GRAPHICAL ABSTRACT HIGHLIGHTS:
Microcirculation response to cold triggers varies between typical ColdU patients and atypical ColdU patients / HCs.
Reflection-mode PPG enables non-contact quantitative estimate of the perfusion.
Changes in perfusion can detect typical ColdU and indicate the disease activity.
PPG-based measurements correlate with CSTs (ICT or TempTest®) in 94% of cases.
INTRODUCTION
Cold urticaria (ColdU) is the second most common subtype of chronic inducible urticaria (CindU) after symptomatic dermographism. ColdU is characterized by wheals and/or angioedema following skin contact with various cold triggers (air, liquids, surfaces, objects). The main hazard of ColdU is the development of potentially life-threatening cold-induced anaphylaxis occurring in approximately one third of patients.
ColdU often starts in early adulthood (18–27 years) and lasts on average for 4–5 years, with spontaneous remission or relief of symptoms in 50% of cases within 5 years. The incidence of ColdU in Central Europe is estimated at 0.05%. ColdU is more frequent in women.
ColdU is diagnosed based upon patient history and cold stimulation tests (CSTs). For CSTs, cold is applied to the volar forearm for 5 min, and the response is evaluated 10 min after the end of stimulation. Appearance of whealing at the site of exposure represents a positive test result (Figure 1A and 1B ). About 75% of all patients with ColdU with positive responses to standard CSTs have typical ColdU. In atypical ColdU, CSTs are negative or induce atypical responses, such as delayed whealing. About 25% of all ColdU patients have atypical ColdU, and CSTs other than the standard ones are needed to elicit whealing and confirm the diagnosis4. Due to its easy accessibility, the most widely used CST is a melting ice cube test (ICT) with an ice cube in a water-filled plastic bag. However, testing with TempTest®, a Peltier element producing a 4–44°C temperature gradient, is preferred over ICT, because it can be used to assess disease activity, i.e. the critical temperature threshold (CTT).
The evaluation of CST responses in routine clinical practice is done by macroscopic inspection and is therefore subjective. In other words, CST sites are visually evaluated for whealing by the testing physician. This may lead to inter- and intra-observer variability, false positive and false negative CST results, and unreliable CTT measurements. For CTT determination with TempTest®, the length of the wheal, starting at the 4°C contact site, reflects the wheal-inducing temperature range in individual patients; the longer the wheal, the higher the CTT. Where the wheal ends is therefore of key importance for informing patients about their CTTs and their risk of reacting to cold. Since the end of TempTest® induced wheals often only measures 1 mm in width, it can be challenging to determine visually where that end is and what the CTT is. These and other issues with reading CSTs need to be addressed. Validated, robust, and objective test readouts lacking today are needed. In the future, better methods for CST response assessment in patients with typical ColdU should be easy to use, reliable, cost-effective, and objective.
Upon skin exposure to cold, patients with ColdU develop wheal- and flare-type skin reactions explained respectively by increased extravasation and vasodilation. These processes are brought about by the degranulation of mast cells. Mast cell mediators, including histamine, induce vasodilation and extravasation, and they also activate sensory skin nerves, which contributes to vasodilation and flare responses. This response to cold is unique to ColdU and does not occur in people without ColdU, in whom cold exposure first induces vasoconstriction and then, upon rewarming, vasodilation. The differences in skin responses to the cold between healthy subjects and ColdU patients are linked to certain changes in skin microvasculature. Based on this, we hypothesized that the assessment of ColdU patients and healthy subjects permits detection of distinct microvasculatory responses and their differentiation.
In vivo microvasculature responses can be assessed, mapped, quantified, and monitored by several methods and techniques, including laser Doppler perfusion and laser contrast speckle imaging, as well as photoplethysmography (PPG). The latter makes use of a light source and a photodetector to measure volumetric variations of cutaneous blood circulation. PPG provides reliable, low-cost, and easy to perform readings of local blood volume changes in the microvasculature of the inspected skin area. By contrast to other techniques, PPG is less sensitive to the patient’s motion, more cost-effective, and easier to implement.
Microcirculation imaging techniques are most commonly targeted at the nailfold area, but for ColdU, the most representative data is acquired by imaging affected skin. CSTs are known to produce ColdU-specific skin circulatory responses. Meyer et al. studied vascular reactions caused by mast cell degranulation after exposure to a cold stimulus and showed that vascular reactions change under the influence of antihistamines.
Here, we used PPG to test our hypothesis that the development of cold-induced skin lesions in patients with typical ColdU is linked to distinct and detectable changes in skin microvasculature. Our long-term aim is to improve ColdU diagnosis and management by providing an objective, easy, reliable, and low-cost measure of typical ColdU CST.
METHODS