Effectiveness of Thermotherapy in Cutaneous Leishmaniasis: Systematic Review

RFHT vs. HECT-CL

The findings of this study indicate a higher efficacy of RFHT compared to HECT-CL as a treatment option for cutaneous leishmaniasis (CL). At day 90, the initial cure rate was 100% (20/20) in the RFHT group and 80% (16/20) in the HECT-CL group. By day 180, one patient in the RFHT group experienced a relapse, resulting in a final cure rate of 95% (19/20). In contrast, no relapses were observed in the HECT-CL group, and the final cure rate remained 80% (16/20). Cure rates between two groups were comparable (p>0.05).

Both groups experienced second-degree burns, with a higher prevalence in the RFHT group. However, all second-degree burns in both groups healed completely without complications [11].

RFHT vs. Miltefosine

The findings of this study indicate that the efficacy of single-dose thermotherapy (TT) is comparable to that of oral miltefosine administered over a 28-day treatment period for cutaneous leishmaniasis (CL) (p = 0.9), with a more favorable side-effect profile. Recurrence rates were 2.1% among patients treated with miltefosine and 4.1% among those who received TT.

Additionally, no significant differences in treatment efficacy were observed based on the infecting Leishmania species (miltefosine, p = 0.3; thermotherapy, p = 0.6) [12].

RFHT vs. IL-SSG

The findings of both studies demonstrated that IL-SSG was significantly effective in treating cutaneous leishmaniasis (CL) (p < 0.05). In one of the studies, no major adverse events were reported in either treatment group. However, transient flare-ups were observed in 31 of 50 nodular ulcers (62%) and in 3 of 5 ulcers (60%), with an increase in lesion size noted for up to two weeks following thermotherapy (TT). These ulcers subsequently healed rapidly [9,13].

RFHT vs. IL-SSG and IM-SSG

A single localized heat treatment was found to be as effective as IL-SSG and more effective than IM-SSG in treating CL (p<0.05). The time to achieve cure was significantly shorter with TT compared to SSG regimens (p < 0.001). Additionally, none of the patients who achieved complete healing experienced relapse during the 100-day follow-up period [13].

RFHT vs. IV-SSG

This study demonstrated that a single heat treatment of lesions was as effective as IV-SSG administered at a dosage of 20 mg/kg/day for 10 days. After treatment initiation, five wound infections related to lesions (19%) were reported in the TT group, compared to one infection (4%) in the IV-SSG group (p = 0.19). However, systemic antimonial therapy with IV-SSG was associated with several serious systemic adverse effects, whereas TT resulted only in localized reactions such as blistering, oozing, and skin erythema [14].

RFHT vs. Meglumine Antimoniate

One study found that the final cure rate with IM Meglumine antimoniate was higher than that with TT for treating CL (p<0.05); however, it was also associated with a higher incidence of side effects. Considering treatment adherence issues, adverse effects, and progressive lack of therapeutic response, TT was deemed more favorable than IM Meglumine antimoniate. Recurrences were observed in six patients (4.1%) in the TT group and four patients (3%) in the with IM Meglumine antimoniate group. Leishmania species were identified in 167 patients, and no significant association was found between treatment type (IM Meglumine antimoniate, p = 0.5; TT, p = 0.6) and the infecting Leishmania species (15). In two additional studies comparing RFHT with IL Meglumine antimoniate, TT demonstrated higher final cure rates and fewer side effects [16].

RFHT Vs RFHT and Miltefosine combination

The combination of TT and a short course of miltefosine was found to be significantly more effective than TT alone for treating uncomplicated CL (p<0.01). Subjects with lesions caused by L. braziliensis and L. peruviana showed a better response to the TT + MLT combination (20 out of 27 patients, or 74.1%) compared to those receiving TT alone (9 out of 21 patients, or 42.8%).According to the above ten studies RFHT was found to be more effective and cost-efficient than IL-SSG (2 studies), IM-SSG) (1 study), and IL and IM meglumine antimoniate (1 study). Combining single-session TT with a short course of miltefosine led to higher cure rates (80.3%) compared to TT alone (57.8%) (p=0.0055). Regarding the mode of TT, RFHT and HECT-CL was comparable while oral miltefosine and intravenous IV-SSG did not show a significant difference in efficacy compared to TT [17].

DISCUSSION

The findings of this systematic review demonstrate that TT is an effective treatment option for CL, particularly when compared to conventional therapies. Among the various TT modalities, RFHT appears to be more promising than other options due to its higher efficacy and greater cost-effectiveness. Higher cure rates were observed when TT was combined with M iltefosine, suggesting a synergistic effect between treatment modalities and warranting further investigation to optimize treatment regimens. The variability in efficacy among different TT techniques, particularly the advantage of RFHT over HECT-CL, emphasizes the importance of selecting the appropriate modality to optimize patient outcomes.

