Evaluation of Thermotherapy for the Treatment of Cutaneous Leishmaniasis in Kabul, Afghanistan: A Randomized Controlled Trial

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1 MILITARY MEDICINE, 177, 3:345, 2012 Evaluation of Thermotherapy for the Treatment of Cutaneous Leishmaniasis in Kabul, Afghanistan: A Randomized Controlled Trial Najibullah Safi, MD*; COL Gary D. Davis, MC USA (Ret.) ; Mohammed Nadir, MD ; Hamida Hamid, MD ; COL Leon L. Robert, Jr., MS USA ; MAJ Alan J. Case, MS ARNG (Ret.) ABSTRACT Anthroponotic cutaneous leishmaniasis (CL) is a common cause of ulcerative lesions and disfiguring scarring among children in Afghanistan. Most lesions occur on the face and are commonly caused by the trypanosome protozoan parasite Leishmania tropica, transmitted by the bite of an infected sandfly (Phlebotomus sergenti). This study compared the effectiveness of a single localized treatment with thermotherapy to 5 days of intralesional administration of Glucantime for the treatment of CL. Three hundred and eighty-two patients with CL were randomly assigned to the two treatment groups and followed for 6 months. The cure rate for the thermotherapy group was 82.5%, compared to 74% in the Glucantime group. The authors concluded that a single localized treatment with thermotherapy was more effective than 5 days of intralesional administration of Glucantime. Additionally, thermotherapy was more costeffective, with fewer side effects, of shorter duration, and with better patient compliance than intralesional Glucantime. BACKGROUND Leishmaniasis includes a spectrum of diseases occurring throughout Asia, Africa, and the Americas that are caused by infection with leishmania parasites transmitted by the bite of infected sandflies. 1 Cutaneous leishmaniasis (CL) presented as nodules or ulcerative lesions can persist from months to years and lead to disfiguring scarring. 2 Some species also cause mucocutaneous and visceral disease, which can result in significant morbidity and mortality. The spectrum of pathologies in any given geographic area depends on the diversity of leishmania species in that region. 2 Anthroponotic CL is characterized by large and/or multiple cutaneous lesions that have an inconsistent tendency to self cure. 3 Most lesions tend to occur on the face, as it is more exposed to the vector. Sandflies often bite the patients on their face, while they are sleeping. The disfiguring scarring from leishmaniasis generally leads to severe stigmatization of affected individuals, especially women patients. Affected women are often considered unfit for marriage. 4 At least 350 million people are at risk of infection in 88 countries. 5 Leishmaniasis is the third most important vector borne disease in the world (after malaria and lymphatic filariasis) and is responsible for an estimated 1.18 million *Primary Health Care Department, World Health Organization Country Office, UNOCA Compound, Jalalabad Road, Kabul, Islamic Republic of Afghanistan. Medical Training Advisory Group (MTAG), NATO Training Mission Afghanistan (NTM-A), Combined Training Advisory Group Army (CSTC-A), Camp Eggers, APO AE Communicable Disease Surveillance and Response Department, World Health Organization Country Office, UNOCA Compound, Jalalabad Road, Kabul, Islamic Republic of Afghanistan. Research Department, National Malaria and Leishmaniasis Control Program, Sanatorium Road, Darulaman District, Kabul, Islamic Republic of Afghanistan. kdepartment of Chemistry and Life Science, United States Military Academy, West Point, NY disability adjusted life years and 57,000 deaths annually. 6 Worldwide, the largest focus of CL is in Kabul, Afghanistan. 7 In Afghanistan, the majority of leishmaniasis cases are caused by Leishmani tropica that is anthroponotically transmitted by the sandfly Phlebotomus sergenti. 8 Over the past 10 years, there has been a sharp increase in Leishmania tropica cases in Afghanistan. Factors contributing to this increased incidence include political instability, ongoing conflict, and lack of a fully functional public health system and health care infrastructure. Because of the mass migration of infected individuals, irregular treatment, and absence of vector control strategies, Leishmania tropica has now spread to areas that previously were nonendemic. 