Barnes and Loutit (1957) first identified in mice a condition we now know as GVHD and separated this secondary radiation disease from primary radiation disease and termed it secondary disease. It was noticed that the mice receiving allogeneic spleen cells post-irradiation developed a lethal secondary disease on the skin and diarrhea and died within a week. This syndrome was developed because of the transplanted cells into the immunologically deficient recipient. Certain similarities are being drawn from this condition in humans known as human GVHD with observations from animal studies.

Occasionally autologous GVHD can develop in the USA following autologous or syngeneic HCT with incidences being about 7 to 10%. This phenomenon is thought to be due to tissue injury resulting from high-dose cytotoxic chemotherapy or secondary cytokine-mediated release of previously shielded self-antigens that the immune system recognizes after transplantation. Rarely present are mild and self-limiting changes that manifest on the skin as GVHD and intermittent liver and gastrointestinal disorders. Similar symptoms may also appear in autologous recipients following the treatment with cyclosporine and interleukin-2 and its removal.

T-GVHD generally manifests 4 to 30 days after transfusion and has similar clinical features to hyperacute GVHD that occurs after allogeneic HCT. This is a frequent and often fatal complication associated with the condition namely marrow aplasia. Irradiation of blood products with more than 2500 cGy can help to reduce the risk of transfusion-associated GVHD especially in high risk patients. Marrow aplasia is estimated to occur in 1 of 500 open-heart operations among immunocompetent individuals in Japan where genetically homogeneous populations frequently share common haplotypes.

The overall frequency of acute GVHD in patients receiving marrow from HLA-identical siblings ranges from 19% to 66% and depends on factors such as the age of the recipient, the sex-matching of the donor, and the parity of the donor.

Chronic GVHD occurs in about 33% of HLA identical sibling transplants, 49% in HLA identical sibling transplants, and up to 64% of matched unrelated donor transplants. The incidence can be as high as 80% in 1-antigen HLA-UUD T-cell-mediated immunological graft rejection.

Histocompatibility genes determine cell recognition of “self” antigens that are controlled by major histocompatibility complex (MHC) genes that encode MHC proteins which are also referred to as human leukocyte antigens (HLA). Class I MHC proteins, are ubiquitous on nucleate cells whereas class II are limited to the antigen presenting cells. This is the case during transplantation where the donor tissue; the tissue is usually obtained from a genetically different individual is an allograft that has MHC proteins which are alien to that of the recipient thereby causing the recipient’s immune system to react.

CD8+ is the cytotoxic T cell that recognizes the tissues of the recipient as foreign, which results in a type IV hypersensitivity reaction to the tissues and causes severe damage to the body’s organs. The pathogenesis of graft-versus-host disease (GVHD) unfolds through three phases:

Afferent Phase: In a case where BM is transplanted, radiation or chemotherapy results in tissue injury in the recipient. This leads to the expression of various proinflammatory cytokines such as IL-1, IL-6, and TNF-alpha also acutely upregulates MHC antigen on the donors cells and makes their APCs more efficient in presenting the alloantigens to the T cells.

Efferent Phase: This includes graft donor cells contact recipient APCs to proliferate and differentiate into activated T cells. The activated T cells also release additional inflammatory cytokines (IL-2 and IFN-gamma) which further boosts immune system function.

Effector Phase: Has been defined as the accumulation of inflammatory T-cells and natural killer cells in target organs with resultant tissue damage of such organs that may culminate in multi-organ dysfunction.

GVHD occurs in different situations such as allogenic bone marrow transplantation, transplantation of lymphoid rich organs and transfusion of non-irradiated blood. The immunologically competent cells are then transplanted to immunodeficient recipient to recognize the host alloantigens. The occurrence and severity of GVHD are dictated by donor/ host factors and stem cell factors, immune modulation, and chemotherapy/ radiation. Donor transplants, HLA disparities, and gender mismatches are associated with increased incidence of acute kidney injury. Additional protocols such as storing the marrow before infusing and using the umbilical cord blood decrease the probability of GVHD. Triple therapy also effectively reduces the risk of GVHD compared to dual therapy.

