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septal perforation moderate, and more than one mucosal site severe.13 The time of evolution of the mucosal and active cutaneous lesions, and the time interval ...
Am. J. Trop. Med. Hyg., 59(1), 1998, pp. 49–52 Copyright q 1998 by The American Society of Tropical Medicine and Hygiene

MUCOSAL LEISHMANIASIS DUE TO LEISHMANIA (VIANNIA) PANAMENSIS IN COLOMBIA: CLINICAL CHARACTERISTICS LYDA ELENA OSORIO, CARMEN MANUELA CASTILLO, AND MARIA TERESA OCHOA Centro Internacional de Entrenamiento e Investigaciones Me´dicas (CIDEIM), Cali, Colombia

Abstract. The Leishmaniases are a group of diseases whose clinical presentation is in part determined by the infecting species. Until recently, mucosal leishmaniasis was attributed exclusively to Leishmania (Viannia ) braziliensis; however, the capacity of other species of the subgenus Viannia to invade mucosal tissue has been documented. This report examines the clinical characteristics of 23 parasitologically diagnosed patients with mucosal leishmaniasis due to L. (V.) panamensis from the Pacific Coast of Colombia seen at CIDEIM between 1985 and 1996. Most of the mucosal lesions 74% (17 of 23) were mild, with a short time of evolution (median 5 2.5 months) and were present concomitantly with an active cutaneous lesion in 61% (14 of 23) of the cases. The simultaneous presentation of mucosal and active cutaneous lesions contrast with classical descriptions of mucosal leishmaniasis caused by L. (V.) braziliensis, and highlights the importance of early diagnosis of mucosal disease by the examination of mucosa in all cases of cutaneous leishmaniasis. Mucosal leishmaniasis is the most serious clinical form of tegumentary leishmaniasis. This disease presentation requires prolonged and closely supervised treatment and an incomplete treatment can lead to severe sequelae and even death.1 Until recently, the mucosal involvement of leishmaniasis in America was attributed exclusively to Leishmania (Viannia) braziliensis. However, the capacity to invade mucosal tissue by dissemination via blood, lymph, or by extension has been documented for other species of the Viannia subgenus: L. panamensis and L. guyanensis.2–5 Mucosal leishmaniasis due to L. mexicana and L. amazonensis of the subgenus Leishmania has also been reported.6, 7 The current concept is that most of the New World Leishmania species appear capable of producing a spectrum of disease manifestations, depending on the immune status of the host, parasite strain, and external factors such as anatomic exposure.8 Mucosal leishmaniasis due to L. (V.) braziliensis has been characterized as a chronic, severe and destructive disease that occurs several years after a skin lesion has healed. In contrast, the mucosal involvement caused by L. (V.) panamensis has been insufficiently studied and has been associated with less severe pathology, possibly because of lower virulence. Consistent with this possibility, infection with L. (V.) panamensis results in less reactogenic responsiveness than L. (V.) braziliensis. This is evident by a lower response to intradermally applied Leishmania antigens (leishmanin) and by lower in vitro lymphocyte proliferation in response to Leishmania antigen in patients infected with L. (V.) panamensis when compared with those infected with L. (V.) braziliensis.9 In the present study, we report the principal characteristics of mucosal leishmaniasis caused by L. (V.) panamensis among residents of the Colombian Pacific Coast.

skin biopsies obtained from the lesion borders. Following local anesthesia, two biopsies were obtained from patients with mucosal lesions suggestive of leishmaniasis. One biopsy was used for culture and for inoculating golden hamsters, the other was used for histopathologic study using a standard hematoxylin and eosin stain.10, 11 Signed informed consent was obtained from each patient. Species identification. Characterization of isolates was accomplished using monoclonal antibodies in a standard indirect ELISA12 and/or by isoenzymatic analyses.2 Phenotypic comparison of strains isolated from cutaneous and mucosal lesions was based upon six enzymes that are polymorphic in species of the Viannia subgenus. These are phosphoglucomutase (PGM, E.C.2.7.5.1), mannose phosphate isomerase (MPI, E.C.5.3.1.8.), glucose-6-phosphate dehydrogenase (G6PD, E.C.1.1.1.49), nucleoside hydrolase (NH, E.C.3.2.2.2), phosphogluconate dehydrogenase (6PGD, E.C.1.1.1.44), and superoxide dismutase (SOD, E.C.1.15.1.1). Statistical analysis. Only patients from whom L. (V.) panamensis was isolated and identified from mucosal lesions were included in this case series. Demographic information, clinical characteristics of mucosal lesions, as well as time of evolution and localization of cutaneous and mucosal lesions were included. Epi-Info version 6.04 (Centers for Disease Control and Prevention, Atlanta, GA) was used for the descriptive analysis. The lesions were grouped by level of severity as follows: limited to a single mucosal site 5 mild, septal perforation 5 moderate, and more than one mucosal site 5 severe.13 The time of evolution of the mucosal and active cutaneous lesions, and the time interval between healing of cutaneous lesions and mucosal involvement were tabulated for each group. A nonparametric test (Kruskall-Wallis) was used to compare severity level (mild and not mild) and time of evolution of mucosal lesions.

