Current status of cutaneous leishmaniasis in Aleppo, Syrian Arab Republic.

Current status of cutaneous leishmaniasis in Aleppo, Syrian Arab Republic M. Douba,1 A. Mowakeh,2 & A. WaIi3 Cutaneous leishmaniasis has been endemic in Aleppo, Syria, for generations. Recently there has been a clear increase in the incidence of the disease, and more patients have shown a lack of response to antimonials. We report the results of a survey, undertaken over the period 2-17 January 1995, at a general hospital in Aleppo, of all patients presenting with cutaneous leishmaniasis. Patients were grouped according to the stage of their disease, and surgical biopsies were carried out for histopathological investigation. Patients who were unresponsive to treatment and proceeded to chronicity were predominantly children aged under 15 years with facial lesions. Histopathological examination showed that the inflammatory changes had reached the upper layers of the subcutaneous tissues in 10 of the 25 chronic cases (40%/o) and three of the four acute cases (75%6). These levels of the skin are not directly reached by the antimonials administered intralesionally. The inadequacy of the intralesional method alone and technical errors in administration are discussed. Introduction Cutaneous leishmaniasis has been endemic in Aleppo, Syrian Arab Republic for generations; its occurence was documented as early as 1745 by Pocock (1). Common local names include "Aleppo boil" and "the one-year sore". The infective agent is Leishmania tropica (2). Oriental cutaneous leish- maniasis caused by Leishmania tropica is known to heal spontaneously within 1-2 years in about 90% of cases, with scar formation and subsequent life-long immunity against the disease in most cases (3). In the mid-1950s, and after a campaign aimed at controlling malaria (1), cutaneous leishmaniasis declined considerably; however, before the end of the 1960s, it had regained momentum. In the early 1970s, treatment with pentavalent antimonials was introduced, with meglumine anti- moniate being used exclusively until sodium stibo- gluconate was introduced in the early 1980s. Substantial success in shortening the course of the disease and in reducing scarring to a minimum was achieved using these compounds. Intralesional ad- ministration of meglumine antimoniate alone was (and remains) the treatment of choice for cutaneous I Dermatologist, Centre for Dermatological Diseases, Ministry of Public Health, Aleppo, P.O. Box 11024, Syrian Arab Republic. Requests for reprints should be sent to this author. 2 Dermatologist and Head, Centre for Dermatological Diseases, Ministry of Public Health, Aleppo, Syrian Arab Republic. 3 Histopathologist, Centre for Dermatological Diseases, Ministry of Public Health Aleppo, Syrian Arab Republic. Reprint No. 5777 leishmaniasis in Aleppo; 3-5 intralesional doses at weekly intervals used to be sufficient for the complete healing of lesions (4, 5). Occasionally, antimonials were given systemically when their intralesional use was not possible owing to the loca- tion, size or number of lesions. A few cases of acute cutaneous leishmaniasis did develop into the chronic or lupoid forms despite treatment, but these did not exceed 3-5% of the total (5, 6). Since 1992, there has been a clear but unex- plained increase in the overall incidence of cu- taneous leishmaniasis in Aleppo, despite repeated governmental insecticide spraying campaigns to combat the sandfly vector. This change was reported in 1993 (7), and has been noted subsequently in Min- istry of Health reports. Moreover, patients began to require more intralesional doses of meglumine antimoniate before they responded. Gradually, how- ever, even with the additional doses, the treatment became ineffective in a considerable proportion of cases, and more and more patients developed the chronic form of the disease.a Such patients were transferred from one clinic to another and were subjected to various treatments repeatedly without a In this study, a case was considered to have become chronic once the duration of a lesion had exceeded 1 year without healing, despite treatment. However, the term "chronic" was applied to patients whose lesions never healed (chronic cutaneous leishmaniasis) and to those who reported having had periods of healing that ranged