AD occurs as a result of complex interactions, such as skin barrier dysfunction, immunologic dysfunction, environmental, and genetic factors. The chronic course of AD manifested with dry and itchy skin presentation may severely deteriorate the patients’ quality of life. In particular, vicious cycles of the scratch and itch cycle cause a continuous mechanical damage to the skin, accelerating several inflammatory reactions, which contributes to a prolonged course of the disease. Therefore, stopping the repetitive scratch and itch cycles and restoring the damaged skin barrier may be an effective therapeutic strategy for itchy atopic skin. Notably, it has been reported that the symptoms of pruritic skin improved significantly with CAP application for an average of 4.7 times a day for 2 minutes. Moreover, CAP can promote the skin regeneration and wound healing by increasing the interleukin(IL)-6 and transforming growth factor-beta (TGF-b) in the skin[12, 13]. Moreover, stimulated angiogenesis during wound healing process was also noted by upregulating growth factors, such as vascular endothelial growth factor, epithelial growth factor, fibroblast growth factor, or by production of reactive oxygen species. In the atopic mice skin, it was observed that the treatment of keratinocytes with CAP effectively downregulated the expression of CCL11, CCL13, and CCL17, which are main driving chemokines for the induction of AD. In this human clinical study, patients with AD showed significant improvement in pruritic VAS (p-value = 0.032) and atopic severity scores, including modified ADAS (p < 0.001), EASI (p = 0.002), and SCORAD score (p-value = 0.001). These results support that CAP would be helpful to relieve symptoms of AD by reducing chronic itching and promoting the recovery of secondary wounds caused by scratching.
Interestingly, CAP also revealed antibacterial effects in the skin. Isbary et al reported that the bacteria in the wound area were reduced when an average of 7.86 treatments with CAP were performed, daily for 5 minutes for chronically unhealed wounds. The sterilizing effect of CAP is meaningful in the treatment of AD, because the skin microbiome and its fluctuations are directly associated with AD. Up to 90% of atopic patients showed dominant S.aureus colonization in skin microbiome and this increased colonization was known to be prominent in disease flare-up period[18, 19]. Recent investigations in children suggested that cutaneous S. aureus colonization may lead to disease development, as well as, function as an exacerbating factor of AD. Therefore, therapeutic attempts to restore the natural skin microflora by reducing colonized S.aureus are plausible strategies to improve the treatment of AD[21, 22]. In this context, medications for AD, such as topical corticosteroids and topical calcineurin inhibitors, play a role in restoring the diversity of skin microbiome. In our microbiome analysis, the mean proportion of S. aureus was significantly decreased in CAP treated group comparative to sham treated group (p-value = 0.047). Considering that atopic patients are susceptible to secondary bacterial infection due to a damaged skin barrier, the results of the present study are noteworthy. Indeed, CAP is able to improve atopic symptoms by promoting the recovery of the diversity of skin microbiome, as well as, to prevent secondary infection of the skin.
We attempted to demonstrate the therapeutic effect of CAP by measuring the change in TEWL as in our previous study. However, the average decrease in TEWL was not significant before and after the treatment of CAP. The function of the skin barrier is affected by multiple extrinsic factors, such as temperature, humidity, and ultraviolet irradiation[24, 25]. Recent studies have also revealed that the function of the skin barrier is associated with patients’ stress. Taken together these findings, there are some limitations in understanding the impact of CAP on the skin barrier function with changes of TEWL.
It is remarkable that there is a difference in response to CAP treatment according to total serum IgE. The group with total IgE > 100 kU/I was significantly improved in modified ADAS score (p-value < 0.001) and EASI score (p-value = 0.002) after CAP treatments. These results are due to the difference between the extrinsic and intrinsic types, suggested subtypes of ADs. Extrinsic and intrinsic types are defined according to IgE-mediated sensitization, according to the presence of specific IgE for food and environmental allergens. Since total serum IgE levels are significantly correlated with the allergen-specific IgE status, total IgE is considered as a clinical marker to differentiate between the extrinsic and intrinsic types in both adults and children[28, 29]. Thus, the group with total IgE > 100 kU/I are considered as extrinsic type of AD which has been described with elevated serum total IgE and disrupted skin barrier function[27, 30]. Ricci G et al also found that the extrinsic type AD showed a higher colonization of S. aureus compared to the intrinsic type children (71% vs. 49%). CAP treatment appears to improve the AD by restoring damaged skin barrier with antibacterial effect especially for causative S.aureus considering that CAP treatment is particularly effective in the group with elevated total IgE in this study, as above-mentioned.
The present pilot study has several limitations. First, this study was a single-center study with a small sample size. Further studies with multi-centered, large sample size are warranted. Second, patients with severe AD had not been included, because most of them were relied on oral immunosuppressants and reluctant to attempt CAP treatment alone. To evaluate the therapeutic effect of CAP alone, we considered that it is desirable to evaluate patients with mild to moderate AD in first place. Third, potential bias may have occurred due to the limited data on the microbiome analysis assessed in this study. Nevertheless, our study is still noteworthy, because this is the first prospective clinical trial of CAP device on AD patients. Until now, there have been no clinical trials of CAP in human AD. In addition, CAP treatment is easy to apply in that it does not have safety problems at all, unlike oral immunosuppressant which have side effects in long term use. This strong point implies that CAP treatment also showed the potential as a burden-free adjuvant therapy. In fact, most of patients in this study showed a substantial satisfaction with CAP treatment without any discomfort. Combinatory treatment with topical agents would be effective treatment options, because CAP is also known to enhance cutaneous transdermal drug delivery by regulating E-cadherin-mediated cell junction. Choi et al demonstrated that combinatory treatment of CAP with conventional anti-inflammatory topical agents could be effective for shortening the healing duration and minimizing the drug amount. In this study, the authors showed that the application of CAP or 1% hydrocortisone alone did not reduce the DNCB-mediated epidermal thickening in mice, but the thickened epidermis was restored by the combined treatment. Further clinical investigations with real human atopic skin are required to prove the effectiveness of CAP as an adjuvant treatment.
In conclusion, CAP has the potential to effectively improve the severity of mild and moderate AD by recovering the diversity of skin microbiome, as well as, promoting wound healing for damaged skin barrier. Patients’ subjective pruritic symptoms will also be alleviated by the treatment of CAP without safety issues. This study supports new findings in treatment response data of CAP would update the new therapeutic approach in the AD field.