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Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease
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Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Aug 15, 2016.

INTRODUCTION — Acute and chronic graft-versus-host disease (GVHD) are multisystem disorders that are common complications of allogeneic hematopoietic cell transplant (HCT). GVHD occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. (See "Pathogenesis of graft-versus-host disease".)

Clinical manifestations of acute GVHD include a classic maculopapular rash; persistent nausea and/or emesis; abdominal cramps with diarrhea; and a rising serum bilirubin concentration. In contrast, patients with chronic GVHD commonly demonstrate skin involvement resembling lichen planus or the cutaneous manifestations of scleroderma; dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract; and a rising serum bilirubin concentration. (See "Clinical manifestations, diagnosis, and grading of chronic graft-versus-host disease", section on 'Clinical and histologic features'.)

This topic review will discuss the clinical manifestations, diagnosis, and grading of acute GVHD. The prevention and management of acute GVHD and issues concerning chronic GVHD are presented separately. (See "Prevention of acute graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)

DEFINITIONS — Graft-versus-host disease GVHD has been classically divided into acute and chronic variants based upon the time of onset using a cutoff of 100 days. However, this conventional division has been challenged by the recognition that signs of acute and chronic GVHD may occur outside of these designated periods. This observation has led to the increased use of clinical findings, rather than a set time period, to differentiate between acute and chronic GVHD. The widely accepted National Institutes of Health (NIH) consensus criteria used to diagnose GVHD classify manifestations of GVHD as "diagnostic" or "distinctive" of chronic GVHD or as common to both acute and chronic GVHD (table 1) [1]. Patients with GVHD are subclassified based upon the timing of presentation and the features present:

Classic acute GVHD – Cases present within 100 days of hematopoietic cell transplant (HCT) and display features of acute GVHD. Diagnostic and distinctive features of chronic GVHD are absent.

Persistent, recurrent, late onset acute GVHD – Cases present greater than 100 days post-HCT with features of acute GVHD. Diagnostic and distinctive features of chronic GVHD are absent.

Classic chronic GVHD – Cases may present at any time post-HCT. Diagnostic and distinctive features of chronic GVHD are present. There are no features of acute GVHD.

Overlap syndrome – Cases may present at any time post-HCT with features of both chronic GVHD and acute GVHD. On occasion, this is colloquially referred to as "acute on chronic" GVHD.

The diagnosis of classic chronic GVHD and overlap syndrome are presented in more detail separately. (See "Clinical manifestations, diagnosis, and grading of chronic graft-versus-host disease", section on 'Diagnosis'.)

EPIDEMIOLOGY — While risk factors for the development of acute graft-versus-host disease (GVHD) have been identified, reliable estimates of GVHD incidence in various cohorts are not available due to variability in the identification, measurement, and documentation of acute GVHD.

Clinically significant acute GVHD occurs in patients who receive an allogeneic hematopoietic cell transplant (HCT) despite intensive prophylaxis with immunosuppressive agents. The exact incidence of acute GVHD after allogeneic HCT is unknown. Reported incidence rates range from 9 to 50 percent in patients who receive an allogeneic HCT from a genotypically HLA-identical sibling [1-3]. Acute GVHD is also common in matched unrelated donors and in haploidentical related donors. (See "Donor selection for hematopoietic cell transplantation" and "Sources of hematopoietic stem cells".)

RISK FACTORS — Numerous studies have identified the following risk factors for the development of acute graft-versus-host disease (GVHD) [4-6]:

Degree of HLA disparity (HLA mismatch or unrelated donor)

Donor and recipient gender disparity (female donor to male recipient)

Intensity of the transplant conditioning regimen

Acute GVHD prophylactic regimen used

Source of graft (peripheral blood or bone marrow greater than umbilical cord blood)

