A second reason to measure cytokines is that novel immune toxicities develop with novel immunotherapies, which has been the story with IEC-HS, she said. Many patients were treated with CD19-directed CAR T for B-ALL with no recognized cases of IEC-HS. “When CD22-directed CAR T and other CAR T for multiple myeloma became available,” Dr. Diorio said, “IEC-HS started to be better recognized, and then retrospectively, perhaps, there was more IEC-HS [than] seen previously.”
The third reason is that it’s important to differentiate between cytokine storm syndromes because a patient with sepsis and a patient with CRS can look similar. “Cytokine panels can help to distinguish them,” she said.
Dr. Diorio is often asked why she does not just test for C-reactive protein. “There is a lot more nuance to cytokine panels than to traditional inflammatory markers,” she explained. “And when you modulate elements of the immune system, you lose your ability to track some of these inflammatory markers.” Once patients have received tocilizumab, she added, “a CRP no longer becomes reliable. You’re left without it.”
Other inflammatory markers such as ferritin increase. “My pediatric patients, unlike adult patients, have ferritins in the thousands at the get-go, so it’s not that useful to track their ferritins,” Dr. Diorio said. “Ferritins also lag over time, and often the change in ferritin occurs after the change in the patient, making it not a particularly useful biomarker for some of these more acute toxicities.”
The clinically available cytokine panel used at CHOP consists of IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor-alpha (TNF-α). “This cytokine panel came online during the COVID pandemic and was highly useful for the management of cytokine storms in the setting of COVID,” Dr. Diorio said, and particularly for multisystem inflammatory syndrome in children (MIS-C). “It was quite useful in discriminating MIS-C from other inflammatory syndromes in undifferentiated children.”
Dr. Diorio and colleagues reported their experience using the multiplexed cytokine panel with same-day results in pediatric medical practice (Gallo PM, et al. J Allergy Clin Immunol. 2025;155[2]:594–604.e5). They found that cytokine levels correlate with severity of illness and can help differentiate between syndromes that present similarly, including familial hemophagocytic lymphohistiocytosis and CRS compared with sepsis.
“One of the most useful tools from a clinical cytokine perspective, broadly, is finding consistently the combination of IL-6 and IL-8 being higher in patients with an infectious toxicity,” Dr. Diorio said. They found that the ratio of [IFN-γ] + [IL-10]/[IL-6] + [IL-8] distinguishes CRS from severe sepsis, with a high ratio favoring CRS and a low ratio favoring sepsis. “But in general, clinically when we see a cytokine panel in a patient with an undifferentiated cytokine storm and they have disproportionate elevations in their IL-6 and IL-8, we are often able to then identify an infectious cause,” she said.
Dr. Diorio presented the case of a 15-year-old male with B-ALL in third relapse who was referred for CAR T-cell therapy. After the patient received lymphodepleting chemotherapy, his preinfusion bone marrow was about 80 percent infiltrated with CD19+ B-ALL blasts, and he developed severe refractory CRS.
“For both CRS and ICANS,” Dr. Diorio said, “the most consistently demonstrated predictor for the development of severe symptoms is disease burden.” In leukemia, a high disease burden is anything greater than 25 percent.
In pediatric patients with leukemia with a high disease burden, the rate of severe CRS (severe enough to be in the ICU) is about 40 to 50 percent, she said. In patients with a low disease burden, the rate of severe CRS is less than five percent. “So this patient, we knew, was likely to get very sick from CRS” because he had a high disease burden.