Mucocutaneous Leishmaniasis -A Review of Clinical Aspects

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MUCOCUTANEOUS LEISHMANIASIS - A REVIEW OF CLINICAL ASPECTS

P. D. Marsden and R.R. Nonata*

INTRODUCTION We shall use a simple classification in this discussion. The skin lesions will .be considered In 1910 Gaspar Vianna suggested at a under the general headings of closed and open conference in Belo Horizonte that antimonial since the usual evolution is from a closed lesion therapy was effective in the treatment of to an open ulcerated one. For mucosal lesions mucocutaneous leishmaniasis and this proved to we will use the three evolutionary stages be the case98. In 1926, Montenegro evaluated described by Klotz e Lindenberg60, namely (1) a skin test antigen which is of diagnostic value. nodulation w ithout ulceration; (2) Early It is some measure o f the slow development of ulceration and (3) Late ulceration. clinicai reasearch in this important human A marked feature of both our clinicai infection that today both these discoveries are observations and those in the literature as still being applied as standard practice and still regards these lesions is the extreme variability the laboratory diagnosis and treatment is far in the course of the disease. For example in from satisfactory. some patients severe mucosal damage appears We have written this review because in our relatively early and children may present clinicai work we have been in doubtsometimes irreparable facial damage. Other patients give a about what is the best line of management for history of a minor skin lesion many years our patients. Turning to the literature we did before the onset o f mucous membrane not always find the answer to our questions. involvement and yet others only have a minor This is, as the title suggests, a review concemed skin lesion. Host immunity and the type of with the patients side of the problem and for parasite probably plays an important part in this reason begins with the clinically important this and the little we know about this subject is aspects. Later on we disciiss the relevance of mentioned in our subsequent discussion. some recent biomedical research to our understanding of how this infection behaves in CUTANEOUS LESIONS man. CLOSED LESIONS

CLINICAL FEATURES The site o f the bite of the sandfly is generally regarded as the site of the initial The lesions of Mucocutaneous leishmaniasis lesion. The frequency with which innoculation are polymorphic and can closely resemble many of promastigotes by sandflies produces a lesion other skin diseases. This has ied to a number of is not known. Determining factors may include classifications o f skin and mucous membrane the number o f flagellates innoculated, the strain lesions by different workers. For example. of Leishmania and the previous immunological Azulay5 in his thesis in 1952 lists eight experience and genetic makeup of the host. classifications. Although these classifications Quite frequently patients are seen with multiple have value they have become extraordinary early lesions ali about the same stage and these complex and since they are largely descriptive it probably represent the bites of several infected is natural to search fo r a simpler one. sandflies.

* University of Brasília, Brazil Subm ittedto publication on 7.20.1975 310 Rev. Soc. Bras. Med. Trop. VOL. IX - NP 6