PATIENTS, MATERIALS, AND METHODS

RESULTS

Study population. Fifty-eight clinical histories of patients with mucosal leishmaniasis evaluated in the clinical units of CIDEIM in Cali and Tumaco, both serving the Colombian Pacific Coast, between January 1985 and December 1996 were reviewed. Cutaneous leishmaniasis was diagnosed by Giemsa-stained smear, culture of aspirated tissue fluid, and

Of the 58 cases with mucosal leishmaniasis, 40 (69%) had a parasitologic diagnosis and the parasite isolated from the mucosa was identified in 30 cases: 23 L. (V.) panamensis, six L. (V.) braziliensis, and one L. (V.) guyanensis. Most of the 23 patients from whom L. (V.) panamensis was isolated from mucosal lesions were adults (age range 5

49

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TABLE 1 Demographic aspects and localization of cutaneous lesions in patients with mucosal leishmaniasis due to Leishmania (Viannia) panamensis Characteristic

No.

%

Gender Male Female

15 8

65 35

Race Black Mestizo White Indigenous

17 3 2 1

74 13 9 4

Age (years) ,15 15–45 .45

4 13 6

17 57 26

Localization of cutaneous lesions Active* Face (contiguous) Face (not contiguous) Upper extremities Lower extremities Trunk

36 4 11 11 6 4

Scars* Face (contiguous) Upper extremities Lower extremities Trunk

TABLE 2 Frequency of affected mucosal tissue and clinical presentation of the mucosal lesions in patients with mucosal leishmaniasis due to Leishmania (Viannia) panamensis Localization of mucosal lesion

Nasal tissue

9 1 4 2 2

* Four patients with multiple active cutaneous lesions and two patients with multiple scars.

7–71 years old, median 5 30 years old), black 74% (17 of 23) and males 65% (15 of 23). The majority (91%, 21 of 23) of the patients had evidence of cutaneous lesions (active or healed), which were located in most cases on the face or upper extremities. Only five cutaneous lesions (four active and one healed) were located contiguous to the mucosal tissue (Table 1). The 23 patients presented a total of 27 mucosal lesions. The nasal septum was the most common localization of mucosal lesion when presented as a single lesion (11) or multiple lesions: septum and turbinate (4) and septum, turbinate and larynx (1). Involvement of the larynx was determined clinically by erythema and swelling of ariepiglotic folds, but laryngoscopy was performed only in four patients. Mucosal lesions appeared more frequently as an ulcer (10), erythema (5) or septal perforation (4) and less frequently as decreased thickness of septum, crust, or granuloma; bleeding was rare (1) (Table 2). Mucosal lesions showed a wide spectrum of clinical severity, with the mild forms being more frequent (74%) than the moderate (17%) or severe (9%) manifestations. The mean duration of mucosal lesions at diagnoses was 23 months, however, lesions evolved over a period of less than one month to 10 years (median 5 4.5 months). Mild lesions more frequently had a short time of evolution and were present concomitantly with active cutaneous lesions of a duration of six months or less. A significant difference (P , 0.05) was observed between the mild and moderate or severe groups with respect to the time of evolution of the mucosal lesions (Table 3). With respect to the relationship between

Septum Turbinate Septum and turbinate

Oral mucosa or lips involving oral mucosa Both Lips and nasal mucosa (nasal and oral) Septum, turbinate, and larynx

N 5 23

%

11 3 4

48 13 18

3 1 1

13 4 4

Characteristic of mucosal lesion

N 5 27

%

Ulcer Erythema Septal perforation Septal perforation and crust Erosion of septum without perforation Granuloma Crust Bleeding and crust Swelling in the ariepiglotic fold and erythema

10 4 3 1 3 3 1 1 1

37 14 11 4 11 11 4 4 4

cutaneous and mucosal lesions, 14 (61%) patients showed simultaneous active lesions, four (17%) had typical scars, and three (13%) had both active and healed cutaneous lesions. Of the two patients not presenting cutaneous lesions, one had a confirmed cutaneous leishmaniasis that was undertreated with meglumine antimoniate (Glucantime;y Rhone-Poulenc, Paris, France) and developed a mucosal disease six months later; the second patient did not have a report of a previous lesion. The time of evolution of the cutaneous lesions in those patients with simultaneous active lesions (14) ranged between one week and 60 months, with 80% being # six months. On the other hand, the mucosal involvement in four patients with a typical scar14 appeared 6–24 months after healing of the primary cutaneous lesion (Table 3). Isoenzyme polymorphism characterization with the six most discriminatory enzymes for L. (Viannia) species showed that strains isolated from cutaneous and mucosal lesions from each patient were phenotypically identical corresponding to L. (V.) panamensis in the six analyzed. Similarly isolates characterized from a draining lymph node, and cutaneous and mucosal lesions from the another patient showed the same isoenzyme phenotype, which was characteristic of a variant of L. (V.) panamensis (Saravia N, CIDEIM unpublished data). DISCUSSION

