Elevated transaminase levels can occur around the initiation of liver GVHD, but are not a predominant feature. Usually presents as diarrhea from either the small intestine or colonic involvement. GVHD staging guides treatment steps.
Acute GVHD is a clinical diagnosis. Laboratory studies are not required other than an elevated bilirubin which is necessary to diagnose liver GVHD.
Acute GVHD biomarkers in the plasma may become useful for diagnostic and prognostic purposes in the next few years, but at present they are only used in research settings. However, biopsies of affected organs skin, upper GI tract, lower GI tract, liver can be useful in confirming the clinical impression. Pathological findings, such as vacuolar interface dermatitis with apoptotic keratinocytes for skin GVHD and epithelial cell apoptosis in the intestinal mucosa for GI GVHD, are often seen. Infectious etiologies for diarrhea should be ruled out, such as Clostridium difficile, rotavirus, and adenovirus infections.
Endoscopic evaluation can help identify other causes of GI symptoms such as nausea, vomiting, and diarrhea such as gastritis or Cytomegalovirus CMV colitis.
Acute GVHD is a clinical diagnosis that is typically only suspected in the appropriate clinical scenario, primarily allogeneic BMT, but rare cases of transfusion-associated or maternal transfer of lymphocytes into an immunocompromised neonate can result in acute GVHD.
Imaging studies are generally not helpful in the diagnosis of acute GVHD. Confirmation of ileus by abdominal CT computed tomography scan can be helpful during management. Prevention is the most important strategy to limit acute GVHD. The primary aim of prevention is to deplete T-cells or prevent their proliferation in response to host antigens.
There are numerous methods to achieve this goal, and institutional preference plays a large part in the selection of a GVHD prevention therapy. Briefly, T-cell depletion, either in vitro or in vivo, can be effective in preventing severe GVHD, but are associated with increased risk of relapse, infection, and delayed immune reconstitution. The combination of a calcineurin inhibitor tacrolimus or cyclosporine with either mycophenolate or methotrexate is the most common GVHD prevention therapy.
As an alternative, highly mismatched haploidentical transplants e. This strategy depletes activated, proliferating T cells while largely sparing quiescient donor T cells. This approach can be particularly useful for patients who lack an HLA-match within their family or the unrelated donor registries. There is no reliable way to predict who will develop progressive GVHD, therefore, some clinicians choose to initiate systemic corticosteroid therapy in patients at high risk for developing a more severe GVHD, such as recipients of unrelated donor transplants or when GVHD has developed within 2 weeks of transplant.
There is no convincing data to advise for or against this approach. Complete gut rest for lower GI tract GVHD is usually initiated promptly to minimize the risk of developing ileus or painful abdominal cramping. Reintroduction of a diet as the disease responds to therapy is a stepwise, slow process, starting with small volumes of clear liquids and advancing with the easiest to digest foods first.
The antigen presentation is caused by the upregulation of the MHC and minor histocompatibility antigens mHA. The adhesion molecule expression causes white blood cells to be attracted to and retained in the damaged area and donor T lymphocytes to attack recipient tissues.
In phase two, donor T cells recognize alloantigens on host APCs. These cytokines then support and drive the proliferation of donor T cells responding to the host antigens. The greater the immunologic disparity between the donor and recipient, the greater the T-cell response. T cells also directly attack host tissue. The ongoing tissue damage results in further cytokine production, thus perpetuating the cascade.
The resulting cytokine production is often referred to as a cytokine storm. In aGVHD the preparative regimen causes the release of inflammatory cytokines and increases the expression of MHC antigens within the host. The MHC antigens are involved in the steps leading to T-cell activation. They contain genes that encode tissue antigens used for tissue typing and these genes lie on the short arm of chromosome 6, the HLA.
This is thought to be secondary to minor histocompatibility antigen differences which are expressed on the cell surface as degraded peptides bound to specific HLA molecules.
Theories suggest that cGVHD may be the result of end-stage alloreactivity from T cells,[28] or caused by poor or dysfunctional immunologic recovery, [22] or the result of autoreactive clones normally deleted in the thymus, although if the thymus is damaged the result is formation of autoantibodies similar to those seen in autoimmune disease. The clinical management of patients with GVHD is challenging.
