1. INTRODUCTION

Human herpesvirus-6 (HHV-6) is a ubiquitous lymphotropic virus with a preference for cluster of differentiation 4 positive (CD4+) T cells, which establishes lifelong latency via integration of its genome into host telomeres [1–3]. In the USA and UK, 97%–100% of primary infections are due to HHV-6 type B, which infects almost all humans by age 3, classically manifesting as a self-limited febrile illness which can include fever and skin rash [4]. After latency, symptomatic reactivation of HHV-6 is best described in the setting of iatrogenic immunosuppression as seen in recipients of allogeneic blood and marrow transplants (BMT) [5,6]. In fact, HHV-6 reactivation is encountered in 36%–45% of allogeneic BMT recipients, and up to 90% of umbilical cord blood transplant patients [7–9]. Active infection in allogeneic BMT has been associated with fever, skin rash, interstitial pneumonitis and delayed engraftment, with HHV-6 associated encephalitis being the most devastating complication [10–13].

The clinical impact of HHV-6 reactivation in autologous BMT patients remains unclear. However, the incidence of viral reactivation has been shown to be comparable to that in allogeneic BMT recipients in a number of studies [14–17]. A recent prospective study published by Balsat et al. showed a cumulative incidence of HHV-6 reactivation rate of 19% by day +40 following autologous BMT [18].

We report an unusual case of encephalitis attributed to HHV-6 in a patient with multiple myeloma (MM) who underwent autologous BMT. This is the second reported case of HHV-6 encephalitis after autologous BMT [19].

2. CASE DESCRIPTION

A 67-year-old female was re-admitted on day +22 following autologous BMT for MM. The patient was noted to have a three-day duration of increased confusion, agitation, and unsteady gait. The patient's MM had been diagnosed four years prior to her current admission. Her previous therapy included induction with 6 cycles of lenalidomide, bortezomib, and dexamethasone followed by high dose melphalan and autologous BMT. Due to progressive disease, she received multiple lines of salvage therapies including lenalidomide, elotuzumab, and dexamethasone, bortezomib and daratumumab, and carfilzomib, pomalidomide, and dexamethasone. After documented response to the last combination, she underwent consolidation therapy with a second autologous BMT following conditioning with melphalan 200 mg/m². Her transplant course was complicated by recurrent fevers at the time of engraftment with the first febrile episode starting on day +9. Extensive work-up was unremarkable, with the exception of HHV-6 type B reactivation, with a viral load of 82,700 copies/mL. Her fever ultimately resolved spontaneously, and the patient remained without complaint until presentation, per above.

Upon admission, HHV-6 encephalitis was suspected. Her serum HHV-6 viral load was 179,000 copies/mL. Her absolute lymphocyte count was 1 × 10⁹/L. Lymphocyte subsets testing was not done. An MRI of the brain showed no parenchymal or leptomeningeal abnormalities. Cerebrospinal fluid (CSF) demonstrated normal glucose, elevated protein at 63 mg/dL (reference range: 15–40), and increased cell count at 43/mm³ (reference range: 0–5), including 95% lymphocytes. Cytology was negative for malignant cells. CSF bacterial and fungal cultures were negative. A polymerase chain reaction (PCR) panel was negative for Herpes simplex virus (HSV), Epstein-barr virus (EBV), cytomegalovirus (CMV), and John Cunningham virus (JC) but positive for HHV-6. Based on peripheral eosinophilia and skin biopsy, the patient was also diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS). The patient was initially treated with foscarnet for a total of 21 days, followed by a course of valganciclovir. She exhibited gradual clinical improvement and progressively returned to her baseline. Concomitantly, her HHV-6 viral load dropped from 179,000 to 6,400 copies/mL at completion of the antiviral treatment. She remained well until she received maintenance therapy with carfilzomib, pomalidomide and steroids due to persistent disease. This resulted in fever and increase in her viral load. Her anti-myeloma treatment was discontinued, and her symptoms subsided without additional antiviral therapy.