Less well established risk factors include increasing age of the host, the cytomegalovirus (CMV) status of the donor and host, donor Epstein-Barr virus (EBV) seropositivity [7], peripheral blood stem cell versus bone marrow transplantation, the presence of a sterile environment (including gut decontamination), and particular HLA haplotype. However, risk factors for acute GVHD differ by underlying disease, requiring distinct risk models for each condition [5]. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)

The incidence and severity of acute GVHD also appears to increase with pretransplant comorbidities. In one study of 2985 patients who underwent myeloablative or reduced intensity conditioning followed by allogeneic hematopoietic cell transplantation (HCT) for myeloid or lymphoid malignancies, the incidence and severity of acute GVHD increased with increasing hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (table 2) [8]. The probability of developing grade 3/4 acute GVHD was 13, 18, and 24 percent for those with HCT-CI score of 0, 1 to 4, and ≥5, respectively. Patients with a higher HCT-CI score also had an increased risk of mortality following grade 2 to 4 GVHD. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'HCT-CI score'.)

In a report from the Center for International Blood and Marrow Transplant Research (CIBMTR), 5561 patients receiving an allogeneic HCT from an HLA-identical sibling donor (3191 patient) or an unrelated donor (2370 patients) evaluated the role of the conditioning regimen and stem cell source on the cumulative incidence of acute GVHD [2]. After a median follow-up of approximately 40 months, the cumulative incidence rates of grade B or greater acute GVHD were 39 and 59 percent among patients receiving sibling donor or unrelated donor transplants, respectively. When analyzed according to the type of donor (sibling versus unrelated), the incidence of acute GVHD was significantly lower among patients treated with:

A myeloablative, non-total body irradiation (TBI)-containing conditioning regimen who received a bone marrow graft from a sibling (odds ratio [OR] 0.56; 95% CI 0.44-0.71).

A reduced intensity conditioning (RIC) regimen who received peripheral blood progenitor cells from a sibling (OR 0.70; 95% CI 0.56-0.88).

A myeloablative conditioning regimen without TBI who received a bone marrow graft from an unrelated donor (OR 0.55; 95% CI 0.40-0.75).

A RIC regimen who received bone marrow or peripheral blood progenitor cells from an unrelated donor (OR 0.47; 95% CI 0.29-0.76).

Despite the infusion of HLA class I and II disparate grafts, the incidence and severity of acute and chronic GVHD among unrelated UCB recipients has thus far been lower than previously reported in recipients of matched unrelated donor marrow or partially-matched family member marrow allograft [9]. (See "Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens", section on 'Graft-versus-host disease'.)

While the conditioning regimen of choice is often dictated by the underlying disorder, these results suggest that the source of donor stem cells (bone marrow, peripheral blood, umbilical cord) may be selected in the context of the planned conditioning regimen to minimize acute GVHD.

CLINICAL AND HISTOLOGICAL MANIFESTATIONS

Timing and organ involvement — Acute graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT) that classically presents in the early post-transplantation period. The initial signs and symptoms of acute GVHD most commonly occur around the time of white blood cell engraftment. Although initial definitions of acute GVHD required an onset of symptoms before 100 days post transplantation, the current National Institutes of Health (NIH) consensus criteria use clinical findings, rather than a set time period, to differentiate between acute and chronic GVHD. As such, patients presenting with typical findings of acute GVHD prior to day 100 are considered to have "classic acute GVHD," whereas patients presenting with the same findings after day 100, typically upon reduction of immunosuppression, are categorized as having "late onset acute GVHD" [10]. Some clinicians also use the terms "early onset acute GVHD" or "hyperacute GVHD" to describe symptoms of acute GVHD occurring within 14 days of transplant [11-13]. (See 'Diagnosis' below.)

