Minireviews
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2019; 11(2): 73-83
Published online Feb 26, 2019. doi: 10.4252/wjsc.v11.i2.73
Human cord blood-derived viral pathogens as the potential threats to the hematopoietic stem cell transplantation safety: A mini review
Ali Noroozi-aghideh, Maryam Kheirandish
Ali Noroozi-aghideh, Department of Hematology, Faculty of Paramedicine, Aja University of Medical Sciences, Tehran 14665-1157, Iran
Maryam Kheirandish, Immunology Department, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine (IBTO), Tehran 14665-1157, Iran
ORCID number: Ali Noroozi-aghideh (0000-0002-2811-2659); Maryam Kheirandish (0000-0002-9856-0844).
Author contributions: The author contributed equally to this work.
Conflict-of-interest statement: Authors of this manuscript have no conflicts of interest to disclose.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Maryam Kheirandish, PhD, Associate Professor, Immunology Department, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine (IBTO), Hemmat high way next to Milad tower, Tehran 14665-1157, Iran. m.kheirandish@ibto.ir
Telephone: +98-21-88629538 Fax: +98-21-88601577
Received: December 12, 2018
Peer-review started: December 12, 2018
First decision: December 24, 2018
Revised: January 14, 2019
Accepted: January 26, 2019
Article in press: January 26, 2019
Published online: February 26, 2019

Abstract

Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) and potential alternative for bone marrow transplantation for patients who lack human leukocyte antigen (HLA)-matched donors. The main practical advantages of UCB over other HSC sources are the immediate availability, lower incidence of graft-versus-host disease, minimal risk to the donor, and lower requirement for HLA compatibility. However, the use of UCB is limited by delayed engraftment and poor immune reconstitution, leading to a high rate of infection-related mortality. Therefore, severe infectious complications, especially due to viral pathogens remain the leading cause of morbidity and mortality during the post-UCB transplantation (UCBT) period. In this context, careful screening and excluding the viral-contaminated UCB units might be an effective policy to reduce the rate of UCBT-related infection and mortality. Taken together, complete prevention of the transmission of donor-derived viral pathogens in stem cell transplantation is not possible. However, having the knowledge of the transmission route and prevalence of viruses will improve the safety of transplantation. To the best of our knowledge, there are few studies that focused on the risk of virus transmission through the UCB transplant compared to other HSC sources. This review summarizes the general aspects concerning the prevalence, characteristics, and risk factors of viral infections with a focus on the impact of viral pathogens on cord blood transplantation safety.

Key Words: Cord blood, Transplantation safety, Viral pathogens

Core tip: Severe infectious complications, especially due to viral pathogens remain the leading cause of the post-transplantation morbidity and mortality. In this context, excluding the viral-contaminated umbilical cord blood (UCB) units might be an effective policy to reduce the infection rate after UCB transplantation (UCBT). Complete prevention of the transmission of donor-derived viral pathogens via UCB is not possible. However, having the knowledge of the transmission route and the prevalence of viruses will improve the transplantation safety by controlled patient management. This minireview summarizes the general aspects concerning the prevalence, characteristics and risk factors of viral infections with a focus on the impact on UCBT safety.



INTRODUCTION

In past years, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has made considerable progress in the treatment of a large variety of malignant and nonmalignant disorders. Human leukocyte antigen (HLA)-identical sibling and HLA-matched unrelated donors are typically the first choices, although it can be achieved for only about 30% of patients. So, umbilical cord blood transplantation (UCBT) is an alternative option for patients with no HLA-matched bone marrow donors[1,2].

Benefits of using cord blood cells include immediate availability of banked UCB units, lower incidence of graft-versus-host disease (GVHD), minimal risk to the donor, and a lower requirement for HLA compatibility between the donor and the recipient[3].

Despite these advantages, UCBT is associated with delayed engraftment and poor immune reconstitution, leading to a high rate of infection-related mortality, up to about 50% in several historical series. Viral infections are important causes of morbidity and mortality in patients undergoing allo-HSCT. Therefore, careful screening and testing of UCB units seems be critical to exclude the potential UCB units with viral contaminations and to reduce the risk of UCB-related virus transmission[4,5].

Fortunately, improvements in molecular diagnostic methods, such as Multiplex polymerase chain reaction (PCR) and Real-time quantitative PCR (RQ-PCR) have facilitated the early diagnosis of viral infections and selection of “virus-safe” UCB units[6-8] (Table 1).

Table 1 Umbilical cord blood transplantation-related viral infection.
Virus typeUCBT-related primary viral infectionUCBT-related virus reactivationRef.
CMVAlbano et al[4]
Abedi et al[6]
Shin et al[80]
Al-Awadhi et al[81]
Tong et al[20]
Beck et al[21]
O’Connor et al[22]
Sinclair et al[23]
Weinberg et al[26]
HCVBenova et al[41]
VZVTomonari et al[44]
Patrick et al[45]
Vandenbosch et al[47]
HHV-6D’Agaro et al[53]
Scheurer et al[48]
Yamane et al[49]
Hill et al[50]
Tomonari et al[51]
Sashihara et al[52]
HHV-7Abedi et al[8]
HHV-8Golchin et al[7]
EBVHassan et al[62]
Haut et al[63]
Ohga et al[64]
Reddiconto et al[65]
Auger et al[61]
Barker et al[67]
Blaes et al[69]
Brunstein et al[70]
Dumas et al[71]
Kalra et al[72]
AVsRobin et al[79]

There have been significant strides in using UCB stem cells in cellular therapy, particularly those for neurologic[9-11] or hematopoietic[12-14] cell differentiation, because of their excellent therapeutic efficacy in bone marrow recovery and regenerative medicine. However, the necessity of increase of transplantation safety is recommended. To the best of our knowledge, there are few studies that focused on the risk of virus transmission through the UCB transplant compared to other HSC sources.

Here, we reviewed the prevalence, characteristics, and risk factors of viral infections in UCB transplantation settings.

COMMON VIRAL INFECTIONS IN HSCT RECIPIENTS
Cytomegalovirus (CMV)

Human CMV, also known as human herpesvirus-5 (HHV-5), is a ubiquitous beta-herpesvirus that infects 60%-95% of healthy adults worldwide[15]. This virus is the most common cause of congenital infection worldwide, impacting about one million newborns annually[16].

