Clinical characteristic and outcome of HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: A retrospective study of Infectious Disease Working Party of EBMT

Clinical characteristic and outcome of HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: A retrospective study of Infectious Disease Working Party of EBMT | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Clinical characteristic and outcome of HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: A retrospective study of Infectious Disease Working Party of EBMT Simone Cesaro, Katia Perruccio, K Ward, Gloria Tridello, Nina Knelange, and 30 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6290272/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Bone Marrow Transplantation → Version 1 posted 9 You are reading this latest preprint version Abstract Human herpes virus-6 (HHV-6) is the main cause of viral encephalitis in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). From January 2005 to December 2014, 97 patients with HHV-6 encephalitis were reported in the EBMT registry. The incidence was 0.45% after the first allo-HCT and varied with the type of donor and of stem cell source: sibling donor 0.06%, unrelated donor 0.68%, haploidentical donor 0.51%, CB 2.14%, bone marrow 0.20%, peripheral blood 0.44%. HHV-6 encephalitis occurred at a median time of 31 days from allo-HCT (range 16–317 days). With a median follow-up of 5.28 years, the 5-yr OS was 24.7% while 72 of 97 patients died: disease relapse/progression 11, infection 23, non-infectious cause 33, not specified 5. Forty-four deaths (61.1%) occurred within 90 days from diagnosis of HHV-6 encephalitis and in 24 HHV-6 encephalitis was considered a contributory cause. Eight-seven patients received treatment mainly with foscarnet or ganciclovir. In multivariate analysis, bone marrow/peripheral blood stem cell source and myeloablative conditioning regimen were significant factors for lower survival. In conclusion, the incidence of HHV-6 encephalitis was low but associated with high mortality irrespective of antiviral treatment. This confirms the need for further research in this setting. Health sciences/Diseases/Infectious diseases Health sciences/Risk factors Human Herpes Virus-6 encephalitis allogeneic stem cell transplantation foscarnet ganciclovir survival Figures Figure 1 Introduction Human herpesvirus (HHV)-6 infection is reported in 30–70% of allogeneic hematopoietic cell transplantation (allo-HCT) recipients 1 – 4 . Although HHV-6 infection has been implicated with several organ diseases, encephalitis is the only end-organ disease where the pathogenicity of HHV-6 is proven 5 – 7 . Moreover, HHV-6 is the most frequent cause of encephalitis after allogeneic HCT 8 , 9 , with an incidence ranging between 0.5–11.6% 4,7 , and an attributable mortality of 12.9% after 100 days from diagnosis 6 . The main risk factors for HHV-6 encephalitis are cord blood transplantation (CB), acute grade II-IV graft versus host disease (GVHD), mismatched unrelated donors (MUD), and engraftment syndrome 3 , 4 , 8 , 10 , 11 . More recently, an unexpectedly higher incidence of HHV-6 encephalitis has been reported in haploidentical allo-HCT performed with some platforms of ex-vivo T-cell depletion characterized by a graft inoculum rich in CD4 + T-cells, which are the natural reservoir of the virus 12 , 13 . In this retrospective study, the clinical characteristics and outcome of HHV-6 encephalitis in patients receiving allo-HCT in centers belonging to the European Society for Blood and Marrow Transplantation (EBMT) were analyzed. Patients and Methods The study was approved by the scientific board of the Infectious Disease Working Party (IDWP) of EBMT and included allo-HCT patients, transplanted from January 2005 to December 2014, who matched the definition of HHV-6 encephalitis (see definitions). The general demographic, clinical, and transplant data of the case patients were extracted from the EBMT registry while additional information on HHV-6 infection and disease was collected using a dedicated case report form. Definitions For this study, HHV-6 encephalitis was defined by the presence of all the following three criteria: (1) clinical signs or symptoms of central nervous system (CNS) dysfunction consistent with encephalitis; (2) detection by PCR of HHV-6 DNA in cerebral spinal fluid (CSF); and (3) absence of other identified causes of CNS dysfunction, including other infectious agents 6 . The time of encephalitis diagnosis was defined as the date of HHV-6 DNA detection in CSF. CNS dysfunction was described as: disorientation in time and place, loss of consciousness, change of personality, behavioral changes, convulsions, memory loss, or dysesthesia not attributable to peripheral neuropathy 12 , 13 . Considering that magnetic resonance imaging (MRI) has been described as normal in up to 30% of patients 12 , 14 , 15 , and the lack of a common diagnostic protocol among participating centers 16 , it was not a part of the inclusion criteria. The contribution of HHV-6 encephalitis in determining the cause of death was based on the clinical judgment of the local investigator. HHV-6 infection was defined as a PCR DNAemia > 1000 copies/mL on plasma or blood 5 . Surveillance, monitoring, or diagnostic assessment of other DNA-virus infections such as cytomegalovirus (CMV), adenovirus (ADV), and Epstein-Barr virus (EBV) by blood or plasma PCR followed the center policies, according to the type of transplant and the risk characteristics of patients. Statistical analyses Descriptive results were reported by using absolute and percentage frequencies for categorical variables, whilst median and range were used for continuous variables. The overall survival was performed by using the Kaplan-Meier methods, and compared by using the log-rank test. The univariate and multivariate analysis was performed by using the Cox regression model. Variables with a p < 0.1 in the univariate analysis entered the multivariate model. A p < 0.05 was considered statistically significant. Results During the study period, 100 patients with HHV-6 encephalitis were reported by the 41 EBMT participating centers. During the study’s period, the number of allo-HCTs performed in the centres that reported cases of HHV-6 encephalitis was 22,492 in 20,148 patients. Three of 100 patients did not meet the study inclusion criteria because no lumbar puncture was performed: two patients had a neurological picture consistent with encephalitis (one altered consciousness/confusion, MRI abnormal; one short term memory loss, altered consciousness and seizures, MRI normal) and HHV-6 DNAemia (viral load of 2.5 x 10 6 copy/ml in one patient, while the viral load was not reported in the second one); the third patient had a clinical picture of encephalitis (short-term memory loss, altered consciousness, seizures) with MRI imaging consistent with limbic encephalitis while the search of HHV-6 in the blood was not performed. These 3 patients were excluded from the analysis. Demographic, underlying disease, and transplant characteristics of the 97 case patients are shown in Table 1 . Sixty-eight percent of patients were male, and 21% were younger than 18 years. The donor type was mainly an unrelated donor (91%), while the source of hematopoietic stem cells was bone marrow (BM) in 11%, peripheral blood (PB) in 67% and CB in 22% of all HCTs. Myeloablative and reduced intensity conditioning regimens were used in 57% and 41% of allo-HCTs, respectively, while it was unknown in 2%. Ninety-two cases of 97 HHV-6 encephalitis occurred (97%) after the first allo-HCT. The frequency of HHV-6 encephalitis was 0.45% (92/20418) among the first allo-HCT and 0.24% (5/2074) in the group of two or more allo-HCTs. Considering the cases of HHV-6 encephalitis after a first allo-HCT, the frequency varied according to the type of donor and the stem cell source: sibling donor 0.06% (4/6918), unrelated donor 0.68% (83/12191), haploidentical donor 0.51% (5/981), p < 0.001, and CB 2.14% (20/936), BM 0.20% (10/5088), PB 0.44% (62/14192), p < 0.001. Characteristics of HHV-6 encephalitis All 97 patients presented neurological signs and symptoms consistent with the clinical diagnosis of encephalitis while 65 patients were also febrile and 32 patients had skin rash. HHV-6 was detected on the cerebrospinal fluid by qualitative PCR in 51 patients (53%) and by a quantitative PCR in 46 patients (47%), the median viral load being 7615 copies/ml, range 215– 18000000. The search of HHV-6 DNA on blood/plasma/serum was performed in 63 of 97 patients (65%) and resulted positive in 51 patients (81%): 