What Is Graft Versus Host Disease

Overview

Graft versus Host Disease (GvHD) is a common complication that arises in patients who have undergone transplantation procedures. In this condition, the immune cells from the transplanted or donated tissue, known as the graft, identify the recipient's tissues (host) as foreign and launch an attack on the recipient's own body cells. GvHD is considered a systemic condition wherein the graft and host exhibit immunological incompatibility despite being of the same species.

The graft refers to allogeneic tissue (genetically dissimilar to the recipient) that is transplanted into the patient (host). The name 'Graft versus Host' derives from the conflict that is initiated between the donor's and recipient's cells.¹

Among various transplantation procedures, hematopoietic stem cell (immature blood cells) transplant is particularly prone to GvHD due to the presence of immune cells, making it the most commonly encountered complication in such cases.

Types of GvHD

There are two types of GvHD, acute and chronic, with each type having two subcategories based on the clinical manifestations appearance:¹

Causes of GvHD

GvHD happens in patients who have undergone a transplant surgery and received a graft under the following conditions:²

• The patient received cells, tissue, or an organ from an allogenic (non-self) source
• The graft is rich in lymphocytes that are immunologically intact and thus able to launch an attack
• The immune cells from the graft recognise the antigens on the cells of the host as non-self
• The patient is not taking immunosuppressants

Signs and symptoms of GvHD

The signs and symptoms of GvHD fall into two categories: acute and chronic.

Signs and symptoms of acute GvHD: Primarily manifest on the skin, gastrointestinal tract (GIT), and liver.

• Skin 

Skin-related manifestations are observed in 70% of patients. The most common signs and symptoms of acute GvHD are jaundice (yellowish pigmentation of the skin) and skin rash (painful maculopapular or pruritic rash) on the palms, shoulders, nape of the neck and soles of the feet. You may also experience a sensation of sunburn accompanied by feelings of itchiness and soreness. In the severe form of acute GvHD, the symptoms can develop to resemble toxic epidermal necrolysis (TEN).

• Gastrointestinal tract 

The GIT-related symptoms manifest in approximately 74% of cases, with common symptoms including diarrhoea and abdominal pain. Nausea, vomiting, inflammation and ulceration of the inner lining of the gut may also accompany these symptoms.

A unique feature of diarrhoea in this context is that it persists even when the patient fasts (refrains from eating or drinking). Initially, it may be watery, but over time, the patient may observe the presence of blood in the stool. Consequently, frequent blood transfusions are required to prevent complications arising from fluid imbalance, which could potentially lead to life-threatening conditions such as hypovolemic shock.³

• Liver 

Liver-related symptoms account for 44% of the total symptom manifestation and typically occur alongside symptoms in the skin and GIT. 

These symptoms rarely occur in isolation from the skin and GI symptoms. Abnormal liver function test results are common, with increased bilirubin and alkaline phosphatase levels being key indicators. In severe cases, physical manifestations may include hepatomegaly along with pale stool and urine.³

Signs and symptoms of chronic GvHD: Chronic GvHD often presents with manifestations that resemble autoimmune disorders, such as Sjogren syndrome, wasting syndrome, chronic immunodeficiency, and primary biliary cirrhosis. These similarities arise from the dysregulated immune response.³ 

The manifestation of chronic GvHD signs and symptoms is more common in patients who have previously experienced the acute form. However, it's not simply progress from the acute to chronic stage. The uncertainties in diagnosis, a limited understanding of the underlying mechanisms, and other clinical complexities make a systematic evaluation almost impossible.⁴

Management and treatment for GvHD

Due to a limited understanding of the pathophysiology of GvHD, treatment and prevention options are very limited. The severity of GvHD can be categorised into Grades 1-4 (based on the International Bone Marrow Transplant Registry), with corresponding treatment strategies for each category.⁵