CMV infection is a leading opportunistic infectious agent in allogeneic HSCT. It has been noted that 30% and 5% of the recipients of allogeneic and autologous HSCT develop CMV disease, respectively. Moreover, the risk of CMV transmission from a seropositive donor to a seronegative recipient is about 30%[17,18].

The initial infection is generally asymptomatic or associated with mild flu-like symptoms. In rare cases, it may cause a serious end-organ disease or systemic syndrome, either early or late period after transplantation with a poor prognosis. In some cases of congenital infections, CMV causes severe and permanent consequences such as sensorineural hearing loss, growth retardation, intellectual disability, and even death nevertheless, there are no effective interventions to interrupt the intrauterine transmission[16,19].

CMV infection can indirectly increase the risk of transplant-related mortality (TRM) by mediating the immunosuppressive effects. In this context, CMV has been related to the development of GVHD and bacterial or fungal superinfection, particularly in CMV-seronegative patients who received seropositive allografts[19,20].

Despite the advances in current preventive antiviral strategies and sensitive diagnostic techniques such as PCR-based assays, CMV remains the important cause of serious viral infections in the recipients of UCBT, as well as in allogeneic marrow or peripheral blood SCT. In this way, CMV reactivation rate following UCBT is noted to be 21%-100% and is similar when compared to peripheral blood or bone marrow SCT[21].

It has been reported that up to 30%-40% of seronegative pregnant women who infected by CMV transmit the virus to their fetus, suggesting a high incidence of cord blood contamination by CMV[16]. It has been shown that CMV can establish a lifelong latency in hematopoietic progenitors and monocytes. Therefore, the virus might be transmitted by these infected cells to the immunocompromised recipient and then become reactivated[22,23] (Table 1). Pergam et al[24] indicated that high allograft white blood cell count is an important risk factor associated with CMV transmission due to the role of myeloid cells as a reservoir of latent CMV. In this context, Abedi et al[6] analyzed 825 UCB-derived buffy coat samples and reported that 17 samples have been positive for CMV latent infection.

The serostatus of the donor and recipient is the most important risk factor for CMV disease in allo-HSCT recipients. In this regard, CMV-seropositive recipients have been identified to be highly susceptible to developing CMV infection and CMV complications are primarily associated with viral reactivation. Seronegative patients who receive seropositive allografts are also susceptible to CMV transmission. As mentioned above, the risk for transmission of latent CMV from a CMV-seropositive donor to a CMV-seronegative patient is relatively low, but it increases TRM, mainly due to an increased risk for severe bacterial or fungal superinfection[24,25]. Therefore, for a CMV-seronegative recipient, it is preferable to select a CMV-seronegative donor to reduce the possibility of CMV transmission through allograft. On the contrary, using a seropositive donor for a seropositive recipient will probably result in a better outcome. This fact may be related to the transfer of primed CMV-specific T cells present in the allograft to the recipient[24].

Since the pediatric recipients of UCB transplant are primarily CMV-seronegative, CMV transmission by allograft is often of more importance than reactivation of the latent virus in the recipient[24,26]. Therefore, excluding the UCB donations from CMV seropositive mothers might be effective to prevent UCB-related CMV transmission.

Hepatitis B virus

Hepatitis B virus (HBV) is a double-stranded DNA virus, classified in the Hepadnaviridae family. Chronic HBV infection is a serious problem of public health affecting over 240 million people worldwide[27].

In the immunocompetent host, HBV infection is responsible for acute hepatitis, which may progress to chronic infection and lead to cirrhosis or hepatocellular carcinoma. Most HBV carriers, however, may never experience severe liver complications during their lifetime. While the risk of acquiring HBV infection via blood transfusion is nowadays extremely low, allogeneic HSCT patients still represent a high-risk group, being susceptible to be infected due to the lack of efficient immunity given both the disease and receiving the conditioning regimen before the transplantation. The prevalence of HBV infection in these patients ranges from 1% to 28%, according to geographic areas. The results of a multicenter study showed that the risk of HBV reactivation, two years after HSCT was 81% for allogeneic and 66% for autologous cases. Patients undergoing HSCT can also develop a de novo HBV infection following the transplantation. The risk of HBV transmission to uninfected recipients of bone marrow transplantation (BMT) is not 100% and the exact risk remains unclear[28,29].

Huang et al[30] exposed UCB-derived HSCs to HBV and demonstrated that HBV not only can infect these cells but also can replicate in them, and then suggested the possible role of HSCs as extrahepatic HBV reservoir. On the other hand, other studies have shown the risk of intrauterine transmission of HBV via peripheral blood mononuclear cells in addition to transplacental leakage and placental infection. These findings suggest the possibility of HBV transmission by UCB mononuclear cells to the recipient and highlight the importance of routine screening of UCB units[31,32]. To the best of our knowledge, very little published data are available about the prevalence and risk factors for HBV transmission by HSC transplant from UCB source.

Hepatitis C virus

Hepatitis C virus (HCV) is a double-stranded RNA virus of the Flaviviridae family. Global incidence of chronic HCV infection is about 170 million people and approximately 3-4 million more are infected each year[29,33]. As for HBV, patients infected with HCV show a mild to moderate liver disease on long-term monitoring depending on age at infection and host immune response[34].

HCV infection in HSCT recipients might be because of both virus reactivation and de novo infection. HCV reactivation after immunosuppressive therapy has led to fulminant hepatic failure in some cases. Accordingly, in a multicenter study by Locasciulli et al[35] the risk of HCV reactivation at 24 mo after HSCT has been 100% and 16% for allogeneic and autologous cases, respectively.

On the other hand, the rate of de novo HCV infection in HSCT recipients of donor-cell origin is controversial. In this context, 50% of the patients receiving an infected marrow became viraemic in a study by Locasciulli et al[36], while Shuhart et al[37] observed a 100% rate of virus transmission in such cases. Moreover, it has been reported that HCV can infect HSCs and therefore, virus transmission from HCV-RNA positive donor to an uninfected recipient is possible[38].

