Infections caused by the protozoan parasite Leishmania include cutaneous (CL), mucosal and visceral leishmaniasis. Over 12 million people currently suffer from leishmaniasis and approximately 2 million are infected annually. Recently, CL has been seen in canine populations in the USA as well as army personnel serving in Leishmania-endemic countries such as Iraq and Afghanistan. CL caused by Leishmania major or by parasites of Leishmania mexicana complex usually manifest as localized skin lesions, which may heal or become chronic, leading to significant tissue destruction and disfigurement. Furthermore, Leishmania amazonensis and Leishmania aethiopica infections can manifest as diffuse cutaneous leishmaniasis, whereas infections caused by Leishmania braziliensis begin as cutaneous infections which can progress to more severe mucocutaneous leishmaniasis that are difficult to treat. Although several chemotherapeutic agents are currently available for CL, there is a strong need for new treatments that are safe, effective in inducing long-term cure and easier to administer in the field.
Current treatments for CL & their drawbacks
Currently, pentavalent antimony drugs such as sodium stibogluconate (Pentostam™; Albert David Ltd India) or meglumine antimoniate (Glucantime™; Rhône Mérieux, France and Farmamondo, Switzerland) are the WHO-recommended drugs for treating CL Citation[1,2]. However, both these drugs are toxic and have poor patient compliance because they are required to be administered daily via the intravenous or intramuscular route for 20 days and sometimes several courses are needed Citation[1]. In addition, drug-resistant parasite strains are rapidly emerging worldwide. Furthermore, although both these drugs are produced and approved for CL in Europe and other Leishmania-endemic parts of the world, they are required to be administered under an Investigational New Drug (IND) protocol in the USA.
Recently, some studies found that topical paramomycin is effective in treatment of CL caused by Leishmania species that have low potential to spread to mucosa Citation[3,4]. However, ensuring 100% patient compliance for this treatment in the field could be a challenge because it involves two applications daily of paramomycin cream on the lesion for 10–15 days. Alternatively, this treatment could be instituted as direct observational therapy (DOT) to ensure compliance, but this may not be cost effective. Antifungal agents such as fluconazole, itaconazole and ketoconazole have been used in treatment of CL with variable success Citation[5,6]. Amphotericin B is also effective against CL in experimental models, but its efficacy in humans remains to be determined.
Why radiofrequency-induced heat therapy could be a first-line treatment for CL
Nonpharmacological therapies such as cryotherapy and heat therapy have been used in treatment of CL Citation[7–16]. While cryotherapy using liquid nitrogen has been found to be promising against CL, this treatment requires multiple applications of liquid nitrogen on the lesion for a period ranging from 1 to 3 weeks Citation[8–10,17,18]. Furthermore, cryotherapy is highly effective in treatment of dryer and smaller (<1 cm) lesions, but needs to be administered in combination with intralesional antimonials to be effective against large lesions Citation[8,9].
Recently, radiofrequency-induced heat (RFH) therapy has been used in the treatment of CL Citation[7,13,15,16,19]. This treatment involves the controlled and localized delivery of radiofrequencies under local anesthesia into lesions for 30–60 sec to generate heat using a using a current field radiofrequency generator. The generated heat penetrates the upper dermis, producing a secondary burn that destroys diseased tissue while causing minimal damage to healthy underlying tissue. Several short-term (4–5 months) follow-up studies have shown that RFH therapy is comparable, or even better than antimonials in the treatment of CL Citation[13,20]. In addition, a 12-month follow-up study by Aronson et al. also found that RFH therapy and systemic sodium stibogluconate treatment were equally as effective in inducing lesion healing in US soldiers who had acquired L. major infection in Iraq Citation[7]. Furthermore, the study found that RFH therapy was much safer than systemic sodium stibogluconate, which caused pancreatitis, abdominal pain, myalgias, arthralgias and mild cytopenia Citation[7]. Recently, we reported that RFH therapy was also highly effective in the treatment of CL in HIV-infected patients from a Leishmania tropica-endemic region of India, who were refractory to the antileishmanial drug sodium stibogluconate Citation[19]. These patients showed no recurrence and remained disease-free 18 months after the treatment Citation[19]. Despite the demonstration of high efficacy of RFH therapy in treatment of CL, the mechanisms which are responsible for RFH therapy-induced cure are not clear. Potential mechanisms could include direct destruction of parasites by heat. Alternatively, TNF-α activity induction in response to heat, and/or by boosting the ongoing immune response due to release of parasite antigen from destroyed tissue that could lead to the rapid upregulation of a protective Th1 response. Recently, Lobo et al. reported that heat therapy elicits a systemic cytokine response similar to that of antimonial treatment in patients infected with L. braziliensis, which causes mucosal leishmaniasis Citation[13].
Conclusion
Radiofrequency-induced heat therapy could be a better alternative to current antileishmanial drugs in the treatment of CL in both immunocompetent and immunocompromised patients, and may represent a new standard therapeutic for this infection. However, more studies are still needed to establish the efficacy of RFH therapy in inducing long-term cure of CL caused by other Leishmania species, such as L. tropica, which are difficult to treat, as well as in conferring protection against recurrent Leishmania infections in individuals living in endemic regions.