Grade 1 (Mild): Localized symptoms, such as skin rash that affect only tha palm of the hand. No involvement of liver or GI symptoms, and no decrease in clinical performance. These symptoms can be managed with prescribed steroids. Topical tacrolimus is an alternative if you have steroid-resistant forms of the disease.⁶

Grades 2-4

• Grade 2 (Moderate): Skin rash, mild involvement of liver or GI (or both), and mild decrease in clinical performance
• Grade 3 (Severe): Skin rash, liver or GI manifestation (or both), and a marked decrease in clinical performance
• Grade 4 (Life-threatening): Organ involvement and extreme decrease in clinical performance

When GvHD reaches a systemic level, treatment needs to be systemic as well. The typical approach involves:² 

• Methylprednisolone at 2 mg/kg/day, administered in divided doses, with each prescription tailored to the patient
• If GvHD progresses to involve the GIT, non-absorbable corticosteroids are preferred, especially in the presence of a GIT infection where steroids should be avoided
• Gradual tapering of steroids is important, often done over months to prevent GvHD from recurring

Chronic GvHD

The tapering period of steroids can extend up to three years, with some exceptions that may require lifelong treatment. 

Cyclosporine may also be prescribed to reduce the steroid dose and the extended tapering-off duration.⁷

Diagnosis

Your healthcare provider can diagnose GvHD through:

1. Physical examination, where they observe specific symptoms classified by their appearance on the skin, liver, and GIT.⁸ One key indicator is the skin rash, which is observed in most patients.
   
   Additionally, various factors should be considered when diagnosing GvHD as certain symptoms may indicate multiple potential conditions. This includes considering the potential for viral hepatitis, hepatotoxicity (liver toxicity associated with immunotherapy), drug-induced liver injury, sinusoidal obstructive syndrome, and hepatocellular malignancy.⁹
   
   In cases where diagnosis is based on GI symptoms, healthcare providers assess iatrogenic symptoms, which are related to chemotherapy, antibiotics, or immunosuppressants. These may include symptoms like nausea, vomiting, anorexia, and diarrhoea.¹⁰

2. Biopsy, where a sample of tissue or cells is removed from the skin, GIT mucosa, or liver and sent to the lab for testing. A biopsy is usually performed to confirm the diagnosis of GvHD.

Risk factors

Certain factors increase the risk of developing GvHD:

1. Characteristics of the donor and host: Factors like chromosomal sex-matching and HLA matching index play a significant role. The higher the match index, the lower the chance of GvHD
2. Source of the cells: Utilising umbilical cord blood and cryopreservation bone marrow before transplantation can reduce the incidence of GVHD
3. Chemotherapy and radiation therapy: These treatments may increase the risk of GvHD by damaging cells and triggering the release of various chemicals into the bloodstream. This, in turn, activates immune cells and increases the likelihood and severity of GvHD manifestations¹¹

Complications

Damage to body organs such as skin, liver, GIT, lungs, and other vital organs may occur due to the hyperactivity of the immune system and can result in severe reactions. This hyperactivity may also compromise the success of the graft. In some cases, the damage can be very severe, leading to fatal outcomes.

FAQs

How can I prevent GvHD?

Unfortunately, there is no way to prevent GvHD, as every patient who has undergone a transplant and received allogeneic cells is at risk of developing it. 

How common is GvHD?

GvHD is very common, occurring in more than 50% of transplants.

What is the difference between GvHD and transplant rejection?

Transplant rejection arises from the recipient's immune system response to the transplanted graft, while GvHD arises when donor-derived immune cells react to allogeneic recipient tissues.

Summary

In summary, GvHD may occur in patients who have undergone transplantation, especially when the transplanted tissue contains a large number of graft immune cells. There are various factors that can affect the severity of GvHD. Currently, the primary treatment is limited to steroids, but preclinical trials suggest that statins could be a promising supplementary treatment option. Early intervention is crucial, thus any symptoms must be treated with the utmost seriousness, and immediate consultation with a doctor is highly recommended.