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Characterizing human herpes virus 6 following hematopoietic stem cell transplantation Anthony J Perissinotti, Alison Gulbis, Elizabeth J Shpall and Joshua Howell J Oncol Pharm Pract published online 9 January 2014 DOI: 10.1177/1078155213519837 The online version of this article can be found at: http://opp.sagepub.com/content/early/2014/01/09/1078155213519837
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Journal of
Oncology Pharmacy Practice
Original Article
Characterizing human herpes virus 6 following hematopoietic stem cell transplantation
J Oncol Pharm Practice 0(0) 1–8 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213519837 opp.sagepub.com
Anthony J Perissinotti1, Alison Gulbis2, Elizabeth J Shpall3 and Joshua Howell4
Abstract Background: Human herpes virus 6 reactivation occurs in approximately 50% of patients following hematopoietic stem cell transplant, however, the significance of human herpes virus 6 reactivation remains uncertain. Methods: A retrospective study was conducted analyzing clinical data of patients testing positive for human herpes virus 6 by quantitative polymerase chain reaction following hematopoietic stem cell transplant from 1 January 1998 to 1 October 2011. Data retrieved were used to describe the clinical course and outcome of human herpes virus 6 positive hematopoietic stem cell transplant patients. Results: Sixty patients were identified who tested positive for human herpes virus 6 by polymerase chain reaction following hematopoietic stem cell transplant. A high proportion of patients were identified in this cohort with acute myeloid leukemia (28.3%), active disease (65%), transplanted with a matched unrelated donor (30%), 1 antigen mismatched (28.3%) matched unrelated donor, or an umbilical cord graft (25%), and those who received antithymocyte globulin (42.4%). Thirty-eight (63.3%) patients were treated for human herpes virus 6 with foscarnet alone or in combination with intravenous immunoglobulin, whereas 18 (30%) did not require treatment survival at Day 100 was 73.3%. Conclusion: This study suggests human herpes virus 6 reactivation occurs shortly after hematopoietic stem cell transplant (median of 25 days (interquartile range, 20–31.75) after hematopoietic stem cell transplant). Many potential risk factors are described in this report. Treatment of human herpes virus 6 predominately consisted of foscarnet with or without intravenous immunoglobulin; however, treatment of human herpes virus 6 was not always warranted. Furthermore, the effect of treatment on patient outcomes is uncertain.
Keywords Human herpes virus 6, hematopoietic stem cell transplantation
Introduction Human herpes virus 6 (HHV-6) has become a significant opportunistic pathogen following hematopoietic stem cell transplantation (HSCT) and is associated with serious morbidity and mortality.1 Approximately 50% of patients become polymerase chain reaction (PCR) seropositive for HHV-6 following HSCT.2,3 Positivity is most commonly due to reactivation of the latent virus during periods of intense immune suppression.2,4 Definitive complications associated with HHV-6 remain uncertain. The virus has been suspected to cause encephalitis, pneumonitis, gastroduodenitis, cytomegalovirus (CMV) reactivation, delayed platelet and neutrophil recovery, graft failure, fever, hepatitis, and
acute graft versus host disease (aGVHD).1 However, the exact pathogenic role of HHV-6 in HSCT patients has yet to be elucidated. Skepticism remains as to 1 Department of Pharmacy, University of Michigan Health System, Ann Arbor, MI, USA 2 Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Stem Cell Transplantation, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Oncology Content, Content and Clinical Services, McKesson Specialty Health, The Woodlands, TX, USA
Corresponding author: Anthony J Perissinotti, Department of Pharmacy, University of Michigan Health System, 1111 Catherine Street, Room 330, Ann Arbor, MI 48109, USA. Email: [email protected]
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whether this virus causes a cascade of deleterious events following HSCT or whether it is merely an innocent bystander in a seriously ill patient.5 To add to the uncertainty, patients may carry HHV-6 asymptomatically, making it difficult to distinguish a clinically relevant infection and asymptomatic infection.6 Risk factors for the development of HHV-6 reactivation as well as clinical markers to distinguish infection from colonization are needed. The prognosis of HHV-6 infection following HSCT is also unclear. The clinical course may range from full recovery, to irreversible neurological compromise, to death.7 Treatment to prevent these complications includes antiviral therapy with ganciclovir, foscarnet, or cidofovir. Although in vitro data suggests these agents possess activity against HHV-6, in vivo data are lacking.8 Furthermore, it is often unknown when or who should be treated with antivirals and whether treatment impacts long-term patient outcomes.9 The primary objective of this study was to describe the clinical course of HHV-6 positive patients following HSCT. The secondary objective was to determine potential predisposing factors for the development of HHV-6 infection, thereby identifying patients who may benefit from early surveillance of HHV-6.
Methods This retrospective study was conducted at the University of Texas MD Anderson Cancer Center under an Institutional Review Board approved protocol. All adult and pediatric patients who tested positive for HHV-6 by quantitative PCR following HSCT from 1 January 1998 to 1 October 2011 were identified through the Stem Cell Transplant Department database. Patients with a history of HSCT and a positive test for HHV-6 by PCR in their blood, cerebrospinal fluid, or bone marrow were included. Medical records were reviewed, and the following data were compiled: patient demographics, transplant indication, disease status, conditioning regimen, conditioning date, transplant date, transplant type, stem cell source, donor relation, GVHD prophylaxis, mono/ polyclonal antibody exposure within 3 months of HHV-6 reactivation, steroid exposure, high-dose steroid exposure, GVHD status, GVHD treatment, CMV prophylaxis, HHV-6 PCR result, symptoms, neutrophil count, engraftment day, ICU admission within 30 days following HHV-6 reactivation, graft failure within 30 days following HHV-6 reactivation, HHV6 treatment, HHV-6 treatment related adverse events, baseline and peak serum creatinine during HHV-6 treatment, duration of HHV-6 treatment, symptom duration, outcome of primary therapy, and overall survival.