3. DISCUSSION

Since HHV-6 was first described in 1986 in 6 patients with lymphoproliferative disorders [20], its pathogenic role has been progressively elucidated, notably via reactivation in the setting of immune dysfunction such as solid organ transplantation, allogeneic BMT, and acquired immune deficiency syndrome (AIDS) [5,21]. In allogeneic BMT, HHV-6 reactivation is observed in 47%–72% of recipients [11] and can cause a broad spectrum of clinical manifestations such as fever, skin rash, myelosuppression and pneumonitis. The most severe consequence of HHV-6 infection is encephalitis, which occurs at a rate of 0%–11.6% in allogeneic BMT and up to 21.4% in cord blood transplants, typically 3–4 weeks post-transplant [10,12,13,22]. Allogeneic BMT recipients receiving myeloablative conditioning, and those receiving grafts from unrelated donors, human leukocyte antigen (HLA) mismatched donors, and umbilical cord donors are at high risk of HHV-6 reactivation and, particularly, HHV-6 encephalitis [9,13]. One study concluded that in 1,344 cases of allogeneic BMT, 1.4% of patients developed encephalitis attributed to HHV-6. The majority of cases were recipients of umbilical cord transplants [23]. Similarly, in another prospective study of 230 allogeneic BMT recipients, 3% of patients developed HHV-6 encephalitis, with more cases detected in umbilical cord recipients compared to recipients of adult donors (7.9% versus 1.2%) [13].

The clinical impact of HHV-6 reactivation in autologous BMT patients is less well defined and is rarely reported, when compared with the knowledge in allogeneic BMT patients. This is likely due to the paucity of cases, and the traditional thinking that autografted patients experience less immunosuppression than allogeneic recipients. In addition, the limited studies in autografted patients have alluded to the benign course of HHV-6 reactivation in these recipients [15,24,25]. Many of these studies were conducted prior to the widespread use of novel immunomodulator agents in MM, such as lenalidomide, pomalidomide, and bortezomib, in addition to targeted therapies such as daratumumab and elotuzumab. The incorporation of novel therapies in the treatment of both MM and lymphoma may be rendering this patient population more susceptible to infectious complications. Both pomalidomide and lenalidomide have been shown to induce the activation of cytotoxic T cells and to enhance the cytotoxicity of natural killer (NK) cells, resulting in an increased frequency of mature regulatory T cells [26]. Bortezomib therapy causes a decrease in NK and CD8+ cells, dendritic cell dysfunction, and selective Th1 cell depletion [27]. This has a known negative impact on the immune system, mainly by decreasing the CD4+ and CD8+ T cell population, as well as selective exhaustion of T helper and dendritic cells. Thirteen percent of patients with MM treated with bortezomib develop Herpes zoster infection or reactivation [28,29]. In a series of 62 MM patients who received autologous BMT, Horowitz et al., reported that at least one third (10 patients) of unexplained post-engraftment fevers were due to HHV-6 reactivation [17]. All those patients had received bortezomib or thalidomide pre-transplant. While most of them did not receive any HHV-6 directed therapy and had relatively benign courses, our patient developed encephalitis and required treatment with antiviral therapy. This could be due to the fact that our patient received a longer course of immunomodulatory treatment and two transplants. Lymphocyte subset analysis was not done in our case. Future studies should determine whether such testing is of value in assessing the risk of HHV-6 activation following treatment with immunomodulatory agents.

When testing for HHV-6 reactivation by PCR, clinicians should be aware that, in some patients, the virus is acquired through vertical transmission, a rare entity known as chromosomal integration, where the virus is integrated into the telomere of every chromosome. Typically, these patients have persistently high viral load when whole blood but not plasma is examined. Though these patients are most often asymptomatic, in rare instances the virus is able to excise itself from the telomere and cause active infection [2].

Ours is only the second described case of HHV-6 encephalitis following autologous BMT. We believe that in the era of immunomodulatory therapy, transplant clinicians should include testing for HHV-6 in patients with unexplained fever following autologous BMT. Clinicians should also include HHV-6 encephalitis in the differential diagnosis in heavily pretreated patients with MM presenting with neurologic findings. Larger prospective studies are needed to determine which patients are at risk of HHV-6 reactivation, and within this group, which patients are at risk of developing complications requiring directed antiviral therapy.

CONFLICT OF INTEREST

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