A 5-year-old Girl with Recurrent Pneumonias

Pediatric Pathways

A 5-year-old Girl with Recurrent Pneumonias

After reading this article and answering the review questions, the reader will be able to:

  1. Review factors that account for missed diagnosis of cystic fibrosis (CF) after newborn screening (NBS)
  2. Recognize when to consider the diagnosis of CF
  3. Identify current and future CF-specific therapies

Case

A 5-year-old girl comes to your office with a history of recurrent pneumonias. She was born at 36 weeks gestation via C-section. At the time, her newborn screening (NBS) results were all normal, including an immunoreactive trypsinogen (IRT) level at the 95th percentile. Since her first year of life, she has had multiple ear infections, recurrent/persistent sinus infections, and a chronic productive cough. She has had several chest X-rays and has frequently been diagnosed with pneumonias. She had tympanostomy tubes placed, but continued to have ear and sinus infections. Her past medical history is otherwise unremarkable, including no history of diarrhea or other gastrointestinal disorders. There is no family history of immune deficiencies, asthma, atopy, or other childhood respiratory disorders.

On physical exam, she appears thin, but otherwise has a normal exam. An extensive work up is unrevealing. She is diagnosed with asthma and treated for nine months with inhaled fluticasone without change in symptoms.

She is referred to a pediatric pulmonologist where additional workup is undertaken. A bronchoscopy reveals thick white secretions throughout her lungs. Her anatomy is normal. A cell count on bronchoalveolar lavage (BAL) reveals >97% neutrophils (a normal cell count includes less than 7% neutrophils). Her BAL fluid grows Streptococcus pneumoniae and Haemophilus influenzae. A chest CT demonstrates opacities of her right upper lobe and left lower lobe, along with diffuse lymphadenopathy (Figure 1).

Figure 1. Chest CT demonstrating opacities in the right upper and left lower lobes.

Figure 1 

The patient goes on to have a diagnostic sweat chloride test. Results are 79 mEq/L on her left arm and 81 mEq/L on her right arm (ref: Normal <40 meq="" l="" abnormal="">60 mEq/L). These results are consistent with CF and she has additional cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis, which reveals two CF-causing CFTR mutations: F508del (the most common CF-causing mutation) and 3849+10kB C>T (a known CFcausing mutation that is often associated with pancreatic sufficiency and normal intestinal absorption).

Overview of CF

CF is the most common lethal autosomal recessive disorder in Caucasians and occurs in ~1 in 3,500 live births in the US. There are currently >30,000 people in the US and ~600 people in Wisconsin with CF. Over the past 30 years, there have been significant improvements in morbidity and mortality for people with CF. The current predicted median survival is 39 years in the US.

CF is the most common lethal autosomal recessive disorder in Caucasians and occurs in ~1 in 3,500 live births in the US. There are currently >30,000 people in the US and ~600 people in Wisconsin with CF. Over the past 30 years, there have been significant improvements in morbidity and mortality for people with CF (Figure 2).

Figure 2. Improvements in predicted survival for people with CF in the US. Courtesy of the 2012 Cystic Fibrosis Foundation Annual Data Report

 Figure 2

The current predicted median survival is 39 years in the US. Figure 2. Improvements in predicted survival for people with CF in the US. Courtesy of the 2012 Cystic Fibrosis Foundation Annual Data Report The ability to diagnose CF in the early newborn period following NBS has contributed to the gains in predicted survival for people with CF. The state of Wisconsin began NBS in 1985 with the Randomized Clinical Trial of CF NBS. Routine screening has been offered to all newborns in Wisconsin since 1994 and throughout the US since 2010. Successful NBS for CF requires the following steps (Figure 3): collection of a blood spot on the Guthrie card shortly after birth followed by an initial measurement of IRT at the State Lab of Hygiene. For an abnormal IRT, state laboratories will re-measure IRT on an additional blood spot specimen or perform DNA analysis and/or gene sequencing, depending on local protocol. Results of these tests are then reported to primary care providers (PCPs). For abnormal results, families are also contacted and instructed to schedule a diagnostic sweat chloride test at an accredited CF Center. In Wisconsin, the five CF Centers are at the University of Wisconsin in Madison, Children’s Hospital of Wisconsin in Milwaukee, St. Vincent’s Hospital in Green Bay, the Marshfield Clinic in Marshfield, and Gundersen Health Systems in La Crosse.

