By Thomas F. Dolan, MD, FAAPIn 1983, a task force on neonatal screening of the Cystic Fibrosis (CF) Foundation took a strong position against screening for CF until more was known about the reliability and validity of the test to be used and whether early diagnosis improved the prognosis of patients.1
Since that time, there has been much improvement in neonatal screening. Currently, recommended newborn screening for CF uses capillary blood spots from the newborn collected on filter paper. This blood is initially subjected to an immuno-reactive test for trypsinogen. Elevated blood trypsinogen levels usually occur in newborns with CF because of early pancreatic damage secondary to ductal obstruction.
However, there are a significant number of false-positive test results. In samples with elevated trypsinogen levels, the DNA in the blood spot is subjected to polymerase chain amplification. The amplified DNA is then analyzed for the most common CF mutation (D508). If the infant has two genes (homozygous) for D508, a diagnosis of CF is established. If the test for D508 shows only one gene or is negative, a screening for the 70 next most common mutations can be performed. This two-tier approach greatly increases the specificity of neonatal testing, and there are few false-positives and negatives. However, it will probably never be 100% accurate because, at last count, there were at least 600 different CF genes that have been identified. Any positive neonatal diagnosis must be confirmed by a positive sweat test, which remains the gold standard.
The second factor that has evoked increasing enthusiasm for neonatal testing for CF has been the realization that there are clear benefits of early diagnosis. It can be expected that identification of affected newborns with early implementation of enzyme and fat soluble vitamin therapy should practically eliminate a variety of metabolic and nutritional problems such as hypokalemic alkalosis, hypoproteinemic edema and anasarca, hemorrhagic disease due to vitamin K deficiency, hemolytic anemia due to vitamin E deficiency, pseudo tumor cerebri corneal ulcerations due to vitamin A deficiency, and rickets due to vitamin D deficiency. Prevention of these complications should reduce hospitalization as well as reduce morbidity. Better nutrition is associated with longer survival and less severe deterioration of pulmonary function.
A study by Farrel and colleagues indicates that the time of diagnosis of CF patients who did not have a diagnosis established in the newborn period was 72 weeks.2 Data from the CF Foundation indicate that 20% of patients are not diagnosed until after 4 years of age.
Several important studies indicate that CF patients, as early as 4 weeks of age, have evidence of inflammation by bronchoalveolar lavage (increased polymorphonuclear leukocytes, cytokinin, and bacteria), despite an absence of clinical or radiographic evidence of pulmonary disease.3 It is well known that the CF lung is histologically normal at birth. Neonatal screening will be essential for the evaluation of newer interventional protocols involving antibiotics, pharmacologic agents that stimulate chloride channels, or agents to block inflammatory cytokinins. Patients participating in controlled studies of the effectiveness of such treatments should start on an even playing field-as near to the newborn period as possible.
Prenatal, as opposed to neonatal, screening may be particularly important for the family of a patient with CF. Other pregnancies may have been undertaken or are underway.
After a diagnosis of CF has been established in a family, there is a significant decrease in the number of subsequent pregnancies. More importantly, the family can make an informed choice including use of prenatal diagnosis in subsequent pregnancies.
I believe that most of the objections in the 1983 position paper against neonatal screening for CF have now been answered.4 Many studies suggest no harmful results from early diagnosis. CF should be added to the list of genetic diseases that are routinely screened for in the newborn. As of today, only Colorado and Wisconsin are doing this on a universal, statewide basis. (Dr. Dolan is Professor of Pediatrics and Respiratory Diseases at Yale University School of Medicine.)
References1. Ad Hoc Committee Task Force on neonatal screening. Cystic Fibrosis Foundation. Neonatal Screening for Cystic Fibrosis: Position Paper.Pediatrics1983;72: 741-745.
2. Farrel PM, et al. Nutritional benefits of neonatal screening for cystic fibrosis. N Engl J Med 1997; 337:963-970.
3. Dankert-Rolse JE, Meerman GJ. Screening for cystic fibrosis-Time to change our position? N Engl J Med 1997;337:997-998.
4. Kahn TZ, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1997;151:1075-1082.
a. is caused by a strain of influenza A that is included in the 1997 influenza vaccine.
b. has been shown to have a person-to-person transmission.
c. is caused by a different virus from the viral strain that caused the 1998 world-wide pandemic.
d. requires air travel restrictions to prevent dissemination.
Milk intake by adolescent girls resulted in all of the following except:
a. an increase in bone density after 18 months.
b. an increase in calcium intake.
c. an increase in bone turnover.
d. a decrease in the incidence of osteoporosis in later life.
Patients with Turner syndrome:
a. have decreased verbal and non-verbal IQs.
b. may inherit their X chromosome from their father or mother.
c. have better social cognitive skills when their X chromosome is maternally derived.
d. have similar cognitive skills independent of whether their X chromosome is maternal or paternal.
Ambulatory blood pressure monitoring (ABM):
a. is not possible in young children.
b. gives a continuous record of blood pressure.
c. can differentiate between situational vs. sustained hypertension.
d. is indicated in the evaluation of any child with age determined hypertension.
When compared to ibuprophen, an equivalent dose of paracetamol:
a. induces a more rapid defervescence.
b. induces a shorter duration of defervescence.
c. induces a greater degree of defervescence.
d. has comparable effects on fever.
True statements about latex allergy include all of the following except:
a. incidence has increased because of the use of rubber gloves.
b. it may produce respiratory symptoms because of adherence of latex particles to glove powder.
c. it may be induced by repeated surgery.
d. it is more frequent in patients exposed to latex in early life.
Neonatal testing for cystic fibrosis as currently performed:
a. is routinely performed as part of neonatal screening for genetic diseases in the United States.
b. uses a two-tiered approach involving immunoassay and DNA analysis.
c. routinely detects heterozygotes for CF.
d. may have harmful effects from early diagnosis.