2025 PACUPrep BCCCP Preparatory Course Graft-Versus-Host Disease (GVHD) Diagnosis and Risk Stratification of GVHD
Diagnosis and Risk Stratification of GVHD

Diagnosis and Risk Stratification of Graft-Versus-Host Disease (GVHD)

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Lesson Objective

Apply diagnostic and classification criteria to assess acute and chronic GVHD and guide initial management.

1. Clinical Manifestations

Acute and chronic GVHD present with organ-specific signs. Early recognition of skin, gut, and liver involvement in acute GVHD, and sclerotic or autoimmune-like changes in chronic GVHD, is critical for diagnosis.

Acute GVHD (Typically ≤100 days post-transplant)

  • Skin: A pruritic maculopapular rash is the most common initial sign. It may coalesce into generalized erythroderma and often spares the scalp.
  • Gastrointestinal: Characterized by secretory diarrhea (often >500 mL/day), crampy abdominal pain, and nausea, which can lead to significant volume depletion.
  • Liver: Presents with a cholestatic pattern of injury, including elevated total bilirubin and alkaline phosphatase, with only mild elevations in transaminases (AST/ALT).

Chronic GVHD (Typically >100 days post-transplant)

  • Skin: Sclerodermatous thickening (fibrosis) and lichenoid eruptions are classic findings.
  • Mucosa: Oral lichenoid lesions, xerostomia (dry mouth), and sicca syndrome are common.
  • Eyes: Keratoconjunctivitis sicca (severe dry eyes) can cause significant discomfort and visual changes.
  • Lungs: Bronchiolitis obliterans presents as a non-infectious cough and progressive airflow obstruction.
  • Other Systems: Joint contractures and hepatic fibrosis can also occur.
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  • In a post-transplant patient with a new rash, maintaining a low threshold for a punch biopsy can significantly expedite diagnosis.
  • Acute GI symptoms overlap with conditioning regimen-related mucositis. Differentiate GVHD by its later onset (typically >day 20 post-transplant), negative stool studies for infection, and endoscopic findings.

2. Laboratory Diagnostics

Laboratory tests are essential to confirm organ involvement, quantify severity, and exclude infectious mimics before initiating potent immunosuppression.

Liver Function Tests (LFTs)

  • Total bilirubin is the key marker for staging liver GVHD, with thresholds at <2, 2–3, 3–6, and >6 mg/dL.
  • Alkaline phosphatase and γ-GT elevations are strong indicators of cholestasis.
  • Mild elevations in AST/ALT are supportive but nonspecific.

Hematology and Inflammation

  • A complete blood count (CBC) helps rule out cytopenias from other causes like marrow suppression or thrombotic microangiopathy (TMA).
  • CRP and ESR are nonspecific markers of inflammation; their trends can be monitored over time.

Infection Exclusion

  • Stool studies: Mandatory workup includes C. difficile toxin assay, bacterial culture, and viral PCR panels.
  • Blood tests: Cultures and antigen/PCR testing for CMV, adenovirus, and other opportunistic pathogens are crucial.
  • A negative infectious workup must be confirmed before administering high-dose steroids.
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A disproportionate rise in bilirubin compared to transaminases strongly favors a diagnosis of hepatic GVHD over drug-induced liver injury (DILI), which typically causes a more hepatocellular (high AST/ALT) pattern.

3. Histopathology and Biopsy

Tissue biopsy remains the gold standard for confirming GVHD when clinical and laboratory findings are equivocal.

Skin Biopsy

  • Findings: Apoptotic (dying) keratinocytes, interface dermatitis (inflammation at the dermal-epidermal junction), and basal vacuolization.
  • Technique: A punch biopsy taken from the active margin of a rash is preferred.

Endoscopic GI Biopsy

  • Findings: Crypt epithelial cell apoptosis (“exploding crypts”), infiltration of lymphocytes into the lamina propria, and occasional ulceration.
  • Technique: Obtaining multiple samples from different locations (e.g., duodenum, ileum, colon) is crucial to reduce sampling error.

Liver Biopsy

  • Indications: Reserved for cases with an atypical LFT pattern or high diagnostic uncertainty due to risks.
  • Findings: Lymphocytic infiltration in the portal tracts, evidence of bile duct damage (endothelitis), and apoptosis in zone 3.
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  • Sampling both affected (inflamed) and adjacent normal-appearing mucosa during endoscopy can improve the diagnostic yield for GI GVHD.
  • Liver biopsy is often deferred in favor of empiric treatment in classic presentations due to the significant risk of bleeding in thrombocytopenic patients.

4. Imaging Studies

Imaging supports the diagnosis but does not replace histology; its primary roles are to help localize disease and exclude other causes of symptoms.

CT/MRI of the Abdomen

  • Features: May show diffuse small-bowel wall thickening, mucosal hyperenhancement (“glowing gut”), and mesenteric edema.

Magnetic Resonance Enterography (MRE)

  • Use: An emerging technique to differentiate active inflammation from established fibrosis, particularly useful in chronic GI GVHD.

Ultrasound & Elastography

  • Hepatic Ultrasound: Can assess bile duct dilation and portal vein flow to help rule out other causes of cholestasis.
  • Transient Elastography (e.g., FibroScan): Provides a noninvasive method for staging liver fibrosis in patients with chronic liver GVHD.
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  • CT findings for GI GVHD are sensitive but not specific; they must be correlated with clinical and biopsy findings.
  • Elastography offers a valuable, biopsy-sparing method to monitor the progression or regression of fibrosis in chronic liver GVHD over time.

5. Grading and Staging

Standardized criteria are used to stratify disease severity, which guides the urgency of therapy and predicts patient outcomes.

