ABC of viral infections in hematology: focus on herpesviruses

Open access

Abstract

Viruses are a form of life that possess genes but do not have a cellular structure. Viruses do not have their own metabolism, and they require a host cell to make new products; therefore, they cannot naturally reproduce outside a host cell. The objective of this paper is to present the basic practical clinical roles of viruses in patients with hematological diseases including malignancies and non-malignan- cies, as well as those undergoing hematopoietic cell transplantation (HCT), with the focus on herpesviruses causing latent infections in severely immunocompromised patients. From the hematologist point of view, viruses can play a major role in four conditions: causing infections; causing lymphoproliferations and/or malignancies; causing (pan)cytopenia; and used as vectors in treatment (e.g., gene therapy, CAR-T cells). Taking into account the role of viruses in hematology, infection is the most frequent condition. Among DNA viruses, the highest morbidity potential for human is expressed by Herpesviridiae (herpesviruses), Adenoviridae (adenovirus; ADV), Polyomavirus (BKV, JCV), and Bocavirus. RNA viruses can play a role in pathogenesis of different clinical conditions and diseases: lymphoproliferative disorders and malignancy, possibly causing NHL, AML, MDS, and others (HCV, HIV, and others); pancytopenia and aplastic anemia (HIV, HCV, Dengue virus); respiratory infections (community-acquired respiratory virus infections; CARV) caused by Orthomyxoviruses (e.g. influenza A/B), Paramyxoviruses (e.g. human parainfluenza virus PIV-1, -2, -3, and -4; respiratory syncytial virus RSV-A and -B), picornaviruses (e.g., human rhinovirus), coronaviruses (e.g., human coronavirus), Pneumoviridiae (e.g., human metapneumovirus), and potentially other viruses.

Introduction

Viruses are a form of life that possess genes but do not have a cellular structure. Viruses do not have their own metabolism, and they require a host cell to make new products; therefore, they cannot naturally reproduce outside a host cell [1]. The complete set of viruses in an organism or habitat is called the virome; for example, all human viruses constitute the human virome [2]. Although there are millions of different types of viruses, only about 5,000 types have been described in detail [3]. A virus has either a DNA or an RNA genome and is called a DNA virus or an RNA virus, respectively.

The objective of this paper is to present the basic practical clinical roles of viruses in patients with hematological diseases including malignancies and non-malignancies, as well as those undergoing hematopoietic cell transplantation (HCT), with the focus on herpesviruses causing latent infections in severely immunocompromised patients.

Classification

The current classification of viruses was developed by The International Committee on Taxonomy of Viruses (ICTV). As of June 2019, 14 orders, 143 families, 64 subfamilies, 846 genera and almost 5000 species of viruses have been defined by the ICTV. The orders are the Caudovirales, Herpesvirales, Ligamenvirales, Mononegavirales, Nidovirales, Ortervirales, Picornavirales, Bunyavirales, Tymovirales, Muvirales, Serpentovirales, Jingchuvirales, Goujianvirales, and Articulavirales (Virus Metadata Resource; https://talk.ictvonline.org/taxonomy/vmr/)

Baltimore classification of viruses is based on the DNA or RNA of virus and method of mRNA synthesis [4]. Viral genomes may be RNA or DNA, single-stranded (ss) or double-stranded (ds), and may or may not use reverse transcriptase (RT). Additionally, ssRNA viruses may be either sense (+) or antisense (−). The vast majority of viruses have RNA genomes. Baltimore classification divides viruses into seven groups (Tab. I).

Table I

Baltimore classification of viruses

GroupCategoryExamples
IdsDNA virusesAdenoviruses, Herpesviruses, Poxviruses
IIssDNA viruses (+ strand or „sense”) DNAParvoviruses
IIIdsRNA virusesReoviruses
IV(+)ssRNA viruses (+ strand or sense) RNAPicornaviruses, Togaviruses
V(−)ssRNA viruses (− strand or antisense) RNAOrthomyxoviruses, Rhabdoviruses
VIssRNA-RT viruses (+ strand or sense) RNA with DNA intermediate in life-cycleRetroviruses
VIIdsDNA-RT viruses DNA with RNA intermediate in life-cycleHepadnaviruses

Role of viruses in hematology

From the hematologist point of view, viruses can play a major role in four conditions: causing infections; causing lymphoproliferations and/ or malignancies; causing (pan)cytopenia; and used as vectors in treatment (e.g., gene therapy, CAR-T cells) (Tab. II)

Table II

Role of viruses in hematology

RoleExamples
Causing infectionsEpisodic infections (CARV) Latent infections (herpesviruses, ADV, BKV, JCV) Hepatotropic infections (HBV, HCV, HEV)
Causing lymphoproliferations and/or malignancyEBV, HTLV (HIV, HCV)
Causing pancytopeniasPVB19, HAV, HCV, HIV, DENV
Used in treatmentRetroviruses, Lentiviruses (vectors for CAR-T cells, gene therapy)
Abbreviations in text.

Taking into the role of viruses in hematology, infection is the most frequent condition. Among DNA viruses, the highest morbidity potential for human is expressed by Herpesviridiae (herpes viruses), Adenoviridae (adenovirus; ADV), Polyomavirus (BKV, JCV), and Bocavirus.

