Graft-versus-host disease

Introduction

Graft-versus-host disease (often abbreviated as GvHD) is a serious immune complication that can happen after a stem cell or bone marrow transplant. In simple terms, the donor’s immune cells see the recipient’s tissues as “foreign” and start attacking them. This condition can have a big impact on one’s health ranging from mild skin rashes to life-threatening organ failure. It’s fairly common in transplants, affecting up to 50% of all allogeneic transplant recipients. Below, we’ll walk through the main symptoms you might notice, the underlying causes, and current treatment approaches, plus what the outlook usually looks like.

Definition and Classification

At its core, graft-versus-host disease is an immunological reaction where donor T cells (from grafted bone marrow or stem cells) attack the host’s organs and tissues. Clinicians classify GvHD into two primary types:

• Acute GvHD – Typically arises within the first 100 days post-transplant; mainly involves skin, liver, and gastrointestinal tract.
• Chronic GvHD – Occurs after 100 days, can mimic autoimmune disorders, often involves multiple systems like eyes, lungs, mucosa, and joints.

Affected systems: skin, liver, GI tract, sometimes lungs, eyes, or musculoskeletal tissues. Acute and chronic forms differ in timing, presentation, and risk factors but share the same general mechanism donor immune cells attacking host tissues.

Causes and Risk Factors

In GvHD, the three main ingredients are: donor immune cells (graft), host tissues (recipient), and a mismatch or memory reaction that ignites the attack. While we understand this triad fairly well, some details remain murky. Here are the key factors:

• HLA mismatch: The more mismatches between donor and recipient’s HLA (human leukocyte antigen) proteins, the higher the risk. Even a single allele difference can tip the scales.
• Donor type: Unrelated donors or mismatched family donors (haploidentical) tend to produce more GvHD than fully matched siblings.
• Age of recipient and donor: Older patients have a tougher time; similarly older donors carry more memory T cells, increasing risk.
• Stem cell source: Peripheral blood stem cells (PBSC) often lead to higher GvHD rates compared to bone marrow or cord blood grafts, likely due to richer T cell populations.
• Conditioning regimen: Intensity of chemotherapy/radiation before transplant myeloablative regimens may leave more tissue damage signals that activate donor T cells.
• Genetic predisposition: Certain cytokine gene polymorphisms (e.g., TNF-α, IL-10) might modulate how aggressively the graft attacks host tissues.
• Immune status and infections: Pre-existing viral infections (CMV, EBV) or bacterial exposure can skew immune responses, amplifying GvHD.

Modifiable vs. non-modifiable: You can’t change your HLA or age, but you can choose conditioning intensity or graft source decisions often guided by transplant teams. Still, unpredictability remains, and even well-matched transplants sometimes trigger severe GvHD.

Pathophysiology (Mechanisms of Disease)

The biological cascade in GvHD happens in roughly three overlapping phases:

• Phase 1: Tissue damage and inflammation. Prep regimens (chemo/radiation) injure host tissues, releasing inflammatory cytokines (TNF-α, IL-1) and danger signals (e.g., ATP, HMGB1). Endothelial cells and antigen-presenting cells (APCs) get activated.
• Phase 2: Donor T cell activation. Transplanted donor T cells recognize host antigens (presented by host or donor-derived APCs) as non-self. This triggers clonal expansion and differentiation into effector T cell subsets (Th1, Th17, cytotoxic CD8+ cells).
• Phase 3: Effector phase and tissue destruction. Activated T cells release cytokines (IFN-γ, TNF-α) and cytotoxic mediators (perforin, granzyme B), leading to direct epithelial damage, apoptosis, and disruption of organ integrity. B cells and innate immune cells also participate, especially in chronic GvHD where auto-antibody production can replicate features of autoimmune diseases.

Overall, normal tolerance mechanisms fail, allowing donor lymphocytes to perpetuate ongoing inflammation and cellular destruction, notably in skin, liver, and gastrointestinal mucosa. Chronic GvHD adds fibrosis, thymic dysfunction, and multi-organ autoimmunity to the mix.

Symptoms and Clinical Presentation

Symptoms for GvHD vary widely. Acute and chronic forms have overlapping but distinct presentations:

• Skin: In acute GvHD, look for erythematous maculopapular rash on palms, soles, and trunk that may blister. Chronic involvement can cause scleroderma-like changes tight, woody skin, or lichen planus-like eruptions.
• Liver: Elevated bilirubin, ALP, ALT, AST. Acute patients get jaundice and cholestasis; chronic GvHD often gives a cholestatic pattern plus dry, itchy skin.
• Gastrointestinal tract: In acute phase up to 60% develop nausea, vomiting, profuse watery diarrhea (can exceed 1–2 liters/day), crampy abdominal pain, anorexia. Chronic GvHD yields strictures, malabsorption, dysphagia, and oral mucosal webs.
• Mouth and eyes: Dry mouth (xerostomia), mucositis, ulcerations, keratoconjunctivitis sicca causing gritty sensation or photophobia.
• Lungs: Bronchiolitis obliterans syndrome nonproductive cough, dyspnea on exertion, wheezing, obliging many to use inhalers.
• Joints and fascia: Stiffness, restricted movement due to fibrosis around joints or tendon sheaths.
• General: Weight loss, fatigue, low-grade fevers, night sweats, increased infection risk due to immunosuppression.