9 Although the possibility of vaccination as a method of leishmaniasis control has been extensively studied, no safe and effective vaccines are currently available and are unlikely for some time. 10 Treatment of CL can be challenging. Many factors influence treatment, including the size, number, and appearance of the lesions, duration of the lesion before treatment, and whether the lesion is primary, a relapse, or reinfection (Figs. 1 4). Likewise, the severity of mucosal involvement, immunosuppression, coinfections, and prior anti-leishmania treatment also affect the course of treatment. The location of the lesion (e.g., face or joints), age of the patient (e.g., adults or children), and gender are factors that often determine the choice of treatment (Fig. 5). Other factors are intrinsic and related to the different leishmania species (Table I). An effective treatment in one geographical area for a given organism may not work in a different geographical area or for a different organism in the same location. Treatment efficacy depends not only on the leishmania species but also on the response of the patient to the parasite. Factors such as immunity, variable clinical response to treatments, drug toxicity, drug resistance, HIV coinfection, and compliance all influence outcome. 11 Antimonials (e.g., meglumine antimoniate and sodium stilbogluconate [SSG]) have been used for more than half a MILITARY MEDICINE, Vol. 177, March

2 FIGURE 2. Close up picture of 5-year-old Afghan boy with a large leishmaniasis lesion on right cheek. FIGURE 1. Picture of 5-year-old Afghan boy with a large leishmaniasis lesion on right cheek. century in the therapy of leishmaniasis. 12 However, antimonials can have serious (usually reversible) adverse effects when given intramuscularly, and they are expensive. 13 Moreover, invasiveness of the standard procedure a lengthy course of painful inoculations often leads patients to default on their full course of treatment. Low compliance appears to be the principal reason behind the emergence of drugresistant parasite strains, especially in areas where there is TABLE I. Baseline Characteristics of Subjects with Leishmaniasis (Males versus Females) Treated with Thermotherapy and Glucantime, Participating in a Randomized Trial, Kabul, Afghanistan Characteristic Male Female p Value Age (Year) Median Age Interval Systolic Blood Pressure (mm Hg) Mean (SD) (13.9) 113 (13) Diastolic Blood Pressure (mm Hg) Mean (SD) 73.5 (10) 71.5 (8.9) Body Weight (kg) Mean (SD) 40.8 (19.4) 40.6 (22.3) anthroponotic leishmaniasis. 14 Hence, alternative treatments that use different dosage schedules, drugs, or methods of treatment are required. Two studies have shown that thermotherapy by radio frequency is effective for the treatment of CL caused by Leishmania braziliensis and Leishmania mexicana. 15,16 In 2003, a study conducted in Afghanistan revealed that thermotherapy by radio frequency was as effective as conventional therapy (intralesional or intramuscular administration of antimonials) in the treatment of small lesions. 17 However, it was less effective in the treatment of large lesions (>2 cm) as compared with conventional therapy. The Afghan Ministry of Public Health estimates that there are over 200,000 cases of CL in Kabul. There is a dearth of clinical data on CL caused by Leishmania tropica, and only limited data on natural or treatment-induced cure rates are available. It is imperative that scientifically valid data sufficient to enable the development of protocols for the most effective and cost efficient treatment of this prevalent and debilitating disease be developed and validated. Primary Objective To determine the effectiveness of local thermotherapy by radio frequency compared with intralesional injection of Glucantime for the treatment of CL in Afghanistan. 346 MILITARY MEDICINE, Vol. 177, March 2012

