A 5-year-old girl comes to your clinic for the first time with complaints of fever, malaise, and increased cough for 2 days. She has a history of asthma for which she uses a steroid inhaler daily and an albuterol inhaler as needed. She has been tried on various over-the-counter cold and allergy remedies, but her respiratory symptoms have been worsening over the past several months with an almost daily cough, and sometimes she expectorates blood-tinged mucus. Her past medical history is notable for an episode of rectal prolapse and “sinusitis” during each of the past two winter seasons. Her mother also reports that her daughter has “always been small for her age.” Your examination reveals a moderately ill-appearing child whose height and weight are at the 5th percentile for age. Her temperature is 101°F (38.3°C) and respiratory rate is 32 breaths/min. She has scant purulent rhinorrhea bilaterally, wheezes in all lung fields, and diminished breath sounds on the right side. Heart sounds and capillary refill are normal, yet she has digital clubbing.
What is the diagnostic approach in the evaluation of this child?
What is the most likely diagnosis?
What is the next step in evaluation?
ANSWERS TO CASE 16: Cystic Fibrosis
Summary: A small-appearing, 5-year-old girl previously diagnosed with asthma, rectal prolapse, and sinusitis presents with fever, scant purulent rhinorrhea, abnormal breath sounds, and digital clubbing.
• Diagnostic approach: Gather perinatal, past medical, family, and dietary histories, newborn screen results, and a thorough systems review. Plot the child’s height and weight on a standard growth curve.
• Most likely diagnosis: Cystic fibrosis (CF).
• Next step in evaluation: Obtain a chest radiograph and perform a sweat chloride test.
1. Know the historical clues and physical signs to distinguish CF from more common conditions.
2. Know how to accurately diagnose CF.
3. Have a basic understanding of the implications and limitations of genetic testing for CF.
A careful review of this child’s frequency and severity of respiratory symptoms, response to medications, and general health is warranted. Her small size and digital clubbing (unusual findings for asthma) suggest alternative diagnoses for her respiratory problems. Recurrent sinusitis is uncommon in young children because their nasal passages are not fully pneumatized; this girl likely was incorrectly diagnosed or has an underlying, predisposing condition for this problem.
CLUBBING: Increase in the angle between the nail and nail base of 180° or greater, and softening of the nail base to palpation. Although the condition can be familial, clubbing is uncommon in children, usually indicating chronic pulmonary, hepatic, cardiac, or gastrointestinal disease.
CYSTIC FIBROSIS (CF): The major cause of chronic debilitating pulmonary disease and pancreatic exocrine deficiency in the first three decades of life. It is characterized by the triad of chronic obstructive pulmonary disease, pancreatic exocrine deficiency, and abnormally high sweat electrolyte concentrations. Characteristic pancreatic changes give the disease its name.
Cystic fibrosis (CF) afflicts 1 of 3500 whites, 1 of 15,000 African Americans, 1 of 9200 Hispanics, and 1 of 32,100 Asian Americans. It almost always involves the respiratory tract; most patients develop bronchiectasis by the age of 18 months, although some may not experience respiratory difficulty for several years. Children are commonly misdiagnosed as asthmatic, but a careful history and physical examination ultimately demonstrates clues of CF. Persistent bronchial obstruction from impaired mucus secretion and damage to the respiratory cilia predisposes patients to secondary bacterial infection, which leads to a cycle of inflammation, tissue damage, further obstruction, and chronic infection. Bacterial pneumonia is initially caused by Staphylococcus aureus, and then by Pseudomonas aeruginosa. Most patients with advanced disease harbor heavy, slime-producing mucoid variants of Pseudomonas aeruginosa,rarely found in other conditions. Once established, these bacteria are virtually impossible to eradicate.
Airway reactivity is present in 50% of patients, but bronchodilator response is unpredictable and varies. Pneumothorax, hemoptysis, and cor pulmonale are frequent complications with advanced disease; pulmonary problems ultimately cause respiratory and cardiac failure. Clubbing and hypertrophic osteoarthropathy signal the underlying organ dysfunction. Chronic nasal congestion and sinus opacification are common, but acute sinusitis occurs infrequently. Children with CF may develop nasal polyps, with resultant nasal obstruction, headaches, and mouth breathing.
