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Gorgas Case 2013-02

History: 82 year-old male patient admitted with one-week history of fever, cough and dyspnea. He has a 13-year history of painless proliferative-infiltrative lesions located on the palate and gums with loss of dentition. Odynophagia occurred over the first 4 years of illness. Treated locally with herbal medicines without formal medical evaluation performed at that time. Three years before admission he noticed a papular lesion on the right nasal mucosa that ulcerated, drained purulent material, and progressed to perforation of the nasal septum over one year. After the development of dysphonia, a mucosal biopsy demonstrated granulomas with negative AFB stains. TB treatment was begun but not completed as he did not improve. No past medical history. Self-amputated a finger many years ago due to a non-healing skin infection.

Epidemiology: Coffee farmer; born and lives in Huánuco (jungle). No known TB exposure. No specific HIV risk factors.

Physical Examination: Afebrile. Inspiratory rales in both lungs. No hepatosplenomegaly. Images A-D show infiltration of the lips with ulcerative lesion and purulent discharge; marked difficulty in opening the mouth. Granulomatous lesions on the palate and gums. Nasal perforation and infiltrative lesions in the nasal mucosa. No skin scars.

Discussion: Biopsies were taken from the nasal mucosa, from an erythematous and granulomatous lesion, and from the oral mucosa. Our approach is to take tissue with inflammation and a granulomatous appearance, particularly from the newest lesions according to patient history. A PCR from an active nasal lesion was positive for L. braziliensis. Direct smears and culture for fungi and mycobacteria were negative.  A typical positive biopsy from the Gorgas cases files is shown [Image E].

L. braziliensis is the only Leishmania species present in the area of the jungle where he lived at the time of his initial infection at least 13 years earlier. However, in South America it is important to definitively distinguish Leishmania species that cause only cutaneous disease (e.g., L. peruviana in Perú) from the mucocutaneous species. Both typically cause one or a few initial skin lesions that are ulcerative but painless in nature and that usually spontaneously heal over time; but apparently did not do so in this case, leading to his self-amputation of his finger. However, with L. braziliensis (the mucocutaneous species), severe destructive recurrence may occur in the mucosal surfaces of the naso- and oropharynx from months to years after treatment or healing of the skin ulcers. L. braziliensis only occurs in the Americas and is the only Leishmania species that causes mucocutaneous disease. In this part of the world the vector is the Lutzomyia sandfly.

The major differential diagnosis in Perú of these oro-pharyngeal lesions would be paracoccidioidomycosis, carcinoma, or lymphoma. This would be an atypical presentation for TB. In Perú leishmaniasis would be by far the most common. The painless nature of the mucosal lesions despite widespread destruction of tissue, involvement of the mucosa, as well as spread to the larynx are consistent only with leishmaniasis. The nasal, pharyngeal and laryngeal lesions could also be consistent with rhinoscleroma, a granulomatous bacterial infection caused by Klebsiella rhinoscleromatis. A search for the scar of the original cutaneous lesion, often subtle, usually on a limb, is a key part of the physical examination. Its absence should lend doubt to the impression of leishmaniasis. In general, oral lesions of paracoccidioidomycosis are painful, are frequently friable and bleed on contact, and gingival and buccal mucosa are frequently involved. Gingiva and buccal mucosa are less often involved in leishmaniasis making this case atypical. The lungs are the primary site of infection in paracoccidioidomycosis and the x-ray is generally abnormal. KOH preps of direct scrapings will be positive in up to 90% of cases of paracoccidioidomycosis with oral lesions.

Distinguishing L. braziliensis from L. peruviana had for many years involved laborious culture techniques followed by electrophoretic isoenzyme analysis. Investigators at our Institute have now published PCR assays using both tissue as well as less invasive specimens [PLoS One. 2011;6(10):e26395; Clin Infect Dis. 2010 Jan 1;50(1):e1-6] for distinguishing the 2 species from cutaneous and mucosal lesions. Early identification of the species that causes the initial cutaneous infection would greatly help to prevent mucocutaneous leishmaniasis because it would allow more aggressive treatment and follow-up. In Perú L. peruviana (cutaneous disease only) occurs only in the high Andes; L braziliensis occurs only in the jungle and in the Amazon.

Recommended standard therapy for mucocutaneous disease is often 28 days of a pentavalent antimonial (sodium stibogluconate 20mg/kg/d). In our Institute, we usually begin with amphotericin B in cases of mucosal involvement. Patients are given pre- and post-treatment hydration and supplemental potassium with daily doses given in an outpatient infusion therapy setting. Liposomal amphotericin may be used in resource rich settings, but based on limited trials it is not better in terms of efficacy even if less toxic and more convenient. On ENT examination the patient was found to have laryngeal involvement defining it as a severe case [see Gorgas Case 2010-01]. Response is expected to be slow, with the expectation of an 80% cure rate at the end of 6-week course (25 mg/kg total dose) of Amphotericin B 6 days per week as an outpatient. For severe refractory cases, the duration of amphotericin B is extended; therapy needs to be individualized.