Acute GVHD is a T-cell–mediated immune complication occurring in 30–60% of allogeneic hematopoietic cell transplant (alloHCT) recipients, with severe (grade III–IV) disease in ~14–15% of cases. It is driven by donor immune cells attacking recipient skin, GI tract, and liver, and accounts for at least 25% of transplant-related deaths. [1-3]
The following figure from the NEJM illustrates the clinical and histopathologic features of acute GVHD across its three target organs:
1. History
- Key HPI questions:
- Timing relative to transplant (classically within first 100 days, but can occur later with RIC regimens or DLI) [2][4]
- New skin rash: onset, distribution, pruritus, pain, blistering
- GI symptoms: nausea, vomiting, anorexia, diarrhea (volume, frequency, bloody vs. watery), abdominal cramping
- Jaundice, dark urine, pale stools
- Symptom characterization:
- Skin: maculopapular rash, often starting on palms/soles and face, progressing to trunk; severe cases with erythroderma and bullae [1][5]
- GI: watery or bloody diarrhea, crampy abdominal pain, persistent nausea/vomiting [1]
- Liver: painless jaundice with cholestatic pattern [1]
- Important negatives: Absence of fever (suggests infection), absence of new medications (drug rash), no recent antibiotic changes (C. difficile)
2. Alarm Features
- Generalized erythroderma with bullous formation and desquamation (Grade IV skin) [6]
- Voluminous bloody diarrhea (>1500 mL/day) or severe abdominal pain with ileus (Grade IV gut) [6]
- Bilirubin >15 mg/dL (Grade IV liver) [6]
- Extreme decrease in performance status even with lesser organ involvement [6]
- Rapid progression despite initial therapy — suggests steroid-refractory disease
- Concurrent sepsis or multiorgan failure
3. Medications
- Prophylaxis (pre-transplant): Calcineurin inhibitor (tacrolimus or cyclosporine) + methotrexate or MMF is standard backbone; post-transplant cyclophosphamide (PTCy)-based regimens increasingly used, especially for haploidentical and mismatched donors; abatacept FDA-approved for aGVHD prophylaxis in MUD/MMUD settings [1][6-7]
- First-line treatment:
- Grade I: Topical steroids (triamcinolone, clobetasol) ± topical tacrolimus; continue/restart baseline immunosuppression [6]
- Grade II–IV: Systemic corticosteroids — methylprednisolone 1–2 mg/kg/day (or prednisone equivalent); upper GI only: 0.5–1 mg/kg/day + topical GI steroids (beclomethasone ± budesonide) [6][8]
- Second-line (steroid-refractory): Ruxolitinib (category 1, FDA-approved) [3][6][8]
- Other agents for steroid-refractory disease: ECP, vedolizumab, etanercept, infliximab, basiliximab, ATG, mycophenolate mofetil, sirolimus, pentostatin, tocilizumab, alpha-1 antitrypsin [6]
- Pediatric: Remestemcel-L-rknd FDA-approved for steroid-refractory aGVHD in patients ≥2 months [6]
- Contraindicated/cautions: Do NOT escalate methylprednisolone beyond 2 mg/kg/day; do NOT add systemic agents to steroids as initial therapy outside of clinical trials [6][8]
The NCCN treatment algorithm for Grade II–IV aGVHD is shown below:
4. Diet
- Acute phase: Bowel rest and TPN should be considered for patients with voluminous diarrhea (>1500 mL/day) or poor oral tolerance [6]
- Monitor for protein-losing enteropathy and deficiencies of magnesium, zinc, thiamine, vitamins B12 and D [6]
- Gradual reintroduction of oral diet as diarrhea resolves; low-residue diet may be better tolerated initially
- Adequate hydration is critical; monitor electrolytes closely
- Long-term: vitamin D and calcium supplementation for patients on prolonged steroids [6]
5. Review of Systems
- Skin: Rash distribution, pruritus, pain, blistering, desquamation
- GI: Nausea, vomiting, anorexia, diarrhea (volume/frequency), hematochezia, abdominal pain
- Hepatic: Jaundice, pruritus, RUQ discomfort
- Constitutional: Fever (raises concern for infection), weight loss, fatigue
- Infectious screen: Cough, dysuria, oral lesions (candidiasis), visual changes (CMV retinitis)
- Oral: Mucositis, xerostomia, dysphagia
6. Collateral History and Family History
- Transplant details: Donor type (matched related, MUD, haploidentical, cord blood), HLA match degree, stem cell source (PBSC vs. bone marrow), conditioning intensity (MAC vs. RIC), GVHD prophylaxis regimen used
- Donor characteristics: Sex (female donor → male recipient increases risk), CMV serostatus, prior alloimmunization [1-2]
- Prior GVHD episodes and response to treatment
- Medication compliance with immunosuppressive prophylaxis; recent taper or discontinuation of calcineurin inhibitors
7. Risk Factors
- HLA mismatch (most significant risk factor) [1-2]