3 FIGURE 3. Picture of 4-year-old Afghan girl with a large leishmaniasis lesion on left cheek. FIGURE 4. Close up picture of 4-year-old Afghan girl with a large leishmaniasis lesion on left cheek. Secondary Objective To develop an evidenced-based protocol for the treatment of CL in Afghanistan. Hypothesis Thermotherapy by radio frequency is as effective as intralesional Glucantime for the treatment of CL in Afghanistan. METHODOLOGY/RESEARCH DESIGN The study was a prospective randomized controlled trial. Current standard therapy (intralesional antimonial therapy) was used as control group. There was no placebo group because this would have been unethical as a result of the severity of CL that Leishmania tropica causes and the social stigma associated with the disease. Study Setting The study was conducted in Kabul City, the capital of the Islamic Republic of Afghanistan. According to official estimates, the population of Kabul City was three million in This study was carried out at the leishmaniasis clinic of the National Malaria and Leishmaniasis Control Program FIGURE 5. The age distribution of the patients with leishmaniasis who participated in randomized trial comparing Glutamine and thermotherapy in Kabul, Afganisthan. MILITARY MEDICINE, Vol. 177, March

4 in Darul-Aman District, Kabul, Afghanistan. This clinic is the principal leishmaniasis treatment center in Kabul. Study Population The study population was comprised of patients with CL, visiting the leishmaniasis clinic of National Malaria and Leishmaniasis Control Program in Darul-Aman District, Kabul, Afghanistan, for treatment. Inclusion criteria were age of more than 5 years, and the presence of a single, parasitologically confirmed CL lesion. Parasitological confirmation was made by obtaining impression smears from dermal scrapings from all 390 patients. The specimens were Giemsa-stained and examined under the microscope at +100 magnification for presence of leishmania amastigotes. Patients were excluded from the study who gave a history of previous infections from anthroponotic CL that was treated with antimonial medications. Patients with lesions located within 2 cms of the eyelids or on the lips or nose were also excluded from the study. Sample Size To detect 8% difference in the cure rate between the current standard therapy (intralesional antimonial therapy) and thermotherapy by radio frequency groups, assuming 90% cure rate 17 in the conventional therapy with an 80% power and a 5% type I error, 174 subjects were needed in each group (348 total subject in the study). To compensate for anticipated loss to follow-up, we inflated the sample size by 10%. Hence, the final sample size, figuring research design, rounded to nearest 10 turned out to be 390 subjects, with 195 assigned to each treatment group. Epi-Info version-6 was used to calculate the required sample size. Randomization Each subject was randomly assigned to a group that received current standard therapy or thermotherapy by radio frequency. Patients were asked to pick one of two identical cardboard pieces out of a box (the cardboard had been labeled with different treatment codes on one of its sides) for their group assignment. After patients were assigned to a treatment group, the cardboard piece picked was returned to the box. Treatment Groups Intervention This group received a single treatment consisting of an application of thermotherapy by radio frequency producing localized heat of 50 C (122 F) for 30 seconds). Current Standard Therapy This group received 5 intralesional injections of Glucantime (2 7 ml depending on the size of the lesion). The injections were given in 7-day intervals for 5 weeks. Procedures Eligible patients coming to the clinic for treatment were briefed about the study, its objectives, and the protocol. Inclusion criteria were age of more than 5 years, and the presence of a single, parasitologically confirmed CL lesion. Parasitological confirmation was made by obtaining impression smears from dermal scrapings. Patients were counseled about possible adverse effect from both treatment regimes, and then enrolled in the study after written consent had been given. For thermotherapy by radio frequency, the lesion and 2 cm border of healthy skin around the lesion were cleaned with antiseptic, anesthetized with 1% Lidocaine HCl, and moistened with sterile saline solution; then heat was applied locally with a portable, battery-operated, localized current field radio-frequency generator (ThermoMed 1.8; Thermosurgery Technologies, Phoenix, Arizona), according to the manufacturer s instructions. A single thermotherapy by radio frequency treatment (application of localized heat of 50 C for 30 seconds) was given. After treatment, 2% Lidocaine gel was applied to lesions and covered with gauze to prevent secondary infections. Five intralesional administrations of Glucantime were applied for participants in 7-day intervals in the standard therapy group. A dose of 1 7 cc