Graft Vs Host Disease: Symptoms, Types, Causes and Treatment

Graft versus host disease (GVHD) is a major complication that can arise after allogeneic hematopoietic stem cell transplantation (HSCT), where the donated immune cells (the graft) attack the recipient’s (the host's) tissues. GVHD is a complex, multi-organ condition that has major implications for patient quality of life, long-term survival, and post-transplant recovery. Understanding the symptoms, types, causes, and available treatments is crucial for patients, families, and healthcare professionals navigating the transplant journey.

Symptoms of Graft Vs Host Disease

GVHD presents a wide range of symptoms, which can vary significantly depending on whether the disease is acute or chronic and which organs are affected. Recognizing these symptoms early can be life-saving and helps guide effective management strategies.

Symptom Area	Key Features	Onset Pattern	Sources
Skin	Rash, redness, blistering, sclerosis, thickening	Acute/Chronic	4 6 10 16
Gastrointestinal	Diarrhea, abdominal pain, nausea, malabsorption	Acute/Chronic	4 6 10 11
Liver	Jaundice, elevated enzymes, bilirubin, liver enlargement	Acute/Chronic	4 6 10 11
Eyes	Dryness, pain, irritation, keratoconjunctivitis, vision loss	Mostly Chronic	2 5 4 7
Mouth	Ulcers, dryness, sensitivity, nutritional issues	Chronic	1 4 7
Lungs	Cough, shortness of breath, bronchiolitis obliterans	Chronic	4 7 14 15
Systemic	Fatigue, malaise, growth retardation (children), fever	Acute/Chronic	1 4 7 8

Table 1: Key Symptoms

Skin Manifestations

• Acute GVHD: Often presents as a red, micropapular rash, beginning on the palms, soles, or face, and can progress to cover the entire body with blistering and necrosis in severe cases 4 6 10.
• Chronic GVHD: Can resemble scleroderma or lichen planus, with thickening and tightening of the skin, sometimes leading to restricted mobility 4 7 14.

Gastrointestinal Symptoms

• Acute: Profuse, watery diarrhea, nausea, vomiting, abdominal pain, and sometimes gastrointestinal bleeding 4 6 11.
• Chronic: May involve malabsorption, persistent diarrhea, and weight loss, sometimes mimicking autoimmune or inflammatory bowel diseases 4 7.

Liver Involvement

• Elevated liver enzymes (S-ALAT, S-ASAT), increased bilirubin, jaundice, and liver enlargement can occur, especially in more severe forms 4 6 11.
• In chronic GVHD, long-term liver disease, including cirrhosis, may develop 4 7.

Ocular and Oral Symptoms

• Eyes: Ocular GVHD affects 60–90% of patients, causing symptoms from mild dryness to severe inflammation, conjunctivitis, and even corneal ulceration or blindness 2 5.
• Mouth: Persistent dry mouth, ulcers, sensitivity, and nutritional difficulties are common in chronic GVHD and can persist even after other symptoms resolve 1 4.

Pulmonary and Systemic Features

• Chronic GVHD can cause lung problems like bronchiolitis obliterans, leading to cough and breathlessness 4 7 14 15.
• Systemic symptoms such as fatigue, malaise, growth retardation (in children), and increased infection risk are common 1 4 7 8.

Types of Graft Vs Host Disease

GVHD is generally classified into two main types—acute and chronic—each with its own timing, clinical features, and implications for management.

Type	Timeframe After Transplant	Key Features	Sources
Acute	Within first 100 days (mostly)	Skin rash, GI symptoms, liver issues	4 6 10 12
Chronic	After 3 months, up to years	Multi-organ fibrosis, autoimmune-like	4 7 8 14 16
Overlap	Both acute and chronic features	Mixed symptoms	9 14 16
TA-GVHD	After transfusion (rare)	Similar to acute GVHD	13

Table 2: Types of GVHD

Acute Graft Vs Host Disease

• Timing: Typically arises within the first 100 days post-transplant, but can occasionally appear later 4 6 10.
• Clinical Presentation: Rapid onset of skin rash, diarrhea, abdominal pain, liver dysfunction (jaundice), and fever. Graded from I (mild) to IV (life-threatening) based on severity and organs involved 4 10 12.
• Organs Affected: Primarily skin, gastrointestinal tract, and liver 4 6.

