On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.79 no.4 Rio de Janeiro July/Aug. 2004
CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION
American tegumentary Leishmaniasis: hospitalized cases in Rio de Janeiro*
Nurimar C. FernandesI; Isabela MorganII; Juan P. MaceiraIII; Tullia CuzziIII; Rosângela A. M. NoeIV
IAdjunct Professor of Dermatology,
Department of Clinical Medicine/FM/UFRJ
IIPostgraduate Student of Dermatology/FM/UFRJ
IIIAdjunct Professor of Pathology, Pathology Department/FM/UFRJ
IVStatistician of the Scientific Investigation Commission /HUCFF/ UFRJ
BACKGROUND: American tegumentary Leishmaniasis
is widely found in Brazil; the state of Rio de Janeiro (capital and hinterland)
is an endemic area where the vector is found inside and outside houses.
OBJECTIVES: prospective study of 48 cases attended at the Teaching Hospital Clementino Fraga Filho - UFRJ, between 1990 - 2002.
METHODS: All patients were submitted to skin or mucosa biopsy, Montenegro skin test and otorhinolaryngologic examination; SbV (10 - 20 mg/kg) with 10, 30 and 90 doses was used in 44 patients; in 4 cases, Amphotericin B (0.5 mg/kg/dose) until cumulative dosage of 30 - 50 mg/kg.
RESULTS: 28 males and 20 females aged 10 - 89 years mostly infected in Rio de Janeiro (38 cases/79.1%) mainly presented ulcers in the extremities and involvement of nasal mucosa; 41 cases (85.4%) were reactive to the Montenegro skin test (>5 mm); 17 cases (35.4%) were positive for amastigotes in tissue sections; an inflammatory chronic granulomatous process was mostly seen. Clinical cure was observed in 47 cases; one patient died on day 10 of treatment.
CONCLUSION: The study of American tegumentary Leishmaniasis (HUCFF - UFRJ) from 1990-2002 showed a well-known "status" considering epidemiological and clinical perspectives as well as therapeutic response to antimony (SbV) and amphotericin B.
Key words: epidemiology; Leishmaniasis; Leishmaniasis, cutaneous.
American tegumentary or mucocutaneous Leishmaniasis is a disease caused by protozoa of the genus Leishmania and characterized by prolonged course and lesions of the skin, cartilage and mucous membrane of the upper respiratory tract. In Brazil, the disease presents two epidemiological patterns:
a) epidemic outbreaks associated to clearing of the forests for construction of highways, installation of towns, wood extraction, agriculture and cattle ranching;1
b) Leishmaniasis not associated to clearing of the forests: migratory process, occupation of hillsides, agglomerates in the periphery of urban centers. Dogs, horses and rodents seem to play an important role as new reservoirs of the parasite, and it has been conjectured that the vectors and parasites have possibly adapted to the modified environments and to the construction of reservoirs.1
Leishmania Viannia braziliensis associated to the phlebotomine Lutzomya intermedia is the agent/vector most frequently found in the State of Rio de Janeiro (capital and hinterland).1 Dwellings and domestic animal shelters in these endemic areas constitute the main stronghold for the vectors. In Rio de Janeiro, it occurs with similar frequency among adults and children of both sexes, corroborating the importance of peridomiciliary transmission.2
The incubation period varies from two or three weeks to two months or more. The lesions appear at the site of the insect bite and therefore are located in exposed areas.
The initial lesion is small, erythematous, solid and elevated, its diameter increases gradually. Frequently it ulcerates and then is covered again by crust, and at that moment, the lymph nodes are usually palpable. The ulcerated lesion develops and reaches a diameter of three to 12 cm, with very characteristic raised border, as in a picture frame and a granular base that bleeds easily. They can be single or multiple and secondary infection is common. Those that do not ulcerate also increase in size and become nodular or verrucous. The cutaneous lesions tend towards spontaneous cicatrization within up to six months, except those of the auricula.