of Glucantime is injected into the base of the margins of the lesion to produce complete blanching. All patients were then followed for four visits at weekly intervals, at which lesion size was reassessed and measured. The lesions were also evaluated for epithelialization and any evidence of secondary infection. The occurrences of adverse effects were evaluated by means of patient interviews and physical examinations during follow-up visits. Definition of Treatment Outcomes Cure was defined as complete re-epithelialization of the lesion with no inflammation and resolution of the papule and/or nodule. Failure was defined as no improvement, with the lesion unchanged or worse compared with its status at the start of treatment. Lesions that showed some improvement but did not meet the criteria for cure were considered treatment failures. Ethical Considerations The Institutional Review Board of the Afghan Armed Forces Academy of Medical Sciences approved the study. Informed consent was taken from all study subjects or guardians of children. Informed consent included an explanation of the purpose of the study, potential complications, adverse effects of each treatment regime, and the intended use of the collected information. The informed consent document was read in Dari or Pashto, for all those individuals who were not able to read, and then written consent was obtained and witnessed. Training of Data Collectors The investigators who obtained cytological smears from dermal scrapings were given standard training concerning collection, staining, and all procedures necessary for parasitological 348 MILITARY MEDICINE, Vol. 177, March 2012

5 confirmation of the CL (despite the fact that all were professionals). Follow-up investigators were given standard instructions for interviewing the patients and methods for asking each question. Data Collection After obtaining informed consent, the questionnaires, basic demographics, vital signs, size, site, and type of lesion were recorded. Patients were randomly assigned to treatment groups and initial treatment given according to protocol. After initial treatment, all patients were scheduled for four subsequent follow-up visits. The first follow-up being 10 days after baseline, the second 1-month after treatment, the third 2 months after treatment, and the fourth and last follow-up visit was scheduled 6 months after treatment. DATA ENTRY AND MANAGEMENT Epi-Data software version 3.1 was used for data entry. The data were entered by two data entry operators in two separate files. The consistency between these two separate files was checked through running validate duplicate file and check consistency commands in Epi-data. The inconsistent data were then validated by reviewing the original questionnaire. Ten percent of the questionnaires were checked randomly to look for data entry errors. The Epi-data file was then converted to Statistical Analysis System (SAS) version 9.1, using DBMS-Copy for windows version 5.0. Frequencies were run on data for logical error checking and for any discrepancy. Each variable was checked for missing data and corrections were made by contacting the patient and/or interviewers as required. STATISTICAL ANALYSES The analyses were done using SAS version 9.1. Descriptive analysis was conducted on all baseline characteristics of the study participants. For continuous variables, mean/median and standard deviation (SD) were calculated and histograms were plotted to assess the distribution of these variables. Categorical variables proportions were reported and tested. Descriptive statistics were computed for intervention and standard therapy groups separately. Mean values of continuous variables were compared between two groups (intervention and nonintervention) by independent t test, whereas median values were compared using the Mann Whitney U test. Pearson c 2 test was used for comparing the proportions. For categorical variables that had a cell count less than five, the Fisher s exact test was used. Baseline characteristics were also compared by gender. To adjust for the effects of other variables on the outcome, logistic regression analyses were applied. Logistic regression was used because the outcome was a dichotomous variable (cure/failure). For each associated factor, the odds ratio (OR) and 95% confidence intervals (CI) were estimated to evaluate the association