An Investigation of Mucosal Leishmaniasis in the Military Health System

ABSTRACT

Leishmaniasis is a protozoal infection with an increased risk of transmission to those serving in the U.S. Military due to theaters of operation in endemic regions. There has, in recent decades, been robust experience with old-world leishmaniasis in the Military Health System (MHS); however, new-world leishmaniasis, which may result in mucosal leishmaniasis, has been less studied. A total of 88 patients from 2012 to 2022 with diagnosis codes for “mucocutaneous leishmaniasis” or “leishmaniasis, unspecified” were identified in the Military Data Repository and reviewed. Within this cohort, upon medical records review, there were 2 cases of leishmaniasis that met inclusion criteria. Case 1 was a 28-year-old active duty male with recent travel to Belize who presented with a mucosal lip lesion that was biopsied and had inconclusive species confirmation but was thought to be either L. braziliensis or L. mexicana. The second case involved a 30-year-old active duty male with a history of travel to French Guiana who had a cutaneous lesion on his left hand that was identified as L. guyanensis, a causative species for mucosal leishmaniasis. Neither had evidence of any further mucosal involvement on otolaryngologic evaluation, and both subsequently received systemic therapy with a good clinical response. Although only 2 cases were identified over an 11-year period, this disease remains an important medical consideration when conducting military operations within Central and South America, as both cases had recent military-specific travel to areas endemic for leishmaniasis.

INTRODUCTION

The Military Health System (MHS) has been greatly burdened by old-world leishmaniasis in the 20th and 21st century. Deployments to endemic regions, particularly Middle Eastern countries, led to high rates of exposure and subsequent disease, totaling over 2,000 incident diagnoses of leishmaniasis in a 15-year period.^1–3 The causative protozoal parasites, predominantly Leishmania (L.) major, L. tropica, and L. infantum, endemic to the region lead to cutaneous and/or visceral leishmaniasis, depending on the species. Transmission is through the bite of a sandfly, and as no chemoprophylaxis or vaccination has been developed, preventative measures largely focus on bite avoidance and vector control.^4,5 Due to this, while there is significant experience and research focused on old-world leishmaniasis, relatively little has been reported recently from the MHS on its new-world counterpart.^6,7

New-world leishmaniasis, with cutaneous, visceral, and mucosal forms, is caused by 18 or more different species but results most frequently from infection by L. (Viannia) mexicana, L (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, L. (V.) mexicana, and L. infantum/ L.chagasi.⁸ Mucosal leishmaniasis, caused by L. (V.) braziliensis, L. (V.) guyanensis, L. (V.) panamensis, and L. amazonensis, may, in its early stages, present solely as cutaneous disease with either an undifferentiated or typical cutaneous ulcerative lesion. Cutaneous lesions may coincide with or be followed, sometimes separated by many years, mucosal lesions of the nasal passages or oropharynx. This mucosal involvement can lead to a wide array of symptoms including nasal congestion, obstruction, and epistaxis. Unlike the isolated cutaneous form, mucosal leishmaniasis is unlikely to resolve without intervention and, if left untreated, can progress to the destruction of the mucosal tissues in the head and neck, such as the nasal septum, palate, pharynx, and larynx. Evaluation and treatment can be time-, labor-, and cost-intensive, requiring the efforts of multiple medical/surgical specialists. Thus, the evaluation for and management of mucosal leishmaniasis has the potential to place a large strain on health care resources, particularly in austere environments, and to cause significant morbidity when the diagnosis is delayed or treatment is unavailable. While there is presently a relatively low U.S. Military presence in areas of mucosal leishmaniasis endemicity within Central and South American countries (Figure 1), theaters of operation for U.S. personnel are vast and continually changing. Thus, this study and report aim to describe recent cases suspicious for mucosal leishmaniasis in the MHS, as well as to highlight some management considerations unique to leishmaniasis in the Americas.

Figure 1.