Statistical analysis was performed with GraphPad PrismÕ 5.04. Quantitative variables are reported as the number (percentage) and continuous variables as the median (interquartile range, IQR).
Definitions HHV-6 positivity was defined as at least one positive HHV-6 PCR test (above the PCR test’s threshold of detection) at any time following HSCT. HHV-6 by PCR was a send out test and not performed at our institution. HHV-6 resolution was defined as a negative PCR test following the initial HHV-6 positive PCR. HHV-6 recurrence was defined as a positive HHV-6 PCR test at any time following HHV-6 resolution. Persistent HHV-6 was defined as an HHV-6 PCR test remaining positive and/or lack of symptom resolution for >30 days. HHV-6 symptom resolution was defined as abatement of symptoms within 30 days. Switch therapy was defined as the discontinuation of primary therapy with the addition of another HHV-6 active agent. Prolonged treatment of HHV-6 was defined as HHV-6 treatment duration of >45 days. Acute GVHD was defined and graded according to Center for International Blood and Marrow Transplant Research criteria. Steroid exposure was defined as the administration of any steroid dose for >48 h within 30 days of HHV-6 reactivation. High-dose steroid exposure was defined as the administration of >1 mg/kg/day of prednisone equivalents for >48 h within 30 days of HHV-6 reactivation. Engraftment was defined as the first of three consecutive days with an absolute neutrophil count >0.5 109/l. Symptoms observed 5 days prior to or 5 days following the HHV-6 PCR positive test were collected and considered due to HHV-6 if no other identifiable cause was found and/or the patient’s medical records contained progress notes which dictated the symptom a possible result of HHV-6. Only symptoms with no other identifiable cause were included. For example, a patient presenting with rash was common, however, many other etiologies are possible. These include drug rash, aGVHD (which included up to 51% of all rash etiologies), or other infections. Whether the rash was due to HHV-6 as opposed to an alternative etiology was determined by the clinician caring for the patient.
Results A total of 60 patients were identified, and their medical records were reviewed. Patient characteristics are listed in Table 1. The median age of the cohort was 54 years (range, 2–74), and 60% of patients were male. The most common indications for transplant were acute myeloid leukemia (28.3%), non-Hodgkin lymphoma (16.7%),
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Table 1. Patient characteristics.
Table 2. Transplant specifics. n ¼ 60
Gender, n (%) Male Female Age, years, median (range) Diagnosis, n (%) Acute myeloid leukemia Myelodysplastic syndrome Acute lymphoblastic leukemia Chronic lymphocytic leukemia Chronic myelogenous leukemia Myeloma Non-Hodgkin lymphoma Hodgkin lymphoma Renal cell carcinoma Disease status, n (%) Complete response Active disease
36 (60) 24 (40) 54 (2–74) 17 7 6 9 2 6 10 2 1
(28.3) (11.7) (10) (15) (3.3) (10) (16.7) (3.3) (1.7)
21 (35) 39 (65)
chronic lymphocytic leukemia (15%), and myelodysplastic syndrome (11.7%). Thirty-nine (65%) patients identified had active disease at the time of transplant. Transplant specifics are listed in Table 2. Patients identified were most commonly found to have received a peripheral blood transplant (53.3%), followed by umbilical cord (25%), and bone marrow transplant (21.7%). Allogeneic transplants (81.7%) were more common among the group compared with autologous transplants (18.3%). Eighteen (30%) patients received a matched unrelated donor (MUD), 17 (28.3%) received 1 antigen mismatched unrelated donor, and 14 (23.3%) received a matched related donor transplant. The most common drugs utilized in the conditioning regimen were fludarabine (70%), melphalan (48.3%), and busulfan (28.3%). Myeloablative regimens were utilized in 39 (65%) patients. The most common mono/polyclonal antibodies patients were exposed to within 3 months prior to positive HHV-6 were antithymocyte globulin (ATG) (43.3%), rituximab (25%), and gemtuzumab (6.7%). The most common GVHD prophylaxis regimens were tacrolimus/methotrexate (46.9%) and tacrolimus/mycophenolate mofetil (26.5%). Of the allogeneic transplant recipients, 25 (51%) developed aGVHD, 12 of which were grades III and IV. Forty-four (73.3%) patients received steroids prior to HHV-6 reactivation, 23 (38.3%) of which were considered high dose (>1 mg/kg/day). Only four patients developed steroid refractory GVHD and required GVHD salvage therapy. CMV reactivation occurred in 30% of patients.
Stem cell source, n (%) Bone marrow Peripheral blood Umbilical cord Transplant type, n (%) Autologous Allogeneic Acute GVHD for allogeneic HSCT, n (%) Yes No Not evaluated Acute GVHD grade for allogeneic HSCT, n (%) I II III–IV Chronic GVHD for allogeneic HSCT, n (%) Yes No Not evaluated Steroids, n (%) High-dose steroids (>1 mg/kg), n (%) GVHD salvage therapy, n (%) CMV prophylaxis, n (%)
13 (21.7) 32 (53.3) 15 (25) 11 (18.3) 49 (81.7) 25 (51) 20 (40.8) 4 (8.2) 3 (12) 10 (40) 12 (48) 10 25 14 44 23 4 23
(20.4) (51) (28.6) (73.3) (38.3) (6.7) (38.3)
The clinical course of the cohort is shown in Figure 1 and listed in Table 3. HHV-6 reactivation occurred at a median of 25 days (IQR, 20–31.75) following transplantation and at a median 13.5 days (IQR, 11–22) following engraftment. GVHD occurred a median of 1 day prior to HHV-6 PCR positivity. The most common symptoms at the time of HHV-6 reactivation were fever (60%), neurological symptoms (33%), and pancytopenia (25%). Neurological symptoms consisted of seizures, personality changes, somnolence, delirium, agitation, or cognitive impairment. Many patients presented with more than one symptom, however, within the cohort 15% of patients presented without symptoms. All symptoms are reported in Figure 2, and patient outcomes are listed in Table 4. Treatment for HHV-6 reactivation predominately consisted of foscarnet in 38 patients and intravenous immunoglobulin (IVIG) in 20 patients. Ganciclovir was utilized in only four patients. Nineteen patients received a combination of foscarnet, ganciclovir, IVIG, cidofovir, or valganciclovir to make up a 2–4 drug regimen either in combination or sequentially. The most common combination was foscarnet with IVIG. Eighteen patients did not receive any treatment. Of the patients who did not receive treatment, 7 received an autologous transplant, while 11 received an allogeneic transplant.
