Keywords

1 Biological Effects of wIRA in Human Skin

Water-filtered infrared-A irradiation (wIRA) is a safe and promising therapeutic modality in dermatology with a number of potential indications. wIRA irradiation can effectively heat the skin and subcutis up to a depth of approx. 2.5 cm with a low thermal load on the skin surface while delivering an effective energy level to deeper tissue layers (see Chap. 3, Fig. 3.5). These properties render wIRA a suitable therapy for dermatologic conditions involving deeper parts of the skin with little risk of associated adverse effects [1, 2].

The effects of wIRA on the skin are mediated through heat-dependent and heat-independent mechanisms. Heat-dependent effects result from a rise in tissue temperature (up to 8–9 °C on the surface and about 4.5 °C in a depth of 2 cm) [see Chap. 5, Fig. 5.5], up to ten-fold increases in skin blood flow [3] and an elevated oxygen partial pressure (ΔpO2 = 25–30 mmHg in a tissue depth of about 2 cm) [see Chap. 5, Fig. 5.5]. These mechanisms enhance the blood flow and increase the supply of oxygen and energy substrates to cells and accelerate the ability of damaged tissue to regenerate and heal [1,2,3,4,5,6].

The photon energy of wIRA (particularly wavelengths between 780–1000 nm) can also be absorbed by endogenous photosensitizers (particularly porphyrins) which in turn initiate photochemical processes that directly affect cells and cellular structures (e.g., cell protrusions, influence on cytochrome c oxidase and neurostimulation). Some of these biological effects correspond to a mild photodynamic effect and lead to further cell regeneration and tissue healing.

Through all these processes, wIRA reduces pain, improves wound healing, reduces hypersecretion of wounds and exerts antifibrotic and immunomodulatory effects [1, 7,8,9,10]. Thus, wIRA has been used as a treatment option for different skin conditions.

2 wIRA Treating Dermatological Disorders

2.1 Wounds

The effects of wIRA have been investigated in various types of wounds. Numerous studies show that wIRA irradiation promotes the healing of chronic wounds, predominantly venous ulcers, as well as acute wounds (surgical wounds or burns) [10,11,12].

Venous ulcers are very common in dermatological care and may pose a considerable therapeutic challenge, since healing is often notoriously slow. These ulcers are mostly located on the medial malleolar region. They are caused by impaired venous blood return towards the heart. Insufficient venous valves and/or insufficient contraction of the calf muscles (calf muscle pump) result in decreased blood flow, venous reflux and ambulatory venous hypertension. This, in turn, leads to an inadequate tissue perfusion with a decreased supply of oxygen and nutrients, as well as an inadequate removal of metabolites. Chronic hypoxia and hypothermia also impede host defense mechanisms against secondary microbial infection and compromise the healing process such that minimal trauma can lead to chronic wounds that often require long-term management. Treatment includes stage-dependent, wound care, compression, surgical removal of necrotic tissue and insufficient veins, and also infection control. Quality of life is significantly decreased in patients suffering from chronic venous ulcers.

wIRA counteracts several of the functional aberrations underlying the pathophysiology of venous ulcers. wIRA can improve the local wound microenvironment by increasing the temperature, the perfusion, and thus the oxygen supply in the affected tissue. wIRA also reduces wound hypersecretion and inflammation and enhances fluid absorption and thus reduces edema formation. A reduction in pain, which may already be noted during the first wIRA treatment, increases mobility and reduces the need for painkillers. Together, this accelerates healing and shortens the duration of hospitalisation [10,11,12].

In a prospective trial, Mercer et al. [13] reported on the response of 10 patients with venous stasis ulcers who were treated two to three times weekly with wIRA. Each irradiation lasted 30 min and the maximum treatment period was two months. Of the 10 patients, 7 experienced complete healing of their ulcers and another 2 achieved a distinct reduction in ulcer size. wIRA also reduced pain and the intake of painkillers. Thermographic imaging at baseline showed a hyperthermic ulcer rim and a hypothermic ulcer base that normalized during wIRA treatment.