HSCT has not a contraindication in HCV infected recipients without any evidence of liver damage. However, HCV-infected HSCT recipients are more prone to develop GVHD and fatal liver failure in comparison with non-infected recipients. Furthermore, outcomes in long-term survivors are significant, and they should be monitored carefully by regular examinations[39,40].

Anti-HCV positive but HCV-RNA negative donors are improbable to infect the recipients and may be selected for transplant donation for the patients without an alternative donor. Accordingly, all anti-HCV-positive donors should be tested for HCV-RNA. However, high-risk anti-HCV negative donors should also be tested for HCV-RNA[33,40].

The risk of vertical HCV transmission is lower than in HBV including 1.7% and 4.3% in children born to women positive for hepatitis C antibody or HCV-RNA, respectively. Despite the possibility of vertical HCV transmission from mother to fetus and possible contamination of UCB units, there is a paucity of published data that have focused on the possibility and outcomes of HCV transmission by UCBT. Future studies using molecular diagnostic methods and clinical monitoring will clarify the prevalence and importance of UCB-related HCV transmission[32,41].

Varicella-zoster virus

Varicella-zoster virus (VZV) or HHV-3 is an exclusively human alphaherpesvirus. The primary infection occurs typically as childhood chickenpox (varicella). As a common feature to all members of the Herpesviridae family, VZV is capable to establish latent infection in its host. It remains in a latent form for decades in cranial nerve ganglia and dorsal root ganglia, and then might become reactivated under the certain conditions. Reactivation of the virus, either spontaneously or following the post-transplant immunosuppression, may cause a painful and debilitating disease known as herpes zoster (shingles)[42,43].

The estimated prevalence of post-SCT VZV infection either primary infection or reactivation in children is as high as 22% to 32% after allogeneic and 9% to 46% after autologous transplantation. Based on previous studies, Older age, pre-transplant irradiation, HLA-mismatched transplantation, chronic GVHD, and recipient pre-transplant VZV seropositivity have been described as predisposing risk factors for VZV disease[44,45]. Accordingly, Umezawa et al.[46] retrospectively analyzed the clinical symptoms of VZV disease and risk factors for disease progression in allogeneic HSCT patients. They suggested that gender and total body irradiation did not affect the development of VZV dissemination, and concluded that delayed antiviral therapy is a serious risk factor for VZV dissemination following the allogeneic HSCT.

It has also been shown that VZV disease is more frequent and more severe after UCBT than other types of HSCT. In this regard, Tomonari[44] showed 80% cumulative incidence of VZV reactivation in adult patients who had undergone UCBT from unrelated donors. In another study, Vandenbosch and colleagues[47] compared the VZV reactivation rate in the total of 114 VZV seropositive children who had received UCBT or T-replete BMT and reported an incidence of 46% of VZV disease at 3 years after UCBT. This higher frequency in UCBT recipients may be related to delayed immune reconstitution after UCBT and therefore, necessitates the preemptive therapy or prophylaxis in these patients.

On the other hand, Patrick et al.[45] conducted a retrospective study to assess the efficacy of routine screening for identification of HSV or VZV viremia following HSCT. They aimed to discuss whether this screening identifies any patients with viremia who had not been identified via clinical manifestations. Finally, they concluded in agreement with the recommendation of the European Conference on Infections in Leukemia that routine screening for VZV is not obligatory in the pediatric HSCT recipients but regular clinical assessment should be performed.

HHV-6

HHV-6 belongs to the beta herpesviridae subfamily and exists as two closely related variants (A and B). Pathogenicity of HHV-6A is uncertain, whereas HHV-6B is the most frequent causative agent of HHV-6-related human diseases[48].

This virus is an opportunistic ubiquitous agent that infects most children in the early years of life. Primary infection is mainly associated with exanthema subitum (also called roseola infantum) and related febrile rash illnesses. Like the other herpesviruses, HHV-6 has the ability to persist in various cells of the host, especially in monocyte/macrophages and then become reactivated from latency during immunodeficiency, especially in HSCT recipients[26].

Several retrospective studies have shown the higher incidence of HHV-6 reactivation in the recipients of UCB than in patients receiving other stem cell sources, and suggested to be related with high mortality rate and fatal complications including acute GVHD, bone marrow suppression, and CNS disease, especially the syndrome of post-transplantation acute limbic encephalitis called HHV-6-PALE[48,49]. Scheurer et al[48] conducted a systematic literature review and meta-analysis to investigate the prevalence and clinical significance of HHV-6 reactivation in UCBT recipients. They showed that prevalence of HHV-6 reactivation and related- encephalitis were significantly higher in UCB than non-UCB recipients, and emphasized the monitoring of UCB recipients for HHV-6 reactivation.

However, literature focusing on HHV-6 primary infection after UCBT and especially, HHV-6 transmission by UCB is scarce. Based on available data, HHV-6 DNA is detectable in plasma samples from 40% to 50% of HSC transplant recipients from adult donors and up to 80% of unrelated UCB recipients within 6 wk after transplantation[50]. Accordingly, Tomonari et al[51] have also shown the higher HHV-6 viral load using quantitative PCR in adult patients who underwent UCBT compared with unrelated BMT.

These reports in addition to the possibility of intrauterine transmission of HHV-6 and contamination of UCB cells suggest the possibility of HHV-6 transmission by UCB allograft and subsequent primary infection. This phenomenon might be associated with less efficient immunity against HHV6 in cord blood[52,53]. While more studies are needed to confirm and define the importance of UCBT in HHV-6 transmission, routine screening for HHV-6 and exclusion of PCR-positive UCB units seems to be efficient to prevent UCB-mediated virus transmission and related serious outcomes.

HHV-7

HHV-7 is a member of the beta herpesviridae family. Like HHV-6, it causes primary infection most commonly in infancy and childhood and is able to cause roseola. However, symptomatic HHV-7 infection is less common and occurs at a later age than with HHV-6. This virus remains latent in the human host and can become reactivated after transplantation. Right now, no clinical symptoms or significant laboratory abnormalities were found to be related to HHV-7 reactivation[54].