The skin, gastrointestinal tract, and liver are the principal target organs in patients with acute GVHD. This was illustrated in a randomized prospective study of acute GVHD prophylaxis in 329 patients undergoing allogeneic HCT, of whom 110 developed grade II to IV acute GVHD as diagnosed by consensus criteria developed prior to the NIH criteria [14]. Involvement of the skin, gastrointestinal tract, and liver were seen in 70, 74, and 44 percent, respectively. Further division of organ involvement was reported as:

Gastrointestinal tract only – 17 percent

Gastrointestinal tract and skin – 24 percent

Gastrointestinal tract, skin, and liver – 24 percent

Gastrointestinal tract and liver – 9 percent

Skin only – 15 percent

Skin and liver – 7 percent

Liver only – 4 percent

Details regarding the clinical signs and symptoms and diagnosis of organ involvement are presented in the following sections.

Skin — In most patients, the first (and most common) clinical manifestation of acute GVHD is a maculopapular rash, usually occurring at or near the time of the white blood cell engraftment (picture 1). The rash initially involves the nape of the neck, ears, shoulders, the palms of the hands (picture 2), and the soles of the feet. It can be described as a sunburn and may be pruritic or painful (picture 3). From these initial areas of presentation, the rash may spread to involve the whole integument, eventually becoming confluent. In severe GVHD, the maculopapular rash forms bullous lesions with toxic epidermal necrolysis mimicking Stevens-Johnson syndrome (picture 4). (See "Cutaneous manifestations of graft-versus-host disease (GVHD)".)

Histologic examination of the skin reveals changes in the dermal and epidermal layers [15,16]. Characteristic findings include exocytosed lymphocytes, dyskeratotic epidermal keratinocytes, follicular involvement, satellite lymphocytes adjacent to or surrounding dyskeratotic epidermal keratinocytes, and dermal perivascular lymphocytic infiltration (picture 5) [17]. The most consistent histologic feature is individual cell death (apoptosis) at the base of crypts (picture 6). However, similar changes can result from cytotoxic therapy used in the preparative regimen for HCT, and bacterial or viral infections or reactivations [18].

The degree of skin involvement is graded depending upon the degree and severity of the lesions as follows (table 3):

Stage 1 – Maculopapular rash over <25 percent of body area

Stage 2 – Maculopapular rash over 25 to 50 percent of body area

Stage 3 – Generalized erythroderma

Stage 4 – Generalized erythroderma with bullous formation, often with desquamation

The stage of skin involvement is combined with information regarding the stage of gastrointestinal tract and liver involvement to determine the overall severity grade of acute GVHD (table 3). (See 'Grading' below.)

Further details regarding the diagnosis of acute cutaneous GVHD are presented separately. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)".)

Gastrointestinal tract

Distribution of disease — Acute GVHD frequently involves both the upper and lower gastrointestinal tract. Gastrointestinal involvement usually presents with diarrhea and abdominal pain, but may also manifest as nausea, vomiting, and anorexia. Confirmation of the diagnosis is provided by pathologic evaluation of tissue obtained by upper endoscopy, rectal biopsy or colonoscopy.

In a prospective study, 27 patients with suspected acute GVHD of the gastrointestinal tract underwent endoscopic evaluation of both the upper and lower gastrointestinal tract with biopsies [19]. Acute GVHD was confirmed in 18 patients (67 percent) with 15 demonstrating diffuse upper and lower gastrointestinal tract involvement. Biopsy of endoscopically normal tissue demonstrated GVHD in both the upper gastrointestinal tract (6 of 10 patients) and lower gastrointestinal tract (6 of 13 patients). Rectal biopsy identified the majority of cases (16 of 18), including all 16 cases with colonic involvement.

This and other studies suggest that most cases of acute GVHD of the gastrointestinal tract can be identified by rectal biopsy [19-21]. However, a negative rectal biopsy does not rule out gastrointestinal GVHD. Further evaluation with upper endoscopy or colonoscopy should be performed for patients with clinical symptoms suggestive of gastrointestinal involvement in the setting of a negative rectal biopsy.