Like Kala Azar the incubation period must workers6, S8, 1 s. and is essentially a parasite be very variable. Lainson (personal granuloma o f the dermis with secondary communication) has well documented evidence changes in the epidermis. The sequence by it may be as short as 15 days. Azulay and which innoculated promastigotes result in Salgado, in 19668, noted 18— 33 days in intracellular amastigotes in tissue macrophages paratroopers dropped into the Amazonian has not been directly observed in the dermis. It forest. Guimarães, in 1955S3, calculated the is not clear whether promastigotes penetrate average incubation period in a field" study as tissue cells or whether they round up to form being about 2 months. amastigotes which are then ehgulfed by If a lesion does develop it initially takes the macrophages. form of an erythematous macule which The initial histology consists of parasitised develops into a papule and then grows into a macrophages and undifferentiated histiocytes. nodule. The site of the lesions is most After a variable period lymphocytes appear frequently the limbs or face probably because indicating the appearance of a cell mediated they are most frequently exposed. In Central immune response. The intensity of this America lesions of the pinna o f the ear caused response varies greatly and is a major factor by Leishmania mexicana are very common12. influencing the chronicity of the lesion. Usually These lesions can take a variety of forms and the lymphocytic infiltration becomes intense may resemble other infections. They can be with associated plasma cells and eosinophils. listed as.follows: Actual intradermal micro abscess formation can occur with polymorp-h invasion. In chronic 1) Papules with a pustular element — a rare lesions well defined granulomas with giant cells form which could be confused with impetigo — may be encounted. Vascular lesion are also therefore called impetiginous. important with endarteritis and new vessel 2) Follicular papules the induration being at formation. Fibrinoid necrosis of venules was the site o f the f ollicles. regarded by Bittencourt and Andrade1 5 to be a 3) A small furuncular like nodule — has to part of what they considered to be a be distinguished from a simple boil or a histological picture suggesting a hypersensitivity Dermatobia hominis infection. reaction. The epidermis may show irregular 4) Discreet nodules multiple and variable in acanthosis, pseudoepitheliomatous hyperplasia, size sometimes d ifficu lt to differentiate on sight hyperkeratosis, parakeratosis, keratin plugs or from skin tuberculosis, sarcoid or leprosy. partial atrophy. On occasion hyperplasia may These are probably the result of blood stream be so marked as to suggest carcinoma. dissemination and have been termed Diffuse induration of the dermis with little leishmanids" although this term has also been apparent surface skin lesion have been applied to lichenoid, hypochromic lesions described. Lymph gland enlargement is appearing many years afterthe initíal infection. common, usually in primary nodes drainingthe Such lesions have a tuberculoid histology often site o f the lesion. Since spread by the without parasites49. Sometimes on a smaller lymphatics to the circulation is believed to be scale they may resemble the apple jelly nodules the method of dissemination, such enlargement of lupus vulgaris (more common in L. tropica) is not suprising even in closed lesions. In open or give rise to a diffuse infiltration w ith a raised lesions secondary bacterial infection plays an margin resembling the lesion o f tuberculoid important role. leprosy. 5) Hyperkeratotic lesions — such lesions The lymph gland histology exibits the same with a histological appearance o f marked basic processes already described in the skin epithelial activation can produce papillomatous lesions. An initial leucocytic infiltration is lesions resembling the framboesia o f secondary rapidly followed by a marked cellular activation yaws. Condylome type lesions as well can be of lymphocytes, plasma cells and histiocytes. confused with the treponematoses. Verrucose Often leishmania can be seen in the latter. granulomatous lesions may resemble Giant cells are less common than in skin lesions histoplasmosis or chromoblastomycosis. but well defined tuberculoid granulomas may Many of these forms are uncommon and are be present and these may even go on to presumeably governed by the tissue reaction to caseation. the invading parasite. The histopatology has Special mention must be made here of been studied by several groups of diffuse cutaneous leishmaniasis (leishmaniasis NOV-DEZ/75 Rev. Soc. Bras. Med. Trop. 311 tegumentaria diffusa) which is usually a closed (Mycoòacterium ulcerans infection). This entity type of lesion and only rarely ulcerates. The has yet to be reported in Brazil but the lesions take the form of erythematous nodules overhanging edge of skin so characteristic of which closely resemble lepromatous leprosy Buruli ulcer is not a feature of such leishmanial both in their individual appearance and their ulcers. A scrofula like lesion, should be symmetrical distribution with prominent ear distinguished from true tuberculous scrofula or involvement. For this reason patients o f diffuse actinomycosis. cutaneous leishmaniasis have been interned in leprosaria. Similar ear lobe nodulation is also MUCOSAL LESIONS seen in Lobo's Keloidal mycosis96. Histology shows histiocytes rich in leishmania with little A variety of mucous membranes may be lymphocytic infiltration. The Montenegro test affected. Pessoa and Barreto, in 194881, is negative. Usually these patients do not summarising Barbosa's large series producesthe respond to treatment but if they do following incidence figures — Nasal lesions, lymphocytic infiltration of the skin lesion has 1790 patientes; buccal lesions, 209; pharyngeal, been noted to begin and Montenegro test has 170 and laryngeal, 50. Rarer sites include the converted in some instances from negative to conjunctiva and genitals. The over ali incidence positive. The significance of this rare form of of mucosal involvement in different series varies leishmaniasis is discussed later. widely and Azulay5 cites 7 sources with percentages varying from 8% — 80.9%. Since OPEN LESIONS the nasal area is by far the most commonly affected the following discussion relates to this The process of ulceration is probably site. Specific complications at other sites are dependant on such factors as tissue oedema, considered later. foci o f necrosis in areas o f heavy inflammatory 1 — Nodulation without ulceration — The cell infiltration and vascular occlusion due to septum of the nose is the commonest site for endarteritis. Ulceration is the usual sequei to this lesion which may be very small. It may also the dermal infiltration and usually the ulcer is occur on the inferior