Gvhd: Symptoms, Types, Causes and Treatment

Graft-versus-host disease (GvHD) is a complex and potentially life-threatening complication that can arise after allogeneic stem cell or bone marrow transplantation. In GvHD, the donor's immune cells attack the recipient's body, leading to a spectrum of symptoms and complications. Understanding GvHD’s symptoms, types, underlying causes, and treatment options is essential for patients, caregivers, and healthcare professionals involved in transplantation care. This article synthesizes research findings to provide a comprehensive, human-centered overview of GvHD.

Symptoms of Gvhd

GvHD manifests with a wide range of symptoms that can vary based on the organs involved, the severity, and whether the disease is in its acute or chronic form. Early recognition of these symptoms is vital, as prompt diagnosis and treatment can significantly influence outcomes and quality of life for transplant recipients.

Symptom	Organ/System	Acute/Chronic	Source(s)
Rash/Redness	Skin	Acute/Chronic	3 10 17
Diarrhea	GI Tract	Acute/Chronic	1 2 10
Abdominal Pain	GI Tract	Acute/Chronic	1 2
Jaundice	Liver	Acute/Chronic	10 6
Dry Mouth/Eyes	Mucosal Glands	Chronic	4 6 7
Scleroderma-like Skin	Skin	Chronic	6 7
Nausea/Vomiting	GI Tract	Acute/Chronic	1 2
Dysphagia	Esophagus	Chronic	4 6
Psychological Distress	CNS	Chronic	5

Table 1: Key Symptoms of GvHD

Skin Symptoms

The skin is often the first and most commonly affected organ in both acute and chronic GvHD. Acute GvHD typically presents with a maculopapular rash, which may progress to involve large portions of the body and, in severe cases, resemble conditions like toxic epidermal necrolysis (TEN) 3 10 17. In chronic GvHD, skin manifestations can include lichenoid changes, scleroderma-like tightening, hyperpigmentation, and ulceration 6 7 17. Early cutaneous signs are crucial for rapid diagnosis and can be isolated or occur alongside other symptoms.

Gastrointestinal Symptoms

Gastrointestinal (GI) involvement in GvHD is common and can range from mild to severe. Acute GvHD often leads to secretory diarrhea, abdominal pain, anorexia, nausea, vomiting, and sometimes GI bleeding 1 2 10. Chronic GvHD can also present with persistent GI symptoms, but histologically confirmed chronic GI involvement is less common than previously thought; acute-type lesions may persist in chronic GvHD cases 2.

Liver and Other Organ Involvement

Liver involvement manifests as elevated liver enzymes and jaundice, which may be accompanied by other signs of hepatic dysfunction 10. Chronic GvHD frequently affects mucosal glands, leading to dryness of the mouth (xerostomia) and eyes (xerophthalmia), as well as dysphagia due to esophageal or upper GI tract involvement 4 6 7. Rarely, other organs such as the lungs (bronchiolitis obliterans), connective tissues, and even the central nervous system may be affected 4 6 14.

Psychological and Quality of Life Impact

Chronic GvHD can have profound psychological effects, with significant proportions of patients experiencing depression, anxiety, and reduced physical functioning. These symptoms are not only distressing but are also associated with poorer clinical outcomes and lower overall survival 5.

Types of Gvhd

GvHD is generally categorized into two major types: acute and chronic. These types differ in clinical presentation, timing, pathophysiology, and management. Understanding the distinctions is key to diagnosis and appropriate treatment.

Type	Onset	Main Features	Source(s)
Acute GvHD	≤100 days post-Tx	Skin, GI tract, liver; rapid onset	8 10 12 13
Chronic GvHD	>100 days post-Tx	Skin, mucous membranes, liver, lungs, autoimmune features	4 6 7 9 14

Table 2: Main Types of GvHD

Acute GvHD

Acute GvHD typically arises within the first 100 days after transplantation, although new definitions emphasize clinical features rather than strict timing 8 10 12 13. It is characterized by:

• Skin: Maculopapular rash, erythema, or desquamation.
• GI Tract: Diarrhea, abdominal pain, nausea, vomiting, and GI bleeding.
• Liver: Elevated bilirubin and transaminases, jaundice.

