Trends in intravenous immunoglobulin use in New South Wales, Australia.

BACKGROUND: Intravenous immunoglobulin (IVIg) is a critical replacement therapy for immunodeficiencies and immunomodulatory treatment for autoimmune and inflammatory diseases. Adequate supply of IVIg is a global issue, necessitating supply restrictions. In Australia, despite strict criteria for use, demand for IVIg has increased over time and exceeds domestic supply. OBJECTIVE: Factors associated with the upward trend in overall IVIg use were examined, including in the number of unique patients, IVIg dosing and treatment frequency and variations by prescribing discipline and disease group. METHODS: De-identified data of IVIg dispensed in the largest Australian state (New South Wales) from 2007 to 2013 were provided by Australian Red Cross Lifeblood. Trends and projections were calculated using log-linear regression of unique patients, treatment episodes and grams of IVIg for overall use and use stratified by discipline and disease group. RESULTS: During the study period, 169 453 treatment episodes were recorded for 12 547 unique patients accounting for 5 827 787 g of IVIg use. Overall, IVIg use increased by 12.0% (11.5-12.6%) per year representing a 97.7% increase (91.6-104%) over the study period. The highest growth was among neurological conditions (16.0% (14.9-17.1%) per year). An increase in the number of unique patients was the primary driver of this growth, augmented by increases in the frequency and average dose per treatment. CONCLUSIONS: Clinically acceptable measures to improve management of IVIg supply are needed including optimising dose, frequency and duration of treatment. Formal evaluation of IVIg versus alternatives, including cost-effectiveness and comparative efficacy, is warranted.

Safety Analysis of Extended Platelet Shelf-Life with Large-Volume Delayed Sampling on BACT/ALERT® VIRTUO® in Australia.

Transfusion-transmitted bacterial infection (TTBI) is the leading cause of transfusion-transmitted infections. Platelet components are more likely to be associated with bacterial contamination due to their storage requirements. Australian Red Cross Lifeblood introduced the bacterial contamination screening (BCS) of all platelet components in 2008. The process was recently updated with the use of BACT/ALERT® VIRTUO®, a large-volume delayed sampling (LVDS) protocol and extending platelet shelf-life to seven days. This article describes the results from the routine BCS of platelet components in Australia. Use of VIRTUO has resulted in lower false-positive rates, reducing wastage and improving platelet inventory. Our findings show that the combination of LVDS and VIRTUO improves the safety of platelet transfusions through earlier time to detection, especially for pathogenic bacterial species. Pathogenic bacteria grew within 24 h of incubation with a clear delineation between pathogenic and non-pathogenic species. The data show this protocol is very safe, with no TTBI cases during this time. There were no TTBI reports in recipients of platelet components that subsequently had a positive culture with Cutibacterium species, probably due to the low pathogenic potential of these organisms and slow replication in aerobic platelet bags. We conclude there is no advantage in incubating culture bottles beyond five days.

The impact of revised definitions for transfusion-associated circulatory overload and transfusion-related acute lung injury on haemovigilance reporting.

BACKGROUND AND OBJECTIVES: Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are serious adverse transfusion reactions. Standardized surveillance definitions are important to ensure consistent reporting of cases. Recently, revised definitions have been developed for TACO and TRALI, the latter of which has not yet been widely implemented. This study aimed to assess the impact of the new TACO and TRALI definitions on haemovigilance reporting. MATERIALS AND METHODS: The Australian Red Cross Lifeblood Adverse Transfusion Reaction database was accessed to identify all cases of suspected or confirmed TACO and TRALI referred from 1 July 2015 to 30 June 2019. Cases were assessed against both the former and new definitions and the results were compared. RESULTS: A total of 73 cases were assessed. There were 48 TACO cases identified. Only 26 of 48 cases strictly met the former 2011 International Society of Blood Transfusion (ISBT) definition of TACO; 6 cases did not meet the definition and 16 cases lacked sufficient clinical details. In comparison, 46 cases met the revised 2018 ISBT definition, with only 2 cases having insufficient details. There were 24 cases of TRALI according to the existing 2004 Canadian Consensus Conference (CCC) definition compared with 25 cases according to the proposed 2019 revised definition. CONCLUSION: The revised TACO definition captured more cases than the former definition. No significant differences were observed in the number of TRALI cases under the proposed new definition. This is the first study to provide validation data for the revised TRALI definition.