The production of mucosal disease by L. (V.) panamensis has been recently recognized, yet it is poorly described. Increased knowledge about the clinical presentation is important in early recognition and treatment of the disease. This report indicates that in the Pacific Coast Region of Colombia, L. (V.) panamensis is more frequently isolated from patients presenting mucosal lesions than L. (V.) braziliensis or L. (V.) guyanensis. The mucosal lesions observed in the patients infected with L. (V.) panamensis tend to be less destructive and to appear concomitantly with an active cutaneous lesion.

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TABLE 3 Relationship between severity of the mucosal lesions and the time of evolution of the mucosal and cutaneous (active or healed) lesion in patients with mucosal leishmaniasis due to Leishmania (Viannia) panamensis*

Severity level†

No.

Mild Moderate Severe Total

17 4 2 23

Median duration of mucosal lesions at diagnosis, Only active months (range) cutaneous lesions

2.5 (,1–60)‡ 60 (48–120) 6 (6) 4.5

12 1 1 14

Interval of time (months) between healing of cutaneous lesion and development of mucosal lesion

Evolution time (months) of active cutaneous lesion #6

8/10§ NA 1 9/11

.6

Only scars

#6

.6

2/10 1 NA 3/11

1 2 1 4

NA NA 1 1

1 2 NA 3

* NA 5 not applicable. † Mild 5 limited to one mucosal site; moderate 5 only septum perforation; severe 5 more than one mucosal site (nose-lips and nose-larynx).12 ‡ Difference between the mild and moderate or severe groups for time of evolution of the mucosal lesions P , 0.05, by Kruskal-Wallis test. § Number of patients with characteristics divided by the number of patients for whom data was available.

In the group of patients infected with L. (V.) panamensis that we analyzed, 61% presented cutaneous and mucosal lesions simultaneously. This finding contrasts with the presence of a scar in 70–90% of patients infected with L. (V.) braziliensis.1, 15, 16 Such a difference cannot be explained by the total proportion of patients with a previous cutaneous lesion, which was similar for both L. (V.) braziliensis and L. (V.) panamensis cases. Saenz and others reported that 76% of the mucosal cases due to L. (V.) panamensis had scars as evidence of prior cutaneous disease.14 Our findings of concomitant active lesions in skin and mucosa in patients seeking medical care only for cutaneous lesions suggest that early in the evolution of mucosal disease active cutaneous disease coexists. Weigle and others reported 63% of mucosal disease to present with simultaneous active cutaneous. The latter cases were detected by an active search for patients in the Colombian Pacific Coast where both L. (V.) panamensis and L. (V.) braziliensis are prevalent.17 In that study, the species producing simultaneous cutaneous and mucosal lesions were not indicated; therefore, our findings could reflect characteristics particular to the population or parasite strains in the region rather than a species related difference. However the active search for cases also favors early diagnosis, and conceivably favors the description of early events in the natural history of mucosal leishmaniasis. The concomitance of mucosal and cutaneous disease suggests that mucosal involvement occurred soon after a skin lesion appeared without a long latent period. The ability of the L. (V.) panamensis to invade mucosal tissue from distant cutaneous lesions was corroborated by noncontiguous localization of skin lesions and the identification of identical isoenzymatic profile for parasites isolated from both lesion sites and the draining lymph node. The phenotypic identity of paired strains from mucosal and cutaneous lesions indicates the metastatic dissemination of parasites from cutaneous sites to mucosal tissues, as corroborated by Saravia and others.2 Mucosal cases with healed cutaneous lesions (four) in this case series were few and the interval between mucosal disease and healing of the skin lesion was shorter than reported by Marsden and others16 and Jones and others18 in patients infected with L. (V.) braziliensis. Nevertheless, the ability of L. (V.) panamensis to remain latent during long periods of time after healing a cutaneous lesion has been reported in recurrent cases by Saravia and others.19 Similar to previous studies in Brazil, we found patients without evidence of cu-