18 patients were tested by qualitative PCR while 33 patients were tested by a quantitative PCR, with a median number of copies/ml of 15630, range 200-4458500. Radiological investigation was performed with computed tomography (CT) scan and MRI in 69 and 81 patients, respectively and abnormalities were reported in 12 cases (17.4%) with CT scans and in 51 cases (63%) with MRI. HHV-6 encephalitis occurred at a median time of 31 days from allo-HCT (range: 16–317 days) without significant differences according to the age group: 27 days (range: 19–225) for age 50 years; or according the stem cell source: 37 days (range: 19–225) for CB recipients and 30 days (range: 16–317) for BM or PB recipients. Outcome The 90-day and 1-year OS were 55% (95% C.I. 46–66), and 41% (95% C.I. 32–52), respectively. With a median follow-up of 5.28 years (95% confidence interval (CI), 5.01–7.83) the 5-yr OS was 24.7% (95% C.I.,17.1–35.6) while 72 of 97 (74.2%) patients died (Fig. 1 ). Five of 25 patients alive at the follow-up were reported to have sequelae related to previous HHV-6 episodes although a detailed description of the type and the severity of sequelae was not available. According to the local investigator’s judgment, the main cause of death was: relapse or progression of the underlying disease 11 (15.3%), infection cause (any) 23 (31.9%), non-infectious cause 33 (45.8%) that was GVHD in 24 of 33 (72.7%), while it was not specified in 5 (6.9%). Forty-four of 72 deaths (61.1%) occurred 90 days after diagnosis of HHV-6 encephalitis. In 24 of 44 90-day deaths (54.5%) the center's investigator defined HHV-6 encephalitis as a contributory cause of death because it was clinically present at death in 2 of 5 relapsed patients, in 14 of 18 patients who died from any infection cause, and in 8 of 19 patients who died from a non-infectious cause. In univariate analysis, the factors associated with lower OS after HHV-6 encephalitis were the type of stem cell source and intensity of conditioning regimen: BM/PB graft 34% (95% CI, 25%-47%) vs. CB 67% (95% CI, 49%, 90%), HR 2.26 p = 0.01; and nonmyeloablative conditioning regimen 28% (95% CI, 17%-45%) vs. myeloablative conditioning regimen, 51% (95% CI, 39%-66%) HR 1.82, p = 0.01 (Table 2 ). Table 2 Univariate analysis of risk factors for overall survival in patients with HHV-6 encephalitis Variable N Overall N = 97 N° events 28 Days OS (95% C.I.) 90 Days OS (95% C.I.) 365 Days OS (95% C.I.) HR 95% CI p-value* All 97 72 77% (69%, 86%) 55% (46%, 66%) 41% (32%, 52%) Sex 97 M 66 (68%) 49 77% (68%, 88%) 58% (47%, 71%) 42% (32%, 56%) 1.00 F 31 (32%) 23 77% (64%, 94%) 48% (34%, 70%) 39% (25%, 60%) 1.05 0.64, 1.73 0.8 Age class 97 ≤ 18 year 20 (21%) 11 90% (78%, 100%) 70% (53%, 93%) 55% (37%, 82%) — — >18 year 77 (79%) 61 74% (65%, 84%) 51% (41%, 63%) 38% (28%, 50%) 1.88 0.99, 3.58 0.055 Underlying disease 92 AL - B-cell lymphoma 52 (57%) 36 79% (68%, 91%) 56% (44%, 71%) 40% (29%, 56%) — — Other 40 (43%) 33 78% (66%, 92%) 53% (39%, 70%) 40% (27%, 58%) 1.22 0.76, 1.96 0.4 Donor type 97 Haplo 5 (5.2%) 4 Identical sibling 4 (4.1%) 4 - Unrelated 88 (91%) 64 77% (69%, 87%) 57% (47%, 68%) 44% (35%, 56%) Stem cell source 97 CB 21 (22%) 11 86% (72%, 100%) 76% (60%, 97%) 67% (49%, 90%) 1.00 BM/PB 76 (78%) 61 75% (66%, 85%) 49% (39%, 61%) 34% (25%, 47%) 2.26 1.18, 4.33 0.014 Myeloablative conditioning regimen 95 No 40 (42%) 34 73% (60%, 88%) 43% (30%, 61%) 28% (17%, 45%) 1.82 1.12–2.94 0.014 Yes 55 (58%) 37 80% (70%, 91%) 64% (52%, 78%) 51% (39%, 66%) 1.00 Number of Allo-HCT 97 1 92 (95%) 68 78% (70%, 87%) 55% (46%, 67%) 42% (33%, 54%) 2 5 (5.2%) 4 60% (29%, 100%) 40% (14%, 100%) 20% (3.5%, 100%) Legend. M, male; F, female; Allo-HCT, allogeneic hematopoietic cell transplantation; CB, cord blood; BM, bone marrow; PB, peripheral blood; Haplo, haploidentical Stem cell source and intensity of conditioning regimen were confirmed in the multivariate analysis as significant factors for overall mortality: BM/PB vs. CB HR 2.21 (95% C.I., 1.12–4.35), p = 0.02; nonmyeloablative conditioning vs. myeloablative conditioning HR 1.76 (95% C.I. 1.09–2.83), p = 0.02. Eighty-seven of 97 patients (89.7%) received an antiviral treatment for HHV-6 encephalitis, as follows: foscarnet monotherapy, 32 patients for a median of 19 days, range 1-111 days; ganciclovir monotherapy, 29 patients for a median of 22 days, range 7-121; ganciclovir followed by foscarnet, 17 patients for a median of 29 days, range 12–75; combination of ganciclovir and foscarnet, 7 patients for a median of 15 days, range 7–38; cidofovir, 2 patients for 4 weeks. Ninety-day mortality after the diagnosis of HHV-6 encephalitis was 56% (18/32) in patients treated with foscarnet, 38% (11/29) in patients treated with ganciclovir, 42% (10/24) in patients treated with the combination of the sequence of ganciclovir plus foscarnet, (10), while the two patients treated with cidofovir were alive. In the group of 10 untreated patients, 5 deaths occurred by 90 days and 3 deaths occurred thereafter. Discussion This study represents an attempt to assess the incidence and the outcome of HHV-6 encephalitis in centers belonging to the EBMT network. Overall, HHV-6 encephalitis was a rare complication with an incidence of 0.45% over a 10-year period. We recognize that this figure is lower than that reported by other authors. Considering that the reporting of infectious complications in the EBMT registry was performed voluntarily and the difficulty in defining the cause of CNS acute disease in allo-HCT patients, we can hypothesize that this incidence is underestimated. In a prospective study performed by the IDWP collecting CNS clinical events over two years (2000–2002), the infectious events were nearly half of the non-infectious events, which were mainly vascular events, and among 58 infectious complications, only two were attributed to HHV-6 CNS infection 17 . Nowadays, the more extended use than one decade ago earlier of PCR assays for CSF analysis and MRI imaging allows an improvement in defining the causes of CNS acute dysfunction. We excluded from our analysis three patients who did not perform the lumbar puncture to confirm the clinical suspicion of HHV-6 encephalitis although the presence of clinical signs and symptoms of encephalitis, together with HHV-6 detection in blood or radiological evidence of limbic encephalopathy, has been accepted to define HHV-6-associated encephalitis 13 . Recently, in a retrospective study in the adult Japanese population the incidence of HHV-6 encephalitis was 3.6% and associated with the use of CB as a stem cell source, the adoption of antiviral prophylaxis different from letermovir and the occurrence of GVHD that needed treatment with steroids 18 . The use of CB was associated with a higher incidence of HHV-6 encephalitis also in this study. HHV-6 encephalitis occurred early after HCT irrespective of the age of the recipient (pediatric vs. adult) and the stem cell source. This is in line with other reports where HHV-6 encephalitis was observed most commonly within 4–6 weeks after transplant 18 , 19 . In the survival analysis, adult age, bone marrow or peripheral blood stem cell source, and non-myeloablative conditioning regimen were associated with lower survival after HHV-6 encephalitis. We think that these factors define a high-risk profile recipient for transplant-related complications and overall mortality. Generally, adult transplant recipients have more comorbidities than pediatric patients, and the use of non-myeloablative conditioning may have a higher relapse risk than a myeloablative HCT, and BM or PB are the preferred stem cell source used for mismatched relative or haploidentical transplant 18 , 19 . We think that the reason why CB grafts had a better survival outcome was that this procedure was adopted in more than half of cases in children and young adults affected by acute lymphoblastic leukemia (data not shown) who had a better transplant outcome than adults transplanted with a BM or PB stem cell source. No drug is officially approved to treat HHV-6 infection or disease. While the treatment of asymptomatic post-transplant HHV-6 DNAemia is not recommended, antiviral treatment of HHV-6 encephalitis with foscarnet or ganciclovir is recommended by guidelines 5 , 20 . Foscarnet and ganciclovir are considered first-line treatments, and the choice is based on the clinician's assessment of the patient’s comorbidities, the risk for side effects, and drug-drug interactions. In this study, the type of antiviral treatment was not associated with significant differences in early mortality. Accordingly, no significant difference in