The diagnosis of gastrointestinal involvement requires pathologic evaluation of the tissue. Once diagnosed, the degree of gastrointestinal involvement is graded based upon the severity of diarrhea as follows (table 3):

Stage 1 – Diarrhea 500 to 1000 mL/day

Stage 2 – Diarrhea 1000 to 1500 mL/day

Stage 3 – Diarrhea 1500 to 2000 mL/day

Stage 4 – Diarrhea >2000 mL/day OR pain OR ileus

The stage of gastrointestinal involvement is combined with information regarding the stage of skin and liver involvement to determine the overall severity grade of acute GVHD (table 3). (See 'Grading' below.)

Lower gastrointestinal tract — Involvement of the lower gastrointestinal tract with acute GVHD is often severe, and is characterized by diarrhea, with or without hematochezia, and abdominal cramping. Confirmation of the diagnosis is performed by pathologic evaluation of tissue obtained by rectal biopsy or colonoscopy.

Patients with acute GVHD can develop severe diarrhea, occasionally exceeding 10 liters a day. The stool may initially be watery, but frequently becomes bloody. Maintenance of adequate fluid balance may be extremely difficult in such patients. The blood loss can result in significant transfusion requirements [22,23]. It is not unusual for patients to require frequent transfusions of packed red blood cells per day to maintain a stable hematocrit.

The diarrhea is secretory and characteristically continues despite fasting and occurs day and night. It can be accompanied by crampy abdominal pain that can also be difficult to manage. Severe ileus may develop in association with acute GVHD or result from increased opioid use required to control the physical discomfort.

From a diagnostic viewpoint, diarrhea, independent of the presence of acute GVHD, is a common occurrence following HCT. During the first several weeks, diarrhea may be due to the preparatory regimen or to the administration of nonabsorbable or systemic antibiotics. Later, superinfection and Clostridium difficile-associated diarrhea must be entertained as possible causes. (See "Approach to the adult with acute diarrhea in resource-rich settings" and "Clostridium difficile infection in adults: Clinical manifestations and diagnosis".)

Radiologic findings are not diagnostic of GVHD, but if performed for other reasons may show luminal dilation with thickening of the small bowel wall (called a "ribbon sign") and air or fluid levels suggestive of ileus. On endoscopy, acute GVHD manifests as spotted erythema, aphthous lesions, and denudation of the mucosa [24,25]. While acute GVHD of the intestine may be suggested by changes on endoscopy, pathologic evaluation of tissue is required for the diagnosis and visually normal mucosa does not eliminate the possibility of involvement [19].

A rectal biopsy is usually helpful in making the diagnosis of acute GVHD affecting the gastrointestinal tract. On histologic examination, crypt cell necrosis is observed with the accumulation of degenerative material in the dead crypts (picture 7) [26]. With severe disease, whole areas may be denuded with total loss of the epithelium, a finding similar to that observed in the skin. Colonoscopy or upper endoscopy is usually also performed.

Infection of the gastrointestinal tract, principally with cytomegalovirus, may mimic the clinical and histologic features of acute GVHD. As a result, selective staining for such pathogens should be performed on the biopsy specimen.

Upper gastrointestinal tract — Involvement of the upper gastrointestinal tract with acute GVHD often presents with anorexia, dyspepsia, food intolerance, nausea, and vomiting [27,28]. Patients may also display gingivitis and mucositis, although these findings are more commonly due to the effects of conditioning regimens [1]. The diagnosis is verified by positive upper endoscopic biopsies of the esophagus and stomach. The differential diagnosis includes herpes simplex virus or candida esophagitis, gastritis, peptic ulcers, and gastrointestinal toxicity due to chemotherapy and/or radiation.

Acute GVHD affecting the upper gastrointestinal tract appears to be more responsive to immunosuppressive therapy than involvement of other areas of the gut. Patients with upper gastrointestinal disease who fail treatment progress to symptomatic lower gastrointestinal involvement, which suggests that this syndrome may be an earlier form of intestinal pathology [27]. Initial studies suggest that patients with steroid refractory gastrointestinal tract involvement have expanded T cell clones within the gastrointestinal tract [29].