taneous lesions. Although cutaneous lesions that do not leave a typical scar are considered rare,1 they can occur as reported in this study. Subclinical infection could also explain the lack of a history of a cutaneous lesion from patients with mucosal leishmaniasis.20 Exogenous factors such as trauma, altered immunocompetence, or a concomitant unrelated illness may be precipitating factors to disease expression following latent infection.1 In those cases in which active dermal lesions are accompanied by scars, it is not possible to determine which episode of infection is responsible for the mucosal involvement unless isoenzyme or other distinguishing polymorphism of strains isolated from the cutaneous and mucosal lesions are compared. The feasibility of isolating and comparing parasites from lesions that occur years apart in individuals with limited access to health care is remote. Nevertheless the polymerase chain reaction combined with restriction analyses may allow organisms persisting in a scar or present in an active cutaneous lesion to be identified without isolation,21 thereby allowing comparison with organisms present in active mucosal lesions. Localization of mucosal lesions was similar to that reported by Marsden and others16 and Jones and others,18 whose findings indicated the nasal septum as the area most frequently involved. A complete examination of the upper respiratory tract of patients with mucosal leishmaniasis is necessary to establish the extension and severity of the disease. Larynx involvement was found only when multiple lesions were present, although laryngeal lesions in the absence of other mucosal lesions have been reported.18 As reported by Saenz and others,14 mucosal lesions caused by L. (V.) panamensis are mild (limited to one mucosal surface) in the majority of patients. Other mucosal tissue involvement or complications, such as perforation of the septum (17%), are less frequent than in mucosal lesions due to L. (V.) braziliensis.13, 15, 16 Differences in the clinical presentation of the mucosal disease caused by L. (V.) panamensis and L. (V.) braziliensis have been reported by Weigle and others20 and postulated to be related to the capability of inducing a destructive immune response.9 However, since the time of evolution of mucosal lesions was associated with the severity in this cases series, the mild mucosal lesions could be explained by early diagnosis, and consequently, a short time of evolution. Because the patients with severe lesions appeared to have a shorter time of evolution than those with moderate lesions, the duration of the disease, although im-

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portant in the clinical course of mucosal lesions, may have been just one factor among others such as the host immune response and the parasite virulence. The pathogenesis of mucosal leishmaniasis has not yet been elucidated. Notwithstanding, factors other than the infecting species have been associated with disease severity. For example, in Bolivia where L. (V.) braziliensis is prevalent, Walton and others reported that individuals of African ancestry present more aggressive mucosal lesions than indigenous patients.22 Localization of cutaneous lesions on the upper half of the body has been reported as a risk factor for mucosal leishmaniasis.23 In this case series most of cutaneous lesions were located on the face and the upper extremities, but these findings were similar to those in patients with cutaneous or mucocutaneous leishmaniasis from the Pacific Coast of Colombia. Gender and age were also comparable to patients with cutaneous lesions only.20 A case-control study may clarify the role of these or other risk factors. In conclusion, the evidence for development of mucosal lesions concomitantly with cutaneous lesions highlights the importance of examining the mucosal tissue in all patients with active cutaneous leishmaniasis and indicates that even early inflammatory changes of the mucosa should be carefully evaluated. Acknowledgments: We thank The Hospital San Andre´s de Tumaco and Servicio de Otorrinolaringologı´a-Hospital Universitario del Valle for collaboration in the evaluation of patients. We appreciate the assistance of Iris Segura and Jaime Mun˜oz in the phenotypic analysis of strains, and Dr. Nancy Saravia for her helpful discussion and review of manuscript. Financial support: This work was supported by COLCIENCIAS contract # 2229-04-001-92, the National Institute of Allergy and Infectious Diseases, the Institute for Collaborative Infectious Disease Research, and the Tropical Medicine Research Center International Development Research Center Phase II. Authors’ address: Lyda Elena Osorio, Carmen Manuela Castillo, and Marı´a Teresa Ochoa, CIDEIM, Avenida 1 Norte # 3-03, Cali, Colombia. REFERENCES

1. Marsden P, 1986. Mucosal leishmaniasis (‘‘Espundia’’ Escomel, 1911). Trans R Soc Trop Med Hyg 80: 859–876. 2. Saravia N, Holguı´n A, McMahon-Pratt D, D’Alessandro A, 1985. Mucocutaneous leishmaniasis in Colombia: Leishmania braziliensis subspecies diversity. Am J Trop Med Hyg 34: 714–720. 3. Saenz RE, De Rodriguez CG, Johnson CM, Berman JD, 1991. Efficacy and toxicity of Pentostam against Panamian mucosal leishmaniasis. Am J Trop Med Hyg 44: 394–398. 4. Naiff RD, Talhari S, Barrett V, 1988. Isolation of Leishmania guyanensis from lesions of the nasal mucosa. Mem Inst Oswaldo Cruz 83: 529–530. 5. Santrich C, Segura Y, Arias A L, Saravia N, 1990. Mucosal disease caused by Leishmania braziliensis guyanensis. Am J Trop Med Hyg 42: 51–55.

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