Graft-versus-host disease L99.1/L99.2

Complex immunological reaction involving various organs, which can occur mainly as a result of allogeneic hematopoietic stem cell transplantation (HSCT). The occurrence of GvHD after transfusions of blood products, organ transplantation (liver, kidney) and after autologous HSCT is rare but has been described.

In the graft-versus-host reaction (GvHR), the donor T lymphocytes contained in the transplant react primarily to the recipient organism. The most common symptoms of GvHR are seen in the skin (epithelial cells), liver, intestine and eye, with the skin being the most commonly affected organ.

Graft-versus-host (GvH)-like reactions (see pseudoscleroderma below) have also been described (rarely) as adverse reactions to various drugs, including phenobarbital, D-penicillamine, gold preparations, hepatitis B vaccines, captopril, spironolactone and allopurinol.

From a clinical point of view (NIH consensus conference 2005), GvH reactions are divided according to their onset into:

• Acute graft-versus-host disease (aGvHD/L99.1-) (onset of disease within the first 100 days after transplantation)
  • Classic acute graft-versus-host disease (aGvHD)
  • Persistent acute graft-versus-host disease (onset 100 days after transplantation)
  • Recurrent acute graft-versus-host disease (onset 100 days after transplantation)
  • Delayed onset of acute graft-versus-host disease
• Chronic graft versus host disease (cGvHD/L99.2-) (onset >100 days after transplantation)
  • Classic chronic graft versus host disease (>100 days after transplantation)
  • Classic chronic graft versus host disease - overlap syndrome (>100 days after transplantation; signs of acute and chronic graft-versus-host disease)

The incidence of unrelated donors is expected to be 4-60%. With HLA incompatibility the risk of GvHD increases to 70-80%.

The number and type of foreign HLA molecules play a role in the development of GvHD. Where possible, blood stem cells are transplanted from HLA-identical donors. However, this does not prevent GvHD.

Three phases are assumed in the development of aGvHD (Ziemer M et al. 2020; Ferrara Jl et al. 2009):

• the activation of antigen-presenting cells of the recipient
• the activation of donor T cells
• the effector phase

The tissue damage induced by the previous conditioning and the resulting release of proinflammatory cytokines with the activation of antigen-presenting cells of the recipient play an important etiological role in triggering aGvHD. But also the interactions of the immune system with the microbiomes of the gastrointestinal tract and the skin. Antigen-presenting cells are activated by the translocation of bacteria and their endotoxically active lipopolysaccharides, which is made possible by the previous conditioning of the now massively toxically damaged intestinal wall. The activation of receptors of the innate immune response (=pathogen-recognition-receptors - PPR) such as Toll-like receptors (TLR) and Nod-like receptors (NLR) by products of the intestinal flora appears to be a key element of the inflammatory cascade in GvHD. Microbial metabolites such as short-chain fatty acids produced in the colon by anaerobic bacteria and tryptophan products of commensal bacteria (e.g. by lactobacilli) have profound effects on the immune system (Ziemer M et al. 2020). The necessary early use of antibiotics plays a major role in the colonization of the intestine by pathogenic bacterial species. The consequence of this intestinal dysbacteriosis is an inflammatory environment with activation of donor cells, cytotoxic T cells and natural killer cells. The main consequence is damage to epithelial cell structures of the skin and intestine.

In > 90% of allogeneic hematopoietic stem cell transplants, the skin is involved in chronic GVHD.

To date, no predictive biomarkers are known that could be used to specifically confirm the diagnosis. The chemokines CXCL9 and CCL17 are being discussed (Chen T et al. 2019).

Alongside infections, GvHD is the most common complication of aHST (allogeneic hematopoietic stem cell transplantation). In the first year after transplantation, only around 30% of patients survive in clinical stage III of aGvHD, and only 10% in clinical stage IV. Chronic GvHD (cGvHD) affects every 2nd patient. It is the most serious long-term complication of aHSCT. The skin is the most frequently affected organ.

1. Chen T et al. (2019) The clinical observation of serum specific biomarkers in patients with chronic graft-versus-host disease. Zhonghua Xue Ye Xue Za Zhi 40: 948-952.

2. Filipovich AH et al. (2005) National Institute of Health consensus development project on criteria for clinical trials in chronic-graft-versus-host-disease. Biol Blood Marrow Transplant 11: 945-956

3. Travnik R et al. (2011) Graft-versus-host-disease (GvHD) - an update. Dermatology 62: 139-155
4. Ziemer M et al. (2020) Skin manifestations of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. Dermatologist 71:557-568.