Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents

Schmidt‐Hieber, Martin; Schwender, Julie; Heinz, Werner; Zabelina, Tatjana; Kühl, Jörn Sven; Mousset, Sabine; Schüttrumpf, Silke; Junghanß, Christian; Silling, Gerda; Basara, Nadežda; Neuburger, Stefan; Thiel, Eckhard; Blau, Igor Wolfgang

doi:10.3324/haematol.2010.029876

Cited by 94 publications

(106 citation statements)

References 34 publications

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“…Human herpesvirus 6 (HHV-6) is a ubiquitous pathogen in many populations, yet virus reactivations from latent infection can be associated with severe inflammatory disease in immunosuppressed patient populations, including post-transplant acute limbic encephalitis (PALE), and cognitive impairment in haematopoietic stem cell transplantation as well as myocarditis (Kühl et al, 2005a, b;Noutsias et al, 2011;Schmidt-Hieber et al, 2011;Seeley et al, 2007;Zerr et al, 2011). By 2 years of age, over 75 % of infants have acquired this pathogen and in adults, HHV-6 seroprevalence is 83-100 % worldwide (Hall et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide

Clark

Catusse

Stacey

et al. 2013

Journal of General Virology

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Human monocytes expressing CCR2 with CD14 and CD16 can mediate antigen presentation, and promote inflammation, brain infiltration and immunosenescence. Recently identified roles are in human immunodeficiency virus infection, tuberculosis and parasitic disease. Human herpesvirus 6B (HHV-6B) encodes a chemokine, U83B, which is monospecific for CCR2, and is distinct from the related HHV-6A U83A, which activates CCR1, CCR4, CCR5, CCR6 and CCR8 on immune effector cells and dendritic cells. These differences could alter leukocyte-subset recruitment for latent/lytic replication and associated neuroinflammatory pathology. Therefore, cellular interactions between U83A and U83B could help dictate potential tropism differences between these viruses. U83A specificity is maintained in the 38-residue N-terminal spliced-truncated form. Here, we sought to determine the basis for the chemokine receptor specificity differences and identify possible applications. To do this we first analysed variation in a natural host population in sub-Saharan Africa where both viruses are equally prevalent and compared these to global strains. Analyses of U83 N-terminal variation in 112 HHV-6A and HHV-6B infections identified 6/ 38 U83A or U83B-specific residues. We also identified a unique single U83A-specific substitution in one U83B sequence, 'U83BA'. Next, the variation effects were tested by deriving N-terminal (NT) 17-mer peptides and assaying activation of ex vivo human leukocytes, the natural host and cellular target. Chemotaxis of CCR2+ leukocytes was potently induced by U83B-NT, but not U83BA-NT or U83A-NT. Analyses of the U83B-NT activated population identified migrated CCR2+, but not CCR5+, leukocytes. The U83BA-NT asparagine-lysine14 substitution disrupted activity, thus defining CCR2 specificity and acting as a main determinant for HHV-6A/B differences in cellular interactions. A flow-cytometry-based shape-change assay was designed, and used to provide further evidence that U83B-NT could activate CCR2+CD14+CD16+ monocytes. This defines a potential antiviral target for HHV-6A/B disease and novel peptide immunomodulator for proinflammatory monocytes.

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Section: Introductionmentioning

confidence: 99%

Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide

Clark

Catusse

Stacey

et al. 2013

Journal of General Virology

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“…7,8 Exposure to neurotoxic medications and disruption of immunity as a part of the HSCT procedure contribute to nervous system complications. 9 In general, CNS infections post-alloHSCT have been associated with higher mortality and rejection rates, whereas long-term neurologic morbidity remains unknown. 5,6 Hence, in addition to characterizing the clinical presentation of encephalitis due to HHV-6 infection, we investigated whether early diagnosis and treatment influences mortality in alloHSCT recipients.…”

