Abstract
We describe a patient with HIV who presented with hemophagocytic lymphohistiocytosis and nonspecific abdominal imaging findings. He was diagnosed with visceral leishmaniasis via bone marrow biopsy and treated in the hospital with amphotericin B infusions. Despite pharmacologic interventions, including amphotericin and miltefosine in addition to antiretroviral therapy, our patient experienced multiple relapses and a challenging clinical course.
KEYWORDS: Hemophagocytic lymphohistiocytosis, HIV, Leishmania mexicana, visceral leishmaniasis
Twenty known species of Leishmania are capable of causing leishmaniasis, a parasitic disease transmitted by the female sand fly. The severity of the disease typically ranges from self-limiting to life threatening depending on the species. The global incidence of visceral leishmaniasis (VL) is estimated to be between 50,000 and 90,000, with the majority of these cases occurring in endemic countries such as South America, Africa, and Asia.1 VL is typically caused by L. donovani and L. infantum, while other species, such as L. mexicana, manifest as cutaneous leishmaniasis. L. mexicana is endemic to the US, with most cases occurring in Texas.2 Interestingly, a dermatotropic species may visceralize to cause VL, especially if a patient is immunocompromised, but existing literature has not demonstrated L. mexicana undergoing this transformation.3 Furthermore, patients with HIV have been shown to have an increased risk for developing VL and have a greater likelihood of relapse.4 Standard treatment may not be curative in patients with active HIV infection.3,5
CASE DESCRIPTION
A 54-year-old man presented to the emergency department complaining of abdominal pain, chest pain, and shortness of breath. Additional symptoms included recurrent nosebleeds and episodic bloody stools for several months prior to presentation. He had recently moved to Texas from Belize. He was diagnosed with HIV 7 months before his presentation and started on a combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. On physical exam, he was cachectic with pale conjunctiva and cervical adenopathy. A dermatologic examination revealed a diffuse patchy rash with areas of redness and hypopigmentation. There were no areas of ulceration or lesions. An abdominal exam was normal with the exception of hepatosplenomegaly.
Computed tomography of his abdomen with contrast revealed hepatosplenomegaly, retroperitoneal adenopathy, and a dilated loop of bowel in the terminal ileum. His hematologic laboratory tests at presentation revealed a white blood cell count of 3.9 × 109/L, hemoglobin of 4.9 g/dL, absolute CD4 count of 126/mcL, hematocrit of 15.1%, mean corpuscular volume of 89.9 fL, and platelet count of 53,000/µL. A peripheral blood smear showed erythrocyte rouleaux and neutropenia with few reactive lymphocytes. Other relevant laboratory results included a total protein count of 11.3 g/dL, albumin level of 2.7 g/dL, and ferritin of 5927 µg/L.
The patient was admitted to the hospital and underwent esophagogastroduodenoscopy, which demonstrated no ulcers, erosions, masses, or blood. Additional tests revealed a negative cryptococcal antigen and parvovirus polymerase chain reaction. His serum (1–3)-beta-D-glucan (BG) was found to be positive with a value of >500 pg/mL. Blastomyces antibodies and Histoplasma antigen were negative. Cultures for acid-fast bacilli and fungal species from bronchoscopy were negative. Acid-fast bacilli and fungal stains from bone marrow were also negative. His laboratory tests also showed a polyclonal increase in gamma globulins. No monoclonal bands were seen in serum immunofixation. Leishmania IgG antibody was negative.
A bone marrow biopsy demonstrated a nonspecific immunophenotype with a mixture of B and T lymphocytes, T lymphocyte predominance, inverted helper to suppressor cell ratio, and no evidence of myeloid immaturity. Gomori methenamine silver stain for fungal species was negative. There were circumscribed poorly formed noncaseating granulomas with an interstitial infiltrate of small, monotonous mature-appearing lymphocytes. There were also numerous intrahistiocytic organisms along the periphery of macrophages as well as extracellular organisms, which was suggestive of leishmaniasis (Figure 1).6
Figure 1.