Involvement of the mucous membrane occurs in most of the cases through blood or lymphatic dissemination, becoming evident three to 10 years after resolution of the skin lesions. Sometimes, however, the entry site can not be identified, and it is supposed that the lesions originate from a sub clinical infection.1 In general, they begin in the nasal mucous membrane, then become edematous and ulcerated; coryza and epistaxis are present. The cartilaginous septum is frequently perforated and later, the wings of the nose ulcerate, exposing underlying structures, with destruction of the nasal fossa, mucous membrane and cartilage. Bone involvement is not frequent. The lips, floor of the mouth, tongue, pharynx and tonsils can be affected and even the larynx, windpipe and bronchi. The mucous membrane then becomes thickened, edematous, painful, bleeds easily and has a fetid odor.
The present work is a prospective evaluation of the patients attended at the Clementino Fraga Filho Teaching Hospital /UFRJ, from 1990 to 2002.
PATIENTS AND METHODS
Forty eight cases of American tegumentary Leishmaniasis were submitted to anamnesis, complete physical exam and the following complementary exams:
1) Complete blood count, blood biochemistry, tests of liver function, amylase, lipase, urinary sediment, parasitological exam of feces, x-ray of pleuropulmonary fields, electrocardiogram and otorhinolaryngologic exam.
2) Montenegro test: Antigen of Leishmania was used at a concentration of 40 mg of proteic nitrogen/ml, standardized by Melo et al.;3 0.1 ml of antigen was intradermally injected in the anterior face of the forearm. After 48 hours, the hardened are was measured using a millimetric ruler. Tests were considered positive when the diameter was >5 mm.
3) The biopsies were performed with a punch or bistoury in the skin and biopsy tweezers in the case of the mucous membrane, the specimens were stained with hematoxylin and eosin and Giemsa. In the cases of simultaneous mucous and cutaneous lesions, the skin was selected for biopsy.
4) Therapeutic regimens. The drug of choice was antimonial pentavalent N-methylglucamine (Glucantime), available in a 5 ml flask containing 1.5 g of N-methylglucamine and 425 mg of pentavalent antimony (SbV); the dosage was calculated for a maximum weight of 60 kg. Care in the administration included verification of the blood pressure before application, patient lying down and fed with lukewarm compresses on the application site.
SbV by endovenous path diluted in glucose 5% (max dose: 15 ml/day) and slow application over two hours.
cutaneous form: 20 mg/kg/day for 30 days
cutaneous form with comorbidity (glomerulonephritis, arterial hypertension, elevation of the creatinine (>2 mg), bilirubin (increased 2X), TGO and TGP (increased 2X), gGt (increased 3X), leukopenia (<1,500 granulocytes), nonspecific alterations of ventricular repolarization, increase in the QT interval, chronic atrial fibrillation): 10 mg/kg on alternate days for 20 days (10 doses)
mucous forms (nasal, labial, palate): 20 mg/kg/day for 30 or 90 days
laryngopharynx mucous forms: 15 mg/kg on alternate days for one week followed by 20 mg/kg/day until reaching 90 doses
b. Amphotericin B diluted in 500 ml of glucose 5%; added to 100 mg of hydrocortisone and 1,000 U of heparin in the flask. Slow infusion over six hours; half hour before the application, 500 mg of ASA and 25 mg of promethazine, orally.
dose: 0.5 mg/kg/dose (max: 50 mg) on alternate days
total dose of treatment: 30 to 50mg/kg.
Persistence of active lesions 12 weeks after the end of two complete courses of SbV;
Recurrence of the disease (reappearance of the lesion within one year after clinical cure);
Contraindication to SbV.
c. Weekly, throughout treatment: Electrocardiogram, blood count, transaminases, platelets count, prothrombin time, sodium, potassium, amylase, lipase, urea, creatinine.
d. Evaluation parameters of clinical cure: Total regression of the cutaneous lesion by the end of the treatment or three months after, with otorhinolaryngologic exam for evaluation of disappearance of the symptoms, regression of the hyperemia, absence of crusts and disinfiltration.1
5) Statistical analysis was performed using the following tests: Chi-square (c2) for comparison of proportions or Fisher's exact test when the Chi-square test could not be evaluated. The 5% level of significance was adopted.