RNA viruses can play a role in pathogenesis of different clinical conditions and diseases: lymphoproliferative disorders and malignancy, possibly causing NHL, AML, MDS, and others (HCV, HIV, and potentially Dengue virus, Zika virus, Chickungunya virus); pancytopenia and aplastic anemia (HIV, HCV, Dengue virus); respiratory infections (community-acquired respiratory virus infections; CARV) caused by Orthomyxoviruses (e.g., influenza A/B), Paramyxoviruses (e.g., human parainfluenza virus PIV-1, -2, -3, and -4; respiratory syncytial virus RSV-A and -B), Picornaviruses (e.g., human rhinovirus), coronaviruses (e.g., human coronavirus), Pneumoviridiae (e.g., human metapneumovirus), and potentially other viruses.

Diagnostics of viral infections in hematological patients

Laboratory test for viral infections with focus on latent and chronic infections should be performed in many hematological conditions, especially at diagnosis of the disease, and before HCT (both in recipient and donor). Additionally, after HCT monitoring for CMV and EBV, reactivation is mandatory in allo-HCT setting, and for several other viruses depending on clinical signs and symptoms (Tab. III)

Table III

Mandatory screening tests for viral infections in hematology

Clinical situationViral test
Malignancy at diagnosisCMV, EBV, HIV, HBV, HCV (serology)
Before HCTCMV, EBV, HIV, HBV, HCV, (HSV, VZV) (serology)
Donor HSCCMV, EBV, HIV, HBV, HCV (serology)
After allo-HCTCMV, EBV (NAT)
ThrombocytopeniaCMV, EBV, HIV
PancytopeniaCMV, EBV, HIV, HAV, HBV, HCV, PVB19
LeukocytosisEBV, CMV, HCV
Respiratory infectionCARV, ADV, CMV
Hemorrhagic cystitisBKV, ADV, CMV
EncephalitisHHV6, CMV, EBV, JCV, VZV, HSV
HepatitisHAV, HBV, HCV, HDV, HEV and other
NAT (nucleic acid test); other abbreviations in text.

Viral infections

Viral infections are a major issue for hematopoietic cell transplant (HCT) recipients. The most important viral pathogens in this group of patients include herpes simplex viruses (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), human herpes 6 virus (HHV6), adenovirus (ADV), BK virus (BKV), influenza, parainfluenza, respiratory syncytial virus (RSV), rhinovirus, and norovirus. Other pathogenic viruses include enteroviruses, HIV, hepatitis, JCV, and parvovirus (PVB19).

Reactivation of latent infections with herpes viruses may lead to various disease manifestations, regardless of its primary acquisition after the transplant. Unlike in the general immunocompetent population, with typical clinical manifestations of infection ranging from asymptomatic to mild or moderate symptoms, HCT recipients may frequently develop much more severe disease.

It is essential to identify patients at risk for reactivation of latent viruses, as active infection and diseases can often be prevented with prophylaxis and preemptive monitoring during the most critical time periods.

Herpes viruses

Herpesviridae create a large family of double-stranded DNA viruses with specific and unique biologic features, enabling them to establish latency program after primary infection in human prior to reactivation later in life. With respect to taxonomy, there are three subfamilies: alpha-, beta-, and gamma-herpes-viridiae, which include nine known human herpesviruses (Tab. IV)

Table IV

Family of Herpesviridiae

SUBFAMILYSpeciesViruses
Alpha-herpes-viridiaeSimplex-virusHHV-1=HSV-1, HHV-2=HSV-2
Varicello-virusHHV-3=VZV
Beta-herpes-viridiaeCytomegalo-virusHHV-5=CMV
Muromagalo-virus
Roselo-virusHHV-6A/HHV-6B, HHV-7
Gamma-herpes-viridiaeLympho-crypto-virusHHV-4=EBV, HHV-8=KSHV
Rhadino-virus
Abbreviations in text.

In the most severely immunocompromised patients, which comprise mainly recipients of allo-HCT from unrelated or mismatched donor, four herpesviruses play a major role in chronic latent and relapsing infections including CMV, EBV, HHV6B, and VZV. So far, no pathogenicity was shown for HHV-6A virus. These four viruses are described and discussed in this article. Basic characteristics of these four herpesviruses are shown in table V [5, 6, 7, 8].

Table V

Basic characteristics of CMV, EBV, HHV6, and VZV infections in HCT setting

CharacteristicsCMVEBVHHV6VZV
TaxonomyHHV-5HHV-4HHV-6HHV-3
FamilyHerpesviridaeHerpesviridaeHerpesviridaeHerpesviridae
Subfamilybetagammabetaalpha
Nucleic acidds DNAds DNAds DNAds DNA
Year first identified1956196419861888
Incubation period3-12 weeks3-7 weeks1-2 weeks2-3 weeks
Seroprevalence in children30-50%30-50%First infection in first two years of life; (CIHHV6: 1%)67% (age: 1-4y)
Seroprevalence in adults>70%>90%>97% (HHV6 B) (CIHHV6 – 1%)>98%
Congenital infectionYes (TORCH)Yes (rare; asymptomatic)Congenital (vertical) CIHHV6 (inherited from mother or father)Yes (TORCH)
Confirmed modes of trans- missionWith blood and other body fluids (saliva)With saliva and other body fluids; Kissing disease (saliva)With saliva and other body fluidsAirborne route or through contact* with contaminated environment
Viral transmission:
BreastfeedingYesYesYesNo
Organ transplantsYesYesYesNo
Blood transfusionsYesYesYesNo
Transfer with HSCYesYesYesNo
*EXPOSURE: face-to-face contact of 5 min or more with a person with varicella or with an immunocompromised patient with disseminated HZ, or intimate contact (touching or hugging) with a person with HZ (acc. to ECIL-2)