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confidence: 99%

Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation

et al. 2013

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“…1,6 Along with seizures and significant mental-status changes, pruritus has been reported in three encephalitis cases in pediatric umbilical cord blood transplant recipients. …”

Section: 2mentioning

confidence: 99%

“…6,7 Median onset of disease has been reported as relatively early post-transplant, at 23 and 62 days. 1,6 Along with seizures and significant mental-status changes, pruritus has been reported in three encephalitis cases in pediatric umbilical cord blood transplant recipients.…”

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confidence: 99%

Severe pruritus and hypothermia as the primary manifestations of Human Herpes Virus-6 encephalitis after pediatric cord blood transplantation

Hudspeth

Brown

Ragucci

et al. 2011

Bone Marrow Transplant

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Viral encephalitis has a reported incidence of 1.2-4% in prospective evaluations of allo-SCT patients. Presenting symptoms most often include altered mental status, fever and seizures, and about half of the patients will have an abnormality on neuroimaging. Unfortunately, mortality rates for allo-SCT patients with viral encephalitis can be up to 80%. 1,2We report the case of a 14-year-old boy who underwent a matched unrelated umbilical cord blood transplant in December 2009 for monosomy 7 myelodysplasia secondary to treatment for multisystem Langerhans cell histiocytosis. The conditioning regimen consisted of BU (4 mg/kg p.o. daily in divided doses from day À9 to À6), CY (50 mg/kg once daily i.v. from day À5 to À2) and equine ATG (15 mg/ kg i.v. twice daily from day À5 to À3). GVHD prophylaxis was CYA 5 mg/kg/day from day À2 and methylprednisolone from day þ 7. The nucleated cell dose was 3.8 Â 10 7 /kg. The initial course was complicated by moderate venoocclusive disease with a peak bilirubin of 137 mmol/L.After 48 h of insomnia, the patient developed increased irritability and visual hallucinations on day 19 that resolved with sleep. Brain magnetic resonance imaging performed on day 21 was normal, and his mental status was at baseline. On day 24, the patient had an intense 7-h episode of generalized pruritus without associated cutaneous findings. The pruritus was so severe that the patient created excoriations with his aggressive scratching. Multiple medications were tried to alleviate the pruritus and calm the patient including diphenhydramine, hydroxyzine, aprepitant, lorazepam, haloperidol, droperidol, quetiapine, olanzapine, gabapentin, zolpidem and ramelteon. Additional protective measures including mittens and restraint with a Posey vest were required. He also had hypothermia with an oral temperature range of 32.9-34.3 1C. Broadspectrum antibiotics were initiated and blood cultures remained negative. Thyroid function testing was normal.Cerebrospinal fluid examination on day 25 was normal with WBC 1/mL, RBC 0/mL, glucose 6.4 mmol/L and protein 0.42 g/L. Cerebrospinal fluid testing included bacterial culture; PCR testing for adenovirus, CMV, HSV 1 and 2, HHV-6, Jakob-Creutzfeldt, VZV; and arbovirus titers. Electroencephalogram was normal. Neurological examination revealed a positional tremor of his upper extremities attributed to CYA, but was otherwise unremarkable. On day 27, the patient had another 7-h episode of unremitting pruritus with aggressive scratching requiring multiple medications including quetiapine. This episode was also characterized by hypothermia with an oral temperature range of 32.8-33.6 1C. On day 28, cerebrospinal fluid results returned detecting HHV-6 viral DNA by PCR. HHV-6 viral DNA was also detected in the plasma. Foscarnet (60 mg/kg/dose every 8 h) was initiated to treat the encephalitis and was dose adjusted on day 11 of the 21-day treatment course (45 mg/kg/dose every 8 h) for renal insufficiency. The patient experienced one more severe episode of generalized pruritus on day 35...

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Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents

Cited by 94 publications

References 34 publications

Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide

Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide

Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation

Severe pruritus and hypothermia as the primary manifestations of Human Herpes Virus-6 encephalitis after pediatric cord blood transplantation

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