- Unrelated donor transplant [1]
- Female donor → male recipient (sex mismatch) [1-2]
- Peripheral blood stem cell graft (vs. bone marrow) [1-2]
- Myeloablative conditioning (vs. reduced-intensity) [1][9]
- Older recipient age [2]
- CMV serostatus mismatch between donor and recipient [2][10]
- Prior alloimmunization of donor [2]
- MICA mismatch [1]
8. Differential Diagnosis
- Drug hypersensitivity reaction — most common skin mimic; less likely to involve palms/soles and face simultaneously; typically no concurrent diarrhea/hyperbilirubinemia [5][11]
- Infectious enterocolitis — CMV colitis, C. difficile, adenovirus, norovirus, astrovirus, parasites (Giardia); stool studies and viral PCR essential [12-15]
- Conditioning regimen toxicity — mucositis, diarrhea from chemoradiation; typically earlier onset (pre-engraftment)
- Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) — hepatomegaly, weight gain, ascites, hyperbilirubinemia; distinguished by clinical criteria and imaging [6]
- Drug-induced liver injury — from calcineurin inhibitors, azoles, TPN
- Engraftment syndrome — fever, rash, pulmonary infiltrates around time of neutrophil recovery
- Thrombotic microangiopathy (TMA) — schistocytes, elevated LDH, renal dysfunction
- Viral exanthem — HHV-6 reactivation can cause rash
9. Past Medical History
- Underlying hematologic malignancy or indication for transplant
- Prior transplant history and prior GVHD episodes
- Conditioning regimen used
- History of autoimmune disease
- Chronic infections (hepatitis B/C, HIV, CMV status)
- Baseline liver and renal function
- Prior immunosuppressive therapy exposure
10. Physical Exam
- Vitals: Fever (infection vs. GVHD), tachycardia, hypotension (dehydration/sepsis)
- Skin: Maculopapular rash — assess BSA using Rule of Nines; check palms, soles, face, ears (early sites); look for bullae, desquamation, Nikolsky sign [5-6]
- Oral: Mucositis, erythema, ulceration
- Abdomen: Tenderness, distension, absent bowel sounds (ileus), hepatomegaly
- Eyes: Scleral icterus
- Rectal: Assess for bloody stool
- General: Performance status assessment (critical for grading)
11. Lab Studies
- Baseline/monitoring:
- CBC with differential (cytopenias may suggest marrow involvement or infection)
- CMP: total bilirubin (key for liver staging), direct bilirubin, AST, ALT, alkaline phosphatase, albumin, creatinine, electrolytes [6]
- LDH, haptoglobin, reticulocyte count (rule out TMA)
- Calcineurin inhibitor trough levels (tacrolimus or cyclosporine)
- Infectious workup:
- Stool studies: C. difficile toxin/PCR, bacterial culture, ova and parasites, viral PCR (CMV, adenovirus, norovirus) [6][12][15]
- CMV viral load (PCR), EBV viral load
- Blood cultures if febrile
- Biomarkers (emerging):
- ST2 and REG3α (Ann Arbor biomarker panel) — commercially available; predicts nonrelapse mortality and steroid-refractory disease [1][16]
- IL-2Rα, IL-6, IL-8, HGF — elevated at aGVHD onset [17]
- sVCAM-1, sTNFR1, TIM3 — under investigation [18-19]
- Glucose monitoring during high-dose steroid therapy [6]
12. Imaging
- Abdominal ultrasound or CT abdomen: Consider for evaluation of liver abnormalities, to rule out VOD/SOS, biliary obstruction, or other hepatic pathology [6]
- CT abdomen/pelvis: May show bowel wall thickening, mucosal enhancement, or ascites in GI GVHD; helps exclude surgical abdomen
- Chest imaging: If pulmonary symptoms present (rule out infection, pulmonary edema)
- Imaging is not required for diagnosis of aGVHD but is used to exclude alternative diagnoses
13. Special Tests
- Organ-directed biopsy (gold standard for confirmation): [6][20]
- Skin biopsy: Basal vacuolar degeneration, apoptotic keratinocytes (civatte bodies), lymphocyte satellitosis [1][11]
- Lower GI biopsy (flexible sigmoidoscopy preferred): Crypt apoptosis, crypt destruction, mucosal denudation; distal colon has highest sensitivity (82–95%) [20]
- Upper GI biopsy: For isolated nausea/vomiting; apoptotic bodies in glandular epithelium [6]
- Liver biopsy: Consider if isolated liver abnormalities without other organ involvement; transjugular approach preferred if thrombocytopenic [6]
- Ann Arbor (MAGIC) Biomarker Risk Score: Commercial assay using ST2 + REG3α; stratifies into low/intermediate/high risk for nonrelapse mortality [1][16]
- Grading systems: Modified Glucksberg criteria or MAGIC criteria [6]
The NCCN staging and grading criteria are shown below:
14. ECG
- Not routinely indicated for aGVHD diagnosis
- Consider if using medications with cardiac risk (e.g., tacrolimus — QT prolongation)