Children with CF grow poorly because of maldigestion from exocrine pancreatic insufficiency. This can lead to abdominal distention, rectal prolapse, minimal subcutaneous fat and muscle mass, and frequent passage of oily, malodorous, floating stools. The resulting fat-soluble vitamin deficiencies may manifest as peripheral neuropathy and hemolytic anemia (vitamin E), night blindness (vitamin A), or mucosal bleeding (vitamin K). If glands become distended with secretions or the intestinal lumen is filled with inspissated material, meconium ileus or intestinal obstruction can occur.
Fatty liver infiltration or focal biliary cirrhosis appears in many CF patients. Hepatomegaly, esophageal varices, and hypersplenism caused by portal hypertension develop in a small proportion of teens, while cholelithiasis is common in adults. In neonates, the blocked intrahepatic bile ducts may cause prolonged conjugated jaundice. Other symptoms are azoospermia, endocervicitis, enlarged salivary glands, and a “salty taste” on the skin (due to eccrine sweat gland dysfunction). Patients and their families require extensive psychosocial support.
The diagnosis of CF is usually based on a positive sweat test in conjunction with one of the following: typical chronic obstructive pulmonary disease, documented exocrine pancreatic insufficiency, and/or a positive family history. Persons with CF have elevated sweat electrolyte concentrations because of abnormalities in the CF transmembrane conductance regulator (CFTR) protein. Appropriate technique is important when attempting to measure sweat chloride in infants, in whom the collection of an adequate sweat quantity may be difficult. Elevated sweat electrolyte levels (false positives) have been reported in conditions such as anorexia nervosa, hypothyroidism, and nephrogenic diabetes insipidus. False-negative results can occur in CF patients with edema and hypoproteinemia. Because the implications of false test results are great, sweat testing is most appropriately obtained when a reasonable clinical suspicion of CF exists (see Table 16-1 for indications) and repeated when the initial test results are in doubt.
Table 16-1 • INDICATIONS FOR SWEAT TESTING
DNA testing may be used when CF is suspected but the results of sweat testing are negative or equivocal. Disease is caused by mutations in the long arm of chromosome 7, the most common being a single phenylalanine deletion at amino acid 508 (Δ 508). Available tests detect that more than 90% of individuals carry two CF gene mutations, but some children have only one or no detectable mutations by this methodology. The disease shows autosomal recessive inheritance.
Because research demonstrates that newborn screening improves nutritional status and growth and reduces hospitalizations, routine testing for CF is now performed for all newborns in the United States. The blood spot screening test detects the pancreatic enzyme immunoreactive trypsinogen (IRT), which is elevated in infants with CF. Second-tier testing for samples with high IRT levels relies on a second IRT test or limited DNA testing. Infants with positive results on the newborn screen undergo sweat chloride testing for definitive confirmation. False-negative results are possible with the IRT newborn screen, so infants with symptoms suggestive of CF (such as meconium ileus) should undergo further testing even if newborn screen results are negative (Figure 16-1).
Figure 16-1. The CF diagnostic process for screened newborns. (From the National Institutes of Health. http://www.ncbi.nlm.nih.gov/pubmed/18639722. Accessed April 23, 2012.)
Long-term management of CF patients is best coordinated by experienced pediatric pulmonary specialists and includes minimizing airway reactivity and infections, optimizing nutritional status, and providing ongoing psychosocial support. The prognosis varies depending on disease severity. Infants with severe lung disease can die in early childhood, but most patients reach adolescence or adulthood. Mean survival for persons with CF now exceeds 35 years.
16.1 A term infant delivered vaginally develops vomiting and abdominal distention after 10 hours of birth. No stool passage has been noted. An abdominal radiograph shows distended small bowel loops and a “bubbly” pattern in a portion of intestine; the colon is narrow. Which of the following should you tell the parents?
