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 (GVHD)".)
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 and diagnosis of chronic graft-versus-host disease", section on 'Clinical manifestations'.)
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 graft-versus-host disease" and "Treatment of acute graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)
DEFINITIONS — GVHD has been classically divided into acute and chronic variants based on 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 on 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 and diagnosis of chronic graft-versus-host disease", section on 'Diagnosis and classification'.)
EPIDEMIOLOGY — While risk factors for the development of acute 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 human leukocyte antigen (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 GVHD [4-6]:
●Major:
•Degree of HLA disparity (HLA mismatch or unrelated donor)
•GVHD prophylaxis regimen
●Minor:
•Donor and recipient sex disparity (female donor to male recipient)
•Intensity of the transplant conditioning regimen
Unlike chronic GVHD, the graft source (ie, peripheral blood versus bone marrow) does not affect the incidence or severity of acute GVHD. 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 [8], 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 "Donor selection for hematopoietic cell transplantation", section on 'Matched sibling donors'.)
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 HCT-specific comorbidity index (HCT-CI) (table 2) [9]. 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 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 reduced intensity conditioning 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 umbilical cord blood recipients has thus far been lower than previously reported in recipients of matched unrelated donor marrow or partially matched family member marrow allograft [10]. (See "Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens", section on 'Graft-versus-host disease (GVHD)'.)
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 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" [11]. 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 [12-14]. (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 [15]. 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 [16,17]. 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) [18]. 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 [19].
The degree of skin involvement is graded depending on 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 [20]. 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 [20-22]. 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 on 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 [23,24]. 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 Clostridioides difficile-associated diarrhea must be entertained as possible causes. (See "Approach to the adult with acute diarrhea in resource-rich settings" and "Clostridioides 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 [25,26]. 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 [20].
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) [27]. 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 [28,29]. 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 [28]. Initial studies suggest that patients with steroid refractory gastrointestinal tract involvement have expanded T cell clones within the gastrointestinal tract [30].
Liver — Liver involvement usually presents in patients with signs of cutaneous and/or gastrointestinal acute GVHD [15]. 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 [31]. 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 "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults")
●Hepatic infections (primarily viral hepatitis) (see "Hepatitis B virus: Clinical manifestations and natural history")
●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 [27,32-34].
The degree of liver involvement is graded based on 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, kidneys, and lungs 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).
●Lung involvement can manifest as interstitial pneumonitis [35].
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 [36,37]. 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 [38].
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 on the MHC haplotype expressed by the recipients [39].
There are isolated case reports of patients with acute and/or chronic GVHD who develop nephrotic syndrome due to membranous nephropathy [40,41]. Murine models of GVHD support a direct pathogenetic association [41]. Most patients have had stabilization in renal function and significant reductions in protein excretion after therapy with steroids and/or cyclosporine. (See "Membranous nephropathy: Treatment and prognosis".)
DIAGNOSIS
Clinical evaluation — The diagnosis of acute 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 [42].
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 on 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 biomarkers for diagnosis and prognosis of acute GVHD is an area of active investigation. An ideal biomarker would predict the appearance and severity of clinical acute GVHD and help to guide management. No individual biomarker or combination of biomarkers is yet ready for clinical application, but examples of serum proteins that are under investigation include:
●ST2 (suppression of tumorigenicity 2) is a member of the interleukin-1 receptor family, and a study of 673 recipients of myeloablative or nonmyeloablative HCT found that high levels of plasma ST2 (as early as 14 days after transplant) correlated with an increased risk of non-relapse mortality (NRM) and resistance to treatment of acute GVHD [43].
●REG3alpha (regenerating islet-derived 3-alpha) is expressed by regenerating cells in the gastrointestinal epithelium (especially Paneth cells), and its concentration increases in the bloodstream as a result of GVHD-associated epithelial mucosa injury [44].
●TNFR1 (tumor necrosis factor receptor 1) reflects inflammation associated with TNF, and serum levels of TNFR1 correlate with clinical outcomes, including GVHD, NRM, and overall survival [45,46].
Studies that utilized combinations of biomarkers in the early post-transplant setting include:
●A multicenter trial analyzed a panel of plasma biomarkers that were collected within 48 hours (before or after) of initiation of glucocorticoid therapy from 492 patients who developed acute GVHD symptoms [47]. The findings were subsequently validated in a set of 300 additional patients, who were treated at multiple centers using different conditioning regimens, degrees of HLA match, and approaches to GVHD prophylaxis and management. ST2, REG3alpha, and TNFR1 were combined to create an algorithm that established three GVHD severity groups. The probability of NRM at six months and response rate (RR) to therapy correlated with the prognostic groups, and the biomarker panel was more predictive than were clinical assessments. They reported the following:
•Group 1: 8 percent NRM, 86 percent RR
•Group 2: 27 percent NRM, 67 percent RR
•Group 3: 46 percent NRM, 46 percent RR
●A multicenter trial that included nearly 1300 patients observed that a two biomarker model using ST2 and REG3alpha levels on day 7 after transplant could distinguish high-risk versus low-risk groups for the following outcomes at six months [48]:
•NRM: 28 versus 7 percent
•GVHD-associated mortality: 18 versus 4 percent
•Severe gastrointestinal GVHD: 17 versus 8 percent
Examples of other methodologies that have examined biomarkers of acute GVHD include:
●Proteomic analysis – Plasma and/or urine polypeptides may enable early diagnosis of acute GVHD [49-53]. As an example, 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 [54]. In another study, elevated levels of plasma REG3alpha correlated with acute gut GVHD and predicted NRM at one year [44].