turbinates56. Because of small with a surface crust. Howeversuch ulcers this it is essential that every patient have a may be large, multiple and severe. In an analysis careful examination of the nose or mouth of 184 patients in Vila Queiroz São Paulo State otherwise a significant complication may be Pessoa and Barreto81 found a single ulcer in missed. Villela et a/103 encountered leishmania 46.8%, tw o in 25,7%, 3 in 9.7% and in 6.6% in apparently normal nasal mucosa of patients multiple ulcers up to 9 were seen in smaller and it is likely that if a phase o f blood stream numbers of patients. dissemination occurs during the course of the In hospital series the proportion of patients disease organisms reach the nose where they with ulcerated lesions is high97 probably then lie dormant. This aspect is further because patients only presented at a relatively discussed in the last section. Walton et a/107 late stage. record the onset o f mucosal lesions in 4 Though the size, site and configuration of patients residing in a non endemic area for 11, the ulcer is variable it often has a characteristic 18, 19 and 24 years respectively before the m argin. This is infiltrated, raised and appearance o f mucosal disease. The mucosa1 erythematous. In forest yaws (pian bois) for granuloma may not be well defined but just instance the lesion iisclearly punched out with take the form of a diffuse infiltration. Frank steep sides and because o f this can be confused polyps may occur69 which have to be with the tertiary stage o f a treponematosis. d iffe re n tia te d from !benign polyps or Ulcers may also resemble those o f varicose rh in o s p o rid o s is . Patients often present (stasis) ulcers, tropical ulcer associated with complaining o f nasal obstruction. The lesion vincents organisms, and vèld sore (cutaneous may be entirely intranasal. diphtheria). An epidermoid or basal cell 2 — Early ulceration — If the granuloma is on carcinoma may mimic cutaneous leishmaniasis. the septum the thin cartilaginous wall of the Occasionally leishmanial ulcers may follow septum will be fairly quickly destroyed by the line o f the lymphatic drainage and resemble extension of the granuloma. Thus it is common sporotrichosis. Some skin ulcers can persist for to encounter patients w ith a septal perforation years and become large deep and fibrotic. A t or w ithout a septum. Similar ulcerations may his stage they may resemble Buruli ulcer occur on the alae and often in addition there is 312 Rev. Soc. Bras. Med. Trop. VOL. IX - NP 6 a generalised infiltration of the nose which may with an open lesion. This is not frequent and be erythematous and succulent in appearance. the usual explanation fo r multiple lesions is The differential diagnosis here includes leprosy lymphatic or blood stream spread. Probably and G cundou o f secondary yaws. A moist contiguous skin surfaces create optimum combination of these processes may give rise to conditions for this type o f spread. a broad drooping nose, the so called tapir nose. 2) Secondary bactériaI infection of open Late ulceration — These advanced cases present ulcers is almost inevitable; although there have with marked tissue loss often causing hideous been no specific studies these are probably the facial distortion. The nose may be totally lost usual skin flora (c. g. cocci). and the patient present with a roughly circular Superinfection with vincents organisms hole making the nasal passages and mouth a (Borrelia vincenti and Bacillus fusiformis) is common cavity. The differential diagnosis reported81. When the lesion is in the nose includes trauma, gangosa (tertiary yaws), lethal secondary bacterial infection may give rise to a midline granuloma and a large basal cell purulent rhinitis. Sinusitis may also be a carcinoma. The advancing border of the lesion complicatiòn and in the throat aspirated may threaten the lower eyelids and if this is the secretion may be responsible for a secondary case no time should be lost in instituting pneumonia. vigorous treatment. 3) Buccal and pharyngeal lesions may give One disease, again perculiar to South rise to sialorrhea and difficulties in deglutition. America which has not been mentioned but 4) In advanced laryngeal lesions there may which enters into every differential diagnosis of be not only loss of speech but also actual mucosal leishmaniasis is South American obstruction to the airway by granuloma or blastomycosis (Paracoccidiodes braziliensis). scarring. Tracheostomy may be necessary. The importance of this differential diagnosis 5) Conjuntival lesions may give rise to cannot be overemphasized. Usually culture and distortion of the palpebral fissure and in rare biopsy will settle the question. As a short cut to instances loss o f the eye. diagnosis a P.A. chest X ray showing 6) Severe cicatrization in the face area may pulmonary infiltration usully indicates reduce the mouth or nose apertures to such blastomycosis unless severe leishmaniasis is small proportions as to prejudice breathing or complicated by aspiration pneumonia or alimentation. pulmonary turberculosis. Rhinoscleroma, a rare 7) Large ulcers may be the site o f a infection due to Klebsiella rhinoscleromatosis secondary myiasis. may also closely resemble nasal leishmaniasis59. 8) Like ali large infected ulcerated areas in Other sites — The sites after the nose most the centre of the face cavernous sinus commonly affected are structures of the mouth thrombosis may be a complication. such as palate, tongue or lip. Apart from 9) Extension to the base o f brain with blastomycosis mentioned above neoplasms are secondary bacterial meningitis is perhaps more the chief differential diagnosis. More rarely the likely if such an ulcer is the seat of myiasis. leishmanial granulomatous process may descend 10) Pupo, in 194687, described bone and from the mouth to involve the pharynx and join t complications as a result of leishmaniasis. larynx the patients presenting with dysphagia, These usually appear to be of a non specific dysphonia or even aphonia. Genital lesions are nature and are a natural sequelae to any deep relatively rare. Ulcers of the glans penis and the ulceration contiguous to a bone or joint. For female perineum have to be distinguished from example the periostal reaction of a tibia venereal infections such as syphilis, soft sore beneath the site of a deep ulceration can be and particularly granuloma inguinale. Genital found in a varicose ulcer. However rarely lesions may be the result o f infected another type of bone lesion may be seen with phlebotomus bites occurring when the genitals absorption of the distai phalanges. Usually are exposea i-* the forest. Ocular lesions are also associated with diffuse cutaneous uncommon nd have been reviewed by leishmaniasis95 it resembles the distai bone Andrade, in 19322. changes of leprosy. The explanation is obscure.