- Baseline ECG before starting ruxolitinib or other agents with potential cardiac effects
- Monitor for arrhythmias in critically ill patients with severe aGVHD and electrolyte derangements
15. Assessment
- Clinical summary: aGVHD is a clinical diagnosis supported by biopsy, occurring typically within the first 3 months post-alloHCT. Biopsies are recommended but treatment should not be delayed pending histology results. [8]
- Severity stratification:
- Grade I (mild): Skin only, <50% BSA, non-bullous → generally managed with topical therapy [6]
- Grade II (moderate): Skin >50% BSA, or stage 1 liver/GI involvement → systemic steroids [6]
- Grade III–IV (severe/very severe): Advanced liver or GI involvement, or erythroderma with bullae → high-dose systemic steroids; mortality 27–92% depending on grade [6][21]
- Steroid-refractory disease: ~40–50% of patients do not respond to first-line steroids; associated with significantly worse survival [10][22]
- Complications: Infections (bacterial, viral, fungal) from immunosuppression; malnutrition; steroid side effects (hyperglycemia, osteoporosis, myopathy, adrenal insufficiency); progression to chronic GVHD
16. Treatment Plan
Initial stabilization
- IV fluid resuscitation for dehydration from diarrhea
- Electrolyte repletion (Mg, K, Ca, Phos)
- Antimicrobial prophylaxis per institutional protocol [6]
Grade I aGVHD
- Continue/restart baseline immunosuppressive prophylaxis
- Topical steroids (triamcinolone, clobetasol; low-potency on face/intertriginous areas) ± topical tacrolimus
- Antihistamines for pruritus
- Observe if asymptomatic/stable rash [6]
Grade II–IV aGVHD
- Continue/restart/escalate baseline immunosuppression to therapeutic levels [6]
- Systemic corticosteroids:
- Upper GI only: methylprednisolone 0.5–1 mg/kg/day + oral beclomethasone ± budesonide [6]
- Skin/lower GI/liver: methylprednisolone 1–2 mg/kg/day (consider 1 mg/kg for grade II) [6]
- Do NOT exceed 2 mg/kg/day [6]
- Consider sirolimus for standard-risk aGVHD (biomarker-guided) [6]
- If response: Taper steroids as clinically feasible [6]
- If steroid-refractory: Add ruxolitinib (category 1, FDA-approved for age ≥12) [6][8]
- Other steroid-refractory options: ECP, vedolizumab, etanercept, infliximab, basiliximab, ATG, mycophenolate, sirolimus, pentostatin, tocilizumab [6]
- Clinical trial enrollment strongly encouraged for steroid-refractory disease [6]
Supportive care
- CMV surveillance in appropriate patients [6]
- Vitamin D + calcium supplementation on steroids [6]
- TPN and bowel rest for voluminous diarrhea [6]
- Cautious use of opioids and octreotide for GI symptoms (risk of ileus) [6]
- Sun avoidance, sunscreen, avoid photosensitizing agents [6]
- Monitor for thiamine deficiency if altered mental status [6]
17. Disposition
- Admission criteria:
- Grade II–IV aGVHD requiring initiation of systemic steroids
- Voluminous diarrhea with dehydration or electrolyte derangements
- Inability to tolerate oral intake
- Suspected concurrent infection/sepsis
- Grade IV disease (erythroderma with bullae, severe GI bleeding, bilirubin >15)
- Observation: Grade I–II with stable symptoms and adequate oral intake may be managed outpatient with close follow-up
- Specialist consultation triggers:
- Transplant hematology/oncology (primary team)
- Dermatology for advanced skin disease [6]
- GI for endoscopy/biopsy [20]
- Infectious disease if concurrent infection suspected
- Nutrition/dietetics for TPN management
18. Follow Up / Return Precautions
- Follow-up timing: Close monitoring (at least weekly) during active treatment; steroid taper guided by clinical response [6]
- Response assessment: Complete resolution or improvement in ≥1 organ without progression in any other organ [6]
- Return precautions — instruct patients to seek immediate care for:
- Worsening or new rash, blistering, skin peeling
- Increasing diarrhea volume, bloody stools, severe abdominal pain
- New jaundice or darkening of urine
- Fever >38°C (infection risk on immunosuppression)
- Inability to eat or drink
- Signs of steroid side effects: severe mood changes, vision changes, muscle weakness
- Expected recovery: Grade I often resolves with topical therapy; Grade II–IV has ~60% overall response to first-line steroids; steroid-refractory disease carries significantly worse prognosis [4][10]
- Long-term monitoring: DEXA scan for steroid-related osteoporosis, ophthalmologic evaluation, dental evaluation, and screening for transition to chronic GVHD [6]
References
1. Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy. — Zeiser R, Blazar BR. The New England Journal of Medicine. 2017.