Hematoxylin and eosin stain of bone marrow core biopsy. (a) Overall image of bone marrow at 500 × magnification. (b) Intraphagocytic and extracellular organisms (red arrow).
DISCUSSION
The patient’s presentation was consistent with hemophagocytic lymphohistiocytosis (HLH) characterized by laboratory findings of elevated ferritin levels, pancytopenia, hepatosplenomegaly, hyperproteinemia, and polyclonal IgG gammopathy. HLH is a rare, life-threatening condition that involves an intense yet ineffective immune response to a certain stimulus characterized by the production of histiocytes that can pathologically destroy healthy hemocytes through hemophagocytosis. Though uncommon, HLH has been previously noted as a complication of VL in endemic areas.7
Our patient was treated with two courses of intravenous amphotericin B, which is the preferred initial treatment for VL in patients with AIDS.3 He was given an initial 46 mg/kg cumulative dose and an additional 30 mg/kg after relapse. His secondary prophylactic protocol consisted of routine intravenous amphotericin B with the addition of a recommended alternative agent, miltefosine.3,8 Several months after his initial presentation, polymerase chain reaction testing at the Centers for Disease Control and Prevention identified L. mexicana as the species responsible for VL in our patient. As previously mentioned, L. mexicana infection typically causes cutaneous leishmaniasis.9 Cutaneous leishmaniasis classically involves painless localized lesions covered with hyperkeratotic eschar or fibrinous material. In contrast, our patient’s presentation of vague abdominal pain, hepatosplenomegaly, and lymphadenopathy is consistent with VL.
Although our patient is from Belize, L. mexicana is endemic to Texas. Therefore, it is not unlikely that our patient contracted this parasite locally. We believe that his immunocompromised state allowed L. mexicana to manifest as VL rather than cutaneous leishmaniasis. In the years following his VL diagnosis, he developed dermatologic manifestations known as post-kala-azar dermal leishmaniasis (PKDL) (Figure 2). PKDL is a disfiguring skin condition resulting from an aberrant host immune response to vestigial parasites.1 The skin lesions of PKDL can range from hypopigmented or erythematous macules to raised plaque-like lesions. These lesions classically involve areas of the face, neck, and upper torso. Progression of VL to PKDL has been reported in 10% to 60% of individuals diagnosed with VL.10 Furthermore, there is increased frequency and severity of PKDL in patients with HIV.10,11
Figure 2.
Dermatologic manifestations of post-kala-azar dermal leishmaniasis following treatment initiation.
The patient experienced multiple relapses and hospitalizations due to his unrelenting disease process. Data have shown that this is not uncommon in patients coinfected with HIV and VL.5 Though he was treated based on guidelines that have proven successful for the treatment of VL,12 it is possible that this species of leishmaniasis exhibited some resistance to amphotericin B, miltefosine, or both. With his elevated BG, there was some initial concern for coexisting fungal infection. However, fungal stains in bone marrow, culture from bronchoscopy, and subsequent serologies were negative for underlying fungal infection. We hypothesize that this may be a false-positive but are uncertain of the cause. The patient was receiving prophylactic trimethoprim-sulfamethoxazole, which has been identified as a possible cause of BG elevation.13 At this time, it is unknown if his progressive decline was due to parasitic resistance or the synergistic effects of VL and HIV preventing immune reconstitution. We believe his negative Leishmania IgG was due to his lack of an immune response. Due to the progression of his disease, the patient is now under hospice care. In consideration of this, further resistance testing will not be conducted.
In summary, we describe the first known case of L. mexicana causing VL and PKDL. Our patient’s repeated relapses could be related to his coinfection with HIV, but it must also be considered that VL from L. mexicana could be due to parasitic resistance to treatment. This atypical presentation of L. mexicana should be further researched, specifically in immunocompromised patients, as resistance to treatment can cause serious and life-limiting complications.
Disclosure statement/Funding
The authors report no funding or conflicts of interest. The patient provided written informed consent to publish the details and images of this case.
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