Once the diagnosis of GVHD is confirmed and staged, frequent assessment is necessary to determine the response to therapy and to assist with comfort and healing. Nursing care of the patient is focused on detection of early signs and symptoms, support of patient comfort, and implementation of the medical plan of care, including fluid and electrolyte replacement, antidiarrheal therapy, antibiotic particularly antifungal therapy, immunosuppressive therapy, and nutritional support.
Topical corticosteroid creams may be applied to the skin in patients with minimal skin involvement. In addition, patients with gut involvement may require narcotic analgesia to control pain.
Table 2 provides an extensive nursing care plan for the patient with acute and chronic GVHD. The mainstay of medical management uses medications for prophylaxis and treatment of GVHD see Table 3. New drugs and strategies that can supplement standard treatment are now available or are in clinical trials, including monoclonal antibodies eg, anti-CD3, anti-CD5, and IL-2 antibodies , mycophenolate mofetil alemtuzumab Campath , antithymocyte globulin, tacrolimus, and sirolimus.
In addition, patients may be required to wear face masks in the presence of other people; stay out of crowds; and avoid fresh plants, fruits, and vegetables.
Patients with cGVHD are usually advised to avoid vaccinations with live viruses such as German measles, tetanus, and polio, until the GVHD problem is completely resolved and the use of immunosuppressive drugs ends.
The conference report outlines recommended treatments for symptoms and gives recommendations for patient education, preventive measures, and appropriate follow-up. Also developed were standard criteria for the diagnosis of cGVHD and a proposed new clinical scoring system that describes the extent and severity of cGVHD for each organ or site.
The primary cause of death in patients with GVHD is infection, and thus there must be a high index of suspicion for infection in this patient population.
All patients should receive antimicrobial prophylaxis. Patients with cGVHD should also receive prophylaxis, such as penicillin, against encapsulated organisms including pneumococcus Streptococcus pneumoniae. Patients are maintained for a lifetime on antimicrobials for prophylaxis against pneumococcus. Additionally, patients should receive antibiotic prophylaxis for dental and all other invasive procedures, according to the endocarditis prophylaxis recommendations of the American Heart Association.
Topical antifungal prophylaxis with clotrimazole Mycelex troches or nystatin swish and swallow should be used in all patients receiving topical steroids for oral GVHD. Reactivation of virus is a problem in patients with acute and chronic GVHD,[43] and patients should be monitored for cytomegalovirus.
Many patients have outbreaks of oral and genital herpes and should receive prophylaxis if they are receiving high doses of immunosuppressive agents. GVHD occurs in the majority of stem cell transplant patients, with up to 40 per cent of cases leading to death. GVHD can occur early acute or late chronic post-transplant. Increasing age of the patient, advanced disease stage, donor type, and second or later transplant were associated with increased risk of infectious death in all phases and for all donor types.
Patient sex showed no associations at all. Peripheral blood as stem cell source was associated with less infectious deaths in all post-transplant phases after autologous HSCT; it was associated with more infectious deaths after allogeneic HSCT in the late phase, reflecting the higher probability of chronic GvHD with peripheral blood. Centres with more than 20 years of disease specific transplant experience had significantly less infectious death in the early and intermediate post-transplant phases.
No significant association could be documented between death from infections and JACIE accreditation status, in contrast to the association with overall mortality. The results of this comprehensive study are clear: the European transplant teams have successfully managed to reduce all-cause mortality after autologous HSCT at all post-transplant time phases.
In allogeneic HSCT, they were successful in reducing deaths from GVHD, infections and other causes in the very early and early post-transplant time phases, despite an increase in the patient pre-transplant risk profile. In contrast, data did not show a reduction of death from relapse after allogeneic HSCT, and no reduced mortality in the late post-transplant phase. The latter observation is of concern, but indicates areas for improvements.
