INTRODUCTION
Leishmaniasis is caused by parasitic protozoans of the genus Leishmania, which are transmitted by the bite of infected sandflies (World Health Organization, 2016). Leishmaniasis is a major health problem throughout the developing world (Miranda-Verastegui et al. Reference Miranda-Verastegui, Llanos-Cuentas, Arevalo, Ward and Matlashewski2005; Nilforoushzadeh et al. Reference Nilforoushzadeh, Jaffary, Ansari, Siadat, Nilforoushan and Firouz2008) with an estimated 900·000–1·3 million new cases and 20 000–30 000 deaths annually (World Health Organization, 2016). The three main forms of the disease are: visceral leishmaniasis, which is fatal if left untreated; cutaneous leishmaniasis (CL), which is the most common form (0·7–1·3 million new cases worldwide annually are estimated) and causes skin lesions, leaving permanent scars and serious disability; and mucocutaneous leishmaniasis, which leads to partial or total destruction of mucous membranes of the nose, mouth and throat (World Health Organization, 2016).
The pentavalent antimony compounds sodium stibogluconate (ST) and meglumine antimoniate (MA) have been the mainstays of antileishmanial therapy for CL (Santos et al. Reference Santos, de Jesus, Machado, Magalhaes, Salgado, Carvalho and Almeida2004; Miranda-Verastegui et al. Reference Miranda-Verastegui, Llanos-Cuentas, Arevalo, Ward and Matlashewski2005; Sadeghian and Nilforoushzadeh, Reference Sadeghian and Nilforoushzadeh2006; Solomon et al. Reference Solomon, Baum, Barzilai, Scope, Trau and Schwartz2007, Reference Solomon, Pavlotzky, Barzilai and Schwartz2013; Munir et al. Reference Munir, Janjua and Hussain2008; Nilforoushzadeh et al. Reference Nilforoushzadeh, Jaffary, Ansari, Siadat, Nilforoushan and Firouz2008; Nascimento et al. Reference Nascimento, Fernandes, Vieira, Campos-Neto, Ashman, Alves, Coler, Bogatzki, Kahn, Beckmann, Pine, Cowgill, Reed and Piazza2010; Neves et al. Reference Neves, Talhari, Gadelha, Silva Júnior, Guerra, Ferreira and Talhari2011; Motta and Sampaio, Reference Motta and Sampaio2012; Trinconi et al. Reference Trinconi, Reimão, Yokoyama-Yasunaka, Miguel and Uliana2014). However, treatment with pentavalent antimony is expensive, lengthy, must be administered parenterally or intralesionally, requires many courses of treatment, and is frequently complicated by toxicity (cardiopathy, pancreatitis and renal and hepatic complications) (Santos et al. Reference Santos, de Jesus, Machado, Magalhaes, Salgado, Carvalho and Almeida2004; Miranda-Verastegui et al. Reference Miranda-Verastegui, Llanos-Cuentas, Arevalo, Ward and Matlashewski2005; Sadeghian and Nilforoushzadeh, Reference Sadeghian and Nilforoushzadeh2006; Nilforoushzadeh et al. Reference Nilforoushzadeh, Jaffary, Ansari, Siadat, Nilforoushan and Firouz2008; Nascimento et al. Reference Nascimento, Fernandes, Vieira, Campos-Neto, Ashman, Alves, Coler, Bogatzki, Kahn, Beckmann, Pine, Cowgill, Reed and Piazza2010; Neves et al. Reference Neves, Talhari, Gadelha, Silva Júnior, Guerra, Ferreira and Talhari2011; Solomon et al. Reference Solomon, Pavlotzky, Barzilai and Schwartz2013). Amphotericin B and pentamidine (pentavalent antimony) are considered second-line treatments and can cause irreversible toxic effects (nephrotoxicity) (Santos et al. Reference Santos, de Jesus, Machado, Magalhaes, Salgado, Carvalho and Almeida2004; Miranda-Verastegui et al. Reference Miranda-Verastegui, Llanos-Cuentas, Arevalo, Ward and Matlashewski2005; Neves et al. Reference Neves, Talhari, Gadelha, Silva Júnior, Guerra, Ferreira and Talhari2011; Motta and Sampaio, Reference Motta and Sampaio2012).
