Histamine skin prick tests: from established diagnostic technique to advanced experimental biomarker

Introduction Skin prick tests have a long history as diagnostic and pharmacodynamic biomarker. Besides visual assessments of the wheal and flare, objective blood flow measurements using laser Doppler imaging (LDI) and laser speckle contrast imaging (LSCI) have been reported. In light of these advancements, an up-to-date characterization of the histamine-evoked response is worthwhile. Methods A single-center study was completed in healthy males. Two parameters were addressed: (1) dermal blood flow (DBF) within a 7.65 mm ring encircling the skin prick site (DBFring), and (2) surface area of the flare (AREA(flare)). First, the dose response was assessed using placebo (0.9% sodium chloride) or histamine (histamine dihydrochloride 1, 3 or 10 mg/mL) skin pricks on the volar surface of subjects' (n=12) forearm. The DBFring was measured by LDI, the AREA(flare) by LDI and by ruler. Secondly, the inter-arm and inter-period reproducibility of the DBFring and AREA(flare), as evoked by histamine (10 mg/mL) and measured by LDI and LSCI, was examined (n=14). Lastly, the effect of aprepitant (125 mg), ketotifen (1 mg) and a single (5 mg) and fourfold (20 mg) dose of desloratadine and levocetirizine on the histamine-induced (10 mg/mL) DBFring and AREA(flare) was evaluated with LSCI (n=13 or 12). Results All three histamine doses induced a time-dependent vasodilation. Ruler recordings did not conclusively correlate with LDI assessments of the AREA(flare). The DBFring and AREA(flare) were reasonably reproducible when measured by using LDI or LSCI, with negligible bias between arms and study periods and poor to moderate within-subject reproducibility (0.23 <= ICC <= 0.71). While the fourfold dose of desloratadine (p=0.0041) and the single and fourfold dose of levocetirizine (p<0.0001) managed to reduce the AREA(flare), only the fourfold dose of levocetirizine (p=0.0052) reduced the DBFring. Discussion/conclusion Caution is warranted when translating years of clinical experience with histamine skin prick tests to objective recordings of the associated changes in skin perfusion. Ruler and LDI assessments of the AREA(flare) do not consistently correlate, and the reproducibility and histamine-dependency of the measurements is not obvious. While 10 mg/mL histamine may be a good choice for qualitative diagnostic evaluations, a lower dose may be better suited to use as a quantitative biomarker.

Automated summary

This study investigated the measurement method of histamine-induced skin blood flow and flare area, as well as the effects of certain drugs on histamine-induced blood flow and flare. The results showed inconsistent correlation between ruler and laser Doppler imaging assessments of the flare area, and the reproducibility and histamine-dependency of the measurements were not obvious. The study suggested that a lower dose of histamine might be more suitable as a quantitative biomarker.