COMPLICAI! QNS PROGNOSIS

1) Montenegro, in 192474 demonstrated Although some patients pass on to mucosal that auto innoculation may occur in patients involvement in a considerable proportion self NOV-DEZ/75 Rev. Soc. Bras. Med. Trop. 313

healing of the skin ulcer occurs without relapse. smears from the innoculation site at six months The scar of a previous leishmanial lesion is and a year after innoculation. Another possible relatively characteristic. Usually on the limb it tecnique for isolating leishmania is is slightly depressed, of smooth atrophic skin xenodiagnosis using specific phlebotomines32. and often hypopigmented in the centre. It has to The difficulties in rearing sandflies make it be distinguished from the scar of a mother yaw, unlikely that this method can be widely used. burn, or varicose ulcer. Reactivation after healing is documented in L. tropica infections Dl AGNOSTIC IMMUNOLOGV of the middle east91 but is more frequent in South American leishmaniasis. Sometimes in a The Montenegro reaction — Furtado48 has patient with mucosal disease no evidence of a tabulated many reports of the use of the previous skin sore can be detected. It is wise Montenegro test and has discussed some of the not to after a firm prognosis. Many patients are difficulties in relation to what would appear to aware of the course o f the disease and will go to be a simple test of delayed hypersensitivity. great lengths to ensure healing of the skin ulcer Usually the antigen consists o f a suspension of in the belief this will prevent nasal dead promastigotes obtained from culture in a complications. The authors have seen patients preservative. The concentration of these w ith renal damage due to prolonged, flagellates per ml of culture is important and unsupervised self administered antimonial governs the sensitivity of the test90. A therapy fo r this reason. concentration of at least 1 x 106 ís desirable and better results are achieved with even higher LABORATORV DIAGNOSIS concentration (1 x 107). Unfortunately this information on the nature of the preparation of Evidence for a diagnosis of mucocutaneous the antigen used in skin test studies is often Leishmaniasis is provided by three types of missing from published studies thus limiting the laboratory examination, namely (1) direct value o f the observations. More refined antigens demonstration of the parasite, ( 2) obtained by sonication34 polvsaccharide Immunological evidence by skin test or extraction44 or soluble extraction have been serology and (3) biopsy. The pathology has tested but results have only been marginally been described but the first two aspects are more accurate. They do have the advantage considered below. however that they can be standardised by Demonstration o f the parasite — As Furtado48 weight. Recently exoantigens have been prepared and tested against the standard pints out the percentage of positive isolations leishmanin antigen. Such exoantigens produce by direct examination of material from the an immediate hypersensitivity reaction in thirty ulcer is inversely related to the duration of the minutes with wheal and flare. T. cruzi lesion. Multiple aspirations with an exoantigens produces a similar immediate intramuscular needle w ill provide material for smears. These stained with giemsa demonstrate response but in contrast to the leishmanial exoatingen a delayed hypersensitivity response leishmania with greater clarity than those identified in formalin fixed H. and E. slides. after 48 hours was not seen indicating the However impression smears made at the time of greater specificity of the latter antigen94. skin biopsy are better. Biopsy is best done from As regards specificity o f the Montenegro the border of the lesion using a skin punch. test. Furtado48 also reviews a number of Several specimens are taken and one of these reports assessing cross reactivity with respect to can be cultured using the method described by other skin conditions. Diverse dermatose Herrer e t al, in 196655. We have had poor including leprosy, blastomycosis and pemphigus results with culture and have found it difficult have been said to give positive reactions, also to predict who might have leishmania systemic or glandular tuberculosis. Further demonstrable in smears or biopsy. Usually in studies are needed to confirm or refute these late lesions with mucosal damage parasites are observations as many consider leishmanin to be rare. The most effective way of isolating the relatively specific. A t Jacobina Pessoa and parasite is to innoculate triturated biopsy Sousa Lopes83 found the skin test to be material into the nose and feetof a hamster63. positive in 3 cases of cured Kala Azar but Often months later lesions appear at the site of negative in untreated cases in the same study. innoculation containing parasites. If no visible They found an incidence of about 10% of lesion appears it is still worthwhile examining positive skin tests in individuais (mainly school 314 Rev. Soc.Bras. Med. Trop. VOL. IX - NP 6 children) without any clinicai evidence of Later studies by Chiari et a/31 and leishmaniasis. This raises the possibility that Guimarães et a/54 using cultural flagellate avirulent strains or subclinical infections may antigens did not find cross reactions such a be responsible for skin test conversion. serious problem as to negate the usefulness of Much work has been done in Africa along the indirect fluorescent antibody test. similar lines in areas o f L. donovani infection of Trypanosoma cruzi and L. donovani infections man but restricting our discussion to L. of man produce sero positivity with L. braziliensis there is strong evidence not only braziliensis patients. A slide of a 8 day old from Brazil but from other South American culture promastigotes treated with 2% formalin and Central American countries that a positive can be kept at — 20°C for three years without Montenegro test in individuais without signs of loss of antigenicity54. Walton e ta l106 have cut leishmaniasis is a com m onfinding3, 14' 42, 70. down the incidence of cross reactions to other A negative test has occurred in patients in infections by using an antigen prepared from whom L. braziliensis parasites have been amastigotes in tissue culture. The chief value of found72 and this finding is presumeably an the IFA from a clinicai point of view would be indication of a poor cell mediated immune if it could be developed as a criterion o f cure response. How soon after infection the and used to evaluate chemotherapy. There is Montenegro test becomes positive is also in some indication this may be possible. doubt and is probably variable. There have been Walton105 and Chiari et alJ1 have noted that reports of positive conversion o f the reaction in the IFA test becomes negative after successful patients under treatment27,36. A positive therapy. reaction persists after resolution of the clinicai lesion80 but its relation to parasite persistence in the body of man is unknown. Although the THERAPY Montenegro test is a reflection o f cell mediated immunity and has been employed for many In any discussion of this subject two years there is little information on other important matters must be considered at the parameters of cêII mediated imm unity. In 1970, beginning. First we still have no accepted Tremonti and Walton101 reported blast criteria of cure. Since this is such an transformation of peripheral lymphocytes of unpredictable disease with frequent patients wijh American cutaneous spontaneous healing ideally every drug trial leishmaniasis. When the lymphoblast should have an adequate control group and the transformation test was assessed in 20 patients trial terminated when statistically significant with cutaneous leishmaniasis73 the percentage improvement is achieved in the group under o f blast transformation ranged from 19-27% therapy. For a variety of practical reasons this but no correlation could be found with the has not been possible to date. As mentioned intensity of the skin test. Convit and Pinardi34 elsewhere in this discussion persistence of claim to have shown a clear difference in the leishmania after healing of the skin lesion has behavior or cultured lymphocytes stimulated been demonstrated so that the presence of with leishmanial tegumentaria diffusa. Where as parasites does not correlate w ith tissue patients with a marked lymphocyte response response. Azulay 19667 agrees there are no and a strong Montenegro test showed a high accepted criteria of cure and feels that healing percentage o f blast formation. of the lesions does not justify suspension of Serology — There have been a number of therapy. Possibily the presence o f parasites studies on the value of a complement fixation after treatment does not correlate well with test using both L. braziliensis and T. cruzi subsequent relapse and tissue breakdown. This antigens4 ,49. Furtado has reviewed early question deserves study as does the value of the work on the indirect fluprescent antibody test fluorescent antibody test in assessing cure. which because of its comparative simplicity is A second consideration is that to date there more likely to be employed in routine is no good scientific observations to shed light diagnosis. However cross reactions with T. cruzi on the undoubtedly true clinicai impression occur24 and these authors have described a that this is a disease characterised by frequent fluorescent inhibition procedure to overcome relapses, late mucosal involvement and in some this problem. Cross reactions with Chagas instances marked tissue destruction. Although disease have also been noted using the passive this is frequently the history in individual haemogglutination test4. clinicai cases how often such complications NOV-DEZ/75 Rev. Soc. Bras. Med. Trop. 315