The mortality rates of moderately to severely affected patients are significantly higher than patients with mild GVHD. With regards to grades of GVHD, grade C had a 5-year survival rate of 25% which is much higher compared to grade 4 which has a 5-year survival rate of 5%. The response to initial therapy has a huge predicting value regarding the overall survival.

Most important adverse risk factors for acute and chronic GVHD are skin involvement of more than 50%, diarrhea, thrombocytopenia, and elevated liver function markers, and lung and liver failure, respectively.

Age Group

Pediatric Patients: Symptom onset is usually acute and may include a skin rash, diarrhea, and liver dysfunction. They may also manifest growth delay and delayed development due to chronic GVHD.

Adult Patients: Signs and symptoms vary from person to person and may involve skin changes, symptoms of the gastrointestinal tract (such as diarrhoea), and changes in the liver. The skin is one of the body organs that may be affected by chronic GVHD with long-term complications.

Skin: Examine for a red rash, blisters, thickened areas of skin, and pigment alterations.

Gastrointestinal: Examine oral mucus for ulceration and assess for abdominal tenderness and hepatosplenomegaly; ask patient if he or she is experiencing diarrhea.

Liver: Check for the presence of jaundice and feel for liver enlargement and tenderness.

Eyes: Examine the dryness, redness, and for the signs of conjunctivitis.

Respiratory: Assess for presence of abnormal breath sound and administer for dyspnea.

Musculoskeletal: Perform an examination of the joints to determine arthritis and stiffness and muscle strength.

Underlying Hematologic Disorder: Hematopoietic cell transplantation recipients due to cancer such as leukemia or lymphoma may be predisposed to the occurrence of GVHD due to the low immune defenses.

Previous Chemotherapy or Radiation Therapy: These treatments can cause allograft tissue damage and increase cytokine production, thereby increasing the risk of GVHD after treatment.

Infection History: Individuals with repeated infections, especially viral infections such as CMV, may be predisposed to develop GVHD because the immune system is out of adapt.

Acute GVHD: Presents usually within the first 100 days after transplantation. Its symptoms begin to appear faster and they can include skin rash, diarrhea, severe abdominal pain, and liver abnormality. The condition can sometimes prove fatal where the brain becomes impacted with toxins and the other organs fail.

Chronic GVHD: Appears after as late as 100 days following transplantation and may last for 1 to 3 years. Symptoms may be gradual and affect several organs like skin (sclerosis, rashes), the mouth (oral mucosal changes) eyes (dryness, alteration in vision acuity) and respiratory tract (shortness of breath) and joints (stiffness).

Acute GVHD

Primary Prophylaxis:

Cyclosporine + Methotrexate (MTX): Six-month cyclosporine with short duration of MTX has been the primary choice. Avoid hypoperfused and hyperperfused states by maintaining cyclosporine levels above 200 ng/mL.

Tacrolimus: Preferred in unrelated-donor transplants because this drug suppresses GVHD better than it is cyclosporine.

Additional Agents:

Prednisone: The prophylactic regimen by adding to this but decreases incidence of GVHD without affecting the overall survival rates.

Antithymocyte Globulin (ATG): Reduces the risks of developing severe acute and chronic GVHD, but may contribute to the risk for an infection.

Extracorporeal Photopheresis (ECP): Combined with pentostatin in treatment of patients who underwent total body irradiation as a versatile regimen.

Primary Therapy for Acute GVHD:

Mild GVHD (Stage I or II): Topical or systemic corticosteroids (systemic steroids) (e.g., triamcinolone 0. 1%).

Moderate to Severe GVHD (Grade II-IV): Repeat original immunosuppressive prophylaxis (cyclosporine or tacrolimus) plus methylprednisolone (initial dose 2 mg/kg/day in divided dosing). The turnaround time for median of patients is 30 to 42 days.

Novel Therapies: Among patients with steroid resistant, relapsed or refractory graft versus host disease, mesenchymal cells added to conventional steroid therapy have shown response rates of 90% but 10% of the patients require second line agent.

Secondary Therapy for Acute GVHD (Steroid-Refractory):

Ruxolitinib (Jakafi): It has been approved by FDA for treatment of steroid refractory acute GVHD in adult patients aged above 12 years of age. Overall the show has a 59% response rate.