from 3 months to 2 years (recurrent cutaneous leishmaniasis), since clinical and histopathological differentiation between these two categories is rather controversial (3), and depends mainly on case history, which is unreliable in most instances. Bulletin of the World Health Organization, 1997, 75 (3): 253-259 © World Health Organization 1997 253 M. Douba et al. recovery (see Table 2). This increasing lack of re- sponse suggested that the parasite might be showing resistance to the antimonial compounds used in treatment. As an initial step to verifying this hypothesis, we carried out a small study to obtain preliminary data and report our findings in this article. Materials and methods Design of the study All patients presenting with cutaneous leishmaniasis at the outpatient clinic of Ibn-Rushd hospital, Aleppo, during the period 2-17 January 1995 were investigated. This hospital is one of 15 similar gov- ernment centres that receive and offer free treat- ment to patients with this disease in Aleppo. Detailed personal information was obtained for each patient, including the type, number, size, dura- tion, and location of lesion(s), date of onset, age of patient at time of onset, earlier treatments received, and periods of healing (if any). The lesions were photographed, and skin biopsies were obtained from some patients. New patients were diagnosed using a direct smear test in addition to clinical diagnosis; other patients would have been diagnosed earlier at the centre at which they presented initially. The Montenegro test could not be conducted as the nec- essary reagents were not available. Biopsies were taken from 31 face lesions, 25 from chronic cases, four from acute cases and two from subacute cases (in which lesions showed a lack of response to treatment). The duration of the le- sions biopsied lay in the range 1.5-8 years for chronic cases, 2-4 months for acute cases and 8-10 months for sub-acute cases. Samples were fixed in 10% formalin-saline and processed for light microscopy. Paraffin sections were stained with haematoxylin and eosin. Study population The 206 patients seen during the survey came from 70 different residential areas in Aleppo city and its surroundings. Patients were divided into four groups according to the course of disease (Table 1): 38 (18.4%) were new patients visiting the hospital for the first time to obtain treatment for acute cutaneous leishmaniasis; and 46 (22.3%) were patients coming to the hospital for their second to sixth weekly visit, and who were still considered to have a chance of recovery. The third group of patients included 58 (28.2%) who had received more than six intra- lesional doses of meglumine antimoniate with no clinical recovery. These patients were considered to be unresponsive to treatment (subacute cutaneous leishmaniasis). The lesions in this group were of less than 1 year old and appeared clinically and histopathologically similar to the acute lesions, while gradually developing into the chronic stage (Fig. 1). The fourth group consisted of 64 (31.1%) patients with chronic cutaneous leishmaniasis. The dura- tion of lesions in this group lay in the range 1.5-8 years. These patients had been subjected to various methods of treatment repeatedly without clinical recovery (Table 2). Description of lesions The number of lesions per patient varied from 1 to 30. In acute cases, the lesions presented in two forms: dry (85%) and ulcerative (15%), which differed in their clinical appearance and development. Some patients had both forms of lesions at the same time. The dry forms were of two types: dry and smooth with no crust and dry with a crust. The smooth type mostly occurs on the face or neck, starting as a bright pink to violaceous papule, ranging from 3 mm to 1 cm in diameter. After 4 months, thin transluscent scales start to cover the lesion. This particular type is most resistant to treatment, especially with the intralesional method, and frequently becomes chronic, with new lesions sometimes appearing around the mother lesion at the sites of injections. In the dry crusted type, a moderately thin, silvery, adherent crust starts forming on the nodule very early. After about 4 months, if untreated, the crust thickens, and occasionally several small red papules (satellite lesions) appear around the