Immune System

Graft-versus-host disease: acute and chronic

Clinical Overview and When to Suspect Graft-versus-Host Disease

— Acute GVHD: classically defined by clinical features (skin rash, GI symptoms, cholestatic hepatitis), not timing alone

— Classic acute: features within 100 days post-transplant

— Late-onset/persistent/recurrent acute: acute features >100 days

— Chronic GVHD: distinct diagnostic features (lichenoid skin, sclerosis, sicca, bronchiolitis obliterans) any time post-transplant

— Overlap syndrome: both acute and chronic features simultaneously

— Allo-HSCT recipient with new maculopapular rash, watery/bloody diarrhea, nausea, anorexia, or rising bilirubin in the first 100 days → think acute GVHD

— HSCT recipient >100 days out with dry eyes, oral lichen planus-like lesions, skin tightening, dyspnea with obstructive PFTs, dysphagia, weight loss → think chronic GVHD

— Any immunocompromised patient (lymphoma, congenital immunodeficiency, intrauterine transfusion, HLA-similar donor) receiving non-irradiated cellular blood products who develops pancytopenia + rash + hepatitis 1–6 weeks later → transfusion-associated GVHD

Board pearl: Transfusion-associated GVHD is prevented by irradiating cellular blood products—a classic Step 3 patient safety item for immunocompromised, intrauterine, or directed-donor transfusions.

Definition: Immune-mediated injury caused by donor T cells recognizing host tissues as foreign, occurring almost exclusively after allogeneic hematopoietic stem cell transplant (allo-HSCT), occasionally after solid organ transplant containing lymphoid tissue (liver, small bowel) or non-irradiated blood transfusion in immunocompromised hosts (transfusion-associated GVHD, near-uniformly fatal).

Classification (NIH consensus):

When to suspect:

Risk factors: HLA mismatch, unrelated donor, older donor/recipient age, sex mismatch (female donor → male recipient), peripheral blood vs bone marrow graft (↑ chronic GVHD), reduced T-cell depletion, prior acute GVHD (strongest predictor of chronic GVHD), CMV serostatus mismatch.

Presentation Patterns and Key History

— Skin (most common, often first): pruritic or painful maculopapular rash starting on palms, soles, ears, neck, and upper back; can progress to generalized erythroderma and bullae/desquamation (Stevens-Johnson-like) in severe disease

— GI tract: secretory, large-volume, often green/bloody diarrhea (>500 mL/day defines stage 1; >2 L/day stage 3), crampy abdominal pain, ileus; upper GI GVHD presents as persistent nausea, anorexia, early satiety, vomiting

— Liver: cholestatic pattern — rising direct bilirubin and alkaline phosphatase, modest transaminitis; rarely the sole manifestation

— Skin: poikiloderma, lichen planus-like papules, sclerotic/morphea-like plaques, fasciitis, nail dystrophy, alopecia

— Mouth: lichenoid white striae, ulcers, xerostomia, restricted oral opening

— Eyes: keratoconjunctivitis sicca, painful gritty eyes (Schirmer <5 mm)

— Lungs: bronchiolitis obliterans syndrome (BOS) — insidious dry cough, dyspnea, obstructive PFTs

— GI/liver: esophageal webs/strictures (dysphagia), weight loss, cholestasis

— MSK: fasciitis, joint contractures, myositis

— Genital: vaginal sclerosis, phimosis

— Transplant date, donor type (matched sibling vs MUD vs haplo vs cord), conditioning regimen, GVHD prophylaxis (typically tacrolimus/cyclosporine + methotrexate or post-transplant cyclophosphamide), prior acute GVHD episodes, current immunosuppression taper status

— Recent infections (CMV, EBV, adenovirus, C. difficile) and antibiotic exposure — critical differentials

— Medications: trimethoprim-sulfamethoxazole, antifungals, new drugs (drug rash mimic)

Step 3 management: A patient day +30 post allo-HSCT with palmar rash + 1.5 L watery diarrhea + bilirubin 3.5 → start workup for stage 3 acute GVHD while ruling out CMV colitis and C. difficile in parallel; do not delay biopsy or therapy waiting for cultures.

Acute GVHD — three target organs (always ask about all three):

Chronic GVHD — multi-system, mimics autoimmune disease:

Key history points:

Physical Exam Findings and Severity Staging

— Stage 1: maculopapular rash <25% BSA

— Stage 2: 25–50% BSA

— Stage 3: >50% BSA (generalized erythroderma)

— Stage 4: bullae, desquamation (TEN-like)

— Look at palms, soles, ears—classic early sites; check for Nikolsky sign in severe disease

— Stage by stool volume/day in adults: 1 = 500–1000 mL; 2 = 1000–1500; 3 = >1500; 4 = severe pain/ileus/frank blood

— Abdominal tenderness, hyperactive bowel sounds, signs of dehydration, orthostatic vitals

— Grade I: skin stage 1–2 only, no GI or liver

— Grade II: skin stage 3 OR GI/liver stage 1

— Grade III: GI or liver stage 2–3

— Grade IV: stage 4 any organ, or grade III with severe functional decline

— Grades III–IV portend high non-relapse mortality

— Mild: 1–2 organs, score ≤1, no lung

— Moderate: ≥3 organs OR any score 2, OR lung score 1

— Severe: any organ score 3, OR lung score 2–3

Key distinction: Acute GVHD severity is driven by skin BSA, stool volume, and bilirubin, while chronic GVHD severity hinges on number of organs involved and lung function—different scoring systems entirely; mixing them up is a common test trap.