Major geographic distribution of leishmania species that cause mucosal leishmaniasis: Leishmania braziliensis, L. guyanensis, L. panamensis, and L. amazonensi.

Map adapted from data distributions presented in: Aronson NE and Magill AJ (2020) Leishmaniasis. In: Hunter’s Tropical Medicine and Emerging Infectious Diseases. Tenth Edition. Elsevier: Philadelphia, and van Hees, C.L.M., Naafs, B. (2016). Cutaneous Leishmaniasis. In: Antibiotic and Antifungal Therapies in Dermatology. Springer, Switzerland.

METHODS

Case Identification

The MHS Data Repository (MDR) was used to identify patient encounters that occurred both in the MHS and the civilian network. Direct care provided in the MHS was collected through the Standard Inpatient Data Record (SIDR) and the Comprehensive Ambulatory Provider Encounter Record (CAPER). The former captures inpatient encounters at military treatment facilities (MTF) whereas the latter provides data on outpatient visits within the MHS. Out-of-network or purchased care files were accessed through TRICARE Encounter Data- Institutional (TED-I) and Non-Institutional (TED-NI). These represent encounters that sent claims to TRICARE for out-of-network care, with TED-I being inpatient care settings and TED-NI being non-inpatient encounters. A query was conducted through the MDR using these data files to identify patient encounters from 2012 to 2022 with the International Classification of Diseases (ICD)-10 diagnoses codes for mucocutaneous leishmaniasis (B55.2) or leishmaniasis, unspecified (B55.9).

Case Investigation

Patients who were identified through the MDR query underwent a retrospective chart review through the electronic medical record. The review was performed to identify the specific encounter coded as well as relevant preceding and succeeding visits to assess if there was suspicion for mucosal leishmaniasis through the following definition:

1. A medical encounter from 2012 to 2022 with an ICD-10 code B55.9 Mucocutaneous Leishmaniasis or B55.2 Leishmaniasis, unspecified.

1. A documented report of an infection by a causative species of mucosal leishmaniasis.

Case Reporting

If a patient met the working case definition for suspicion of mucosal leishmaniasis, a more detailed chart review was conducted. Research Electronic Data Capture (REDCap) was used to collect and consolidate several measures for each case. Patient information such as demographics, military status, potential exposures, travel, and medical history were gathered. Specific clinic encounters were reviewed to determine symptomatology, diagnostic measures undertaken, treatment received, and the extent of follow-up to comprise a thorough case report on each.

Regulatory considerations: This work is a subset of the Deployment and Travel Medicine:

Knowledge, Attitudes, Practices, and Outcomes Study (KAPOS), which is approved by the Institutional Review Board of the Uniformed Services University of the Health Sciences. KAPOS is a retrospective cohort study that evaluates travel-associated disease across U.S. Department of Defense beneficiaries and receives financial support through the Infectious Disease Clinical Research Program, a Department of Defense program executed through the Uniformed Services University of the Health Sciences through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health [Inter-Agency Agreement Y1-AI-5072], and from the Defense Health Program, U.S. Department of Defense [HU0001190002].

RESULTS

In total, there were 88 unique individuals identified through the MDR from 2012 to 2022, with nearly half (43/88) having direct care encounters in the MHS facilities (Figure 2). Of the 88 reviewed, 79 were coded as ICD-10 B55.9: leishmaniasis, unspecified, which were distributed as follows: no record of leishmaniasis identified (16), asymptomatic screening for leishmaniasis (21), confirmed case of cutaneous leishmaniasis from a species not associated with mucosal leishmaniasis (9), other unspecified conditions (3), confirmed case of visceral leishmaniasis (1), and a single suspected case of mucosal leishmaniasis (1). Nine cases were identified through ICD B55.2 mucocutaneous leishmaniasis with the following distribution: no patient record available for review (4), no record of leishmaniasis identified (3), other unspecified condition (1), and a single suspected case of mucosal leishmaniasis (1). Of the 32 individuals who had no patient record found, over half were non-service members (18/32). The 2 cases identified, one from each ICD code, are further detailed below in the report of cases.