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Engraftment
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Death
HHV-6 PCR Positive
Conditioning
PCR Negative
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
aGVHD Transplant
Treatment complete
Symptom resolution
Figure 1. Median clinical course of HHV-6 PCR positive HSCT patients. The median course observed was as follows: patients were conditioned on Day 5, transplanted on Day 0, engrafted on Day +13.5, patients experienced aGVHD on Day +24, HHV-6 reactivation occurred on Day +25, symptoms resolved by Day +37, HHV-6 PCR resolved on Day +43.5, treatment was continued until Day +56.5 following a median duration of 31.5 days (IQR, 14.8–59.5), and finally, death occurred on Day +92.
Table 3. Clinical course. Symptom resolution, n (%) Yes 36 No 15 No HHV-6 specific symptoms 9 Initial PCR quantitative value, copies/ml, 7029 median (IQR) Duration of HHV-6 symptoms after treat- 12 ment initiation, days, median (IQR) Duration of PCR positivity, days, median 18.5 (IQR) PCR decrease over time, n (%) Yes 32 No 6 Not repeated 22 Neutrophil count at onset of HHV-6, K/ml, 2.2 median (IQR) Engraftment day, days, median (IQR) 13.5 Days to HHV-6 positivity, days, median 25 (IQR) HHV-6 positivity to death, days, median 67 (IQR) HHV-6 date to first aGVHD, days, median 1 (IQR)
(60) (25) (15) (1428–123,853) (5–23) (9–39.5)
(53.3) (10) (36.7) (0.6–4.8) (11–22) (20–31.75) (38–237.5) (25.5 to 8.5)
Eighteen (30%) patients receiving therapy required a hold or discontinuation of primary therapy due to an adverse event. Seventeen patients receiving foscarnet experienced an adverse drug reaction (ADR) requiring discontinuation, 1 patient receiving cidofovir discontinued treatment, and 0 patients receiving ganciclovir, valganciclovir, or IVIG experienced an ADR which required treatment discontinuation. The most common ADR was acute renal failure. Fifteen patients
discontinued HHV-6 treatment due to acute renal failure and for three patients the reason for discontinuation was unclear. Among the cohort, serum creatinine increased by a median of 38.75% (IQR, 18.8–57.6) from baseline. Nine patients (15%) developed chronic renal dysfunction. The mean new baseline for patients developing chronic renal insufficiency was 1.8-fold their baseline (SD ¼ 0.34). One patient required ongoing dialysis. The median duration of symptoms was 12 days (IQR, 5–23), the median duration of PCR positivity was 18.5 days (IQR, 9–39.5), and the median duration of treatment was 31.5 days (IQR, 14.8–59.5). Twentytwo (38%) patients had resolution of symptoms and 15 (25%) had persistent disease. Fifteen percent of patients had HHV-6 recurrence, 33% were admitted to the ICU, 37% had resolution of symptoms, and 27% of patients expired by Day 100. Seventeen percent of patients receiving treatment experienced graft failure, while 22% not receiving treatment experienced graft failure. A one log reduction in PCR was observed in 82% of patients who were treated and in 90% of untreated patients. Patients receiving treatment were more likely to be admitted to the ICU (43% versus 11%) and more likely to have expired by Day 100 (31% versus 17%). A subgroup of 18 patients whom were treated for a prolonged period of time (>45 days) were analyzed. These patients were more likely to have received a cord transplant (50%) and 1 antigen mismatched unrelated allograft (50%). The median duration of symptoms was 23 days (IQR, 12.5–52), the median duration of PCR positivity was 32 days (IQR, 17.5–62), and the median duration of treatment was 63 days (IQR, 51.25–77) among this group. Eleven percent of these patients experienced graft failure, 16.7% of patients had HHV-6 recurrence, 28% were admitted
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70% 60%
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60% 50% 40%
33%
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Figure 2. Clinical manifestations of HHV-6 PCR positive HSCT patients. This bar graph represents the incidence of presenting signs and symptoms of HHV-6 PCR positive HSCT patients. Fever with no other identifiable cause was present in 60% of patients. Patients experienced various neurological symptoms which include seizures, personality changes, somnolence, delirium, agitation, or cognitive impairment. CMV reactivation occurred in 30% of patients. Many patients were also CMV positive prior to becoming HHV-6 positive. The bar graph represents CMV reactivation following HHV-6 positivity and not already CMV positive patients. Pancytopenia occurred in 25% of patients at the time of HHV-6 diagnosis and 20% of patients experienced engraftment delay. Fifteen percent of patients presented asymptomatically. Seven percent of patients presented with a rash with no other identifiable cause. Many patients presented with rash, however, other potential causes were identified and therefore could not definitively attributed to HHV-6. Various other signs and symptoms of HHV-6 are reported in this bar graph.
to the ICU, 61% had resolution of symptoms, and the median days to mortality after the first HHV-6 positive PCR were 107 days (IQR, 56–317).