Owing to its selective tropism for CD4+ T lymphocytes and possibility of worsening the immunodeficiency state, the HHV-7 infection might be a serious threat in transplant recipients and impair the transplant engraftment. Mirandola et al[55] incubated cord blood CD34+ cells with HHV-7 and showed that HHV-7 affects the differentiation and survival of CD34+ hematopoietic progenitors. Consistently, Gonelli et al[56] showed that HHV-7 induces apoptosis of cord blood CD61+ megakaryocytic cells in vitro and may impair the development of megakaryocytic cells. Accordingly, Chan et al[57] noted the association of HHV-7 reactivation with delayed neutrophil engraftment following BMT. These findings are real causes for concern in patients with high risk of HHV-7 infection, such as HSCT patients.

Abedi et al[8] assayed a large number of UCB samples by quantitative real-time PCR and reported that 3.2% and 0.48% were positive for HHV-7 DNA in buffy coat and plasma as latent and active infections, respectively. In contrast, none of the samples were positive for HHV-7 DNA in the study by Weinberg[26].

Based on the high seroprevalence of HHV-7 in the general population and the role of this virus in myelopoiesis impairment, it seems that detection of HHV-7 in UCB donors could be a useful tool for prevention of UCB- associated HHV-7 transmission[55].

HHV-8

HHV-8, also called Kaposi sarcoma (KS)-associated herpesvirus, is a gamma-herpesvirus. Apart from KS, HHV-8 is the causative agent of lymphoproliferative disorders such as primary effusion lymphoma and multicentric Castleman's disease in immunosuppressed adults. HHV-8 has also been related to fatal hematopoiesis impairment in an autologous stem cell recipient[58,59].

The certain ways of HHV-8 transmission are unclear. Previous studies have suggested the sexual mode of virus transmission in homosexual men and horizontal transmission via saliva in endemic areas. Notably, HHV-8 from seropositive donor cell origin may be transmitted to the recipient[7,58].

Previous studies have indicated the minimum risk for vertical transmission of HHV-8 from mother to child during pregnancy, and therefore, the low seroprevalence of HHV-8 infection in UCB samples[7,26]. Accordingly, Golchin et al[7] surveyed a large number of UCB samples by real-time PCR and reported an only 1.38% HHV-8 prevalence in UCB mononuclear cells. However, HHV-8 has the ability to infect cord blood mononuclear cells and cause post-UCBT infection, and therefore it deserves the attention in UCBT settings[26].

Accordingly, defining the HHV-8 serostatus and avoiding matches between HHV-8-positive donors and HHV-8-negative recipients appear to be effective to prevent virus transmission by UCBT in areas of high endemicity.

Epstein-Barr virus

Epstein-Barr virus (EBV) is a widespread gammaherpesvirus that infects over 90% of humans. In healthy individuals, EBV infection is tightly controlled by the immune system. After primary infection, EBV establishes a lifelong asymptomatic latent infection in B-cells of immunocompetent hosts. Later, immunosuppressive therapy given at HSCT may lead to EBV reactivation and subsequent EBV diseases, particularly life-threatening post-transplant lymphoproliferative disease (PTLD)[60,61]. Some studies have also reported the cases of UCB-transplanted patients who developed the EBV-related PTLD from graft-cell origin and proved the transmission of EBV infection by donor cells[62-65] (Table 1). EBV reactivation frequently occurs in patients having allogeneic HSCT and several risk factors for the development of EBV disease after HSCT have been reported, such as T-cell depletion, donor stem cell source, HLA mismatch, severe acute GVHD, EBV serostatus, the presence of CMV disease and possibly younger age[60,61].

Blood EBV DNA level has proven to be a predictive biomarker in allogeneic HSCT patients. In a clinical follow-up project, Li et al[61] evaluated the impact of EBV load on the survival of patients who had received transplant form different sources of stem cells, and found that patients with very low or high EBV-DNA load early after transplantation had a poor prognosis, compared to patients with intermediate levels.

Sundin and others have demonstrated that PTLD mostly originates from donor-derived cells, and risk for PTLD increases in positive donor/negative recipient (D+/R−) pairs. Therefore, selection of EBV-seronegative donors could reduce the risk of PTLD development[66-68]. There are also reports concerning the higher incidence of PTLD in patients who underwent UCBT compared with other HSC sources, especially when anti-thymocyte globulin is added to conditioning regimen[69,70]. Contrary to these findings, in a retrospective multicenter study, Dumas et al[71] studied 175 UCBT recipients for whom EBV RQ-PCR monitoring was performed, and concluded conversely that UCBT recipients are not more susceptible to EBV events if EBV load is regularly monitored and preemptive treatment performed.

Despite the low incidence of congenital EBV infection, the occurrence of EBV-associated PTLD is possible at least in unrelated UCBT setting and adds one additional fatal complication following UCBT. Therefore, EBV screening by sensitive and reliable tests may play an important role in the future evaluation of UCB units to use in transplantation[71,72].

Human adenoviruses

Human adenoviruses (AVs) are non-enveloped double-stranded DNA viruses that belong to the Adenoviridae family. AVs are divided into six subgroups (A through G) based on common biologic, immunologic, morphologic and genetic features[73].

In immunocompetent individuals, AV primary infection is mostly subclinical and self-limiting, although some severe courses have been described[74]. However, AV infection is more clinically important in patients with impaired immunity, particularly in HSCT patients and causes fatal complications. It is also more common to children than adults following the HSCT. In this regard, two studies compared the rates of AV isolation in children and adults after BMT and found 21% and 23% of children to be positive compared with 9% in adults, respectively[75,76].

In the allogeneic HSCT setting, AV infection can arise from de novo infection or reactivation of the latent endogenous virus. De novo infection can occur by transmission of the exogenous virus in D+/R− pairs. In this context, previous studies have demonstrated the 4-fold higher risk of primary AV infections in patients that received HSC graft from seropositive donors compared to seronegative ones. However, reactivation of endogenous latent AV seems to be the main cause of AV-associated fatal complication in immunocompromised patients[74,77,78].

Main risk factors predisposing an invasive AV infection include childhood, donor AV serostatus, severe GVHD, HLA-mismatched transplantation, CMV viremia, and T-cell depletion. Furthermore, UCBT is suggested to be an independent risk factor for AV infection probably due to the lack of mature lymphocytes in CB, as cellular components of antiviral defense[79].