Centre-based comparison of double versus single prevention strategy on transfusion-transmitted cytomegalovirus in at-risk haemopoietic stem cell transplant patients and a state survey on cytomegalovirus-seronegative ordering practises.

BACKGROUND: Universal leucocyte depletion reduces the risk of transfusion-transmitted cytomegalovirus; however, many clinicians still prescribe cytomegalovirus seronegative units. AIM: Our retrospective study aims to confirm the low risk of transfusion-transmitted cytomegalovirus with leucocyte depletion alone and demonstrate the ongoing variability in cytomegalovirus seronegative transfusion prescribing. METHODS: Over a 9-year period (July 2009-July 2018), occurrences of transfusion transmitted cytomegalovirus in cytomegalovirus seronegative donor/recipient haemopoietic stem cell transplant pairs were compared at one allogeneic haemopoietic stem cell transplant centre providing cytomegalovirus seronegative blood products and leucocyte depletion (double prevention) versus another providing leucocyte depletion only (single prevention). Retrospective chart audit identified patient demographics, blood product exposure and cytomegalovirus infection by polymerase chain reaction. A separate audit examined cytomegalovirus seronegative blood product ordering in a broader range of hospital types. RESULTS: We identified 122 and 66 cytomegalovirus-negative donor/recipient haemopoietic stem cell transplant pairs using double and single transfusion prevention strategy respectively. Transfusion exposure to red cells and pooled platelets was similar, although more apheresis platelets were used in the double prevention group. The cytomegalovirus infection rate was 3 (2.4%) and zero in the double and single prevention groups respectively. Cytomegalovirus seronegative unit ordering was not limited to hospitals with obstetric or neonatal populations, suggesting ongoing reliance of cytomegalovirus seronegative units outside this population. CONCLUSIONS: The analysis suggests a double prevention strategy does not provide additional protection against transfusion-transmitted cytomegalovirus. There is ongoing variability in the acceptance of leucocyte depletion alone despite the low risk of cytomegalovirus infection.

Immunoglobulin replacement therapy in chronic lymphocytic leukaemia patients with hypogammaglobulinaemia and infection.

OBJECTIVES: To analyse total national utilisation of immunoglobulin (Ig) replacement therapy (IgRT) for Chronic Lymphocytic Leukaemia patients with acquired hypogammaglobulinaemia and severe and/or recurrent bacterial infections. METHODS: In 2007, the National Blood Authority first published Criteria for the clinical use of intravenous immunoglobulin in Australia. The Australian Red Cross Lifeblood assessed, approved, and recorded all supply with patient demographics, distribution data, intravenous Ig (IVIg) volumes and treatment episodes. IVIg was the sole product used in Australia from 2008-2013 inclusive. RESULTS: From 2008 to 2013 across Australia, 2734 individual CLL patients received 48,870 treatment episodes using a total 1,324,926 g of IVIg therapy. Six IVIg products were available, with domestically manufactured Intragam® P accounting for 89.7% of supply. The average age for first dose was 74 years. Males received 60.6% of the total treatment episodes representing 20% more than females. The average pre-treatment IgG level was 4.03 ± 2.03 g/L (range 0.30-10.50 g/L). A sustained average annual increased IVIg utilisation of 5.5% was observed. There was significant regional variation consistent with differences in prescriber preferences across states and territories. CONCLUSION: This study provides a globally unique insight into IgRT supply and demand in CLL patients by analysis of total national use in Australia over a 6-year period.

X-irradiation and gamma-irradiation inactivate lymphocytes in blood components.

BACKGROUND: Irradiation of selected blood components is standard practice for the prevention of transfusion-associated graft-versus-host disease (TA-GvHD). Currently, gamma-irradiation is the most widely used form of irradiation, but there is an increasing interest in X-irradiation, which is considered to be functionally equivalent and safer. However, there is a paucity of contemporary data regarding the ability of X-irradiation to inactivate lymphocytes in blood components. Therefore, the effect of gamma- and X-irradiation on lymphocyte viability and function in blood components was compared. STUDY DESIGN AND METHODS: Lymphocytes were isolated from venous blood by density gradient centrifugation, spiked into plasma/SSP+ to simulate a blood component, and either gamma- or X-irradiated. The phenotype of the isolated lymphocytes was confirmed. Lymphocyte viability was measured using a LIVE/DEAD assay, and function was assessed using mixed lymphocyte culture and CD69 expression post-phorbol-12 myristate 13-acetate (PMA) stimulation. RESULTS: Lymphocyte viability and CD69 expression following PMA stimulation were significantly reduced by both gamma-irradiation and X-irradiation in simulated blood components. Allorecognition and allostimulation were also significantly reduced by both gamma-irradiation and X-irradiation. CONCLUSION: Lymphocyte viability and function are reduced to a similar extent by gamma- and X-irradiation in simulated blood components. As such, X-irradiation is suitable for the irradiation of blood components and, in terms of lymphocyte inactivation, could be used instead of gamma-irradiation.

