Q&A: Overcoming delays in cystic fibrosis diagnosis, treatment

Key takeaways:

• Black/African American and Asian infants are often diagnosed with cystic fibrosis later than white infants.
• A new campaign plans to help these infants receive a timely diagnosis through data distribution.

Following newborn screening, a cystic fibrosis diagnosis is often delayed or missed in non-white infants, which can result in hospitalization and early life malnutrition, according to a Lurie Children’s Hospital press release.

To lessen the frequency of missed diagnoses and commence cystic fibrosis (CF) treatment early, the CDC’s Chronic Disease Awareness Program is funding the AChieving Equity for Disease prevention in Cystic Fibrosis (ACED-CF) campaign led by the Ann & Robert H. Lurie Children’s Hospital of Chicago.

This campaign will widely distribute study findings to primary care providers and public health officials through infographics tailored to each audience and deliver reports to state newborn screening programs to promote actions that improve timeliness of care, according to the release.

To learn more about missed/delayed CF cases, precautions to take after receiving test results and the ACED-CF campaign, Healio spoke with Susanna A. McColley, MD, attending physician in pulmonary and sleep medicine at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics at Northwestern University Feinberg School of Medicine.

Healio: How common are delayed or missed CF diagnoses among infants who are not white? What racial group experiences the most frequent delays/missed cases?

McColley: It’s important to understand that infants with CF can become malnourished by 4 weeks of age. The goal of CF newborn screening is to diagnosis infants by 4 weeks. Between 2010 and 2018, 35% of infants were diagnosed after 30 days of age, and 12.5% were diagnosed after 2 months of age. Infants who were demographically categorized as white and not Hispanic were, on average, diagnosed at 22 days, whereas infants of all other races and ethnicities were, on average, diagnosed at 31 days. Overall, 11% of diagnoses were after 180 days — almost 6 months. The proportion of infants with delayed diagnosis was highest in Black/African American and Asian infants.

Our research also showed that Black/African American and Asian infants are at the highest risk of false-negative newborn screening tests. However, it is hard to be sure how many people who are not yet diagnosed had false-negative newborn screening tests. Before newborn screening, the mean age of CF diagnosis was around 6 months, but the median was 5 years. Some people with CF have milder phenotypes. For example, the pancreas functions adequately — and they may not have respiratory symptoms until later childhood or even adulthood. It’s important to diagnose these infants, too, because they will benefit from monitoring and medicines to prevent presentation with severe lung disease.

Healio: What are some of the consequences of a delayed CF diagnosis? How will this impact patients and their families in the short and long term?

McColley: Overall, the most important consequence is early life malnutrition. Although the main cause of death in people with CF is lung disease, early life nutrition predicts later lung disease and the likelihood of surviving to adulthood. Both weight and height are important. We recently published a paper that shows infants with CF who are diagnosed later (a median age of 47 days, just under 7 weeks) have decreased height for age at 5 years compared with infants who were diagnosed at a median age of 14 days. The infants diagnosed later also had a higher risk for being hospitalized for pulmonary exacerbation of CF during the first year of life.

There are rare, catastrophic symptoms of CF that are seen in early life. CF causes increased salt loss in the sweat, so babies can get dangerously low levels of sodium and chloride in their system, which can cause seizures, heart rhythm abnormalities and death. Fat soluble vitamin deficiencies occur because CF pancreatic disease causes fat malabsorption. Vitamin K deficiency can cause severe bleeding, including in the brain. Vitamin A deficiency can cause severe corneal damage.

Because we used a database for this work, we didn’t report family experiences. We have met with families of children with CF through our partner, the National Organization of African Americans with CF (NOAACF) and through the Cystic Fibrosis Foundation. First and foremost, infants with CF can grow poorly, have frequent bowel movements and be irritable from abdominal pain that occurs with malabsorption. This is distressing to families. To compound that distress, families have reported being blamed and even reported to child protective services when their babies aren’t growing.

Healio: Newborns from minoritized groups are less likely to have the most common CF variant (F508del), which makes for delays in CF diagnosis because screening mainly evaluates for mutations that are specific to white individuals. What precautions can clinicians take if a newborn screen test of a non-white infant comes back negative?