Chronic GVHD

Early Treatment:

Initial Therapy:

Prednisone: Research on the topics of this article has shown that it is an effective intervention for reducing treatment-related mortality.

Prednisone and Cyclosporine: Recommended for high-risk patients with platelet counts ≤ 100,000/mm3.

Transplantation

Dietary Modifications:

Nutritional Counseling: Educating on food choices that enhance the immune system and avoid foods that cause inflammation, increasing antioxidant intake, and consuming enough water.

Avoidance of Irritants: Avoiding foods that might irritate the bowel and therefore advising against spicy foods and drinks such as alcohol and caffeine.

Skin Care:

Gentle Skincare Regimens: Focusing on the need to usegentle, unscented products to manage skin that has been affected by GVHD-associated dermatitis.

Moisturization: Educating a patient to apply moisturizers frequently in order to avoid skin dryness and promote skin health.

Physical Therapy:

Range of Motion Exercises: Increasing the range of motion in joints and avoiding contractures that can develop due to sclerotic changes occurring in chronic GVHD.

Strength Training: Preventing muscle deterioration caused by a long illness is one of the reasons for developing muscle strength and endurance.

Psychosocial Support:

Counseling and Support Groups: Providing encouragement and management techniques for patients and families struggling with chronic GVHD challenges.

Mindfulness and Stress Reduction: Teaching the students more on stress reducing practice such as meditation and yoga in order to enhance the overall health of the mind.

Phototherapy:

Ultraviolet Light Therapy (UVB): Using different aspects of phototherapy in treating skin manifestations of chronic GVHD include sclerotic alterations and cutaneous inflammation.

Transplantation

Corticosteroids are the most effective GVHD drugs with multiple metabolic mechanisms and effects and significantly impact immunity. Glucocorticoid-induced adverse effects and their therapeutic range demanding careful risk-benefit evaluation of treatment options.

The aim is to use the lowest effective dosage of corticosteroids to avoid very high doses and to reduce the amount as much as possible. Patients undergoing allogeneic stem-cell transplantation typically receive adaptive medicine therapy in the form of CSP or tacrolimus in combination with MTX and/ or prednisone to prevent GVHD.

Acute GVHD: Administered IV methylprednisolone for 5 or 14 days and thereafter followed by a slow tapering with oral agents such as prednisone within several to several months.

Chronic GVHD: Oral prednisone, or combined with CSP, and a similar tapering schedule over 6 to 9 months if response is positive.

Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol): An analog of the naturally occuring glucocorticoids that possess potent anti-inflammatory activity but are less likely than prednisolone to be retained in the body with the concomittant water and sodium retention.

Prednisone (Rayos): They steroidal anti-inflammatory agent it also inhibits polymorphonuclear leukocyte migration and reverses increased capillary permeability.

Cyclosporine (Sandimmune, Neoral, Gengraf): A naturally occurring cyclic polypeptide that acts as down-regulators of cell-mediated immune response. All dosages are calculated based on ideal body weights. Note: The kidney disease drug Sandimmune is not bioequivalent with the kidney disease drug Neoral.

Sirolimus (Rapamune): Attenuates IFN-γ-induced mTOR signaling by competing with immunophilin FKBP for binding with the drug. Approved in renal transplantation for use in the prevention of rejection of transplanted liver in children and adults and for the treatment and prevention of acute GvHD as an adjunct to tacrolimus and MTX.

Tacrolimus (Prograf, Astagraf XL, Envarsus XR): A simultaneously immunosuppressive and anti-inflammatory macrolide with quadruple effect of prolonging the lives of hosts and xenotransplants. Empirically in low doses and with corticosteroids given simultaneously or soon after.

Mycophenolate Mofetil (CellCept, Myfortic): A lipid soluable ester of mycophenolic acid which blocks macrophage proliferation.It inhibits the synthesis of purine nucleotides and the proliferation of lymphocytes and therefore prolongs the survival of allogeneic grafts in experimental animal models.

Azathioprine (Imuran, Azasan): Another 6-MP analogue is an active metabolite of 6-thioguanine that has a stronger suppressing effect on cell-mediated hypersensitivity and cellular cytotoxicity in comparison with antibodies. In other words it is believed to act slowly and its half-life depends on the dormant effect.

