By Deborah Borfitz
February 23, 2021 | Therapies targeting a specific antibody, molecule, or cell promise to revolutionize the treatment of severe asthma by replacing the need to take oral corticosteroids. While steroid drugs like prednisone and methylprednisolone can stem a life-threatening asthma attack, long-term use can cause serious side effects such as high blood pressure, diabetes, and harm to the eyes and bones.
But growing use of biologics comes with its own set of issues, points out Craig Wheelock, associate professor in the department of medical biochemistry and biophysics at Karolinska Institute in Solna, Sweden. The monoclonal antibody Xolair (omalizumab), for example, only works in roughly two-thirds of patients. It is also expensive, requires multiple injections every 2-4 weeks, and the potential side effects include anaphylaxis.
What’s urgently needed, says Wheelock, is a better way to separate responders from non-responders to the new biologic treatment regimens. And that’s the aim of a new urine-based assay developed by researchers at the Karolinska Institute.
A mass spectrometry-based methodology developed in the Wheelock laboratory measures the urinary concentration of two eicosanoid metabolites—prostaglandin D2 (PGD2) and leukotriene E4 (LTE4)—which are well-known mediators of asthmatic airway inflammation. However, this marks the first time that the PGD2 and LTE4 molecules have been quantified in a large cohort and benchmarked against standard asthma biomarkers.
As recently detailed in a study published in the American Journal of Respiratory and Critical Care Medicine (DOI: 10.1164/rccm.201909-1869OC), urinary levels of the compounds were found to correlate strongly with known type 2 markers, for example circulating levels of immune cells known as eosinophils that are tied to disease severity, he says. Like other predictive biomarkers, including blood-based tests for immunoglobin E and periostin, they provide inconclusive information for treatment selection.
Even if the urinary lipid biomarkers perform on par with blood-based assays, Wheelock adds, they would still have the advantage because the test is noninvasive, and samples are easier to collect and not volume-limited. In the study, the markers were also shown to work equally well in adults and school-aged children. A urine test can be done even in babies by extracting urine from diapers, he notes.
Researchers further stratified the severe asthmatics to learn that those with the highest levels of PGD2 and LTE4 were the ones with type 2 inflammation, characterized by increased asthma exacerbations and decreased lung function—and levels were independent of oral corticosteroid treatment. This highlights the need for alternative treatments for this group of patients, says Wheelock, which is where biologic therapy might best come into play.
For the study, urinary concentrations of 11 eicosanoid metabolites were quantified in roughly 600 individuals who were part of the pan-European U-BIOPRED (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes) project, including close to 100 with mild-to-moderate asthma and about 400 with severe asthma. From normal values established in 100 healthy participants, the research team observed a progressive increase in most metabolites in relation to asthma severity.
The urinary test is currently useful in sorting out treatment plans for severe cases of allergy-induced asthma, the type characterized by type 2 inflammation, but is still limited to research settings, says Wheelock. For one clinical study underway at the Karolinska Institute, urinary samples are being taken from 1,200 asthmatics to quantify PGD2 and LTE4 concentration levels to benchmark against standard biomarkers of type 2 asthma, he says.
A smaller, 30-patient study is following patients over time taking different types of therapy, says Wheelock. In addition, the research team is working on studies with multiple pharmaceutical companies and healthcare providers using the assay on various types of asthmatics to identify responders to asthma treatment.
Odds are good that pulmonologists in Sweden will be among the first to have access to the urinary assay. While the country is relatively small, has reduced air quality issues relative to major urban centers around the world, and offers universal healthcare, incidence of asthma is still increasing and is currently upwards of 10% of the population, says Wheelock.
One day, other metabolites could be added to the assay to identify different disease phenotypes, such as exercise- and obesity-induced asthma, Wheelock says. His lab routinely uses metabolomics to screen vast numbers of metabolites, which is expected to inform the selection of molecules to include in future versions of the urinary panel.
The limitation of such clinical definitions is that they’re empirically based on patients’ presentation rather than the mechanistic underpinnings of their symptoms. Asthma phenotypes may all turn out to be heterogenous syndromes with different molecular drivers of severity and treatment response, he says.