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Signs, Symptoms, Prevention and Treatment of Graft Versus Host Disease
Kristy Shuffett
NURS 4003-WEB Nursing Research
Lindsey Wilson College
10/30/2018
Abstract
This literature review paper encompasses research regarding graft versus host disease (GVHD). Studies that relate to graft versus host disease in patients have been included. Analysis throughout these research articles, signs and symptoms, prevention, diagnosis, treatment, and how to live with graft versus host disease will be explored. In order to help patients to achieve a quality of life with graft versus host disease, nurses need to know what interventions to implement and how to perform these actions. The studies contained in this analysis have limitations related to health care that will be included in this literature review.
Keywords: Graft Versus Host Disease, Solid Organ Transplant, Organs, Symptoms, Treatment, Quality of Life, Chronic, Acute, Transplant, and Graft.
Signs, Symptoms, Prevention and Treatment of Graft Versus Host Disease
Graft versus host disease (GVHD) is a rare complication of organ transplant that is associated with high mortality rate related to late diagnosis (Auerbach & Schott, 2016, p. e7). “Graft versus host disease occurs in approximately 40% – 60% of all allotransplanted recipients and results of death in up to 20% of these recipients” (Villa, Rahman, McFadden, & Cogle, 2016, p. 3). GVHD has similar signs and symptoms as that of infection, which causes the delay in diagnosis of GVHD (Auerbach & Schott, 2016, p. e7). According to Baker & McKierman (2011), GVHD has two phases acute and chronic, which have incidence of 30% – 60%, and mortality rate of 50% (p. 429). It is crucial for nurses to know about graft versus host disease with transplant patients and to be aware of how to address it. It’s very likely that any nurse will encounter a transplant recipient who is at risk for this disease or has already contracted it. The purpose of this paper is to bring awareness, educate readers about graft versus host disease in solid organ transplant recipients, and to recognize the early signs and symptoms to help the patient to achieve a higher quality of life with this disease. Pathophysiology, characteristics, symptoms of graft versus host disease, and treatment opinions will be discussed within this paper.

Literature Search
For this research paper information was gathered from EBSCO host database found under Nursing and Health Sciences category. A key term that was used to find articles was graft versus host diseases which consisted of 37,083 results. To get results narrowed down the key terms used were “pediatric,” “small bowel,” and “solid organ transplant,” which narrowed the articles to 13,997. Articles that consisted of graft versus host disease in animals were excluded because the focus is exclusively on graft versus host disease in humans. Articles that had very little information were also excluded because the accuracy of the results would not be precise. To fully narrow down and improve the quality of information of GVHD, the articles were in full text, scholarly peer reviewed, and written in the last ten years. An assortment of articles was selected to inform and educate readers about graft versus host disease.

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Pathophysiology of Graft Versus Host Disease
The cause of graft versus host disease occurs after transplant of a solid organ or organs. According to Sanfang et al. (2016), graft versus host disease occurs when allo-reactive donor T lymphocytes are activated by major histocompatibility antigens or minor histocompatibility antigens on host antigen-presenting cells (APCs), with the eventual attack of recipient tissues or organs. Activation of APCs is important for the priming of GVHD and is mediated by innate immune signaling pathways (Sanfang et al., 2016). Current evidence indicates that intestinal microbes and innate pattern-recognition receptors on host APCs, including both Toll-like receptors and nucleotide oligomerization domain like receptors, are involved in the pathogenesis of GVHD (Sanfang et al., 2016, p. 1).

The authors Sanfang et al. explain how GVHD is identified, whereas researchers Green ; Hind support the criteria that was developed by Billingham of GVHD. Green ; Hind’s (2016) article states that Billingham developed the criteria of GVHD in 1966, which explains that the graft must contain immunologically competent cells, the host must express antigens that are not present in the donor, and the patient must be unable to mount a response to clear the transplanted cells (Green & Hind, 2016). GVHD represents an exaggerated response by the host and donor immune systems that have positive underlying disease, previous infection, and conditioning regimens related to damage of the intestine (Green & Hind, 2016). The donor tissue is then exposed to a foreign environment (Green & Hind, 2016). These two processes together create what is called a “cytokine storm” of pro?inflammatory which causes the APCs to increase (Green & Hind, 2016, p. 608).