occur in a community exposed to infection is preparations have been antimony-n-methyl- unknown. It is not known whether such glutamine, Glucantime (Rhodia) and sodium complications are a feature of reinfection. Most antimony gluconate, Pentostam (Burroughs important of ali it is not known how therapy Wellcome). Since the former is manufactured in modifiesthis disease pattern. Brazil it has been much more widely used in L In short we know nothing of the> evolution braziliensis infections though Pentostam has of the disease in a population with or without also given good results45. No controlled trial therapy and this makes it very d ifficult to has been done on which is best but there is devise a sound scheme o f management of such probably little difference. Both drugs have the patiests. advantage that they can be given This is partly because of the difficulty of intramuscularly as well as intravenously which follow up of patients diagnosed in hospital. is particularly helpful when treating small This problem is illustrated by an attempt by children. Castro28 to follow up 23 patientstreatedwith Various treatment schedules have been Amphotericin B. Only nine patients returned recommended. Theoneweuseisasfollows. The for follow up observations after one year and dose must be related to the patients weight and only 4 after 3 years. is calculated on the basis of a total dose of drug Many drugs have been tried in the treatment o f 1 gm /kilogram . This is administered of this disease but none have superceded intravenously over a 10 days period with the antimonials as the mainstay of therapy. In cases patient resting in bed and receiving one resistant to antimonials the literature suggests injection a day. After 1 month's, rest this that Amphotericin B has produced the best treatment is repeated and the same process results. These two lines of therapy will be first repeated yet again to give a total of three discussed and other drugs subsequently treatment courses with a final total dose considered. Before considering details of 3gm/kilo body wt. Glucantime is available in treatment with the main drugs used in therapy 5cc ampoules containing 1.5g o f drug which it is necessary to mention their main toxic contains 425 mg of antimony. The mechanism effects. Pentavalent antimonials are much less of action o f such an antimonial on leishmania is toxic than trivalent but like ali heavy metais still poorly understood. It is possible it is they can produce cardiac, hepatic, renal or broken down in the body and acts in the cerebral complications. Amphotericin B is a trivalent form. Studies in vitro bear little very toxic drug. The most important toxic relevance to the action in man. In view of the effect is renal damage. In one study many years relatively low toxicity of glucantime and after treatment with this drug the majority or pentostam it is possible to administer therapy patients had evidence of renal impairment23. on an outpatient basis. Ideally therefore patients should be treated w ith these drugs in hospital. A serum transaminase and bromosulphalein test done to AMPHOTERICIN B (Fungizone) assess hepatic function, an electrocardiogram to detect cardiac abnormalities and a urine This drug can never be used on an outpatient examined and blood urea estimated to exclude basis. Still the main drug effective in the deep the possibility of renal impairment before systemic mycoses its value in the deep systemic commencing treatment. mycosés its value in mucocutaneous leishmaniasis was verified simultaneously by Furtado and Lacaz et al, in 1959. Since then it ANTIMONIALS has been used with success by various South American workers1 *>93. Practice varies widely Azulay7 lists 18 antimonial preparations both as regards the initial and subsequent doses that have been used in the treatment of this of this drug but acommon regimen is as follows. disease. Tartar emetic the trivalent antimonial had to be abandoned because of its serious Amphotericin B is dissolved in 500 ml o f 5% toxic side effects and the necessity for dextrose and injected by slow intravenous drip intravenous administration. However over a period of 6 hours on alternate days. The pentavalent antimonials have proved to be initial dose is 0.5 mg/kg/day and depending on effective in this as well as other forms of to le ra n ce th is is gradually raised to leishmaniasis. The two must widely used 1 mg/kg/day. Effective total doses are lower 316 Rev. Soc. Bras. Med. Trop. VOL. IX - NP 6 than in systemic fungai infections. In one study newer drugs have also been tried and these will such total doses varied between 4.4 mg/kg and be briefly reviewed here. 55.6 mg/kg with a mean o f 28.7 mg/kg 8. Cure Cycloguanil pamoate (Camolar) A depository without relapse has been reported in follow ups antimalarial related to paludrine, it contains up to ten years. 140mg of active compound in each cc. com- Side effects however are considerable with bined with mineral oil and benzyl benzoate. fever, anorexia, nausea almost invariable. Given in a single dose by deep intramuscular Venous thrombosis at the drip site is another injection. For children of 4-6 years of age problem. This can be lessened by slow diluted 140mg is sufficient, 280mg for those 5-10 and infusions and adding 25-50 mg of 350mg is the adult dose1 9,',n'5 7,1 04. The hydrocortisone sodium succinate to the drip first 3 authors used this drug in 50, 26 and 20 bottle. Kidney toxicity is strictly dose patients respectively in whom leishmania had dependent and renal function should be been found. The criterion of cure was clinicai monitored twice a week until azotemia is healing of the lesion and cure rates of 88, 73 stable. Bennett13 prefers to keep the blood and 88% respectively were obtained. Bryceson urea below 50 mg and the serum creatinine et a!1 9 concluded, however, that the drug had below 3.5 mg/100 ml. Hypokalemia occufs in no effect on L. tropica infections in Ethiopia. 25% of patients and requires oral The drug has side effects at the side of s u p p le m e n tio n . Permanent reduction in innoculation with persistent muscle pain and glomerular filtration rate probably occurs in ali occasionally abscess formation. patients receiving a therapeutic course of Niridazole (Ambilhar) This antischistosomal Amphotericin B fo r fungus infection. One drug has been used in the dosage it is used for electron microscopy study revealed tubular this infection namely 25 mg/kilogram daily for changes but the glomeruli appeared normal26. 