Chronic Graft Vs Host Disease

• Timing: Usually develops after 3 months, sometimes even years following transplantation 4 7 8.
• Clinical Features: Characterized by autoimmune-like, fibrotic changes affecting multiple organs—skin, mouth, eyes, lungs, liver, GI tract, and more. Can lead to significant disability and long-term organ dysfunction 4 7 8 14 15.
• Classifications: Sub-classified as limited (localized) or extensive (generalized), and graded as mild, moderate, or severe based on organ involvement and symptom burden 4 9 10.

Overlap and Rare Forms

• Overlap Syndrome: Features of both acute and chronic GVHD can coexist, challenging diagnosis and management 9 14 16.
• Transfusion-Associated GVHD (TA-GVHD): A rare but severe form that occurs following transfusion of non-irradiated blood products, mostly in immunocompromised patients 13.

Causes of Graft Vs Host Disease

The underlying cause of GVHD is immune incompatibility—donor immune cells (especially T cells) recognize the recipient’s tissues as foreign and launch an attack. However, several factors influence risk and severity.

Cause/Risk Factor	Description	Outcome/Impact	Sources
Donor T cells	Immunocompetent cells capable of attacking host	Initiates GVHD	3 4 12 15
HLA Mismatch	Differences in major/minor HLA antigens	Increased risk/severity	4 10 12
Conditioning Regimens	Tissue damage from chemo/radiation	Promotes inflammation	12 11
Donor-Recipient Factors	Age, sex mismatch, viral status, stem cell source	Modulate risk	4 7 10 11
Blood Product Transfusion	Viable donor lymphocytes in transfused blood	TA-GVHD	13
Immune Reconstitution	Replacement of host immune system with donor cells	Chronic GVHD	9 14 15

Table 3: Causes and Risk Factors for GVHD

Immunological Mechanisms

• Donor T Cells: The primary instigators. Donor T cells respond to host antigens presented by antigen-presenting cells (APCs), leading to an immune cascade 3 4 12.
• Cytokine Storm: Host tissue damage from pre-transplant conditioning (chemo/radiation) releases cytokines, activating APCs and stimulating donor T cells 12.
• B Cell Involvement: Especially in chronic GVHD, B cells contribute through autoantibody and alloantibody production, promoting tissue fibrosis 14 15.

Genetic and Donor-Recipient Factors

• HLA Disparity: Differences in human leukocyte antigen (HLA) loci between donor and recipient increase the risk and severity of GVHD, but it can still occur even with fully matched (HLA-identical) donors 4 10 12.
• Other Risk Factors: Female donors to male recipients, older age, previous acute GVHD, certain viral infections (e.g., herpesviruses), and use of peripheral blood stem cells or buffy-coat cells 4 7 10 11.

Environmental and Procedural Triggers

• Conditioning Regimens: Chemo/radiation used before transplantation damages host tissues, which increases antigen presentation and inflammation, making GVHD more likely 12 11.
• Transfusion-Associated GVHD: Occurs when viable donor lymphocytes in transfused blood attack the recipient, particularly if blood is not irradiated and in immunocompromised patients 13.

Treatment of Graft Vs Host Disease

Managing GVHD is complex and requires a balance between suppressing harmful immune responses and preserving the beneficial graft-versus-tumor effect. Treatments vary depending on the type, severity, and organs involved.