Figure 3. Algorithm for newborn screening for CF. The second test after measurement of IRT varies by state and region. Modified from Nakano et al. AJN 2014;114:36

 Figure 3

CF can be diagnosed when two known CF-causing CFTR mutations are identified, as in NBS or prenatal screening, or when there are symptoms of CF and evidence of CFTR dysfunction, i.e., an abnormal sweat test (Table 1). Most states screen for the most common 23 CFTR mutations that cause CF; this identifies at least one mutation in 97% of people with CF in the US.

Table 1. Symptoms consistent with a diagnosis of CF

  • Failure to thrive
  • Meconium ileus
  • Chronic sinupulmonary disease
  • Digital clubbing
  • Rectal prolapse
  • Pancreatitis or pancreatic insufficiency
  • Unexplained liver disease
  • Salt loss syndromes
  • Absence of the vas deferens

Modified from Farrell et al. J Pediatr 2008;153:S4

Newborn Screening for CF

There are several factors that may lead to a missed diagnosis after NBS (Table 2). The most common cause of a false negative result is a biologic false negative, i.e., low IRT values. The rationale for choosing cut-off levels for IRT values has been discussed and debated extensively. In Wisconsin, a floating cutoff value of IRT >96th percentile is used to trigger DNA analysis. In the case presented above, the patient’s IRT value was at the 95th percentile, despite having two known CF-causing mutations. This has occurred for <3% of people with CF in Wisconsin who have undergone NBS, occurring about once every 3 years.

Table 2. Factors that may contribute to missed diagnosis of CF after NBS

  • Specimen is not obtained (e.g., home birth), obtained incorrectly, or mislabeled
  • Lab error
  • Inappropriate IRT cutoff values
  • Low IRT levels (biologic false negative)
  • Uncommon CFTR mutations are present, but not screened for
  • Results are not communicated to the primary care providers
  • Sweat test is not performed

Modified from Rock et al. Pediatr Pulmonol 2011;46:1166

Therapies for CF

Since the introduction of dornase alpha (Pulmozyme), the first CF-specific therapy approved by the FDA in 1995, multiple daily therapies have been developed for people with CF (Table 3). Additionally, there are a variety of methods to provide daily airway clearance.

Table 3. Daily medications commonly used by people with CF

Oral

  • Salt supplementation
  • Fat-soluble vitamins
  • Pancreatic enzymes
  • Nutritional supplements (e.g., Pediasure, Duocal, Scandishakes)
  • Azithromycin

Inhaled

  • Albuterol
  • Dornase alpha
  • Hypertonic saline
  • Tobramycin (3 FDA-approved products)
  • Aztreonam

Each of these therapies is designed to treat the effects of the dysfunctional CFTR protein. In 2012, the FDA approved the first oral medication that directly affects (or “modulates”) the CFTR protein, ivacaftor (also known as Kalydeco). This medication is only helpful for 7% of people with CF who have specific CF-causing CFTR mutations. Studies are ongoing to determine if CFTR modulators may be effective in people with CF with other CFTR mutations, including the most common mutation, F508del.

Despite chronic daily therapies, children with CF frequently experience exacerbations of their lung disease, often triggered by viral respiratory infections. At the first sign of new respiratory symptoms, it is recommended that children with CF begin an intervention plan (Table 4). Goals for therapy include a return to baseline symptom status and lung function. If symptoms are severe or prolonged, treatment with intravenous antibiotics may be necessary. On average, about 1 in 3 children with CF are hospitalized annually for a pulmonary exacerbation.

Table 4. Intervention plan for acute increase in respiratory symptoms

  • Increase airway clearance to 3-4x daily at the first sign of an increased cough
  • Begin antibiotics if symptoms are severe or not improving after 4-5 days
  • Choice of antibiotics is typically governed by bacteria that have been identified on previous sputum cultures

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References

  • Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, Durie PR, Legrys VA, Massie J, Parad RB, Rock MJ, Campbell PW 3rd and the Cystic Fibrosis Foundation. Guidelines for the diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153(2):S4-S14
  • Rock MJ, Levy H, Zaleski C, Farrell PM. Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening. Pediatr Pulmonol 2011;46(12):1166-1174
  • Davies JC, Ebdon AM, Orchard C. Recent advances in the management of cystic fibrosis. Arch Dis Child. 2014; Epub ahead of print

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