mother lesion about 0.5-1 cm away from the margin. In the ulcera- tive form, lesions present as well-defined ulcers about 1-5 cm in diameter, with a thick brown firmly adhering crust at the centre. The skin around the ulcer (2 mm-2 cm) is inflamed, and assumes a dusky violet hue. This form of the disease responds very well to treatment, and rarely becomes chronic. In chronic cases, some lesions are dull-red plaques, with healing centres, and raised, active, spreading borders leading to gyrate or annular struc- tures; others take the form of soft papules ranging in colour from pink to brick red and are covered with thin whitish scales. Such papules appear at or near the border of a scar or even within the scar itself. The intralesional method of treatment A 1-ml sterile, disposable syringe with a No. 26 nee- dle was used. For a lesion 1 cm in diameter, 1-2 ml of meglumine antimoniate was injected into the upper- WHO Bulletin OMS. Vol 75 1997254 Cutaneous leishmaniasis in Aleppo, Syrian Arab Republic ci)c' N CM C-) CY ,It a) 'M CC N s _ Cf N CD CM C\j t U) a 0 U) U) 0) Cu CO) CY) C) CO N T- CM R _Z (0 U) v-0 N ON _l ::t n 00 N N CM t C cc c- CM cc (D cc 0C\) c( M N a cc 04 R I- ccM cs 0 Ci C\u N- C6 CY)(0 0) 0 N 0OC C\ C) C) (c '0 C\i 0CM co (D co C) t U) 7 v- CD 0 0) aC _ Ci C3lc3 :C C) c .c i5) r- 0 5o CL > > C WHO Bulletin OMS. Vol 75 1997 C .2. 0 02) 0 C 0 CO .2- 0) C] 0 .'Z 0) Jo cn 0- 0C) Cm) A0) -0) Cl)£ E C) -0 E o .oD E >) cn D) 0) > 0) 1 0)(D ( D - > 0 OCX zO- (D X C UJ0 cn cn ,D M CD Lo CA 0 c 6 A? Z cu oCL ,0 3 .% U) 0) CO n C Cu _. co 0 0) 0 CA ._ co E 00 0 0 0 C. la co CD ._ E 0 0 0) 0 N C\o ce) cG (D CY) cs 0) 0 Ul) N cc (.0 O C\J S co cii ur (O _ co 0 C60) CD 001) 0 0) Cu C,) 01) 0) C01) a) .1- a) C0 CO 255 M. Douba et al. Fig. 1. Leishmanial plaque of 1-year's duration, still active despite intralesional treatment, and showing developnient into chronic stage. and mid-dermis exclusively, at four points around the lesion, beyond the inflamed area. The lesion became swollen and white in colour. The treatment was repeated at weekly intervals for 6 consecutive weeks. Results The majority of patients (71.8%) were children un- der 15 years of age. The proportion was even higher (93.8%) in patients with chronic cutaneous leish- maniasis (Table 1). The face was the most frequent location for le- sions, with almost 70% of patients having at least one sore on the face and 81.3% of chronic patients hav- ing lesions exclusively on the face (Table 1). Table 2 indicates the amounts of drugs ad- ministered to patients with chronic cutaneous leish- maniasis without success. Histopathology No sign of necrosis was detected in any of the biop- sies. In four (16%) of the 25 biopsies from chronic lesions there was an ill-defined granulomatous in- filtrate intermingled with lymphocytes and histio- cytes. The duration of these lesions was 1.5-3 years. In 18 (72%) of the biopsies, the dermal infiltrate consisted of well-defined tuberculoid granulomas surrounded by a dense zone of lymphocytes and a few plasma cells. The duration of these lesions exceeded 3 years. In the remaining three (12%) biopsies, the dermal infiltrate was diffuse and com- posed of macrophages, lymphoid cells and some plasma cells. The duration of these lesions was less than 2 years. The inflammatory infiltrate was examined and in 10 cases (40%) inflammatory changes reached the upper layers of the subcutane- ous tissues (Fig. 2), while in the remaining 15 (60%) the changes did not extend beyond the dermis. A- mastigotes were detected in various proportions in 5 (20%) of the biopsies but there was no correlation between the presence of parasites and the duration of the lesion. In biopsies from the two sub-acute cases, the inflammatory infiltrate was diffuse with ill-defined chronic granulomatous changes. In biopsies from the four acute cases, the dermal infiltrate consisted predominantly of large macro- phages filled with great numbers of Leishmania or- ganisms in addition to lymphoid cells and a few plasma cells. In three of these cases (75%), the in- flammatory changes had reached the upper layers of the subcutaneous tissues. Discussion The intralesional use of pentavalent antimonials as the sole treatment for cutaneous leishmaniasis has mainly been reported or recommended only for very small