Cytokine Profile in Fatal Human Immunodeficiency Virus–Tuberculosis–Epstein-Barr Virus–Associated Hemophagocytic Syndrome FREE

Hemophagocytic syndrome (HPS), characterized by fever, lymphadenopathy, hepatosplenomegaly, and pancytopenia, results from the abnormal function and proliferation of macrophages and their uncontrolled phagocytosis of various reticuloendothelial cell lines. Secondary (or “reactive”) HPS is associated with infection, malignancy, or autoimmune diseases, whereas primary HPS has no identifiable cause and may be genetic. Reactive HPS has been described in association with infectious agents, but Epstein-Barr virus (EBV) is the most commonly associated infection, and EBV-associated HPS is almost universally fatal.¹ At present, there is no diagnostic or treatment consensus, so HPS is generally dealt with on a case-by-case basis, depending on the associated infection(s) identified.

A 46-year-old Chinese man diagnosed as having human immunodeficiency virus (HIV) infection 8 months earlier presented with fever, lower back pain, bilateral lower limb numbness, and foot drop. He had been receiving highly active antiretroviral treatment in the 4 months before admission, during which his CD4 cell count had increased (37/μL to 204/μL) and his HIV load decreased (130 000 to 820 copies/mL). A magnetic resonance image of his lower spine revealed an epidural mass over the L5 lamina, compressing the thecal sac, and findings from a computed tomography–guided biopsy showed caseating granulomatous inflammation, although mycobacterial cultures were negative. Antimycobacterial therapy was started.

Progressive pancytopenia with high fever (38.8°C) developed over the next 4 weeks. A bone marrow examination confirmed a histological diagnosis of HPS. Again, results from mycobacterial staining and cultures were negative. A real-time quantitative EBV assay² showed a plasma EBV DNA rise from 2062 to 26 480 copies/mL over 3 weeks. No other viruses were detected in the plasma. A course of intravenous immunoglobulin, foscarnet sodium (3 g/d), and etoposide (150 mg/d for 5 days) was given. The EBV DNA became undetectable after 1 week. To reduce adverse effects, highly active antiretroviral treatment was discontinued 5 weeks after starting antituberculosis therapy and 3 days before starting foscarnet therapy. The HIV load at this time was undetectable (< 400 copies/mL).

The patient's condition, however, deteriorated with fulminant sepsis and multiorgan failure, requiring intensive care. Three sets of blood cultures from different sites grew Staphylococcus epidermidis. Although the patient responded well to empirical broad spectrum antibiotics and was extubated 4 days later, he remained neutropenic, thrombocytopenic, and in renal failure and died a week later.

Because this patient's infections (HIV, tuberculosis, and EBV) were effectively suppressed, a possible role for cytokines was investigated. Plasma T_H1 cytokine interferon gamma (IFN-γ), T_H1-related chemokine MIG/CXCL9, and interferon-induced protein 10 (IP-10)/CXCL10 levels were found to be markedly elevated to 103, 17, and 9 times their upper normal limits, respectively, before foscarnet treatment. After 8 days of foscarnet treatment and EBV suppression, these levels normalized. Plasma interleukin (IL)-8/CXCL8 and IL-6 levels were also elevated, approximately 7-fold, before foscarnet treatment. CXCL8, IL-6, and monocyte chemoattractant protein 1 (MCP-1)/CCL2 levels continued to increase while the patient was receiving foscarnet (Table). More details of the methods and results for this case report can be found online at http://ihome.cuhk.edu.hk/~b576778/Online%20Appendix.pdf.

Patients with advanced HIV infection may have increased plasma levels of IFN-γ and IL-2, as well as macrophage chemokines MIP-1α/CCL3 and MIP-1β/CCL4.^3- 4 Epstein-Barr virus infection can induce CXCL10 expression, and CXCL-9 and CXCL10 may be secreted by IFN-γ–stimulated macrophages that are overproduced in HPS.⁵ Hence, the markedly elevated plasma IFN-γ, CXCL9, and CXCL10 levels could be due to the combined HIV-TB-EBV–induced hyper-T_H1 immune response. Although foscarnet, an anti-EBV agent, would have significantly curtailed the T_H1 immune response, the subsequent elevation of IL-6, CXCL8, and CCL2 may have been due to the immune restoration associated with the rising CD4 cell count.⁶ Together with any residual hyperactive T_H1 cell-mediated immunity, this continued increase of IL-6, CXCL8, and CCL2 levels may have resulted in an exaggerated host immune response and fatal outcome.

This case suggests that immunosuppressive agents (ie, steroids and anticytokine antibodies) may be beneficial in such severe HPS cases and demonstrates that cytokine profiling enhances the understanding and management of immune-mediated diseases.

Correspondence: Dr Tang, Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR (julian.tang@cuhk.edu.hk).

Author Contributions: All authors had full access to all of the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Tang. Acquisition of data: C. K. Wong, B. C. K. Wong, K. C. A. Chan, Joynt, Yap, Lam, N. Lee, S. S. Lee, and Tang. Analysis and interpretation of data: C. K. Wong, B. C. K. Wong, K. C. A. Chan, Lam, N. Lee, Cockram, Sung, P. K. S. Chan, Lo, and Tang. Drafting of the manuscript: C. K. Wong, Yap, N. Lee, Cockram, and Tang. Critical revision of the manuscript for important intellectual content: B. C. K. Wong, K. C. A. Chan, Joynt, Lam, N. Lee, S. S. Lee, Cockram, Sung, P. K. S. Chan, Lo, and Tang. Administrative, technical, and material support: B. C. K. Wong, K. C. A. Chan, Yap, and Tang. Study supervision: C. K. Wong, Joynt, Lam, N. Lee, S. S. Lee, Cockram, Sung, P.K.S. Chan, Lo, and Tang.

Financial Disclosure: None reported.

Additional Information: An online appendix is available at: http://ihome.cuhk.edu.hk/~b576778/Online%20Appendix.pdf.