Skin exam (acute GVHD):

GI exam (acute GVHD):

Liver staging (acute GVHD): by total bilirubin — 1: 2–3; 2: 3.1–6; 3: 6.1–15; 4: >15 mg/dL

Overall acute GVHD grade (Glucksberg/MAGIC):

Chronic GVHD scoring (NIH): each organ 0–3 across 8 organs (skin, mouth, eyes, GI, liver, lungs, joints/fascia, genital); global severity:

Don't miss: check oxygen saturation and obtain PFTs in any HSCT survivor with cough/dyspnea—BOS is silent until advanced and is the leading non-relapse cause of late mortality.

Diagnostic Workup — Initial Labs, Stool Studies, and Imaging

— CBC with differential (lymphocyte recovery? eosinophilia favors drug reaction or chronic GVHD)

— CMP: direct hyperbilirubinemia + ↑ alk phos > AST/ALT pattern supports hepatic GVHD; check albumin (protein-losing enteropathy)

— Coags, lactate, lipase if abdominal pain

— Donor chimerism (high donor T-cell chimerism supports alloreactivity)

— C. difficile PCR/toxin

— Stool culture, ova & parasites

— CMV PCR (blood) and consider stool/biopsy CMV; norovirus, rotavirus, adenovirus PCR

— Cryptosporidium in selected hosts

— Right upper quadrant Doppler ultrasound to exclude sinusoidal obstruction syndrome (SOS/VOD) — look for hepatomegaly, ascites, reversed portal flow, weight gain

— Drug-induced liver injury review (azoles, TMP-SMX, methotrexate)

— Viral hepatitis panel, HSV/VZV/adenovirus PCR if very high transaminases

— Abdominal CT in GI GVHD: diffuse small bowel wall thickening, "ribbon bowel," mucosal enhancement, mesenteric edema — non-specific but supportive

— Chest CT and PFTs in any chronic GVHD eval: air trapping on expiratory views suggests BOS

— MAGIC algorithm: serum ST2 and REG3α stratify GI GVHD risk and steroid responsiveness; available at specialized centers, not required for diagnosis but increasingly used to prognosticate

— Elevated suggests high-risk, steroid-refractory disease

Board pearl: A post-HSCT patient with painful hepatomegaly, weight gain, ascites, and hyperbilirubinemia within 21 days of conditioning is SOS/VOD, not GVHD—treat with defibrotide, not steroids; getting this wrong is a classic distractor.

Baseline labs in suspected acute GVHD:

Stool workup (mandatory before attributing diarrhea to GVHD):

Hepatic GVHD workup — rule out mimics:

Imaging:

Biomarkers (Step 3 awareness):

Diagnostic Workup — Biopsy and Confirmatory Studies

— Findings: vacuolar interface dermatitis, apoptotic keratinocytes (especially at the base of rete ridges), satellite lymphocyte adjacent to dying keratinocyte (satellitosis), sparse lymphocytic infiltrate

— Differential on histology: drug eruption (more eosinophils), viral exanthem, engraftment syndrome

— Flexible sigmoidoscopy with rectosigmoid biopsy has high yield even with normal mucosa; EGD with duodenal biopsy for upper GI symptoms

— Histology: apoptotic crypt epithelial cells ("exploding crypts"), crypt dropout, lamina propria lymphocytic infiltrate; severe disease shows complete denudation

— Simultaneously stain/PCR for CMV — coexists in 20–30% and changes management dramatically

— Indicated when diagnosis unclear or to differentiate from SOS, drug injury, viral hepatitis

— Findings: lymphocytic infiltrate of small bile ducts, bile duct epithelial damage/dropout, cholestasis (looks like PBC histologically)

— Often deferred due to thrombocytopenia; transjugular approach if needed

— Diagnostic features (alone establish dx): poikiloderma, lichen-planus-like features, sclerotic skin, esophageal web, BOS confirmed by PFT + CT, fasciitis

— Distinctive features (need biopsy or other organ involvement): nail dystrophy, vitiligo, xerostomia

— Schirmer test, PFTs (FEV1, FEV1/FVC, DLCO), oral exam, genital exam

CCS pearl: In acute GI GVHD workup, order in parallel: flex sig with biopsy, stool C. diff PCR, CMV blood PCR, and start empiric methylprednisolone—don't sequence them; advance the simulated clock with all four cooking simultaneously.

Tissue biopsy is the gold standard but should not delay therapy in classic presentations.