and localized lesions (8) and in cases where the infective species do not cause chronic or recurrent cutaneous leishmaniasis (9). Systemic therapy with antimonials for the treatment of primary cutaneous leishmaniasis has been specifically recommended if the infective agent is L. tropica (3), as in Aleppo, because of the potential risk of development of chronic infection. The success achieved in Aleppo using intra- lesional meglumine antimoniate in speeding up re- covery from acute cutaneous leishmaniasis, and its WHO Bulletin OMS. Vol 75 1997256 Cutaneous leishmaniasis In Aleppo, Syrian Arab Republic Table 2: Details of previous treatments received by the 64 study patients with chronic cutaneous leishmaniasis No. of patients Type of treatmenta No. of sessions, treatment 18 Intralesional alone 3-50, intralesional 4 Systemic alone 10-20, systemic 22 Intralesional then systemic 2-68, intralesional 2-20, systemic 8 Intralesional then cryocauteryb 1-50, intralesional 2-10, cryocautery 3 Intralesional then intralesional 25-30, intralesional steroids 1-2, intralesional steroids 2 Intralesional then systemic 16-25, intralesional then cauterization 10, systemic before cauterization 2 Intralesional then cryocautery then 10, intralesional intralesional steroids 5, cryocautery 3, intralesional steroids 5 Intralesional then systemic 15-20, intralesional then cryocautery then intralesional 1-14, systemic steroids 1-2, cryocautery 1-2, intralesional steroids a Unless otherwise indicated, intralesional and systemic treatment was with pentavalent antimonials. b Cryocautery was performed using CO2 "snow". superiority compared with other methods in terms of being less hazardous to the patients and much cheaper, has led to its widespread use in Aleppo over a prolonged period. Systemic therapy alone using meglumine antimoniate or sodium stibogluconate gave results that were less satisfactory than those obtained with intralesional treatment alone using meglumine antimoniate (5). Even in instances when the use of systemic therapy was recommended owing to the size or number of lesions, we found that simultane- ous use of the drug intralesionally and systemically (combined treatment) considerably enhanced its effectiveness (M. Douba, unpublished data, 1990). This situation continued in Aleppo until a few years ago, when response to treatment started to decline gradually. Today, lack of response to treatment has be- come very common, and the rate of chronic cuta- neous leishmaniasis has exceeded all previously reported levels. The increasing ineffectiveness of the method of treatment that had been successful for 25 years led us to suspect that the parasite had become resistant to pentavalent antimonials. To confirm this hypothesis, isolation of the parasite from resistant patients and in-vitro studies are recommended. We have been unable to conduct such studies owing to lack of facilities. The rate of chronic and recurrent cutaneous leishmaniasis reported in the literature has never ex- ceeded 10% (3). In this study, the rate of the chronic form was 31.1%. We consider that a substantial num- ber of these cases are not exhibiting true chronicity but rather "treatment-induced chronicity". The use of the intralesional method of treatment alone and exclusion of systemic treatment might be the cause of this chronicity. Inadequate initial treatment inter- feres with the development of natural immunity, and can result in partial healing and partial immunity as well as in the development of a state that resembles chronicity. It appears that patients can remain in this phase for years before possible recovery. Another phenomenon that is worth noting is the clear and unexplained increase in total incidence of cutaneous leishmaniasis in Aleppo (7). This could be a logical consequence of the increase in chronicity and hence growth of the human reservoir of the parasite. Infected individuals who move to newly inhabited residential areas could easily transfer the infection (the resistant strain in particular) to suscep- tible individuals, since their lesions are continuously active and generally located on exposed areas of the body. In Aleppo, the disease is no longer restricted to the poor, previously "endemic" areas; the 206 patients in this study came from 70 different residen- tial areas. WHO