Treatment Approach	Description	Usage/Stage	Sources
Corticosteroids	Immunosuppressive, first-line therapy	Acute & Chronic	4 10 16 17 18 19
Calcineurin Inhibitors	Cyclosporine, tacrolimus (often with methotrexate)	Prophylaxis & treatment	4 7 10 17 18
Antithymocyte Globulin	Targets T cells	Steroid-refractory	4 19
Mycophenolate Mofetil	Immunosuppressive, sometimes replaces methotrexate	Prophylaxis & salvage	4 8 18
Biologics/Novel Agents	Anti-IL-2, anti-TNFα, rituximab, kinase inhibitors	Refractory disease	8 14 15 18 19
Cellular Therapies	Mesenchymal stem cells, regulatory T cells	Experimental, refractory	4 18 19
Supportive Care	Infection prophylaxis, symptom management	All stages	11 16 17

Table 4: Treatment Strategies for GVHD

First-Line and Prophylactic Therapies

• Corticosteroids: Remain the cornerstone for both acute and chronic GVHD. About half of patients respond, but the other half develop steroid-refractory disease, which is harder to treat 4 10 16 17 18 19.
• Calcineurin Inhibitors: Cyclosporine or tacrolimus, often combined with methotrexate, are standard for prophylaxis and may be continued in combination with steroids 4 10 17 18.
• Mycophenolate Mofetil: Sometimes used in place of methotrexate or as salvage therapy, but its comparative effectiveness is debated 4 8 18.

Second-Line and Emerging Therapies

• Antithymocyte Globulin (ATG): Used for steroid-refractory cases, but outcomes for advanced GVHD remain poor 4 19.
• Novel Agents: Include biologics targeting interleukins (IL-2, IL-17, IL-21), anti-TNFα, rituximab (anti-CD20 for B cells), kinase inhibitors, and more. These are mainly used in cases that do not respond to standard therapies 8 14 15 18 19.
• Cellular Therapies: Mesenchymal stem cells and regulatory T cells are promising experimental approaches, especially for refractory cases 4 18 19.

Supportive and Organ-Specific Management

• Supportive Care: Infection prophylaxis, nutritional support, pain management, and rehabilitation are essential to optimize outcomes and quality of life 11 16 17.
• Organ-Specific Treatments: For example, ocular GVHD may be managed with topical corticosteroids, cyclosporine A, artificial tears, and autologous serum drops 2 5. Lung, liver, and skin involvement may require tailored interventions.

Treatment Challenges and Future Directions

• No single standard exists for steroid-refractory GVHD; practice varies by institution and region 17 19.
• Balancing immune suppression to control GVHD without losing the beneficial graft-versus-leukemia (GVL) effect is a constant challenge 4 14 15 19.
• Ongoing research focuses on personalized approaches, new immunomodulatory drugs, and cellular therapies to improve survival and long-term quality of life 18 19.

Conclusion

Graft versus host disease is a complex, multi-systemic complication of allogeneic stem cell transplantation, with significant implications for patient survival and quality of life. Early recognition, risk assessment, and individualized treatment are crucial for optimizing outcomes.

Key Takeaways:

• Symptoms: GVHD can affect the skin, gut, liver, eyes, mouth, lungs, and more, with acute and chronic forms showing distinct patterns 1 4 6 7 10.
• Types: Acute GVHD typically occurs within the first 100 days post-transplant, while chronic GVHD can develop months or years later and often resembles autoimmune disease 4 7 8 9.
• Causes: The disease is primarily driven by donor T cells attacking host tissues, with risk influenced by HLA mismatch, conditioning regimens, and other donor-recipient factors 3 4 10 12 15.
• Treatment: First-line treatments include corticosteroids and calcineurin inhibitors, but many patients require additional immunosuppressive or novel therapies. Supportive care and organ-specific management are vital 4 10 16 17 18 19.
• Outlook: Research continues to develop safer, more effective treatments for both prevention and management, aiming to reduce GVHD incidence while preserving beneficial anti-tumor effects 14 15 18 19.

By staying informed about the latest advances and strategies, patients and clinicians can work together to manage GVHD more effectively and improve long-term outcomes after transplantation.