TT is a local treatment modality that involves the application of controlled heat directly to the lesion using portable, battery-operated devices such as RFHT and HECT-CL. This approach is effective because Leishmania amastigotes are sensitive to elevated temperatures. TT promotes healing through heat-induced tissue destruction and upregulation of the Th1 immune response, thereby facilitating ulcer resolution [11]. Indications for TT include papules, nodules, or ulcers measuring less than 4 cm in diameter, with a maximum of four lesions per patient. Lesions located near the eyes, nose, or lips are generally excluded. Despite certain limitations, TT remains a cost-effective and relatively safe treatment option for CL.

The ThermoMed device used for RFHT involves a relatively high initial cost and is typically restricted to facilities with adequate healthcare infrastructure. In contrast, the HECT-CL device is more affordable and can be operated by minimally trained personnel in community settings. A topical anesthetic cream is usually sufficient to provide analgesia prior to treatment [11].

Cost estimates suggest that a single application of TT using the ThermoMed device costs approximately USD 1.54 per patient, whereas the HECT-CL device costs around USD 2. The HECT-CL device can be reused for seven consecutive days, bringing the total cost of one treatment course to approximately USD 3.20. Furthermore, a single HECT-CL pack may be used for multiple patients, thereby reducing overall treatment expenses. Because the HECT-CL device generates heat through a chemical reaction, it is suitable for patients in whom RFHT is contraindicated, such as individuals with pacemakers [11,13].

Systemic antimonials, including SSG and meglumine antimoniate, are commonly used treatments for CL [18]. A recent meta-analysis indicated that pentavalent antimonials administered at a dosage of 20 mg/kg/day for 20 days remain among the most effective treatments for CL [14]. No significant differences in final cure rates have been observed between meglumine antimoniate and sodium stibogluconate [18]. However, antimonials are associated with several adverse effects, including arthralgia, myalgia, pancreatitis, transaminitis, headache, bone marrow suppression, and skin rashes. Additional side effects include nausea, vomiting, abdominal pain, and reactivation of herpes zoster [13,18]. Although most adverse effects are reversible and resolve within three to twelve days after initiation of therapy without requiring discontinuation, some patients experience prolonged myalgia and arthralgia that resolve only after treatment cessation [15].

SSG can be administered intravenously, intramuscularly, or intralesionally. Intralesional SSG treatment typically requires two to ten hospital visits, which may be inconvenient and negatively affect patient compliance [14,15,19]. Reduced adherence raises concerns regarding the potential development of resistance to SSG, which has already been reported [13)]. The total cost of standard SSG therapy exceeds USD 11.09, making it more expensive than TT [18, 19]. Considering cost, adverse effects, and patient compliance, TT represents a viable alternative treatment for CL.

Miltefosine primarily affects the gastrointestinal system, with common adverse effects including anorexia, nausea, vomiting, and diarrhea [12]. Although these symptoms are usually mild, more severe gastrointestinal complications have been reported in some cases. A fatal case of acute pancreatitis associated with miltefosine has also been documented. Elevations in serum aminotransferase and creatinine levels have been observed; however, these changes are generally mild, reversible, and dose-dependent [14,12]. Animal studies have demonstrated embryotoxic, fetotoxic, and teratogenic effects of miltefosine [12]. Due to these risks and the lack of controlled studies in pregnant women, miltefosine is contraindicated during pregnancy [14]. Additionally, insufficient data exist regarding its safety during breastfeeding; therefore, its use is not recommended in lactating women.

The combination of a single application of local TT with a short course of miltefosine was significantly more effective than TT alone in treating uncomplicated CL. Lesions treated with combination therapy healed more rapidly than those treated with TT alone. The additive effect likely results from the systemic therapy targeting circulating or residual parasites at the lesion periphery that may not be eliminated by local heat treatment alone. Furthermore, when used in combination therapy, the duration of miltefosine treatment is shorter than when used as monotherapy, potentially reducing both costs and adverse effects [17]. Although miltefosine offers the convenience of oral administration, its disadvantages include high cost, potential fetotoxicity, and increasing reports of treatment failure. Moreover, miltefosine monotherapy has not consistently demonstrated superior efficacy, highlighting the need for further pharmacokinetic, pharmacodynamic, and clinical studies, particularly evaluating combination regimens.

Overall, TT has been shown to be more favorable than several systemic and oral treatments for CL. It is generally safer, requires fewer treatment sessions, does not require laboratory monitoring, improves patient adherence, and is less costly [16]. Consequently, TT may be considered a first-line treatment option for patients in whom systemic therapies are contraindicated, including those with renal, hepatic, or cardiac disease, as well as pregnant women and infants. TT has also been shown to stimulate a protective immune response and may be effective in immunocompromised patients, including individuals with HIV who do not respond to intralesional SSG therapy [11].

The existing evidence supporting the efficacy, safety, and cost-effectiveness of TT suggests that it can be utilized as an effective alternative therapy for CL. This review highlights the potential value of TT as a practical and accessible treatment option in endemic settings.

CONCLUSION

The analysis indicates that RFHT is a superior, cost-efficient treatment for CL compared to other treatment options. Combining TT with MLT improves cure rates significantly. A quantum of benefits can be derived from TT as an alternative treatment method hence it is cost effective, well tolerated and has less side effects. Further research is warranted to refine these treatment protocols and confirm their long-term benefits.

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