efficacy has been reported between foscarnet and ganciclovir monotherapy. A better response rate and a lower sequelae rate after HHV-6 encephalitis have been reported for both antivirals when used at a full dose (foscarnet > 180 mg/kg, ganciclovir > 10 mg/kg), but these did not lead to differences in terms of 30 days and 100 days overall survival after HHV-6 encephalitis 6 . Cidofovir, though effective in vitro against HHV-6, has limited data on efficacy and can be considered an option as rescue or an alternative after treatment with foscarnet or ganciclovir 5 , 21 , 22 . Brincidofovir, a prodrug of cidofovir, might be an option in the future but currently is not available 23 . In conclusion, in this retrospective study, the incidence of HHV-6 encephalitis was low, but high mortality was confirmed irrespective of antiviral treatment. The risk factors associated with higher mortality and lower OS were adult age, the use of BM or PB as a stem cell source, and the nonmyeloablative condition regimen. Even though this study refers to patients transplanted more than a decade ago, it describes a very large series of post-allo-HCT HHV-6-related encephalitis and confirms the role of HHV-6 in the occurrence of encephalitis complications. Future research is needed to assess is usefulness of HHV-6 DNAemia monitoring, the correlation of HHV-6 infection with the development of HHV-6-related organ diseases, and the role of pre-emptive antiviral treatment in preventing HHV-6 encephalitis. Declarations Authorship and author contributions K.N.W. designed the study, N.K. collected the data, G.T. performed the statistical analysis, K.P. and S.C. analyzed the data and wrote the paper; the remaining authors were responsible for caring for the patients and reporting the data. All authors approved the final version of the manuscript. Disclosures This is a Registry study conducted under the scientific supervision of IDWP-EBMT. All authors have no conflict of interest concerning this study to disclose. References Yamane A, Mori T, Suzuki S, Mihara A, Yamazaki R, Aisa Y et al. Risk factors for developing human herpesvirus 6 (HHV-6) reactivation after allogeneic hematopoietic stem cell transplantation and its association with central nervous system disorders. Biol Blood Marrow Transplant 2007; 13: 100–106. Zerr DM, Corey L, Kim HW, Huang M-L, Nguy L, Boeckh M. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis 2005; 40: 932–940. Ogata M, Satou T, Kadota J, Saito N, Yoshida T, Okumura H et al. Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study. Clin Infect Dis 2013; 57: 671–681. Scheurer ME, Pritchett JC, Amirian ES, Zemke NR, Lusso P, Ljungman P. 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Demographic and transplant characteristics of patients with HHV-6 encephalitis Number of HHV-6 encephalitis episodes 97 Age at allo-HCT, median (range) 48.4 (0.4-77.5) 18 year 20 (21%) 77 (79%) M/F 66/31 Underlying disease Acute leukaemia, Myelodysplastic/Myeloproliferative, Chronic leukaemia, Lymphoma Hodgkin/Non Hodgkin Plasma cell disorders Bone marrow failure Inherited disorders 44 (45%) 24 (25%) 10 (10%) 8 (8%) 6 (6%) 2 (2%) 3 (3%) Donor type Sibling Unrelated donor Haploidentical donor 4 (4%) 88 (91%) 5 (5%) Conditioning regimen Myeloablative Non-myeloablative Not specified 55 (57%) 40 (41%) 2 (2%) Stem cell source Bone marrow Peripheral blood Cord blood 11 (11%) 65 (67%) 21 (22%) 1 st allo-HCT/ > 2 nd allo-HCT 92/5 Interval allo-HCT-HHV-6 encephalitis median, range 31 days, 16 days – 317 days Neurological symptoms Short term memory loss Altered consciousness, encephalopathy, confusion, Seizures 51/94 (54.3%) , N.S. in 3 89/96 (92.7%), N.S. in 1 58/95 (61.1%), N.S. in 2 Other symptoms/signs fever rash 65 (67%) 32/92 (34%); N.S. in 5 HHV-6 DNA on CSF by PCR qualitative PCR quantitative PCR median range (copies/ml) 51/97 (53%) 46 (47%) 7615 (215 – 18000000) CT scan, yes abnormal findings 69/97 (71%) 12/69 (17.4%) MRI imaging, yes abnormal findings 81/97 (84%), 51/81 (63%) Other viral infection (by PCR DNA-emia) before HHV-6 encephalitis (N° days) after HHV-6 encephalitis (N° days) Co-infection 1 CMV (77), 1 ADV (99) 1 BKPyV (14), 1 ADV (26), 1 HHV-7 (26) 1 CMV Median follow-up time (from encephalitis) 5.28 years, (95% C.I., 5.01-7.83) Deaths, total number 72 Cause of death relapse/progression infectious non-infectious missing 11/72 (15%) 23 (32%) 33 (46%) 5 (7%) 5-yr OS 24.7% (95% C.I., 17.1-35.6) Legend. HHV-6, Human Herpes Virus-6 encephalitis; M, male; F, female; Allo-HCT: allogeneic hematopoietic cell transplant; N.S.: not specified; CT, computed tomography; MRI, magnetic resonance imaging; CMV, cytomegalovirus; ADV, adenovirus; BKPyV, BK polyoma virus; HHV-7, human herpes virus-7; OS, overall survival; C.I., confidence interval Table 2 is available in the Supplementary Files section. Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files HHV6Table2v018SC.docx Table 2 Annex1.docx Cite Share Download PDF Status: Published Journal Publication published 03 Jun, 2025 Read the published version in Bone Marrow Transplantation → Version 1 posted Editorial decision: revise 14 Apr, 2025 Review # 1 received at journal 11 Apr, 2025 Review # 2 received at journal 10 Apr, 2025 Reviewer # 2 agreed at journal 02 Apr, 2025 Reviewer # 1 agreed at journal 01 Apr, 2025 Reviewers invited by journal 28 Mar, 2025 Submission checks completed at journal 24 Mar, 2025 First submitted to journal 23 Mar, 2025 Editor assigned by journal 23 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6290272","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":435498201,"identity":"0319793f-62b6-4dca-b609-1a16e1237c10","order_by":0,"name":"Simone Cesaro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIiWNgGAWjYDACZhReBQqPsYEILWcQTAmglkbselCMbUPRgt0a+XbuxMcFFQzy/PyHn334OM9OzuD2ATaJjzts6vgZmNsfYNFicJh3s/GMMwyGM2ekGc+cuS3Z2OBcApvkzDNpEpIN2B1mwMy7TZq3jSHB4AaDMZDNnDizh4HZmLftsITBAexa5JtBWv4xJNifP/6ZmXdOPUTL37b/OLUwHAZpaQDawpADtKXhcGI/DwPjY8a2Azi1gP3Cc0zCcMaNnGLGGceOG/PzMDY+7G1LlpzZzNg4A5vD+s9ufMxTYyPP3398M8OHmmo5Nh7mAwd+ttnx87O3P/iAzWEQIIHMgcUGMxaFo2AUjIJRMAqIAgDG31m3Fka2EwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8698-9547","institution":"Pediatric Hematology Oncology, Ospedale Donna Bambino","correspondingAuthor":true,"prefix":"","firstName":"Simone","middleName":"","lastName":"Cesaro","suffix":""},{"id":435498202,"identity":"b7477f2c-9d49-4d16-8c57-188b2e5adcc9","order_by":1,"name":"Katia Perruccio","email":"","orcid":"https://orcid.org/0000-0003-0431-3197","institution":"Pediatric Oncology Hematology","correspondingAuthor":false,"prefix":"","firstName":"Katia","middleName":"","lastName":"Perruccio","suffix":""},{"id":435498203,"identity":"62561af6-d3ca-456c-b35f-fe3f1c07a609","order_by":2,"name":"K Ward","email":"","orcid":"","institution":"University College Hospital, London","correspondingAuthor":false,"prefix":"","firstName":"K","middleName":"","lastName":"Ward","suffix":""},{"id":435498204,"identity":"444d11d1-43cf-43c4-a143-29b652662fb4","order_by":3,"name":"Gloria Tridello","email":"","orcid":"","institution":"Policlinico G.B. 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Valdecilla","correspondingAuthor":false,"prefix":"","firstName":"Mónica","middleName":"","lastName":"López-Duarte","suffix":""},{"id":435498229,"identity":"c0ba79b1-ed1f-45ed-b4fe-58bd136fbdaa","order_by":28,"name":"Adrien Alegre Amor","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Adrien","middleName":"Alegre","lastName":"Amor","suffix":""},{"id":435498230,"identity":"9c19862e-4da5-4ab8-9085-8d81a9463e01","order_by":29,"name":"Maija Itälä-Remes","email":"","orcid":"","institution":"Turku University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Maija","middleName":"","lastName":"Itälä-Remes","suffix":""},{"id":435498231,"identity":"ad587014-37cb-40c0-a281-c7124b303d5a","order_by":30,"name":"Malgorzata Mikulska","email":"","orcid":"https://orcid.org/0000-0002-5535-4602","institution":"University of Genoa (DISSAL) and Ospedale Policlinico San Martino","correspondingAuthor":false,"prefix":"","firstName":"Malgorzata","middleName":"","lastName":"Mikulska","suffix":""},{"id":435498232,"identity":"af5517c1-9ec4-4dbe-aed3-381a3dfa9dd8","order_by":31,"name":"Jan Styczynski","email":"","orcid":"https://orcid.org/0000-0002-3158-119X","institution":"Collegium Medicum Nicolaus Copernicus University","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Styczynski","suffix":""},{"id":435498233,"identity":"87161680-0ec8-4825-91ce-847b34771087","order_by":32,"name":"Rafael De la Cámara LLanzá","email":"","orcid":"https://orcid.org/0000-0002-8189-5779","institution":"Hospital