TRANSACTIONS OF THE ROYAI. SOCIETY OF TROPKAL

Long-term follow-up infection and treated

MEDICINE AND HYGIENE (1990) ‘34. 367-370

of patients with Leishmania with Glucantime’@

(Viannia)

braziliensis

E. M. Netto’, P. D. Marsden’, E. A. Llanos-Cuentas’, J. M. L. Costa’, C.C. Cuba’, A. C. Barreto’, R. Badarb3, W. D. Johnson’ and T. C. Jones2 ‘Nticleo de Medicina Tropical e Numpio, Universidade de Brasilia, DF, Brazil; ‘Division of International Medicine, Cornell University Medical College, New York, USA; ‘Universidade

Federal da Bahia,

Salvador,

Bahia,

Abstract Seventy-nine patients with cutaneous (62) or mucosal (17) infection with Leishmania (Viannia) braziliensis in Tr&s Brasos, Bahia, Brazil, were followed for at least 4 years after initiating treatment with antimony. Cutaneous relapses occurred in 6/62 (lo%), mucosal relapse after cutaneous infection in 2/62 (3%), and mucosal relapse after mucosal disease in 2117(17%). It is concluded that relapse (cutaneous and mucosal) is rare after adequate antimony therapy and that no definite prediction of relapse (clinical, serological or by skin reaction) is possible. Introduction LLANOS-CUENTAS(1984) concluded that clinical healing was still the best criterion of cure of mucocutaneous leishmaniasis. He studied 182 patients with cutaneous leishmaniasis over a 2-year period, and 57 with espundia for a 33-month period, in the area of Tres Braces, Bahia, Brazil, where Leishmania (Viannia) braziliensis is responsible for virtually all infections (LLANOS-CUENTAS et al., 1984; MARSDENet al:, 1984; ROSAet al., 1988). It is this parasite which 1s most often associated with relapse in the form of mucosal metastatic lesions. In this communication relapse is defined as reactivation at the same or another site after complete clinical healing, in contrast to patients who are either partially or completely unresponsive to initial treatment. We report here our follow-up of 62 (43%) of the original series of 145 patients with cutaneous diseasewho were treated with Glucantime@, and 17 (30%) of the patients with mucosal disease, over a period of at least 4 years. Materials and Methods Sixty-two patients with cutaneous disease and 17 with mucosal diseasemet the criteria for entering this study. These criteria were follow-up for at least 4 years (cutaneous) or 5 years (mucosal) after initial diagnosis of the primary lesion and diagnosis of leishmaniasis by clinical observation, parasite demonstration and/or positive immunological tests (Table 1). Patients were recorded on a clinical case report form giving clinical information relating to the size, site and nature of the skin or mucosal lesion, its duration, and previous treatment (if any) before consultation. A diagram of these features in the clinical record was annually updated. Patients were examined for evidence of erythema and/or infiltration of the original scar or the development of a fresh lesion. In patients with mucosal disease an anterior rhinoscopy was done, with examination of the mouth and throat. Indirect laryngoscopy was done and

Brazil

posterior rhinoscopy attempted. If an area of active granuloma was suspected this was biopsied. At the same time a leishmanin skin test was performed and seracollected for the indirect fluorescent antibody test (CUBA et a!., 1981). Only patients treated with Glucantime@were studied, since that is the most effective drug available to us. The total dosesof Sb’ prescribed were calculated for each patient. When Glucantime@ was not available, nifurtimox was given to the patients with cutaneous lesions in an oral dose of 10 mg/kg/d for 30 d. The patients receiving nifurtimox (MARSDENet al., 1979)have not been included in this analysis since this drug has only weak antileishmanial activity. Results Cutaneous disease

Eight of 62 patients (12.9%) had recurrences of their leishmaniasis after treatment of their primary skin lesion. In 2 patients (3.2%) relapse occurred in the mucosa. Of the other 6 patients, 4 (6.5%) had their relapse at the site of the original scar and 2 (65%) had cutaneous relapse at a new skin site (Tables 2 and 3). Table 3 shows the characteristics of the 10 patients who relapsed (8 cutaneous, 2 mucosal). The mean duration of disease, mean serological titre and the mean total dose of Glucantime@were all similar to those of the 56 who did not relapse, although relapsing patients had more Sb” after relapse and 2 of 6 remained active (Tables 3 and 4); these 2 patients were still serologically positive after 4 years’ follow up. In one of the 2 patients (AP) who had a mucosal relapse after cutaneous infection, it occurred during Table

1. Diagnostic

Type of disease Cutaneous Mucosal

details of patients

studied

No. of patients

Skin test positive

Serology positive

62 17

54 (87%) 16 (94%)

61 (98%) 16 (94%)