The sample comprised twenty-eight male cases and 20 female cases, in the age group from 10 to 89 years and exercising the most varied professional activities (only seven farm workers/14.58%) (Table 1). After grouping into age bands of 10 to 29, 30 to 49, 50 to 69 and over 70 years old, it was observed that there was no significant difference in the age distribution between sexes (p = 0.33). In 38 (79.1%) cases, the disease was probably acquired in the Rio de Janeiro region. Ulcers prevailed in the lower limbs (29 cases /48 patients) and in the upper limbs (20 cases/48 patients). Mucous lesions were present in 8/48 patients, with a prevalence in the nasal mucous membrane (16 cases/8 patients) (Table 2). Thirty two patients (66.6%) referred to a disease duration of up to six months; 41 cases (85.4%) presented a positive Montenegro test, of which 20 (41.6%) presented induration between five and 10 mm; of the seven cases with negative Montenegro test, six referred to a disease duration of up to six months (Table 3). It was observed that the disease duration did not influence the response to Montenegro test (p = 0.37).
The histopathological picture of granulomatous inflammatory reaction with lymphoid, histiocyte and epithelioid cells, was associated in some cases to multinucleated giant cells and eosinophils. Amastigote forms were found in 17 cases (35.4%) (Table 4). According to the Kappa test, no significant agreement was observed between Montenegro test and histopathological exam, or in other words, the disagreement between the two diagnostic techniques was statistically significant (k = 0.33, p = 0.90, n = 48).
Thirty eight cutaneous cases were treated with SbV and there was clinical remission, although one case developed a single episode of urticaria with angioedema; the outline was maintained with prior administration of Glucantime, hydrocortisone (100 mg by infusion) and promethazine (25 mg, orally); three patients presented associated comorbidities.
In one case of the mucous form (perforation of the septum and adhered crusts), 30 doses achieved remission; in one case of the mucous form (crude granulation of the palate), 30 doses were sufficient to induce remission. Two patients with the mucous form (vegetation in inferior lip, ulcerated palate, edema and erythema of the nose and destruction of the septum) followed the regimen for 90 days with clinical remission; in one mucous case (increased volume of the nose, destruction of the septum, edematous epiglottis with irregular surface and hoarseness) the outline was initially progressive, reaching 90 doses, with clinical regression.
A patient with Down's syndrome and crusted erosions lesions in the trunk and legs and arms coursed with urinary infection, septic shock and died after the tenth dose of Glucantime (20 mg SbV/kg/day).
In four cases amphotericin B was used: One patient had been treated two years previously with 60 injections of Glucantime, and the nasal septum presented a granular aspect; one patient with destruction of the septum and treated initially with Glucantime for 30 days, presented recurrence one year after; another patient, one year after 22 doses of SbV, presented papulonodular lesions in base infiltrated in the frontal, malar, chin area (mentum) and ulceration of the lower lip with hemorrhagic points, and, at the eighth dose of SbV, the patient developed leukopenia (1366); one patient with cutaneous form after developing pyrogenic reaction to Glucantime. All patients treated with amphotericin B presented clinical regression of the lesions.
Diagnosis of the disease in this sample of patients was based on clinical and epidemiological criteria, positive Montenegro test, detection of the parasite in lesions and suggestive histopathological alterations. The homogeneous age distribution between genders and varied professional activities reflects the profile of the disease in the State2 (Table 1). Tegumentary Leishmaniasis has been present in Rio de Janeiro State since the beginning of the last century (1915). The areas of probable acquisition of the disease in 79.1% of cases were the metropolitan west side, Baixada Fluminense and Great Rio.
Ulcerated lesions in the lower limbs were the most frequent finding, corroborating data in the general literature;4-6 six cases were observed of ascending lymphangitis (Table 2). Lymphangitis and adenomegaly are considered part of the disease at 90 days and characteristics of the subspecies Leishmaniabraziliensis guyanensis.1 NHowever, these findings can be verified in other species. Both these manifestations demand a differential diagnosis with sporotrichosis, a subcutaneous mycosis in which the lymphangitis develops with nodulation. The nasal mucous membrane was the most involved, confirming previous observations4-6 (Table 2). Mucous manifestations included infiltration and erythema of the nose with perforation of the anterior nasal septum; accompanied by perforation of adherent crusts and granular aspect; bilateral nasal obstruction, rhinorrhea and pruritus as associated manifestations; edematous epiglottis with hoarseness, hard and soft palates and with hyperemia and coarse granulation, ulcer of the soft palate and vegetation of lower lip.