Figure 2.

Distribution of identified cases.

Flow chart of patients meeting inclusion criteria through chart review to identification of cases suspicious for mucosal leishmaniasis (ML). Horizontal exits from the flow chart represent those further excluded from the study, with its justification listed below. Complete vertical progression through the flow chart indicates those meeting the definition for suspected cases of ML and thus underwent case reporting.

REPORT OF CASES

Case 1

This involves a 28-year-old active duty male who had recently completed a 1-month jungle warfare course in Belize. He presented to the Emergency Department 2 months after returning for a nonpainful, nodular lesion on the vermillion border of his left upper lip that progressed to a 1.5 × 1.5 cm ulcer. It had failed to respond to topical antivirals, and he was prescribed valacyclovir in the emergency department for presumed herpes simplex virus. The lesion worsened, becoming painful with buccal mucosal involvement and submandibular lymphadenopathy. He was then referred by primary care to dermatology and oral surgery for a biopsy. Upon dermatologic evaluation, he reported soreness and swelling of his lip, with recent oozing of serous fluid. At that time, he denied any nasal/postnasal drainage, nasal congestion, sinus pain, unusual bleeding, or constitutional symptoms. His biopsy revealed leishmaniasis, thought to be L. mexicana or L. braziliensis; however, culture and polymerase chain reaction (PCR) were unable to confirm the species. He underwent nasopharyngoscopy by otolaryngology, which revealed no further mucosal lesions down to the glottis. The patient was then treated by the infectious disease service with liposomal amphotericin, which was at the time emerging as a treatment alternative to sodium stibogluconate.⁹ He received 3 mg/kg on days 1 to 5 and 10 with complete resolution of the lip lesion within 4 to 6 weeks. At 3- and 6-months post-treatment, the patient developed painful lesions on the left upper extremity and right lower extremity, respectively. His left arm lesion was biopsied, cultured, and underwent PCR, again confirming Leishmania at the genus level. The arm lesion was treated with cryotherapy whereas the leg lesion was left untreated. Throughout this period, he did not develop any further mucosal lesions or experience any nasal symptoms. Both extremity lesions fully healed within 3 months without further systemic therapy.

Case 2

This is a 30-year-old active duty male who was evaluated by dermatology 3 months after returning from a 2-month jungle warfare course in French Guiana. He presented for a lesion on the left hand that began as a single papule, which subsequently progressed to multiple papules, and then a 3-cm non-healing ulcer over the course of 3 weeks. He underwent punch biopsies which revealed leishmaniasis. A repeat biopsy submitted for PCR analysis revealed L. guyanensis. The patient was referred to otolaryngology for evaluation and no evidence of mucosal involvement on nasopharyngoscopy was found. He was treated by the infectious disease service and underwent a course of liposomal amphotericin 3 mg/kg on days 1 to 5 and 10 to 11. The patient denied any nasal or constitutional symptoms throughout the entire workup and treatment. He was followed up at 1-month post-treatment without any mention of further symptoms or persistence of a non-healing lesion. Although there was no explicit statement of resolved disease, in each of the 8 years following the initial presentation, the patient had many unrelated health care visits documented without indication of further leishmanial disease.