2. Bone Marrow Versus Peripheral Blood Allogeneic Haematopoietic Stem Cell Transplantation for Haematological Malignancies in Adults. — Kiene S, Albrecht M, Theurich S, et al. The Cochrane Database of Systematic Reviews. 2024.
3. Acute Graft-Versus-Host Disease. — Malard F, Holler E, Sandmaier BM, Huang H, Mohty M. Nature Reviews. Disease Primers. 2023.
4. Extracorporeal Photopheresis Versus Standard Treatment for Acute Graft-Versus-Host Disease After Haematopoietic Stem Cell Transplantation in Children and Adolescents. — Buder K, Zirngibl M, Bapistella S, et al. The Cochrane Database of Systematic Reviews. 2022.
5. Clinical Differentiation of Acute Cutaneous Graft-Versus-Host Disease From Drug Hypersensitivity Reactions. — Byun HJ, Yang JI, Kim BK, Cho KH. Journal of the American Academy of Dermatology. 2011.
6. Hematopoietic Cell Transplantation. — Updated 2026-04-03. National Comprehensive Cancer Network.
7. FDA Orange Book. — FDA Orange Book. 2026.
8. Prophylaxis and Management of Graft-Versus-Host Disease After Stem-Cell Transplantation for Haematological Malignancies: Updated Consensus Recommendations of the European Society for Blood and Marrow Transplantation. — Penack O, Marchetti M, Aljurf M, et al. The Lancet. Haematology. 2024.
9. Graft-versus-Host Disease Prophylaxis with Cyclophosphamide and Cyclosporin. — Curtis DJ, Patil SS, Reynolds J, et al. The New England Journal of Medicine. 2025.
10. Polyclonal Anti-Thymocyte Globulins for the Prophylaxis of Graft-Versus-Host Disease After Allogeneic Stem Cell or Bone Marrow Transplantation in Adults. — Chakupurakal G, Freudenberger P, Skoetz N, Ahr H, Theurich S. The Cochrane Database of Systematic Reviews. 2023.
11. A Clinical and Histological Comparison Between Acute Cutaneous Graft-Versus-Host Disease and Other Maculopapular Eruptions Following Hematopoietic Stem Cell Transplantation: A Retrospective Cohort. — Chanprapaph K, Leerunyakul K, Niparuck P, Rutnin S. International Journal of Dermatology. 2021.
12. Diarrhea After Allogeneic Stem Cell Transplantation: Beyond Graft-Versus-Host Disease. — Robak K, Zambonelli J, Bilinski J, Basak GW. European Journal of Gastroenterology & Hepatology. 2017.
13. Etiology and Outcome of Diarrhea After Marrow Transplantation: A Prospective Study. — Cox GJ, Matsui SM, Lo RS, et al. Gastroenterology. 1994.
14. Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients. — Lingamaneni P, Katiyar V, Kumar R, et al. Journal of Clinical Oncology. 2021.
15. Giardia Lamblia Mimicking Acute Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report. — Ma S, Yan H, Shi W, et al. Medicine. 2020.
16. Association of acute graft versus host disease clinical outcomes and the Ann Arbor Biomarker Risk Probability Using the Commercial Assay. — Mountjoy L, McNally H, Buras M, et al. Journal of Clinical Oncology. 2021.
17. Pattern of a Serum Biomarker Panel in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients - A Single Center Study From Low/Middle Income Country. — Fakhry M, Elhemaly A, Hammad M, et al. Pediatric Transplantation. 2025.
18. The Soluble VCAM-1 Level Is a Potential Biomarker Predicting Severe Acute Graft Versus Host Disease After Allogeneic Hematopoietic Cell Transplantation. — Heo SK, Noh EK, Lee YJ, et al. BMC Cancer. 2022.
19. Plasma Biomarkers of Acute GVHD and Nonrelapse Mortality: Predictive Value of Measurements Before GVHD Onset and Treatment. — McDonald GB, Tabellini L, Storer BE, et al. Blood. 2015.
20. The Role of Endoscopy in the Management of Patients With Diarrhea. — Shen B, Khan K, Ikenberry SO, et al. Gastrointestinal Endoscopy. 2010.
21. Graft‐versus‐host disease. — Rook's Dermatology Handbook. 2023.
22. Cellular Therapies for the Prevention and Treatment of Acute Graft-Versus-Host Disease. — Peltier D, Anh Do-Thi V, Devos T, Blazar BR, Toubai T. Stem Cells. 2025.