A. You would like to consult a pediatric surgeon because you suspect that their child has Hirschsprung disease.
B. The child most likely has necrotizing enterocolitis, a condition more commonly seen in premature infants. Therefore, you question the child’s supposed gestational age.
C. You are concerned about the possibility of meconium ileus and would like to obtain some family history.
D. You believe that the child simply is constipated and would like to change to a soy-based formula to see whether the baby tolerates this better.
E. The child’s symptoms and radiograph findings most likely are normal.
16.2 Appropriate clinical management of the patient in Question 16.1 includes which of the following?
A. Change from enteral to intravenous feeds; obtain genetics consultation for the next morning.
B. Change from enteral to intravenous feeds, obtain a blood culture, and initiate antibiotics.
C. Change from enteral to intravenous feeds, place a nasogastric tube, and obtain a emergency pediatric surgery consultation.
D. Change from cow’s milk to soy-based infant formula and continue to observe the infant.
E. Do not change your current management.
16.3 A 10-year-old boy has a history of recurrent sinusitis and multiple episodes of pneumonia. A sweat electrolyte test result is within the normal range. Which of the following can be removed from your differential diagnosis now?
B. Primary ciliary dyskinesia (Kartagener syndrome)
C. Gastroesophageal reflux disease (GERD)
D. Cystic fibrosis
E. Severe combined immunodeficiency
16.4 A 2-month-old infant presents with 5 days of wheezing and diarrhea. Parents report a subjective fever. She continues to breastfeed well. Laboratory abnormalities that could suggest cystic fibrosis include all of the following except:
A. Hyponatremia and hypochloremia
B. Metabolic alkalosis
D. Elevated prothrombin time (PT)
E. Anemia with a reticulocyte count of 10%
16.1 C. Meconium ileus, inspissated meconium obstructing the distal ileum, is thought to be caused by deficiency of proteolytic enzymes. Obstruction begins in utero, resulting in underdevelopment of distal lumina. It is almost always associated with CF. Intestinal atresia and Hirschsprung disease (congenital aganglionic megacolon) cause similar clinical pictures, but the radiographic findings for this child are most consistent with meconium ileus. Necrotizing enterocolitis also causes emesis and abdominal distension but occurs primarily in extremely low-birth-weight infants (ie, <1000 g); the colon would be expected to be of normal size. Constipation is not consistent with this baby’s clinical picture or the described radiographic picture.
16.2 C. Meconium ileus is a surgical emergency, as volvulus and perforation with peritonitis are not uncommon complications.
16.3 E. Children with severe combined immunodeficiency will present in the first few months of life, and without stem cell transplant most die in the first year of life. CF cannot be ruled out since there can be false-negative test results; the sweat chloride test should be repeated and a full review of systems for other gastrointestinal or genitourinary symptoms should be done. Bronchiectasis and chronic sinusitis are characteristic of ciliary dyskinesia syndromes. Recurrent pneumonia and sinusitis can occur as complications of GERD and atopic disease.
16.4 C. Infants with CF will lose excess amounts of sodium chloride in their sweat resulting in a hyponatremic, hypochloremic metabolic alkalosis. Malabsorption of fats and protein are major causes of morbidity for patients with CF; these infants will need supplements of the fat-soluble vitamins (A, D, E, and K). Breastfed infants are already at risk for vitamin K deficiency, which manifests as an elevated PT. Elevated reticulocyte counts are seen with hemolysis (and acute bleeding) and would be seen with vitamin E deficiency. Neutropenia can occur with viral infections but is not a hallmark of CF.
Cystic fibrosis (CF) involves a defect in mucus secretion and eccrine sweat gland function, resulting in various visceral lumina obstructions and excessive electrolyte secretion.
Extrapulmonary signs and symptoms, such as digital clubbing, recurrent sinusitis, growth retardation, and fat malabsorption, are clues to the diagnosis of cystic fibrosis.
A negative sweat chloride test result does not preclude cystic fibrosis.
Meconium ileus in the newborn period is nearly pathognomonic for cystic fibrosis.
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