Hemophagocytic lymphohistiocytosis secondary to AIDS-related histoplasmosis and visceral leishmaniasis

Background

Hemophagocytic Lymphohistiocytosis (HLH) is an uncommon disorder with high associated mortality, characterized by dysregulated immune activation leading to cytokine storm, hemophagocytosis and multi-organ damage. Secondary HLH –the most frequent presentation– is usually triggered by infections, autoimmune diseases and/or malignancies.^1,2 HIV-related secondary HLH can occur as the initial presentation of both advanced and acute HIV infection, and in the setting of AIDS-related opportunistic infections (OIs). ³ Visceral Leishmaniasis (VL) is a systemic disease caused by parasites from the genus Leishmania, endemic in regions of Asia, Africa, Latin America and Mediterranean basin. Incidence of VL in non-endemic countries has increased steadily due to international travelling. In people living with HIV, VL usually presents as an OI. ⁴ Histoplasma capsulatum is a dimorphic fungus, endemic in central and south-central United States and Latin America. ⁵ Among HIV-positive individuals, disseminated histoplasmosis (DH) occurs as an OI and is considered an AIDS-defining illness. ⁶ We present the case of a patient with advanced HIV, who developed HLH in the setting of coexisting VL and DH.

Case report

A 32-year-old Venezuelan man was admitted to our outpatient clinic with two weeks of diarrhea and fever, and a recently diagnosed HIV infection. Baseline HIV-1 RNA was 5.6 log₁₀ and CD4⁺ cell count 11 cells/μl. Previous medical history, physical examination and chest X-ray were unremarkable; routine blood tests were only notable for mild pancytopenia. Stool culture and enzyme immunoassay for the detection of Clostridioides difficile toxins were negative. antiretroviral therapy (ART) was promptly initiated with ritonavir-boosted darunavir plus tenofovir/emtricitabine. ⁷ Seven days later the patient was admitted due to persistent fever, severe hepatosplenomegaly, progressive pancytopenia, transaminitis and acute kidney injury; he subsequently developed multi-organ failure requiring advanced life support. Bronchoalveolar lavage and bone marrow aspirate were performed. Giemsa staining revealed Leishmania spp. amastigotes and intracellular yeasts consistent with Histoplasma capsulatum (Figure 1). Pathology exam showed hemophagocytosis and no evidence of neoplasia. Lysis-centrifugation blood cultures grew H. capsulatum, and serology tests (Rk39 for Leishmania spp. and immunodiffusion test for H. capsulatum) were negative. A diagnosis of secondary HLH was established (Table 1).OPEN IN VIEWER

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Table 1.

Diagnostic criteria for HLH used in the HLH-2004 trial*.

The diagnosis of HLH may be established by:

A. A molecular diagnosis consistent with HLH

-OR-

B. Five of 8 criteria listed below are fulfilled:

1. Fever 38.3°C

2. Splenomegaly

3. Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood):

Hemoglobin <9 g/dL

Platelets <100 × 103/mL

Neutrophils <1 × 103/mL

4. Hypertriglyceridemia (fasting, >265 mg/dL) and/or hypofibrinogenemia (<150 mg/dL)

5. Hemophagocytosis in bone marrow or spleen or lymph nodes or liver

6. Low or absent NK-cell activity

7. Ferritin >500 ng/mL

8. Elevated Soluble CD25 (soluble IL-2 receptor alpha)

Criteria met in our patient.

*Table adapted from Carl E. Allen et al. Pathophysiology and epidemiology of hemophagocytic lymphohistiocytosis. ASH Education Book - 5 December 2015 vol. 2015 no. 1 177–182.

Since liposomal-Amphotericin is not routinely available in resource-limited settings like ours, and following World Health Organization Guidelines,^6,8 treatment with Amphotericin B Deoxycholate was started, along with high-dose methylprednisolone pulses and intravenous gammaglobuline for HLH syndrome. Despite aggressive treatment and support measures, the patient died 14 days after admission.

Discussion

HLH is a rare syndrome characterized by immune dysregulation, resulting in extreme inflammation and multi-organ damage. ¹ Its incidence is not easy to define due to diagnostic challenges. ⁹ Infection-associated secondary HLH has been associated with viruses (including HIV), bacteria, parasites and fungi (including Leishmania spp. and Histoplasma capsulatum respectively). ⁹ The course of disease is usually aggressive, with low survival rates. ² Diagnosis requires the presence of at least five out of the eight criteria defined by the Histiocyte Society in 2004 (Table 1) ¹⁰ and early detection requires high clinical suspicion, which can be challenging when coexisting with other overlapping diseases.^1,11 There are no validated treatment protocols for secondary HLH in adults,^1,10 although patients may show improvement after treatment of the underlying disease. ⁹ In severe cases, concomitant steroid and/or immunosuppressant therapy may be required.^10–12

Late presentation and HIV-associated OIs such as DH and VL are still a major public health challenge in LMIC. ⁶ VL may present with unspecific symptoms and atypical manifestations including gastrointestinal, pulmonary or cutaneous involvement;^4,6 similar clinical features have been described for DH, ⁶ secondary HLH ¹ and even for advanced HIV infection. In our case, differential diagnoses included OIs and oncohematological disorders. Since the reliability of serological tests for Histoplasma capsulatum and Leishmania spp. in the setting of severe immunosuppression is limited, ⁶ direct visualization of intracellular amastigotes in tissue samples is considered the gold standard for diagnosis of VL in people living with HIV, with high specificity but variable sensitivity (52–85% for bone marrow aspirate). ¹³ Histoplasma capsulatum can be cultured from multiple clinical samples, but growth requires days/weeks; ⁶ and direct visualization of intracellular yeasts in tissue samples has high specificity but is hindered by suboptimal sensitivity. ¹⁴ Lack of specificity in the presenting symptoms, low clinical suspicion and delay in diagnostic methods may contribute to a late initiation of specific treatment and increased mortality.

Evidence supporting the use of immunosuppressants for the treatment of secondary HLH in the setting of active OI is limited. However, increased mortality associated with delayed immunosuppressive treatment has been reported. ⁹ In our case, the severity of clinical presentation and lack of initial response to specific therapy prompted us to initiate it.

Immune Reconstitution Inflammatory Syndrome (IRIS) related to both leishmaniasis and histoplasmosis has been previously described as a potential trigger for HLH among people living with HIV.^15,16 Although the rapid clinical deterioration occurring in our patient shortly after ART initiation would be atypical, IRIS may be considered as a differential or co-existing diagnosis.^17,18 Unfortunately, CD4 count and viral load could not be repeated before the patient died. Nevertheless, these results would unlikely modify clinical management since OI specific treatment along with immunosuppressants were already implemented, and ART interruption is not usually recommended in the setting of IRIS. ⁶

To our knowledge, this is the first report of simultaneous occurrence of VL and DH in a severely immunocompromised host since the pre-ART era report from Manfredi R et al. ¹⁹ It is also the first reported case of HLH secondary to both of these OIs. This case highlight the importance of having a raised awareness for HLH in people living with HIV with persistent, unexplained constitutional symptoms without a clear diagnosis, or with a documented OI with no improvement despite specific treatment. Additionally, these particular OIs should be consider among migrant populations from endemic areas.