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-centre 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 (AREAflare). 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, and the AREAflare by LDI and by ruler. Secondly, the inter-arm and inter-period reproducibility of the DBFring and AREAflare, 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 AREAflare 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 AREAflare. The DBFring and AREAflare 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 AREAflare, only the fourfold dose of levocetirizine (p = 0.0052) reduced the DBFring. 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 AREAflare do not consistently correlate, and the reproducibility and histamine dependency of the measurements are 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.

1.
Position paper: allergen standardization and skin tests. The European Academy of allergology and clinical Immunology. Allergy. 1993;48(14 Suppl):48–82.
2.
Lewis T, Grant RT. Vascular reactions of the skin to injury, Part II. The liberation of histamine-like substance in injured skin. Heart. 1924;11:209.
3.
Darsow U, Ring J, Scharein E, Bromm B. Correlations between histamine-induced wheal, flare and itch. Arch Dermatol Res. 1996;288(8):436–41.
4.
Schmelz M, Michael K, Weidner C, Schmidt R, Torebjörk HE, Handwerker HO. Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport. 2000;11(3):645–8.
5.
Purohit A, Melac M, Pauli G, Frossard N. Twenty-four-hour activity and consistency of activity of levocetirizine and desloratadine in the skin. Br J Clin Pharmacol. 2003;56(4):388–94.
6.
Grant JA, Riethuisen JM, Moulaert B, DeVos C. A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol. 2002;88(2):190–7.
7.
Grant JA, Danielson L, Rihoux JP, DeVos C. A double-blind, single-dose, crossover comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine versus placebo: suppression of histamine-induced wheal and flare response for 24 h in healthy male subjects. Allergy. 1999;54(7):700–7.
8.
Purohit A, Duvernelle C, Melac M, Pauli G, Frossard N. Twenty-four hours of activity of cetirizine and fexofenadine in the skin. Ann Allergy Asthma Immunol. 2001;86(4):387–92.
9.
Estelle F, Simons R, Mcmillan J, Simons KJ. A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares during 24 hours in normal subjects. J Allergy Clin Immunol. 1990;86(4):540–7.
10.
Devalia JL, Baltes E, Hanotte F, De Vos C. A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers. Allergy. 2001;56(1):50–7.
11.
Strimbu K, Tavel JA. What are Biomarkers? Curr Opin HIV AIDS. 2010;5(6):463–6.
12.
Stern MD. In vivo evaluation of microcirculation by coherent light scattering. Nature. 1975;254(5495):56–8.
13.
Olsson P, Hammarlund A, Pipkorn U. Wheal-and-flare reactions induced by allergen and histamine: evaluation of blood flow with laser Doppler flowmetry. J Allergy Clin Immunol. 1988;82(2):291–6.
14.
Wårdell K, Jakobsson A, Nilsson GE. Laser Doppler perfusion imaging by dynamic light scattering. IEEE Trans Biomed Eng. 1993;40(4):309–16.
15.
Clough GF, Boutsiouki P, Church MK. Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy. 2001;56(10):985–8.
16.
Briers JD. Laser speckle contrast imaging for measuring blood flow. Opt Appl. 2007;37(1).
17.
Lehmann S, Deuring E, Weller K, Scheffel J, Metz M, Maurer M, et al. Flare size but not intensity reflects histamine-induced itch. Skin Pharmacol Physiol. 2020;33(5):244–52.
18.
Staberg B, Klemp P, Serup J. Patch test responses evaluated by cutaneous blood flow measurements. Arch Dermatol. 1984;120(6):741–3.
19.
Grant SM, Goa KL, Fitton A, Sorkin EM. Ketotifen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders. Drugs. 1990;40(3):412–48.
20.
Sanchez MM, Binkowitz BS. Guidelines for measurement validation in clinical trial design. J Biopharm Stat. 1999;9(3):417–38.
21.
Koo TK, Li MY. A guideline of selecting and reporting intraclass correlation coefficients for reliability research. J Chiropr Med. 2016;15(2):155–63.
22.
Briers JD. Laser Doppler, speckle and related techniques for blood perfusion mapping and imaging. Physiol Meas. 2001;22(4):R35–R66.
23.
Malling H-J. Skin prick testing and the use of histamine references. Allergy. 1984;39(8):596–601.
24.
Van Neste D, Rihoux JP. Inhibition of the cutaneous response to histamine by H1-blocking agents: quantitative evaluation of microvascular changes in the skin after histamine challenge and a comparison of the effects of a single intake of cetirizine and terfenadine. Skin Pharmacol Physiol. 1988;1(3):192–9.
25.
Wahlberg JE. Current topics in contact dermatitis. In: Frosch P, Dooms-Goossens A, Lachapelle J-M, Rycroft RJG, Scheper RJ, editors. Assessment of erythema: a comparison between the naked eye and laser Doppler flowmetry. Berlin: Springer; 1989. p. 549–53.
26.
Nelson HS. Variables in allergy skin testing. Allergy Proc. 1994;15(6):265–8.
27.
Dreborg S, Backman A, Basomba A, Bousquet J, Dieges P, Malling H-J. Skin tests used in type 1 allergy testing. Position paper prepared by the subcommittee on skin tests of the European Academy of Allergology and Clinical Immunology. Allergy. 1989;44:22–30.
28.
Andersen HH, Lundgaard AC, Petersen AS, Hauberg LE, Sharma N, Hansen SD, et al. The lancet weight determines wheal diameter in response to skin prick testing with histamine. PLoS One. 2016;11(5):e0156211.
29.
Van Neste D. Skin response to histamine dry skin prick test: influence of duration of the skin prick on clinical parameters and on skin blood flow monitoring. J Dermatol Sci. 1990;1(6):435–9.
30.
de Vet HCW, Terwee CB, Knol DL, Bouter LM. When to use agreement versus reliability measures. J Clin Epidemiol. 2006;59(10):1033–9.
31.
Godse K, Tandon N, Patil S, Nadkarni N. Higher doses for heavy hives. Indian J Dermatol. 2013;58(2):149–50.
32.
Ständer S, Luger TA. NK-1 antagonists and itch. Handb Exp Pharmacol. 2015;226:237–55.
33.
Gillard M, Benedetti MS, Chatelain P, Baltes E. Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines. Inflamm Res. 2005;54(9):367–9.
34.
Devillier P, Bousquet J. Inhibition of the histamine-induced weal and flare response: a valid surrogate measure for antihistamine clinical efficacy? Clin Exp Allergy. 2007;37(3):400–14.
35.
Frossard N, Walsh GM. Comparing the H1 profile of second-generation antihistamines. Allergy. 2000;55(Suppl 60):40–5.
36.
Parsons ME, Ganellin CR. Histamine and its receptors. Br J Pharmacol. 2006;147(Suppl 1):S127–35.
37.
Caselli A, Spallone V, Marfia GA, Battista C, Pachatz C, Veves A, et al. Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction. J Neurol Neurosurg Psychiatry. 2006;77(8):927–32.
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