Characteristics of Acute and Chronic Graft Versus Host Disease
Patients that have GVHD may encounter acute or chronic symptoms. A study Rahidi (2016) introduces a mathematical mode “to provide further insight into the pathogenesis of SOT?aGVHD and the best therapeutic approach given the rarity of SOT-aGVHD, prospective clinical trials are unfeasible” (Rashidi, 2016, p. 1173). The article describes acute graft versus host disease (aGVHD) as donor T cells attacking host tissues (Rashidi, 2016). The mathematical models show that “The rarity of solid organ transplants acute graft versus host disease (SOT?aGVHD) is often attributed to the fact that as opposed to hematopoietic stem cell transplantation (HSCT) recipients, SOT recipients are less immunosuppressed and more capable of mounting an immune response eradicating donor T cells” (Rashidi, 2016). Up to five percent of small bowel transplants and one percent of liver transplant are more likely to experience GVHD, more than other solid organ transplants, probably due to the fact there are a larger number of donor T cells that are transferred with the transplant (Rashidi, 2016). After transplantation, acute GVHD will typically occur within 2-8 weeks.
Chronic graft versus host disease (cGVHD) is defined as occurring 100 days after the transplanted organ, in the article by Wiener et al. (2014). This late complication of transplantation is the leading cause of morbidity and mortality in children undergoing transplantation and carries a 59 % survival rate at 5 years after cGVHD diagnosis (Wiener et al., 2014). Chronic GVHD develops in 20–60 % of transplant recipients. (Wiener et al., 2016, p. 296). This study also mentions that “the waxing and waning nature of cGVHD and the diversity of its clinical manifestations make management and assessment of this disease very complicated” (Wiener et al., 2014, p. 296). This study used qualitative methods and was aimed to elicit descriptions of cGVHD symptoms. Experiences directly from children ages five through seventeen described their symptoms and comprehension of symptoms concepts across the development spectrum (Wiener et al., 2014, p. 295).

Symptoms of Graft Versus Host Disease
Graft versus host disease has many symptoms that are difficult to diagnose. Issues can be seen on the outside of the body and spread through the internal organs causing disruption of homeostasis and cell death. According to Green & Hind’s study (2016), they use qualitative and quantitative methods by searching “PubMed for English-language full test manuscripts between 1990 and 2015 for eligible studies. A total of 28 publications were found pertaining to pediatric GVHD following solid organ transplantation” (Green ; Hind’s, 2016, p. 607). This study has discovered that maculopapular rash found in 87% of patients can progress by spreading over the entire body (Green & Hind’s, 2016). As the severity of the rash increases it can blister and desquamate (Green ; Hind’s, 2016). In 43% of the effect cases the GI tract was affected with combinations of vomiting, anorexia, diarrhea, and abdominal pain (Green & Hind’s, 2016). GVHD had less effect on patients that had retained their native liver (Green ; Hind’s, 2016). “Fever was reported in 11% of patients, all of which were liver transplantation recipients. Other affected organs include the lungs (7%), the ocular mucosae (4%), and the kidneys (1%)” (Green & Hind, 2016, p. 609).

Treatment
Graft versus host disease is problematic to treat because it is a major transplantation complication. Studies, trials and medication have been tested but still have not been successful in finding the right remedy to completely eradicate the disease. According to Villa, Rahman, McFadden & Cogle (2016), the Food and Drug Administration has not approved any kind of treatment for GVHD. Prednisone, which is a corticosteroid, is the first line of treatment when it comes to GVHD regardless if it is acute or chronic (McFadden & Cogle 2016). The use of corticosteroids helps in suppressing the immune response, therefore reducing inflammation (McFadden & Cogle 2016). One of the challenges that is associated with the use of steroids is that it limits patient’s response. Individual patients that are resistant to steroids will have to find an alternative treatment (McFadden ; Cogle 2016). Toxicity is a possible risk, and the long-term use of steroids brings the survival rate to 5-30 % (McFadden ; Cogle ,2016, p. 10). According to Green ; Hind (2016), a first line treatment that can be used is adding or reducing immunosuppression medications given to the patients. Adding immunosuppression further leads to the suppression and alleviation of graft versus host disease, whereas reducing the immunosuppression will allow the host immune system to destroy the graft of the organ transplanted (Green ; Hind, 2016, p. 614-615).

Other studies have also found a treatment that could be suitable for graft versus host disease. An article by Baker ; Mckierman (2011), presents Extracorporeal Photopheresis (ECP) and states that:
ECP has emerged as a suitable, well-tolerated treatment adjunct that has an immunomodulatory benefit without an immunosuppressive effect. Unlike corticosteroids, ECP lacks cumulative toxicity. Studies indicated that ECP allows for accelerated tapering of corticosteroids, thus decreasing the effects seen with prolonged steroid use (p. 430).

Within this study 71 patients with chronic GVHD were treated with ECP (Baker ; Mckierman, 2011). 61% patients responded to ECP, with 20% showing a complete response (Baker ; Mckierman, 2011). “The highest responses to ECP with chronic GVHD involving the skin (59%), liver (71%), oral mucosa (77%), and eye (67%)” (Baker ; Mckierman, 2001, p.430). Fifty-four percent of patients with bronchiolitis obliterans responded significantly to treatment (Baker ; Mckierman, 2011). “ECP may be a beneficial steroid-sparing treatment option in patients with steroid- refractory chronic GVHD” (Baker ; Mckierman, 2001, p.430).