Discussion This study represents one of the largest reports characterizing the clinical course of HHV-6 positive patients following HSCT. In addition, our findings confirm and extend those of previous studies, which have described potential risk factors for HHV-6 reactivation.10,11 In this study, HHV-6 reactivation occurred most often within the first month of HSCT which is consistent with prior reports describing median reactivation between 23 and 62 days.10–12 HHV-6 reactivation in the study population frequently developed shortly after engraftment and with the initial presentation of aGVHD. Interestingly, prior reports of HHV-6 and aGVHD presenting sequentially have also been observed.11,13–15 This association is even more compelling for higher grades of aGVHD.11,13 Whether there is a cause-effect relationship between HHV-6 and aGVHD cannot be determined from our study design; however, prior reports have suggested HHV-6 may trigger aGVHD.2,11,16,17 Proposed mechanisms include HHV-6 inducing tissue damage, HHV-6 infecting monocytes and cytotoxic T cells, HHV-6 up-regulating
HLA I and II expression, and/or HHV-6 increasing production of various cytokines, all of which can initiate and potentiate aGVHD.11,13–15 GVHD has also been suggested to augment HHV-6 dissemination.18 The development of aGVHD and its treatment can result in profound immunosuppression allowing unopposed replication of HHV-6 which further enhances aGVHD, thus creating a vicious cycle.14 Further describing the clinical course, we specifically gathered data on the most commonly reported symptoms, with the purpose of characterizing the number of patients manifesting these symptoms.1 It was difficult to discern the etiology of the symptoms when concomitant pathogens were isolated. Many patients had CMV reactivation (30%) and/or had a concomitant pathogen isolated at the time of HHV-6 positivity. Due to the retrospective nature, it is not possible to definitively state these symptoms were solely due to HHV-6. However, symptoms were included if it was unclear whether HHV-6 or the concomitant pathogen was the cause. Identified symptoms lasted for 2 weeks and generally subsided prior to the occurrence of a negative PCR test, however, a quarter of the study population’s symptoms never resolved. PCR quantitative values did not appear to be substantially elevated, but the clinical significance of this is unknown. Currently, there is no defined threshold of
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Table 4. Patient outcomes. Outcome of primary treatment, n (%) Resolution 22 (36.7) Switch therapy 5 (8.3) Persistent 15 (25) No treatment 18 (30) Duration of treatment, days, median (IQR) 31.5 (14.8–59.5) Treatment agent, n (%) Ganciclovir 4 (6.7) Foscarnet 38 (63.3) Cidofovir 3 (5) IVIG 20 (33.3) Valganciclovir 6 (10) Valacyclovir (prophylaxis) 1 (1.7) No treatment 18 (30) 1 agent 19 (31.7) 2 agents 18 (30) 3 agents 3 (5) 4 agents 2 (3.3) Discontinue primary therapy due to adverse event, n (%) Yes 18 (30) No 24 (40) No treatment 18 (30) Graft failure (within 30 days), n (%) 10 (16.7) Received treatment 6/42 (14.3) No treatment 4/18 (22.2) ICU admission (within 30 days), n (%) 20 (33.3) Received treatment 18/42 (42.9) No treatment 2/18 (11.1) Mortality at Day 100, n (%) 16 (26.7) Received treatment 13/42 (31) No treatment 3/18 (16.7)
viral load which constitutes symptomatic HHV-6 reactivation.19 Patients’ PCR tests were not collected routinely, with 37% did not have a follow-up to determine persistence versus resolution. For three patients with persistently elevated PCR tests, the HHV-6 viral load remained at >1 million copies/ml. Those patients were also asymptomatic and antiviral treatment had no apparent impact on the viral load, demonstrating that despite high viral loads, patients may not necessarily have active HHV-6 infection. Recent evidence suggests the virus may chromosomally integrate into host cells, where the entire HHV-6 genome is incorporated into a host cell’s chromosome. This integration leads to a persistently high viral load and can lead to the misdiagnosis that a patient is actively infected with HHV-6.20,21
Potential predisposing factors for HHV-6 reactivation were allogeneic transplant, acute myeloid leukemia (AML), active disease, MUD transplant, 1 antigen mismatched unrelated donor, umbilical cord graft, and ATG which were consistent with published reports.10,11 We did not perform an adjusted cox modeling to statistically substantiate these to be risk factors, however, these transplant characteristics were identified in a high proportion of patients. Unique to this study was 65% of the study population had active disease, but the significance of this is unknown. Patients with active disease represent a high risk transplant population as they have a more resistant malignancy, high risk for relapse, longer time without a functional immune system, and are more heavily pretreated.22 Patients of this nature, with multiple risk factors, may benefit from HHV-6 surveillance or even pre-emptive or prophylactic therapy.1,23 For the treatment of HHV-6, patients most commonly received foscarnet. Although in vitro studies have shown antiviral activity with foscarnet, ganciclovir, and cidofovir, clinicians utilized foscarnet as their drug of choice.8 No randomized comparative trials have been conducted to determine clinical superiority among one antiviral therapy over another.21,24 Since most HHV-6 reactivation occurred in close proximity to engraftment, ganciclovir was often avoided. Foscarnet for 14–21 days, with or without IVIG, followed by maintenance foscarnet was the most common treatment regimen utilized in the study population. The duration of maintenance foscarnet was difficult to discern as several patients subsequently developed CMV disease which prolonged therapy with foscarnet. The IVIG was generally given as 500 mg/kg daily or every other day. Patient’s receiving prophylaxis dosing of IVIG for IgG
Characterizing human herpes virus 6 following hematopoietic stem cell transplantation Anthony J Perissinotti, Alison Gulbis, Elizabeth J Shpall and Joshua Howell J Oncol Pharm Pract published online 9 January 2014 DOI: 10.1177/1078155213519837 The online version of this article can be found at: http://opp.sagepub.com/content/early/2014/01/09/1078155213519837