Liver — Liver involvement usually presents in patients with signs of cutaneous and/or gastrointestinal acute GVHD [14]. Rarely, patients have moderate to severe hepatic GVHD without evidence of other organ involvement. Although liver involvement may be suggested by abnormalities in liver function tests in the setting of cutaneous or gastrointestinal GVHD, liver biopsy is required to document GVHD of the liver.

Hepatic involvement is manifested by abnormal liver function tests, with the earliest and most common finding being a rise in the serum levels of conjugated bilirubin and alkaline phosphatase. Serum cholesterol is usually elevated, while coagulopathy and hyperammonemia are very rare but may develop in severe cases. Patients may also demonstrate painful hepatomegaly, dark urine, pale stool, fluid retention, and pruritus. Fever, anorexia, and nausea are common nonspecific symptoms.

The abnormalities in liver function tests reflect the pathology associated with liver GVHD: damage to the bile canaliculi, leading to cholestasis. Temporary dilatation of the common bile duct has been described in this setting [30]. However, a rise in the serum concentration of bilirubin or alkaline phosphatase is nonspecific. (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)" and "Liver biochemical tests that detect injury to hepatocytes".)

In this setting, the most common confounding disorders include:

Hepatic sinusoidal obstructive syndrome (also known as hepatic veno-occlusive disease) is a relatively common toxicity associated with the use of high dose therapy. (See "Diagnosis of hepatic sinusoidal obstruction syndrome (veno-occlusive disease) following hematopoietic cell transplantation".)

Hepatic infections (primarily viral hepatitis) (see "Clinical manifestations and natural history of hepatitis B virus infection")

Effects from the preparatory regimen

Drug toxicity, including the drugs used for GVHD prophylaxis (cyclosporine and/or methotrexate) (see "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease")

Although the concurrent presence of the characteristic rash provides suggestive clinical evidence, biopsy is the most definitive method to diagnose GVHD of the liver. However, this may not be feasible because of the possibility of acute bleeding due to severe thrombocytopenia soon after HCT. A transjugular hepatic biopsy may be preferred if an adequate amount of tissue can be obtained. The primary histologic finding is extensive bile duct damage (eg, bile duct atypia and degeneration, epithelial cell dropout, lymphocytic infiltration of small bile ducts), leading to occasionally severe cholestasis [26,31-33].

The degree of liver involvement is graded based upon the serum total bilirubin level as follows (table 3):

Stage 1 – Bilirubin 2 to 3 mg/dL

Stage 2 – Bilirubin 3 to 6 mg/dL

Stage 3 – Bilirubin 6 to 15 mg/dL

Stage 4 – Bilirubin >15 mg/dL

The stage of liver involvement is combined with information regarding the stage of cutaneous and gastrointestinal tract involvement to determine the overall severity grade of acute GVHD (table 3). (See 'Grading' below.)

Other organs — As described above, the skin, liver, and gastrointestinal tract are the principal target organs in patients with acute GVHD. Less commonly, involvement of the hematopoietic system, eyes, and kidneys has been described. Changes in these other organ systems cannot be used to establish the diagnosis of acute GVHD.

Hematopoietic involvement can result in thymic atrophy, cytopenias (especially thrombocytopenia), and hypogammaglobulinemia (especially IgA deficiency).

Ocular involvement can result in photophobia, hemorrhagic conjunctivitis, and lagophthalmos (inability to shut the eyes completely).

Renal involvement can manifest as nephritis or nephrotic syndrome (eg, membranous nephropathy).

Early studies reported that the principal focus of the graft-versus-host reaction occurred in the lymphoid organs of the host. Immune competence was therefore affected, leading to frequent and possibly fatal infectious complications. In murine models, acute GVHD can affect hematopoiesis, leading to a reduction of precursor hematopoietic cells but not a clear decrease in peripheral blood counts [34,35]. In humans, the effect of GVHD on the hematopoietic system is usually not dramatic. Persistent thrombocytopenia is a frequent manifestation and a profound drop in the serum concentration of immunoglobulins (such as IgA) may be observed.