La Princesa","correspondingAuthor":false,"prefix":"","firstName":"Rafael","middleName":"De la Cámara","lastName":"LLanzá","suffix":""},{"id":435498234,"identity":"b3a1385c-daa4-46c4-ba3f-c0fe4544eac9","order_by":33,"name":"Per Ljungman","email":"","orcid":"https://orcid.org/0000-0002-8281-3245","institution":"Karolinska University Hospital / Huddinge","correspondingAuthor":false,"prefix":"","firstName":"Per","middleName":"","lastName":"Ljungman","suffix":""},{"id":435498235,"identity":"7bc7d930-1bdb-4360-bc65-b7a7b4bd2349","order_by":34,"name":"Diana Averbuch","email":"","orcid":"","institution":"Hadassah University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Diana","middleName":"","lastName":"Averbuch","suffix":""}],"badges":[],"createdAt":"2025-03-23 21:55:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6290272/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6290272/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41409-025-02638-7","type":"published","date":"2025-06-03T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81012723,"identity":"7566081d-abf9-4d09-bc6f-154b07b5a8d4","added_by":"auto","created_at":"2025-04-21 08:31:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35464,"visible":true,"origin":"","legend":"\u003cp\u003eProbability of overall survival in the patients with HHV-6 encephalitis\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6290272/v1/ed39bdf22e67b06227f04c26.png"},{"id":83887238,"identity":"541955df-6675-4b4d-8e2b-7c0ddb647dba","added_by":"auto","created_at":"2025-06-04 07:08:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1057115,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6290272/v1/f4736acc-9731-4d91-bff5-91ddd124e2aa.pdf"},{"id":81012725,"identity":"aa8aba33-eb9e-4e53-ab50-eadf917c1dcd","added_by":"auto","created_at":"2025-04-21 08:31:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":22412,"visible":true,"origin":"","legend":"Table 2","description":"","filename":"HHV6Table2v018SC.docx","url":"https://assets-eu.researchsquare.com/files/rs-6290272/v1/98466bb8fec8b89f234f4988.docx"},{"id":81012724,"identity":"05e1b6ac-e116-4e4d-9804-74bc0809f268","added_by":"auto","created_at":"2025-04-21 08:31:27","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14977,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Annex1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6290272/v1/dbf299b738512638acd50c14.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Clinical characteristic and outcome of HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: A retrospective study of Infectious Disease Working Party of EBMT","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman herpesvirus (HHV)-6 infection is reported in 30\u0026ndash;70% of allogeneic hematopoietic cell transplantation (allo-HCT) recipients\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Although HHV-6 infection has been implicated with several organ diseases, encephalitis is the only end-organ disease where the pathogenicity of HHV-6 is proven\u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Moreover, HHV-6 is the most frequent cause of encephalitis after allogeneic HCT\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, with an incidence ranging between 0.5\u0026ndash;11.6% \u003csup\u003e4,7\u003c/sup\u003e, and an attributable mortality of 12.9% after 100 days from diagnosis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The main risk factors for HHV-6 encephalitis are cord blood transplantation (CB), acute grade II-IV graft versus host disease (GVHD), mismatched unrelated donors (MUD), and engraftment syndrome\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. More recently, an unexpectedly higher incidence of HHV-6 encephalitis has been reported in haploidentical allo-HCT performed with some platforms of \u003cem\u003eex-vivo\u003c/em\u003e T-cell depletion characterized by a graft \u003cem\u003einoculum\u003c/em\u003e rich in CD4\u0026thinsp;+\u0026thinsp;T-cells, which are the natural reservoir of the virus \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this retrospective study, the clinical characteristics and outcome of HHV-6 encephalitis in patients receiving allo-HCT in centers belonging to the European Society for Blood and Marrow Transplantation (EBMT) were analyzed.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eThe study was approved by the scientific board of the Infectious Disease Working Party (IDWP) of EBMT and included allo-HCT patients, transplanted from January 2005 to December 2014, who matched the definition of HHV-6 encephalitis (see definitions). The general demographic, clinical, and transplant data of the case patients were extracted from the EBMT registry while additional information on HHV-6 infection and disease was collected using a dedicated case report form.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions\u003c/h2\u003e \u003cp\u003eFor this study, HHV-6 encephalitis was defined by the presence of all the following three criteria: (1) clinical signs or symptoms of central nervous system (CNS) dysfunction consistent with encephalitis; (2) detection by PCR of HHV-6 DNA in cerebral spinal fluid (CSF); and (3) absence of other identified causes of CNS dysfunction, including other infectious agents \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The time of encephalitis diagnosis was defined as the date of HHV-6 DNA detection in CSF. CNS dysfunction was described as: disorientation in time and place, loss of consciousness, change of personality, behavioral changes, convulsions, memory loss, or dysesthesia not attributable to peripheral neuropathy\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Considering that magnetic resonance imaging (MRI) has been described as normal in up to 30% of patients\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, and the lack of a common diagnostic protocol among participating centers \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, it was not a part of the inclusion criteria.\u003c/p\u003e \u003cp\u003eThe contribution of HHV-6 encephalitis in determining the cause of death was based on the clinical judgment of the local investigator.\u003c/p\u003e \u003cp\u003eHHV-6 infection was defined as a PCR DNAemia\u0026thinsp;\u0026gt;\u0026thinsp;1000 copies/mL on plasma or blood\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Surveillance, monitoring, or diagnostic assessment of other DNA-virus infections such as cytomegalovirus (CMV), adenovirus (ADV), and Epstein-Barr virus (EBV) by blood or plasma PCR followed the center policies, according to the type of transplant and the risk characteristics of patients.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eDescriptive results were reported by using absolute and percentage frequencies for categorical variables, whilst median and range were used for continuous variables. The overall survival was performed by using the Kaplan-Meier methods, and compared by using the log-rank test. The univariate and multivariate analysis was performed by using the Cox regression model. Variables with a \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in the univariate analysis entered the multivariate model. A \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period, 100 patients with HHV-6 encephalitis were reported by the 41 EBMT participating centers. During the study\u0026rsquo;s period, the number of allo-HCTs performed in the centres that reported cases of HHV-6 encephalitis was 22,492 in 20,148 patients.\u003c/p\u003e\n\u003cp\u003eThree of 100 patients did not meet the study inclusion criteria because no lumbar puncture was performed: two patients had a neurological picture consistent with encephalitis (one altered consciousness/confusion, MRI abnormal; one short term memory loss, altered consciousness and seizures, MRI normal) and HHV-6 DNAemia (viral load of 2.5 x 10\u003csup\u003e6\u003c/sup\u003e copy/ml in one patient, while the viral load was not reported in the second one); the third patient had a clinical picture of encephalitis (short-term memory loss, altered consciousness, seizures) with MRI imaging consistent with limbic encephalitis while the search of HHV-6 in the blood was not performed. These 3 patients were excluded from the analysis.\u003c/p\u003e\n\u003cp\u003eDemographic, underlying disease, and transplant characteristics of the 97 case patients are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Sixty-eight percent of patients were male, and 21% were younger than 18 years. The donor type was mainly an unrelated donor (91%), while the source of hematopoietic stem cells was bone marrow (BM) in 11%, peripheral blood (PB) in 67% and CB in 22% of all HCTs. Myeloablative and reduced intensity conditioning regimens were used in 57% and 41% of allo-HCTs, respectively, while it was unknown in 2%.