Demonstration of parasites 51 (82%) 13 (76%)

Table 2. Relapses rates in patients with cutaneous aad mucosai leishmanhsis Relapse Cutaneous Mucod Cutaneous Mucod Total

6 (9.7%)

2 (3.2%) 2 (11.8%)

10 (12.7%)

No relapse

Total

54 (87.1%) 15 (88.2%)

62 17

69 (87.3%)

79

368 Table 3. Details of ten patients with L. (v.) brainYen& infection who relapsed

Primary titre’

1 6 12

128 64 20

26 8 14

Frontal ulcer Leg ulcer 2 leg ulcers

4 30 6

2 new ulcers same site A new ulcer same site A new ulcer same site

160 80 20

17 17 51

Cured Active Cured

21 6

40 80 80

17 20

Knee Leg ulcer ulcer Left leg ulcer

36 2 39

A 66 new new ulcer lesionssame over site body Right leg ulcer

320 20 -

345 17

Cured Active

9/F 7/F

241

160

10 6

Gluteal Leg ulcer ulcer

37 5

NC N’

160 80

12b 13

Cured

49lM 24/M

24 12

649 320

43 86

N,PF N,P,F’

45 10

N,P,F,L’

640 320

100 179d

Active

Age/ Sex

Patient

Cutaneous JT 39lM AEA 12/M RCB 12/M % MPS

Time between freatment and relapse Clinical sign (months) of relapse

Disease duration (months) before treatment

23lF 13/M 17lF

Total Sb’ Initial primary infection (g) lesion

Total Sb’ Outcome 0” Relapse relapse A$ titre’ 1989 (9)

Cutsmous to mucosal ;: Mucossl g

‘Reciprocal of maximum the. %lucantime@ failed to cure; amphotericin B produced good outcome. ‘F=pharyngeal, L=laryngeal, N=nasal, and P=palatal granumomata. dAfter 84 d continuous therapy with Sb’ at 20 mgikgid the disease remained dormant for 29 months and then relapsed.

Table 4. Details

of patients

with cutaneous

disease

Mean Mean titre total No. of Mean age Duration of disease’ (reciprocal) Sb’ (g) patients (years) No relapse

6

54 (2%)

7

8

Relpase

$39)

17 (k%, 128 (4G-320)

17’

‘Mean duration of disease in months before first sign of clinical healing. ‘These patients received a mean of 17 g Sb’ before, and 23.5 g Sb after, relapse. Table

5. Details

of patients with mucosal disease Mean

Mean

titre total No. of Mean age Duration of patients (years) disease’ (reciprocal) Sb’ (g) No relapse

15 $50)

Relapse

(l-32770)

2 (2459)

(1254)

120 (&320) 480 (320-640)

33 202

‘Mean duration of disease in months before treatment.

the administration of Glucantime@after a total doseof 10 g Sb’. The patient received more Sb’ (12 g) but, becauseof the aggressive nature of the disease, was referred to the hospital for amphotericin B treatment, with a good outcome. The patient RCB was the only one to relapse several times at different skin sites. His casehistory has been described elsewhere (NETTO & MARSDEN, 1990), but an unusual clinical feature was a persistently negative leishmanin skin test. Mucosal disease

Of the 17 patients with mucosal disease,2 relapsed

(11.7%). These are detailed in Tables 2, 3 and 5. Higher total Glucantime@doses were used in these patients compared with the rest of the group. MB was the only patient to relapseafter 2.5 g of amphotericin B. The detailed serological results of both MB and JRS are shown in the Figure. In patient MB a negative serological titre was never recorded, in spite of 3 periods of clinical healing after specific therapy. JRS did show a significant drop in titre associated with healing, but the titre rose again associatedwith relapse 45 months later. Long-term skin ulceration.

We examined the records of the original series of 182 patients with cutaneous disease(LLANOS-CUENTAS, 1984; LLANOS-CUENTAS et al., 1984) and identified patients whose lesions failed to heal after the main follow-up period of 4 years and were recorded as still active. These are briefly described below. A 50 yearsold man with 10 years’ follow-up showed apparent healing of his leishmanial ulcer 4 months after 10 mg/kg of nifurtimox for 30 d. On the affected leg he developed a stasis ulcer within a year, which was erroneously recorded as a leishmanial ulcer for 9 years. A 24 years old man also had an open ulcer for 4 years, but examination showed a heavily cicatrized scar with a tiny deficiency in the centre exactly over the anterior edge of a prominent tibia. This opened and closed and obviously represented a point of great healing difficulty. He had been treated with 20 mg/kg of Sb’ (Glucantime@)for 10 d plus cryotherapy with liquid nitrogen. The latter may have causedexcessive scarring at a critical site. His serology has been negative for 4 years. The third oatient, a 63 Yearsold woman (FSC), was followed for- 5 yeais. Tfie strain isolated‘ from this patient was characterized as L. (V.) braziliensis by monoclonal antibody techniques. This patient appeared to have genuine recurrences. Throughout