Severity is graded based on the extent of involvement in these organs. Acute GvHD can be life-threatening and requires prompt intervention 8 13 15.

Chronic GvHD

Chronic GvHD generally develops after the 100-day mark, but its diagnosis now depends on specific clinical and histological criteria, not just timing 4 9 14. Chronic GvHD presents with a broader and often more insidious range of symptoms:

• Skin: Lichenoid or scleroderma-like changes, hyperpigmentation, ulceration, and contractures.
• Mucous Membranes: Dry mouth (sicca syndrome), dry eyes, oral ulcers, and dysphagia.
• Liver: Persistent liver dysfunction.
• Lungs: Bronchiolitis obliterans, presenting with chronic cough and shortness of breath.
• Other: Autoimmune features, such as joint involvement, muscle weakness, and serosal inflammation 6 7 14.

Chronic GvHD is a leading cause of late morbidity and mortality in transplant survivors.

Causes of Gvhd

The underlying cause of GvHD is rooted in immune system incompatibility between the donor and recipient, leading to an immune attack on the recipient’s tissues. However, the pathogenesis involves a complex interplay of multiple factors.

Factor	Mechanism/Role	Risk Impact	Source(s)
Donor T Cells	Attack recipient tissues	Direct cause	8 10 12 13
HLA Mismatch	Increases immune recognition	Higher risk	10 12
Conditioning Regimen	Damages host tissue, triggers inflammation	Promotes GvHD	12 13
Prior Acute GvHD	Predisposes to chronic GvHD	Major risk	14
Age (Donor/Recipient)	Older age increases risk	Higher risk	1 14
Non-T cell-depleted graft	More donor T cells	Higher risk	14
Thymic Dysfunction	Impaired negative selection, autoimmunity	Promotes chronic GvHD	11

Table 3: Causative and Risk Factors for GvHD

Immune Mismatch and Donor T Cell Activity

The central event in GvHD is the recognition of recipient antigens as foreign by donor T lymphocytes. This immune reaction leads to widespread tissue injury 8 10 12 13. The degree of human leukocyte antigen (HLA) mismatch between donor and recipient plays a substantial role in susceptibility and severity 10 12.

Role of Conditioning Regimens

Pre-transplant conditioning using chemotherapy and/or radiation damages host tissues, releasing inflammatory cytokines and exposing recipient antigens. This inflammatory milieu primes donor T cells for activation upon transplantation, setting the stage for GvHD 12 13.

Chronic GvHD: Autoimmunity and Immune Dysregulation

Chronic GvHD is more complex and involves not only persistent alloreactivity but also features of autoimmunity and immune deficiency. Factors include:

• Impaired Thymic Selection: Poor negative selection in the thymus allows autoreactive donor-derived T cells to survive, contributing to chronic GvHD and autoimmunity 11.
• Previous Acute GvHD: The most significant risk factor for chronic GvHD is a history of acute GvHD 14.
• Other Factors: Older age, non-T cell-depleted grafts, and possibly the use of peripheral blood stem cells (still debated) increase risk 1 14.

Additional Contributors

Chronic GvHD has been linked to immune abnormalities (e.g., autoantibodies, hypergammaglobulinemia) and is marked by a syndrome of both immune deficiency and autoimmune manifestations 6 7.

Treatment of Gvhd

Managing GvHD requires a nuanced, individualized approach, as both prevention and treatment strategies have evolved substantially. Treatment depends on the type, severity, and organ systems involved.