Current therapies for CL are limited by low efficacy, the requirement for prolonged treatment, and increasing development of clinical resistance and recurrence (Miranda-Verastegui et al. Reference Miranda-Verastegui, Llanos-Cuentas, Arevalo, Ward and Matlashewski2005, Reference Miranda-Verastegui, Tulliano, Gyorkos, Calderon, Rahme, Ward, Cruz, Llanos-Cuentas and Matlashewski2009; Trinconi et al. Reference Trinconi, Reimão, Yokoyama-Yasunaka, Miguel and Uliana2014; World Health Organization, 2016). New drugs and different therapeutic regimens have been evaluated. Many investigators have attempted to find an appropriate, highly effective oral or topical treatment with relatively minor adverse effects (Nilforoushzadeh et al. Reference Nilforoushzadeh, Jaffary, Ansari, Siadat, Nilforoushan and Firouz2008).
The aim of this systematic review was to explore new topical treatment options for CL, evaluate their reported therapeutic efficacy and safety, and describe their adverse effects.
METHODS
Literature search
A systematic literature review was conducted in the PubMed and Web of Knowledge databases, covering the period from 11 July 2004 to 8 July 2014. The methodology was defined by the PRISMA statement (Preferred Reporting of Systematic Reviews and Meta-Analysis) (Shamseer et al. Reference Shamseer, Moher, Clarke, Ghersi, Liberati, Petticrew, Shekelle and Stewart2015) (Fig. 1).
Flow diagram of study selection for the systematic review.
In the first phase of the study, four researchers (TRN, TFPM, CAM and PWN) conducted the search and screened the titles and abstracts. To recover publications in PubMed, we used MeSH (Medical Subject Headings) terms. The four researchers conducted searches independently, to define the number of MeSH terms. Any disagreements were resolved by consensus. The MeSH terms were validated by two experts (JVT, TGVS). The MeSH terms were organized into three groups: group 1, ‘antiprotozoal agents’ OR ‘drug therapy’ OR ‘treatment outcome’ OR ‘complementary therapies’ OR ‘photochemotherapy’ OR ‘anti-infective agents’ OR ‘medication therapy management’ OR ‘organometallic compounds/chemistry’ AND group 2, ‘leishmaniasis, mucocutaneous’ OR ‘leishmaniasis’ OR ‘leishmaniasis, cutaneous’ OR ‘leishmania’ AND group 3, ‘clinical trial’. The Web of Knowledge was searched by topic, which ensures good sensitivity.
Study selection
Inclusion criteria
Publications that describe a topical treatment for CL, independently of the clinical stage of the disease, were initially included in the study. Only original research, in English, and with a summary available was included.
Exclusion criteria
Reviews, case reports, comments to the editor, letters, interviews, guidelines and errata were excluded.
Quality assessment
For the second phase, the full text of papers was randomly distributed to the researchers of group 1. In the case of disagreement, the inclusion or exclusion of the paper was decided by consensus. In the third phase, the papers selected by group 1 were distributed to four independent evaluators (TGVS, MVCL, SMAA and IGD – group 2) for certification. The final selection of publications was done by consensus among the researchers of both groups. The only articles remaining were those whose authors used statistical methods for data analysis and included the clinical protocol criteria, such as efficacy and safety, and reported the positive or negative results of the treatment. Additional references from the original articles were surveyed in order to identify other publications of interest.
Data extraction
In the fourth phase, the researchers from group 1, with the support of two experts (JJVT and TGVS), organized the structure of the topics to compose the tables. Table 1 (study, country, design, period of study, age range or mean in years, gender, patients enrolled, statistics), Table 2 (study, Leishmania species, treatments, number of patients who completed the treatment, clinically cured ‘%’ patients or lesions, therapy failure ‘%’, relapse or recurrence ‘%’), Table 3 (treatments, adverse effects ‘%’, study) and Table 4 (therapy, dose, administration/time, efficacy, safety). The articles were distributed to researchers from group 1 to complete the tables of findings, and the entries were checked by the group 2 researchers. The term ‘efficacy’ or variations, described in Table 4, was classified in the table as described by the authors of the studies. All numbers recorded in Table 2 are ‘per-protocol’. Relapse was reported as reappearance of the lesion after complete healing. Some authors considered relapse as therapeutic failure.