Herpes simplex virus. HSV-1 and HSV-2 infection is usually associated with mucocutaneous disease in the orofacial region (85%–90%), and rarely in the esophageal and genital area. Rare manifestations are meningitis, encephalitis, pneumonia, and hepatitis. Mucocutaneous HSV disease is diagnosed clinically and can be confirmed by PCR. HSV meningitis and encephalitis should be confirmed by PCR in cerebrospinal fluid. Antiviral drug prophylaxis is not recommended in HSV-seronegative patients after HCT (except anti-VZV prophylaxis). HSV-seropositive patients should receive antiviral drug prophylaxis after allo-HCT. Intravenous acyclovir 250 mg/m2 or 5 mg/kg every 12 h, oral acyclovir 3 x 200 to 2 x 800 mg/day, oral valaciclovir 2 x 500 mg/day, or famciclovir 2 x 500 mg/day can be used, for a period of at least 4 weeks after HCT in VZV-seronegative patients. Intravenous acyclovir remains the therapy of choice for severe mucocutaneous or visceral HSV disease. Intravenous acyclovir 250 mg/m2 or 5 mg/kg every 8 h for 7–10 days is the therapy of choice for severe mucocutaneous or visceral HSV disease. Oral acyclovir, from 5 x 200 to 5 x 400 mg/day, valaciclovir 2 x 500 mg/day, or famciclovir 2 x 500 mg/day for 10 days are considered as alternatives for less serious manifestations of HSV disease. For HSV pneumonia or HSV meningitis and encephalitis, i.v. acyclovir 500 mg/m2 or 10 mg/kg every 8 h for at least 14–21 days is recommended. HSV resistance occurs in approximately 5%–15% of patients and foscarnet or cidofovir is second-line therapy [5].

HHV-7 primary infection in young children (<5y) causes exanthema subitum (roseola) and rarely status epilepticus with fever. Reactivation of HHV-7 occurs in about 10% of patients after allo-HCT. Clinically, overt HHV-7 detection after HCT is rare and might be associated with CNS disease (encephalitis or myelitis). Diagnosis of HHV-7 is made by qPCR. Usually, infection with HHV-7 does not require specific treatment [6].

HHV-8 (KSHV, Kaposi’s sarcoma-associated herpesvirus) is the cause of Kaposi’s sarcoma (KS), as well as primary effusion lymphoma and Castleman’s disease. KS is extremely rare after HCT with skin involvement, fever, and marrow aplasia with plasmocytosis. Pediatric cases might have visceral involvement. Diagnosis of HHV-8 is made by qPCR. KS can be confirmed histopathologically as malignant tumor. In skin manifestation, surgical excision or electrochemotherapy is the preferable approach. For other manifestations, possible options include the following: interferon-alpha, chemotherapy, and radiotherapy [9,10]. The use of antiviral treatment is not recommended.

Herpes viruses seroprevalence: increasing with age

The human herpesviruses, such as CMV, EBV, HHV6, and VZV, are being the agents of a global infection although differences in the seroprevalence exist between countries: it is the well-documented fact in case of CMV [5, 6, 7, 8]. CMV acquisition in a general population is characterized by an age-dependent rise in seropositivity, which correlates most closely with socioeconomic level as well as race, similarly to other herpesviruses [11]. Seroprevalence of CMV varies from about 40%–50% in highly developed countries to over 90% of population in the developing countries, with the rate from about 30% in childhood to over 50% of women of childbearing age and even up to 60%–70% in adults. However, the incidence slightly decreases with the calendar year. Nevertheless, in population of highly developed countries, CMV acquisition still occurs at a rate of 1%–7% per year [8, 9, 11, 12, 13].

There is an exception in case of HHV-6, as apart from seroprevalence after acquired infection, mainly in early childhood, there is a congenital phenomenon of chromosomally integrated HHV-6 (CIHHV-6), resulting from vertical transmission: inherited from mother or father. It occurs both in HHV-6A or HHV-6B with prevalence about 1% in the general population. In case of CIHHV-6, the virus HHV-6 present in every nucleated cell, and HHV-6 DNA can be easily detected in hair follicles and nails. In most cases, there is one copy of HHV-6 DNA/ leukocyte [14,15].

Clinical symptoms: many manifestations

Some of herpesviruses have a potential to play a role in pathogenesis of different diseases with various manifestations. This is well observed in case of EBV and CMV, and it happens also for HHV6 and VZV (Tab. VI)

Table VI

Clinical syndromes and symptoms

Clinical symptomsCMVEBVHHV6 A/BVZV
AsymptomaticYesYesYes None (HHV-6A)Possible
Mild (general population)CMV disease (mononucleosis-like)MononucleosisExanthema subitum (±HHV7)Varicella Herpes zoster
SeverePneumonia, GI infection, hepatitis, BM suppression, retinitisPTLD*, end-organ diseases, HLH, chronic fatigue syndromeEncephalitis; CNS dysfunction; pneumonia; BM suppression; hepatitis; IPSVisceral (encephalitis, pneumonitis, hepatitis); Neuralgia
*PTLD: Heterogeneous group of EBV diseases with neoplastic lymphoproliferation, developing after transplantation and caused by iatrogenic suppression of T-cell function

Also CIHHV-6 can be associated with several diseases. There is a good evidence of association with aGVHD and CMV reactivation [14]. It is probably associated with angina pectoris in general population, and there are known cases of hemophagocytosis with thrombotic microangiopathy in SCID patients, as well as encephalitis post-HCT.