Runde et al[77] studied the prevalence and risk factors of AV infection in allo-HSCT recipients and showed that AV antibody status of the donor had a strong impact on the development of AV infection in the recipients. Their finding supports indirectly the hypothesis that AV infection following HSCT is not always the result of virus reactivation, and the virus might be transmitted by infected cells from AV seropositive donors to the recipients. This hypothesis is proved if the same AV is detected by molecular analyses in donors and corresponding recipients.

To the best of our knowledge, there are few studies that have focused on the risk of AV transmission by UCB transplant compared to other HSC sources. However, the presence of AV DNA positive cells besides naivety of T cells serves UCB as a putative source of AV infection in the immunocompromised recipients.

CONCLUSION

The amount of threat for transmission of infections carried with allogeneic transplantation, notably of viruses, is largely unknown and difficult to assess. The approach to virological screening of UCB stem cell donors varies with national and regional regulations. Over recent years, UCBT has become a valuable alternative for patients who lack a suitably matched bone marrow donor. However, UCBT is associated with several limitations, in particular, the low number of mature lymphocytes and poor immune reconstitution. Given these limitations, virus transmission via UCB may cause serious infectious complication in the immunocompromised recipients, and therefore, excluding the viral-contaminated UCB units might be an effective policy to reduce the rate of UCBT-related infection and mortality. Taken together, complete prevention of the transmission of donor-derived viral pathogens in SCT is not possible. However, having the knowledge of the transmission route and the prevalence of viruses will improve the safety of transplantation.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Cell and tissue engineering

Country of origin: Iran

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P- Reviewer: Labusca L, Jun YM S- Editor: Dou Y L- Editor: A E- Editor: Bian YN