Baseline characteristics of clinical trials included in the analysis of new perspectives in the treatment of cutaneous leishmaniasis
NR (not reported), G1 (Group 1), G2 (Group 2), M (male), F (female).
Characteristics of clinics, therapeutics and epidemiological of clinical trials included in the study
a Per protocol, PR (15% paromomycin), PR–GE (15% paromomycin plus 0·5% gentamicin), PR–MBCL (15% paromomycin plus 12% methylbenzonium chloride), MA (meglumine antimoniate), ST (sodium stibugluconate), ALA–PDT [Photodynamic therapy; 10% 5-aminolevulinic acid hydrochloride plus visible red light (633 nm)], AS (after the start of treatment), AE (after the end of treatment), NR (not reported), G1 (Group 1), G2 (Group 2), G3 (Group 3).
b Completely improved end 6·5% partially improved.
c Completely improved and 29·4% partially improved.
d Completely improved and 40·0% partially improved.
Description of adverse effects of the new drugs for the treatment of CL
PR (15% paromomycin), ALA–PDT [Photodynamic therapy; 10% 5-aminolevulinic acid hydrochloride plus visible red light (633 nm)]; NR, not reported.
Conclusion on new drugs for the treatment of CL in the systematic review
PR (15% paromomycin), ALA–PDT [Photodynamic therapy; 10% 5-aminolevulinic acid hydrochloride plus visible red light (633 nm)].
RESULTS AND DISCUSSION
Literature review
CL is endemic worldwide. About 95% of CL cases occur in the Americas, the Mediterranean basin, the Middle East and Central Asia. Over two-thirds of new CL cases occur in six countries: Afghanistan, Algeria, Brazil, Colombia, the Islamic Republic of Iran and the Syrian Arab Republic (World Health Organization, 2016). In the Old World, CL is caused by five species of Leishmania: L. infantum, L. tropica, L. major, L. aethiopica and L. donovani. In the New World, CL is caused by several species of the subgenera Leishmania and Viannia, mainly L. amazonensis, L. mexicana, L. braziliensis, L. guyanensis and L. panamensis (World Health Organization, 2010). Efficacy rates of CL treatments are difficult to interpret. The geographical variation in efficacy and the additional variation in the susceptibility of Leishmania species are high. For instance, Cota et al. (Reference Cota, de Sousa, Fereguetti, Saleme, Alvarisa and Rabello2016) found a significantly lower spontaneous cure rate for L. braziliensis infection (6·4%) than for L. mexicana (44%), in addition to a 20% relapse rate in patients with initial healing. CL is by nature a self-healing disease, and treatment may only accelerate the healing process (Dorlo et al. Reference Dorlo, Balasegaram, Beijnen and de Vries2012).
In this systematic review, we initially identified 350 articles in the PubMed and 151 in the Web of Knowledge databases. The final systematic review involved eight studies with 1744 patients (Fig. 1), in accordance with the PRISMA statement. Studies were considered regardless of the stage of leishmaniasis treated, and included several treatment regimens.
Characteristics of studies and patients
The largest number of studies were conducted in Iran (four of eight), followed by Afghanistan (two of eight). All were clinical trials, published during an 8-year period (2003–2011), and covered patients 4–85 years of age; overall, 51·5% of the subjects were females (Arana et al. Reference Arana, Mendoza, Rizzo and Kroeger2001; Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Reithinger et al. Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005; Asilian and Davami, Reference Asilian and Davami2006; Layegh et al. Reference Layegh, Pezeshkpoor, Soruri, Naviafar and Moghiman2009; Safi et al. Reference Safi, Davis, Nadir, Hamid, Robert and Case2012; Ben Salah et al. Reference Ben Salah, Ben Messaoud, Guedri, Zaatour, Ben Alaya, Bettaieb, Gharbi, Belhadj Hamida, Boukthir, Chlif, Abdelhamid, El Ahmadi, Louzir, Mokni, Morizot, Buffet, Smith, Kopydlowski, Kreishman-Deitrick, Smith, Nielsen, Ullman, Norwood, Thorne, McCarthy, Adams, Rice, Tang, Berman, Ransom, Magill and Grogl2013; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013) (Table 1).