Risk factors and incidence of reactivation

Risk factors of herpes virus recurrence after allo-HCT depend on the following: recipient (virus serology; age), donor (virus serology match; age; sex match; HLA match; type of family/unrelated donor; stem cell source), transplant (type of conditioning: TBI-or chemotherapy-based; T-cell depletion; intensity of myeloablative or reduced intensity conditioning, RIC), immunosuppressive treatment (prophylaxis, occurrence and treatment of acute and/or chronic GVHD; immunosuppressive drugs used in prophylaxis and/or therapy), as well as immune recovery after HCT (speed of immune reconstitution for B cells, T cells, NK cells; recovery of virus-specific cytotoxic T lymphocytes, CTLs) [8]. Incidence of reactivation in patients after HCT is presented in table VII

Table VII

Incidence of reactivation in patients after HCT

IncidenceCMVEBVHHV6VZV
Reactivation (without prophylaxis)30%–35%Median 29% (0.1%–63%)30%–70%25%–50%
Symptomatic clinical disease after HCT1%–2% up to 11% at 1y [8]3% (1% MFD, up to 11% MMUD/haplo) [7]0.5% (BM/PB) 8.3%–11.6% (CBT) [14,16]30%–60% (without prophylaxis) [5]
MFD (matched family donor); MMUD (mismatched unrelated donor); CBT (cord blood transplantation); BM (bone marrow); PB (peripheral blood)

The highest risk of CMV recurrence and CMV disease is reported for HCT CMV-seropositive recipients (R), regardless on donor (D) serostatus. The odds ratio for CMV recurrence is higher for R+ vs R- CMV-serostatus transplants (odds ratio: OR=8.0), D-/R+ vs D+/ R+ CMV-serostatus transplants (OR=1.2), unrelated/mismatched vs matched-family donor transplants (OR=1.6), and acute graft-versus-host-disease vs others (OR=3.2) [8].

The highest risk for EBV reactivation and development of EBV-PTLD is in the case of donor seropositivity, as in majority of cases EBV-PTLD after HCT is of donor origin [7].

In several studies, the relative frequency of herpes viruses reactivations was analyzed in population of patients after allo-HCT, sometimes also with frequency of other latent viruses. Schmidt-Hieber et al. [17] showed in CNS (patients with encephalitis) incidence of 1.2% (32/2628), including: HHV6, 19%; EBV, 19%; HSV, 13%; JCV, 9%; VZV, 6%; ADV, 3%; more than one virus, 16% (CMV+HHV6+JCV; HHV6+HHV7; CMV+HHV6; HSV+EBV; CMV+VZV+HSV+EBV). The 1-year survival of patients after viral encephalitis was below 40%.

Table VIII

Diagnostics of reactivation and disease after HCT

DiagnosticsCMVEBVHHV6VZV
Material for screeningBlood (p/s)Blood (p/s)No screeningNo screening
Material for diagnosis diseaseBlood (p/s), CNS fluid, Biopsy specimenBlood (p/s), CNS fluid, Biopsy specimenWhole blood (p/s); (+hair follicles, nails for CIHHV6); CNS fluidBlood (p/s), CNS fluid
Diagnosis of reactivationPCRPCRPCRClinical + PCR
Most frequent disease manifestationsPneumonia, GI tractPTLDEncephalitisVaricella/Zoster
BiopsyRequired for proven diagnosis (except retinitis)Required for proven diagnosisNot requiredNot necessary
Definitive diagnosisBiopsy (CMV proteins)Biopsy (EBER, viral proteins)HHV6-DNA in CSF; exclusion of CIHHV6Clinical symptoms +DNA-emia
ImagingVariousPETBrain MRI often normalNo
Additional methodsDNA-emia (PCR)DNA-emia (PCR)DNA-emia (PCR)Clinical + PCR
p/s (plasma/serum); PET (positron emission tomography); CNS (central nervous system); other abbreviations in text.

Wu et al. [18] also analyzed the incidence of viral CNS reactivation of herpesviruses, with overall incidence of 12.4%. The most frequent were as follows: EBV, 57.1%; HSV1, 19.0%; CMV, 14.3%; VZV, 4.8%, and mixed 4.8% (EBV+CMV).

Polish analyses [19, 20, 21] showed the incidence of viral reactivation in children: CMV, 29.2%; EBV, 24.3%; BKV, 22.8%; ADV, 5.2%, and the incidence of HHV6 was 1.5%; however, this virus was not usually being tested in all centers. The respective incidence in adults’ patients included the following: CMV, 24.7%; BKV, 5.9%; ADV, 2.9%; EBV, 1.9% [21].

Diagnostics before HCT: serology

Because of incidence and several strategies of prophylaxis and preemptive therapy, it is an universal agreement expressed in a number of guidelines, that in allo-HCT setting, both recipient and donor should be tested serologically (i.e., IgG antibodies) for CMV and EBV, while not for HHV6 and VZV markers. In auto-HCT setting, only CMV serology is usually required, but not EBV, HHV6, or VZV markers. Principles of diagnostics of reactivation and end-organ disease are shown in table VIII The definitive diagnosis of reactivation is confirmed by the presence of viral DNA detected by PCR. In case of HHV6, one must exclude CIHHV6, while in case of VZV diagnosis is usually clinical.

The proven diagnosis of herpes virus end-organ disease must be done from biopsy in case of CMV and EBV, from the presence of CSF DNA in case of HHV6, and clinical diagnosis with blood DNA for VZV.

Prophylaxis

With the variety of viruses, there is a variety of evidences on viral prophylaxis (Tab. IX) Only in case of CMV, there is a good quality of evidence to use antivirals. Nevertheless, so far it was not a recommended strategy because of its toxicity of antiviral drugs. Introduction of letermovir might possibly change this practice, what is happening already in many centers in other countries [22].