Skin biopsy (acute GVHD):

GI endoscopy with biopsy:

Liver biopsy (used selectively):

Chronic GVHD confirmation:

PFTs for BOS: FEV1 <75% predicted with FEV1/FVC <0.7, plus air trapping on CT or no infection, defines BOS

Risk Stratification and First-Line Management Logic

— Calcineurin inhibitor (tacrolimus or cyclosporine) + short-course methotrexate — classic for matched donor myeloablative

— Post-transplant cyclophosphamide (PTCy) day +3/+4 + tacrolimus + mycophenolate — standard for haploidentical, increasingly used in matched donors

— Sirolimus, ATG, abatacept in select protocols

— All recipients should receive PJP, HSV/VZV, antifungal, and CMV prophylaxis for at least 6–12 months

— Grade I (skin only, <50% BSA): topical corticosteroids (high-potency to body, low-potency to face); optimize calcineurin inhibitor level; no systemic steroids

— Grade II–IV: systemic methylprednisolone 2 mg/kg/day (or prednisone 2 mg/kg PO) is first-line; continue calcineurin inhibitor

— Assess response at day 5–7; lack of improvement or progression = steroid-refractory disease

— Ruxolitinib (JAK1/2 inhibitor) is now FDA-approved first-line for steroid-refractory acute GVHD (REACH-2 trial)

— Alternatives: ECP (extracorporeal photopheresis), MMF, ATG, alemtuzumab, fecal microbiota transplant (investigational for GI)

— Mild (1–2 organs, no functional impact): topical therapy only

— Moderate–severe: prednisone 0.5–1 mg/kg/day ± calcineurin inhibitor

— Steroid-refractory chronic GVHD: ibrutinib, ruxolitinib, belumosudil (ROCK2 inhibitor), ECP

Step 3 management: Don't escalate systemic immunosuppression for grade I skin-only acute GVHD—topical steroids first; systemic steroids increase infection risk and don't improve survival in mild disease.

Prophylaxis (set up before transplant—Step 3 expects you to recognize regimens):

Acute GVHD treatment thresholds:

Steroid-refractory acute GVHD:

Chronic GVHD treatment threshold:

Pharmacotherapy — First-Line Regimens and Dosing

— Methylprednisolone 2 mg/kg/day IV divided BID (or prednisone 2 mg/kg PO if tolerating)

— Continue tacrolimus (target trough 5–15 ng/mL depending on stage post-transplant) or cyclosporine

— For isolated upper GI GVHD: lower-dose prednisone 1 mg/kg may suffice

— Taper: if responsive by day 5–7, begin slow taper after 1–2 weeks of full dose; rapid tapers risk flare

— Ruxolitinib 10 mg PO BID (reduce for thrombocytopenia/cytopenias); monitor for CMV reactivation, cytopenias, hepatotoxicity

— Discontinue gradually; abrupt withdrawal can cause cytokine rebound

— Prednisone 1 mg/kg/day with calcineurin inhibitor

— Taper to alternate-day dosing once stable to limit toxicity

— Ibrutinib 420 mg PO daily — BTK inhibitor, FDA-approved; watch for bleeding, atrial fibrillation, infection

— Ruxolitinib 10 mg BID — FDA-approved for steroid-refractory chronic GVHD (REACH-3)

— Belumosudil 200 mg daily — ROCK2 inhibitor for sclerotic and fibrotic disease, ≥2 prior lines

— Extracorporeal photopheresis — preferred for skin-predominant, steroid-sparing

— Octreotide for high-output diarrhea

— Loperamide cautiously after C. diff/CMV excluded

— Ursodeoxycholic acid 12–15 mg/kg/day for hepatic GVHD and prophylaxis

— TPN if severe GI GVHD with malabsorption

— Aggressive infection prophylaxis: TMP-SMX, acyclovir, posaconazole/voriconazole, monthly IVIG if hypogammaglobulinemic

— Bone density management: calcium, vitamin D, bisphosphonate on chronic steroids

Board pearl: Always check CMV PCR weekly while on high-dose steroids or ruxolitinib—reactivation is common and often the cause of "GVHD not responding."

Acute GVHD — systemic first-line:

Steroid-refractory acute GVHD — second-line:

Chronic GVHD — systemic first-line:

Steroid-refractory or steroid-dependent chronic GVHD:

Adjunctive supportive care (always orderable in CCS):

Expanded Pharmacology and Procedural/Cellular Therapies

— Patient's leukocytes collected by apheresis, exposed to 8-methoxypsoralen + UVA, reinfused

— Induces apoptosis of pathogenic T cells, expands regulatory T cells

— Indications: steroid-refractory or steroid-dependent acute or chronic GVHD, particularly skin/oral/liver

— Schedule: 2 consecutive days every 1–2 weeks initially, tapering with response

— Advantages: minimal infection risk, steroid-sparing; downside: central line required, time-intensive

— Skin: triamcinolone 0.1% to body, hydrocortisone 1–2.5% to face; tacrolimus 0.1% ointment as steroid-sparing

— Mouth: dexamethasone swish-and-spit (0.5 mg/5 mL QID), tacrolimus rinses, topical clobetasol gel

— Eyes: preservative-free artificial tears, cyclosporine 0.05% drops, autologous serum tears, scleral lenses; ophthalmology co-management

— Genital: topical estrogen, clobetasol, vaginal dilators

— Fluticasone inhaled + Azithromycin 250 mg 3×/week + Montelukast 10 mg daily

— Caveat: azithromycin showed increased relapse risk when used as BOS prophylaxis (ALLOZITHRO); use only for established BOS

— Pulmonary referral, consider lung transplant evaluation for severe progressive BOS

— Oral beclomethasone + budesonide for upper GI/non-severe lower GI — high first-pass metabolism limits systemic effects

— Bowel rest, electrolyte repletion, zinc, glutamine supplementation

CCS pearl: In refractory chronic skin GVHD with sclerosis, advance the clock with ECP twice weekly + belumosudil + physical therapy referral—combination beats monotherapy and PT preserves range of motion.

