Systematic Review of Cases of Transfusion Associated Graft-Versus-Host-Disease (TA-GVHD): Analysis of Patient Characteristics and Outcomes
Authors: Ostro Jackie , Kopolovic Ilana , Lin Yulia , Dzik Walter H. , Cserti Christine , Tsubota Hideki , Keir Amy , Messner Hans A. , DenHollander Neal , Callum Jeannie 
Published: October 2019

Abstract
Introduction:
TA-GVHD is a rare, usually fatal complication from blood transfusions wherein donor lymphocytes engraft and mount an immune response against recipient tissues. Immunocompromised hosts who are unable to recognize and destroy foreign lymphocytes are at theoretical risk of TA-GVHD, and a variety of immune incompetencies thus form the indications for cellular blood component irradiation. Much of our understanding on who is at risk of TA-GVHD as well as policies regarding who should receive irradiated components derive from case reports and small case series. We performed a systematic review of cases of TA-GVHD to refine evidence-based guidelines for the use of gamma-irradiated blood components, assess the usefulness of the Centers for Disease Control (CDC) criteria in making the diagnosis of TA-GVHD and to define the minimum details of a case of TA-GVHD that should be reported.
Methods:
Our systematic review, which was registered with PROSPERO, included all reported cases of TA-GVHD from 1947 until September 2013 with no restrictions on language or date. Titles and abstracts were reviewed by two independent reviewers. References were assessed for additional cases. Data collected included patient demographics, details regarding the transfusion(s), clinicolaboratory features outlined in the CDC criteria (rash, diarrhea, fever, hepatomegaly, liver dysfunction, marrow aplasia and pancytopenia), patient outcomes and results of HLA and chimerism studies.
Results:
After duplicates were removed, 2130 publications were available for review, with 348 cases of TA-GVHD included in the analysis. The median age was 58 years (IQR 18, 68) with 61.6% males. The most frequent underlying diagnoses were non-cardiac surgery (n=81, 23.3%), cardiac surgery (n=71, 20.4%) and hematologic malignancy (n=66, 19.0%). According to our institutional guidelines for irradiation of blood components (Massachusetts General Hospital, Sunnybrook Health Sciences Centre, The Hospital for Sick Children and University Health Network), 121 cases (34.5%) met the criteria for requiring irradiation of blood components.
Among the 245 patients in whom time of symptom onset was reported, the first symptom of TA-GVHD occurred a median of 11 (IQR 8, 14) days from the implicated transfusion. Patients had an average of 3.6 symptoms and/or signs of TA-GVHD using the CDC definition, with rash being the most common finding in 80.2% of cases (Figure 1). A biopsy was performed in 67.5% of cases, with skin as the most common site in 97.0% of cases. Chimerism studies were done in 103 cases (29.7%) to confirm the diagnosis. According to the CDC case definition, 215 (62.0%) had definitive and 73 (21.0%) had probable TA-GVHD. The case imputability based on the CDC definition was definite, probable, possible and doubtful in 28.5, 2.3, 50.0 and 2.0% of cases, respectively. The implicated blood component was red blood cells in 132 cases (37.9%), whole blood in 92 cases (26.4%), and platelets in 20 cases (5.7%). The treatment for TA-GVHD was immunosuppression therapy (IST) in 48.9%, bone marrow transplant (BMT) in 2.3%, and no intervention in 46.7%. Of those treated with IST or BMT, 10.7% survived, whereas 5.6% of the untreated survived, p = 0.063. Overall, 29 patients (8.4%) survived; of these, 3 (10.3%) received BMT, 16 (55.2%) IST and 10 (31.0%) no therapy.
Conclusions:
To our knowledge this is the largest systematic review of reported cases of TA-GVHD. This review describes the diversity of patient characteristics and presentations of TA-GVHD. Firstly, patients at risk for TA-GVHD encompass all levels of immune integrity, and reliance on the patient's underlying diagnosis to dictate the need for irradiated blood components limits mitigation, as blood component or donor-recipient factors may be more important considerations. Secondly, the analysis of cases revealed limitations and inconsistencies in reported details, underscoring the need for consensus on reporting criteria, without which TA-GVHD case confirmation is challenging.
Figure 1: Percentage of patients with the symptoms and signs of TA-GVHD according to the CDC case definition Figure 1:. Percentage of patients with the symptoms and signs of TA-GVHD according to the CDC case definition

Disclosures
No relevant conflicts of interest to declare.