Table IX

Possibilities of prophylaxis

ProphylaxisCMVEBVHHV6VZV
Non-specific prophylaxisSelecting CMV-matched donorSelecting EBV-negative donorNot knownAvoiding contact
Specific prophylaxisUsed as a strategyWeak recommendationNot recommendedMandatory in IgG+ (allo ≥12 months; auto 3-6 months)
MethodAntivirals: GCV (ganciclovir), LMV (letermovir)Anti-CD20NOAcyclovir (valaciclovir)
Possible passive immunization after exposureCMV-IgNot availableNot availableVZ-Ig

Passive immunization (specific immunoglobulins) is available for CMV (CMV-Ig) and VZV (VZ-Ig), whereas it is not available for EBV and HHV6. VZ-Ig is recommended for prophylaxis after exposure (up to 2 years after HCT) in IgG-negative transplant recipients [5]. CMV-Ig is recommended as an option only for treatment of CMV pneumonia, whereas it is not recommended for prophylaxis or preemptive treatment [22].

Preemptive approach

Preemptive approach is currently recommended as a post-transplant strategy for CMV and EBV reactivation, whereas it is not recommended for HHV6 and not necessary for VZV infection. This approach is a result of frequency of reactivations and therapeutic possibilities: antivirals for CMV (ganciclovir GCV and foscarnet FSC in first/second line, and cidofovir CDV in third line of therapy) [22], and anti-CD20 for EBV (rituximab) [23]. Preemptive therapy (also known as preemptive prophylaxis) should be based on a routine screening for blood DNA-emia by qPCR and administration of drugs in case of positive viremia, usually defined locally by specific cutoff value. It is recommended to start preemptive approach within first 4 weeks after HCT and to continue it at least up to day +100 or longer in case of risk factors for reactivation or presence of graft-versus-host disease and immunosuppressive therapy.

Treatment

The first-line treatment of end-organ disease is based on administration of GCV (2 x 5 mg/kg) or FSC (2 x 90 mg/kg) for CMV disease, rituximab 375 mg/m2 weekly for EBV disease, GCV or FSC for HHV6 disease, and acyclovir (3 x 500 mg/m2 intravenously or 5 x 800 mg; pediatric dose 4 x 20 mg/kg orally) (Tab. X) [5, 6, 22, 23].

Table X

Treatment of end-organ disease

TreatmentCMVEBVHHV6VZV
Treatment (first line)GCV/FSCAnti-CD20 +reduction of ISTGCV/FSCACV
Treatment (second line)CDV GCV+FSCFSC/GCV GCV+FSCVACV, brivudin, famciclovir
Treatment (resistant cases)GCV+FSC CDV+chemotherapyFSC; CDV (weekly; +probenecid)
Cellular therapy: Cytotoxic T-lymphocytesCMV-CTL*EBV-CTL* (Tabelecleucel)HHV6-CTL*NO
Off-the-shelf CTLsYes*Yes*Yes*
Multi-specific CTLsYes (CMV, EBV, HHV6, ADV, BKV)*
* limited availability; GCV (ganciclovir); FSC (foscarnet); CDV (cidofovir); (V)ACV (val)acyclovir); IST (immunosuppressive therapy); other abbreviations in text.
Table XI

Impact of herpes virus infections on transplant outcomes

OutcomeCMV [22, 33, 34]EBV [7, 35, 36]HHV6 [14–16]VZV [5, 37]
OS (overall survival)Decreased OSNo effectDecreased OS?Decreased OS
RI (relapse incidence)No effectReplication: ↓RI?No effectNo effect
NRM (non-relapse mortality)Replication: ↑NRMReplication: ↑NRM?Replication: ↑NRM?
Acute GVHDNo?No?YES (↑ in CIHHV6)No
Chronic GVHD↑ in repeated CMV infectionsIncreased (if: donor IgG+)No?No

Vaccination

VZV is the only herpes virus for which vaccine is available/approved: live attenuated (LAZV: Zostavax, and LAVV: Varivax), heat-inactivated (V212; Phase III) (auto-HCT) [24], and recombinant (Shingrix; approved 2017; RZV, Phase III, ZOE-HSCT Trial) (presented during EBMT Annual Meeting 2019). So far, live attenuated vaccines are contraindicated both after allo- and auto-HCT at least up to 24 months after HCT. Afterwards, one dose of LAVV can be considered in VZV-seronegative adult patients (two doses in children) with no GvHD, without immunosuppressive treatment, no relapse of underlying disease, and no treatment of immunoglobulins during the previous months; the second dose can be considered in adult seronegative patients or had no history of VZV infection [25, 26, 27, 28, 29]. In transplant setting, inactivated vaccines should be preferred to LAVZ. Still, more data are needed on allo-HCT [25, 26, 27, 28, 29].

Outcome of infection

Herpes virus infection is always regarded as a serious complications. The most frequent end-organ diseases have relatively poor outcome, with about 50% survival for CMV pneumonia, 70% for EBV-PTLD, and 50% for HHV6 encephalitis [30, 31, 32]. Only in case of VZV, the outcome is close to 100%; this is because of effective prophylaxis with acyclovir for at least 12 months after HCT. Positive risk factor for good outcome of infection is reduction of immunosuppressive treatment, if possible. On the other hand, another pitfalls of treatment of herpes virus infection are adverse events of antiviral therapy.

Herpes virus infections might have also an impact on transplant outcomes. The results are ambiguous. The summary, based on large studies, is presented in table XI

Conclusions

Because of high worldwide seroprevalence and latency, infections with herpesviruses are, and will be, frequent. Current strategies of management of CMV and EBV are based on mandatory monitoring of DNA-emia and administration of preemptive therapy if DNA-emia is positive; however, pharmacological prophylaxis is a renewed possibility in case of CMV (letermovir) and is an option for EBV infection (rituximab). In case of HHV-6, no routine screening is recommended; however, in case of encephalitis, encephalopathy, myelosuppression, respective diagnostics should be performed, including test for CIHHV6. Finally, with acyclovir prophylaxis, it seems that VZV is under control of transplantologists and hematologists, and there are also possibilities for vaccination against this infection.