Published by: http://www.sagepublications.com
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Journal of
Oncology Pharmacy Practice
Original Article
Characterizing human herpes virus 6 following hematopoietic stem cell transplantation
J Oncol Pharm Practice 0(0) 1–8 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213519837 opp.sagepub.com
Anthony J Perissinotti1, Alison Gulbis2, Elizabeth J Shpall3 and Joshua Howell4
Abstract Background: Human herpes virus 6 reactivation occurs in approximately 50% of patients following hematopoietic stem cell transplant, however, the significance of human herpes virus 6 reactivation remains uncertain. Methods: A retrospective study was conducted analyzing clinical data of patients testing positive for human herpes virus 6 by quantitative polymerase chain reaction following hematopoietic stem cell transplant from 1 January 1998 to 1 October 2011. Data retrieved were used to describe the clinical course and outcome of human herpes virus 6 positive hematopoietic stem cell transplant patients. Results: Sixty patients were identified who tested positive for human herpes virus 6 by polymerase chain reaction following hematopoietic stem cell transplant. A high proportion of patients were identified in this cohort with acute myeloid leukemia (28.3%), active disease (65%), transplanted with a matched unrelated donor (30%), 1 antigen mismatched (28.3%) matched unrelated donor, or an umbilical cord graft (25%), and those who received antithymocyte globulin (42.4%). Thirty-eight (63.3%) patients were treated for human herpes virus 6 with foscarnet alone or in combination with intravenous immunoglobulin, whereas 18 (30%) did not require treatment survival at Day 100 was 73.3%. Conclusion: This study suggests human herpes virus 6 reactivation occurs shortly after hematopoietic stem cell transplant (median of 25 days (interquartile range, 20–31.75) after hematopoietic stem cell transplant). Many potential risk factors are described in this report. Treatment of human herpes virus 6 predominately consisted of foscarnet with or without intravenous immunoglobulin; however, treatment of human herpes virus 6 was not always warranted. Furthermore, the effect of treatment on patient outcomes is uncertain.
Keywords Human herpes virus 6, hematopoietic stem cell transplantation
Introduction Human herpes virus 6 (HHV-6) has become a significant opportunistic pathogen following hematopoietic stem cell transplantation (HSCT) and is associated with serious morbidity and mortality.1 Approximately 50% of patients become polymerase chain reaction (PCR) seropositive for HHV-6 following HSCT.2,3 Positivity is most commonly due to reactivation of the latent virus during periods of intense immune suppression.2,4 Definitive complications associated with HHV-6 remain uncertain. The virus has been suspected to cause encephalitis, pneumonitis, gastroduodenitis, cytomegalovirus (CMV) reactivation, delayed platelet and neutrophil recovery, graft failure, fever, hepatitis, and
acute graft versus host disease (aGVHD).1 However, the exact pathogenic role of HHV-6 in HSCT patients has yet to be elucidated. Skepticism remains as to 1 Department of Pharmacy, University of Michigan Health System, Ann Arbor, MI, USA 2 Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Stem Cell Transplantation, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Oncology Content, Content and Clinical Services, McKesson Specialty Health, The Woodlands, TX, USA
Corresponding author: Anthony J Perissinotti, Department of Pharmacy, University of Michigan Health System, 1111 Catherine Street, Room 330, Ann Arbor, MI 48109, USA. Email: [email protected]
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whether this virus causes a cascade of deleterious events following HSCT or whether it is merely an innocent bystander in a seriously ill patient.5 To add to the uncertainty, patients may carry HHV-6 asymptomatically, making it difficult to distinguish a clinically relevant infection and asymptomatic infection.6 Risk factors for the development of HHV-6 reactivation as well as clinical markers to distinguish infection from colonization are needed. The prognosis of HHV-6 infection following HSCT is also unclear. The clinical course may range from full recovery, to irreversible neurological compromise, to death.7 Treatment to prevent these complications includes antiviral therapy with ganciclovir, foscarnet, or cidofovir. Although in vitro data suggests these agents possess activity against HHV-6, in vivo data are lacking.8 Furthermore, it is often unknown when or who should be treated with antivirals and whether treatment impacts long-term patient outcomes.9 The primary objective of this study was to describe the clinical course of HHV-6 positive patients following HSCT. The secondary objective was to determine potential predisposing factors for the development of HHV-6 infection, thereby identifying patients who may benefit from early surveillance of HHV-6.
Methods This retrospective study was conducted at the University of Texas MD Anderson Cancer Center under an Institutional Review Board approved protocol. All adult and pediatric patients who tested positive for HHV-6 by quantitative PCR following HSCT from 1 January 1998 to 1 October 2011 were identified through the Stem Cell Transplant Department database. Patients with a history of HSCT and a positive test for HHV-6 by PCR in their blood, cerebrospinal fluid, or bone marrow were included. Medical records were reviewed, and the following data were compiled: patient demographics, transplant indication, disease status, conditioning regimen, conditioning date, transplant date, transplant type, stem cell source, donor relation, GVHD prophylaxis, mono/ polyclonal antibody exposure within 3 months of HHV-6 reactivation, steroid exposure, high-dose steroid exposure, GVHD status, GVHD treatment, CMV prophylaxis, HHV-6 PCR result, symptoms, neutrophil count, engraftment day, ICU admission within 30 days following HHV-6 reactivation, graft failure within 30 days following HHV-6 reactivation, HHV6 treatment, HHV-6 treatment related adverse events, baseline and peak serum creatinine during HHV-6 treatment, duration of HHV-6 treatment, symptom duration, outcome of primary therapy, and overall survival.