Acute GVHD may also result in decreased responsiveness to active immunization. One study, for example, found a less effective immune response to polio vaccination in patients with GVHD [36].

With acute GVHD, the induction of autoimmune disease occurring in association with autoantibody production may require the expression of particular class II haplotypes. In a murine model of GVHD, for example, the onset of lupus-like nephritis in animals producing pathogenic IgG antinuclear antibodies was dependent upon the MHC haplotype expressed by the recipients [37].

There are isolated case reports of patients with acute and/or chronic GVHD who develop nephrotic syndrome due to membranous nephropathy [38,39]. Murine models of GVHD support a direct pathogenetic association [39]. Most patients have had stabilization in renal function and significant reductions in protein excretion after therapy with steroids and/or cyclosporine. (See "Treatment of idiopathic membranous nephropathy".)

DIAGNOSIS

Clinical evaluation — The diagnosis of acute graft-versus-host disease (GVHD) should be considered in any patient who has undergone allogeneic hematopoietic cell transplantation (HCT). Acute GVHD can occur at any time point in the post-HCT setting, but most commonly occurs within the first few months after transplantation or following a reduction of immunosuppression. The diagnosis of acute GVHD can be readily made on clinical grounds alone in the patient who presents with a classic rash, abdominal cramps with diarrhea, and a rising serum bilirubin concentration within the first 100 days following transplantation [40].

In many cases, however, the diagnosis is less straightforward and competing causes for isolated abnormalities must be considered and excluded. A rash alone may be caused by antibiotics or a myriad of other drugs with which these patients are often treated, diarrhea may be infectious in nature, and hyperbilirubinemia may be related to biliary sludge or a side effect of multiple drugs. (See "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia" and "Drug-induced liver injury".)

Histologic confirmation — Histologic confirmation may be helpful to corroborate a clinical impression of possible acute GVHD. The skin and gastrointestinal tract are relatively easy to biopsy. As previously mentioned, percutaneous liver biopsy poses a significant risk of major bleeding since most patients are thrombocytopenic at the time of presentation with GVHD. Transjugular liver biopsy is a safer alternative if it can be adequately performed. (See "Transjugular liver biopsy".)

NIH consensus criteria — The National Institutes of Health (NIH) consensus criteria used to diagnose GVHD classify manifestations of GVHD as "diagnostic" or "distinctive" of chronic GVHD, or as common to both acute and chronic GVHD (table 1) [1]. Patients with GVHD are subclassified based upon the timing of presentation and the features present:

Classic acute GVHD – Cases present within 100 days of HCT and display features of acute GVHD. Diagnostic and distinctive features of chronic GVHD are absent.

Persistent, recurrent, late onset acute GVHD – Cases present greater than 100 days post-HCT with features of acute GVHD. Diagnostic and distinctive features of chronic GVHD are absent.

Classic chronic GVHD – Cases may present at any time post-HCT. Diagnostic and distinctive features of chronic GVHD are present. There are no features of acute GVHD.

Overlap syndrome – Cases may present at any time post-HCT with features of both chronic GVHD and acute GVHD. On occasion, this is colloquially referred to as "acute on chronic" GVHD.

Biomarkers — Use of serum biomarkers for the diagnosis of acute GVHD is an active area of investigation. Biomarkers or panels of biomarkers are generally used in combination with each other or with other findings. An ideal biomarker would be able to not only predict the appearance of clinical acute GVHD but also guide management. There are many candidate biomarkers but none are ready for clinical application.