X- and gamma-irradiation have similar effects on the in vitro quality of stored red cell components.

BACKGROUND: Blood components are irradiated to inactivate lymphocytes to prevent transfusion-associated graft versus host disease. As there are little data regarding the effects of X-irradiation on red blood cell components (RBCs), the in vitro quality of stored red cells (standard, pediatric, washed, and intra-uterine transfusion [IUT]) following X- or gamma-irradiation was compared. STUDY DESIGN AND METHODS: RBCs were pooled, split, and processed to produce standard (<14 days and < 5 days post-collection), pediatric (<5 days post-collection), washed (<14 days post-collection), or IUT RBCs (<5 days post-collection). Standard RBCs were either X- or gamma-irradiated (n = 10 pairs). A further 10 replicates were prepared by pooling and splitting three matched RBCs (X-, gamma-, and non-irradiated). All other RBCs were either X- or gamma-irradiated (n = 20 pairs). Red cell indices, hemolysis, potassium release, metabolism, microparticles, ATP, and 2,3-DPG were measured pre-irradiation and 6 h, 1, 2, 3, 7, 10, and 14 days post-irradiation, depending on the component type. Data were analyzed using two-way repeated measures ANOVA. RESULTS: There were no significant differences in any in vitro quality measurements, with the exception of marginally higher potassium release in washed, IUT, and RBCs <5 days old (p < .0001) following X-irradiation. Both irradiation types increased generation of microvesicles, particularly in components that were older at the time of irradiation or stored for longer post-irradiation. CONCLUSION: X- and gamma-irradiation have similar effects on the in vitro quality of RBCs, indicating that either technology is suitable for blood component irradiation.

Elective surgery in patients with inherited bleeding disorders: A retrospective analysis.

INTRODUCTION: Published guidelines are available to assist in the management of patients with inherited bleeding disorders in the elective surgical setting however good quality outcome data is lacking. AIM: - Evaluate the outcomes of adult patients with inherited bleeding disorders, who received factor replacement for elective surgery in NSW/ACT, Australia. - Assess adherence to relevant guidelines including Haemophilia Treatment Centre (HTC) utilisation and appropriate factor replacement. METHOD: A retrospective analysis was performed between 2000 and 2018 to describe patient characteristics, surgical details, factor provision and outcomes. Univariate analysis was used to determine variables associated with guideline adherence. Covariates with p < 0.1 were included in the multivariate analysis. RESULTS: A total of 1065 surgeries were performed on 571 patients. Diagnoses included Haemophilia A (43.5%), Haemophilia B (9.7%), von Willebrand disease (VWD) (45.3%) and rare bleeding disorders (RBDs) (1.6%). Bleeding complications were reported in 14 surgeries and 19 patients received factor replacement beyond standard duration of prophylaxis. Approximately 50% of all surgeries were performed in a HTC. Multivariate analysis demonstrated that diagnosis, surgical specialty, sex and year (p < 0.001) were associated with non-compliance with variable pattern within each category. Factor replacement was as expected except for plasma-derived Factor VIII/VWF usage in patients with VWD undergoing major bleeding risk surgery. VWD classification (p < 0.001) was associated with this deviation. CONCLUSION: Low complication rates demonstrate that elective surgery in Australia is being safely performed in patients with inherited bleeding disorders however non-compliance with published guidelines exists highlighting areas of practice and policy discrepancies that warrant further exploration.

Red blood cell transfusion in patients with anti-Yta.