The most frequent Leishmania species were L. tropica (four of eight) and L. major (two of eight) (Table 2). The treatments administered were thermotherapy, paromomycin (PR) and combinations, CO2 laser, photodynamic therapy (PDT) and cryotherapy. A mean of 190·1 patients completed the studies. Most papers addressed the cure rates, regardless of the number of lesions, while some reported the numbers of both treated and healed lesions. Most studies evaluated healing after 3 months (three articles) (Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Reithinger et al. Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005; Asilian and Davami, Reference Asilian and Davami2006) or 6 months (three articles) (Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007; Safi et al. Reference Safi, Davis, Nadir, Hamid, Robert and Case2012; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013).
Six articles reported cure rates over 80% (Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Asilian and Davami, Reference Asilian and Davami2006; Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007; Safi et al. Reference Safi, Davis, Nadir, Hamid, Robert and Case2012; Ben Salah et al. Reference Ben Salah, Ben Messaoud, Guedri, Zaatour, Ben Alaya, Bettaieb, Gharbi, Belhadj Hamida, Boukthir, Chlif, Abdelhamid, El Ahmadi, Louzir, Mokni, Morizot, Buffet, Smith, Kopydlowski, Kreishman-Deitrick, Smith, Nielsen, Ullman, Norwood, Thorne, McCarthy, Adams, Rice, Tang, Berman, Ransom, Magill and Grogl2013; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013); two of them after a 3-month follow-up period (Armijos et al. Reference Armijos, Weigel, Calvopiña, Mancheno and Rodriguez2004; Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ) and three after 6 months (Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013). Six studies reported failure rates, three of them lower than 10% (Armijos et al. Reference Armijos, Weigel, Calvopiña, Mancheno and Rodriguez2004; Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013). Four articles reported no recurrences after the treatments (Reithinger et al. Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005; Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007; Layegh et al. Reference Layegh, Pezeshkpoor, Soruri, Naviafar and Moghiman2009; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013), and three studies did not report the recurrence rate (Asilian and Davami, Reference Asilian and Davami2006; Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Safi et al. Reference Safi, Davis, Nadir, Hamid, Robert and Case2012), while the remaining studies reported low rates (1·8–6·3%).
The most common adverse effects of topical treatments were redness/erythema, pain, pruritus, burning, oedema, vesicles and hyper- or hypopigmentation (Armijos et al. Reference Armijos, Weigel, Calvopiña, Mancheno and Rodriguez2004; Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Reithinger et al. Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005; Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007; Layegh et al. Reference Layegh, Pezeshkpoor, Soruri, Naviafar and Moghiman2009; Safi et al. Reference Safi, Davis, Nadir, Hamid, Robert and Case2012; Ben Salah et al. Reference Ben Salah, Ben Messaoud, Guedri, Zaatour, Ben Alaya, Bettaieb, Gharbi, Belhadj Hamida, Boukthir, Chlif, Abdelhamid, El Ahmadi, Louzir, Mokni, Morizot, Buffet, Smith, Kopydlowski, Kreishman-Deitrick, Smith, Nielsen, Ullman, Norwood, Thorne, McCarthy, Adams, Rice, Tang, Berman, Ransom, Magill and Grogl2013; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013) (Table 3).