Authors’ contributions/Wkład autorówJS – the only author
Conflict of interestConflict of interest/Konflikt interesu: Author has received lecture fees from MSD, Gilead, Teva, Astellas, and Fresenius; was a participant of Advisory Board for Novartis, Biotests, and Roche; and was a participant of scientific meetings supported by Gilead, MSD, Astellas, Roche and Jazz.
Financial support/FinansowanieNo financial support.
Ethics/EtykaThe work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/ EU for animal experiments; Uniform Requirements for manuscripts submitted to Biomedical journals.

References/ Piśmiennictwo

  • [1]

    Wimmer E Mueller S Tumpey TM Taubenberger JK. Synthetic viruses: a new opportunity to understand and prevent viral disease. Nat Biotechnol 2009;27:1163-72.

    • Crossref
    • PubMed
    • Export Citation
  • [2]

    Parker MT. An ecological framework of the human virome provides classification of current knowledge and identifies areas of forthcoming discovery. Yale J Biol Med 2016;89:339-51.

    • PubMed
    • Export Citation
  • [3]

    O’Leary NA Wright MW Brister JR et al. Reference sequence (RefSeq) database at NCBI: current status taxonomic expansion and functional annotation. Nucleic Acids Res 2016;44:D733-45.

    • Crossref
    • PubMed
    • Export Citation
  • [4]

    van Regenmortel MH Mahy BW. Emerging issues in virus taxonomy. Emerg Infect Dis 2004;10:8-13.

    • Crossref
    • PubMed
    • Export Citation
  • [5]

    Styczynski J Reusser P Einsele H et.al. Management of HSV VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant 2009;43:757-70.

    • Crossref
    • PubMed
    • Export Citation
  • [6]

    Ljungman P de la Camara R Cordonnier C et al. Management of CMV HHV-6 HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant 2008;42:227-40.

    • Crossref
    • PubMed
    • Export Citation
  • [7]

    Styczynski J. Managing post-transplant lymphoproliferative disorder. Expert Opinion Orphan Drugs 2017;5:19-35.

    • Crossref
    • Export Citation
  • [8]

    Styczynski J. Who Is the Patient at Risk of CMV Recurrence: A Review of the Current Scientific Evidence with a Focus on Hematopoietic Cell Transplantation. Infect Dis Ther 2018;7:1-16.

    • Crossref
    • PubMed
    • Export Citation
  • [9]

    Manicklal S Emery VC Lazzarotto T Boppana SB Gupta RK. The „silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013;26:86-102.

    • Crossref
    • Export Citation
  • [10]

    Cesaro S Tridello G Van der Werf S et al. Incidence and outcome of Kaposi sarcoma after hematopoietic stem cell transplantation: a retrospective analysis and a review of the literature on behalf of Infectious Diseases Working Party of EBMT. Bone Marrow Transplant 2019 (accepted for publication).

  • [11]

    Ljungman P Brand R. Factors influencing cytomegalovirus seropositivity in stem cell transplant patients and donors. Haematologica 2007;92:1139-42.

    • Crossref
    • PubMed
    • Export Citation
  • [12]

    Hyde TB Schmid DS Cannon MJ. Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Rev Med Virol 2010;20:311-26.

    • Crossref
    • PubMed
    • Export Citation
  • [13]

    Cannon MJ Schmid DS Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 2010;20:202-13.

    • Crossref
    • PubMed
    • Export Citation
  • [14]

    Hill JA Magaret AS Hall-Sedlak R et al. Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. Blood 2017;130:1062-69.

    • Crossref
    • PubMed
    • Export Citation
  • [15]

    Hill JA Mayer BT Xie H et al. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood 2017;129:2316-25.

    • Crossref
    • PubMed
    • Export Citation
  • [16]

    Ward KN. Child and adult forms of human herpesvirus 6 encephalitis: looking back looking forward. Curr Opin Neurol 2014;27:349-55.

    • Crossref
    • PubMed
    • Export Citation
  • [17]

    Schmidt-Hieber M Schwender J Heinz WJ et al. Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents. Haematologica 2011;96:142-49.

    • Crossref
    • PubMed
    • Export Citation
  • [18]

    Wu M Huang F Jiang X et al. Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation. PLoS One 2013;8:e77805.

    • Crossref
    • PubMed
    • Export Citation
  • [19]

    Styczyński J Czyżewski K Siewiera K et al. Viral infections in children undergoing hematopoietic stem cell transplantation. Acta Haematol Pol 2015;46:312-17

  • [20]

    Styczyński J Czyżewski K Frączkiewicz J et al. Viral infections in children undergoing hematopoietic stem cell transplantation: report 2016 of Polish Pediatric Infectious Working Group of Polish Society of Pediatric Oncology and Hematology. Acta Haematol Pol 2017;48:23-27

  • [21]

    Czyżewski K Styczyński J Giebel Set al. Age-dependent determinants of infectious complications profile in children and adults after hematopoietic cell transplantation: lesson from the nationwide study. Ann Hematol 2019 (e-pub ahaed of print).

    • PubMed
    • Export Citation
  • [22]

    Ljungman P de la Camara R Robin Cet al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 2019 (e-pub ahaed of print).

  • [23]

    Styczynski J van der Velden W Fox CPet al. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica 2016;101:803-11.

