Nasal IL-13 production indicates patients with late allergic responses to birch

Key takeaways:

• Eight of 20 provoked patients had high IL-13 levels between 2 and 24 hours after provocation.
• These patients also had drops in nasal airflow and increased nasal obstruction at 6 hours.

Adults with late allergic responses to birch experienced IL-13 responses that correlated with cytokine and clinical responses to provocation, according to a study published in The Journal of Allergy and Clinical Immunology.

These responses may indicate biomarkers that could be used to predict late allergic responses and craft personalized therapy, Nicholas James Campion, MBChB, researcher, department of otorhinolaryngology, Medical University of Vienna, and colleagues wrote.

The study involved 30 patients with birch allergy, including 20 (eight men; mean age, 30.2 years) who were challenged with birch pollen extract (BPE) and 10 (two men; mean age, 30.7 years) who received a placebo, both on three consecutive days.

The researchers also collected nasal secretions on days 1 and 3 at specific time points within 24 hours of the provocation to measure 33 inflammatory mediators.

After the provocation, the mean area under the curve (AUC) for portable inspiratory flow (PNIF) measurements for the BPE group was significantly smaller than the AUC for the placebo group (P = .002), the researchers said.

The BPE group also experienced significantly greater symptom burdens than the placebo group based on VAS (P < .0001) and Total Nasal Symptom Score (TNSS; P < .0001).

During late allergic responses (LARs), defined as a 25% or greater increase in nasal airflow as measured by PNIF and increase in nasal obstruction symptoms based on TNSS from baseline through 6 hours after provocation, VAS represented 27.7% and TNSS represented 29.1% of the symptom burden in the BPE group.

Specifically, symptom burdens during LAR included nasal obstruction (32.8%), rhinorrhea (33.1%), nasal itch (22.1%) and sneezing (14.5%).

Additionally, the BPE group had significantly higher IL-4 (P = .0311) and IL-5 (P = .0002) AUC values than the control group on days 1 and 3 of the challenge. During day 1, the BPE group also had earlier and stronger IL-1 beta responses and decreased IL-18 concentrations.

The researchers observed IL-6 secretion 40 minutes after provocation during day 1, with “minor” secretion during day 3, in the BPE group as well. Overall, the only cytokines with significant differences included IL-6 (P = .0490) and IL-18 (P = .0276), the researchers said.

The BPE group had higher concentrations of TSLP and sST2 on days 1 and 3 than the control group too, but there were no differences in IL-33 or IL-25.

Provocation immediately induced tryptase, the researchers continued, with eosinophil-derived neurotoxin (EDN) and monocyte chemoattractant protein (MCP) induced an hour after exposure, in the BPE group. The BPE group also had significantly higher AUC values for EDN (P = .0001) and tryptase (P = .0244) than the control group, but not MCP-1.

Based on these results, the researchers said the early allergic response was robust and driven by mast cells, whereas the LAR was more heterogenous and dominated by type 2 cytokines.

With repeated nasal sampling on days 1 and 3, both groups experienced induced secretion of IL-16, MCP-2 and TNF-alpha. Concentrations of these cytokines progressively increased and peaked well above baseline values 8 hours after provocation during both visits, the researchers said.

IL-17A and IL-22 exhibited a similar secretion profile, the researchers continued, adding that repetitive sampling or diurnal variation of nasal cytokines may be responsible for this pattern.

Concentrations of eotaxin, MPO, TGF-B and other mediators all markedly fell below baseline values immediately after challenges during both visits for both groups, the researchers continued, before returning to baseline levels. BAFF, IL-7, IL-8, IL-12p70, Gro-alpha, NGAL and other cytokines displayed similar trends, the researchers said.

Compared with the first provocation, GM-CSF, IL-4, IL-5, IL-6, IL-13, TSLP and tryptase had lower peak concentrations after the third provocation, although the peak concentrations for EDN increased on day 3.

The researchers also found eight patients in the BPE group whose IL-13 concentrations were above the 90th percentile of the placebo group for at least one time point between 2 hours and 24 hours after the first provocation (IL-13^R).

These patients experienced a secondary drop in PNIF that reached significance at 6 hours compared with the other members of the BPE group (P = .0185) and the placebo group (P = .0018). Everyone in the IL-13^R group and one of the patients in the BPE group who did not have high concentrations of IL-13 experienced a clinical LAR as well.

The IL-13^R group had higher VAS and TNSS symptom burdens than the other members of the BPE group, the researchers said, but these differences were not clinically significant.

However, there were significant differences in nasal obstruction, rhinorrhea, nasal itch and sneezing during the LAR between the IL-13^R group and the other members of the BPE group and the placebo group, the researchers said.

There also were significantly higher concentrations of IL-5, IL-6, IL-22, sST2, TSLP, GM-CSF and MCP-1 among the IL-13^R group compared with the other members of the BPE group (P < .05 for all).

The researchers additionally called it remarkable that there were no significant differences in nasal cytokine responses between the other members of the BPE group and the placebo group.

The IL-13^R group and the other members of the BPE group had very similar responses during early allergic response, the researchers continued, adding that the IL-13^R group had higher baseline concentrations of IL-5 and MCP-1 as well.

Also during early allergic response, there were strong correlations between tryptase and nasal obstruction, VAS, TNSS and PNIF, the researchers said.

As measured by VAS and TNSS, clinical symptoms during LAR were associated with IL-4, IL-5, IL-13, TSLP, sST2, EDN and IL-6 secretion, particularly nasal obstruction, the researchers continued.

With these findings, the researchers said that a cohort of patients experienced robust nasal IL-13 responses during LAR following birch challenges with associations with nasal obstruction and a diverse inflammatory response in the nasal mucosa.

Once these data have been confirmed in a larger population, the researchers said, physicians could make clear and personalized treatment recommendations to patients based on their response to IL-13 during the late phase after allergen provocation, with MCP-1 and IL-5 potentially identifying individuals who may be susceptible to LAR as well.