Data on administration and treatment time for the treatments that were classified as ‘Efficacious’ and as having ‘Acceptable risk with monitoring’ are listed in Table 4. PR and combinations, PDT, cryotherapy and thermotherapy were all considered ‘Clinically useful treatments’ (Reithinger et al. Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005; Asilian and Davami, Reference Asilian and Davami2006; Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007; Layegh et al. Reference Layegh, Pezeshkpoor, Soruri, Naviafar and Moghiman2009; Safi et al. Reference Safi, Davis, Nadir, Hamid, Robert and Case2012; Ben Salah et al. Reference Ben Salah, Ben Messaoud, Guedri, Zaatour, Ben Alaya, Bettaieb, Gharbi, Belhadj Hamida, Boukthir, Chlif, Abdelhamid, El Ahmadi, Louzir, Mokni, Morizot, Buffet, Smith, Kopydlowski, Kreishman-Deitrick, Smith, Nielsen, Ullman, Norwood, Thorne, McCarthy, Adams, Rice, Tang, Berman, Ransom, Magill and Grogl2013; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013). Only CO2 laser was classified as a ‘Possibly useful treatment’ (Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ).
Thermotherapy/heat therapy was applied in one to four weekly sessions. PR and combinations were evaluated in twice-daily applications for 20 days. CO2 laser, cryotherapy and PDT were administered by local application once a week, for a total of one to six sessions.
The risk of bias in individual studies was discussed by Reithinger et al. (Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005), Layegh et al. (Reference Layegh, Pezeshkpoor, Soruri, Naviafar and Moghiman2009) and Safi et al. (Reference Safi, Davis, Nadir, Hamid, Robert and Case2012).
Modes of treatment
The World Health Organization and other experts suggest the use of local treatments for CL, because this approach limits the risk of adverse effects, may reduce cost, and may enhance compliance and preserve the efficacy of treatments (El-On et al. Reference El-On, Jacobs, Witztum and Greenblatt1984; Soto et al. Reference Soto, Toledo, Gutierrez, Arboleda, Nicholls, Padilla, Berman, English and Grogl2002; Sosa et al. Reference Sosa, Capitan, Nieto, Nieto, Calzada, Paz, Spadafora, Kreishman-Deitrick, Kopydlowski, Ullman, McCarthy, Ransom, Berman, Scott and Grogl2013).
Paromomycin
PR acts by interfering in the protein synthesis of the Leishmania parasite without affecting mammalian cells (Fernández et al. Reference Fernández, Malchiodi and Algranati2011). A study conducted in Tunisia, with 15% PR and PR plus 0·5% gentamicin (PR–GE) for CL caused by L. major found cure rates of 83·6% for PR and 81·5% for PR–GE (Ben Salah et al. Reference Ben Salah, Ben Messaoud, Guedri, Zaatour, Ben Alaya, Bettaieb, Gharbi, Belhadj Hamida, Boukthir, Chlif, Abdelhamid, El Ahmadi, Louzir, Mokni, Morizot, Buffet, Smith, Kopydlowski, Kreishman-Deitrick, Smith, Nielsen, Ullman, Norwood, Thorne, McCarthy, Adams, Rice, Tang, Berman, Ransom, Magill and Grogl2013). In a similar study of patients with L. panamensis from Panama; the cure rate of the index lesion was 87% for PR–GE and 60% for PR; including all treated lesions, and the final cure rates were 94 and 67%, respectively (Sosa et al. Reference Sosa, Capitan, Nieto, Nieto, Calzada, Paz, Spadafora, Kreishman-Deitrick, Kopydlowski, Ullman, McCarthy, Ransom, Berman, Scott and Grogl2013).
In Iran, PR plus 12% methylbenzethonium chloride (PR–MBCL) was used for CL caused by L. major; 41·2% of lesions were healed at 90 days after treatment (Asilian and Davami, Reference Asilian and Davami2006). PR–MBCL was also evaluated in Guatemala for CL caused by L. braziliensis and L. mexicana, with an 85·7% cure rate at the 12-month follow-up (Arana et al. Reference Arana, Mendoza, Rizzo and Kroeger2001), and in Ecuador provided a 79·3% cure rate 12 weeks after treatment (Armijos et al. Reference Armijos, Weigel, Calvopiña, Mancheno and Rodriguez2004).