    • Crossref
    • PubMed
    • Export Citation
  • [24]

    Winston DJ Mullane KM Cornely OA et al. Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international multicentre randomised double-blind placebo-controlled trial. Lancet 2018;391:2116-27.

    • Crossref
    • PubMed
    • Export Citation
  • [25]

    Mikulska M Cesaro S de Lavallade H et al. Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 2019;19:e188-e199.

    • Crossref
    • PubMed
    • Export Citation
  • [26]

    Cordonnier C Einarsdottir S Cesaro Set al. Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 2019;19:e200-e212.

    • Crossref
    • PubMed
    • Export Citation
  • [27]

    Cordonnier C Mikulska M Einarsdottir S Cesaro S Ljungman P: 2017 ECIL 7 vaccine guidelines. Lancet Infect Dis 2019;19:694-95.

    • Crossref
    • PubMed
    • Export Citation
  • [28]

    Hus I Piekarska A Roliński J et al. Szczepienia ochronne u dorosłych chorych na nowotwory hematologiczne oraz u chorych z asplenią – zalecenia PTHiT i sekcji do spraw zakażeń PALG. Acta Haematol Pol 2018;49:93-101.

    • Crossref
    • Export Citation
  • [29]

    Piekarska A Giebel S Basak G et al. Szczepienia ochronne u chorych dorosłych po przeszczepieniu komórek krwiotwórczych – zalecenia sekcji do spraw zakażeń PALG. Acta Haematol Pol 2017;48:1-9.

    • Crossref
    • Export Citation
  • [30]

    Erard V Guthrie KA Seo S et al. Reduced Mortality of Cytomegalovirus Pneumonia After Hematopoietic Cell Transplantation Due to Antiviral Therapy and Changes in Transplantation Practices. Clin Infect Dis 2015;61:31-39.

    • Crossref
    • PubMed
    • Export Citation
  • [31]

    Styczynski J Gil L Tridello G et al. Response to rituximab-based therapy and risk factor analysis in epstein barr virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 2013;57:794-802.

  • [32]

    Ogata M Oshima K Ikebe T et al. Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2017;52:1563-70.

    • Crossref
    • PubMed
    • Export Citation
  • [33]

    Green ML Leisenring W Xie H et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 2016;3:e119-27.

    • Crossref
    • PubMed
    • Export Citation
  • [34]

    Ljungman P Brand R Hoek J et.al. Infectious Diseases Working Party of the European Group for B Marrow T: Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis 2014;59:473-81.

    • Crossref
    • Export Citation
  • [35]

    Styczynski J Tridello G Gil L et al. Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation. J Clin Oncol 2016;34:2212-20.

    • PubMed
    • Export Citation
  • [36]

    Dierickx D Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. N Engl J Med 2018;378:549-62.

    • Crossref
    • PubMed
    • Export Citation
  • [37]

    Seo HM Kim YS Bang CH et al. Antiviral prophylaxis for preventing herpes zoster in hematopoietic stem cell transplant recipients: A systematic review and meta-analysis. Antiviral Res 2017;140:106-15.

    • Crossref
    • PubMed
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [1]

    Wimmer E Mueller S Tumpey TM Taubenberger JK. Synthetic viruses: a new opportunity to understand and prevent viral disease. Nat Biotechnol 2009;27:1163-72.

    • Crossref
    • PubMed
    • Export Citation
  • [2]

    Parker MT. An ecological framework of the human virome provides classification of current knowledge and identifies areas of forthcoming discovery. Yale J Biol Med 2016;89:339-51.

    • PubMed
    • Export Citation
  • [3]

    O’Leary NA Wright MW Brister JR et al. Reference sequence (RefSeq) database at NCBI: current status taxonomic expansion and functional annotation. Nucleic Acids Res 2016;44:D733-45.

    • Crossref
    • PubMed
    • Export Citation
  • [4]

    van Regenmortel MH Mahy BW. Emerging issues in virus taxonomy. Emerg Infect Dis 2004;10:8-13.

    • Crossref
    • PubMed
    • Export Citation
  • [5]

    Styczynski J Reusser P Einsele H et.al. Management of HSV VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant 2009;43:757-70.

    • Crossref
    • PubMed
    • Export Citation
  • [6]

    Ljungman P de la Camara R Cordonnier C et al. Management of CMV HHV-6 HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant 2008;42:227-40.

    • Crossref
    • PubMed
    • Export Citation
  • [7]

    Styczynski J. Managing post-transplant lymphoproliferative disorder. Expert Opinion Orphan Drugs 2017;5:19-35.

    • Crossref
    • Export Citation
  • [8]

    Styczynski J. Who Is the Patient at Risk of CMV Recurrence: A Review of the Current Scientific Evidence with a Focus on Hematopoietic Cell Transplantation. Infect Dis Ther 2018;7:1-16.

    • Crossref
    • PubMed
    • Export Citation
  • [9]

    Manicklal S Emery VC Lazzarotto T Boppana SB Gupta RK. The „silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013;26:86-102.

    • Crossref
    • Export Citation
  • [10]

    Cesaro S Tridello G Van der Werf S et al. Incidence and outcome of Kaposi sarcoma after hematopoietic stem cell transplantation: a retrospective analysis and a review of the literature on behalf of Infectious Diseases Working Party of EBMT. Bone Marrow Transplant 2019 (accepted for publication).

  • [11]

    Ljungman P Brand R. Factors influencing cytomegalovirus seropositivity in stem cell transplant patients and donors. Haematologica 2007;92:1139-42.