Extracorporeal photopheresis (ECP):

Mesenchymal stromal cell therapy: experimental, regional approval (e.g., remestemcel-L in pediatric steroid-refractory acute GVHD in some countries).

Topical regimens (essential to know):

Bronchiolitis obliterans (lungs) — "FAM" regimen:

GI GVHD specific:

Special Populations — Elderly and Renal/Hepatic Impairment

— Increasing use of reduced-intensity conditioning (RIC) allows transplant in fit older adults; GVHD incidence similar or higher due to less T-cell depletion

— Higher steroid toxicity burden: hyperglycemia, osteoporosis, myopathy, delirium, infection

— Prefer earlier introduction of steroid-sparing agents (ruxolitinib, ECP)

— Aggressive fall prevention, bone health (DEXA, bisphosphonate), and glycemic monitoring

— Calcineurin inhibitors (tacrolimus, cyclosporine) are nephrotoxic—the most common cause of post-HSCT AKI/CKD

— Target lower troughs in CKD; monitor magnesium (CNI cause hypomagnesemia) and replete to prevent seizures

— TMA (transplant-associated thrombotic microangiopathy): schistocytes + AKI + LDH↑ + thrombocytopenia in HSCT patient on CNI—stop or reduce CNI, switch GVHD prophylaxis, consider eculizumab; do not transfuse platelets reflexively

— Mycophenolate dose adjusted; ruxolitinib reduce dose if CrCl <30

— Avoid NSAIDs, IV contrast where possible

— Hepatic GVHD itself + drug-induced injury + iron overload + viral reactivation (HBV, HCV) all coexist

— Reactivate HBV prophylaxis: entecavir or tenofovir in HBcAb+ recipients

— Tacrolimus/cyclosporine metabolized hepatically—reduce doses, monitor levels closely

— Avoid hepatotoxins; ursodeoxycholic acid for cholestasis

— Check ferritin—iron overload accelerates fibrosis; consider phlebotomy or chelation in survivors

Key distinction: In a post-HSCT patient with rising creatinine + thrombocytopenia + schistocytes, the answer is usually CNI-induced TMA, NOT TTP—don't order ADAMTS13 reflexively or start plasma exchange; the fix is to modify immunosuppression.

Older adult HSCT recipients (≥60–70 years):

Renal impairment:

Hepatic impairment:

Frailty assessment: HCT-CI (comorbidity index) guides intensity choices and steroid tolerance.

Special Populations — Pediatrics, Pregnancy, and Solid Organ Transplant

— Acute GVHD presents similarly but engraftment syndrome (fever, rash, capillary leak at neutrophil recovery) is a major mimic

— Remestemcel-L (mesenchymal stromal cells) FDA-approved for steroid-refractory acute GVHD in children

— Growth and endocrine surveillance: thyroid, gonadal axis, growth velocity, delayed puberty—routine endocrinology follow-up

— Educational/developmental support; school re-entry planning

— Vaccinations restart ~6–12 months post-HSCT or per chronic GVHD activity (live vaccines deferred until immunosuppression stopped ≥3 months)

— Fertility is reduced (myeloablative conditioning); offer fertility preservation pre-transplant (oocyte/sperm cryopreservation)—an informed consent must-do

— Pregnancy possible after RIC or with assisted reproduction; counsel about preterm birth, low birth weight risks

— Active GVHD or ongoing immunosuppression should defer pregnancy; mycophenolate is teratogenic (category D)—stop ≥6 weeks pre-conception, switch to azathioprine or steroids; methotrexate also contraindicated

— Tacrolimus, cyclosporine, prednisone are compatible with pregnancy with monitoring

— Breastfeeding: avoid on most immunosuppressants except low-dose prednisone

— Rare but high-mortality; classic in small bowel and liver transplant due to large lymphoid load

— Presents as rash, diarrhea, pancytopenia (not the graft organ failing—the donor lymphocytes attack recipient marrow)

— Diagnose by donor chimerism in recipient blood

— Treatment is poorly defined; high-dose steroids, ATG, ruxolitinib; mortality >70%

Board pearl: A Hodgkin lymphoma patient on fludarabine who receives non-irradiated PRBCs and 3 weeks later develops rash, diarrhea, hepatitis, and pancytopenia has transfusion-associated GVHD—near 100% fatal; the question is really about prevention via irradiation.

Pediatric GVHD:

Pregnancy after HSCT:

Solid organ transplant GVHD:

Transfusion-associated GVHD: prevent via gamma or X-ray irradiation of cellular blood products in at-risk groups (HSCT, intrauterine, exchange transfusions, Hodgkin's, fludarabine-treated, directed donations from relatives, severe T-cell immunodeficiency).