Warning signs: severe abdominal pain, hematochezia, rising bilirubin above 3 mg/dL, or rapid spread of rash beyond 50% of body surface area signal need for urgent medical evaluation.

Diagnosis and Medical Evaluation

Diagnosing graft-versus-host disease relies on clinical judgment supported by labs and sometimes biopsies:

• History & exam: Onset timing relative to transplant, pattern of rash, stool frequency, and mouth/oral exam.
• Laboratory tests: Complete blood count (CBC), comprehensive metabolic panel (LFTs), bilirubin, albumin. Stool studies to rule out infection (C. difficile, CMV).
• Skin biopsy: Helps confirm acute GvHD by showing satellite cell necrosis, apoptotic keratinocytes. Chronic GvHD skin biopsies may show dermal fibrosis and a lichenoid pattern.
• Liver biopsy: Reserved for unclear cholestasis shows periportal inflammation with bile duct damage in chronic GvHD.
• Endoscopy with GI biopsies: Helpful if diarrhea is severe and infectious causes excluded. Histology: crypt cell apoptosis, mucosal atrophy.
• Pulmonary function tests (PFTs): For suspected bronchiolitis obliterans, showing obstructive pattern.

Differential diagnoses include drug reactions (e.g., chemotherapeutic toxicity), viral infections (e.g., CMV colitis), idiopathic pulmonary syndrome post-transplant, and thrombotic microangiopathy. A multidisciplinary transplant team often guides the diagnostic pathway.

Which Doctor Should You See for Graft-versus-host Disease?

When symptoms arise, you usually first consult your transplant hematologist/oncologist or a bone marrow transplant specialist. For skin manifestations, a dermatologist experienced in post-transplant care is key. If GI symptoms dominate, a gastroenterologist can perform endoscopy and biopsies. Pulmonary complaints often lead you to a pulmonologist for lung function tests and imaging.

Thinking “which doctor to see?” your transplant center coordinator is often the best first call. They’ll triage you: urgent GI bleeding or severe liver issues warrant immediate ER evaluation. Telemedicine can be a great first step to interpret lab results, ask follow-up questions, or seek a second opinion after discharge. Still, online visits don’t replace physical exams or labs when your liver enzymes are climbing so do keep that in mind.

Treatment Options and Management

Managing GvHD balances suppressing harmful donor immune cells without tipping you into fatal infections. First-line therapies include:

• Systemic corticosteroids: Prednisone (1–2 mg/kg/day) for acute GvHD, tapered over weeks to months based on response.
• Calcineurin inhibitors: Tacrolimus or cyclosporine often used in combination with steroids to improve efficacy.
• Monoclonal antibodies: In steroid-refractory cases, agents like ruxolitinib (a JAK1/2 inhibitor) or anti-TNF (in select centers) can be lifesaving.
• Topical treatments: For skin and mucosal involvement steroid creams, tacrolimus ointment, specialized mouthwashes.
• Extracorporeal photopheresis (ECP): An apheresis-based treatment that modulates immune responses, especially helpful in cutaneous or lung-chronic GvHD.

Supportive care: nutritional support, pain management, prophylactic antimicrobials (antivirals, antifungals), and physical therapy for joint stiffness. Each regimen carries risk: steroids can cause osteoporosis, hyperglycemia, weight gain; calcineurin inhibitors may trigger nephrotoxicity or hypertension.

Prognosis and Possible Complications

Outcomes in GvHD vary. Mild acute GvHD (skin-only stage I) has excellent prognosis with up to 80% response to steroids. Severe acute stage III–IV can have mortality rates exceeding 50%, especially when gut or liver are involved. Chronic GvHD affects up to half of long-term survivors and is now the leading cause of non-relapse mortality after transplant.

Potential complications if poorly controlled:

• Infections—bacterial, viral (CMV reactivation), fungal (aspergillus)
• Organ failure—fibrosis of lung (bronchiolitis obliterans) or liver cirrhosis
• Secondary malignancies—due to prolonged immunosuppression
• Quality of life issues—joint contractures, chronic pain, dry eyes/mouth

Factors improving prognosis include early detection, matched sibling donors, lower-grade acute GvHD, and availability of second-line therapies.

Prevention and Risk Reduction

The best defense against GvHD starts before the transplant. Key strategies include:

• Stringent donor matching: Prioritizing HLA-identical siblings or well-matched unrelated donors minimizes mismatch-related risks.
• Graft manipulation: T cell depletion (ex vivo or in vivo with anti-thymocyte globulin) reduces incidence but may slightly increase relapse risk.
• Prophylactic immunosuppression: Most centers use calcineurin inhibitors with methotrexate or mycophenolate mofetil right after graft infusion to dampen initial T cell activation.
• Reduced-intensity conditioning (RIC): Less aggressive chemo/radiation regimens help older or frail patients avoid excessive tissue injury and subsequent GvHD.
• Monitoring & early intervention: Weekly labs (LFTs, CBC), prompt evaluation of new rash or diarrhea, and low threshold for biopsy help catch GvHD at stage I–II when it’s most responsive.