Bulletin OMS. Vol 75 1997 257 M. Douba et al. Fig. 2. Histopathological section of chronic leish- maniasis lesion (2-years' duration) showing the in- flammatory changes in the subcutaneous tissues. If the intralesional method is responsible for the evolution of resistance to the drug, there are two points to consider: errors in carrying out the tech- nique; and the inadequacy of the intralesional tech- nique as the sole method of treatment. The apparent simplicity of the intralesional technique permits persons who are not medically qualified to administer the drug to patients, espe- cially in poor endemic areas where there is consider- able overload of work. Errors in the application of the technique include administration of insufficient amounts of the drug per injection, an insufficient number of injections per lesion, wrong selection of sites for injections, harmful injections that pene- trate deeper than the dermis into the subcutaneous tissues, and haphazard scheduling and early inter- ruption of treatment. Such errors mean that the different parts of a lesion receive different concen- trations of the drug. It is not uncommon to see a patient with two lesions, one responding well to treatment and ultimately recovering leaving a scar, and the other developing into chronicity. Treatment that is inadequate in dose or duration leads to relapse and drug resistance (10). Use of the intralesional technique alone is not suitable for the treatment of the less common clinical expressions of cutaneous leishmaniasis, such as the pseudo-epitheliomatous forms (nose), psoriasiform plaques (elbows, knees) and verrucous forms (an- kles). Intralesional treatment alone inevitably leads to chronicity of these lesions. Moreover, satellite lesions newly developing as papules around the mother lesion are often not covered by the treat- ment because they are not yet clearly visible. Conse- quently, certain foci of parasite clusters remain that are not reached by the drug, which could constitute the reservoir for the future nodules that are observed in cases of recurrent cutaneous leishmaniasis. An- other drawback of the intralesional technique is that the drug is injected into the upper- and mid-dermis exclusively. However, in this study, in 10 of the 25 chronic patients (40%), and in three of the four acute cases (75%), the inflammatory changes had reached the upper layers of the subcutaneous tissues. This level of skin is not directly reached when the drug is injected intralesionally. Recently, we have used combined intralesional and systemic treatment with antimonials for several acute cases and obtained much better results than with intralesional treatment alone (M. Douba, un- published data, 1995). However, double-blind, ran- domized clinical trials with placebo are needed in order to prove the superiority of the combined method or of systemic treatment alone. Investigations are also required to determine why the chronicity occurs mostly in children and in lesions located on the face, in particular. Anatomical characteristics specific to the skin of the face could be crucial, but in the meantime we recommend that children with lesions located on the face should be considered to be at high-risk of chronicity. Such patients should be given combined systemic and intralesional treatment, ensuring that the dose of anti- monials conforms to that recommended by WHO. In the long term, efforts should be made to find an alternative treatment for acute cutaneous leish- maniasis, which is both low in cost and easy to ad- minister. There have been several reports promoting the use of paromomycin to treat cutaneous leish- maniasis, but our experience with this ointment has so far been disappointing, and it is also expensive. In our opinion the real problem lies in the grow- ing population of unresponsive chronic patients. As WHO Bulletin OMS. Vol 75 1997258 Cutaneous leishmaniasis in Aleppo, Syrian Arab Republic long as their lesions are still active, control of cutane- ous leishmaniasis is beyond reach. Our results emphasize the need for further stud- ies to try to control this disfiguring disease, which is becoming a threat to every family in Aleppo. Acknowledgements We thank Dr Z. Shawaf, histopathologist, University Hospital, Aleppo, for his assistance in the histopatho- logical