The largest randomized controlled trial (RCT) in patients with chronic venous stasis ulcers included 51 patients, all receiving basic treatment with compression, wound cleansing and non-adhesive wound dressings [14]. Of these 51 patients, 25 received 5 weekly treatments for 30 min with a wIRA radiator, whereas the other 26 patients were irradiated with visible light (VIS) only. Treatment was given for a maximum of 9 weeks. In the event of earlier complete wound healing, treatment was continued for at least another week. In comparison with VIS alone, wIRA therapy resulted in a significantly greater reduction of the ulcer area (−151 cm2 vs. −49 cm2). A greater proportion of patients experienced complete ulcer healing (20% vs. 12%), improved granulation and increased epithelialisation of the ulcer rim, less wound exudation, and also an immediate relief of pain in about 25% of the patients. The irradiations were mostly carried out as a home treatment using a loan device and were reported by the patients as easy to perform. Taken together, this trial provided sound evidence that wIRA can be a useful addition to the therapeutic armamentarium for patients with chronic venous ulcers [14].

The results of all prospective trials that have used wIRA irradiation in different types of wounds (chronic venous stasis ulcers, infected and colonized wounds, surgical wounds and burns) have been reviewed [10]. The duration and frequency of irradiation in these studies have varied between 20 min twice daily and 30 min twice weekly. The numerous effects of wIRA on wounds that were observed in these studies are summarized in Table 18.1.

Table 18.1 Reported wIRA effects on wounds (modified from [15])
Full size table

In summary, wIRA appears to be an effective adjuvant treatment for chronic and acute wounds and may also accelerate wound healing in the perioperative setting [11, 16, 17]. Of note, wIRA treatment is virtually devoid of side effects and is well accepted by the patients. The usual treatment protocol employs three 30-min irradiations per week. Whether more frequent irradiations (up to six daily sessions of 30 min) [11] might further enhance the therapeutic efficacy remains to be substantiated. Home treatment with wIRA is feasible and easy to handle and can be offered to patients on a case-by-case basis. Future studies are required to delineate the optimum treatment protocol and to establish standardized criteria for the use of wIRA in wound management.

2.2 Sclerotic Skin Diseases

Sclerotic skin diseases can be categorized into systemic and localized forms that differ in etiology, pathophysiology, clinical presentation, associated extracutaneous organ involvement, therapy and prognosis. Systemic sclerotic diseases comprise systemic sclerosis (limited and diffuse form), scleromyxedema, scleroderma and nephrogenic systemic fibrosis [18, 19]. Cutaneous and internal organ fibrosis can, however, also occur in chronic graft versus host disease (GVHD), particularly after allogeneic bone marrow transplantation [20].

Systemic sclerosis (SS) is characterized by multiple skin changes (diffuse progressive induration of the skin, sclerodactyly, joint contractures, microstomia, pigmentary changes, telangiectasias, calcinosis cutis and pterygium inversum unguis) and involvement of internal organs, particularly the gastrointestinal tract, kidneys and lungs. In addition to sclerosis and inflammation, vascular abnormalities resulting in impaired tissue perfusion and lowered tissue temperature are also found in systemic sclerosis. Up to 90% of patients with SS suffer from Raynaud’s phenomenon (RP) which is characterized by intermittent arteriolar vasospasm of the digits, most often triggered by cold temperature or stress. Prolonged ischemia in Raynaud’s phenomenon can lead to ulceration and necrosis of the digits.

Localized scleroderma (LS), also known as morphea, has recently been reclassified into five main types: limited, generalized, linear (including LS en coup de sabre), or mixed LS and eosinophilic fasciitis (Shulman syndrome) [18, 19]. LS differs from systemic sclerosis, in that the sclerosing process is confined to the skin and does not involve other organs. It is characterized by chronic inflammation in the dermal and subcutaneous compartment of the skin and excessive accumulation of collagen. Clinically, LS manifests with single, multiple or generalized sclerotic plaque(s). Depending on the type of LS, the sclerotic process might also affect the joints and result in restricted joint motility. In contrast to SS, no vascular abnormalities are found in LS.

Common therapies for sclerotic skin disorders include immunosuppressive agents like methotrexate, cyclosporine, systemic corticosteroids and azathioprine. Phototherapies, particularly UVA-1 and psoralen plus UVA (PUVA) photochemotherapy are also effective treatments for these conditions. In addition to anti-inflammatory effects, both UVA-1 and PUVA have been shown to significantly upregulate the expression of matrix metalloproteinase-1 (MMP-1; collagenase) in cultured fibroblasts and sclerotic tissue which is essential for degrading accumulated collagen deposits.

