Case Report: Mucocutaneous Leishmaniasis Masquerading as Idiopathic Midline Granulomatous Disease

Abstract.

Mucocutaneous leishmaniasis (MCL) is a rare infection caused by several species within the genus Leishmania. We present a patient with multifocal MCL masquerading as idiopathic midline granulomatous disease, featuring the unusual complication of ocular leishmaniasis, as a result of prolonged immunosuppressive therapy. We review clinical features, diagnosis, and treatment of this syndrome.

CASE REPORT

A 44-year-old woman with a history of idiopathic midline granulomatous disease on chronic immunosuppressive treatment presented with progressive rash for 8 months and intermittent fevers and chills for 2 months. Five years before presentation, she was diagnosed with idiopathic midline granulomatous disease of the sinonasal cavity and endolarynx. Histopathology from multiple nasal biopsies showed necrotizing granulomatous inflammation without microorganisms. She was treated with multiple immunosuppressive agents, including prednisone, azathioprine, rituximab, infliximab, cyclophosphamide, and monthly intravenous immunoglobulin, with minimal improvement. One year prior, she developed acute airway obstruction requiring tracheostomy due to exophytic growth from granulation tissue on her posterior pharyngeal wall. Two months prior, she was hospitalized and treated for candidemia, cytomegalovirus viremia, and invasive pulmonary aspergillosis. She underwent punch biopsy of a right leg nodule, revealing panniculitis and vasculitis. Her medications on presentation included prednisone 30 mg, dapsone, valganciclovir, and voriconazole.

The patient immigrated to the United States from El Salvador 13 years prior and resided in New Jersey. She had not traveled out of the state. She denied any past substance use. Prior HIV test was negative.

On examination, she was afebrile and appeared chronically ill, with moon facies and a tracheostomy. She had a perforated nasal septum and a 2 × 3-cm pedunculated lesion on the posterior pharyngeal wall. There were multiple tender, erythematous, blanching nodules on both lower extremities extending to her abdomen and upper extremities, with scattered petechiae and ecchymoses on her arms (Figure 1).

Figure 1.

Cutaneous leishmaniasis of the upper (A) and lower (B) extremities. This figure appears in color at www.ajtmh.org.

Her hemoglobin was 8.8 g/dL (reference 12.0–16.0 g/dL) and platelet count was 77,000 cells/L (reference 150–450 × 10³/uL). Her white blood cell count, electrolytes, creatinine, and transaminase levels were normal.

Histopathology of an excisional biopsy of a subcutaneous nodule demonstrated numerous small spheroid organisms located primarily within macrophages on hematoxylin and eosin staining (Figure 2). Skin and all prior biopsy specimens were sent to the CDC, where molecular testing and DNA sequencing confirmed the presence of Leishmania (Viannia) panamensis in skin, as well as in nasal septum, false vocal cord, and cricoid biopsies from 3 years ago. Bone marrow biopsy was negative for Leishmania.

Figure 2.

Full-thickness skin biopsy with amastigotes (black arrows). Hematoxylin and eosin stain, magnification ×100 (A) and ×400 (B). This figure appears in color at www.ajtmh.org.

The patient was treated with intravenous liposomal amphotericin B (LAmB) 3 mg/kg per day for 4 weeks, followed by 3 mg/kg every week for 8 weeks, and then 3 mg/kg every 3 weeks, with improvement of her skin lesions (Figure 3) at the completion of 6 months of therapy. Her prednisone dose was also gradually tapered to 3 mg daily over the course of 6 months, along with discontinuation of all other immunosuppressive therapy. Several weeks after completing a 6-month cumulative dose of LAmB 6,940 mg (130 mg/kg), she developed exophytic conjunctival masses on her left upper and lower eyelids (Figure 4) and underwent excisional biopsies of both lesions. Immunohistochemical staining performed at CDC confirmed Leishmania. She was restarted on LAmB 3 mg/kg per day for 4 weeks, before returning to a maintenance dose of 3 mg/kg every 3 weeks. Her oropharyngeal lesion was surgically resected and her tracheostomy site was successfully decannulated. Her second course of LAmB was completed after a cumulative dose of 6,270 mg (100 mg/kg) over 5 months and she completed her gradual prednisone taper.

Figure 3.

Improvement of cutaneous lesions of the lower extremities after treatment with liposomal amphotericin B. This figure appears in color at www.ajtmh.org.

Figure 4.

Exophytic conjunctival masses on the left upper and lower eyelids. This figure appears in color at www.ajtmh.org.

At 6-month follow-up, she had no recurrence of skin or conjunctival lesions. She completed therapy for pulmonary aspergillosis and disseminated cytomegalovirus infection without recurrence.

DISCUSSION

Our patient with mucocutaneous leishmaniasis (MCL) highlights an unusual clinical manifestation of Leishmania, with devastating consequences due to prolonged immunosuppression. Diagnosis of MCL is challenging and requires understanding of the unique aspects of the parasite, disease endemicity, clinical manifestations, and recommended diagnostic testing.