The analysis confirmed well established disease, patient, donor, transplant and center-related risk factors for death from all causes and from infection after transplant [ 1 , 2 , 21 ]. Novel is the observation that not all factors are equally relevant during all post-transplant time phases.
Advanced disease stage at time of transplant remains associated with increased risk of mortality from all causes throughout the whole post-transplant phase, and so is increasing age of the recipient, with the exception of the very early phase where other factors dominate. During all post-transplant phases, allogenicity dominates.
As observed earlier, accreditation status of the center is associated with mortality of the patients and with overall improvement over calendar year time [ 22 ]. The same risk factors were associated with death from infections.
Late disease stage was in all post-transplant phases associated with more infectious deaths. Increasing age contributed to risk of death from infection in a hierarchical effect by decade. Of interest, despite an increase in age in cohort 2, deaths from infections were still reduced, reflecting the possible benefit of better management of infectious complications, through novel diagnostic methods, drugs and guidelines [ 9 , 10 , 11 , 23 , 24 , 25 ].
Cord blood as a stem cell source was associated with a higher rate of infectious deaths in the first three post-transplant phases, but no longer after 1 year.
Peripheral blood as a stem cell source was associated with a lower rate of deaths in the first three phases, not in the last. These results might have been influenced by an additional, indirect late GVHD effect of peripheral blood stem cells. Of note, disease specific center experience in years was strongly associated with reduced infectious deaths in the early post-transplant phase [ 22 ]. There are major caveats in this study. It looks at very heterogeneous data over a long time period with many changes in disease indications, choice of donor type, stem cell source.
Data were derived from a multitude of centers from many countries with different micro- and macroeconomic backgrounds. Some data, such as cytogenetic profiles were not in the data set.
Some decisions had to be arbitrary, such as the use of economic factors as of the year Still, the consistency of the findings in the four post-transplant phases, and the confirmation of key risk factor elements are strong arguments that the data are valid.
They were as well in line with our pre-set hypotheses, that factors associated with overall mortality and from infections would differ depending on the post-transplant phase. This was the case, but is of concern. Mortality was reduced early post-transplant, but increased in the late phase after allogeneic HSCT.
Hence, improvements were more rapidly visible than deteriorations; the increase in late mortality years after the transplant might not be recognized to the same extent, with patients frequently at distance from the center. Lethal infections caused by bacteria and fungi were reduced at any time point, but not infections of unknown origin.
The constant pattern in all reporting centers, over calendar year time and over all post-transplant phases indicates that it might be a real entity, but without the same awareness as any specified infection.
There is no information in the data set, whether the appropriate tests were not done, were not successful, or whether organ-related infections, such as pneumonia with negative microbiological work up were simply classified as such [ 15 ]. The focus on specified risk groups will support such strategies.
Late infectious mortality as an entity remains of concern. It presents a complicated issue, probably resulting from the negative effects of many variables such as GVHD, inadequate immune recovery, poor graft function, increasing co-morbidities with increasing age. It might reflect as well the variable expertise of health care providers in the different transplant centers for the long-term follow-up of their patients. What are the consequences of this report? The positive message is that outcomes were and can be improved.
With similar efforts in late post-transplant care, it will be possible to improve outcome beyond 1 year as well. The first step is to become aware of the reality, to shift efforts, and to focus on preventable and reversible late complications.
Older patients, those with a second or later transplant and those with mismatched allogeneic transplants remain at higher risk, even years after transplant. They might require targeted follow-up programs.
Prospective studies assessing causes of death 5 years or more after HSCT could help to characterize and possibly to target efforts to prevent late mortality. Public health bodies and transplant teams need to recognize that fatal events can occur many months or years after the transplant procedure. Early detection and rapid treatment, particularly of infections, requires allocation of resources.
Support includes data collection and data analysis which are integral parts of any transplant therapy [ 26 ]. Given the long time horizons, this will require support in planning and resources by public health bodies [ 27 , 28 , 29 ].
Furthermore, in the era of precision medicine and targeted therapies, HSCT has to provide best outcome regarding overall survival, quality of life and costs compared to any other treatment strategy [ 16 ].
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