    • Crossref
    • PubMed
    • Export Citation
  • [12]

    Hyde TB Schmid DS Cannon MJ. Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Rev Med Virol 2010;20:311-26.

    • Crossref
    • PubMed
    • Export Citation
  • [13]

    Cannon MJ Schmid DS Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 2010;20:202-13.

    • Crossref
    • PubMed
    • Export Citation
  • [14]

    Hill JA Magaret AS Hall-Sedlak R et al. Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. Blood 2017;130:1062-69.

    • Crossref
    • PubMed
    • Export Citation
  • [15]

    Hill JA Mayer BT Xie H et al. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood 2017;129:2316-25.

    • Crossref
    • PubMed
    • Export Citation
  • [16]

    Ward KN. Child and adult forms of human herpesvirus 6 encephalitis: looking back looking forward. Curr Opin Neurol 2014;27:349-55.

    • Crossref
    • PubMed
    • Export Citation
  • [17]

    Schmidt-Hieber M Schwender J Heinz WJ et al. Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents. Haematologica 2011;96:142-49.

    • Crossref
    • PubMed
    • Export Citation
  • [18]

    Wu M Huang F Jiang X et al. Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation. PLoS One 2013;8:e77805.

    • Crossref
    • PubMed
    • Export Citation
  • [19]

    Styczyński J Czyżewski K Siewiera K et al. Viral infections in children undergoing hematopoietic stem cell transplantation. Acta Haematol Pol 2015;46:312-17

  • [20]

    Styczyński J Czyżewski K Frączkiewicz J et al. Viral infections in children undergoing hematopoietic stem cell transplantation: report 2016 of Polish Pediatric Infectious Working Group of Polish Society of Pediatric Oncology and Hematology. Acta Haematol Pol 2017;48:23-27

  • [21]

    Czyżewski K Styczyński J Giebel Set al. Age-dependent determinants of infectious complications profile in children and adults after hematopoietic cell transplantation: lesson from the nationwide study. Ann Hematol 2019 (e-pub ahaed of print).

    • PubMed
    • Export Citation
  • [22]

    Ljungman P de la Camara R Robin Cet al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 2019 (e-pub ahaed of print).

  • [23]

    Styczynski J van der Velden W Fox CPet al. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica 2016;101:803-11.

    • Crossref
    • PubMed
    • Export Citation
  • [24]

    Winston DJ Mullane KM Cornely OA et al. Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international multicentre randomised double-blind placebo-controlled trial. Lancet 2018;391:2116-27.

    • Crossref
    • PubMed
    • Export Citation
  • [25]

    Mikulska M Cesaro S de Lavallade H et al. Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 2019;19:e188-e199.

    • Crossref
    • PubMed
    • Export Citation
  • [26]

    Cordonnier C Einarsdottir S Cesaro Set al. Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 2019;19:e200-e212.

    • Crossref
    • PubMed
    • Export Citation
  • [27]

    Cordonnier C Mikulska M Einarsdottir S Cesaro S Ljungman P: 2017 ECIL 7 vaccine guidelines. Lancet Infect Dis 2019;19:694-95.

    • Crossref
    • PubMed
    • Export Citation
  • [28]

    Hus I Piekarska A Roliński J et al. Szczepienia ochronne u dorosłych chorych na nowotwory hematologiczne oraz u chorych z asplenią – zalecenia PTHiT i sekcji do spraw zakażeń PALG. Acta Haematol Pol 2018;49:93-101.

    • Crossref
    • Export Citation
  • [29]

    Piekarska A Giebel S Basak G et al. Szczepienia ochronne u chorych dorosłych po przeszczepieniu komórek krwiotwórczych – zalecenia sekcji do spraw zakażeń PALG. Acta Haematol Pol 2017;48:1-9.

    • Crossref
    • Export Citation
  • [30]

    Erard V Guthrie KA Seo S et al. Reduced Mortality of Cytomegalovirus Pneumonia After Hematopoietic Cell Transplantation Due to Antiviral Therapy and Changes in Transplantation Practices. Clin Infect Dis 2015;61:31-39.

    • Crossref
    • PubMed
    • Export Citation
  • [31]

    Styczynski J Gil L Tridello G et al. Response to rituximab-based therapy and risk factor analysis in epstein barr virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis 2013;57:794-802.

  • [32]

    Ogata M Oshima K Ikebe T et al. Clinical characteristics and outcome of human herpesvirus-6 encephalitis after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2017;52:1563-70.

    • Crossref
    • PubMed
    • Export Citation
  • [33]

    Green ML Leisenring W Xie H et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 2016;3:e119-27.

    • Crossref
    • PubMed
    • Export Citation
  • [34]

    Ljungman P Brand R Hoek J et.al. Infectious Diseases Working Party of the European Group for B Marrow T: Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis 2014;59:473-81.

    • Crossref
    • Export Citation
  • [35]

    Styczynski J Tridello G Gil L et al. Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation. J Clin Oncol 2016;34:2212-20.

    • PubMed
    • Export Citation
  • [36]

    Dierickx D Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. N Engl J Med 2018;378:549-62.

    • Crossref
    • PubMed
    • Export Citation
  • [37]

    Seo HM Kim YS Bang CH et al. Antiviral prophylaxis for preventing herpes zoster in hematopoietic stem cell transplant recipients: A systematic review and meta-analysis. Antiviral Res 2017;140:106-15.

    • Crossref
    • PubMed
    • Export Citation
Search
Journal information
Impact Factor


CiteScore 2018: 0.17

SCImago Journal Rank (SJR) 2018: 0.112
Source Normalized Impact per Paper (SNIP) 2018: 0.108

Metrics
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 88 88 21
PDF Downloads 38 38 8