Complications and Adverse Outcomes

— Bacterial: gram-negative bacteremia from gut translocation, line infections, Clostridioides difficile

— Viral: CMV reactivation/colitis/pneumonitis, EBV-driven PTLD, adenovirus, BK virus, HHV-6, respiratory viruses, VZV

— Fungal: invasive aspergillosis (#1 mold), mucormycosis, candida; PJP if prophylaxis dropped

— Encapsulated organisms (functional hyposplenism): vaccinate + consider penicillin prophylaxis in chronic GVHD with low IgG

— Skin: permanent sclerosis, contractures, ulceration

— Lungs: bronchiolitis obliterans is largely irreversible—prevention/early detection is everything; cryptogenic organizing pneumonia (COP) may also occur and responds to steroids

— Eyes: corneal scarring, vision loss

— GI: esophageal strictures, malabsorption, malnutrition

— Liver: biliary cirrhosis-like picture

Step 3 management: New focal neurologic deficit + seizure + HTN + visual changes in a tacrolimus-treated HSCT patient → PRES; get MRI (T2/FLAIR posterior white matter), stop or reduce calcineurin inhibitor, control BP, treat seizures.

Infection (the leading cause of GVHD-related death):

Steroid toxicities: hyperglycemia, osteopenia/avascular necrosis (hip, knee), myopathy, cataracts, glaucoma, mood disturbance, adrenal insufficiency on taper

Calcineurin inhibitor toxicities: AKI/CKD, hypertension, PRES (posterior reversible encephalopathy syndrome) with seizures and visual changes, hypomagnesemia, hyperkalemia, TMA, tremor, gingival hyperplasia (cyclosporine)

End-organ GVHD damage:

Secondary malignancies: ↑ risk of squamous cell carcinomas (skin, oral cavity)—especially in patients with chronic mucocutaneous GVHD; aggressive sun protection and annual derm/dental exams mandatory

Avascular necrosis: suspect new hip/knee pain on chronic steroids—MRI early; weight-bearing modification, surgical referral

Psychosocial: depression, anxiety, body image issues, fatigue, sexual dysfunction—screen routinely

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Any new grade II–IV acute GVHD

— Severe diarrhea (>1.5 L/day) with electrolyte derangement

— Bilirubin rising >3 mg/dL without alternate explanation

— Suspected or confirmed steroid-refractory disease for trial of second-line agents

— New systemic infection requiring IV antimicrobials

— Stage 4 skin GVHD (TEN-like) — burn unit or ICU; fluid/electrolyte management, infection prevention

— Stage 4 GI GVHD with hemodynamic instability, severe GI bleed, ileus/perforation

— Septic shock (common given immunosuppression + mucosal barrier disruption)

— Respiratory failure from BOS exacerbation, COP, infection, or diffuse alveolar hemorrhage (DAH)

— PRES with seizures, status epilepticus

— TMA with renal failure requiring RRT

— Transplant hematology/oncology: directs immunosuppression decisions

— Infectious diseases: opportunistic infection coverage, prophylaxis stewardship

— Dermatology: confirms skin GVHD, manages topicals, biopsy

— Gastroenterology: endoscopic biopsy, nutrition planning

— Ophthalmology for chronic ocular GVHD

— Pulmonology for BOS evaluation

— Palliative care early for symptom burden and goals-of-care, especially refractory severe GVHD with infection

— Nutrition, PT/OT, social work, psychiatry

CCS pearl: When you admit a febrile neutropenic post-HSCT patient with new diarrhea and rash, order broad-spectrum antibiotics (cefepime), blood/urine/stool cultures, CMV PCR, C. diff PCR, methylprednisolone, IV fluids, electrolyte repletion, and transplant consult—all in the first orders block; sequential ordering loses simulated time and points.

Admit to inpatient transplant service:

ICU triage criteria:

Consults to mobilize early:

Goals of care: Refractory grade IV acute GVHD or severe progressive chronic GVHD with multi-organ failure carries >80% mortality—frank prognostic discussion with patient and family is part of the standard of care

Key Differentials — Same-Category (Post-HSCT) Causes

— Occurs at neutrophil recovery (typically day +7 to +15)

— Triad: noninfectious fever, erythrodermic rash, capillary leak with weight gain/pulmonary infiltrates/hypoxemia

— Overlaps clinically with hyperacute GVHD; responds rapidly to short-course steroids

— Key distinction: timing at engraftment + capillary leak features

— Within first 21 days post-conditioning

— Painful hepatomegaly, weight gain >5%, ascites, hyperbilirubinemia (Baltimore/Seattle criteria)

— Treatment: defibrotide; supportive—diuretics, paracentesis; not steroids

— Can perfectly mimic GI/liver GVHD

— Diagnosis: CMV PCR + tissue immunohistochemistry showing CMV inclusion bodies

— Treatment: ganciclovir/valganciclovir or letermovir prophylaxis failure → foscarnet

— Often coexists with GVHD—must treat both

— TMP-SMX, voriconazole, posaconazole, sirolimus, busulfan all implicated

— Eosinophilia, temporal relation to drug start, lack of GI involvement favor drug

— Schistocytes + LDH↑ + AKI + thrombocytopenia + hypertension

— Often calcineurin-inhibitor mediated; can mimic GVHD-driven multi-organ injury

Key distinction: Apoptotic crypt epithelial cells without viral inclusions = GVHD; owl-eye inclusions = CMV; both = coinfection requiring dual therapy. Always send tissue for both H&E and CMV IHC.