Montenegro test with late hypersensitivity is positive in 90% of the individuals with active or previous disease;1 tit becomes positive as of the third month of infection, remaining positive for the rest of the life. It can become negative in the following cases: in the disseminated and cutaneous-diffuse forms, in visceral Leishmaniasis and in immunodeficient patients. In the mucous lesions, the response to the test is more intense (ulceration and local necrosis). In this sample, 85.4% of the cases were positive, with readings from five to 10 mm in 20 (41.6%) of the cases (Table 3). None of the negative patients presented comorbidities and the predominant disease duration was up to six months (Table 3).
The histopathological alterations vary according to the disease duration and clinical aspect of the lesions.1 In this sample the chronic granulomatous process prevailed. As the granulomatous process becomes organized, the number of parasites decreases, such that they are rarely found in old lesions. However, identification of the parasites is fundamental for histopathological diagnosis. The percentage of positive exams varies according to the authors (25.4%, 63.7%, 18.8% and 47% )4,6,9-11 and in this work it occurred in 35.4% of the cases (Table 4).
Edema and acute respiratory insufficiency can occur in cases involving lesions of the larynx and pharynx; it is advisable to begin the treatment with a smaller dosage. This was the conduct followed in the case of lesion of the epiglottis.
The cases of nasal mucous lesion were routinely x-rayed (paranasal sinuses) for evaluation of purulent rhinitis and sinusitis. In a case with perforation of the nasal septum, bilateral obstruction and purulent secretion, ampicillin was initiated (50 mg/kg/day/via oral) for three weeks.
The side effects observed with pentavalent antimonial were arthralgia, myalgia, epigastralgia, migraine, constipation, anorexia, fever, rash, angioedema, elevation of urea, creatinine, transaminases, amylase and lipase, leukopenia, eosinophilia, electrocardiographic alterations (nonspecific alterations of the ventricular repolarization, ventricular extrasystole and prolongation of the segment QT). The case of angioedema with exclusively cutaneous form and a single episode, was successfully treated with corticoid and antihistamine, using a regimen similar to that of amphotericin B.
Oliveira Neto and col.,7,8 in Rio de Janeiro, treated the cutaneous form with SbV using an intramuscular dose of 3.8 to 8.8 mg/kg/day for 30 days; after five years, the lesions continued cicatrized and there was no mucous involvement. The use of doses below those recommended by the WHO/Health Ministry in patients with comorbidities appears to the author to be a safe alternative in the cutaneous form.
The side effects of amphotericin B are of two types: immediate, such as fever, chills, nausea and vomiting, that can be avoided with acetylsalicylic acid and antihistamine; and late by a cumulative effect with elevation of urea and creatinine, reduction in serum potassium and anemia. Phlebitis due to intravenous infusion of the drug can be avoided with application of local heat and administration of heparin and hydrocortisone in the serum. These are normally recommended for first applications with 0.25 mg/kg until a good tolerance is obtained, and is then increased 0.5 mg/kg and later to the maximum maintenance dose (1 mg/kg). Nevertheless, a dose of 0.5 mg/kg, in spite of prolonging treatment time, seems to the author to be a more simple management.
The patient that died presented more than 10 cutaneous lesions, characterizing the disseminated form. Multiple or disseminated lesions associated to infection by Leishmania braziliensis have been described.7 These cases are polymorphic and frequently associated to mucous involvement, Montenegro test is positive and there is good therapeutic response to antimonial.13
The course of the case to sepsis and death was not associated with the antimonial therapeutics. Urinary infection is the most frequent source of nosocomial infection. However, urinary sepsis now seems to be infrequent in seriously sick patients, except in a situation of obstruction or instrumentation of the urinary tract.14
The frequency and severity of the side effects maintain a direct relationship with the number of doses and duration of the treatment. They usually appear at the end of two weeks, when there is stabilization of the increasing serum level.5 Urticaria is considered rare, but anaphylactic shock can occur in the first applications.5
The prospective analysis of 48 cases registered at the Teaching Hospital Clementino Fraga Filho/UFRJ showed a profile of professional activities that corroborates the importance of peridomiciliary transmission; greater frequency of ulcers in the lower limbs and nasal mucous membrane; sensitivity of Montenegro test; and good response to antimonial and amphotericin B.
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Received on September 09, 2003.
Approved by the Consultive Council and accepted for publication on March 12, 2004.
* Work done at the Services of Dermatology and Pathological Anatomy, University Hospital Clementino Fraga Filho.