Viral Infections Post Allogeneic Hematopoietic Cell Transplantation (Allo HCT)

Serious viral infections usually occur within the first six months following allogeneic hematopoietic transplant...


Introduction
Serious viral infections usually occur within the first six months following allogeneic hematopoietic transplant (AlloHCT) [1]. Following AlloHCT, EBV DNAemia can be detected in 31% of T-cell replete and 65% T-cell depleted (TCD) graft recipients.
The incidence of PTLD is 224, 54 per 100,000 transplants during the first and second year following (AlloHCT) [2,3]. The risk factors for EBV PTLD include a high degree of HLA mismatch; ex vivo or in vivo T-cell depletion; and the intensity and duration of immunosuppression used for prophylaxis or treatment of graft versus host disease (GVHD) [3,4].
EBV PTLD develops in approximately 1% of patients post (AlloHCT). It is highly related to EBV reactivation. Risk factors that associate with high incidence of EBV-related PTLD include older age at transplant, T cell depletion-containing conditioning regimens, antithymocyte globulin (ATG) use, and grafts derived from unrelated or HLA-mismatched donors. PTLD can also develop in patients who received autologous stem cell transplants, but the frequency is much lower than AlloSCT [3][4][5][6][7] PTLD in AlloSCT cases occurs in younger age group, with shorter duration of onset as compared to (SOT) solid organ transplantation. EBV PTLD occurs more commonly in pediatric patients than in adults. The Delayed T cell reconstitution following T cell depletion accounts for infectious complications including PTLD which is associated with increased mortality [5,6].
EBV PTLD can occur later in the most severely immunocom- Achieving a balance of reduction in immunosuppression and pre-The use of anti-viral agents such as acyclovir, valganciclovir, and ganciclovir are common for HSV, CMV, and EBV prophylaxis, though data is very limited for prevention of EBV PTLD [4][5][6][7].

Other Viral Infections
Other viral infections that occur early post-transplant include CMV, HHV6, BK and adenovirus, and usually correspond to degree of immunosuppression post-transplant [6,8]. However, the current literature lacks information on outcomes of viral infections as well as the influence of graft sources, such as comparison of outcomes between umbilical cord blood transplant (UCBT) and haploidentical transplant (haplo) with post-transplant cyclophosphamide (PTCy) [14]. These infections usually occur within in early post-transplant period prior to effective immune reconstitution [1][2][3]. Despite advances in antimicrobial therapy, severe infections still remain a major cause of death after alternative donor HCT [7][8][9].
In a study that compared 48 recipients of single UCBT with 144 recipients of unrelated BM or PB Allo HCTs, a Spanish group showed that the UCBT group had a higher risk of developing an infection, but infection-related mortality (25%) was similar in the two groups at 3 years [7][8][9]. HLA mismatch did not affect outcome in the UCBT group. The Minnesota group has demonstrated comparable rates of CMV infection between double cord blood transplant (dUCBT) and matched related donor (MRD) transplantation [7][8][9]. Cord blood contains fewer T cells than other stem cell sources, and cord blood lymphocytes have specific immunologic characteristics, such as different response pattern to cytokines and a greater proportion of naive T cells. In haploidentical transplant recipients, there is more NK cell alloreactivity, with therapeutic advantage after transplantation [12]. In a prospective analysis of immune reconstitution in dUCBT recipients and matched unrelated donor (MUD) recipients, Jacobson et al found that CD3 recovery was significantly delayed in the dUCBT group compared with the MUD group for as long as 6 months after allo HCT, including naive (CD45RO−) and memory

(CD45RO+) CD4 T cells, regulatory (CD4CD25) T cells, and CD8
T cells [7][8][9]. These unique properties of UCB may contribute to a high risk of infection reported in some studies. Novel strategies are now being developed to combat viral infections including the virusspecific or trivirus-specific (adenovirus, Epstein-Barr virus, and cytomegalovirus) cytotoxic T lymphocytes [11][12][13]. Early diagnostic information regarding viral infections is critically important in the current era of emerging new therapies for viral infections.

