULTS The mean annual health care cost for treating CF is US

Newborn screening for cystic fibrosis

15,571. Costs for patients with mild, moderate, and severe disease are US

A home respiratory support programme for children by parents and layperson carers

10,151, US