DISCUSSION

With only 2 cases of new-world leishmaniasis for which risk of mucosal disease was identified, this study highlights the role that geographic distribution of forces and intensity of exposure plays in this disease. With both long-term bases of operations and rotational units within the Southern Command Area of Responsibility, leishmaniasis and mucosal leishmaniasis, in particular, remain an important medical threat.¹⁰ Prior to the first Gulf War and subsequent operations in Iraq, Afghanistan, and the broader region, much of the experience with leishmaniasis was from cases acquired in Central America, particularly Panama.¹ In their description of clinical outcomes from 96 patients treated with sodium stibogluconate, while only 1 case of mucosal leishmaniasis was reported, Martin et al report more than half of their total cases were cutaneous infections caused by species capable of causing mucosal leishmaniasis. In their 1968 paper on leishmaniasis among U.S. troops stationed in the Canal Zone, Walton, Person, and Bernstein highlight impacts on military operations that remain pertinent today, particularly on the increased risk of acquisition during jungle training, the impact of seasonality and climate, and the potential to adversely impact mission readiness.⁶ Then, as now, recognition of suspected cases, identification of a species capable of causing mucosal leishmaniasis, evaluation by otolaryngology, and provision of effective systemic treatment¹¹ are key steps in the provision of care which may also necessitate evacuation to higher echelons of care. Thus, in the right operational context, as highlighted through the number of incident cases of cutaneous disease during operations in Iraq and Afghanistan, the threat of mucosal leishmaniasis has the potential to disrupt deployed units.³ Furthermore, the potential for delay and chronicity with which mucosal lesions may present make it a consideration that medical personnel must account for whenever a patient with compatible lesions and travel history presents for care, regardless of the interval duration.

A thorough history and physical examination should be performed to identify any mucosal signs and symptoms, which may be subtle. To fully evaluate, it often requires the involvement of an otolaryngologist and nasopharyngoscopy, with biopsy of abnormal mucosal areas for histopathologic and molecular analysis as per the Infectious Disease Society of America and the American Society of Tropical Medicine & Hygiene (IDSA/ASTMH) guidelines.¹¹ Both cases described here underwent a similarly streamlined evaluation; however, treatment options for the 2 were less clear-cut. Case 1 presented with a lip lesion that likely represented the initial point of inoculation rather than metastatic spread, which was not subsequently demonstrated, and could be categorized as complex cutaneous leishmaniasis, potentially caused by a mucosal leishmaniasis-causative species. However, having this oral lesion without definitive species identification makes it impossible to fully rule out the risk of developing into or already having a primary diagnosis of mucosal leishmaniasis. Regardless, in either setting, systemic therapy is recommended. Case 2 provides a different context as he had exclusively cutaneous lesions from a confirmed mucosal leishmaniasis-causative species. In such cases, the primary recommendation for systemic treatment remains, but with uncertainty about the likelihood of mucosal progression, in cases where spontaneous healing is occurring, risk-benefit calculations require close consideration. Watchful waiting and close follow-up could be reserved for select cases with assurances of longitudinal follow-up, which may be problematic in a military context. Ultimately, both patients underwent systemic IV therapy with liposomal amphotericin, although only case 2 met the recommended 20 to 60 mg/kg total treatment dose.¹¹ The evaluation and treatment plan detailed here reveals the complexity of medical care those with suspected mucosal leishmaniasis must receive.

CONCLUSIONS

The evaluation and treatment plan detailed here reveals the complexity of medical care those with suspected mucosal leishmaniasis require. Those diagnosed with mucosal leishmaniasis or infection by a causative species of mucosal leishmaniasis should undergo comprehensive evaluation by multiple medical specialists throughout their disease process. These 2 patients were no exception, receiving, in total, evaluation/treatment by 6 different specialties throughout their disease course. Additionally, both cases described were identified after returning from deployment, highlighting the potential for the onset of signs and symptoms well after departure from the endemic region. Thus, not only are force health protection measures necessary to prevent infections, but also for counseling service members on the importance of reporting future skin lesions or any unexplained chronic nasopharyngeal symptoms to their health care providers.

FUNDING

This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (Inter-Agency Agreement Y1-AI-5072), and from the Defense Health Program, U.S. Department of Defense (HU0001190002).

CONFLICT OF INTEREST STATEMENT

None declared.

DATA AVAILABILITY

Original source and study data is subject to access restrictions per a data-sharing agreement with the Defense Health Agency.