McColley: The first test done for CF newborn screening is a biochemical test called immunoreactive trypsinogen (IRT). This is a pancreatic zymogen that is elevated in the bloodstream of newborns with CF. Different newborn screening programs have different thresholds for IRT that influence whether the blood sample goes for genetic testing at all. Even with sensitive thresholds, some infant tests will be below the threshold based on a number of factors. This will cause a false-negative test even if common variants are present.

In addition to having a lower frequency of F508del, the first described and most common disease-causing CFTR variant, minoritized people with CF are much more likely to have variants that are not tested for during CF newborn screening. The risk is highest among Black/African American and Asian people with CF. Some states test for only 23 CFTR variants, using a panel that represents primarily people with CF who have European ancestry, and one state still tests only for F508del. However, even with a wide range of variants, some infants can be missed. As with any screening test, there will be false negatives, so clinical signs and symptoms of CF should always lead to a referral to a CF center or, at least, a diagnostic sweat chloride test at an accredited facility. The most common symptoms are poor growth with or without obvious steatorrhea (fatty stools), recurrent or persistent respiratory symptoms such as cough, wheezing or pneumonia, or a combination of these. It’s also important for neonatologists and pediatric surgeons to know that a bowel obstruction called meconium ileus is often associated with a false-negative newborn screening test. Finally, infants with positive screening tests who do not have a confirmed diagnosis but have symptoms, including poor growth in the first 2 to 3 weeks of life, should be presumptively treated with pancreatic enzymes and salt supplements. These treatments are well tolerated and can save lives if the infant has CF.

Healio: Should screening panels become broader to better test for mutations that might indicate CF in non-white populations?

McColley: Screening panels should become broader. More than 700 CFTR variants are known to cause CF. The testing for all variants can be done using a next-generation sequencing platform, which some states are already using for newborn screening. It’s also important to have IRT thresholds that are sensitive enough. Finally, infants need to go promptly for diagnostic evaluation even if they have only one CFTR variant on their newborn screening test, because other genetic sequence changes (so-called “private” variants, deletions and duplications) won’t be detected even when all known variants are represented on a screening test.

Healio: ACED-CF is a campaign to raise awareness for CF in non-white infants following screening. How does this campaign plan to educate providers, patients and public health officials?

McColley: As you might imagine, different groups take different approaches. We’ve generated two versions of an infographic that has summarized key findings of our research, one for health care providers and one for public health practitioners. These are being disseminated widely through several avenues, including Lurie Children’s Hospital and NOAACF. We are developing a CME program and a maintenance of certification activity for pediatricians, focusing on immediate referral for infants with a positive CF newborn screening test, the risk for false-negative tests, and primary care office management of positive newborn screening tests. Our partners at the Center for Public Health Innovation, led by Marci Sontag, PhD, sent reports on state newborn screening metrics, age at first CF center evaluation, and nutritional indices to state newborn screening programs so they can see their outcomes and work with CF centers in their regions to improve timeliness. They are also leading learning collaboratives that include those public health professional and CF center leaders to understand newborn screening processes and identify ways to improve timeliness. Our awareness campaign for the general public is more complex as there are no comprehensive data on general public knowledge of CF or newborn screening, or experience of newborn screening and diagnosis in families with CF. We are completing surveys that will inform creation of our public awareness materials, which will then be evaluated in focus groups of parents.

Healio: Are there any research projects planned out of this campaign on the topic of CF screening and minoritized groups?

McColley: The CDC grant has a comprehensive evaluation plan that is based on program reach and, we hope, changes in policy or practice made in response to the campaign. In the future, we hope to study whether age at first evaluation and health of people with CF has changed over time. Of course, we will not be able to attribute improvement to these efforts alone because ongoing scientific advances are improving treatment for people with CF.

I’d like to acknowledge that the research leading to this CDC grant was funded by the Cystic Fibrosis Foundation, and that The Legacy of Angels Foundation is funding ongoing research and dissemination efforts.

Reference:

• Diagnosis of cystic fibrosis often missed or delayed, especially in non-white infants. https://www.newswise.com/articles/diagnosis-of-cystic-fibrosis-often-missed-or-delayed-especially-in-non-white-infants. Published July 24, 2023. Accessed July 24, 2023.
• Martiniano SL, et al. J Pediatr. 2023;doi:10.1016/j.jpeds.2023.113595.