Engraftment syndrome:

Sinusoidal obstruction syndrome (SOS/VOD):

CMV colitis or hepatitis:

Drug-induced rash or hepatotoxicity:

Transplant-associated TMA:

Diffuse alveolar hemorrhage (DAH) / idiopathic pneumonia syndrome: dyspnea, hypoxia, bloody BAL—differentiate from BOS (obstructive) and infection

Cord colitis syndrome: after cord blood transplant, chronic diarrhea with granulomatous colitis—treat with metronidazole-class antibiotics

Key Differentials — Other-Category Causes

— Morbilliform drug rash: more eosinophils, less interface vacuolization

— DRESS: fever, eosinophilia, lymphadenopathy, hepatitis, rash 2–6 weeks after culprit drug—mimics severe GVHD

— SJS/TEN: extensive epidermal necrosis with mucosal involvement—histologically may be indistinguishable from grade 4 GVHD; clinical context (drug timing) is key

— C. difficile: pseudomembranes, toxin/PCR positive; treat with fidaxomicin or oral vancomycin

— Norovirus, rotavirus, adenovirus, cryptosporidium (especially with T-cell suppression)

— These do not have crypt apoptosis on biopsy

— Drug-induced cholestasis (azoles, TMP-SMX)

— Sepsis-related cholestasis

— Iron overload

— Biliary obstruction—ultrasound/MRCP

— Scleroderma (look for Raynaud's, anti-Scl-70/centromere—usually negative in GVHD)

— Sjögren's syndrome (sicca symptoms)—anti-Ro/La typically absent in GVHD

— Lichen planus, psoriasis (oral and skin overlap)

— Eosinophilic fasciitis vs GVHD fasciitis—histology and clinical context

— Idiopathic pulmonary fibrosis vs BOS—BOS is obstructive, IPF is restrictive; CT pattern differs (mosaic/air trapping vs UIP)

— Post-radiation pneumonitis or fibrosis in patients who had TBI

Board pearl: When a post-HSCT patient presents with rash + GI symptoms + hepatitis, the answer is almost never a single diagnosis—GVHD, CMV, and drug toxicity frequently coexist, and biopsy + viral PCR + medication review must all happen before locking onto one cause.

Drug eruptions (non-transplant context applied to HSCT patient):

Infectious enteritis (non-CMV):

Viral hepatitis (HBV reactivation, HEV, HSV hepatitis): serologies, PCR

Cholestatic disorders mimicking liver GVHD:

Cutaneous lymphoma or lymphocyte infiltrates: rare relapse mimic, biopsy distinguishes

Chronic GVHD mimics:

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Prednisone taper schedule written explicitly (e.g., 1 mg/kg × 2 weeks, then taper by 10% every 1–2 weeks based on response)

— Tacrolimus with target trough and lab draw schedule (weekly initially)

— PJP prophylaxis: TMP-SMX DS three times weekly (or atovaquone/dapsone/pentamidine if intolerant) — continue ≥6 months and while on immunosuppression

— Antiviral prophylaxis: acyclovir or valacyclovir for HSV/VZV; letermovir for CMV in seropositive patients during high risk window

— Antifungal prophylaxis: posaconazole or voriconazole during high-dose steroids and active GVHD

— Encapsulated organism prophylaxis: penicillin VK in chronic GVHD with low IgG

— Calcium 1000–1200 mg + vitamin D 1000–2000 IU daily; bisphosphonate if DEXA shows osteopenia/osteoporosis or chronic steroid use

— PPI for steroid-related ulcer prevention if other risk factors

— Magnesium replacement with CNIs

— Topical steroids/tacrolimus/lubricants as needed for organ-specific disease

— Begin inactivated vaccines at 6–12 months post-HSCT (influenza, pneumococcal—PCV20 or PCV15+PPSV23, Tdap, Hib, hepatitis B, HPV, COVID-19, RSV per current schedule)

— Live vaccines (MMR, varicella, zoster live) deferred until ≥24 months post-HSCT, off immunosuppression ≥3 months, no active GVHD; recombinant zoster (Shingrix) preferred and given earlier

— Household contacts: routine immunization including annual influenza; avoid live oral polio

Step 3 management: Don't give live vaccines to a patient on prednisone ≥20 mg/day or any biologic immunosuppression—the recombinant zoster vaccine (Shingrix) is the preferred shingles option for HSCT survivors.