In a pioneering study on 58 patients with systemic sclerosis, Foerster et al. [21] made use of the transdermal heating of wIRA and investigated its effect on scleroderma-associated RP. Ten irradiations with wIRA not only significantly attenuated cold response and reduction of subjectively felt RP severity but also decreased the modified Rodnan skin score (a validated score to measure overall skin sclerosis) and scleroderma-associated arthralgia.

Based on demonstrating beneficial effects of wIRA in a child with linear scleroderma [22] and in a small case series of three patents with morphea [23], von Felbert et al. [24] treated ten patients with localized scleroderma (aged 6–62 years) who had not responded to previous conventional therapies. wIRA irradiations of 20–30 min duration were administered two to five times weekly for a maximum of 18–48 sessions, depending on the intermediate therapeutic outcome. Marked improvements (reduction of erythema and sclerosis and diminished pruritus and discomfort) were observed in 7 of the 10 patients, with durometry confirming a decrease in skin sclerosis in 3 patients. Of note, none of the responding patients relapsed during a follow-up period of 1–7.5 years, pointing towards a sustained therapeutic effect of wIRA in patients with LS. No side effects of wIRA were reported.

The mechanisms via which wIRA affects sclerotic tissue remain to be elucidated. Using a filtered near-infrared light source (Ifraray-A, model IRA-800, emission mostly between 700 and 1300 nm) Danno et al. [25] found a significant upregulation of MMP-2 (gelatinase) in cultured fibroblasts after exposure to infrared-A irradiation. Likewise, TGF-β1 secretion by cultured keratinocytes was enhanced by the irradiation. TGF-β1 has been shown to stimulate the production of MMP-2 while reducing the synthesis of MMP-1 and MMP-3 (stromelysin). Discordant with UV-based phototherapies, exposure of cultured human fibroblasts to wIRA at fluences of up to 1200 J/cm2 did not cause systematic induction of MMP-1 expression [26]. It remains to be unravelled how these experimental findings can be reconciled with the observed clinical effects of wIRA in patients with SS or LS, since studies attempting to unravel its mode of action in diseased skin are so far lacking.

Currently, an explorative prospective bicentric intraindividual comparison study investigating the effects of wIRA in patients with morphea and sclerotic cutaneous GVHD is being performed at two phototherapy centers in Austria. For this, wIRA is being directed to a selected target area thrice weekly for 30 min over a total study period of 20 weeks. The primary endpoint of the study will be the change in skin thickness, as measured by high frequency ultrasound sonography (22 MHz) which is a sensitive and reliable tool for assessing the extent of cutaneous sclerosis. Secondary endpoints are treatment-induced changes in the modified Rodnan skin score, skin hardness (measured by durometry), range of motion and the patient global impression of change scale. Termination of the study and analysis of the data are expected for the second half of 2022.

In summary, the use of wIRA represents an exciting concept and strategy in the treatment of sclerosing skin disorders that often pose a therapeutic challenge. However, data on the effectiveness of wIRA remain scarce and further studies are required to further assess the future value and role of wIRA for managing these diseases.

2.3 Common Cutaneous Warts

Cutaneous warts are caused by infection of keratinocytes by human papillomaviruses (HPV). They most often occur in childhood with a prevalence rate of up to 33% among children between 6 and 12 years of age. Spontaneous regression is common, and a clearance rate of 50% has been reported in schoolchildren within an observation period of 1 year. Apart from watchful waiting, treatment options include chemical, physical and surgical removal, or immunostimulating agents. However, occasionally treatment-resistant disseminated cutaneous warts can be present in children and adults, particularly in the context of immunosuppression [27].