10 days in the form of oral tablets22, 47. Patients must be carefully selected for Baranski22 repeated this treatment up to 5 Amphotericin B therapy as the treatment times, a dangerous policy in view of the side scheme involves a prolonged stay in hospital effects of this drug. Although the authors felt it and a capacity to tolerate side effects. This had some activity clearly today this drug has no situation should be explained to the patient and place. his collaboration ensured. This drug treatment D araprim (Pyremethamine) Another while undoubtedly effective should be reserved antimalarial and a folie acid antagonist it has for patients w ith Progressive destructive lesions been tried w ithout success in mucosal lesions who have not responded to antimonial therapy. by Viegas and Furtado102 and Solano and Vargas100. OTHER DRUGS Flagyl — A 5 nitroimidazole with good activity against Trichomonas vaginalis and intestinal A multitude of other drugs have been tried protozoa this has been given in high doses in this infection but none have produced w ithout much effect by Furtado and Viegas46. consistent successful results such that they can Walton e t a/110 have confirmed this finding. be reviewed in the same way as the two Bayer 2502 (Lampit, nifurtimox) A current previously mentioned. Azulay7 in hisceview treatment for Chagas disease 6 patients have mentions a number of drugs which have been been treated w ith a dose o f 480 mg per day fo r tried with little success among them sodium 25 - 30 days. In the only patient w ith mucosal arsenite, bismuth, atebrin, yatren, germanine, involvement the treatment was continued until sulphanilamide and furazolidine. One group of the 70th day. A good clinicai response was drugs he mentions, the aromatic diamidines noted in ali patients89. Further trials are should perhaps be reevaluated fo r use in certain indicated. cases in view of its success in treating diffuse Rifampicin (Rifaldin) A new antituberculous cutaneous leishmaniasis in Ethiopia. agent, good success was reported in L. tropica Bryceson20 reported cure in 7 out of 31 infections by El Din Selim and Kandil4 1, using patients treated with lomidine (pentamidine a dose o f 1.200 mg per day for adults and dimethansulphonate). In drug resistant cases of 20 mg/kg/day for children. Recently Dourado Leishmania braziliensis infection this might be (personal communication) has obtained good worth a triãl. Especially as Lopes and clinicai healing with this drug in patients will L. Almeida68 felt it was effective. However some braziliensis infections w ith only skin lesions in a NOV-DEZ/75 Rev. Soc. Bras. Med. Trop. 317 similar dosage sometímes continued for several successful results have been obtained though months. Although neither investigator mention little has been published to date5. One side effects these are known to be severe and difficulty is that a relapse will result in loss of include hepatitis, acute renal insufficiency, the graft. Because of this before undertaking coagulation defects and a curious type of auto reconstructive surgery a waiting period of 3 immune response1 6. These and the cost of the months to a year after the termination of drug are likely to lim it its usefulness. successful medicai treatment is desirable. Other drugs which have been tried w ithout effect include T hiabendazole and ASPECTS OF RESEARCH OF CLINICAL Nagoxin92, n i . It is obvious from this short RELEVANCE discussion that workers have been trying to find better drugs and the search will continue. Involvement of the mucous membranes in However it is d ifficu lt to evaluate these results cutaneous leishmaniasis is characteristic of the since the number of patients treated is so small, South American infection (L. braziliensis). there is no comparison with standard therapy, However there have been isolated reports of and the criteria of cure is often clinicai healing mucosal involvement associated with visceral or which could be spontaneous. It can safely be dermal leishmaniasis from the Sudan61, said to date that no new drug has been so Y u g o sla via 52 and Ira n 112. Cutaneous successful as to become standard therapy. leishmaniasis occurs in most Central and South American countries with the exception of HEAT THERAPY Chile33. The proportion of patients in clinicai It is well established that leishmania are heat studies with mucous membrane involvement is sensitive and that small alterations in very variable from 80% in some parts of Brazil temperature can profundly influence the to less than 5% in Guyana. Lainson (Personal bahavior of leishmania in culture67. It has been Comunication) explains this on the basis of suggested that the common sites of secondary overlapping o f different species. "As you travei lesions in Leishmania brazitiensis infection, southward in Brazil the incidence of espundia namely the nose or externai ear, is determined due to L.b. braziliensis increases as pian bois by the lower temperature at these skin (L.b. guyanensis) decreases". Early reports of surfaces1. In animais healing of lesions has been the geographical distribution have been produced by increasing the room reviewed by Pessoa and Barreto81. These temperature114 yet suprisingly little work has authors in their extensive monograph document been done on using heat or fever therapy in the disease in many Brazilian States. The disease treatment in man. Baker and Gutierrez probably exists in States where it has yet to be Ballesteros9 used a vapour heat process used for documented. For example 107 cases of the destruction of insect larvae in fru it and mucocutaneous leihmaniasis were collected in reported success in L. brazitiensis infection in Goias by one hospital service over a period of 4 man and L. enríetti in theguineapig. Bryceson20 years1 °. Previously there were no records from in his studies on diffuse cutaneous leishmaniasis this state. Mucosal involvement seems to be rare in Ethiopia noted that an attack of measles in some surveys. For example in field studies of dramatically improved three patients with patients in Amapa43 and indians in the Mato marked skin involvement and suggests that the Grosso25 no mucosal lesions were obsen/ed. It fever during the measles attack could be has been suggested that the Indian is more responsible. Bray and Ashford17 following up resistant to this type of lesion. Since we have this suggestion induced a Plasmodium vivax little information on the actual incidence of infection in a patient with diffuse cutaneous mucosal lesions in communities it could be that leishmaniasis and obtained a response. Recently they do exist but are sufficiently rare not to be success has been reported with the use o f hot represented in studies of small rural water or ultraviolet and infrared rays in the populations. Convit and Pinardi33 note that in treatment of east African cutaneous Venezuela in areas where mucosal forms are not leishmaniasis77. usually seen if an epidemic occurs with a large number o f cases muocutaneous lesions appear SURGERY in a few patients. Cicatrization o f oronasal lesions may require There have been few studies of the clinicai plastic surgery after medicai treatment with evolution o f lesions on settled communities and reconstruction of the upper lip and nose. Very such studies w o u ld provide valuable 318 Rev. Soc. Bras. Med. Trop. VOL. IX - NP 6

