HIV infection presenting proliferation of CD8+ T lymphocyte and hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis is a rare hyperinflammatory disorder characterised by CD8+ T lymphocyte activation and hypercytokinemia. Autoimmune disorders including hemophagocytic lymphohistiocytosis have been described in HIV patients; however, it is a rare initial presentation of HIV infection. We present an unusual case of HIV infection presenting with hemophagocytic lymphohistiocytosis.

Keywords

HIV AIDS acute retroviral syndrome hemophagocytic lymphohistiocytosis HLH

We report the case of a 24-year-old man without any prior medical illness who presented to the hospital with complaint of abdominal pain, nausea, vomiting and chills over two days.

On admission he was tachycardic (heart rate 110 beats per minute) and febrile (38.8℃). Physical examination revealed splenomegaly and lymphadenopathy in the cervical and inguinal regions. His initial laboratory workup revealed anaemia with haemoglobin of 6.5 g/dL and thrombocytopenia with platelet count of 99,000/dL. The ferritin level was elevated to 18,829 mg/dL, hypertriglyceridemia of 428 mg/dL and hypofibrinogenemia of 68 mg/dL. Viral workup was done which revealed HIV on ELISA and Western blot assay with a CD4 count of 331 cells/µL and viral load of 150,902 RNA copies/mL. Further viral serological studies were negative for Epstein Barr virus (EBV), cytomegalovirus (CMV), hepatitis A, B and C. Blood culture and urine cultures did not grow any pathogen.

A peripheral blood smear was done to further evaluate the decreased blood count, which showed pancytopenia and atypical lymphocytes. A bone marrow biopsy was performed for further evaluation, which showed hemophagocytosis, abundant CD8+ lymphocytes and tri-lineage hyper-cellularity. The T-cells were predominantly cytotoxic T-cells (CD8+, TIA1+ and granzyme B+) with no significant aberrancies of other pan-T antigens (CD3, CD5). He was diagnosed with hemophagocytic lymphohistiocytosis (HLH) according to the HLH-2004 diagnostic criteria (Table 1). A biopsy of the right groin lymph node was also done, which showed hemophagocytosis and atypical T-lymphoid proliferation with CD4+ and CD8+ T lymphocytes with expression of all pan T-cell antigens (CD2, CD3, CD5 and CD7).

Table 1.

HLH diagnostic criteria with patient characteristics.

HLH criteria	Case
Fever > 38.5℃	Present
Splenomegaly	Present
White count (ANC < 1000/µL)	810
Haemoglobin (<9 g/dL)	6.5
Platelets (<100,000)	99,000
Ferritin (>500 mg/dL)	18,828
Triglycerides (>265 mg/dL)	428
Fibrinogen (<150 mg/dL)	68
Bone marrow biopsy with hemophagocytosis	Present
Low or absent NK activity	Not done
Elevated soluble CD 25 (2 standard deviations) (normal upper limit 1105 units/mL)	Present (3472 units/mL)

During the course of hospitalisation, he developed acute kidney injury and nephrotic range proteinuria (albumin/creatinine ratio of 3915 mg/gm). A kidney biopsy was subsequently performed, which was consistent with HIV-associated immune complex glomerulonephritis. Electron microscopy showed extensive immune complex deposits in the subendothelium as well as effacement of the epithelial foot processes.

Highly active anti-retroviral therapy with tenofovir, emtricitabine, raltegravir, darunavir and ritonavir was initiated. Dexamethasone was also started for HLH treatment. Etoposide and cyclosporine A were not administered to avoid further kidney injury. He made substantial improvement with treatment. His viral load decreased to 88 RNA copies/mL and CD4 count increased to 346 cells/µL. The ferritin decreased to 2626 mg/dL. He had a protracted hospitalisation but his clinical status significantly improved over time and he was discharged from the hospital with resolution of his symptoms.

Discussion

HIV infection presents with a myriad of clinical manifestations, including anorexia, weight loss, abdominal pain, lymphadenopathy, myalgia, arthralgia, neurologic features, constitutional and mucocutaneous features, oral candidiasis and pharyngitis, among others.¹

HLH is a systemic inflammatory disorder marked by hyperinflammatory manifestations and bone marrow suppression. Primary HLH is a genetic disorder mostly seen in paediatric patients, whereas secondary HLH is more common in the immunosuppressed adult population.² Amongst adults, viruses are the most common triggers, with herpes viruses accounting for 62%, EBV for 43% and CMV for 9% of reported viral cases of HLH.³ It is a well-known phenomenon in HIV patients.^4,5 However, HLH as the initial presentation of HIV is unusual.

Our patient had HLH diagnosed by the HLH-2004 diagnostic criteria as shown in Table 1. There was no evidence of sepsis or lymphoproliferative disorders. Treatment was initiated for HLH and HIV with significant improvement in the clinical status.

Our patient had prominently increased cytotoxic CD8+ T-cell activity in the bone marrow and lymph node biopsy. The pathogenesis of HLH involves hyperactivation of CD8+ T-cells and hypercytokinemia, resulting in multiple organ dysfunction.⁶ A case report by Wada et al. showed clonal expansion of highly activated CD8+ T-cells in the peripheral blood of a HLH patient, which decreased after steroid therapy.⁷ Another study by Toga et al. showed a significant increase in the subpopulation of CD8+ T-cells with CD5 down-regulation in patients with EBV-HLH, but not in patients with infectious mononucleosis or in control subjects.⁸ These findings suggest a prominent role of CD8+ T-cells in the pathogenesis of HLH. Furthermore, acute retroviral syndrome is marked by the proliferation of CD8+ T-cells targeted against the HIV virus,⁹ and CD8+ T-cell maturation is known to be skewed during HIV infection.¹⁰ Uncontrolled proliferation of CD8+ T-cells in acute HIV may predispose to HLH.

The diagnosis of HLH in HIV patients is very challenging because it can mimic several other conditions. It is important to diligently seek and treat any other precipitating factors. The HLH-2004 guideline recommends fulfilment of at least five out of eight diagnostic criteria as outlined in Table 1.² However, patients generally present with non-specific symptoms and a high degree of suspicion is required to make a timely diagnosis. The management is equally challenging. Treatment should be ideally started with high-dose dexamethasone, etoposide and cyclosporine A and intrathecal methotrexate should be added for patients with central nervous system HLH not responding to dexamethasone after two weeks of treatment.² However, treatment with the full HLH-04 regimen may not be feasible because of renal or hepatic dysfunction, as in our patient. Additionally, immunosuppressive therapy in HIV patients who are already immunosuppressed may predispose them to serious infections. Therefore, astute clinical judgment is indispensable for the diagnosis and management of HLH in HIV patients.

In summary, HIV-positive patients presenting with severe acute symptoms should be suspected of having HLH and appropriate diagnostic and therapeutic measures should be instituted. Furthermore, the role of CD8+ T-cells in the pathogenesis of HLH in HIV should be evaluated in future studies.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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