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