Acute graft-versus-host disease

This illustrated PrimeView summarizes the diagnosis, mechanisms, epidemiology and treatment of acute graft-versus-host disease, and accompanies the Primer article on this topic by Malard et al.


Diagnosis
Acute GVHD is graded as I (mild), II (moderate), III (severe) and IV (very severe), based on the quantification of skin rash, serum bilirubin level, diarrhoea and persistent nausea.

Skin acute GVHD
The first and most common manifestation of acute GVHD in most patients is a maculopapular rash that is often itchy and can be painful. This generally occurs 14-21 days after alloHCT and initially develops on sun-exposed areas such as the nape of the neck or the shoulders, or less frequently the palms of the hands and the soles of the feet.

Liver acute GVHD
The liver is the least frequently involved organ in acute GVHD and liver acute GVHD is usually observed along with skin and/or GI acute GVHD. Liver acute GVHD is characterized by an increased total serum bilirubin level (hyperbilirubinaemia), which can lead to jaundice.

GI acute GVHD
Diarrhoea is the prominent symptom of lower GI acute GVHD and in severe disease can be accompanied by abdominal pain and ileus (temporary lack of movement in the intestines). Anorexia, nausea and/or vomiting are symptoms of upper GI acute GVHD. Upper and lower GI acute GVHD can occur in combination or isolation.

Management
Mild skin acute GVHD should be treated with topical steroid alone, whereas higherseverity skin acute GVHD, GI acute GVHD, and liver acute GVHD should be treated with methylprednisolone as first-line treatment. Ruxolitinib is the second-line treatment for steroid-refractory or steroid-dependent acute GVHD. Third-line treatment options include several drugs, for example, anti-tumour necrosis factor or anti-IL-2R, and treatments such as extracorporeal photopheresis (a blood treatment designed to kill the donor T cells).
Prophylaxis is important when patients undergo alloHCT as it has been shown to reduce the number of patients that will develop acute GVHD. One of the most common prophylaxes is the combination of a calcineurin inhibitor with the anti-metabolite drug methotrexate.

Outlook
Prophylaxis and treatment of acute GVHD has advanced in the past few years. However, there remain some important unmet needs in acute GVHD, particularly for patients with steroid and ruxolitinibresistant disease. Management of severe acute GVHD also remains challenging in low-and middle-income countries, owing to the cost and lack of availability of ruxolitinib and third-line treatments. Efforts must be made to ensure there is global access to treatments for acute GVHD.
Acute GVHD is a risk factor for chronic GVHD, a leading cause of mortality in patients who receive alloHCT.

Epidemiology
Numerous risk factors for acute GVHD have been identified, including degree of human leukocyte antigen (HLA) disparity (unrelated donor or HLA mismatched donor), stem cell source (a higher risk of acute GVHD with peripheral blood and bone marrow graft versus umbilical cord blood), donor and recipient sex disparity, high intensity of alloHCT conditioning regimen and type of GVHD prophylaxis. Other risk factors, such as cytomegalovirus negativity in both donor and recipient and older donor age have also been reported. Some studies have reported that ethnicity affects risk of developing acute GVHD; however, conflicting results have been obtained from other studies.
AlloHCT is a curative therapy for both malignant and non-malignant haematological diseases; however, GVHD is a life threatening complication of alloHCT.

Mechanisms
The pathophysiology of acute GVHD occurs in three phases: initiation phase, T cell activation and the effector phase. During the initiation phase, the alloHCT conditioning regimen damages patients' tissues and causes release of inflammatory cytokines that lead to activation of host antigen presenting cells. During the T cell activation phase, donor T cells respond to HLA differences on a recipient's tissue. Finally, during the effector phase, activated alloreactive donor CD8+ T cells kill target tissues via apoptosis. Apoptosis is most prominent in the stem cell niches of acute GVHD target tissues: keratinocytes in the skin, intestinal stem cells and associated basal Paneth cells, and neuroendocrine cells in GI crypt.