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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