of each variable with the outcome. Significant differences were determined based on two-tail t tests (p > 0.05). RESULTS Table II shows the baseline demographic characteristics of the treatment groups. There were no significant differences between treatment groups. The median age was 14 years with intervals ranging between 5 and 75 years, whereas the median ages for thermotherapy by radio frequency and Glucantime groups were 14 and 13 years, respectively, but the age distribution was skewed. The majority of the patients in this study were under 20 years of age as first infections with CL often occur in children. Table III shows that most of the patients (42.7%) visiting the leishmaniasis clinic were from 7th Nahia (district), followed by 15.7 % from 6th Nahia, 9.7 % from 13th Nahia, and others from the remaining 14 Nahia of Kabul. Lesions were primarily located on the face/neck (83% of patients), as well as on the hands/arms (14.1%), legs (2.1%), TABLE II. Baseline Demographic Characteristics of Subjects with Leishmaniasis Treated with Thermotherapy versus Glucantime, Participating in a Randomized Trial, Kabul, Afghanistan Characteristic Thermotherapy Group (n = 189) Glucantime Group (n = 193 ) p Value Age (Year) Median a Age Interval Sex of Subjects (n, %) Male 85 (48.0) 92 (52.0) 0.59 b Female 104 (50.7) 101 (49.3) Systolic Blood Pressure (mm Hg) Mean (SD) (13.5) (13.6) c Diastolic Blood Pressure (mm Hg) Mean (SD) 72.4 (7.9) 72.2 (10.7) c Body Weight (kg) Mean (SD) 42.5 (23.3) (18.3) 0.10 c a Mann Whitney U Test. b Pearson c 2 test of independence. c Two independent sample t test. MILITARY MEDICINE, Vol. 177, March

6 TABLE III. Frequency of Patients Visiting the Leishmaniasis Clinic from Different Nahias (geographical unit of area) of Kabul, Afghanistan Residence Area of the Patients Frequency Percent Nahia Nahia Nahia All Other Nahias TABLE IV. Baseline Characteristics of Lesions in Subjects with Leishmaniasis Treated with Thermotherapy versus Glucantime, Participating in a Randomized Trial, Kabul, Afghanistan Characteristic Thermotherapy Group (n = 189) Glucantime Group (n = 193) Location of Lesion (n, %) Face/Neck 161 (50.8) 156 (94.2) Upper Extremity 26 (48.1) 28 (51.9) Lower Extremity 02 (25) 06 (75) Trunk 0 (0) 03 (100) Type of Lesion (n, %) Ulcer 0 (0) 6 (100) Nodule 69 (41.1) 99 (58.9) Papule 120 (57.7) 88 (42.3) Size of the Lesion (cm 2 ) Median 1 2 Size Interval and trunk (0.8%). About 55% of all lesions were papules, 44% nodules, and the rest were ulcers (Table IV). More papules (57.7%) were treated by thermotherapy compared to (42.3%) those which were treated by Glucantime. Nodules were mostly treated by Glucantime (58.9%), whereas all ulcers were treated by Glucantime. The lesion size interval was [1 4 cm 2 ] with median of 1 cm 2 for thermotherapy by radio frequency and 2 cm 2 for Glucantime. At 6 months, the overall cure rate was 78.2% for both treatments; in the Glucantime group 74% (143/193) and in the thermotherapy by radio frequency group, the cure rate was 82.5% (Table V). Using the cure/failure as outcome measures for the treatments, the odds of cure among the patients treated by thermotherapy by radio frequency were 1.65 times that treated by Glucantime (Table V). Type and size of lesion, were significantly associated with the outcome variable (cure/failure). Type of lesion was significantly associated with treatment outcome in this sample, taking papules as reference (Table V). Those who had nodules were 41% less likely and those with ulcers were 80% less likely to be cured compared with those with papules. Size of lesion was also significantly associated with treatment outcome, taking 1 cm 2 lesion as reference (Table IV). Those who had 2 cm 2 lesion were 22% less likely and those with 4 cm 2 were 73% less likely to be cured as compared to those with 1 cm 2 lesions. Although, we found that size of the lesion was significantly associated with outcome, treatment TABLE V. Univariate Analysis; Factors Affecting the Outcome (Cure/Failure) Variable Crude OR 95% CI for OR p Value Treatment Thermotherapy Glucantime 1.0 Age of the Subject Sex of the Patient Female Male 1.0 Location of Lesion 0.32 Upper Extremity Lower Extremity Trunk Face/Neck 1.0 Body Weight Type of the Lesion 0.03 Nodule Ulcer Papule 1.0 Size of the Lesion (cm 2 ) TABLE VI. Multivariable Analysis of the Factors Associated with Treatment