References
1.  Ballen KK, Koreth J, Chen YB, Dey BR, Spitzer TR. Selection of optimal alternative graft source: mismatched unrelated donor, umbilical cord blood, or haploidentical transplant. Blood. 2012;119:1972-1980.  [PubMed]  [DOI]
2.  Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122:491-498.  [PubMed]  [DOI]
3.  Montoro J, Piñana JL, Moscardó F, Sanz J. Infectious Complications after Umbilical Cord-Blood Transplantation from Unrelated Donors. Mediterr J Hematol Infect Dis. 2016;8:e2016051.  [PubMed]  [DOI]
4.  Albano MS, Ciubotariu R, Dobrila L, Tarnawski M, DeLeon M, Watanabe C, Krishnan S, Scaradavou A, Rubinstein P. Cytomegalovirus viral load in cord blood and impact of congenital infection on markers of hematopoietic progenitor cell potency. Transfusion. 2017;57:2768-2774.  [PubMed]  [DOI]
5.  Meissner-Roloff M, Gaggia L, Vermeulen M, Mazanderani AFH, du Plessis NM, Steel HC, Pepper MS. Strategies for screening cord blood for a public cord blood bank in high HIV prevalence regions. Glob Health Epidemiol Genom. 2018;3:e9.  [PubMed]  [DOI]
6.  Abedi E, Kheirandish M, Sharifi Z, Samiee S, Kokhaei P, Pourpak Z, Ashraf MJ. Quantification of Active and Latent Form of Human Cytomegalovirus Infection in Umbilical Cord Blood Donors by Real-Time PCR. Int J Organ Transplant Med. 2017;8:140-145.  [PubMed]  [DOI]
7.  Golchin N, Kheirandish M, Sharifi Z, Samiee S, Kokhaei P, Pourpak Z. Quantification of viral genome in cord blood donors by real time PCR to investigate human herpesvirus type 8 active infection. Transfus Apher Sci. 2015;53:378-380.  [PubMed]  [DOI]
8.  Abedi E, Kheirandish M, Sharifi Z, Samiee S, Kokhaei P, Pourpak Z, Ashraf MJ. Quantitative polymerase chain reaction for detection of human herpesvirus-7 infection in umbilical cord blood donors. Transpl Infect Dis. 2015;17:21-24.  [PubMed]  [DOI]
9.  Rafieemehr H, Kheyrandish M, Soleimani M. Neuroprotective Effects of Transplanted Mesenchymal Stromal Cells-derived Human Umbilical Cord Blood Neural Progenitor Cells in EAE. Iran J Allergy Asthma Immunol. 2015;14:596-604.  [PubMed]  [DOI]
10.  Kheirandish M, Gavgani SP, Samiee S. The effect of hypoxia preconditioning on the neural and stemness genes expression profiling in human umbilical cord blood mesenchymal stem cells. Transfus Apher Sci. 2017;56:392-399.  [PubMed]  [DOI]
11.  Rafieemehr H, Kheirandish M, Soleimani M. Improving the neuronal differentiation efficiency of umbilical cord blood-derived mesenchymal stem cells cultivated under appropriate conditions. Iran J Basic Med Sci. 2015;18:1100-1106.  [PubMed]  [DOI]
12.  Aghideh AN, Kheirandish M, Abolghasemi H, Gharehbaghian A. Platelet growth factors suppress ex vivo expansion and enhance differentiation of umbilical cord blood CD133+ stem cells to megakaryocyte progenitor cells. Growth Factors. 2010;28:409-416.  [PubMed]  [DOI]
13.  Dezaki ZA, Kheirandish M. Hypoxia Preconditioning Promotes Survival And Clonogenic Capacity of Human Umbilical Cord Blood Mesenchymal Stem Cells. IJBC. 2018;10:43-49.  [PubMed]  [DOI]
14.  Rafieemehr H, Kheirandish M, Soleimani M. A New Two Step Induction Protocol for Neural Differentiation of Human Umbilical Cord Blood- Derived Mesenchymal Stem Cells. IJBC. 2015;7:111-116.  [PubMed]  [DOI]
15.  Wu SJ, Villarreal DO, Shedlock DJ, Weiner DB. Synthetic DNA approach to cytomegalovirus vaccine/immune therapy. Adv Exp Med Biol. 2015;848:131-148.  [PubMed]  [DOI]
16.  Itell HL, Nelson CS, Martinez DR, Permar SR. Maternal immune correlates of protection against placental transmission of cytomegalovirus. Placenta. 2017;60 Suppl 1:S73-S79.  [PubMed]  [DOI]
17.  Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am. 2011;25:151-169.  [PubMed]  [DOI]
18.  Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TM, Campos SV, Ramos JF, Latif AZ, Litvinov N, Maluf NZ, Caiaffa Filho HH, Pannuti CS, Lopes MH, Santos VA, Linardi Cda C, Yasuda MA, Marques HH. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015;70:515-523.  [PubMed]  [DOI]
19.  Solano C, Navarro D. Clinical virology of cytomegalovirus infection following hematopoietic transplantation. Future Virol. 2010;5:111-124.  [PubMed]  [DOI]
20.  Tong J, Sun Z, Liu H, Geng L, Zheng C, Tang B, Song K, Yao W, Liu X. Risk factors of CMV infection in patients after umbilical cord blood transplantation: a multicenter study in China. Chin J Cancer Res. 2013;25:695-703.  [PubMed]  [DOI]
21.  Beck JC, Wagner JE, DeFor TE, Brunstein CG, Schleiss MR, Young JA, Weisdorf DH, Cooley S, Miller JS, Verneris MR. Impact of cytomegalovirus (CMV) reactivation after umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2010;16:215-222.  [PubMed]  [DOI]
22.  O'Connor CM, Murphy EA. A myeloid progenitor cell line capable of supporting human cytomegalovirus latency and reactivation, resulting in infectious progeny. J Virol. 2012;86:9854-9865.  [PubMed]  [DOI]
23.  Sinclair J. Human cytomegalovirus: Latency and reactivation in the myeloid lineage. J Clin Virol. 2008;41:180-185.  [PubMed]  [DOI]
24.  Pergam SA, Xie H, Sandhu R, Pollack M, Smith J, Stevens-Ayers T, Ilieva V, Kimball LE, Huang ML, Hayes TS, Corey L, Boeckh MJ. Efficiency and risk factors for CMV transmission in seronegative hematopoietic stem cell recipients. Biol Blood Marrow Transplant. 2012;18:1391-1400.  [PubMed]  [DOI]
25.  Ciáurriz M, Zabalza A, Beloki L, Mansilla C, Pérez-Valderrama E, Lachén M, Bandrés E, Olavarría E, Ramírez N. The immune response to cytomegalovirus in allogeneic hematopoietic stem cell transplant recipients. Cell Mol Life Sci. 2015;72:4049-4062.  [PubMed]  [DOI]
26.  Weinberg A, Enomoto L, Li S, Shen D, Coll J, Shpall EJ. Risk of transmission of herpesviruses through cord blood transplantation. Biol Blood Marrow Transplant. 2005;11:35-38.  [PubMed]  [DOI]
27.  Caligiuri P, Cerruti R, Icardi G, Bruzzone B. Overview of hepatitis B virus mutations and their implications in the management of infection. World J Gastroenterol. 2016;22:145-154.  [PubMed]  [DOI]
28.  Chakrabarti S, Mukherjee S. Prevention and treatment of hepatitis virus infections in hematopoietic stem cell transplant recipients. Mediterr J Hematol Infect Dis. 2009;1:e2009017.  [PubMed]  [DOI]