Leishmaniasis refers to a spectrum of diseases caused by the parasite Leishmania, which is transmitted by infected sandflies. The disease is endemic to many regions of the tropics, subtropics, and southern Europe. Of the three major clinical syndromes associated with Leishmania (cutaneous, mucosal, and visceral), mucosal is the least common.^1,2 Mucosal leishmaniasis (ML) is caused primarily by Viannia subgenus species (L. braziliensis, L. guyanensis, and L. panamensis) in Central and South America in the New World. The highest risk of ML occurs in the “mucosal belt” in the countries of Bolivia, Peru, and Paraguay. Mucosal leishmaniasis is a metastatic complication of cutaneous leishmaniasis (CL) in less than 5% of cases and develops either concurrently with CL or years to decades after healing of CL.^1,2

Parasite and host immune factors greatly influence the clinical syndrome and severity of infection. T-cell–dependent (Th1) cytokine response is required to control intracellular Leishmania replication and killing.³ Patients with underlying immunosuppression (e.g., patients on chronic steroids^4,5 or other immunosuppressive agents,⁶ organ transplant recipients,⁷ or those with HIV infection⁸) are at increased risk for severe disease, with disease onset occurring usually around 2–5 years after initiation of chronic corticosteroid therapy^4,5 as in our patient or around 18–144 months after organ transplantation dependent on intensity of immunosuppression.⁷ Although our patient had disseminated mucosal disease, with likely reactivated cutaneous disease due to her prolonged immunosuppression, she did not have evidence of visceral disease—as suggested by her negative bone marrow and lack of hepatosplenomegaly. This is consistent with her infecting Leishmania species (Viannia subgenus), which predilects for mucocutaneous disease, as opposed to visceral leishmaniasis, which is primarily associated with L. donovani or L. infantum/chagasi.^1,2 Her anemia and thrombocytopenia were not related to visceral involvement and were likely secondary to cytotoxic immunosuppressive agents including valacyclovir and dapsone.

Mucosal leishmaniasis is characterized by mucosal destruction. Initial and prominent features include chronic nasal symptoms, which may progress to mucosal destruction of the naso-oropharynx and larynx, with complications of disfigurement, aspiration, bleeding, and respiratory compromise.^1,2 Mucosal leishmaniasis should be suspected in a patient from an endemic area with compatible clinical symptoms, including idiopathic midline granulomatous disease of unknown etiology.

A less frequent clinical manifestation of MCL, as demonstrated in our patient, is a conjunctival disease. Ocular leishmaniasis is a rare occurrence, representing 1.6% of lesions in 1,989 patients⁹ and 2.5% in 2,066 patients with CL.¹⁰ The various presentations of ocular infection include ptosis, ectropion, ulcerative blepharitis, conjunctivitis, and anterior uveitis,¹¹ with the eyelid being the most common site of ocular disease.^11,12 Involvement of the palpebral conjunctiva, as in our patient, has primarily been reported in the setting of disseminated infection due to immunosuppression.^12,13 As previously described, our patient’s ocular disease was treated with systemic therapy and surgical excision, with a substantial component of her recovery attributed to tapering of immunosuppression.

Multiple diagnostic testing methods should be performed to maximize diagnostic yield for Leishmania. Definitive diagnosis requires identification of the parasite in histology, culture, or molecular analyses via PCR (available at the CDC). Of these, PCR is the most sensitive diagnostic test, particularly as ML tends to be “pauciparasitic” with low yield on histopathology.¹ Preparation of tissue specimens with formalin and paraffin can significantly degrade the sensitivity of PCR, and therefore, alternative preservatives or preparation of frozen sections should be considered. In our patient, molecular testing allowed for a retrospective diagnosis from biopsies obtained 3 years prior. Species identification should also be pursued with culture or molecular testing, as this informs clinical treatment and prognosis.¹⁴ Culture yield is maximized when specimens are placed directly into specialized media, available from reference labs such as CDC. Identification of a Viannia species should prompt evaluation of possible ML with a comprehensive ear, nose, and throat evaluation.¹

Treatment of ML is limited by current treatment options and available data. Therapeutic options include intravenous or intramuscular pentavalent antimony (sodium stibugloconate or meglumine antimoniate), intravenous LAmB or amphotericin B, and oral miltefosine.^1,15–19 Of these, miltefosine is the only FDA-approved treatment for ML due to New World Viannia subgenus. Availability of pentavalent antimony compounds are limited in the United States, requiring a CDC-sponsored Investigational New Drug (IND) application. Liposomal amphotericin B with cumulative doses of 20–60 mg/kg has been used to effectively treat ML in immunocompetent hosts.^20,21 Ocular leishmaniasis involving the eyelid or conjunctiva has been successfully treated with pentavalent antimony,^22–26 miltefosine,²⁷ intralesional amphotericin B,¹² or with surgical excisional alone.¹¹ Close follow-up is recommended for ML, as treatment response is generally less responsive than for CL, and post-treatment relapse is more common.^1,2 Therapy often results in clinical cure without a “parasitological” cure, leaving a risk for reactivated disease, particularly after immunosuppression as in our patient.

CONCLUSION

Mucocutaneous leishmaniasis, including ocular involvement, is an uncommon manifestation of Leishmania and is caused primarily by Leishmania Viannia subgenus in South and Central America. Diagnostic testing for Leishmania should be considered in patients with compatible symptoms who have been exposed to an endemic area. Distinguishing between leishmaniasis and idiopathic midline granulomatous disease is critical, as the immunosuppressive agents used in idiopathic midline granulomatous disease can also lead to devastating clinical manifestations of Leishmania.