\u003c/p\u003e\n\u003cp\u003eNinety-two cases of 97 HHV-6 encephalitis occurred (97%) after the first allo-HCT. The frequency of HHV-6 encephalitis was 0.45% (92/20418) among the first allo-HCT and 0.24% (5/2074) in the group of two or more allo-HCTs. Considering the cases of HHV-6 encephalitis after a first allo-HCT, the frequency varied according to the type of donor and the stem cell source: sibling donor 0.06% (4/6918), unrelated donor 0.68% (83/12191), haploidentical donor 0.51% (5/981), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, and CB 2.14% (20/936), BM 0.20% (10/5088), PB 0.44% (62/14192), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e\n\u003ch3\u003eCharacteristics of HHV-6 encephalitis\u003c/h3\u003e\n\u003cp\u003eAll 97 patients presented neurological signs and symptoms consistent with the clinical diagnosis of encephalitis while 65 patients were also febrile and 32 patients had skin rash. HHV-6 was detected on the cerebrospinal fluid by qualitative PCR in 51 patients (53%) and by a quantitative PCR in 46 patients (47%), the median viral load being 7615 copies/ml, range 215\u0026ndash; 18000000.\u003c/p\u003e \u003cp\u003eThe search of HHV-6 DNA on blood/plasma/serum was performed in 63 of 97 patients (65%) and resulted positive in 51 patients (81%): 18 patients were tested by qualitative PCR while 33 patients were tested by a quantitative PCR, with a median number of copies/ml of 15630, range 200-4458500.\u003c/p\u003e \u003cp\u003eRadiological investigation was performed with computed tomography (CT) scan and MRI in 69 and 81 patients, respectively and abnormalities were reported in 12 cases (17.4%) with CT scans and in 51 cases (63%) with MRI.\u003c/p\u003e \u003cp\u003eHHV-6 encephalitis occurred at a median time of 31 days from allo-HCT (range: 16\u0026ndash;317 days) without significant differences according to the age group: 27 days (range: 19\u0026ndash;225) for age\u0026thinsp;\u0026lt;\u0026thinsp;18 years, 31 days (range: 19\u0026ndash;317) for age 19\u0026ndash;49 years, and 33 days (range: 16\u0026ndash;203) for age\u0026thinsp;\u0026gt;\u0026thinsp;50 years; or according the stem cell source: 37 days (range: 19\u0026ndash;225) for CB recipients and 30 days (range: 16\u0026ndash;317) for BM or PB recipients.\u003c/p\u003e\n\u003ch3\u003eOutcome\u003c/h3\u003e\n\u003cp\u003eThe 90-day and 1-year OS were 55% (95% C.I. 46\u0026ndash;66), and 41% (95% C.I. 32\u0026ndash;52), respectively. With a median follow-up of 5.28 years (95% confidence interval (CI), 5.01\u0026ndash;7.83) the 5-yr OS was 24.7% (95% C.I.,17.1\u0026ndash;35.6) while 72 of 97 (74.2%) patients died (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Five of 25 patients alive at the follow-up were reported to have sequelae related to previous HHV-6 episodes although a detailed description of the type and the severity of sequelae was not available. According to the local investigator\u0026rsquo;s judgment, the main cause of death was: relapse or progression of the underlying disease 11 (15.3%), infection cause (any) 23 (31.9%), non-infectious cause 33 (45.8%) that was GVHD in 24 of 33 (72.7%), while it was not specified in 5 (6.9%). Forty-four of 72 deaths (61.1%) occurred 90 days after diagnosis of HHV-6 encephalitis. In 24 of 44 90-day deaths (54.5%) the center's investigator defined HHV-6 encephalitis as a contributory cause of death because it was clinically present at death in 2 of 5 relapsed patients, in 14 of 18 patients who died from any infection cause, and in 8 of 19 patients who died from a non-infectious cause.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn univariate analysis, the factors associated with lower OS after HHV-6 encephalitis were the type of stem cell source and intensity of conditioning regimen: BM/PB graft 34% (95% CI, 25%-47%) vs. CB 67% (95% CI, 49%, 90%), HR 2.26 \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01; and nonmyeloablative conditioning regimen 28% (95% CI, 17%-45%) vs. myeloablative conditioning regimen, 51% (95% CI, 39%-66%) HR 1.82, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01 (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate analysis of risk factors for overall survival in patients with HHV-6 encephalitis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eOverall \u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;97\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eN\u0026deg;\u003c/p\u003e \u003cp\u003eevents\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28 Days\u003c/p\u003e \u003cp\u003eOS (95% C.I.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e90 Days\u003c/p\u003e \u003cp\u003eOS (95% C.I.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e365 Days\u003c/p\u003e \u003cp\u003eOS (95% C.I.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003ep-value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAll\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e77% (69%, 86%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e55% (46%, 66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e41% (32%, 52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e66 (68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e77% (68%, 88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e58% (47%, 71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e42% (32%, 56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e31 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e77% (64%, 94%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e48% (34%, 70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e39% (25%, 60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.64, 1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge class\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;18 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e20 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e90% (78%, 100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e70% (53%, 93%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e55% (37%, 82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;18 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e77 (79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e74% (65%, 84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e51% (41%, 63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e38% (28%, 50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.99, 3.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnderlying disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAL - B-cell lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e52 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e79% (68%, 91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e56% (44%, 71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e40% (29%, 56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e40 (43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e78% (66%, 92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e53% (39%, 70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e40% (27%, 58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.76, 1.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDonor type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaplo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e5 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIdentical sibling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e4 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnrelated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e88 (91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e77% (69%, 87%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e57% (47%, 68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e44% (35%, 56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStem cell source\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e21 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e86% (72%, 100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e76% (60%, 97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e67% (49%, 90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBM/PB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e76 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75% (66%, 85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e49% (39%, 61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e34% (25%, 47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.18, 4.