studies. We are also grateful to Mrs S. Soufi for coordination of the project and tabulation of data. Resume Situation actuelle de la leishmaniose cutanee b Alep (Republique arabe syrienne) A Alep (Republique arabe syrienne), on a constat6 une nette augmentation du nombre de patients atteints de leishmaniose cutanee qui ne repondent pas a l'administration intralesionnelle de d6riv6s pentavalents de l'antimoine, consideree depuis le debut des ann6es 70 comme le traitement de pre- miere intention de la maladie. Autrefois, l'injection intralesionnelle d'antimoniate de meglumine suf- fisait pour obtenir la guerison complete et l'on n'observait pas plus de 3 a 5% de cas chroniques ou recurrents. 11 n'en est plus de meme aujourd'hui. L'absence de reponse au traitement a entraine une augmentation preoccupante des cas chroniques. On a donc soupqonn6 une r6sistance du parasite au m6dicament et une petite enquete a ete entreprise. Cette enquete a porte sur tous les patients qui se sont pr6sentes avec une leishmaniose cutan6e a l'hopital Ibn-Rushd du 2 au 17 janvier 1995. Les patients ont ete class6s en fonction du stade de la maladie et des traitements qu'ils avaient suivis anterieurement. Des biopsies ont et6 pratiqu6es sur 31 d'entre eux pour analyse. Sur les 206 sujets examines, 38 (18,4%) 6taient de nouveaux patients jamais trait6s aupara- vant (cas aigues), et 46 (22,3%) venaient pour la deuxieme a la sixieme fois recevoir leur injection intral6sionnelle hebdomadaire de derive stibie pen- tavalent. En outre, 58 malades (28,2%), qui avaient requ plus de six injections intral6sionnelles sans amelioration clinique, ont ete consideres comme r6fractaires au traitement. Les 64 autres patients (31,1%) presentaient une leishmaniose cutan6e chronique etablie. L'examen des biopsies a montre que la reac- tion inflammatoire atteignait la partie superieure des tissus sous-cutanes dans 10 cas chroniques sur 25 (40%) et dans les trois quarts (75%) des cas aigus. L'administration d'antimoniate de m6glumine dans les l6sions est tenue pour responsable de la r6sis- tance de Leishmania tropica et du developpement d'une "chronicit6" iatrogene. En effet, le m6dica- ment n'atteint pas la meme concentration aux dif- ferents niveaux du tissu cutan6, ce qui entraine une cicatrisation partielle ou temporaire des lesions. En outre, si le medicament est administr6 de faqon incorrecte (quantit6 insuffisante, mauvais choix des sites d'injection, non respect du calendrier d'ad- ministration, interruption pr6coce du traitement), il peut arriver que des foyers parasitaires, notamment des Isions satellites, ne soient pas trait6s. 11 est recommande de combiner le traitement general et les injections locales, notamment chez les patients qui presentent un risque 6leve d'evolu- tion chronique. 11 faudrait egalement entreprendre des recherches pour trouver une autre m6thode de traitement de la leishmaniose cutan6e aigue qui soit a la fois peu couteuse et facile a appliquer. References 1. Chehadeh AK. Skin diseases, vol. 1. Aleppo, Aleppo University Press, 1986: 374-397. 2. Belazzoug S et al. Un nouveau zymogeme de Leishmania tropica, agent du Bouton d'Alep (Syrie). Archives de llnstitut Pasteur, Alg6rie, 1988, 56: 95- 99. 3. Moschella SL, Hurley HJ. Dermatology, vol. 1. 3rd ed. Philadelphia, PA, W.B. Saunders, 1992: 1115- 1141. 4. Harms G et al. A randomized trial comparing a pentavalent antimonial drug and recombinant interferon-gamma in the local treatment of cutaneous leishmaniasis. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1991, 85: 214-216. 5. Douba M. [Clinical and laboratory evaluation of the treatment of cutaneous leishmaniasis]. Master's the- sis, Aleppo University, 1990 (in Arabic). 6. Hadaya MR. [Cutaneous leishmaniasis in the governorate of Aleppo]. Master's thesis, Aleppo Uni- versity, 1986 (in Arabic). 7. Ashford RW et al. Evidence for a long-term increase in the incidence of Leishmania tropica in Aleppo, Syria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1993, 87: 247-249. 8. Degos R. Dermatologie, vol. 2 Paris, Flammarion Medecine-Sciences, 1965: 741 b-743a. 9. Moschella SL. Year book of dermatology. Mosby, 1994: 225. 10. Rook AW et al. Textbook of dermatology, vol. 2. Oxford, Blackwell Scientific Publications, 1992:1217- 1264. WHO Bulletin OMS. Vol 75 1997 259