Discharge medication template for stabilized GVHD patient:

Vaccination plan (re-immunization):

Cancer surveillance: annual skin exam, oral cancer screening (especially with chronic oral GVHD), cervical cancer screening, age-appropriate routine screens

Follow-Up, Monitoring Parameters, and Rehab/Counseling

— First 100 days: weekly visits with labs (CBC, CMP, tacrolimus level, magnesium)

— Day 100–365: every 1–4 weeks based on stability

— Year 2+: every 3–6 months if no active GVHD

— Lifelong annual long-term follow-up at transplant center

— CMV PCR weekly during high-dose immunosuppression; EBV PCR periodically (PTLD risk)

— PFTs every 3 months in first year, then annually; sooner with any respiratory symptom—catch BOS early

— Schirmer test and ophthalmology every 6–12 months

— Annual dermatology for skin GVHD and SCC surveillance

— Annual DEXA on chronic steroids

— Lipid panel, HbA1c, BP — metabolic syndrome from steroids/CNIs is the leading late cardiovascular driver

— TSH annually (radiation/conditioning thyroiditis common)

— Gonadal function: FSH/LH, testosterone, estradiol; refer to endocrinology and reproductive medicine

— Iron studies/ferritin for iron overload from transfusions

— PT/OT to prevent contractures in sclerotic chronic GVHD; daily stretching critical

— Pulmonary rehab for BOS

— Voice/swallow therapy for oral/esophageal involvement

— Nutritional counseling, dietitian for malabsorption

— Sun protection (broad-spectrum SPF 50+, protective clothing) — both for skin GVHD and SCC prevention

CCS pearl: When advancing the simulated clock on a stable chronic GVHD patient, schedule 2-week follow-up with CBC, CMP, tacrolimus trough—not 6 weeks; rapid changes in disease activity demand close monitoring while on active immunosuppression.

Monitoring cadence (ambulatory transition):

Targeted surveillance:

Rehabilitation:

Psychosocial: screen for depression (PHQ-9), anxiety, PTSD, sexual dysfunction; refer to psycho-oncology

Caregiver support: caregivers are central to adherence and infection prevention; assess burnout

Ethical, Legal, and Patient Safety Considerations

— Discuss acute and chronic GVHD risk explicitly as part of pre-transplant consent; quantitative risk varies by donor/conditioning

— Discuss infertility risk and offer fertility preservation (oocyte/sperm cryopreservation) before conditioning—failure to offer is a recurrent malpractice and ethics concern

— Discuss secondary malignancy, chronic disease burden, late mortality

— Irradiate cellular blood products for HSCT recipients (before, during, indefinitely after), congenital T-cell deficiency, Hodgkin lymphoma, intrauterine/neonatal exchange transfusion, recipients of HLA-matched or directed donor units (including first-degree relatives), patients on fludarabine/bendamustine/alemtuzumab

— Failure → transfusion-associated GVHD → near-100% mortality

— Hospital quality programs audit irradiation compliance

— Discharge from inpatient transplant to community oncologist/PCP must include: explicit immunosuppression taper plan, prophylaxis duration, vaccination plan, and clear escalation triggers (fever, new diarrhea, dyspnea)

— Med reconciliation errors with tacrolimus dosing (mg vs mL liquid; brand vs generic switching) are reportable sentinel-class events

— Tacrolimus is on the ISMP high-alert medication list

Board pearl: A young woman scheduled for allogeneic HSCT for AML who is not offered oocyte cryopreservation has a legitimate informed-consent grievance—fertility preservation counseling is a documented standard before gonadotoxic conditioning.

Informed consent for transplant — GVHD disclosure:

Transfusion safety (mandatory patient safety item):

Transitions of care (Step 3 favorite):

Drug interaction safety: azoles ↑↑ tacrolimus/cyclosporine levels—levels MUST be rechecked within 3–5 days of any azole change

Goals-of-care and palliative care: refractory grade IV GVHD with multi-organ failure warrants early palliative consult; advance directives, surrogate identification, and discussion of mechanical ventilation/dialysis preferences are part of standard care, not abandonment

Mandatory reporting: opportunistic infections (TB), cancer registry reporting for post-transplant malignancies

High-Yield Associations and Rapid-Fire Clinical Facts

Key distinction: GVHD is a donor-versus-host problem (immune cells attack recipient); graft rejection is host-versus-graft (recipient immune cells attack donor cells/organ)—opposite directionality, opposite immunology.

Allogeneic HSCT only causes classic GVHD; autologous HSCT does not (no donor alloreactivity) — exception: rare autologous-GVHD-like syndromes

Acute GVHD targets three organs: skin, gut, liver (mnemonic: "SGL" or "rash, runs, jaundice")

Chronic GVHD looks like autoimmune disease: lichen planus, scleroderma, Sjögren's, PBC, bronchiolitis obliterans—all in one patient

Bronchiolitis obliterans = obstructive PFTs (FEV1/FVC <0.7) with air trapping; COP = restrictive, ground glass — opposite physiology, both post-HSCT

Strongest predictor of chronic GVHD = prior acute GVHD

Peripheral blood stem cells → more chronic GVHD than bone marrow

Post-transplant cyclophosphamide (PTCy) is the modern haploidentical platform — reduces both acute and chronic GVHD

Ruxolitinib = JAK1/2 inhibitor, first-line for steroid-refractory acute AND chronic GVHD (REACH-2, REACH-3)

Ibrutinib, ruxolitinib, belumosudil = three FDA-approved drugs for chronic GVHD beyond steroids