information relating to prognosis. Guimarães53 macrophage migration. The poor capacity of describes a community where a small epidemic the host to respond to the parasite in diffuse was associated with tree felling. Of 306 persons cutaneous leishmaniasis is also shown in the bad examined 39 had characteristic lesions and of response to treatment. Bryceson20 in Ethiopia these 34 out of 36 had positivá Montenegro found pentamidine dimethanesulphonate was reactions. Only two patients had nasal the most effective drug and under the influence involvement and these proved resistant to of treatment the leishmanin test frequently treatment with tartar emetic and fuadin. In became positive suggesting the beginings of an general the initial response to these drugs was cell mediated immune response. The cause of good but there is no information on long term the defect in cell mediated immune response in follow up. In three patients spontaneous cure diffuse cutaneous leishmaniasis is unknown. A t was noted. one time a specific type of leishmania (L. pi- Preston, in 197486, has'pointed out that the fanoi) was held responsible. However it appears innoculation of leishmania into man is followed the same organism can produce simple by three types of sequelae namely subclinical, cutaneous leishmaniasis18 and the isoenzyme self healing lesion, or a non healing lesion. Non structure of Ethiopian isolates from diffuse healing appears to be associated with tw o types cutaneous leishmaniasis (D.C.L.) is similar to o f host response, either anergic forms those from simple cutaneous leishmaniasis84. characterised by a supressed immonogical Zeledon115 on these grounds has suggested response as characterised by the rare diffuse that L. mexicana pifanoi is a species inque- cutaneous leishmaniasis or more commonly renda. Lainson and Shaw (personal communic- allergic forms with an enhanced immunological ation) have shown D.C.L. in Brazil to be due to response on the part of the host. The two main L. mexicana amazonensis which produces un- suggestions to explain these different responses co m p lica te d cutaneous leishmaniasis in are: immunologically competent persons in the 1. An innate property of the host in terms same geographical area. It is possible L. pifanoi of his ability to mount an immune response. is synonymous with L. m. amazonensis but 2. The type o f leishmania innoculated. since they have not examined the Venezuelan There is much evidence to support both material designated L. pifanoi they prefer to suggestions but at the time of w riting it is too use the name L. mexicana pifanoi for the early to conclude which is the more important. moment, but evidence is building up against Indeed it is likely that while both may be considering L pifanoi as a distinct species. relevant the role they play may vary with the Bryceson20 noted in Ethiopia that the individual case. primary lesion of D.C.L. is frequently on the leg The immunological response of the host has in contrast to oriental sore where 99% were on been recently reviewed by Bryceson21 and the face. Half the patients with leg lesions had Convit and Pinardi33 and these authors seem in addition defective lymphatic function in the largely in agreement. Bryceson has pointed out leg. He argues that the induction of an immune that the histological picture of leishmaniasis can response in a lymph node which is damaged or be classified along the lines of the Ridley Jop- preoccupied with competing antigens might be ling scale for leprosy and used as an index of reduced or allow the development of a State of the host's cell mediated immunity. His table is tolerance. Bray18 reviewing his experience reproduced in table I illustrating these histologi of the failure of transfer factor to activate cal variations. There is usually a close corre- immune response suspects that the relevant lation between skin sensitivity to leishmanin clone of lymphocytes no longer exists in D.C.L. and the histological picture. The immunological A t the opposite and of the spectrum is lupoid d efect in diffuse cutaneous leishmaniasis leishmaniasis39. The extreme tuberculoid appears to be specific for such patients respond picture representing a failure to eliminate the normally to tuberculin and lepromin. Also both parasite despite exaggerated sensitivity to Convit and Pinardi33 in Venezuela and Bray18 leishmanial antigens. In our experience of L. in 1974, in Ethiopia have demonstrated de- braziliensis infections in man this form is fective lynphocyte transformation in diffuse uncommon. cutaneous leishmaniasis. Bray's group have also In South American mucocutaneous shown defective leucocyte migration, an absen- leishmaniasis ali variants of the histological ce of lymphocyte activation products con- types set out in Bryceson's table can occur. taining a mitogenic factor and inhibition of Cutaneous leishmaniasis of the new world has NOV-DEZ/75 Rev. Soc. Bras. Med. Trop. 319 complex epidemiological aspects with a large development of malnutrition or tuberculosis. animal reservoir particularly in small rodents. Walton and Valverde109 have also encountered Lainson and Shaw64, 6S> 66 have emphasised patients who developed lesions at the site of that such leishmaniasis is predominantly a skin injury. This last suggestion seems to us to zoonosis with man only an incidental host be worth further irivestigation. The nose is playing little role in the transmission of the frequently blown or picked — it is the parasite in nature. The same authors have commonest site of a mucosal lesion. Toothpicks produced a classification of the organisms are in common use and the mouth is the next p ro d u c ip g cutaneous and mucocutaneous commonest site. In guinea pig leishmaniasis (L. leihmaniasis which is an extension of the enrietti) one could investigate the suggestion trin o m ia l system used by Pessoa82 and th a t m echanical in ju ry can precipitate considers geographical distribution, clinicai leishmanial lesions in the presence of chronic features and growth in culture and the hamster. leishmanial infection. Finally it must be noted TKis classification is set out in an abbreviated again that temperature is probably important in form in table II and it represents an advance in the development of metastatic lesions as our attempts to understand the varied clinicai demonstrated in the infected hamster11 3. presentations of cutaneous and mucocutaneous Leishmania enrietti of the guinea pig, leishmaniasis in man. It remains to be seen to discovered by Medina in 1946 inPanamá76 has that extent this classification will be confirmed proved useful laboratory model of mammalian by future experience. Unfortunately antigenic cutaneous leishmaniasis. Guinea pigs usually characterisation of such a complex does not develop a single lesion on the ear which appear feasible due to the number of common ulcerates and heals in a few months; like most antigens but some progress has been made with human cutaneous leishmaniasis this is a biochemical approach to taxonomy using accompanied by delayed hypersensitivity and isoenzyme and D.N.A. analysis. The results often followed by long lasting immunity to te nd to s u p p o rt Lainson and Shaw's reinfection. classification29, 50. Paraense78 studied the spread of this Turning to another problem the question parasite through the body of the guinea pig in arises as to why the mucosal involvement has its an a tte m p t to establish how leishmania unusual anatomical pattern with a preference metastasise. He found that parasites are carried for the nose and how nasal lesions arise. in macrophages from the innoculation site to Probably the dissemination of leishmania from local lymph glands where many are destroyed. the site of innoculation is initially by the Others however by post glandular lymphatic lymphatic system and then haematogenous channels gain the blood stream and are spread. As mentioned earlier leishmania have thence widely disseminated. He found parasites been found in normal nasal mucosa in this in the feet, nasal mucosa, scrotum and eyelid infection103 and in normal skin in Kala of guinea pigs innoculated in the ear. Azar85. There seems little doubt that Bryceson21 and his group (1972) have made leishmania can lie dormant in the tissues for many contributions to our understanding of the many years and the onset of cutaneous development of studies of the host immune leishmaniasis has been reported as long as 13 response w h ic h may have relevance to years after leaving the endemic area71. Walton equivalent human infections. In this model the has been mainly responsible for raising a incubation period depends upon the infecting number of interesting speculations regarding dose of flagellates. Also and perhaps relevant to the manner in which a mucosal lesion might be human South American leishmaniasis, the precipitates. Walton and Valverde108 have subsequent course of the disease is influenced noted in Bolivia that necrotising lesions of the by the size of the initial innoculum. Animais face are much more common in patients of receiving large doses of flagellates developed negro descent than in Amerinds and that such large initial lesions and more metastases. The negro patients have a greater sensitivity to development of delayed hypersensitivity as leishmanin suggesting an exaggerated cell measured by the skin test coincided with the mediated immune response presumeably of appearance of the clinicai lesion. The cell genetic origin Further Walton et a l101 have mediated immune response measured after 4 published case histories of Bolivian patients weeks (the longest incubation period) showed who developed mucosal lesions years after the that lymph node cells transformed in the in itia l skin infection associated w ith the presence of leishmanial antigen. Migration of 320 Rev. Soc. Bras. Med. Trop. VOL. IX - NP 6 macrophages was inhibited by this antigen. It CONCLUSION was felt that two host mechanisms operated in the host tissues to eliminate the parasite — It is obvious from this discussion that enhanced macrophage phagocytosis and advances in our diagnosis and management of lymphocytic cytotoxicity, and experimental this important infectious disease of man are to evidence suggested the later was more be expected. Already much useful information im p o rta n t. S tudies o f antibodies using has come from recent immunological and immunofluorescent techniques on the serum of epidem iological studies. In view of the o o infected gujnea pigs detected complement unsatisfactory nature of therapy clinicians will fixing antibody after . the second week of continue to test new drugs probably in better infection. This antibody appeared to be controlled trials. There is a need to understand unrelated to the healing process or to the more about the natural history of the disease pathogenesis of local tissue damage. with and w ithout therapy. Unfortunately other animal models have not proved as helpful. In some rodent studies it has been difficult to differentiate strains of L. ACKNOWLEDGEMENTS braziliensis although skin lesions can be readily produced35. Drug evaluation in rodents also We wish to thank the Conselho Nacional de fails to yield information applicable to man40. Pesquisa of Brazil for financial support and the H owever these latter authors made the Biblioteca Regional de Medicina da Organização interesting observation that amastigotes can Panamericana da SaElde, S90 Paulo, for help often be found in healed lesions. Rhesus with the literature. Prof. A. Prata provided ■ym monkeys have been successfully infected , many facilities and Prof. H. Dourado valuable and more recently marmosets. It is líkely source material. Drs. R. Lainson, J.J. Shaw and primate models will provide useful information A.D.M. Bryceson kindly reviewed the in the future. manuscript and offered suggestions.