The most common adverse effects of PR and combinations were erythema, vesicles, oedema, skin irritation and pain (Arana et al. Reference Arana, Mendoza, Rizzo and Kroeger2001; Armijos et al. Reference Armijos, Weigel, Calvopiña, Mancheno and Rodriguez2004; Asilian and Davami, Reference Asilian and Davami2006; Ben Salah et al. Reference Ben Salah, Ben Messaoud, Guedri, Zaatour, Ben Alaya, Bettaieb, Gharbi, Belhadj Hamida, Boukthir, Chlif, Abdelhamid, El Ahmadi, Louzir, Mokni, Morizot, Buffet, Smith, Kopydlowski, Kreishman-Deitrick, Smith, Nielsen, Ullman, Norwood, Thorne, McCarthy, Adams, Rice, Tang, Berman, Ransom, Magill and Grogl2013; Sosa et al. Reference Sosa, Capitan, Nieto, Nieto, Calzada, Paz, Spadafora, Kreishman-Deitrick, Kopydlowski, Ullman, McCarthy, Ransom, Berman, Scott and Grogl2013).
PR and combinations are potentially effective for CL treatment, and have acceptable side-effects. However, the efficacy against CL caused by the various species of Leishmania remains to be investigated.
Thermotherapy
Laboratory studies have shown that Leishmania parasites do not multiply in macrophages at temperatures >39 °C in vitro. Thermotherapy promotes the destruction of parasites by heat associated with an immediate collagen contraction with posterior tissue remodelling (Alster and Tanzi, Reference Alster and Tanzi2004; Alavi-Naini et al. Reference Alavi-Naini, Fazaeli and O'Dempsey2012). These observations led to studies investigating the efficacy of treatments with heat-generating infrared light, direct-current electrical stimulation, ultrasound and laser light (Reithinger et al. Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005). A thermotherapy was applied locally with a portable, battery-operated, localized current field radiofrequency (RF) generator (ThermoMed 1·8; Thermosurgery Technologies).
Thermotherapy was as effective as conventional therapy for small lesions caused by L. tropica in Afghanistan. The odds of cure among the patients treated with thermotherapy were 1·65 higher than those for patients treated with MA, although the type of lesion was significantly associated with the treatment outcome (better response in papules < or = 1 cm2) (Safi et al. Reference Safi, Davis, Nadir, Hamid, Robert and Case2012) with use the of a portable, battery-operated, localized current field RF generator (ThermoMed 1·8; Thermosurgery Technologies, Phoenix, Arizona). However, Reithinger et al. (Reference Reithinger, Mohsen, Wahid, Bismullah, Quinnell, Davies, Kolaczinski and David2005) showed that thermotherapy was more efficient (75%) than intramuscular sodium ST (45%). Thermotherapy and intralesional ST for L. tropica in India showed similar 6-month cure rates of over 98%, with no relapses after 1 year (Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013) using accurate field RF generator (ThermoMed 1·8; Thermosurgery Inc., Phoenix, AZ, USA).
Thermotherapy also proved to be more efficient than intralesional MA in Iran, with a cure rate of 80·7 vs 56·7%, also with no relapses (Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007). This procedure was performed with an RF heat generator (4 MHz, maximum Output 90 W; Ellman International Inc., NY, USA). In Pakistan, by the final 180-day evaluation, 83% of the patients had been cured (Shah et al. Reference Shah, Memon, Auwj-e-Shamim, Baqi and Witzig2014). The efficacy of thermotherapy for CL caused by L. panamensis and L. braziliensis in Colombia was 64% for protocol and 58% for intention-to-treat, with odds of recurrence of 4·1% (López et al. Reference López, Robayo, Vargas and Vélez2012, Reference López, Cruz, Godoy, Robledo and Vélez2013).
Adverse effects reported for thermotherapy were hyperpigmentation, secondary infections and satellite lesions (Asilian and Davami, Reference Asilian and Davami2006; Sadeghian et al. Reference Sadeghian, Nilfroushzadeh and Iraji2007; Bumb et al. Reference Bumb, Prasad, Khandelwal, Aara, Mehta, Ghiya, Salotra, Wei, Peters and Satoskar2013). Pain at the lesion site was also reported (López et al. Reference López, Robayo, Vargas and Vélez2012, Reference López, Cruz, Godoy, Robledo and Vélez2013).