Implication to Practice
Obligations related to nursing practice consist of two identifying factors. One being signs and symptoms of graft versus host disease. Two being communicating with specialists that can identify pertinent signs and symptoms mentioned above to properly diagnose the client in a timely manner without prolonging treatment. Nurses should always collaborate with inter-professional team members to maximize quality of care for each individual patient. By implementing team nursing, patients may be assessed in a timely and accurate manner. Nursing management should be focused on educating their clients, and the clients family members on their disease.
The change project I would implement is educating the client and family members. This allows them to better understand the disease process while simultaneously motivating the patient to be involved regarding their plan of health care. The nurse should always consider the voice of each patient and let that voice be heard in making important decisions based on their plan of care. Education is important because once signs and symptoms are known it will allow the patient to recognize the onset of disease and early treatment can be implemented. Nurses should also teach importance of adherence to medication regimens and for the nurse to follow up with patient to re-ensure the effectiveness of treatment and instruction. Nurses should also include educational classes on the disease of graft versus host for the staff and facility. With this educational implantation, both parties would benefit. Educational classes could consist of looking at new studies, treatments, interventions, and being involved with patients that are positive for GVHD. Educational classes should be built of off evidence-based sources such as specialists in GVHD. Classes should be influenced by interventions in provision of patient centered care. If education of individuals with GVHD is implemented effectively by the nursing staff, the disease can be recognized in early stages and can be treated to ensure that the client may have a higher quality of life.
Limitations
There are multiple limiting factors regarding graft versus host disease. Each individual patient is affected differently, therefore making it difficult to summarize the effects of GVHD. Interventions and methods of treatment for individual patients will have to be investigated to find the right treatment for that individual. A one-on-one ratio is difficult to achieve due to the inadequacy of funds which causes a gap in practice. Shortage of employees, money, and time in the health care field play a significant role in limitations for the disease that comes with transplant. Lack of funding also affects GVHD education provided to health care professionals.
Gaps in knowledge of graft versus host disease has been seen in the various studies in regards of recognizing signs and symptom and early treatment for patients that are positive for GVHD. Numerous studies contained limited participants and trials which could skew the results. Continuing research should be implemented, and funds need to be raised to create new interventions that will provide special care for patients with GVHD. Even though limitations exist, this research assists in caring for individuals that may encounter GVHD.

Conclusion
Graft versus host disease is rare with a high mortality rate among those who have had a solid organ transplant. This disease is difficult to diagnosis because the symptoms can be mistaken for an infection. GVHD effects multiple systems of the body, and every individual is different; therefore, treatment varies with each individual. The Food and Drug Administration has not approved a protocol treatment for GVHD, however the use of steroids is the first line of treatment. Another treatment option that is used consists of adding or subtracting the immunosuppression medication during the flare up of the disease to help stabilize the patient. Studies have also shown one medication called EPC that could be used to help treat GVHD. EPC helps the tapering of steroids, which helps to eliminate the long-term side effects of steroids. Rapid recognition and treatment are key to improving patient survival. It is crucial that nurses are educated on signs and symptoms of GVHD so that the patients can be diagnosed earlier, and treatment can begin as soon as possible. To help patients achieve a higher quality of life with this disease we need to provide more adequate education and awareness about GVHD.

References
Auerbach, J. S., ; Schott, C. K. (2016). Solid-organ graft-versus- host disease after liver transplant: A case report. Critical Care Nurse, 36(3), e7–e11.
Baker, M., ; McKiernan, P. (2011). Management of chronic graft-versus-host disease. Clinical Journal of Oncology Nursing, 15(4), 429–432. https://doi.org/10.1188/11.CJON.429-432
Green, T., ; Hind, J. (2016). Graft-versus-host disease in paediatric solid organ transplantation: A review of the literature. Pediatric Transplantation, 20(5), 607–618.
Rashidi, A. (2016). A mathematical model provides new insights into solid organ transplant-associated acute graft-versus-host disease. Clinical Transplantation, 30(9), 1173–1177.
Sanfang Tu, Danli Zhong, Weixin Xie, Wenfa Huang, Yangyang Jiang, ; Yuhua Li. (2016). Role of toll-like receptor signaling in the pathogenesis of graft-versus-host diseases. International Journal of Molecular Sciences, 17(8), 1–12. https://doi.org/10.3390/ijms17081288
Wiener, L., Baird, K., Crum, C., Powers, K., Carpenter, P., Baker, K., … Jacobsohn, D. (2014). Child and parent perspectives of the chronic graft-versus-host disease (cGVHD) symptom experience: A concept elicitation study. Supportive Care in Cancer, 22(2), 295–305.
Villa, N. Y., Rahman, M. M., McFadden, G., ; Cogle, C. R. (2016). Therapeutics for graft-versus-host disease: From Conventional Therapies to Novel Virotherapeutic Strategies. Viruses (1999-4915), 8(3), 1–30. https://doi.org/10.3390/v8030085

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