Routine tests may predict fungal allergy risk in CF children: Study
Elevations in biomarkers were detectable several years prior to diagnosis
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Routine blood tests can accurately predict the development of an allergic response to the fungus Aspergillus in children with cystic fibrosis (CF), a study suggests.
A higher risk of the lung allergic response, called allergic bronchopulmonary aspergillosis (ABPA), was found among those with elevated biomarker levels for up to five years before diagnosis, particularly antibodies against Aspergillus. In contrast, those with low levels of multiple biomarkers were unlikely to develop ABPA.
“In children with CF, elevations in immune biomarkers were detectable several years prior to ABPA diagnosis and persisted over time,” suggesting that “immunological dysregulation associated with ABPA risk begins early in childhood and is not transient,” researchers wrote.
The study, “Common inflammatory markers predict risk of ABPA development in children with cystic fibrosis,” was published in the Journal of Cystic Fibrosis.
Timely ABPA diagnosis is challenging
Up to one in five people with CF develop ABPA, an allergic lung reaction to the fungus Aspergillus fumigatus. The reaction triggers chronic airway inflammation, leading to symptoms such as wheezing, severe coughing, mucus plugs, and fever.
Diagnosis is typically confirmed using a combination of chest imaging and blood tests for immune biomarkers, such as eosinophil cells and antibodies called immunoglobulin E (IgE). Both eosinophils and IgE are often elevated together in allergic diseases.
Still, a timely diagnosis remains challenging due to several factors, including a lack of symptoms or symptoms that are similar to CF exacerbations (a rapid worsening of respiratory symptoms). The fungus can also colonize the lungs of CF patients without progression to ABPA.
“Given the diagnostic complexity and potential for irreversible lung damage by the time ABPA is detected, improved methods for early risk identification are needed,” wrote researchers in Australia who assessed the utility of routine biomarkers in predicting ABPA in children with CF.
All 3 biomarkers consistently higher in CF patients who later developed ABPA
The team analyzed clinical data from 346 children and adolescents with CF, ages 0-18, all of whom had at least one measurement of eosinophil count, total IgE, and IgEs specific for Aspergillus (Asp-sp IgE). Among them, about 1 in 20 (5.4%) developed ABPA during the 20-year study period (2000-2020).
When the researchers examined the data, they found that for five years before an ABPA diagnosis, all three biomarkers were consistently higher in CF patients who later developed ABPA than in those who did not.
Total IgE levels and Asp-sp IgE, in particular, remained above the diagnostic threshold in CF children who developed ABPA. Eosinophil counts were also higher in the ABPA group. Over time, total IgE rose from about 500 IU/mL to 1000 IU/mL in the three years preceding diagnosis, and Asp-sp IgE nearly tripled over the final 2.5 years before diagnosis, increasing from about 10 IU/mL to nearly 30 IU/mL. Eosinophil counts also rose and reached diagnostic threshold levels in the two years before diagnosis.
An assessment of the earliest available biomarker measurement (baseline) showed a higher cumulative incidence of ABPA in CF children with elevated baseline biomarker levels, particularly Asp-sp IgE.
After 14 years of follow-up, more than five times as many children with high Asp-sp IgE at baseline developed ABPA as those with low Asp-sp IgE (18.3% vs. 3.6%). IgE and eosinophil counts showed similar trends, although with smaller differences.
Children with concurrent baseline elevations in two biomarkers had the highest cumulative ABPA incidence (up to 40.6%), and those with one elevated biomarker had an intermediate risk (up to 19%). In comparison, children with neither biomarker elevated consistently had the lowest ABPA incidence throughout follow-up (below 6.2%).
Those with all three biomarkers below clinical thresholds had a negligible risk, with cumulative incidences of 0.8% at 5 years and 4.5% at 12 years.
Our findings suggest that elevations in immune biomarkers associated with ABPA risk emerge early, are sustained over time, and can be used to stratify risk in children with CF.
The team then conducted a predictive analysis to determine how well each blood test performed in the years before an ABPA diagnosis.
When blood test results were normal, they were highly reliable at indicating low risk — the chance of not developing ABPA was very high (94% to 99%) across all tests and time periods. When test results were high, they weren’t very good at predicting ABPA, with a prediction accuracy of 10% to 32%, “underscoring the limited ability of threshold exceedance alone to predict future disease,” the team wrote.
The ability of the Asp-sp IgE test to detect risk increased as diagnosis approached, rising from 80% at five years before diagnosis to 92% to 93% at one to two years before diagnosis. Its ability to correctly identify low-risk children remained around 60% to 71%.
Total IgE remained fairly stable, with a sensitivity (true-positive rate) of 60% to 67% and high accuracy (87% to 89%) in identifying low-risk children. Eosinophil counts were less sensitive (38% to 52%) but remained very good at identifying low-risk children (85% to 86%).
“Our findings suggest that elevations in immune biomarkers associated with ABPA risk emerge early, are sustained over time, and can be used to stratify risk in children with CF,” the researchers wrote. “Combinations of biomarkers may help identify individuals at very low risk of ABPA who may require less intensive surveillance.”
