Recurrent American cutaneous leishmaniasis.

To the Editor: Leishmaniasis recidivans is an unusual clinical Old World disease primarily associated with Leishmania tropica (1). Recurrence of previously cured cutaneous leishmaniasis (CL) lesions is found in American CL, for which a specific nosologic form known of disease known as leishmaniasis recidiva cutis (LRC) has been identified. Although <30 cases of LRC have been reported from Brazil, Colombia, Peru and Ecuador; these cases were caused mainly by L. braziliensis, L. amazonensis, and L. panamensis (2). We report 7 cases of recurrent American CL caused by L. guyanensis in French Guiana.

Forty-eight military personnel who lived in France spent 3 months in French Guiana in 2004 and took part in a military training program in the rainforest for 15 days. Despite similar exposure conditions, American CL, confirmed by positive direct examination of Giemsa-stained tissue smears, developed in 21 persons. These patients were treated with 1 or 2 courses of either 3 intravenous or 2 intramuscular injections of pentamidine isethionate (4 mg/kg on alternate days). All lesions were cured 1-3 months after treatment had ended. Recurrence of the CL lesion was observed in 7 patients after a disease-free interval of 3-6 months (Table).

New lesions appeared on the edge of a healed scar for each patient, regardless of the location of the primary lesion (Table), and were diagnosed at Rennes University Hospital (positive direct examination or culture) in 2005. For positive cultures, L. guyanensis was identified by genomic and isoenzymatic characterization at the Centre National de Reference des Leishmania, Universite de Montpellier, Montpellier, France. Patients were treated with 4 intravenous injections of pentamidine isethionate (4 mg/kg every other day) and were cured without recurrence within 2 years. No differences in age or underlying diseases were noted in patients with recurrent CL.

L. (Viannia) guyanensis is highly prevalent in several leishmaniasisendemic areas of Brazil, Colombia, French Guiana, Guyana, Surinam, Peru, and Ecuador. This organism accounts for >95% of the 5 Leishmania species found in French Guiana, commonly causes localized LCL, and occasionally causes disseminated CL and mucocutaneous leishmaniasis (3). Dedet et al. reported that 6.8% of patients with CL caused by L. guyanensis had a recurrent lesion at the site of a previously cured lesion, which occurred after a mean interval of 7.3 months (4). A total of 33% of our patients had a cured primary infection in <3 months but they had a recurrence after a disease-free interval 3-6 months after treatment.

Additional information on such a recurrent form of CL is needed. Clinical symptoms in our patients were suggestive of LRC as described by Berlin (1), i.e., a recurrence at the site of an original ulcer, generally within 2 years and often on the edge of a scar. LRC may not be uncommon in the New World but rather underreported (2). Few cases of LRC have been reported; these were caused by L. braziliensis, L. amazonensis, and L. panamensis (2, 5, 6). In CL caused by L. guyanensis, borderline clinical symptoms prevent clear distinction of the recurrent form of LRC from early treatment failures or reinfections. In our patients, the risk for reinfection was excluded because the military personnel lived in France and left French Guiana several months before the recurrence.

Although pentavalent antimony is the recommended treatment for American CL, pentamidine isethionate is widely used in French Guiana. Retrospective analysis showed that 5%-25% of early treatment failures occurred after 1 or 2 intramuscular injections of 4-7 mg/kg of pentamidine isethionate, depending on different risk factors (7,8). Our observational study was not designed to evaluate treatment efficiency; we observed 2 (9.5%) of 21 early relapses and 7 (33%) of 21 late-onset recurrences in this series. Although we lacked statistical power because of small numbers, a difference was observed in recurrence by treatment method in 7 (44%) of 16 with recurrent disease who received 3 intravenous pentamidine isethionate injections compared with 0 (0%) of 5 who received 2 intramuscular injections. Re-treatment with a regimen of 4 intravenous injections of pentamidine, under medical surveillance because of possible adverse effects, cured the disease. Physicians in countries in which L. guyanensis is endemic should be aware of these complicated forms of CL after treatment, forms that prompt long-term follow-up and evaluation of specific therapeutic protocols.

Finally, the mechanism of late-recurring leishmaniasis is poorly understood. Mendonga et al. suggested that clinical cure of American CL is rarely associated with sterile cure (i.e., elimination of the parasite) (9). Immunologic data based on skin hypersensitivity and histopathologic and immunohistochemical findings support the concept that LRC is a late-onset reactivation after persistence of living parasites around or in cured leishmaniasis by as-yet unknown stimuli such as local trauma (2 of our patients reported chronic lesions of the chin caused by a razor blade and 2 others had chronically scratched the scar lesion on their ears) or corticosteroid, and after an incomplete host immune response to an earlier episode (2, 5,10). Further immunologic studies of patients and identification of genetic characteristics of L. guyanensis are needed to address this question.

Acknowledgment

We thank J.-P. Dedet for critically reviewing the manuscript.

References

(1.) Berlin C. Leishmania recidiva cutis. Leishmanid Arch Dermatol Syphilol. 1940;41:874-86.

(2.) Calvopina M, Uezato H, Gomez EA, Korenaga M, Nonaka S, Hashiguchi Y. Leishmaniasis recidiva cutis due to Leishmania (Viannia) panamensis in subtropical Ecuador: isoenzymatic characterization, Int J Dermatol. 2006;45:116-20.

