Nonlethal,attenuated, transfusion‐associated graft‐versus‐host disease in an immunocompromised child: case report and review of the literature

BACKGROUND: Transfusion‐associated graft‐versus‐host disease (TA‐GVHD) is a rare complication of transfusion of nonirradiated blood components. It usually affects children in high‐risk groups, including those who have primary immunodeficiencies (PIDs). It usually presents with skin, hepatic, digestive, and hematologic involvement and is normally fatal. CASE REPORT: We report the case of a nonlethal, attenuated, TA‐GVHD in a 7‐month‐old boy. The disease was marked by the presence of a severe rash but lacked all the other usual manifestations. We speculate that the unusually benign course of this disease, which has normally a fulminant course, was due to the fact that this child was under high‐dose corticotherapy at the time of the engraftment. This fortunate coincidence led to the survival of this child and allowed the diagnosis of a combined immunodeficiency. CONCLUSION: A high index of suspicion is required for the diagnosis and proper management of PID. The administration of nonirradiated blood components in the first year of life, sometimes before the clinical suspicion of a PID, is of great concern. TA‐GVHD may be more prevalent than reported in the literature and it is possibly a nonidentified cause of death in recipients with unexplained death and nondiagnosed PID.     

Immunomonitoring of graft‐versus‐host minor histocompatibility antigen correlates with graft‐versus‐host disease and absence of relapse after graft

BACKGROUND: After HLA‐identical hematopoietic stem cell transplantation, minor histocompatibility (mH) antigen alloreactivity plays a dominant role in the development of graft‐versus‐host disease (GVHD) and graft versus leukemia (GVL). STUDY DESIGN AND METHODS: We have analyzed the mH alloreactivity (enzyme‐linked immunospot [ELISpot] for interferon‐γ[IFN‐γ] assay) from 24 donor/recipient pairs over a period of 2 years of follow‐up and correlated such alloreactivity with the development of GVHD or absence of relapse. Circulating specific T cells anti‐mH with multimer HLA‐peptides were also studied. RESULTS: We show by ELISpot IFN‐γ assay that alloreactivity during the first 3 months from donor versus recipient or donor versus mismatched identified mH antigens is associated with acute GVHD and GVL effect. In addition, we demonstrate that the donor‐versus‐recipient reactivity observed after the third month is highly associated with chronic GVHD and GVL (p = 0.0007). Finally, we show by multimer HLA‐peptide assay that mH epitope‐specific T cells present after 3 months are statistically related to the GVL effect. CONCLUSIONS: Our results provide a robust method to monitor mH antigen graft‐versus‐host reaction and suggest that current identified mH have predictive value on GVHD and GVL.     

Platelet gel for treatment of mucocutaneous lesions related to graft‐versus‐host disease after allogeneic hematopoietic stem cell transplant

BACKGROUND: Platelet (PLT) gel has been successfully used in tissue regeneration of diabetic/surgical wounds through the releasing of growth factors such as basic fibroblast growth factor and PLT‐derived growth factor. Therefore, the PLT gel could represent a therapeutic tool in treating the deep and painful wounds sometimes occurring during graft‐versus‐host disease (GVHD). STUDY DESIGN AND METHODS: The aim of this study was to verify the efficacy and safety of PLT gel for treating GVHD ulcers. Allogeneic hemocomponents were used to obtain PLT gel with an automated system for the on‐site preparation and application of patient (autologous) or healthy blood donor (allogeneic)‐derived fibrin sealant or PLT‐rich fibrin (Vivostat system, Vivostat A/S). Six patients with multiple lesions involving dermis (Grade I, n = 2), subcutaneous (Grade II, n = 4), or oral mucosa and related to GVHD underwent PLT gel as local therapy. RESULTS: After the second PLT gel application, the pain disappeared in all cases and the granulation tissue was observed in the four patients with Grade II lesions. After a median of eight PLT gel applications (range, 4‐10), five of six patients showed a complete response, while one patient with a partial response died early from multiorgan failure. No side effects were documented. CONCLUSION: These preliminary data show that the PLT gel may be used as a safe and effective tool in the management of mucosal skin lesions related to the GVHD.     

Extracorporeal photochemotherapy in graft‐versus‐host disease: a longitudinal study on factors influencing the response and survival in pediatric patients

BACKGROUND: Extracorporeal photochemotherapy (ECP) is a valid therapeutic option in the treatment of acute and chronic graft‐versus‐host disease (aGVHD and cGVHD, respectively). No standard clinical and laboratory criteria of response to ECP treatment are available at the moment. STUDY DESIGN AND METHODS: Clinical and laboratory variables on 73 pediatric patients with aGVHD (n = 50) and cGVHD (n = 23) were correlated with response to ECP and survival. RESULTS: An overall response (OR) was obtained in 34 of 50 (68%) aGVHD and in 16 of 23 (69.5%) cGVHD patients. Steroid tapering within 30 days of 1.3 mg/kg in OR (p = 0.004) was the sole highly significant correlation with response found in aGVHD while no correlation emerged for cGVHD (p = 0.28). Among aGVHD patients, response to ECP was inversely associated with death: among OR, deaths were 13 of 34 (38.2%), while among nonresponders, deaths were 15 of 16 (93.8%; p < 0.001). On the other hand, decrease of steroid dose at 30 days was associated with survival: for each 1 mg/kg reduction, the hazard ratio was 2.2, and the 95% confidence interval was 1.5 to 3.2 (p < 0.001). No other clinical or laboratory variables statistically associated with survival were found. CONCLUSIONS: Our results demonstrate that steroid tapering within the first 30 days of ECP treatment in aGVHD and response to ECP in acute and chronic GVHD are the only variables influencing response and survival, respectively.     