Cardona-Arias et al. (Reference Cardona-Arias, Vélez and López-Carvajal2015) stated that the efficacy of thermotherapy is statistically similar to that of systemic treatment. Thermotherapy is safer, requires fewer treatments and no laboratory monitoring, improves patient adherence and is less costly, and should be the first treatment option for CL in areas where the prevalence of the mucocutaneous form is low and in patients with contraindications for systemic treatment.
Thermotherapy is effective, relatively safe and caused acceptable superficial or minimal scarring. Its indication depends on the location and size/number of lesions. The method is suitable for areas with rudimentary medical infrastructure; occasionally it is applied in a single session, and is more effective than other methods. The rates of clinically cured patients show interpolated results (69·4–98·0%) between the two types of equipment used for RF therapy in thermotherapy. However, further studies to determine the factors that predispose patients to satellite lesions would be of value to increase overall safety and possibly develop thermotherapy into a first-line treatment for CL.
Cryotherapy
For CL caused by L. tropica in Iran, although the cryotherapy group showed a good response, the therapeutic failure rates were significantly higher than in the intralesional MA group (Layegh et al. Reference Layegh, Pezeshkpoor, Soruri, Naviafar and Moghiman2009). Cryotherapy alone (57%) was as effective as intralesional MA (55%), and cryotherapy plus intralesional MA was the most effective treatment (90%); none of the cured lesions recurred during the follow-up period in Iran (Asilian et al. Reference Asilian, Sadeghinia, Faghihi and Momeni2004a ). For CL caused by L. major, 84% of the lesions were cured after 1–4 sessions of cryotherapy, with no recurrence, but the size and location of the lesions affected the clinical response (better results were obtained with lesions <1 cm and on the head) (Mosleh et al. Reference Mosleh, Geith, Natsheh, Schonian, Abotteen and Kharabsheh2008). Cryotherapy acts by destroying infected tissue and is best suited for single lesions (González et al. Reference González, Pinart, Reveiz and Alvar2008).
Reported adverse effects of cryotherapy were erythema and oedema at the site, and hypo- or hyperpigmentation (Asilian et al. Reference Asilian, Sadeghinia, Faghihi and Momeni2004a ; Layegh et al. Reference Layegh, Pezeshkpoor, Soruri, Naviafar and Moghiman2009). Burning and secondary infections were also reported (Mosleh et al. Reference Mosleh, Geith, Natsheh, Schonian, Abotteen and Kharabsheh2008).
Cryotherapy is effective, particularly when combined with MA, and offers the advantage of a small number of sessions, reducing the treatment time.
CO2 laser
The CO2 laser acts by specific thermolysis of infected tissue, with minor side-effects in normal tissue allowing collagen synthesis and remodelling (Walia and Alster, Reference Walia and Alster1999; González et al. Reference González, Pinart, Reveiz and Alvar2008). In Iran, the CO2 laser was more effective than MA (93·7 vs 83·8%) (Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ). Over 93% complete response and no recurrence of CL were also described in Iran (Shamsi Meymandi et al. Reference Shamsi Meymandi, Zandi, Aghaie and Heshmatkhah2011). In Cuba, ten patients were treated with a single session, and all lesions were cured, with no relapses over a 2-year follow-up period (Rodríguez et al. Reference Rodríguez, Inguanzo, Ramos and Pérez1990).
The most common adverse effects in CO2 laser treatment were hyperpigmentation, persistent redness and hypertrophic scarring (Asilian et al. Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ; Shamsi Meymandi et al. Reference Shamsi Meymandi, Zandi, Aghaie and Heshmatkhah2011).
Asilian et al. (Reference Asilian, Sharif, Faghihi, Enshaeieh, Shariati and Siadat2004b ) stated that CL can be treated with CO2 laser in a single session, which is more cost-effective than systemic antimony. CO2 laser is effective within a few sessions, with relatively mild side-effects, and more studies are needed to determine the efficacy for the various Leishmania species.