Defibrotide treats SOS/VOD, not GVHD — classic distractor

Apoptotic crypt cells ("exploding crypts") = GI GVHD; owl-eye inclusions = CMV

Schirmer test <5 mm in 5 minutes = severe dry eye, supports ocular chronic GVHD

Letermovir prevents CMV reactivation in seropositive allo-HSCT recipients

Irradiated blood products prevent transfusion-associated GVHD

Pediatric steroid-refractory acute GVHD → remestemcel-L (MSCs)

TMA on calcineurin inhibitor → reduce/switch CNI, NOT plasma exchange

Graft-versus-leukemia (GVL) effect is the therapeutic flip side: complete T-cell depletion eliminates GVHD but increases relapse — clinicians balance both

FAM regimen for BOS: Fluticasone + Azithromycin + Montelukast (use only for established BOS, not prophylaxis)

Live vaccines deferred ≥24 months post-HSCT and only if off immunosuppression ≥3 months, no active GVHD

Board Question Stem Patterns

Step 3 management: Stems frequently bundle two simultaneous pathologies—GVHD plus CMV, GVHD plus C. diff, GVHD plus TMA—reward candidates who treat both in parallel rather than sequentially.

Pattern 1 — Classic acute GVHD: "A 45-year-old man underwent allo-HSCT 30 days ago for AML. Today he has a maculopapular rash on palms, soles, and trunk covering 40% BSA, 1.8 L watery diarrhea, and total bilirubin 4.5 mg/dL." Next step: methylprednisolone 2 mg/kg/day + sigmoidoscopy with biopsy + CMV PCR + C. diff PCR.

Pattern 2 — Steroid-refractory acute GVHD: "Day 7 of methylprednisolone 2 mg/kg, the patient's diarrhea volume has increased and bilirubin is rising." Answer: ruxolitinib.

Pattern 3 — SOS distractor: "Day 14 post-conditioning, weight gain 8%, tender hepatomegaly, ascites, bilirubin 6." Answer: defibrotide, not steroids.

Pattern 4 — Transfusion-associated GVHD: "Hodgkin lymphoma patient on fludarabine received non-irradiated PRBCs from his brother; 3 weeks later: rash, diarrhea, pancytopenia." Answer to "how prevented?" = gamma irradiation of cellular blood products.

Pattern 5 — Chronic GVHD with BOS: "18 months post-HSCT, dyspnea, dry cough, FEV1 60% predicted, FEV1/FVC 0.55, air trapping on CT." Answer: bronchiolitis obliterans syndrome, treat with FAM regimen + systemic immunosuppression escalation.

Pattern 6 — TMA mimic: "Tacrolimus-treated HSCT patient: schistocytes, LDH 800, platelets 40K, creatinine 2.8." Answer: reduce or switch calcineurin inhibitor; don't start plasma exchange.

Pattern 7 — PRES: "Tacrolimus-treated patient: seizure, headache, cortical blindness, BP 190/110, MRI shows posterior white matter edema." Answer: PRES — hold tacrolimus, control BP.

Pattern 8 — Vaccination question: "When can MMR be given after HSCT?" Answer: ≥24 months, off immunosuppression ≥3 months, no active GVHD.

Pattern 9 — Coinfection: "Acute GI GVHD on steroids, now worsening diarrhea—biopsy shows owl-eye inclusions." Answer: CMV colitis—add ganciclovir, continue GVHD therapy.

Pattern 10 — Fertility ethics: "Young woman about to undergo conditioning—what counseling is required?" Answer: fertility preservation (oocyte cryopreservation).

One-Line Recap

Graft-versus-host disease is donor T-cell alloreactivity against recipient tissues after allogeneic HSCT, presenting acutely as a rash–diarrhea–cholestasis triad and chronically as a multi-organ autoimmune-mimic syndrome, with systemic steroids as first-line and ruxolitinib as the modern second-line agent for steroid-refractory disease in both phenotypes.

Board pearl: When the stem mentions allo-HSCT and any combination of rash, diarrhea, or jaundice, your first move is to start systemic steroids while simultaneously biopsying and ruling out infection—speed and parallelism win both the simulated clock and the test question.

Acute GVHD = skin (palms/soles maculopapular rash) + gut (secretory diarrhea, upper GI nausea) + liver (direct hyperbilirubinemia, ↑ alk phos); grade by BSA + stool volume + bilirubin; first-line methylprednisolone 2 mg/kg/day; refractory → ruxolitinib.

Chronic GVHD ≠ just timing — defined by features: lichenoid/sclerotic skin, sicca, oral lichen planus, bronchiolitis obliterans (obstructive PFTs, "FAM" therapy), esophageal webs, fasciitis; first-line prednisone ± CNI; refractory → ibrutinib, ruxolitinib, belumosudil, ECP.

Always rule out mimics in parallel — never sequentially: CMV (owl-eye inclusions), C. difficile, drug rash, SOS/VOD (defibrotide, not steroids), TMA (modify CNI, not plasmapheresis), engraftment syndrome, PRES.

Patient safety pillars: irradiate cellular blood products to prevent transfusion-associated GVHD; offer fertility preservation before conditioning; defer live vaccines ≥24 months and off immunosuppression; tacrolimus is a high-alert med requiring tight level monitoring and azole-interaction vigilance; transitions-of-care must include explicit taper, prophylaxis, and escalation plans.