Statistical analysis was performed with GraphPad PrismÕ 5.04. Quantitative variables are reported as the number (percentage) and continuous variables as the median (interquartile range, IQR).
Definitions HHV-6 positivity was defined as at least one positive HHV-6 PCR test (above the PCR test’s threshold of detection) at any time following HSCT. HHV-6 by PCR was a send out test and not performed at our institution. HHV-6 resolution was defined as a negative PCR test following the initial HHV-6 positive PCR. HHV-6 recurrence was defined as a positive HHV-6 PCR test at any time following HHV-6 resolution. Persistent HHV-6 was defined as an HHV-6 PCR test remaining positive and/or lack of symptom resolution for >30 days. HHV-6 symptom resolution was defined as abatement of symptoms within 30 days. Switch therapy was defined as the discontinuation of primary therapy with the addition of another HHV-6 active agent. Prolonged treatment of HHV-6 was defined as HHV-6 treatment duration of >45 days. Acute GVHD was defined and graded according to Center for International Blood and Marrow Transplant Research criteria. Steroid exposure was defined as the administration of any steroid dose for >48 h within 30 days of HHV-6 reactivation. High-dose steroid exposure was defined as the administration of >1 mg/kg/day of prednisone equivalents for >48 h within 30 days of HHV-6 reactivation. Engraftment was defined as the first of three consecutive days with an absolute neutrophil count >0.5 109/l. Symptoms observed 5 days prior to or 5 days following the HHV-6 PCR positive test were collected and considered due to HHV-6 if no other identifiable cause was found and/or the patient’s medical records contained progress notes which dictated the symptom a possible result of HHV-6. Only symptoms with no other identifiable cause were included. For example, a patient presenting with rash was common, however, many other etiologies are possible. These include drug rash, aGVHD (which included up to 51% of all rash etiologies), or other infections. Whether the rash was due to HHV-6 as opposed to an alternative etiology was determined by the clinician caring for the patient.
Results A total of 60 patients were identified, and their medical records were reviewed. Patient characteristics are listed in Table 1. The median age of the cohort was 54 years (range, 2–74), and 60% of patients were male. The most common indications for transplant were acute myeloid leukemia (28.3%), non-Hodgkin lymphoma (16.7%),
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Table 1. Patient characteristics.
Table 2. Transplant specifics. n ¼ 60
Gender, n (%) Male Female Age, years, median (range) Diagnosis, n (%) Acute myeloid leukemia Myelodysplastic syndrome Acute lymphoblastic leukemia Chronic lymphocytic leukemia Chronic myelogenous leukemia Myeloma Non-Hodgkin lymphoma Hodgkin lymphoma Renal cell carcinoma Disease status, n (%) Complete response Active disease
36 (60) 24 (40) 54 (2–74) 17 7 6 9 2 6 10 2 1
(28.3) (11.7) (10) (15) (3.3) (10) (16.7) (3.3) (1.7)
21 (35) 39 (65)
chronic lymphocytic leukemia (15%), and myelodysplastic syndrome (11.7%). Thirty-nine (65%) patients identified had active disease at the time of transplant. Transplant specifics are listed in Table 2. Patients identified were most commonly found to have received a peripheral blood transplant (53.3%), followed by umbilical cord (25%), and bone marrow transplant (21.7%). Allogeneic transplants (81.7%) were more common among the group compared with autologous transplants (18.3%). Eighteen (30%) patients received a matched unrelated donor (MUD), 17 (28.3%) received 1 antigen mismatched unrelated donor, and 14 (23.3%) received a matched related donor transplant. The most common drugs utilized in the conditioning regimen were fludarabine (70%), melphalan (48.3%), and busulfan (28.3%). Myeloablative regimens were utilized in 39 (65%) patients. The most common mono/polyclonal antibodies patients were exposed to within 3 months prior to positive HHV-6 were antithymocyte globulin (ATG) (43.3%), rituximab (25%), and gemtuzumab (6.7%). The most common GVHD prophylaxis regimens were tacrolimus/methotrexate (46.9%) and tacrolimus/mycophenolate mofetil (26.5%). Of the allogeneic transplant recipients, 25 (51%) developed aGVHD, 12 of which were grades III and IV. Forty-four (73.3%) patients received steroids prior to HHV-6 reactivation, 23 (38.3%) of which were considered high dose (>1 mg/kg/day). Only four patients developed steroid refractory GVHD and required GVHD salvage therapy. CMV reactivation occurred in 30% of patients.