Photodynamic therapy
PDT utilizes reactive oxygen species produced by a photosensitizer molecule in the presence of low-intensity visible light, to kill mammalian or microbial cells (Kharkwal et al. Reference Kharkwal, Sharma, Huang, Dai and Hamblin2011). The clinical efficacy of PDT using 10% 5-aminolevulinic acid hydrochloride plus visible red light (633 nm) (ALA–PDT) was evaluated in patients with CL caused by L. major in Iran. The complete cure rate (lesions without amastigotes after 28 days) was 93·5% (Asilian and Davami, Reference Asilian and Davami2006).
An overall cure rate of 89% for CL caused by L. major and L. tropica (Enk et al. Reference Enk, Nasereddin, Alper, Dan-Goor, Jaffe and Wulf2015) was obtained with daylight-activated PDT. Kharkwal et al. (Reference Kharkwal, Sharma, Huang, Dai and Hamblin2011) reported that L. tropica infection resistant to various therapeutic regimes was effectively treated with PDT. Based on a review of six papers, van der Snoek et al. (Reference van der Snoek, Robinson, van Hellemond and Neumann2008) suggested that PDT with porphyrin precursors is relatively effective in treating CL.
With ALA–PDT, adverse effects included pruritus, burning, redness, discharge, oedema and pain (Asilian and Davami, Reference Asilian and Davami2006). Hypo- or hyperpigmentation were also reported (van der Snoek et al. Reference van der Snoek, Robinson, van Hellemond and Neumann2008).
Although only one study was evaluated here, ALA–PDT is a promising treatment for CL. A disadvantage of PDT is that it requires trained personnel and specific equipment. Its efficacy for other Leishmania species remains to be demonstrated.
CONCLUSION: EVIDENCE COMPARISON
Relevant review published on interventions for Old World cutaneous leishmaniasis (OWCL), revealed that there are no randomized clinical trials evidence that antimonials, intralesional or systemic, are of benefit in treating OWCL. Few treatments for CL have been well evaluated in randomized clinical trials [randomized controlled trials (RCTs)]. The inclusion criteria of this research were to evaluate the RCTs on treatments in immune-competent people with OWCL confirmed by smear, histology, culture or polymerase chain reaction (González et al. Reference González, Pinart, Reveiz and Alvar2008). In our systematic review, the criteria were publications that describe topical treatment for CL, independently of the clinical stage of the disease.
González et al. (Reference González, Pinart, Reveiz and Alvar2008) reported that RCT review findings provided only reasonable evidence of benefit for 15% of topical PR + 12% of MBCL twice daily for 28 days or PDT weekly for 4 weeks in L. major infections. In addition, there was reasonable RCT PDT weekly for 4 weeks was more efficacious than topical 15% PR + 12% MBCL twice daily for 28 days. There was reasonable RCT evidence in L. tropica physical therapies such as CO2 laser and cryotherapy. The findings of our systematic review provide strong evidence that the new treatments thermotherapy, PR and combinations, CO2 laser, ALA–PDT, showed high cure rates with few adverse effects, relapses or recurrences, while cryotherapy showed a moderate cure rate. More studies are needed, with different species of Leishmania in different regions, to assess the overall effectiveness and safety of these treatments.
STRENGTHS AND LIMITATIONS OF THE STUDY
The accuracy of the search for the publications was guaranteed by the databases, the MeSH Terms and the repeated searches and analysis by consensus. The findings of the papers were organized and detailed in numerous tables, ensuring a good and faithful presentation of the data.
The lack of comparability of methods, including cure rates, follow-up periods, drug concentrations, Leishmania species treated, or the individual host response makes it almost impossible to compare the results of different studies. Creating multiple research centres, and sharing and comparing drugs and treatment methods are important to improve the results, side-effects and cure rates. Scientific publications have described and discussed the limitations of the studies, but this important information is not commonly available. Of the eight studies reviewed here, only three discussed their limitations.
SUPPLEMENTARY MATERIAL
The supplementary material for this article can be found at https://doi.org/10.1017/S0031182017000385.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge Dr Diane McMahon-Pratt of Yale University for her valuable suggestions and careful analysis of the manuscript.
FINANCIAL SUPPORT
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
CONFLICTS OF INTEREST
None.