One candidate biomarker is suppression of tumorigenicity 2 (ST2), which is a member of the interleukin-1 receptor family. In a study of 673 recipients of myeloablative or nonmyeloablative HCT, patients with high ST2 measured as early as 14 days after transplant had an increased risk of non-relapse mortality [41]. The ST2 level appeared to predict the response of acute GVHD to treatment. Patients with low ST2 levels who developed acute GVHD were more likely to respond to treatment regardless of how serious their graft-versus-host disease was graded, while patients with high ST2 levels were less likely to respond to treatment. Prospective studies are necessary to validate this biomarker and determine whether prophylaxis or treatment should be altered based upon ST2 levels.

Analysis of the pattern of plasma and urine polypeptides using proteomics has shown promise in enabling early diagnosis of acute GVHD [42-47]. As an example, it has been proposed that a panel of markers including Interleukin-2 receptor-alpha, tumor necrosis factor receptor-1, Interleukin-8, and hepatocyte growth factor can confirm the diagnosis of acute GVHD at the onset of clinical symptoms and provide prognostic information independent of GVHD severity [48]. In another study, the use of Reg3 has been found useful for the diagnosis of acute gut GVHD [49].

Another study used flow cytometry to analyze the expression of CD30 on peripheral blood T cell subsets in 26 patients with acute GVHD and 27 patients who had undergone allogeneic HCT but did not have acute GVHD [50]. Patients with acute GVHD had a greater percentage of CD8 positive T cells that expressed CD30. Plasma levels of soluble CD30 were also significantly higher in patients with acute GVHD (median 62 versus 17 ng/mL).

Analysis of the plasma microRNA signature might provide a noninvasive biomarker for acute GVHD. In one study, evaluation of a panel of six microRNAs was able to distinguish HCT recipients who had acute GVHD from patients without acute GVHD, and was able to predict the severity of acute GVHD [51]. Four were combined into a panel that was predictive of acute GVHD, and the levels of miRNA biomarkers were positively associated with acute GVHD severity. More importantly, those elevated miRNAs can be detected before onset of acute GVHD. These data are being validated in a larger cohort of patients.

An early study in experimental animals and human subjects with biopsy-proven intestinal GVHD has suggested that imaging of the colon via 18F-FDG PET scanning may be a sensitive and specific technique for distinguishing intestinal GVHD from other competing diagnoses [52].

DIFFERENTIAL DIAGNOSIS — In most cases, acute graft-versus-host disease (GVHD) is a diagnosis of exclusion and other possible causes of clinical symptoms must be considered. The differential diagnosis depends upon the presenting signs and symptoms of acute GVHD. Most alternative diagnoses can be excluded on biopsy of the involved tissue.

Skin involvement – The differential diagnosis of patients presenting with signs and symptoms of GVHD of the skin includes other causes of rash, including drug eruptions, viral exanthems, engraftment syndrome, and radiation dermatitis. This is discussed in more detail separately. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Differential diagnosis'.)

Gastrointestinal tract – The differential diagnosis of GVHD of the gastrointestinal tract includes other causes of nausea, vomiting, diarrhea, and weight loss. These include infectious causes (eg, C difficile infection, CMV reactivation), drug effects, chemoradiation toxicity, inflammatory diarrhea, short bowel syndrome, peptic ulcer disease, neoplasms, and systemic disease (eg, diabetes mellitus). (See 'Gastrointestinal tract' above and "Approach to the adult with chronic diarrhea in resource-rich settings" and "Approach to the adult with nausea and vomiting".)

Liver involvement – The differential diagnosis of hepatic GVHD includes other causes of abnormal liver function tests (increased conjugated bilirubin and alkaline phosphatase) (table 4 and table 5). Common confounding disorders also include hepatic sinusoidal obstructive syndrome, hepatic infections (primarily viral hepatitis), effects of the preparatory regimen, and drug toxicity. At times a specific diagnosis is difficult without biopsy. (See 'Liver' above and "Classification and causes of jaundice or asymptomatic hyperbilirubinemia" and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)

A continuum of clinical findings may be observed in patients with acute and chronic GVHD, as both disorders commonly affect similar organs, principally the skin, liver, and gastrointestinal tract [1]. However, the target organs affected by, and the clinical and histologic features associated with, chronic GVHD may differ from those observed with acute disease. As an example, autoimmune phenomena, such as autoantibody formation, are more common with chronic GVHD. Importantly, diagnostic or distinctive signs of chronic GVHD must be absent in order to make the diagnosis of acute GVHD [1]. Patients with signs or symptoms seen in both entities are considered to have the overlap subtype of chronic GVHD. (See "Clinical manifestations, diagnosis, and grading of chronic graft-versus-host disease".)