Stem cell source, n (%) Bone marrow Peripheral blood Umbilical cord Transplant type, n (%) Autologous Allogeneic Acute GVHD for allogeneic HSCT, n (%) Yes No Not evaluated Acute GVHD grade for allogeneic HSCT, n (%) I II III–IV Chronic GVHD for allogeneic HSCT, n (%) Yes No Not evaluated Steroids, n (%) High-dose steroids (>1 mg/kg), n (%) GVHD salvage therapy, n (%) CMV prophylaxis, n (%)
13 (21.7) 32 (53.3) 15 (25) 11 (18.3) 49 (81.7) 25 (51) 20 (40.8) 4 (8.2) 3 (12) 10 (40) 12 (48) 10 25 14 44 23 4 23
(20.4) (51) (28.6) (73.3) (38.3) (6.7) (38.3)
The clinical course of the cohort is shown in Figure 1 and listed in Table 3. HHV-6 reactivation occurred at a median of 25 days (IQR, 20–31.75) following transplantation and at a median 13.5 days (IQR, 11–22) following engraftment. GVHD occurred a median of 1 day prior to HHV-6 PCR positivity. The most common symptoms at the time of HHV-6 reactivation were fever (60%), neurological symptoms (33%), and pancytopenia (25%). Neurological symptoms consisted of seizures, personality changes, somnolence, delirium, agitation, or cognitive impairment. Many patients presented with more than one symptom, however, within the cohort 15% of patients presented without symptoms. All symptoms are reported in Figure 2, and patient outcomes are listed in Table 4. Treatment for HHV-6 reactivation predominately consisted of foscarnet in 38 patients and intravenous immunoglobulin (IVIG) in 20 patients. Ganciclovir was utilized in only four patients. Nineteen patients received a combination of foscarnet, ganciclovir, IVIG, cidofovir, or valganciclovir to make up a 2–4 drug regimen either in combination or sequentially. The most common combination was foscarnet with IVIG. Eighteen patients did not receive any treatment. Of the patients who did not receive treatment, 7 received an autologous transplant, while 11 received an allogeneic transplant.
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Engraftment
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Conditioning
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5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
aGVHD Transplant
Treatment complete
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Figure 1. Median clinical course of HHV-6 PCR positive HSCT patients. The median course observed was as follows: patients were conditioned on Day 5, transplanted on Day 0, engrafted on Day +13.5, patients experienced aGVHD on Day +24, HHV-6 reactivation occurred on Day +25, symptoms resolved by Day +37, HHV-6 PCR resolved on Day +43.5, treatment was continued until Day +56.5 following a median duration of 31.5 days (IQR, 14.8–59.5), and finally, death occurred on Day +92.
Table 3. Clinical course. Symptom resolution, n (%) Yes 36 No 15 No HHV-6 specific symptoms 9 Initial PCR quantitative value, copies/ml, 7029 median (IQR) Duration of HHV-6 symptoms after treat- 12 ment initiation, days, median (IQR) Duration of PCR positivity, days, median 18.5 (IQR) PCR decrease over time, n (%) Yes 32 No 6 Not repeated 22 Neutrophil count at onset of HHV-6, K/ml, 2.2 median (IQR) Engraftment day, days, median (IQR) 13.5 Days to HHV-6 positivity, days, median 25 (IQR) HHV-6 positivity to death, days, median 67 (IQR) HHV-6 date to first aGVHD, days, median 1 (IQR)
(60) (25) (15) (1428–123,853) (5–23) (9–39.5)
(53.3) (10) (36.7) (0.6–4.8) (11–22) (20–31.75) (38–237.5) (25.5 to 8.5)
Eighteen (30%) patients receiving therapy required a hold or discontinuation of primary therapy due to an adverse event. Seventeen patients receiving foscarnet experienced an adverse drug reaction (ADR) requiring discontinuation, 1 patient receiving cidofovir discontinued treatment, and 0 patients receiving ganciclovir, valganciclovir, or IVIG experienced an ADR which required treatment discontinuation. The most common ADR was acute renal failure. Fifteen patients
discontinued HHV-6 treatment due to acute renal failure and for three patients the reason for discontinuation was unclear. Among the cohort, serum creatinine increased by a median of 38.75% (IQR, 18.8–57.6) from baseline. Nine patients (15%) developed chronic renal dysfunction. The mean new baseline for patients developing chronic renal insufficiency was 1.8-fold their baseline (SD ¼ 0.34). One patient required ongoing dialysis. The median duration of symptoms was 12 days (IQR, 5–23), the median duration of PCR positivity was 18.5 days (IQR, 9–39.5), and the median duration of treatment was 31.5 days (IQR, 14.8–59.5). Twentytwo (38%) patients had resolution of symptoms and 15 (25%) had persistent disease. Fifteen percent of patients had HHV-6 recurrence, 33% were admitted to the ICU, 37% had resolution of symptoms, and 27% of patients expired by Day 100. Seventeen percent of patients receiving treatment experienced graft failure, while 22% not receiving treatment experienced graft failure. A one log reduction in PCR was observed in 82% of patients who were treated and in 90% of untreated patients. Patients receiving treatment were more likely to be admitted to the ICU (43% versus 11%) and more likely to have expired by Day 100 (31% versus 17%). A subgroup of 18 patients whom were treated for a prolonged period of time (>45 days) were analyzed. These patients were more likely to have received a cord transplant (50%) and 1 antigen mismatched unrelated allograft (50%). The median duration of symptoms was 23 days (IQR, 12.5–52), the median duration of PCR positivity was 32 days (IQR, 17.5–62), and the median duration of treatment was 63 days (IQR, 51.25–77) among this group. Eleven percent of these patients experienced graft failure, 16.7% of patients had HHV-6 recurrence, 28% were admitted
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Figure 2. Clinical manifestations of HHV-6 PCR positive HSCT patients. This bar graph represents the incidence of presenting signs and symptoms of HHV-6 PCR positive HSCT patients. Fever with no other identifiable cause was present in 60% of patients. Patients experienced various neurological symptoms which include seizures, personality changes, somnolence, delirium, agitation, or cognitive impairment. CMV reactivation occurred in 30% of patients. Many patients were also CMV positive prior to becoming HHV-6 positive. The bar graph represents CMV reactivation following HHV-6 positivity and not already CMV positive patients. Pancytopenia occurred in 25% of patients at the time of HHV-6 diagnosis and 20% of patients experienced engraftment delay. Fifteen percent of patients presented asymptomatically. Seven percent of patients presented with a rash with no other identifiable cause. Many patients presented with rash, however, other potential causes were identified and therefore could not definitively attributed to HHV-6. Various other signs and symptoms of HHV-6 are reported in this bar graph.
to the ICU, 61% had resolution of symptoms, and the median days to mortality after the first HHV-6 positive PCR were 107 days (IQR, 56–317).