(3.) Rotureau B, Ravel C, Nacher M, Couppie P, Curtet I, Dedet JP, et al. Molecular epidemiology of Leishmania (Viannia) guyanensis in French Guiana. J Clin Microbiol. 2006;44:468-73.

(4.) Dedet JP, Pradinaud R, Gay F. Epidemiological aspects of human cutaneous leishmaniasis in French Guiana. Trans R Soc Trop Med Hyg. 1989;83:616-20.

(5.) Oliveira-Neto MP, Mattos M, Souza CS, Fernandes O, Pirmez C. Leishmaniasis recidiva cutis in New World cutaneous leishmaniasis. Int J Dermatol. 1998;37:846-9.

(6.) Cannavo SP, Vaccaro M, Guarneri F. Leishmaniasis recidiva cutis. Int J Dermatol. 2000;39:205-6.

(7.) Lightburn E, Morand JJ, Meynard JB, Kraemer P, Chaudier B, Pages F, et al. Management of American cutaneous leishmaniasis: outcome of high-dose pentamidine isethionate treatment of 326 cases. Med Trop (Mars). 2003;63:35-44.

(8.) Roussel M, Nacher M, Fremont G, Rotureau B, Clyti E, Sainte-Marie D, et al. Comparison between one and two injections of pentamidine isethionate, at 7 mg/kg in each injection, in the treatment of cutaneous leishmaniasis in French Guiana. Ann Trop Med Parasitol. 2006;100:307-14.

(9.) Mendonca MG, de Brito ME, Rodrigues EH, Bandeira V, Jardim ML, Abath FG. Persistence of Leishmania parasites in scars after clinical cure of American cutaneous leishmaniasis: is there a sterile cure? J Infect Dis. 2004;189:1018-23.

(10.) Marovich MA, Lira R, Shepard M, Fuchs GH, Kreutzer R, Nutman TB, et al. Leishmaniasis recidivans recurrence after 43 years: a clinical and immunologic report after successful treatment. Clin Infect Dis. 2001 ;33:1076-9.

Jean-Pierre Gangneux, * Sylvie Sauzet, ([dagger]) Sebastien Donnard, ([dagger]) Nicolas Meyer, * Anne Cornillet, * Francine Pratlong, ([double dagger]) and Claude Guiguen *

* Centre Hospitalier Universitaire Faculte de Medecine de Rennes, Rennes, France; ([dagger]) Service Medical du 11eme Regiment d'Artillerie de Marine, Saint-Aubin du Cormier, France; and ([double dagger]) Universite de Montpellier, Montpellier, France

Address for correspondence: Jean-Pierre Gangneux, Laboratoire de Parasitologie-Mycologie, Hopital Pontchaillou, 2 Rue Henri Le Guilloux, 35033 Rennes CEDEX 9, France; email: [e-mail]

All material published in Emerging Infectious Diseases is in the public domain and may be used and reprinted without special permission; proper citation, however, is required.

Table. Epidemiologic characteristics, strain identification,
and treatment of 21 cases of American cutaneous leishmaniasis,
French Guiana, 2004-2005 *

                          Primary infection

             Lesion(s),         PI             Time to
Case          location       treatment          healed
no.            (no.)         ([dagger])      lesions, mo

1           Thorax (1)     IV, 4 mg/kg on         1
                           alternate days
                                x 3
2           Right          IV, 4 mg/kg on         3
            forearm (1)    alternate days
                                x 3
3           Left leg (1)   IV, 4 mg/kg on         1
            and chin (3)   alternate days
                                x 3
4           Chin (3)       IV, 4 mg/kg on         1
                           alternate days
                                x 3
5           Behind left    IV, 4 mg/kg on         1
            ear (1)        alternate days
                                x 3
6           Left ear (1)   IV, 4 mg/kg on         1
                           alternate days
                                x 3
7           Right ankle    IV, 4 mg/kg on        2.5
            (5)            alternate days
                                x 3
8-21        Various        IV, 4 mg/kg on        1-3
                           alternate days
                             x 3 (for 9
                            patients) or
                            IM, 4 mg/kg
                            on alternate
                           days x 2 (for
                            5 patients)
                             ([dagger])

                                            Leishmaniasis
                 Primary infection          recidiva cutis

Case        Disease-free       Direct           Strain
no.         interval, mo    examination     identification

1                4               +            Leishmania
                                              guyanensis
                                                MON-45
2                6               +          L. guyanensis
                                                MON-45

3                4               +             Negative
                                               culture

4                4               +             Negative
                                               culture

5                3               +          L. guyanensis
                                               MON-131

6                6               +             Negative
                                               culture

7                4               +             Negative
                                               culture

8-21             -               -                -

            Leishmaniasis recidiva
                     cutis
Case
no.         PI treatment      Outcome

1           IV, 4 mg/kg        Cured
            on alternate
              days x 4
2           IV, 4 mg/kg        Cured
            on alternate
              days x 4
3           IV, 4 mg/kg        Cured
            on alternate
              days x 4
4           IV, 4 mg/kg        Cured
            on alternate
              days x 4
5           IV, 4 mg/kg        Cured
            on alternate
              days x 4
6           IV, 4 mg/kg        Cured
            on alternate
              days x 4
7           IV, 4 mg/kg        Cured
            on alternate
              days x 4
8-21             -               -

* PI, pentamidine isethionate; IV, intravenous; IM, intramuscular.

([dagger])IV versus IM administration of pentamidine isethionate
was not associated with recurrent forms.