Glucksberg Acute GVHD Grading (Grades I–IV)

This system combines individual organ staging into an overall grade.

Glucksberg Organ Staging for Acute GVHD
Organ Stage 1 Stage 2 Stage 3 Stage 4
Skin <25% BSA rash 25–50% BSA rash >50% BSA rash Generalized erythroderma / blisters
Gut >500 mL/day diarrhea >1,000 mL/day diarrhea >1,500 mL/day diarrhea Severe pain with or without ileus
Liver Bilirubin 2–3 mg/dL Bilirubin 3.1–6 mg/dL Bilirubin 6.1–15 mg/dL Bilirubin >15 mg/dL

Composite Grades:

  • Grade I: Stage 1-2 skin disease only.
  • Grade II: Stage 3 skin disease, or Stage 1 gut/liver involvement.
  • Grade III: Stage 2-3 gut or Stage 2-3 liver involvement.
  • Grade IV: Stage 4 skin, gut, or liver involvement (life-threatening).

NIH Chronic GVHD Severity Score

  • Mild: Involvement of ≤1 organ with no significant functional impairment.
  • Moderate: Involvement of ≥1 organ with mild functional impairment.
  • Severe: Involvement of ≥2 organs or significant functional loss in any single organ.

Overlap Syndrome: When features of both acute and chronic GVHD are present concurrently. Management is typically guided by the dominant and most severe manifestations.

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Precise grading is not just an academic exercise; it directly correlates with steroid responsiveness and non-relapse mortality. Staging must be accurately determined before initiating treatment to set appropriate expectations and plan for potential second-line therapies.

6. Prognostic Implications

Higher grades of GVHD predict poorer outcomes. Emerging biomarkers may soon refine risk stratification beyond clinical staging alone.

Clinical Predictors

  • Grade III–IV acute GVHD is associated with high non-relapse mortality and a high likelihood of steroid dependence or resistance.
  • Patients with limited chronic GVHD have significantly better long-term survival compared to those with extensive disease.

Biomarkers (Investigational)

  • Soluble ST2 (sST2): An elevated level at the onset of GVHD predicts steroid resistance and higher mortality.
  • Regenerating islet-derived protein 3-alpha (REG3α): A protein released from damaged gut epithelium that correlates with the severity of GI GVHD.
  • Combined clinical-biomarker scores have been shown to outperform staging alone in predicting outcomes.
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A diagnosis of high-risk acute GVHD (Grade III or IV, or high-risk biomarker profile) should prompt early consideration of enrollment in clinical trials for second-line therapy, rather than waiting for failure of high-dose steroids.

7. Differential Diagnosis and Pitfalls

It is critical to distinguish GVHD from its mimics, such as infections, drug reactions, and other post-transplant vascular syndromes, to avoid administering inappropriate and potentially harmful therapy.

Common Mimics

  • Infectious Colitis: Caused by pathogens like C. difficile or CMV, which can produce profuse diarrhea identical to GI GVHD.
  • Drug Eruptions: Many medications used post-transplant (e.g., antibiotics, antivirals) can cause maculopapular rashes.
  • Sinusoidal Obstruction Syndrome (SOS/VOD): Presents with tender hepatomegaly, hyperbilirubinemia, and fluid retention/weight gain.
  • Thrombotic Microangiopathy (TMA): Characterized by schistocytes on blood smear, rising LDH, and progressive thrombocytopenia and anemia.
GVHD Differential Diagnosis Flowchart A flowchart showing the diagnostic pathway for a post-transplant patient with symptoms. It starts with the clinical presentation (rash, diarrhea, or LFTs) and branches to consider GVHD versus its mimics like infection, drug reaction, SOS, or TMA, emphasizing the need for biopsy and specific tests. Post-Transplant Patient with New Symptoms Rash Diarrhea / Nausea ↑Bilirubin / ↑Alk Phos Consider: Drug Eruption, Viral Rash Punch Biopsy Consider: Infection (CMV, C. diff) Stool Studies + Endoscopy/Biopsy Consider: SOS/VOD, DILI, TMA Biliary Obstruction Ultrasound + Specific Labs/Biopsy
Figure 1: Differential Diagnosis Pathway. A systematic approach is crucial. For each major symptom complex, GVHD must be distinguished from common mimics using targeted investigations before committing to high-dose immunosuppression.
Pearl IconA shield with an exclamation mark, indicating a clinical pearl. Clinical Pearls
  • Worsening cytopenias or evidence of hemolysis (schistocytes, high LDH) should immediately trigger an evaluation for TMA or marrow suppression, not just an escalation of GVHD therapy.
  • A dedicated, multidisciplinary GVHD board or meeting (involving BMT, pathology, dermatology, and gastroenterology) significantly improves diagnostic accuracy and management in complex cases.

References

  1. Aladağ E, Kelkitli E, Göker H. Acute graft-versus-host disease: a brief review. Turk J Hematol. 2020;37(1):1–4.
  2. Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373(9674):1550–1561.
  3. Filipovich AH, Weisdorf D, Pavletic S, et al. NIH consensus development project on criteria for clinical trials in chronic GVHD: I. Diagnosis and staging. Biol Blood Marrow Transplant. 2005;11(12):945–956.
  4. Flinn AM, Gennery AR. Recent advances in graft-versus-host disease. Faculty Rev. 2023;12(4).
  5. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute GVHD predicting response, survival, mortality. Biol Blood Marrow Transplant. 2015;21(4):761–767.
  6. Shono Y, van den Brink MRM. Gut microbiota injury in allogeneic HSCT. Nat Rev Cancer. 2018;18(5):283–295.
  7. Zeiser R, Blazar BR. Acute graft-versus-host disease: biologic process, prevention, therapy. N Engl J Med. 2017;377(22):2167–2179.
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