Discussion This study represents one of the largest reports characterizing the clinical course of HHV-6 positive patients following HSCT. In addition, our findings confirm and extend those of previous studies, which have described potential risk factors for HHV-6 reactivation.10,11 In this study, HHV-6 reactivation occurred most often within the first month of HSCT which is consistent with prior reports describing median reactivation between 23 and 62 days.10–12 HHV-6 reactivation in the study population frequently developed shortly after engraftment and with the initial presentation of aGVHD. Interestingly, prior reports of HHV-6 and aGVHD presenting sequentially have also been observed.11,13–15 This association is even more compelling for higher grades of aGVHD.11,13 Whether there is a cause-effect relationship between HHV-6 and aGVHD cannot be determined from our study design; however, prior reports have suggested HHV-6 may trigger aGVHD.2,11,16,17 Proposed mechanisms include HHV-6 inducing tissue damage, HHV-6 infecting monocytes and cytotoxic T cells, HHV-6 up-regulating
HLA I and II expression, and/or HHV-6 increasing production of various cytokines, all of which can initiate and potentiate aGVHD.11,13–15 GVHD has also been suggested to augment HHV-6 dissemination.18 The development of aGVHD and its treatment can result in profound immunosuppression allowing unopposed replication of HHV-6 which further enhances aGVHD, thus creating a vicious cycle.14 Further describing the clinical course, we specifically gathered data on the most commonly reported symptoms, with the purpose of characterizing the number of patients manifesting these symptoms.1 It was difficult to discern the etiology of the symptoms when concomitant pathogens were isolated. Many patients had CMV reactivation (30%) and/or had a concomitant pathogen isolated at the time of HHV-6 positivity. Due to the retrospective nature, it is not possible to definitively state these symptoms were solely due to HHV-6. However, symptoms were included if it was unclear whether HHV-6 or the concomitant pathogen was the cause. Identified symptoms lasted for 2 weeks and generally subsided prior to the occurrence of a negative PCR test, however, a quarter of the study population’s symptoms never resolved. PCR quantitative values did not appear to be substantially elevated, but the clinical significance of this is unknown. Currently, there is no defined threshold of
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Table 4. Patient outcomes. Outcome of primary treatment, n (%) Resolution 22 (36.7) Switch therapy 5 (8.3) Persistent 15 (25) No treatment 18 (30) Duration of treatment, days, median (IQR) 31.5 (14.8–59.5) Treatment agent, n (%) Ganciclovir 4 (6.7) Foscarnet 38 (63.3) Cidofovir 3 (5) IVIG 20 (33.3) Valganciclovir 6 (10) Valacyclovir (prophylaxis) 1 (1.7) No treatment 18 (30) 1 agent 19 (31.7) 2 agents 18 (30) 3 agents 3 (5) 4 agents 2 (3.3) Discontinue primary therapy due to adverse event, n (%) Yes 18 (30) No 24 (40) No treatment 18 (30) Graft failure (within 30 days), n (%) 10 (16.7) Received treatment 6/42 (14.3) No treatment 4/18 (22.2) ICU admission (within 30 days), n (%) 20 (33.3) Received treatment 18/42 (42.9) No treatment 2/18 (11.1) Mortality at Day 100, n (%) 16 (26.7) Received treatment 13/42 (31) No treatment 3/18 (16.7)
viral load which constitutes symptomatic HHV-6 reactivation.19 Patients’ PCR tests were not collected routinely, with 37% did not have a follow-up to determine persistence versus resolution. For three patients with persistently elevated PCR tests, the HHV-6 viral load remained at >1 million copies/ml. Those patients were also asymptomatic and antiviral treatment had no apparent impact on the viral load, demonstrating that despite high viral loads, patients may not necessarily have active HHV-6 infection. Recent evidence suggests the virus may chromosomally integrate into host cells, where the entire HHV-6 genome is incorporated into a host cell’s chromosome. This integration leads to a persistently high viral load and can lead to the misdiagnosis that a patient is actively infected with HHV-6.20,21
Potential predisposing factors for HHV-6 reactivation were allogeneic transplant, acute myeloid leukemia (AML), active disease, MUD transplant, 1 antigen mismatched unrelated donor, umbilical cord graft, and ATG which were consistent with published reports.10,11 We did not perform an adjusted cox modeling to statistically substantiate these to be risk factors, however, these transplant characteristics were identified in a high proportion of patients. Unique to this study was 65% of the study population had active disease, but the significance of this is unknown. Patients with active disease represent a high risk transplant population as they have a more resistant malignancy, high risk for relapse, longer time without a functional immune system, and are more heavily pretreated.22 Patients of this nature, with multiple risk factors, may benefit from HHV-6 surveillance or even pre-emptive or prophylactic therapy.1,23 For the treatment of HHV-6, patients most commonly received foscarnet. Although in vitro studies have shown antiviral activity with foscarnet, ganciclovir, and cidofovir, clinicians utilized foscarnet as their drug of choice.8 No randomized comparative trials have been conducted to determine clinical superiority among one antiviral therapy over another.21,24 Since most HHV-6 reactivation occurred in close proximity to engraftment, ganciclovir was often avoided. Foscarnet for 14–21 days, with or without IVIG, followed by maintenance foscarnet was the most common treatment regimen utilized in the study population. The duration of maintenance foscarnet was difficult to discern as several patients subsequently developed CMV disease which prolonged therapy with foscarnet. The IVIG was generally given as 500 mg/kg daily or every other day. Patient’s receiving prophylaxis dosing of IVIG for IgG