29.  Locasciulli A, Montante B, Morelli E, Gulino V, Proia A, Pinazzi MB. Hepatitis B and C in hematopoietic stem cell transplant. Mediterr J Hematol Infect Dis. 2009;1:e2009016.  [PubMed]  [DOI]
30.  Huang Y, Yan Q, Fan R, Song S, Ren H, Li Y, Lan Y. Hepatitis B Virus Replication in CD34+ Hematopoietic Stem Cells From Umbilical Cord Blood. Med Sci Monit. 2016;22:1673-1681.  [PubMed]  [DOI]
31.  Borgia G, Maraolo AE, Gentile I. Hepatitis B mother-to-child transmission and infants immunization: we have not come to the end of the story yet. Infect Dis (Lond). 2017;49:584-587.  [PubMed]  [DOI]
32.  Mavilia MG, Wu GY. Mechanisms and Prevention of Vertical Transmission in Chronic Viral Hepatitis. J Clin Transl Hepatol. 2017;5:119-129.  [PubMed]  [DOI]
33.  Shi Y, Lan Y, Cao F, Teng Y, Li L, Wang F, Li J, Zhou J, Li Y. Infected hematopoietic stem cells and with integrated HBV DNA generate defective T cells in chronic HBV infection patients. J Viral Hepat. 2014;21:e39-e47.  [PubMed]  [DOI]
34.  Manns MP, Buti M, Gane E, Pawlotsky JM, Razavi H, Terrault N, Younossi Z. Hepatitis C virus infection. Nat Rev Dis Primers. 2017;3:17006.  [PubMed]  [DOI]
35.  Locasciulli A, Bruno B, Alessandrino EP, Meloni G, Arcese W, Bandini G, Cassibba V, Rotoli B, Morra E, Majolino I, Alberti A, Bacigalupo A; Italian Cooperative Group for Blood and Marrow Transplantation. Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: a retrospective study by the Italian group for blood and marrow transplantation. Bone Marrow Transplant. 2003;31:295-300.  [PubMed]  [DOI]
36.  Locasciulli A, Testa M, Valsecchi MG, Bacigalupo A, Solinas S, Tomas JF, Ljungman P, Alberti A. The role of hepatitis C and B virus infections as risk factors for severe liver complications following allogeneic BMT: a prospective study by the Infectious Disease Working Party of the European Blood and Marrow Transplantation Group. Transplantation. 1999;68:1486-1491.  [PubMed]  [DOI]
37.  Shuhart MC, Myerson D, Childs BH, Fingeroth JD, Perry JJ, Snyder DS, Spurgeon CL, Bevan CA, McDonald GB. Marrow transplantation from hepatitis C virus seropositive donors: transmission rate and clinical course. Blood. 1994;84:3229-3235.  [PubMed]  [DOI]
38.  Pascutti MF, Erkelens MN, Nolte MA. Impact of Viral Infections on Hematopoiesis: From Beneficial to Detrimental Effects on Bone Marrow Output. Front Immunol. 2016;7:364.  [PubMed]  [DOI]
39.  Socié G, de Latour RP, McDonald GB. Hepatitis C virus and allogeneic stem cell transplantation still matters! Haematologica. 2009;94:170-172.  [PubMed]  [DOI]
40.  Thomas P, Santiago T, Dallas MH. Treatment of hepatitis C in a pediatric patient using simeprevir and sofosbuvir immediately after an umbilical cord blood transplantation. Bone Marrow Transplant. 2016;51:735-737.  [PubMed]  [DOI]
41.  Benova L, Mohamoud YA, Calvert C, Abu-Raddad LJ. Vertical transmission of hepatitis C virus: systematic review and meta-analysis. Clin Infect Dis. 2014;59:765-773.  [PubMed]  [DOI]
42.  Kennedy PG, Rovnak J, Badani H, Cohrs RJ. A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation. J Gen Virol. 2015;96:1581-1602.  [PubMed]  [DOI]
43.  Mueller N, Gilden D, Cohrs R, Mahalingam R, Nagel M. Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency. Neurol Clin. 2008;26:675-697.  [PubMed]  [DOI]
44.  Tomonari A, Iseki T, Takahashi S, Ooi J, Takasugi K, Shimohakamada Y, Ohno N, Nagamura F, Uchimaru K, Tani K, Tojo A, Asano S. Varicella-zoster virus infection in adult patients after unrelated cord blood transplantation: a single institute experience in Japan. Br J Haematol. 2003;122:802-805.  [PubMed]  [DOI]
45.  Patrick K, Ali M, Richardson SE, Gassas A, Egeler M, Krueger J, Lowry J, Allen U, Schechter T. The yield of monitoring for HSV and VZV viremia in pediatric hematopoietic stem cell transplant patients. Pediatr Transplant. 2015;19:640-644.  [PubMed]  [DOI]
46.  Umezawa Y, Kakihana K, Oshikawa G, Kobayashi T, Doki N, Sakamaki H, Ohashi K. Clinical features and risk factors for developing varicella zoster virus dissemination following hematopoietic stem cell transplantation. Transpl Infect Dis. 2014;16:195-202.  [PubMed]  [DOI]
47.  Vandenbosch K, Ovetchkine P, Champagne MA, Haddad E, Alexandrov L, Duval M. Varicella-zoster virus disease is more frequent after cord blood than after bone marrow transplantation. Biol Blood Marrow Tr. 2008;14:867-871.  [PubMed]  [DOI]
48.  Scheurer ME, Pritchett JC, Amirian ES, Zemke NR, Lusso P, Ljungman P. HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis. Bone Marrow Transplant. 2013;48:574-580.  [PubMed]  [DOI]
49.  Yamane A, Mori T, Suzuki S, Mihara A, Yamazaki R, Aisa Y, Nakazato T, Shimizu T, Ikeda Y, Okamoto S. 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.  [PubMed]  [DOI]
50.  Hill JA, Koo S, Guzman Suarez BB, Ho VT, Cutler C, Koreth J, Armand P, Alyea EP, Baden LR, Antin JH, Soiffer RJ, Marty FM. Cord-blood hematopoietic stem cell transplant confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis. Biol Blood Marrow Transplant. 2012;18:1638-1648.  [PubMed]  [DOI]
51.  Tomonari A, Takahashi S, Ooi J, Iseki T, Takasugi K, Uchiyama M, Konuma T, Futami M, Ohno N, Uchimaru K, Tojo A, Asano S. Human herpesvirus 6 variant B infection in adult patients after unrelated cord blood transplantation. Int J Hematol. 2005;81:352-355.  [PubMed]  [DOI]
52.  Sashihara J, Tanaka-Taya K, Tanaka S, Amo K, Miyagawa H, Hosoi G, Taniguchi T, Fukui T, Kasuga N, Aono T, Sako M, Hara J, Yamanishi K, Okada S. High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients. Blood. 2002;100:2005-2011.  [PubMed]  [DOI]
53.  D'Agaro P, Burgnich P, Comar M, Dal Molin G, Bernardon M, Busetti M, Alberico S, Poli A, Campello C; SIGO Italian Group. HHV-6 is frequently detected in dried cord blood spots from babies born to HIV-positive mothers. Curr HIV Res. 2008;6:441-446.  [PubMed]  [DOI]
54.  Grinde B. Herpesviruses: latency and reactivation - viral strategies and host response. J Oral Microbiol. 2013;5.  [PubMed]  [DOI]
55.  Mirandola P, Secchiero P, Pierpaoli S, Visani G, Zamai L, Vitale M, Capitani S, Zauli G. Infection of CD34(+) hematopoietic progenitor cells by human herpesvirus 7 (HHV-7). Blood. 2000;96:126-131.  [PubMed]  [DOI]
56.  Gonelli A, Mirandola P, Grill V, Secchiero P, Zauli G. Human herpesvirus 7 infection impairs the survival/differentiation of megakaryocytic cells. Haematologica. 2002;87:1223-1225.  [PubMed]  [DOI]