Apoptosis of ileal crypt epithelia after allogeneic bone marrow transplantation without graft‐versus‐host disease

Intestinal crypt cell apoptosis may occur after allogeneic bone marrow transplantation without clinically overt graft‐versus‐host disease. We describe this phenomenon in a case of a 12‐year‐old girl who had segments of the ileum resected because of a relapse of acute lymphoblastic leukemia. The diagnostic difficulties are discussed.     

Acute graft‐versus‐host disease and bronchiolitis obliterans after autologous stem cell transplantation in a patient with multiple myeloma

Sixty‐seven‐year‐old patient, diagnosed with multiple myeloma who had received autologous stem cell transplantation, following bortezomib, dexamethasone and thalidomide conventional regimen, achieving complete response, developed rash, diarrhea, and severe respiratory failure, 80 days after the transplantation procedure. He was diagnosed with graft‐versus‐host disease and bronchiolitis obliterans syndrome.     

Treatment of whole blood with riboflavin plus ultraviolet light,an alternative to gamma irradiation in the prevention of transfusion‐associated graft‐versus‐host disease?

BACKGROUND: Exposure of blood products to gamma irradiation is currently the standard of care in the prevention of transfusion‐associated graft‐versus‐host disease (TA‐GVHD). Regulatory, technical, and clinical challenges associated with the use of gamma irradiators are driving efforts to develop alternatives. Pathogen reduction methods were initially developed to reduce the risk of microbial transmission by blood components. Through modifications of nucleic acids, these technologies interfere with the replication of both pathogens and white blood cells (WBCs). To date, systems for pathogen and WBC inactivation of products containing red blood cells are less well established than those for platelets and plasma. STUDY DESIGN AND METHODS: In this study, the in vitro and in vivo function of WBCs present in whole blood after exposure to riboflavin plus ultraviolet light (Rb‐UV) was examined and compared to responses of WBCs obtained from untreated or gamma‐irradiated blood by measuring proliferation, cytokine production, activation, and antigen presentation and xenogeneic (X‐)GVHD responses in an in vivo mouse model. RESULTS: In vitro studies demonstrated that treatment of whole blood with Rb‐UV was as effective as gamma irradiation in preventing WBC proliferation, but was more effective in preventing antigen presentation, cytokine production, and T‐cell activation. Consistent with in vitro findings, treatment with Rb‐UV was as effective as gamma irradiation in preventing X‐GVHD, a mouse model for TA‐GVHD. CONCLUSION: The ability to effectively inactivate WBCs in fresh whole blood using Rb‐UV, prior to separation into components, provides the transfusion medicine community with a potential alternative to gamma irradiation.     

Comparison of the CELLEX™ and UVAR‐XTS™ closed‐system extracorporeal photopheresis devices in the treatment of chronic graft‐versus‐host disease

Extracorporeal Photopheresis (ECP) is a cellular immunotherapy frequently used for steroid‐refractory graft‐versus‐host disease (GVHD). Chronic GVHD (cGVHD), response to ECP is associated with survival benefit. The UVAR‐XTS^TM system and the more recently developed CELLEX^TM device (both Therakos^TM) are the mainstay for ECP‐delivery in the UK and US. No comparison of treatment outcomes has been reported. We retrospectively compared cGVHD response and steroid reduction and withdrawal in patients treated exclusively over 12 months with either the XTS (n = 51) or CELLEX (n = 50). Our hypothesis was that there would be no difference in clinical outcome or steroid changes in the 2 matched cohorts. We also compared infection incidence, infection‐related death (IRD), and treatment time. Significant clinical improvement and regular capacity to reduce or cease steroids was encountered in both cohorts; at 6 months of ECP 70% of cutaneous cGvHD patients had partial or complete responses and 85% of patients receiving steroids pre‐ECP had reduced dosage. In the XTS group we unexpectedly encountered both superior steroid reduction (86% dose at least halved vs. 61% for CELLEX, P = 0.01) and withdrawal (15 vs. 5 CELLEX, P = 0.01) and a trend for superior skin disease response in the CELLEX‐treated cohort at 3 months. No inter‐relationship was evident. Halving or greater reduction of steroid dose by 3 or 6 months was associated with reduced risk of IRD in the XTS cohort as was withdrawal at 6 months for the combined cohorts. By 6 months, XTS‐treated patients had experienced fewer antibiotic‐requiring infections (mean 1.9 vs. 2.8, P = 0.025). Origins for the disparities are unclear and warrant investigation.