Transplantation

The pharmacological mechanism of thalidomide is to inhibit inflammations excessive TNF-alpha and the formation of tumor necrosis factors as well as diminish the expression of molecules of adhesion the case of leukocytes.

Thalidomide: The immunologic effects can be significantly modified depending on the condition but can largely be attributed to anti-inflammatory properties that are due to the inhibition of excessive levels of TNF-alpha production and the regulation of specific cell surface adhesion molecules involved in leukocyte migration.

Transplantation

Methoxsalen and PUVA can be considered for the treatment of cutaneous lesions of GVHD and may result in improved survival of patients with steroid resistant GVHD.

Methoxsalen: Natural occurring photoactive substance which acts as photosensitizing agent. UVA remains potentially damaging when it is taken orally and causes cell injury on subsequent exposure to the skin via the whole-blood circulation. UVA can also penetrate more deeply in the skin causing an inflammatory reaction in the skin which manifests itself as erythema at 48 to 72 hours after exposure. It has been found that its mechanism of action is related to formation of covalent bonds with DNA upon photoactivation that result in DNA adduct formation including single and double strand adducts.

Transplantation

Specialty wise: Transplantation

These medications target cell growth and helps in the prevention of cell proliferation.

Methotrexate (Trexall): An antimetabolite used in the treatment of some neoplastic diseases and in the treatment of severe recalcitrant psoriasis and adult rheumatoid arthritis. It inhibits the chemical processes of DNA synthesis and repair and cellular replication in cycles in actively dividing tissues. Given over the short period for acute GVHD after allograft in combination with CSP or tacrolimus. Novel agents for antineoplastic therapy include those constructed from fusion proteins that bind to specific cells and carry toxin or chemotherapy drugs that are extremely cytotoxic and lethal to cells.

Pentostatin (Nipent): It inactivates adenosine deaminase; this causes the rise of deoxyadenosine and deoxyadenosine 5’-triphosphate levels that next to inhibit DNA or RNA synthesis and also leads to cell death.

Ruxolitinib (Jakafi): It is a kinase inhibitor that targets Janus Associated kinases (JAKS), JAK1, and JAK2. It inhibits JAK-STAT pathways which mediates the process of immunity studying and development, growth and activation of leucocytes. Used for the treatment of steroid refractory acute GVHD and as a therapy for patients older than 12 years of age who have chronic GVHD after failure of one to two lines of systemic treatment.

Belumosudil (Rezurock): It is approved for clinical research. This impacts inflammation and fibrosis control. Used for alternative treatment of treatment of chronic GVHD patients aged 12 years and above who have relapsed or are refractory to at least 2 consecutive systemic therapies.

Transplantation

Ibrutinib is the first FDA-approved medication for the treatment of cGVHD.

Ibrutinib: Ibrutinib is a BTK inhibitor that acts to suppress BTK-dependent BTK enzymatic activity. This inhibition reduces the transmission of signals to B-cell surface receptors that are involved in the controls of B-cell trafficking, chemotaxis, and adhesion. It is indicated for the treatment of chronic GVHD in adult patients who have not responded sufficiently to one or more prior systemic therapies.

Transplantation

These agents are monoclonal antibodies that bind to certain antigens found either on normal or malignant cells. They can also be used to target specific molecules that would be inactive. Monoclonal antibodies developed for specific targets implicated in the genesis and development of GVHD such as alemtuzumab, infliximab and other investigational agents have been introduced relatively recently.

Infliximab (Remicade, Inflectra, Renflexis): A monoclonal antibody of the IgG1k class that counteracts the activity of the cytokine TNF-α by preventing its attachment to TNF-α receptors. This works in reducing the number of infiltrating inflammatory cells and the level of produced TNF-α in an inflamed area.

Rituximab (Rituxan): A monoclonal antibody produced by the fusion of mouse cells to human cells and directed against the CD20 antigen on the surface of normal and malignant B lymphocytes. IgG1 kappa monoclonal antibody fragment of the antibody to human tumor necrosis factor with human constant regions and murine unique regions.

Alemtuzumab (Campath, Lemtrada): A humanized monoclonal antibody targeting CD52 that is expressed on B cells, T cells, and almost all CLL cells. It is an antibody that attaches to the CD52 receptor proteins on lymphocytes restricting their growth rate.

