HSV-2–related hemophagocytic lymphohistiocytosis in a fingolimod-treated patient with MS

Fingolimod is an oral, disease-modifying therapy used to treat multiple sclerosis (MS).¹ However, severe viral infections, including disseminated varicella-zoster virus infection,¹ herpes simplex encephalitis,^1,2 varicella-zoster virus encephalitis and vasculopathy,³ or progressive multifocal leukoencephalopathy,⁴ have been reported during fingolimod therapy. Hemophagocytic lymphohistiocytosis (HLH), often triggered by certain viral infections, is a fatal disease characterized by fever, pancytopenia, elevated liver enzymes, hyperferritinemia, hepatosplenomegaly, and hemophagocytosis.⁵ A triggering infection causes persistent activation of lymphocytes and histiocytes, resulting in exaggerated immune responses and hemophagocytosis. We describe an autopsied case of disseminated herpes simplex virus type 2 (HSV-2) infection presenting with HLH, following 0.5 mg fingolimod and corticosteroid therapies.

Case report.

A 56-year-old man had relapsing-remitting MS for 4 years, since 2008 (figure 1, A and B; table e-1 at Neurology.org/nn). He was not sexually active and did not have past or current oral/genital herpes infections. Fingolimod 0.5 mg was begun 10 months before admission, when the Expanded Disability Status Scale score was 5.0. Anti–varicella-zoster virus immunoglobulin G (enzyme immunoassay) was positive, although anti–herpes simplex virus immunoglobulin G was not obtained. His white cell and lymphocyte counts decreased during the fingolimod therapy (table e-2). He was admitted on the fourth relapse (table e-1), presenting with muscle weakness in both legs. Two courses of methylprednisolone pulse therapy at 1 g/d for 3 days temporarily enabled him to walk. However, it was followed by fever, sore throat, and jaundice. A laboratory test showed marked pancytopenia, elevated liver enzymes, and hyperferritinemia (table e-2). CT showed hepatosplenomegaly, and bone marrow aspiration revealed hemophagocytosis. These findings were consistent with HLH.⁵ Antiviral drugs could not be used because of lack of proof indicating a certain viral infection. The patient died 18 days after admission (figure e-1). An autopsy was performed with the consent of his family. This adverse event was reported to the Food and Drug Administration via Novartis Pharmaceuticals.

Figure 1. Radiologic and pathologic findings.

(A) Axial T2-weighted image of the spinal cord. (B) Fluid-attenuated inversion recovery image of the brain. (C) The liver was dark red in color reflecting massive hemorrhagic necrosis. (D) H&E staining showed degenerative hepatocytes containing large, pink to purple intranuclear inclusion bodies (Cowdry type A) that push the cell chromatin out to the edges of the nucleus (arrows). This finding suggested herpes infection. Single hepatic cell necrosis is also shown (arrowhead). (E, F) Immunohistochemistry for herpes simplex virus type 2. Viral antigens were identified in the liver (E) and bone marrow (F). (G) H&E staining showed remarkable hemophagocytosis (arrows) within the bone marrow. Scale bars: 3 cm (C), 20 μm (D–G). H&E = hematoxylin & eosin.

The autopsy was performed 2 hours and 20 minutes post mortem. On gross inspection, the liver showed massive hemorrhagic necrosis (figure 1C), with degenerative hepatocytes that contained large, pink to purple intranuclear inclusion bodies (Cowdry type A) on hematoxylin & eosin staining, suggesting herpes infection (figure 1D). To identify the viruses potentially causing HLH, multivirus real-time PCR, which can detect more than 160 human pathogenic viruses in pathologic samples, was performed as previously described.⁶ The HSV-2 DNA was detected in the liver and most of the other pathologic samples (appendix e-1, tables e-3 and e-4). Viral copies per cell (organ) were as follows in descending order: 3.946 (liver), 1.439 (rectum), 1.427 (adrenal gland), 0.936 (esophagus), 0.416 (tongue), 0.160 (spleen), 0.041 (bone marrow), 0.015 (kidney), and 0.011 (bladder). Retrospective analysis of serum taken at the diagnosis of HLH (after methylprednisolone pulse therapy) revealed an elevated HSV-2 DNA concentration of 331,650 copies/μL (appendix e-2, table e-2). Immunohistochemistry using an anti–HSV-2 monoclonal antibody also identified HSV-2 antigen at multiple sites (figure 1, E and F, table e-4). Remarkable hemophagocytosis was observed within the bone marrow (figure 1G), liver, and spleen. Neuropathologic findings were consistent with MS.

Discussion.

Herein, we describe disseminated HSV-2 infection in a patient with MS treated with fingolimod and corticosteroids. HSV is one of the most common viruses that develop HLH, which results from T cell/NK cell dysregulation and eventual cytokine overproduction.⁵ The pronounced viremia of HSV-2 in our case suggests that this virus potentially had a causative role in the emergence of HLH.⁷

Fingolimod may be associated with HLH, considering that a similar HLH case has been reported.⁸ A 39-year-old man with MS who had received 0.5 mg fingolimod for 15 months without adjunctive corticosteroids presented with fever, jaundice, and night sweats, but an autopsy was not performed and the causative virus was not determined. Our report, however, demonstrated HSV-2 as a potential virus for HLH in fingolimod-treated patients.

Fingolimod prevents MS relapses through inhibition of sphingosine-1-phosphate signaling that is essential for lymphocyte migration from lymphoid tissues. Since fingolimod decreases the numbers of naive and central memory T cells in the peripheral blood that are protective against novel or recurrent viral infection,⁹ fingolimod-treated patients are likely vulnerable to herpes infections. Thus, in our case, fingolimod might be associated with massive HSV-2 dissemination, which was possibly augmented by adjunctive corticosteroids.^1,2,9

Our case suggests that careful monitoring of herpes infection is needed, particularly if corticosteroids are added on fingolimod therapy.