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMyeloablative conditioning regimen\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e40 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e73% (60%, 88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e43% (30%, 61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e28% (17%, 45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1.12\u0026ndash;2.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e55 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e80% (70%, 91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e64% (52%, 78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e51% (39%, 66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of Allo-HCT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e92 (95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e78% (70%, 87%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e55% (46%, 67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e42% (33%, 54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e5 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60% (29%, 100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e40% (14%, 100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20% (3.5%, 100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003cb\u003eLegend.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eM, male; F, female; Allo-HCT, allogeneic hematopoietic cell transplantation; CB, cord blood; BM, bone marrow; PB, peripheral blood; Haplo, haploidentical\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eStem cell source and intensity of conditioning regimen were confirmed in the multivariate analysis as significant factors for overall mortality: BM/PB vs. CB HR 2.21 (95% C.I., 1.12\u0026ndash;4.35), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.02; nonmyeloablative conditioning vs. myeloablative conditioning HR 1.76 (95% C.I. 1.09\u0026ndash;2.83), \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.02.\u003c/p\u003e \u003cp\u003eEighty-seven of 97 patients (89.7%) received an antiviral treatment for HHV-6 encephalitis, as follows: foscarnet monotherapy, 32 patients for a median of 19 days, range 1-111 days; ganciclovir monotherapy, 29 patients for a median of 22 days, range 7-121; ganciclovir followed by foscarnet, 17 patients for a median of 29 days, range 12\u0026ndash;75; combination of ganciclovir and foscarnet, 7 patients for a median of 15 days, range 7\u0026ndash;38; cidofovir, 2 patients for 4 weeks.\u003c/p\u003e \u003cp\u003eNinety-day mortality after the diagnosis of HHV-6 encephalitis was 56% (18/32) in patients treated with foscarnet, 38% (11/29) in patients treated with ganciclovir, 42% (10/24) in patients treated with the combination of the sequence of ganciclovir plus foscarnet, (10), while the two patients treated with cidofovir were alive. In the group of 10 untreated patients, 5 deaths occurred by 90 days and 3 deaths occurred thereafter.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study represents an attempt to assess the incidence and the outcome of HHV-6 encephalitis in centers belonging to the EBMT network. Overall, HHV-6 encephalitis was a rare complication with an incidence of 0.45% over a 10-year period.\u003c/p\u003e \u003cp\u003eWe recognize that this figure is lower than that reported by other authors. Considering that the reporting of infectious complications in the EBMT registry was performed voluntarily and the difficulty in defining the cause of CNS acute disease in allo-HCT patients, we can hypothesize that this incidence is underestimated. In a prospective study performed by the IDWP collecting CNS clinical events over two years (2000\u0026ndash;2002), the infectious events were nearly half of the non-infectious events, which were mainly vascular events, and among 58 infectious complications, only two were attributed to HHV-6 CNS infection \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Nowadays, the more extended use than one decade ago earlier of PCR assays for CSF analysis and MRI imaging allows an improvement in defining the causes of CNS acute dysfunction. We excluded from our analysis three patients who did not perform the lumbar puncture to confirm the clinical suspicion of HHV-6 encephalitis although the presence of clinical signs and symptoms of encephalitis, together with HHV-6 detection in blood or radiological evidence of limbic encephalopathy, has been accepted to define HHV-6-associated encephalitis\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRecently, in a retrospective study in the adult Japanese population the incidence of HHV-6 encephalitis was 3.6% and associated with the use of CB as a stem cell source, the adoption of antiviral prophylaxis different from letermovir and the occurrence of GVHD that needed treatment with steroids\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The use of CB was associated with a higher incidence of HHV-6 encephalitis also in this study.\u003c/p\u003e \u003cp\u003eHHV-6 encephalitis occurred early after HCT irrespective of the age of the recipient (pediatric vs. adult) and the stem cell source. This is in line with other reports where HHV-6 encephalitis was observed most commonly within 4\u0026ndash;6 weeks after transplant \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the survival analysis, adult age, bone marrow or peripheral blood stem cell source, and non-myeloablative conditioning regimen were associated with lower survival after HHV-6 encephalitis. We think that these factors define a high-risk profile recipient for transplant-related complications and overall mortality. Generally, adult transplant recipients have more comorbidities than pediatric patients, and the use of non-myeloablative conditioning may have a higher relapse risk than a myeloablative HCT, and BM or PB are the preferred stem cell source used for mismatched relative or haploidentical transplant\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. We think that the reason why CB grafts had a better survival outcome was that this procedure was adopted in more than half of cases in children and young adults affected by acute lymphoblastic leukemia (data not shown) who had a better transplant outcome than adults transplanted with a BM or PB stem cell source.\u003c/p\u003e \u003cp\u003eNo drug is officially approved to treat HHV-6 infection or disease. While the treatment of asymptomatic post-transplant HHV-6 DNAemia is not recommended, antiviral treatment of HHV-6 encephalitis with foscarnet or ganciclovir is recommended by guidelines\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Foscarnet and ganciclovir are considered first-line treatments, and the choice is based on the clinician's assessment of the patient\u0026rsquo;s comorbidities, the risk for side effects, and drug-drug interactions. In this study, the type of antiviral treatment was not associated with significant differences in early mortality. Accordingly, no significant difference in efficacy has been reported between foscarnet and ganciclovir monotherapy. A better response rate and a lower sequelae rate after HHV-6 encephalitis have been reported for both antivirals when used at a full dose (foscarnet\u0026thinsp;\u0026gt;\u0026thinsp;180 mg/kg, ganciclovir\u0026thinsp;\u0026gt;\u0026thinsp;10 mg/kg), but these did not lead to differences in terms of 30 days and 100 days overall survival after HHV-6 encephalitis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Cidofovir, though effective \u003cem\u003ein vitro\u003c/em\u003e against HHV-6, has limited data on efficacy and can be considered an option as rescue or an alternative after treatment with foscarnet or ganciclovir\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Brincidofovir, a prodrug of cidofovir, might be an option in the future but currently is not available \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn conclusion, in this retrospective study, the incidence of HHV-6 encephalitis was low, but high mortality was confirmed irrespective of antiviral treatment. The risk factors associated with higher mortality and lower OS were adult age, the use of BM or PB as a stem cell source, and the nonmyeloablative condition regimen. Even though this study refers to patients transplanted more than a decade ago, it describes a very large series of post-allo-HCT HHV-6-related encephalitis and confirms the role of HHV-6 in the occurrence of encephalitis complications. Future research is needed to assess is usefulness of HHV-6 DNAemia monitoring, the correlation of HHV-6 infection with the development of HHV-6-related organ diseases, and the role of pre-emptive antiviral treatment in preventing HHV-6 encephalitis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthorship and author contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eK.N.W. designed the study, N.K. collected the data, G.T. performed the statistical analysis, K.P. and S.C. analyzed the data and wrote the paper; the remaining authors were responsible for caring for the patients and reporting the data. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a Registry study conducted under the scientific supervision of IDWP-EBMT. All authors have no conflict of interest concerning this study to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYamane A, Mori T, Suzuki S, Mihara A, Yamazaki R, Aisa Y \u003cem\u003eet al.\u003c/em\u003e Risk factors for developing human herpesvirus 6 (HHV-6) reactivation after allogeneic hematopoietic stem cell transplantation and its association with central nervous system disorders. Biol Blood Marrow Transplant 2007; 13: 100\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZerr DM, Corey L, Kim HW, Huang M-L, Nguy L, Boeckh M. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. 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Bone Marrow Transplant 2013; 48: 574\u0026ndash;580.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWard KN, Hill JA, Hubacek P, de la Camara R, Crocchiolo R, Einsele H \u003cem\u003eet al.\u003c/em\u003e Guidelines from the 2017 European Conference on Infections in Leukaemia for management of HHV-6 infection in patients with hematologic malignancies and after hematopoietic stem cell transplantation. \u003cem\u003eHaematologica\u003c/em\u003e 2019; 104: 2155\u0026ndash;2163.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgata M, Oshima K, Ikebe T, Takano K, Kanamori H, Kondo T \u003cem\u003eet al.\u003c/em\u003e Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2017; 52: 1563\u0026ndash;1570.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgata M, Fukuda T, Teshima T. Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: what we do and do not know. Bone Marrow Transplant 2015; 50: 1030\u0026ndash;1036.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHill JA. Human herpesvirus 6 in transplant recipients: an update on diagnostic and treatment strategies. Curr Opin Infect Dis 2019; 32: 584\u0026ndash;590.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbidi MZ, Hari P, Chen M, Kim S, Battiwala M, Dahi PB \u003cem\u003eet al.\u003c/em\u003e Virus detection in the cerebrospinal fluid of hematopoietic stem cell transplant recipients is associated with poor patient outcomes: a CIBMTR contemporary longitudinal study. Bone Marrow Transplant 2019; 54: 1354\u0026ndash;1360.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiyashita N, Endo T, Onozawa M, Hashimoto D, Kondo T, Fujimoto K, \u003cem\u003eet al.\u003c/em\u003e Risk factors of human herpesvirus 6 encephalitis/myelitis after allogeneic hematopoietic stem cell transplantation. 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Biol Blood Marrow Transplant 2016; 22: 2250\u0026ndash;2255.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMori Y, Miyamoto T, Nagafuji K, Kamezaki K, Yamamoto A, Saito N \u003cem\u003eet al.\u003c/em\u003e High incidence of human herpes virus 6-associated encephalitis/myelitis following a second unrelated cord blood transplantation. Biol Blood Marrow Transplant 2010; 16: 1596\u0026ndash;1602.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShintaku M, Kaneda D, Tada K, Katano H, Sata T. Human herpes virus 6 encephalomyelitis after bone marrow transplantation: report of an autopsy case. Neuropathology 2010; 30: 50\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerzero G, Campanini G, Vegezzi E, Paoletti M, Pichiecchio A, Simoncelli AM \u003cem\u003eet al.\u003c/em\u003e Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts. Neurol Neuroimmunol Neuroinflamm 2021; 8: e942.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakaya J, Araki A, Mori K, Kaneko K. Usefulness of diffusion-weighted MRI in human herpesvirus-6 encephalitis. Acta Paediatr 2007; 96: 137\u0026ndash;138.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmidt-Hieber M, Engelhard D, Ullmann A, Ljungman P, Maertens J, Martino R \u003cem\u003eet al.\u003c/em\u003e Central nervous system disorders after hematopoietic stem cell transplantation: a prospective study of the Infectious Diseases Working Party of EBMT. J Neurol 2020; 267: 430\u0026ndash;439.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTerao T, Matsuoka K, Fuji S, Kawamura S, Toya T, Doki N \u003cem\u003eet al.\u003c/em\u003e Association between human herpesvirus-6 encephalitis and antiviral prophylaxis after allogeneic hematopoietic stem cell transplantation in the letermovir era. Bone Marrow Transplant 2024; 59: 1224\u0026ndash;1231.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHandley G, Yepes A, Eliassen E, Dominguez G, Pasikhova Y, Klinkova O, \u003cem\u003eet al.\u003c/em\u003e Outcomes of Haploidentical Stem Cell Transplant Recipients With HHV-6B Reactivation. Open Forum Infect Dis 2024; 11: ofae564.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgata M, Uchida N, Fukuda T, Ikegame K, Kamimura T, Onizuka M \u003cem\u003eet al.\u003c/em\u003e Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis after allogeneic hematopoietic stem cell transplantation: the Japan Society for Hematopoietic Cell Transplantation. Bone Marrow Transplant 2020; 55: 1004\u0026ndash;1013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP\u0026ouml;hlmann C, Schetelig J, Reuner U, Bornh\u0026auml;user M, Illmer T, Kiani A \u003cem\u003eet al.\u003c/em\u003e Cidofovir and foscarnet for treatment of human herpesvirus 6 encephalitis in a neutropenic stem cell transplant recipient. Clin Infect Dis 2007; 44: e118-120.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgut H, Bonnafous P, Gautheret-Dejean A. Laboratory and clinical aspects of human herpesvirus 6 infections. Clin Microbiol Rev 2015; 28: 313\u0026ndash;335.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKampouri E, Little JS, Crocchiolo R, Hill JA. Human herpesvirus-6, HHV-8, and parvovirus B19 after allogeneic hematopoietic cell transplant: the lesser-known viral complications. Curr Opin Infect Dis 2024; 37: 245\u0026ndash;253.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eDemographic and transplant characteristics of patients with HHV-6 encephalitis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"683\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eNumber of HHV-6 encephalitis episodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eAge at allo-HCT, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e48.4 (0.4-77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026lt;\u003c/u\u003e 18 year\u003c/p\u003e\n \u003cp\u003e\u0026gt;18 year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e20 (21%)\u003c/p\u003e\n \u003cp\u003e77 (79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eM/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e66/31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eUnderlying disease\u003c/p\u003e\n \u003cp\u003eAcute leukaemia,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMyelodysplastic/Myeloproliferative,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eChronic leukaemia,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLymphoma Hodgkin/Non Hodgkin\u003c/p\u003e\n \u003cp\u003ePlasma cell disorders\u003c/p\u003e\n \u003cp\u003eBone marrow failure\u003c/p\u003e\n \u003cp\u003eInherited disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44 (45%)\u003c/p\u003e\n \u003cp\u003e24 (25%)\u003c/p\u003e\n \u003cp\u003e10 (10%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (8%)\u003c/p\u003e\n \u003cp\u003e6 (6%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (2%)\u003c/p\u003e\n \u003cp\u003e3 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eDonor type\u003c/p\u003e\n \u003cp\u003eSibling\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eUnrelated donor\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eHaploidentical donor\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (4%)\u003c/p\u003e\n \u003cp\u003e88 (91%)\u003c/p\u003e\n \u003cp\u003e5 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eConditioning regimen\u003c/p\u003e\n \u003cp\u003eMyeloablative\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNon-myeloablative\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNot specified\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e55 (57%)\u003c/p\u003e\n \u003cp\u003e40 (41%)\u003c/p\u003e\n \u003cp\u003e2 (2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eStem cell source\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBone marrow\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePeripheral blood\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCord blood\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (11%)\u003c/p\u003e\n \u003cp\u003e65 (67%)\u003c/p\u003e\n \u003cp\u003e21 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e allo-HCT/\u003cu\u003e\u0026gt;\u003c/u\u003e 2\u003csup\u003end\u003c/sup\u003e allo-HCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e92/5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eInterval allo-HCT-HHV-6 encephalitis\u003c/p\u003e\n \u003cp\u003emedian, range\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e31 days, 16 days \u0026ndash; 317 days\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eNeurological symptoms\u003c/p\u003e\n \u003cp\u003eShort term memory loss\u003c/p\u003e\n \u003cp\u003eAltered consciousness, encephalopathy, confusion,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSeizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51/94 (54.3%)\u0026nbsp;, N.S. in 3\u003c/p\u003e\n \u003cp\u003e89/96 (92.7%), N.S. in 1\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58/95 (61.1%),\u0026nbsp;N.S.\u0026nbsp;in 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eOther symptoms/signs\u003c/p\u003e\n \u003cp\u003efever\u003c/p\u003e\n \u003cp\u003erash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e65 (67%)\u003c/p\u003e\n \u003cp\u003e32/92 (34%); N.S. in 5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eHHV-6 DNA on CSF by PCR\u003c/p\u003e\n \u003cp\u003equalitative PCR\u003c/p\u003e\n \u003cp\u003equantitative PCR\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; median range (copies/ml)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51/97 (53%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e46 (47%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7615 (215 \u0026ndash; 18000000)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eCT scan, yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; abnormal findings\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e69/97 (71%)\u003c/p\u003e\n \u003cp\u003e12/69 (17.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eMRI imaging, yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; abnormal findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e81/97 (84%), \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51/81 (63%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eOther viral infection (by PCR DNA-emia)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; before HHV-6 encephalitis (N\u0026deg; days)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; after HHV-6 encephalitis (N\u0026deg; days)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Co-infection\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 CMV (77), 1 ADV (99)\u003c/p\u003e\n \u003cp\u003e1 BKPyV (14), 1 ADV (26), 1 HHV-7 (26)\u003c/p\u003e\n \u003cp\u003e1 CMV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eMedian follow-up time\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(from encephalitis)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e5.28 years, (95% C.I., 5.01-7.83)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eDeaths, total number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e72\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003eCause of death\u003c/p\u003e\n \u003cp\u003erelapse/progression\u0026nbsp;\u003c/p\u003e\n \u003cp\u003einfectious\u0026nbsp;\u003c/p\u003e\n \u003cp\u003enon-infectious\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emissing\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11/72 (15%)\u003c/p\u003e\n \u003cp\u003e23 (32%)\u003c/p\u003e\n \u003cp\u003e33 (46%)\u003c/p\u003e\n \u003cp\u003e5 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 375px;\"\u003e\n \u003cp\u003e5-yr OS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e24.7% (95% C.I., 17.1-35.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eLegend.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHHV-6, Human Herpes Virus-6 encephalitis; M, male; F, female; Allo-HCT: allogeneic hematopoietic cell transplant; N.S.: not specified; CT, computed tomography; MRI, magnetic resonance imaging; CMV, cytomegalovirus; ADV, adenovirus; BKPyV, BK polyoma virus; HHV-7, human herpes virus-7; OS, overall survival; C.I., confidence interval\u003c/p\u003e\n\u003cp\u003e\u003cb\u003eTable 2 is available in the Supplementary Files section.\u003c/b\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Human Herpes Virus-6, encephalitis, allogeneic stem cell transplantation, foscarnet, ganciclovir, survival","lastPublishedDoi":"10.21203/rs.3.rs-6290272/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6290272/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHuman herpes virus-6 (HHV-6) is the main cause of viral encephalitis in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). From January 2005 to December 2014, 97 patients with HHV-6 encephalitis were reported in the EBMT registry. The incidence was 0.45% after the first allo-HCT and varied with the type of donor and of stem cell source: sibling donor 0.06%, unrelated donor 0.68%, haploidentical donor 0.51%, CB 2.14%, bone marrow 0.20%, peripheral blood 0.44%. HHV-6 encephalitis occurred at a median time of 31 days from allo-HCT (range 16\u0026ndash;317 days). With a median follow-up of 5.28 years, the 5-yr OS was 24.7% while 72 of 97 patients died: disease relapse/progression 11, infection 23, non-infectious cause 33, not specified 5. Forty-four deaths (61.1%) occurred within 90 days from diagnosis of HHV-6 encephalitis and in 24 HHV-6 encephalitis was considered a contributory cause. Eight-seven patients received treatment mainly with foscarnet or ganciclovir. In multivariate analysis, bone marrow/peripheral blood stem cell source and myeloablative conditioning regimen were significant factors for lower survival.\u003c/p\u003e \u003cp\u003eIn conclusion, the incidence of HHV-6 encephalitis was low but associated with high mortality irrespective of antiviral treatment. This confirms the need for further research in this setting.\u003c/p\u003e","manuscriptTitle":"Clinical characteristic and outcome of HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: A retrospective study of Infectious Disease Working Party of EBMT","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 08:31:23","doi":"10.21203/rs.3.rs-6290272/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-04-14T14:08:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-04-11T20:54:14+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-04-10T16:05:26+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-04-02T13:13:57+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-04-01T13:00:38+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-03-28T18:10:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-24T12:06:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bone Marrow Transplantation","date":"2025-03-23T21:54:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-23T21:54:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bone-marrow-transplantation","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bmt","sideBox":"Learn more about [Bone Marrow Transplantation](http://www.nature.com/bmt/)","snPcode":"41409","submissionUrl":"https://mts-bmt.nature.com/cgi-bin/main.plex","title":"Bone Marrow Transplantation","twitterHandle":"@bmtjournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"860bec7b-4ec9-47ea-91f9-ceeaf12ae620","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46376254,"name":"Health sciences/Diseases/Infectious diseases"},{"id":46376255,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-06-04T07:08:15+00:00","versionOfRecord":{"articleIdentity":"rs-6290272","link":"https://doi.org/10.1038/s41409-025-02638-7","journal":{"identity":"bone-marrow-transplantation","isVorOnly":false,"title":"Bone Marrow Transplantation"},"publishedOn":"2025-06-03 04:00:00","publishedOnDateReadable":"June 3rd, 2025"},"versionCreatedAt":"2025-04-21 08:31:23","video":"","vorDoi":"10.1038/s41409-025-02638-7","vorDoiUrl":"https://doi.org/10.1038/s41409-025-02638-7","workflowStages":[]},"version":"v1","identity":"rs-6290272","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6290272","identity":"rs-6290272","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}