Evidence of a beneficial role of wIRA in the treatment of recalcitrant common warts on the hands and feet has been provided by a randomized, placebo-controlled trial on 80 patients that were divided into 4 groups of 20 patients each. After pretreatment with salicylic acid and curettage, the patients received four different types of photodynamic therapy. Group 1: application of 20% 5-aminolaevulinic acid cream followed by irradiation with visible light (VIS) and wIRA; group 2: application of 20% placebo cream followed by irradiation with VIS and wIRA; group 3: application of 20% 5-aminolaevulinic acid cream followed by irradiation with VIS; group 4: application of placebo cream followed by irradiation with VIS. One to three PDT sessions were performed at 3-week intervals. Additional exposure to wIRA significantly increased the therapeutic response. In particular, the number of completely cured patients and vanished warts in the two wIRA groups 1 and 2 amounted to 42% and 72%, respectively, 18 weeks after termination of treatment, whereas the respective values for patients in group 3 and 4 were only 7% and 34%. These data indicate that wIRA might be a useful adjuvant measure for resolving treatment-resistant common warts [28].

2.4 Further Dermatological Indications for wIRA

A number of studies have shown that IR in conjunction with contact cooling can effectively and safely reduce facial skin laxity [29,30,31,32]. The underlying mechanisms are considered to be mainly heat-dependent. Dermal heating induces a breakdown of hydrogen bonds and a change in collagen structure with subsequent formation of new collagen. The generation of inflammatory responses leads to fibroblast proliferation and upregulation of collagen expression.

An interesting concept is the use of wIRA as a penetration enhancer for topically applied drugs. To this end, Otberg et al. [33] have been able to show an increased epidermal penetration depth of the hydrophilic dye fluorescein when applied immediately before or after irradiation of the skin with wIRA over 30 min. This effect was attributed to a wIRA-induced rise in hydration of the stratum corneum that was confirmed by laser scanning microscopy.

Importantly, wIRA may also be considered in photodynamic therapy (PDT) as an alternative light source to red-light emitting halogen or LED lamps. PDT is a highly effective and widely used treatment for patients with non-melanoma skin cancer and particularly field cancerization with multiple actinic keratoses. PDT is based on the topical application of a photosensitizer prodrug (5-aminolevulinic acid, 5-ALA, and methyl aminolaevulinate, MAL) which is preferentially metabolized in malignant cells to protoporphyrin IX (PP IX), within which it acts as a powerful photosensitizer. Subsequent illumination with PP IX activating wavebands (mostly red light with a peak around 630 nm) initiates photodynamic reactions that ultimately result in the destruction of malignant cells. The major side effect of PDT is pain during illumination which occasionally necessitates discontinuation of treatment. Two randomized controlled studies in patients with multiple actinic keratoses comparing PDT with a broadband VIS + wIRA radiator versus an LED lamp or an incoherent halogen light source have demonstrated that illumination with the VIS + wIRA device significantly lowered pain scores, while at the same time resulted in comparable clearance rates [34, 35].

3 Practical Considerations

Treatment procedures with wIRA are essentially simple. A device such as the hydrosun®750 radiator allows a homogeneous irradiation of a 25 cm in diameter treatment area. The distance between radiator exit and the skin is set at 30 cm and is assured through an attached holding rod. The beam is delivered in a perpendicular angle and irradiance at skin surfaces amounts up to 200 mW/cm2 (±10%). The treatment usually lasts 20–30 min and generates a warm, most often pleasant feeling in the irradiated skin area. In case a patient complains about excessive heat, the distance to the radiator exit can be extended. Rarely, the heat feeling is perceived as pain and irradiation needs to be stopped. Special care should be taken in wound patients with impaired sensory perception, for example, due to diabetic polyneuropathy. However, despite its frequent use, there are as yet no reports on wIRA-induced skin burns. Although there is no evidence that accidental wIRA exposure might be harmful to the eyes, for safety reasons, the patients’ eyes are protected by infrared radiation blocking goggles during the application period.

4 Conclusion and Future Outlook

In conclusion, wIRA is an interesting and promising (photo-)therapeutic modality for a heterogeneous group of dermatological skin disorders. wIRA is easy to use and has an excellent benefit-to-risk ratio. The treatment hardly causes any acute side effects and is not known to be associated with any long-term hazards. Thus, wIRA can be used across all age groups, in pregnant and breast-feeding women, in immune-competent and immune-compromised patients and in patients with a history of cancer. Given its safety, wIRA can also be performed as a home treatment. Future studies are required to shed more light on its mode of action and generate additional clinical data on its effectiveness and optimized protocols for treating skin disorders.