Tripling of PPG amplitude predicts positive CST response
In 93.6% of all tested individuals, CST results matched those of PPG,
categorized as negative and positive based onR PPG ≤3 and >3, respectively. With
this cutoff, PPG correctly predicted 93.7% of typical and atypical
ColdU patients (Table 2 ). As for the HCs, 93.3% demonstrated
negative PPG responses, i.e. insignificant microcirculation change due
to the exposure to cold, and were thus correctly identified in line with
their CST results.
4 DISCUSSION
Our study demonstrates that the results of cold provocation testing in
patients with typical ColdU can be accurately and objectively assessed
by PPG. This suggests that the implementation of photoplethysmographic
measurements in everyday clinical practice may improve the diagnostic
work-up of patients with ColdU. PPG may be especially helpful for
differentiating typical and atypical ColdU and for testing patients with
typical ColdU for their temperature thresholds. Unlike the current
practice of visual evaluation, PPG makes it possible to perform a
quantitative and objective assessment of the skin response of ColdU
patients to cold exposure.
PPG measurements before and after ICT showed that microcirculation
responses to ICT are different in typical ColdU patients and HCs. After
exposure to cold, the relative increase in PPG amplitude was
significantly higher in ColdU patients than in HCs. These results
indicate a high sensitivity of PPG-based measurements in detecting
perfusion changes in patients with a positive CST, as well as a high
negative prognostic accuracy. Our proposed non-invasive and
easy-to-implement approach may thus become the basis for new
technologies and devices for ColdU diagnosis, complementing current ICTs
and improving the assessment of ColdU disease activity and treatment
effectiveness.23 The identifiedR PPG threshold value may further be used in
clinical practice to distinguish typical ColdU from atypical ColdU. The
ability of PPG to detect and quantify even small increases in skin blood
flow is underscored by the distinct pre-post CST changes in PPG
amplitudes, where tripling of PPG amplitudes is predictive of positive
CST responses, in patients with typical ColdU.
Our finding that patients with ColdU demonstrate normal baseline skin
blood perfusion is not surprising. In ColdU, urticarial lesions appear
only when the skin is exposed to sub-threshold temperatures. It was
therefore expected that the PPG-based assessment of skin blood flow at
baseline would not show differences in blood perfusion between ColdU
patients and HCs. This also supports the notion that there are no major
long-term changes in the skin microvasculature of patients with ColdU.
It would be interesting to compare baseline PPG signatures of ColdU
patients and patients with CSU, where chronic inflammatory changes such
as increased mast cell numbers and neovascularization have been
described.
The most important finding of our study is that cold-induced whealing in
patients with typical ColdU is linked to markedly increased blood
perfusion and PPG amplitudes. This demonstrates that whealing comes with
distinct and detectable changes in skin microvasculature and PPG metrics
that permit objective skin readings of provocation test responses. This
finding may be relevant beyond ColdU, for example, for the assessment of
skin responses to provocation testing in symptomatic dermographism and
solar urticaria.
How can PPG-based measurements improve CTT readings in ColdU? Our
findings suggest that PPG can precisely determine the edge of a
cold-induced wheal, which is critical for assessing the CTTs of
individual ColdU patients, i.e. the highest temperature that suffices to
produce a wheal. TempTest®-based CSTs in patients with
typical ColdU produce linear wheals that start and end where the skin is
exposed to 4°C and the CTT, respectively. PPG objectively identifies the
end of a TempTest®-induced wheal unlike how the CTT is
currently determined, i.e. by inspection, which is subjective and
subject to intraoperator and interoperator variability of measurements.
Accurate PPG-based CTT measurements may, thus, benefit the monitoring of
treatment responses in routine practice and clinical trials.
Our study has several limitations. These include the small sample size
and the lack of diversity of patients in terms of age and skin type.
Further studies are needed to confirm and extend our results.
Taken together, our findings suggest that photoplethysmographic
assessments of ColdU CST responses appear to be accurate and can provide
objective verification of positive and negative test results. Thus, PPG
may assist in diagnosing ColdU, distinguishing typical and atypical
ColdU, and making threshold testing more precise.
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