GRADING — Several systems for grading acute graft-versus-host disease (GVHD) have been developed. The two most popular are the Glucksberg grade (I-IV) and the International Bone Marrow Transplant Registry (IBMTR) grading system (A-D) [22,53]. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract (table 3). The stages of individual organ involvement are combined with (Glucksberg) or without (IBMTR) the patient’s performance status to produce an overall grade, which has prognostic significance (table 3 and table 6). Grade I(A) GVHD is characterized as mild disease, grade II(B) GVHD as moderate, grade III(C) as severe, and grade IV(D) life-threatening [54,55].

The IBMTR grading system defines the severity of acute GVHD as follows [53]:

Grade A – Stage 1 skin involvement alone (maculopapular rash over <25 percent of the body) with no liver or gastrointestinal involvement

Grade B – Stage 2 skin involvement; Stage 1 to 2 gut or liver involvement

Grade C – Stage 3 involvement of any organ system (generalized erythroderma; bilirubin 6.1 to 15.0 mg/dL; diarrhea 1500 to 2000 mL/day)

Grade D – Stage 4 involvement of any organ system (generalized erythroderma with bullous formation; bilirubin >15 mg/dL; diarrhea >2000 mL/day OR pain OR ileus)

Grading is important in terms of assessing the response to prophylaxis or treatment, impact upon survival, and association with graft-versus-leukemia effect. Patients with moderate to severe GVHD have a significantly higher mortality rate compared with those with mild disease. As an example, estimated five-year survival rates of patients with grade III (C) and grade IV (D) acute GVHD are 25 and 5 percent, respectively [55]. However, caution must be used when applying these estimated survival rates to current patient population given changes in post-HCT care. Current preventive regimens may alter overall outcomes and expressions of the disease. (See "Prevention of acute graft-versus-host disease".)

Importantly, patients with the same grade but different patterns of skin, gut, or liver involvement often have significantly different outcomes. On occasion, patients will present with stage IV GVHD of a single organ; although most clinicians would consider such a manifestation severe disease, the particular organ involved has clear prognostic implications. As an example, a patient with stage IV cutaneous GVHD alone would be expected to have a much more favorable outcome than a patient with stage IV gastrointestinal GVHD alone, although both have overall grade IV GVHD. As a result, attempts have been made to create a new staging system that provides better prognostic information and permits patient comparison [56]. No new staging system has yet found universal acceptance.

SUMMARY

Graft-versus-host disease (GVHD) occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient.

The skin, liver, and gastrointestinal tract are the principal target organs in patients with acute GVHD. (See 'Clinical and histological manifestations' above.)

The diagnosis of acute GVHD can be made readily on clinical grounds in the patient who presents with a classic maculopapular rash, abdominal cramps with diarrhea, and a rising serum bilirubin concentration within two to three weeks following hematopoietic cell transplantation (HCT). (See 'Diagnosis' above.)

In many cases, however, the diagnosis is less straightforward and competing causes for isolated abnormalities must be considered and excluded. Histologic confirmation may be helpful to corroborate a clinical impression of possible acute GVHD. (See 'Histologic confirmation' above and 'Differential diagnosis' above.)

The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract (table 3). The stages of individual organ involvement are combined to produce an overall grade, which has prognostic significance (table 3). Grade I(A) GVHD is characterized as mild disease, grade II(B) GVHD as moderate, grade III(C) as severe, and grade IV(D) life-threatening. (See 'Grading' above.)

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