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370 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 371

study, but failed to demonstrate a benefit in a randomized phase III of minor histocompatibility antigens relevant to allogeneic HCT, of
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clinical trial. Donor-derived CMV-specific cytotoxic lymphocytes which only a handful have been identified to date. Efforts are underway
have also been used investigationally with some success. 346 to utilize genome-wide association studies to broaden our knowledge of
HSV and VZV are two other members of the herpesvirus family these determinants of GVT effects and GVHD. 358
that cause significant morbidity in the posttransplantation setting. These The most important risk factor for the development of acute
viruses share the characteristics of latency, reactivation, and neurotro- GVHD is the degree of HLA disparity between donor and recipient.
pism. Virtually all HSV disease occurring after HCT is a result of reac- The increased incidence of acute GVHD with fully HLA-matched unre-
tivation, and the serologic status of the transplant recipient determines lated donors compared to HLA-identical sibling donors is likely related
the risk for disease and the requirement for prophylaxis. Oral mucositis, to increased disparity in minor histocompatibility antigens or unrec-
cutaneous infections, esophagitis, genital herpes, and pneumonia are ognized disparities in the phenotypically matched major histocompat-
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the most common clinical manifestations. Acyclovir is highly effective ibility loci. Other risk factors for acute GVHD development include
for the prevention and treatment of HSV and should be administered conditioning intensity, use of TBI, and possibly graft source (although
to all HSV-seropositive transplant recipients, beginning before or dur- the effect of graft source on acute GVHD incidence is not consistently
ing conditioning. Acyclovir prophylaxis is often continued for at least observed). 72,359
1 year after HCT (or longer if patients remain on immunosuppressive Classically, acute GVHD was defined temporally by its occurrence
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therapy), as this approach reduces the risk of late HSV recurrence. before day +100 after allogeneic HCT. With RIC, acute GVHD can
Acyclovir is well tolerated immediately after transplantation with no occur beyond day +100, and the distinction between acute and chronic
effect on the recovery of neutrophil counts. Valacyclovir is an acceptable GVHD is now based on organ involvement and histology rather than
alternative. Patients do not require concomitant acyclovir prophylaxis time of onset. Acute GVHD affects the skin, gastrointestinal (GI)
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while receiving maribavir, foscarnet, valganciclovir, ganciclovir, or cido- tract, and liver (although liver involvement is increasingly rare, for
fovir for treatment of another virus, because these agents have adequate reasons which are not entirely clear). The overall incidence of acute
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anti-HSV activity. Acyclovir resistance is rare in HSV and can be treated GVHD after allogeneic HCT is 40 to 60 percent, although the inci-
using foscarnet. 348 dence may vary widely in specific settings depending on conditioning
Recurrent VZV disease can occur after both allogeneic and autol- regimen, HLA matching, and graft source.
ogous HCT. The initial manifestations of recurrence are localized in Skin involvement manifests as a rash, which may be localized and
approximately half of patients. Treatment with acyclovir within 24 to 48 maculopapular or diffusely erythematous with bullae and desquama-
hours of the onset of herpes zoster prevents dissemination and shortens tion in very severe cases. Definitive diagnosis requires skin biopsy and
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the course of cutaneous disease. The failure of VZV infections to resolve interpretation by an experienced pathologist. However, skin biop-
quickly or their recurrence shortly after acyclovir therapy is discontinued sies are often inconclusive, and the diagnosis is often made on clinical
is usually a function of the limited host immune response and is gener- grounds in patients with a skin rash consistent with acute GVHD aris-
ally not a result of acyclovir resistance. For the rare cases of acyclovir- ing during the appropriate timeframe after allogeneic HCT. Decision
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resistant VZV, foscarnet is the most commonly used alternate therapy. analysis supports the concept that the diagnosis of skin GVHD can be
Acyclovir, given for at least 1 year after HCT, is highly effective in pre- made clinically and does not require skin biopsy in patients with a pre-
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venting VZV recurrence. Pilot studies of vaccination with live attenu- test likelihood of acute GVHD of 30 percent or greater (the majority of
ated VZV in allogeneic HCT recipients suggest that this approach is safe allogeneic HCT recipients). 362
and effective in selected patients (median of 4 years posttransplantation, GI manifestations of acute GVHD can affect the upper GI tract
off systemic immunosuppression, blood CD4+ cell count >200/μL), (presenting as nausea, emesis, anorexia, and weight loss), the lower
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but larger studies are required before vaccination can be widely recom- GI tract (presenting as diarrhea with or without abdominal cramping
mended. Heat-inactivated VZV vaccination has also been reported as and hematochezia), or both. Upper-GI involvement with acute GVHD
efficacious in recipients of autologous HCT. 351 is likely underdiagnosed, since the symptoms may be mild and post-
transplant anorexia and nausea are often nonspecific and multifacto-
ACUTE GRAFT-VERSUS-HOST DISEASE rial. Diagnosis requires upper endoscopy and endoscopic biopsy, with
Acute GVHD remains one of the most serious and challenging com- interpretation by an experienced pathologist. The diagnosis of upper-GI
acute GVHD is clinically important, because this syndrome often
plications of allogeneic HCT. The requirements for the development of responds dramatically to even low-dose treatment and, if left untreated,
acute GVHD were described more than 40 years ago: the graft must con- can cause significant nutritional compromise.
tain immunologically competent cells, the recipient must express tissue Lower-GI involvement with acute GVHD is a more serious and
antigens not found in the donor, and the recipient must be immunolog- feared complication of allogeneic HCT. These patients present with sub-
ically suppressed such that an effective response against transplanted stantial diarrhea, often several liters per day, accompanied by pain and
cells cannot occur. HLA disparities are potent triggers of GVHD, but bleeding. The diarrhea of acute GVHD is secretory, related to epithelial
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in the setting of HLA-matched donor/recipient pairs GVHD is medi- injury, and typically persists around the clock. Abdominal computed
ated by minor histocompatibility antigen disparities which provoke a tomography (CT) findings, particularly bowel-wall thickening, are
donor T-cell response. 353,354 There are two primary classes of MHC anti- common in acute GVHD, but CT findings alone are insufficient for
363
gens in humans: HLA class I antigens have a broad distribution and are diagnosis. Patients with suspected lower-GI GVHD should undergo
expressed on nearly all cells, whereas HLA class II antigen expression endoscopic evaluation and biopsy as soon as feasible, although in the
is restricted to macrophages, dendritic cells, B cells, and activated T setting of myeloablative conditioning it is often difficult to differentiate
cells. Minor histocompatibility antigens are endogenous cellular pro- regimen-related GI injury from acute GVHD endoscopically or histo-
teins which are subject to significant genetic polymorphism and are logically before day +20. Flexible sigmoidoscopy is viewed as a suffi-
presented to donor T cells as small peptides bound in the grooves of cient diagnostic test in most cases, 364,365 and is far easier to perform than
the major histocompatibility antigens. Some minor histocompat- full colonoscopy as it does not require an aggressive preparatory regi-
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ibility antigens associated with GVHD include CD31, HA-1, and the men. Visual inspection of the gut mucosa is often sufficient to advance
male-specific DBY gene. 356,357 There are likely hundreds if not thousands a diagnosis of acute GVHD and initiate treatment, particularly if
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