pediatrics
Cystic Fibrosis
Diagnosis of Cystic Fibrosis
Newborn screening May also be suggested by a positive prenatal screening test result, family history, or symptomatic presentation Confirmed by a sweat test showing elevated sweat chloride on 2 occasions Identifying 2 CF-causing variants (1 on each chromosome) is consistent with the diagnosis May rarely be confirmed, in atypical cases, by demonstrating abnormal ion transport across the nasal epithelium or abnormal intestinal current measurements Most cases of CF are first identified by newborn screening, but up to 10% are not diagnosed until adolescence or early adulthood. Despite advances in genetic testing, the sweat chloride test remains the standard for confirming a CF diagnosis in most cases because of its sensitivity and specificity, simplicity, and availability. Universal newborn screening for CF is now standard in the United States. Screening is based on detecting an elevated concentration of immunoreactive trypsinogen (IRT) in the blood. There are 2 methods of following up on an elevated IRT level. In one method, a second IRT is done, which, if also elevated, is followed by a sweat test. In the other, more commonly used method, an elevated IRT level is followed byCFTRmutation testing, and, if 1 or 2 variants are identified, then a sweat test is done. For diagnosis, both methods have 90 to 95% sensitivity. In this test, localized sweating is stimulated withpilocarpine, the amount of sweat is measured, and the chloride concentration is determined. Although the sweat chloride concentration increases slightly with age, the sweat test is valid at all ages: Normal:≤30 mEq/L (≤30 mmol/L) (CF is unlikely.) Intermediate: 30 to 59 mEq/L (30 to 59 mmol/L) (CF is possible.) Abnormal:≥60 mEq/L (≥60 mmol/L) (This result is consistent with CF.) The results are valid after 48 hours of life, but an adequate sweat sample (>75 mg on filter paper or>15 mcL in microbore tubing) may be difficult to obtain before 2 weeks of age. False-negative results are rare but may occur in the presence of edema and hypoproteinemia or an inadequate quantity of sweat. False-positive results are usually due to technical error. Transient elevation of sweat chloride concentration can result from psychosocial deprivation (eg, child abuse, neglect) and can occur in patients with anorexia nervosa. A positive sweat test result should be confirmed by a second sweat test or by identification of 2 CF-causing variants. A small subset of patients have a mild or partial CF phenotype and sweat chloride values that are persistently in the intermediate or even normal range. In addition, there are patients who have single-organ manifestations such as chronic or recurrent pancreatitis, isolated bronchiectasis, or congenital bilateral absence of the vas deferens along with findings suggestive of abnormal CFTR function. They do not meet criteria for a CF diagnosis and are classified as having a CFTR-related disorder. In some of these patients, the diagnosis of CF can be confirmed by the identification of 2 CF-causing variants, 1 on each chromosome. If 2 CF-causing variants are not identified, ancillary evaluations such as pancreatic function testing and pancreatic imaging, high-resolution chest CT, sinus CT, pulmonary function testing, urogenital evaluation in males, and bronchoalveolar lavage including assessment of microbial flora may be useful. Additional potentially helpful diagnostic tests include expandedCFTRgenetic analysis and measurement of nasal transepithelial potential difference (based on the observation of increased sodium reabsorption across epithelium that is relatively impermeable to chloride in patients with CF) and measurement of intestinal currents. Infants who have a positive newborn screening result and evidence of possible CFTR dysfunction but do not meet the diagnostic criteria for CF are classified as having CFTR-related metabolic syndrome (CRMS), also called CF screen positive, inconclusive diagnosis (CFSPID). CRMS/CFSPID is diagnosed in infants who have a positive newborn screen, are asymptomatic, and haveeitherof the following: Sweat chloride concentrations in the intermediate range and 0 or 1 CF-causing variant Sweat chloride concentrations in the normal range and 2CFTRvariants, at least 1 of which has unclear phenotypic consequences Most children with CRMS/CFSPID remain healthy, but over time around 10% will develop symptoms and meet criteria for a diagnosis of CF or a CF-related disorder. Patients with CRMS/CFSPID should be evaluated and monitored regularly in a CF care center. Pancreatic function should be assessed at the time of diagnosis, usually by measuring the concentration of human pancreatic elastase in stool. Human pancreatic elastase measurement is valid even in the presence of exogenous pancreatic enzymes. Infants who are initially pancreatic sufficient and who carry 2 "severe" variants should have serial measurements to detect progression to pancreatic insufficiency. Chest imaging is done at times of pulmonary deterioration or exacerbations and routinely every 1 to 2 years. High-resolution chest CT may be helpful to more precisely define the extent of lung damage and to detect subtle airway abnormalities. Chest x-rays and CT may show hyperinflation, mucoid impaction, and bronchial wall thickening as the earliest findings. Subsequent changes include areas of infiltrate, atelectasis, and hilar adenopathy. With advanced disease, segmental or lobar atelectasis, cyst formation, Bronchiectasis , and pulmonary artery and right ventricular hypertrophy occur. Branching, fingerlike opacifications that represent mucoid impaction of dilated bronchi are characteristic. Sinus CT studies are indicated in patients with significant sinus symptoms or nasal polyps in whom endoscopic sinus surgery is being considered. These studies almost always show persistent opacification of the paranasal sinuses. This chest x-ray shows right lower lobe collapse. Findings are typical for CF but not specific. By permission of the publisher. From Berman L:Atlas of Anesthesia: Critical Care. Edited by R Miller (series editor) and RR Kirby. Philadelphia, Current Medicine, 1997. This chest x-ray of a man with cystic fibrosis shows increased lung markings consistent with bronchiectasis. PHOTOSTOCK-ISRAEL/SCIENCE PHOTO LIBRARY This CT scan shows greatly dilated bronchi throughout the lungs. Findings are typical for CF but not specific. By permission of the publisher. From Berman L:Atlas of Anesthesia: Critical Care. Edited by R Miller (series editor) and RR Kirby. Philadelphia, Current Medicine, 1997. Overview of Tests of Pulmonary Function are the best indicators of clinical status and response to therapy. In patients over 5 years of age, spirometry should be done routinely and at times of clinical decline. In infants, respiratory status can be monitored by using a raised-volume rapid thoracoabdominal compression technique, which generates a partial flow-volume curve. In children 3 to 6 years of age, the multiple breath washout procedure can be used to generate a lung clearance index as a measure of ventilation inhomogeneity ( Pulmonary function tests done by spirometry indicate A reduction in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced expiratory flow between 25% and 75% expired volume (FEF25-75), and FEV1/FVC ratio An increase in residual volume and the ratio of residual volume to total lung capacity Fifty percent of patients have evidence of reversible airway obstruction as shown by improvement in pulmonary function after administration of an inhaled bronchodilator. . Bronchoscopy is indicated when it is important to precisely define the patient’s lower airway microbial flora (eg, to direct antibiotic selection) or to remove inspissated mucus plugs. CF carrier screening is available in the United States and is recommended for couples who are planning a pregnancy or seeking prenatal care. If both potential parents carry aCFTRvariant, prenatal screening of the fetus can be done by chorionic villus sampling or amniocentesis. Prenatal counseling in such cases is complicated by the wide phenotypic variability of CF and incomplete information on the clinical consequences of many of theCFTRvariants that are identified through screening. 