Blood Test Could Ease Diagnosis of Kids' Inflammatory Conditions

Elevations in a single cytokine species were uniquely characteristic of Kawasaki disease in children versus other inflammatory disorders with similar presentations, researchers said, paving the way for a blood test to aid differential diagnosis.

High levels of one particular interleukin (IL) protein -- IL-17A -- were diagnostic for Kawasaki disease as opposed to other pediatric fever conditions, with astonishingly high accuracy: an area under the receiver operating characteristic curve (AUC) of 0.95, according to Pui Y. Lee, MD, PhD, of Boston Children's Hospital, and colleagues.

"Elevation of all three IL-17-family cytokines [including IL-17-C and -F] was observed in >50% of KD [Kawasaki disease] patients, including 19 of 20 with coronary artery aneurysms, but was rare in all other comparator groups," the group reported in Arthritis & Rheumatology.

"Our findings support further investigation of the IL-17 cytokine family as diagnostic markers for KD and as potential risk factors for [coronary artery aneurysm] development," Lee and colleagues added.

Kawasaki disease is a form of vasculitis in children affecting mid-sized vessels. It's been recognized for a half-century, yet its underlying pathology remain mysterious, with diagnoses based on what Lee's group called "ambiguous clinical manifestations" such as fever, rash, and limb edema. These symptoms are also seen in a host of other conditions, such as viral infections, certain toxin exposures, and multisystem inflammatory syndrome in children (MIS-C), which each require different treatments.

The researchers noted, too, that "up to one-third of cases with [aneurysms] do not fulfill the classic diagnostic criteria" for Kawasaki disease.They emphasized that diagnosing Kawasaki disease quickly is imperative because coronary artery deformities develop in up to 30% of cases if the condition is not treated successfully.

Consequently, Lee's group sought to identify blood-based biomarkers that could aid in the differential diagnosis of children's inflammatory diseases, using a technology called the proximity extension assay (PEA). This method is capable of quantifying multiple proteins simultaneously in a single sample as small as 1 μL, the researchers said.

Lee and colleagues first obtained blood samples from 104 children: 23 diagnosed with Kawasaki disease, 25 with MIS-C, 26 with other fever disorders, 46 with various juvenile rheumatologic disorders (including 13 with macrophage activation syndrome), and 30 healthy individuals. Samples were then analyzed via PEA for 42 different cytokine species including interleukins, chemokines, interferons, tumor necrosis factors, and others.

Potential diagnostic markers were then checked in a separate validation cohort consisting of 37 Kawasaki disease patients and 28 febrile controls.

IL-17 proteins (including subspecies C and F as well as A) performed the best, not only for discriminating Kawasaki disease from febrile conditions, but also against MIS-C.

"[E]levation of the IL-17 cytokine family is a hallmark of Kawasaki disease," Lee and colleagues concluded.

That their approach was generally correct was confirmed by findings in patients with rheumatologic musculoskeletal conditions such as systemic juvenile idiopathic arthritis (sJIA). Cytokine profiles that Lee's group derived matched those from previous studies: for example, IL-18 was elevated in sJIA with macrophage activation syndrome, while interferon-induced chemokine levels were increased in juvenile dermatomyositis.

However, the researchers cautioned that more research remains to be done. "Although we provide data from an independent validation cohort of KD and febrile controls, a key limitation of our study is that all samples were obtained from a single center. Additional validation with samples from multiple sites is needed to confirm the generalizability of these findings," they noted. Another limitation was that some children in the rheumatologic condition cohort were receiving immunosuppressants that likely affected their cytokine profiles.

"Future studies are also needed for longitudinal analysis, which will be helpful in characterizing how IL-17 levels correspond to treatment response," Lee and team wrote.

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