●Flow cytometry – Activated peripheral blood T cells may reflect acute GVHD. In one study, patients with acute GVHD (26 patients) had a higher percentage of peripheral blood CD8-positive T cells that co-expressed CD30 than those who did not have acute GVHD (27 patients) [55]. Plasma levels of soluble CD30 were also higher in patients with acute GVHD (median 62 versus 17 ng/mL).
●MicroRNA – Plasma microRNAs may provide a biomarker for acute GVHD. In one study, a panel of four microRNAs (miR-423, miR-199a-3p, miR-93*, and miR-377) distinguished HCT recipients who had acute GVHD from those without acute GVHD, and levels of these microRNA biomarkers correlated with acute GVHD severity [56]. Importantly, the elevated miRNAs were detectable before onset of acute GVHD.
●Imaging – Positron emission tomography (PET) scanning may be a sensitive and specific technique for distinguishing intestinal GVHD from other diagnoses in patients with biopsy-proven intestinal GVHD [57].
DIFFERENTIAL DIAGNOSIS — In most cases, acute GVHD is a diagnosis of exclusion and other possible causes of clinical symptoms must be considered. The differential diagnosis depends on 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, Clostridioides difficile infection, cytomegalovirus 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-abundant 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 and diagnosis of chronic graft-versus-host disease".)
GRADING — Several systems for grading acute 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) [23,58]. 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 [59,60].
The IBMTR grading system defines the severity of acute GVHD as follows [58]:
●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)
Diagnosing and grading acute GVHD is based on clinical findings and frequently varies between transplant centers and independent reviewers. The lack of standardized approaches contributes to difficulties with randomized multicenter clinical trials. The Mount Sinai Acute GVHD International Consortium (MAGIC) established an international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in international GVHD research. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation [61].
Grading is important in terms of assessing the response to prophylaxis or treatment, impact on 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 [60]. However, caution must be used when applying these estimated survival rates to current patient populations given changes in post-HCT care. Current preventive regimens may alter overall outcomes and expressions of the disease. (See "Prevention of 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 [62]. No new staging system has yet found universal acceptance.
SUMMARY
●Description – Graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic cell transplantation (HCT) 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.
Acute GVHD (aGVHD) usually occurs <100 days after HCT, while chronic GVHD (cGVHD) usually occurs ≥100 days after HCT; however, these conditions are distinguished by clinical findings, rather than time of onset. An overlap syndrome, with features of both cGVHD and aGVHD, can also occur.
●Risk factors – Increased risk for GVHD has been associated with:
•Major:
-HLA disparity – Degree of human leukocyte antigen (HLA) difference between graft and host.
-Prophylaxis – Regimen for aGVHD prophylaxis.
•Minor:
-Sex disparity – Especially female donor to male recipient.
-Conditioning regimen – Increased intensity of the transplant conditioning regimen.
●Presentation – Skin, liver, and gastrointestinal (GI) tract are the principal target organs in aGVHD. (See 'Clinical and histological manifestations' above.)
●Diagnosis – Suspect aGVHD in a patient with rash, abdominal cramps/diarrhea, and rising serum bilirubin within weeks after allogeneic HCT. (See 'Diagnosis' above.)
Diagnosis of aGVHD is readily made clinically in patients with a characteristic maculopapular rash (picture 1 and picture 2 and picture 3), cramps/diarrhea, and rising bilirubin.
Histologic confirmation of skin or GI tract may be helpful to confirm the diagnosis and to exclude other causes. Percutaneous liver biopsy poses a significant risk of major bleeding since most patients are thrombocytopenic at the time of presentation; transjugular liver biopsy is a safer alternative. (See 'Histologic confirmation' above.)
●Differential diagnosis – Varies with clinical findings; most alternative diagnoses can be excluded with biopsy of involved tissue. (See 'Differential diagnosis' above.)
Examples include:
•Rash – Drug eruptions, viral exanthems, engraftment syndrome, radiation dermatitis.
•GI tract – Other causes of nausea/vomiting and diarrhea, including infectious causes (eg, Clostridioides difficile infection, cytomegalovirus reactivation), drug effects, chemoradiation toxicity, inflammatory diarrhea, short bowel syndrome, peptic ulcer disease.
•Liver – Other causes (table 5) include hepatic sinusoidal obstructive syndrome (SOS; also called veno-occlusive disease), viral hepatitis, effects of the preparatory regimen, and drug toxicity; a specific diagnosis may be difficult without liver biopsy.
●Grading – Models for grading severity of aGVHD combine individual organ involvement to produce an overall disease grade, which can be summarized as follows (see 'Grading' above):
•Grade I (A) – Mild
•Grade II (B) – Moderate
•Grade III (C) – Severe
•Grade IV (D) – Life-threatening
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