Transplantation

Antithymocyte globulin is an immunosuppressive agent containing immunoglobulins that exert cell-mediated immunity largely and the humoral immunity to a lesser degree.

IVIG (human) is a sterile intravenous preparation consisting of a highly purified mixture of immunoglobulin G, polyvalent antibodies that are derived from plasma of many donors.

Antithymocyte globulin-equine (Atgam): Immunosuppressive agent containing Ig. Immunosuppressive properties that are equal to other ALSAs. They are the qualitative and the quantitative differences in the degree of some of the effects that may occur, among other factors from the source of the antigenic material, the animal used in the preparation of the antiserum or the way of manufacturing.

Human,Intravenous Immune Globulin: A concentrated completely monospecific substance that consists of polyvalent antibodies that can be detected in the population donor’s blood plasma in an isoimmune response. It needs to be given through another infusion line; it should not be mixed with other medications or solution.

Management of GVHD mainly involves the use of pharmacological agents and various procedures to alleviate symptoms and improve the prognosis of affected patients. undefined

Extracorporeal Photopheresis (ECP): ECP is a procedure that comprises obtaining the patient’s blood, treating it with a photosensitizer, light irradiation with ultraviolet A (UVA) light and then reinfusing the blood back to the patient. This procedure helps control the immune response and is most useful in managing chronic GVHD.

Methoxsalen (Oxsoralen Ultra): Methoxsalen is a photoactive agent that has been used in ECP; after being exposed to the UVA radiation, it brings about cell damage as well as modulation of immune responses.

Endoscopic Procedures: Colonoscopy and upper GI endoscopy are some of the endoscopic techniques employed in the diagnosis and management of GVHD that affects the gastrointestinal tract. These procedures allow pathological examination of biopsies taken from affected mucosa to determine the extent of involvement.

Topical Steroids: In endoscopic procedures, local application of steroids solutions to the inflamed lesions can be effective in controlling inflammation in the GI tract.

Total Skin Electron Beam Therapy (TSEBT): TSEBT is one of the types of radiotherapy that involve the administration of electron radiation to the outer skin area of a patient. It used in cases of cutaneous GVHD which has failed to respond to other treatments.

Topical Corticosteroids: Used after TSEBT to treat this skin condition and encourage the skin to begin healing. HSCT is a curative treatment modality for many diseases and is highly effective in terms of over all survival and outcome. There is a possibility that allogeneic HSCT contributes to the development of GVHD, and, at the same time, the only means of treating severe cases of GVHD. It mostly consist in the adoption of stem cells from a matched donor for the reestablishment of blood formation and immune activity.

Prophylactic Immunosuppressants: Antimetrophyte agents such as cyclosporine, tacrolimus, and methotrexate are administrated pre- and post-HSCT to prevent GVHD.

High-Dose Corticosteroids: Orally administered to manage acute GVHD after transplantation

Transplantation

The pre-transplant phase includes risk assessment, conditioning regimen, donor selection, and post-transplant phase care. Examples of preventive measures are calcineurin inhibitors, methotrexate, mycophenolate mofetil and anti-thymocyte globulin as well.

Pharmacotherapy can be utilized post-transplantation using medications while monitoring and supportive care can be provided after the transplant has been performed. Acute GVHD is assessed clinically with histopathological features and treated from corticosteroids to second-line agents.

It is distinguished from other related diseases and managed using immunosuppressive drugs. Follow-up care is defined as the strategies of monitoring, restoration, and support after treatment delivery. Surveillance requires constant observation for late onset or recurrent GVHD, or for complications or physical, psychological or social consequences.

Rehabilitation services and supportive care programs include physical problems, psychological and social outcomes. Survivorship focuses on wellness, prevention, and health management for a diverse range of medical issues such as immunization, cancer prevention, detection, and prevention, and lifestyle changes.

For prevention and management if GVHD, research and innovation are critical. It can be stated that managing clinical trials and translational research can improve the patient’s conditions with reduced toxicity effects. Approaches to modulate supportive care could reduce the impact of GVHD and its predisposing conditions on patients’ well-being.