Lifestyle tips: maintain a balanced diet to support gut microbiome diversity (emerging evidence links microbiome health to GvHD severity), keep up with vaccinations per transplant guidelines, and avoid known environmental triggers (e.g., high-dose sun exposure can aggravate skin GvHD).

Myths and Realities

Misconception 1: “GvHD only happens in the first month.” Reality: While acute GvHD classically occurs before day 100, chronic GvHD can develop anytime—sometimes years later. I’ve seen patients present at 2 years post-transplant with new dry eyes and sclerotic skin changes.

Myth 2: “T cell depletion eliminates GvHD risk completely.” Truth: It lowers incidence but not to zero, and may increase infection or cancer relapse rates. It’s a balancing act.

Myth 3: “Only the skin is affected.” Fact: Skin is often the first sign, but liver, gut, eyes, lungs, and joints can all suffer. Chronic lung GvHD (bronchiolitis obliterans) is under-recognized and can silently wreck pulmonary function.

Myth 4: “Once treated, GvHD won’t come back.” Nope—flaring during tapering of immunosuppression is common. Some patients need long-term low-dose therapy or periodic ECP sessions.

Myth 5: “Diet won’t matter.” Emerging studies link healthy gut flora to milder GvHD. A fiber-rich, diverse diet may aid recovery (though controlled human trials are ongoing).

Conclusion

Graft-versus-host disease remains a formidable challenge after allogeneic transplant. Early recognition of rashes, liver enzyme spikes, or GI symptoms and swift collaboration with transplant teams are crucial. While acute and chronic forms differ in timing and tissue patterns, both require a nuanced balance between suppressing harmful immune responses and avoiding life-threatening infections. Advances in prophylaxis, immunomodulatory drugs, and cellular therapies have improved outcomes, yet vigilant monitoring and patient-centered care remain key. If you or a loved one faces suspected GvHD, don’t wait reach out to transplant specialists who can guide you toward timely evaluation and the most up-to-date treatments.

Frequently Asked Questions (FAQ)

• Q1: What is the main difference between acute and chronic GvHD?
  A1: Acute GvHD appears within 100 days post-transplant with rashes, GI symptoms, and liver involvement; chronic GvHD emerges later, resembling autoimmune diseases with skin fibrosis, dry eyes, and lung issues.
• Q2: How soon after transplant should I watch for GvHD signs?
  A2: Acute GvHD often starts 2–4 weeks post-transplant, but vigilance extends through the first 100 days; chronic GvHD can occur anytime after, even years later.
• Q3: Can diet affect my GvHD risk?
  A3: Early research suggests a diverse, fiber-rich diet supports healthy gut flora, which may reduce GvHD severity, though more trials are needed.
• Q4: Is steroid treatment the only option?
  A4: Steroids are first-line for acute GvHD, but refractory cases may need ruxolitinib, anti-TNF agents, ECP, or additional immunosuppressants.
• Q5: How long is GvHD treatment typically needed?
  A5: Duration varies; acute GvHD might resolve in months, while chronic GvHD often requires prolonged immunosuppression or intermittent therapies for years.
• Q6: Can GvHD cause long-term organ damage?
  A6: Yes. Left untreated or severe cases may lead to liver cirrhosis, lung fibrosis (bronchiolitis obliterans), and joint contractures.
• Q7: What lifestyle changes help manage GvHD?
  A7: Balanced diet, regular exercise, skin protection from sun, oral hygiene, and prompt reporting of new symptoms all aid management.
• Q8: Are children at different risk than adults?
  A8: Pediatric patients generally have lower acute GvHD rates, potentially due to a more resilient thymus, but still need close monitoring.
• Q9: How is GvHD severity graded?
  A9: Acute GvHD grades I–IV based on extent of rash, bilirubin levels, and diarrhea volume; chronic GvHD has mild, moderate, and severe categories by organ involvement.
• Q10: Do I need emergency care for GvHD?
  A10: Yes—if you have sudden high-volume diarrhea, bleeding, worsening jaundice, or a fast-spreading rash you should seek urgent evaluation.
• Q11: Can telemedicine replace in-person visits?
  A11: Telemedicine helps interpret lab results, follow up on stable symptoms, and get second opinions, but physical exams and biopsies require in-person care.
• Q12: Does T cell depletion guarantee no GvHD?
  A12: T cell depletion lowers GvHD risk but doesn’t eliminate it. Plus, it may slightly increase infection or relapse risk.
• Q13: Are there genetic tests for GvHD risk?
  A13: Not routine. Research is exploring cytokine gene polymorphisms (TNF-α, IL-10) as risk markers, but clinical use remains limited.
• Q14: How do I prepare for a possible GvHD diagnosis?
  A14: Know your baseline labs, keep a symptom diary, maintain transplant center contacts, and arrange for prompt lab work post-transplant.
• Q15: What’s the outlook for GvHD survivors?
  A15: Many achieve long-term remission, though chronic GvHD can impact quality of life. Early treatment and multidisciplinary care greatly improve results.