TABLE 1. The histological spectrum of Leishmaniasis After Bryceson, 1972

M.M. Macrophage Thin intact epidermis, clear subepidermal zone. Dermal infiltration with macrophages, often vacuolated, full of parasitest histiocytes, many vessels containing monocytes, absence of lymphocytes.

M.l. Macrophage Intermediate M.M. together w ith scanty lymphocytes scattered throughout òr grouped deeply beneath the lesion.

1.1. Intermediate Epidermis thickened, intact early, may ulcerate later. No clear zone. Lymphocyte intimately mixed whith large, fleshy, histiocytçs, moderate numbers of parasites or M.M. areas along side IT or TT areas.

IT Intermediate Tuberculoid Epidermis ulcerated; where intact, shows reduplication of the layers, nuclear damage, and hyperkeratosis. Lymphocytes predominate, early arrangement into tubercles around clumps of epitheloid cells, parasites scanty.

TT Tuberculoid Epidermis ulcerated. Tubercle formation, often with giant cells. Parasites rare or invisible. NOV-DEZ/75 Rev. Soc. Bras. Med. Trop. 321

TABLE 2. Aspects of a Classification of American Cutaneous Leishmaniasis as proposed by Lainson and Shaw. 1972

Leishmania Mexicana Complex Behavior in Behavior culture in hamster

L. mexicana mexicana Causes chiclero ulcer, bay sore usually Luxuriant Rapid development single lesion often self healing ear Growth of histocytomas lesions often chronic destructive no in a few months. naso pharygeal involvment.

L. mexicana amazonensis Single or limited lesions in man in Ditto Ditto Amazon basin. I L. mexicana pifanoi Only known from cases of anergid Ditto Ditto diffuse cutaneous leishmaniasis.

Leishmania Braziliensis Complex L. Braziliensis Few small to very large Progressive Scanty Slow growth lesions, frequent mucous membrane growth few parasites involvement.

L. braziliensis guyanensis Pian bois, single or multiple ulcers Scanty Slow growth metastases often seen as nodules along growth few parasites lymphatics.

L. braziliensis panamensis Single or multiple ulcers lymphatic Grows Slow growth spread. R arely naso pharyngeal reasonably moderate number involvement. well of parasites

L. peru viana Uta. single or limited lesions self Grows well Little healing no mucous membrane information involvement.

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