Approach	Use/Indication	Examples/Notes	Source(s)
Prophylaxis	Prevent GvHD post-transplant	Immunosuppressants, ATG	8 15
First-line Therapy	Acute GvHD	Steroids (glucocorticoids)	10 13 15
Second-line Therapy	Steroid-refractory cases	Monoclonal antibodies, MMF, rapamycin, phototherapy	13 15 16 17
Chronic GvHD Treatment	Established chronic GvHD	Steroids, cyclosporine, thalidomide, photopheresis, anti-CD20	14 15 17 18
Infection Prophylaxis	All GvHD patients	Antibacterials, antifungals	10 16
Supportive/Psychological Care	Symptom management/QoL	Counseling, rehabilitation	5

Table 4: GvHD Treatment and Management Strategies

Prevention: Prophylaxis

Preventing GvHD is a cornerstone of transplantation protocols. Strategies include:

• Immunosuppressive Drugs: Calcineurin inhibitors (cyclosporine, tacrolimus), methotrexate, and mycophenolate mofetil are commonly used.
• Anti-T Cell Globulin (ATG): Used in high-risk patients to reduce donor T cell activity 8 15.
• Graft Manipulation: T cell depletion of the graft can reduce GvHD risk but may increase relapse rates.

Treatment of Acute GvHD

• First-line Therapy: Systemic corticosteroids (e.g., prednisone) remain the mainstay for acute GvHD treatment 10 13 15. Lower doses may be considered in mild cases with limited organ involvement 15.
• Second-line and Refractory Cases: Options for steroid-refractory acute GvHD include:
  • Monoclonal antibodies (anti-TNF, anti-IL2R)
  • Mycophenolate mofetil, rapamycin
  • Phototherapy for skin involvement
  • Novel agents under clinical investigation 13 15 16 17

Treatment of Chronic GvHD

• Immunosuppressive Therapy: Corticosteroids and calcineurin inhibitors form the basis of treatment. Response rates vary, and some manifestations (e.g., bronchiolitis obliterans) are less responsive 14.
• Adjunct and Emerging Therapies:
  • Thalidomide, anti-CD20 monoclonal antibodies, and extracorporeal photopheresis are options for refractory or specific forms of chronic GvHD 14 18.
  • Targeted therapies based on new mechanistic insights are under development, aiming to suppress GvHD while preserving graft-versus-tumor effects 18.
• Topical and Local Treatments: For skin and mucosal involvement, topical steroids, calcineurin inhibitors, and other agents may provide relief and allow for lower systemic immunosuppression 17.

Supportive Care and Psychological Management

• Infection Prophylaxis: Due to immune suppression, patients are highly susceptible to bacterial, fungal, and viral infections, necessitating vigilant prophylaxis and monitoring 10 16.
• Quality of Life and Psychological Support: Patients with chronic GvHD are at increased risk for depression and anxiety. Addressing psychological distress is crucial, as it impacts survival and overall well-being 5.
• Physical Rehabilitation: Chronic GvHD can cause contractures and physical impairment, making early intervention by rehabilitation specialists important 6.

Conclusion

Graft-versus-host disease remains a major challenge after allogeneic stem cell transplantation, affecting patients’ survival and quality of life. A nuanced understanding of its symptoms, types, causes, and treatments is crucial for optimizing patient outcomes. Key points include:

• GvHD presents with diverse symptoms, most commonly affecting the skin, GI tract, liver, and mucosal surfaces, with psychological symptoms increasingly recognized.
• Acute and chronic GvHD differ in timing, presentation, and management, but both can be severe and multi-organ.
• The core cause is immune incompatibility and donor T cell attack, with risk influenced by factors such as HLA mismatch, age, and prior acute GvHD.
• Prevention and treatment involve immunosuppression, novel targeted therapies, infection prophylaxis, and comprehensive supportive care.
• Quality of life and psychological well-being are essential aspects of care, especially for chronic GvHD survivors.

By integrating timely recognition, evidence-based treatment, and holistic support, the outlook for patients with GvHD continues to improve.