CMV Infection
CMV infection occurs in 50%-80% of the population and CMV virus is maintained in a latent reservoir in mononuclear leukocytes. Containment of CMV in its latent state affects a large proportion of host immune repertoire. In young adults, 1%-2% of CD4 and CD8 T cells are CMV-reactive, which rise to up to 30%-40% in the elderly. For the majority of CMV-infected individuals, asymptomatic reactivation is effectively countered by innate and adaptive immunity. In the immunocompromised AlloSCT patients, unconstrained viral replication and dissemination can lead to CMV disease, and increased mortality due to end-organ damage. The efficacy of conventional antiviral therapies including ganciclovir and foscarnet is limited in the setting CMV disease with end-organ involvement [15]. have not yet clearly demonstrated superiority/lesser toxicity in comparison with conventional agents [15].
Immunotherapeutic strategies to hasten T cell recovery after alloSCT remains a compelling alternative option as an adjunct to drug treatments. CMV-seropositive patients in receipt of T celldepleted CMV-seronegative donor or cord blood grafts are at highest risk from CMV-associated morbidity and mortality. Patients with severe graft-versus-host disease (GVHD) and drug-induced T cell dysfunction are also at high risk of CMV-related morbidity.
Recovery of CMV-specific CD4 responses is also critical to effective antiviral responses, and restoration of both antigen-specific CD4 and CD8 T cell populations to deliver long-term control of CMV is critical in this scenario [11][12][13].

Other Upper Respiratory Infections
The conditioning regimen have an impact on the incidence of respiratory virus infections, but patients with myeloablative and non-myeloablative conditioning have similar incidences for respiratory virus infections. However, in contrast to patients receiving non-myeloablative conditioning, LRI are significantly increased during the first 100 days post myeloablative ASCT [11,12]. LRIs [11,12].

Treatment of Respiratory Viral infections Post ASCT
CMV-specific T cell lines. An alternative to CMV-specific T cell clones is the use of CMV-specific T cell lines. In a clinical study, a single infusion of CMV-specific CD4 T cells showed plasma CMV clearance in 63% of patients. The HLA-A2-restricted pp65 peptide NLVPMVATV (NLV) is also being used but major disadvantage of the HLA-A2-restricted NLV peptide approach is the restriction of benefit to HLA-A2+ patients only. There are compelling data to suggest that virus-specific transferred T cells can engraft and expand and have the potential to mediate clinical responses [13][14][15].
A clinical study of trispecific CTLs administered prophylactically after demonstrated CMV-specific reactivity in 70% of patients with no increase in the incidence of GVHD. In this study, CMV-and EBV-specific T cell numbers rose in the absence of viral reactivation, but adenoviral-CTL expansion was only observed in the context of adenoviral infection. More recent studies have used nucleofection to introduce DNA plasmids encoding multiple immunogenic antigens from CMV, EBV, and adenovirus into APCs, or have used viral antigen-derived 15-mer peptide libraries (pepmix) with APCs to deliver a product with a broader CMV-reactive T cell repertoire [13][14][15].

Conclusion
Increased number of viral infections both systemic and upper respiratory tract occur post allogeneic transplant due to ineffective immune reconstitution. Early diagnosis and treatment are critically important to reduce morbidity and mortality associated with these infections post ASCT. Viral infections cause morbidity and mortality in immunosuppressed following AlloSCT recipients due to inability of host immune system to limit viral replication and dissemination, and loss of T cell function is central to this effect.
Immunotherapeutic strategies to accelerate reconstitution of virusspecific immunity and to hasten T cell recovery after HSCT remain a compelling alternative to drug treatments. CMV-and EBV-directed virus-specific T cells (VSTs) are being used in the settings of both SOT and AlloHST with profound immunosuppression. Emerging evidence supports the use of VSTs for treatment of broader range of viral targets, including varicella-zoster virus, adenovirus, and BK virus [11][12][13][14][15].