369

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O* 320~

160ao4020O-. >

0

I

I

1

2

3

4

1

,

I

I

1

I

5

s

1

8

9

10

YEARS OF FOLLOWUP

Fiwre. Indirect fluorescent antibody titres (reciprocals) of hvo patients with mucosal diseaseduring ten years, follow-up, to show how titres rise wib clinical activity of the diseas;.

the 5-year follow-up period scarring occurred, but this was associated with persistent infiltration and sometimes hard keratinized nodules. On her last examination 5 years later, 3 such areasof activity were present within a scar9 cm in diameter below the right knee and biopsy showed i&&ration of the fibrosis tissue with round cells. In total she had received 5 courses of Glucantime@, 20 mg/kg/d of Sb’ on each occasion, for 10 d, but freely admits that sometimes she does not take all the course although side effects have not been a problem. It is planned to admit her to hospital for prolonged antimonial therapy. Discussion We have reported our recent results regarding unresponsiveness to various schedules of antimony therapy among hospital patients with mucosal leishmaniasis (SAMPAIOet al., 1986). However, follow-up of such patients is difficult and the data presented here regarding relapse come from our longitudinal study in the field area of Tres Braces. The most important finding is that detectable relapse is rare in the mucosa of patients treated for cutaneous disease with the antimony dosesindicated in Tables 2 and 3 followed for a 4-year period. Only 2 patients (3.2%) relapsed. LLANOS-CUENTAS(1964) concluded that repeated clinical examination was still the best way of detecting relapse, even though (asour Figure shows) a persistently raised immunofluorescent antibody (IFA) titre can be helpful in individual patients. Also, our retrospective analysis of mucosal patients suggests that after 4 years we would have seen at least 50% of

those who will relapse (LLANOS-CUENTAS,1984; LLANOS-CUENTAS et al., 1984).This meansthat, with longer follow-up, our figure of mucosal relapse could rise to 6%. LLANOS-CUENTAS(1984) has discussed the difficulties of ensuring regular therapy with Glucantime@ in this area. Thus, of 77 patients with cutaneous ulcers whose treatment was closely supervised, only 45% took the two courses of Glucantirne@ in the prescribed manner (LLANOS-CUENTAS et al., 1984). People with mucosal lesions tend to adhere more closely to the prescription but the same problems of compliance,.apply. The low incidence of recurrence in the mucosa is notable and in contrast to 18 patients treated with the weak anti-leishmanial agent nifurtimox (MARSDENet al., 1979). Of these, 3 patients developed mucosal disease(16*7%)-a significantly higher number than those treated with Glucantime@. This shows the danger of giving weak anti-leishmanial agents for cutaneous leishmaniasis due to L. (V.) braziliensis. The significance of inadequate or no therapy as a risk factor in the development of mucosal diseasehas been discussed elsewhere (LLANOS-CUENTAS et al., 1984; MARSDEN,1986). Much higher doses of Glucantime@were used for patients with established mucosal diseasewhen they initially consulted the clinic (Tables 4 and 5), and yet 2 patients (12%) relapsed, showing how unpredictable is the responseof this diseaseto therapy. One of these patients (MB) had received 84 days’ continuous therapy with the antimonial at a doseof 20 mg Sb”/kg

and appearedclinically cured, but after 2 years relapse et al., 1986). He was treated with occurred pentamidine and, as on previous occasions, had a good clinical response. This patient has had active mucosal disease now for nearly 20 years despite repeated antimonial and amphotericin B therapy. Currently he appears to have responded to pen&idine. There is no evidence of defective lvmnhocvte or macrophage function and he always has’ a strong positive leishmanin skin test. The number of cutaneous relapses was relatively small, and all except 2 of these relapses occurred at the site of the original skin lesion. LLANOS-CUENTAS (1984) recorded one case of relapse at a distant skin site, but it appears that relapses with L. (V.) bruziZiensis usually occur at the same site. This reinforces the view that this is relapse and not reinfection, which would not necessarily occur at the same site. This is our impression also from the retrospective survey of caseswith prolonged activity of more than a year; the lesions continue to extend slowly from the site of inoculation. We have recorded elsewhere our only patient (RCB) with multiple skin relapse, who always had a negative Montenegro reaction. Skin ulceration in 3 patients persisted longer than the mean follow-up period of 4 years. Two of these did not indicate persistenceof the leishmaniasis, showing the value of an experienced observer, but patient FSC was a genuine case of leishmaniasis recidivans. Since clinical evaluation is a crude measure of parasite cure we hope, like WALTON (1980), that the indirect immunofluorescence test will act as a warning signal for reactivation. In individual cases such ai those illustrated in the Fiaure. this test is valuable. as we have previously shown (~ARSDEN et al., 1979). However, looking at the groups as whole, there are still many positive serum reactors after a considerable time in the group of patients who did not relapse (Tables 3,4 and 5). We are still examining the results of serial IFA tests over a IO-year period to ascertain the value of this test as a prognostic guide. A more sensitive test is the Leiskmania-specific immunoglobulin G enzyme-linked immunosorbent assay, which indicates patients with significant serology but no evidence of clinical activity. We must perfect our clinical evaluation with a modern rhinoscope and repeat the follow-up of our patients to gain further information, but it is doubtful whether the basic messageof -this communication will be changednamely that relapse of L. (V.) bruziliensis infection after adequate antimonial treatment is rare. The fact that some patients may have taken less than the prescribed dosemakesthis finding even more significant. Similar data over a short period exist from Colombia in an area where L. b. panamensis is the