57.  Chan PK, Peiris JS, Yuen KY, Liang RH, Lau YL, Chen FE, Lo SK, Cheung CY, Chan TK, Ng MH. Human herpesvirus-6 and human herpesvirus-7 infections in bone marrow transplant recipients. J Med Virol. 1997;53:295-305.  [PubMed]  [DOI]
58.  Heyrman B, De Becker A, Schots R. A case report of immunosuppression-related Kaposi's sarcoma after autologous stem cell transplantation. BMC Res Notes. 2016;9:188.  [PubMed]  [DOI]
59.  Cuzzola M, Irrera G, Iacopino O, Cuzzocrea A, Messina G, Console G, Iacopino G, Morabito F. Bone marrow failure associated with herpesvirus 8 infection in a patient undergoing autologous peripheral blood stem cell transplantation. Clin Infect Dis. 2003;37:e102-106.  [PubMed]  [DOI]
60.  Li Q, Rane L, Poiret T, Zou J, Magalhaes I, Ahmed R, Du Z, Vudattu N, Meng Q, Gustafsson-Jernberg Å, Winiarski J, Ringdén O, Maeurer M, Remberger M, Ernberg I. Both high and low levels of cellular Epstein-Barr virus DNA in blood identify failure after hematologic stem cell transplantation in conjunction with acute GVHD and type of conditioning. Oncotarget. 2016;7:30230-30240.  [PubMed]  [DOI]
61.  Auger S, Orsini M, Céballos P, Fegueux N, Kanouni T, Caumes B, Klein B, Villalba M, Rossi JF. Controlled Epstein-Barr virus reactivation after allogeneic transplantation is associated with improved survival. Eur J Haematol. 2014;92:421-428.  [PubMed]  [DOI]
62.  Hassan R, Stefanoff CG, Maradei S, Fernandes GA, Barros MH, Carestiato FN, Romano SO, Bouzas LF, Zalcberg IR. EBV-associated post transplant lymphoproliferative disorder of the 'loser' graft cell origin following double unrelated umbilical cord blood transplantation. Bone Marrow Transplant. 2009;44:193-195.  [PubMed]  [DOI]
63.  Haut PR, Kovarik P, Shaw PH, Walterhouse D, Jenson HB, Kletzel M. Detection of EBV DNA in the cord blood donor for a patient developing Epstein-Barr virus-associated lymphoproliferative disorder following mismatched unrelated umbilical cord blood transplantation. Bone Marrow Transplant. 2001;27:761-765.  [PubMed]  [DOI]
64.  Ohga S, Kanaya Y, Maki H, Takada H, Ohshima K, Kanda M, Nomura A, Suminoe A, Matsuzaki A, Hara T. Epstein-Barr virus-associated lymphoproliferative disease after a cord blood transplant for Diamond-Blackfan anemia. Bone Marrow Transplant. 2000;25:209-212.  [PubMed]  [DOI]
65.  Reddiconto G, Chiusolo P, Fiorini A, Farina G, Laurenti L, Martini M, Marchetti S, Fadda G, Leone G, Sica S. Assessment of cellular origin and EBV status in a PTLD after double cord blood transplantation. Leukemia. 2007;21:2552-2554.  [PubMed]  [DOI]
66.  Sundin M, Le Blanc K, Ringdén O, Barkholt L, Omazic B, Lergin C, Levitsky V, Remberger M. The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation. Haematologica. 2006;91:1059-1067.  [PubMed]  [DOI]
67.  Barker JN, Doubrovina E, Sauter C, Jaroscak JJ, Perales MA, Doubrovin M, Prockop SE, Koehne G, O'Reilly RJ. Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes. Blood. 2010;116:5045-5049.  [PubMed]  [DOI]
68.  Heslop HE, Savoldo B, Rooney CM. Cellular therapy of Epstein-Barr-virus-associated post-transplant lymphoproliferative disease. Best Pract Res Clin Haematol. 2004;17:401-413.  [PubMed]  [DOI]
69.  Blaes AH, Cao Q, Wagner JE, Young JA, Weisdorf DJ, Brunstein CG. Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2010;16:287-291.  [PubMed]  [DOI]
70.  Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JA, Wagner JE. Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood. 2006;108:2874-2880.  [PubMed]  [DOI]
71.  Dumas PY, Ruggeri A, Robin M, Crotta A, Abraham J, Forcade E, Bay JO, Michallet M, Bertrand Y, Socié G, Ionescu I, Gluckman E, Milpied N, Rocha V. Incidence and risk factors of EBV reactivation after unrelated cord blood transplantation: a Eurocord and Société Française de Greffe de Moelle-Therapie Cellulaire collaborative study. Bone Marrow Transplant. 2013;48:253-256.  [PubMed]  [DOI]
72.  Kalra A, Roessner C, Jupp J, Williamson T, Tellier R, Chaudhry A, Khan F, Taparia M, Jimenez-Zepeda VH, Stewart DA, Daly A, Storek J. Epstein-barr virus DNAemia monitoring for the management of post-transplant lymphoproliferative disorder. Cytotherapy. 2018;20:706-714.  [PubMed]  [DOI]
73.  Russell WC. Adenoviruses: update on structure and function. J Gen Virol. 2009;90:1-20.  [PubMed]  [DOI]
74.  Lion T. Adenovirus infections in immunocompetent and immunocompromised patients. Clin Microbiol Rev. 2014;27:441-462.  [PubMed]  [DOI]
75.  Baldwin A, Kingman H, Darville M, Foot AB, Grier D, Cornish JM, Goulden N, Oakhill A, Pamphilon DH, Steward CG, Marks DI. Outcome and clinical course of 100 patients with adenovirus infection following bone marrow transplantation. Bone Marrow Transplant. 2000;26:1333-1338.  [PubMed]  [DOI]
76.  Howard DS, Phillips II GL, Reece DE, Munn RK, Henslee-Downey J, Pittard M, Barker M, Pomeroy C. Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 1999;29:1494-1501.  [PubMed]  [DOI]
77.  Runde V, Ross S, Trenschel R, Lagemann E, Basu O, Renzing-Köhler K, Schaefer UW, Roggendorf M, Holler E. Adenoviral infection after allogeneic stem cell transplantation (SCT): report on 130 patients from a single SCT unit involved in a prospective multi center surveillance study. Bone Marrow Transplant. 2001;28:51-57.  [PubMed]  [DOI]
78.  Walls T, Shankar AG, Shingadia D. Adenovirus: an increasingly important pathogen in paediatric bone marrow transplant patients. Lancet Infect Dis. 2003;3:79-86.  [PubMed]  [DOI]
79.  Robin M, Marque-Juillet S, Scieux C, Peffault de Latour R, Ferry C, Rocha V, Molina JM, Bergeron A, Devergie A, Gluckman E, Ribaud P, Socié G. Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome. Haematologica. 2007;92:1254-1257.  [PubMed]  [DOI]
80.  Shin S, Roh EY, Oh S, Song EY, Kim EC, Yoon JH. Excluding Anti-cytomegalovirus Immunoglobulin M-Positive Cord Blood Units Has a Minimal Impact on the Korean Public Cord Blood Bank Inventory. Cell Transplant. 2017;26:63-70.  [PubMed]  [DOI]
81.  Al-Awadhi R, Al-Harmi J, Alfadhli S. Prevalence of cytomegalovirus DNA in cord blood and voided urine obtained from pregnant women at the end of pregnancy. Med Princ Pract. 2013;22:194-199.  [PubMed]  [DOI]