Financial & competing interests disclosure
The authors thank Themosurgery Inc. for providing funding and leasing the Thermomed 1.8. heat therapy machine for their studies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Abramowicz M, Zuccotti G. Drugs for Parasitic Infections. The Medical Letter Inc. Treatment Guidelines from The Medical Letter.5(Suppl.), e1–e15 (2007).
- Hepburn NC. Management of cutaneous leishmaniasis. Curr. Opin. Infect. Dis.14, 151–154 (2001).
- Ben Salah A, Buffet PA, Morizot G et al. WR279,396, a third generation aminoglycoside ointment for the treatment of Leishmania major cutaneous leishmaniasis: a Phase 2, randomized, double blind, placebo controlled study. PLoS Negl. Trop. Dis.3, e432 (2009).
- Ben Salah A, Zakraoui H, Zaatour A et al. A randomized, placebo-controlled trial in Tunisia treating cutaneous leishmaniasis with paromomycin ointment. Am. J. Trop. Med. Hyg.53, 162–166 (1995).
- Albanese G, Giorgetti P, Santagostino L, Crippa D, Sala G. Cutaneous leishmaniasis. Treatment with itraconazole. Arch. Dermatol.125, 1540–1542 (1998).
- Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, Faris RM, Maguire JH. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N. Engl. J. Med.346, 891–895 (2002).
- Aronson NE, Wortmann GW, Byrne WR et al. A randomized controlled trial of local heat therapy versus intravenous sodium stibogluconate for the treatment of cutaneous Leishmania major infection. PLoS Negl. Trop. Dis.4, e628 (2010).
- Asilian A, Sadeghinia A, Faghihi G, Momeni A. Comparative study of the efficacy of combined cryotherapy and intralesional meglumine antimoniate (Glucantime) vs. cryotherapy and intralesional meglumine antimoniate (Glucantime) alone for the treatment of cutaneous leishmaniasis. Int. J. Dermatol.43, 281–283 (2004).
- Bassiouny A, El Meshad M, Talaat M, Kutty K, Metawaa B. Cryosurgery in cutaneous leishmaniasis. Br. J. Dermatol.107, 467–474 (1982).
- Gurei MS, Tatli N, Ozbilge H et al. Efficacy of cryotherapy and intralesional pentostam in treatment of cutaneous leishmaniasis. J. Egypt Soc. Parasitol.30, 169–176 (2000).
- Layegh P, Pezeshkpoor F, Soruri AH, Naviafar P, Moghiman T. Efficacy of cryotherapy versus intralesional meglumine antimoniate (glucantime) for treatment of cutaneous leishmaniasis in children. Am. J. Trop. Med. Hyg.80, 172–175 (2009).
- Leibovici V, Aram H. Cryotherapy in acute cutaneous leishmaniasis. Int. J. Dermatol.25, 473–475 (1986).
- Lobo IM, Soares MB, Correia TM et al. Heat therapy for cutaneous leishmaniasis elicits a systemic cytokine response similar to that of antimonial (Glucantime) therapy. Trans. R. Soc. Trop. Med. Hyg.100, 642–649 (2006).
- Nilfrousihzadeh MA, Jaffray F, Reiszadeh MR, Ansari N. The therapeutic effect of combined cryotherapy, paramomycin, and intralesional meglumine antimoniate in treating lupoid leishmaniasis and chronic leishmaniasis. Int. J. Dermatol.45, 989–991 (2006).
- Sadeghian G, Nilfroushzadeh MA, Iraji F. Efficacy of local heat therapy by radiofrequency in the treatment of cutaneous leishmaniasis, compared with intralesional injection of meglumine antimoniate. Clin. Exp. Dermatol.32, 371–374 (2007).
- Willard RJ, Jeffcoat AM, Benson PM, Walsh DS. Cutaneous leishmaniasis in soldiers from Fort Campbell, Kentucky returning from Operation Iraqi Freedom highlights diagnostic and therapeutic options. J. Am. Acad. Dermatol.52, 977–987 (2005).
- el Darouti MA, al Rubaie SM. Cutaneous leishmaniasis. Treatment with combined cryotherapy and intralesional stibogluconate injection. Int. J. Dermatol.29, 56–59 (1990).
- Mosleh IM, Geith E, Natsheh L, Schonian G, Abotteen N, Kharabsheh S. Efficacy of a weekly cryotherapy regimen to treat Leishmania major cutaneous leishmaniasis. J. Am. Acad. Dermatol.58, 617–624 (2008).
- Prasad N, Ghiya BC, Bumb RA et al. Heat, oriental sore and HIV. Lancet377, 610 (2011).
- Berman JD, Neva FA. Effect of temperature on multiplication of Leishmania amastigotes within human monocyte-derived macrophages in vitro. Am. J. Trop. Med. Hyg.30, 318–321 (1981).