Outcome Variable AOR 95% CI for AOR p Value Treatment Thermotherapy Glucantime 1.0 Size of the lesion (cm 2 ) < AOR, adjusted odds ratio. was not significantly associated with outcome in this level (Table VI). DISCUSSION AND CONCLUSION We found that a single treatment with localized heat is more effective than the administration of intralesional Glucantime for the treatment of the CL. There was no observed significant effect of patient characteristics (age, sex, and weight) on cure rates. Several studies have reported the successful administration of intralesional antimony to cure Old World CL, but few studies have compared thermotherapy by radio frequency with antimonials. One study in Afghanistan compared intralesional and intramuscular antimony versus thermotherapy by radio frequency 18 ; cure rates were 69.4% for thermotherapy by radio frequency, 75.3% for intralesional SSG, and 44.8% of patients treated with intramuscular SSG. Taking in consideration the results from this study, and ours, we concluded that thermotherapy by radio frequency should be considered as an alternative to antimony for the treatment of 350 MILITARY MEDICINE, Vol. 177, March 2012

7 CL. Thermotherapy by radio frequency is likely a cost-effective alternative to traditional treatment in those areas of endemicity where the number of cases of leishmania infection is high and focal. There are two main advantages to thermotherapy by radio frequency compared with antimony treatment: First, patient compliance rates are improved primarily because of the absence of the serious adverse effects of antimonial treatment. Reported side effects of the antimonial treatment include anorexia, vomiting, nausea, abdominal pain, malaise, myalgia, arthralgia, headache, lethargy, and a metallic taste from the medication. However, these side effects have been reported to occur with more frequency and severity with intramuscular or intravenous infusion of antimonial medications. Antimonial treatment in this study was by intralesional injection through a fine needle and side effects were minimal and mild. Additionally treatment is administered nonparenterally and the treatment is shorter (i.e., 1 day as compared to five treatments at 7-day intervals for antimony). Second, the shorter administration schedule also increases the patient turnover rate, a prerequisite for controlling the patient caseload and, hence, disease transmission. The thermotherapy by radio frequency method used in our study was a handheld device that limited the need for additional medical equipment, making it suitable for field conditions in areas with rudimentary medical infrastructure. The size of the lesion significantly influenced the degree of treatment outcome; i.e., the larger the lesion, the less likelihood of cure, regardless of the method of treatment. Despite randomization, the thermotherapy group in this study had slightly less advanced and smaller lesions than the Glucantime group that would bias the results toward the thermotherapy group. In addition, because there were no ulcerative lesions in the thermotherapy group, we are not able to comment on the effectiveness of thermotherapy for those types of lesions. However, we concluded that thermotherapy by radio frequency proved an effective, safe, and relatively noninvasive procedure for treating patients with CL in a medically austere environment, such as Afghanistan, with limited resources. ACKNOWLEDGMENTS The authors wish to express their appreciation to Mrs. Carolyn Hudson Firestone, for her generous support that made this research possible. REFERENCES 1. Desjeux P: The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg 2001; 95: Herwaldt B: Leishmaniasis. Lancet 1999; 354: Griffiths W: Old World cutaneous leishmaniasis. In: The Leishmaniasis in Biology and Medicine, Vol. 2. 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Am J Trop Med Hyg 1997; 57: Central Statistics Office of the Islamic Republic of Afghanistan: Comparison of thermotherapy by radiofrequency and intra-lesional or intramuscular administration of antimonials in the treatment of small lesions leishmaniasis [CD-ROM]. Kabul, Afghanistan, Afghanistan Statistical Yearbook. SY1382, Reithinger R, Mohsen M, Wahid M, et al: Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: a randomized, controlled trial. Clin Infect Dis 2005; 40: MILITARY MEDICINE, Vol. 177, March