dominant parasite (WEIGLEet al., 1985). To date no mucosal relapse has been reported from this area, where espundia is much less common than in Tres Braces. Acknowledgement

This work wassupportedby grant AI 16282from the US National Institute of Allergy and Infectious Diseases. References

Cuba, C. C., Marsden, P. D., Barreto, A. C., Rocha, R., Samnaio. R. N. & Parzlaff. L. (1981). Parasitoloaical and imnknoloeical diaanosis ‘of American mucoc&neous leishman&is. Bulletin of the Pan American Health Organization,

15, 249-259.

Llanos-Cuentas, E. A. (1984). Estudo clinico evolutivo da leishmaniose em circa end&&a de leishmaniose braz&nsis braziliensis, Tr& BraGos, Bahia. Thesis, University of

Brasilia. Llanos-Cuentas, E. A., Marsden, P. D., Lago, E. L., Barreto, A. C., Cuba, C. C. & Johnson, W. D. (1984). Human mucocutaneous leishmaniasis m Tres Braces, Bahia-Brazil. An area of Leishmania braziliensis braziliensti transmission. II. Cutaneous disease.Presentation and evolution. Revista da Sociedade Brasilkra de Medicina Tropical, 17, 169-177. Marsden, P. D. (1986). Mucosal leishmaniasis (“espundia” Escomel, 1911). Transactians of the Royal So&y of Tropical Medicine and Hygiene, 80, 859-876.

Marsden, P. D., Cuba, C. C., Barreto, A. C., Sampaio, R. N. & Rocha?R. (1979). Nifurtimox in the treatment of South American leishmaniasis. Transactions of the Royal Society of Tropical Medicine and Hygiene, 73, 391-394. Marsden, P. D., Llanos-Cuentas, E. A., Lago, E. L., Cuba, C. C., Barreto, A. C., Costa, J. M. L. & Jones, T. C. (1984). Human mucocutaneous leishmaniasis in T&s Braces, Bahia-Brazil. An area of Leishmania braziliensis bruziliensistransmission. III. Mucosal disease: presentation and initial evolution. Rezista da Sociedade Brasiliera de Medieinc Tropical, 17, 179-186. Netto, E. M. & Marsden, P. D. (1990). An unusual relapsing caseof skin leishmaniasis. Revista da Sociedade de Bra&era Medicina Tropical, in press. Netto, E. M., Cuba, C. C., Costa, J. M. L., Barreto, A. C., Rosa, C. & Marsden, P. D. (1986). Recurrence of South American tegumentary leishmaniasis. Lancer, i, 501. Rosa, A. C., Cuba, C. C., Vexenat, A., Barreto, A. C. & Marsden, P. D. (1988). Predominance of Leishmania braziliensis braziliensis in the regions of Tres Braces and Cone de Pedra, Bahia, Brazil. Transactions of the Royal Sociery of Tropical Medicine and Hygiene, 82, 409-410. Sampaio, R. N., Sampaio, J. H. D. & Marsden, P. D. (1986). Pentavalent antimonial treatment in mucosal leishmaniasis. Lancer, i, 1097. Walton, B. C. (1980). Evaluation of chemotherapy of American leishmaniasis by the indirect fluorescent antibody test. American 3ourn~l of Tropical Medicine and Hygiene, 29, 747-752.

Weigle, K. A., Walderrama, L., Santrich, C. & Saraiva,N. G. (1985). Recurrence of tegumentary leishmaniasis. Lancet, ii, 557-558.

Received 1 September 1989; revised 8 December 1989; accepted for publication 19 December 1989