BACKGROUND: Yta is a high frequency red blood cell (RBC) antigen, present in 99.7% of studied populations. It is extremely immunogenic, and when anti-Yta is present, provision of Yt(a-) blood is often challenging. The objectives of our study were to assess the incidence and severity of acute hemolytic transfusion reactions to Yt(a+) donor RBCs in recipients with preformed anti-Yta and to identify any patient factors associated with severe hemolytic reactions. STUDY DESIGN AND METHODS: Patients with anti-Yta identified by the Red Cell Reference Laboratories of the Australian Red Cross Lifeblood over the past 20 years were included. Their transfusion records were collected via the referring laboratory to ascertain if any patients received RBC transfusion and if there was any evidence of transfusion reactions. RESULTS: Fifty-two patients with anti-Yta were identified; only 12 were confirmed to have received a RBC transfusion. Nine received Yt(a+) or untyped allogeneic RBCs, including four patients who received a total of 16 indirect antiglobulin test (IAT) crossmatch incompatible, likely Yt(a+) RBCs. None of the nine patients had documented acute hemolytic reactions. CONCLUSION: There are limited published data describing the clinical significance of anti-Yta . Based on our data, it appears that transfusing patients with anti-Yta using incompatible crossmatched RBCs does not pose a significant risk of an acute hemolytic transfusion reaction when the antibody reaction strength is weak ≤2+ (0-4) by IAT crossmatch. For strong examples of the antibody, in the absence of other assay data, such as the monocyte monolayer assay, Yt(a-) blood should continue to be sourced where possible.

Clinical consequences of the extremely rare anti-PP1Pk isoantibodies in pregnancy: a case series and review of the literature.

BACKGROUND: The absence of the red cell antigens P, P1 and Pk , known as 'p', represents an extremely rare red cell phenotype. Individuals with this phenotype spontaneously form anti-PP1Pk isoantibodies, associated with severe haemolytic transfusion reactions, recurrent spontaneous abortion and haemolytic disease of the fetus and newborn (HDFN). METHODS: We report a series of four successful pregnancies in three women with anti-PP1Pk isoantibodies, one complicated by HDFN, another by intrauterine growth restriction, all managed supportively. We also review the literature regarding the management of pregnancy involving anti-PP1Pk isoimmunization. RESULTS: The literature surrounding anti-PP1Pk in pregnancy is limited to a very small number of case reports. The majority report management with therapeutic plasma exchange (TPE) with or without intravenous immunoglobulin. The relationship between titre and risk of pregnancy loss remains unclear, though a history of recurrent pregnancy loss appears important. Although a positive cord blood direct antiglobulin test is frequently noted, clinically significant HDFN appears uncommon, though possible. CONCLUSION: Early initiation of TPE in high risk patients should be strongly considered. If possible, pregnancies should be managed in a high-risk obstetric or maternal fetal medicine service. The fetus should be monitored closely with interval fetal ultrasound and middle cerebral artery peak systolic volume Doppler to screen for fetal anaemia. Timely sourcing of compatible blood products is likely to be highly challenging, and both directed and autologous donation should be contemplated where appropriate. The International Red Cell Donor Panel may also provide access to compatible products.

No evidence for widespread Babesia microti transmission in Australia.

BACKGROUND: A fatal case of autochthonous Babesia microti infection was reported in Australia in 2012. This has implications for Australian public health and, given that babesiosis is transfusion transmissible, has possible implications for Australian blood transfusion recipients. We investigated the seroprevalence of antibodies to B. microti in Australian blood donors and in patients with clinically suspected babesiosis. STUDY DESIGN AND METHODS: Plasma samples (n = 7,000) from donors donating in at-risk areas and clinical specimens from patients with clinically suspected babesiosis (n = 29) were tested for B. microti IgG by immunofluorescence assay (IFA). IFA initially reactive samples were tested for B. microti IgG and IgM by immunoblot and B. microti DNA by polymerase chain reaction. RESULTS: Although five donors were initially reactive for B. microti IgG by IFA, none was confirmed for B. microti IgG (zero estimate; 95% confidence interval, 0%-0.05%) and all were negative for B. microti DNA. None of the patient samples had B. microti IgG, IgM, or DNA. CONCLUSIONS: This study does not provide evidence for widespread exposure to B. microti in Australian blood donors at local theoretical risk, nor does it provide evidence of B. microti infection in Australian patients with clinically suspected babesiosis. Given that confirmed evidence of previous exposure to B. microti was not seen, these data suggest that transmission of this pathogen is currently uncommon in Australia and unlikely to pose a risk to transfusion safety at present.

A national review of the clinical use of group O D- red blood cell units.

BACKGROUND: There has been an international decline in the demand for red blood cell (RBC) units. In Australia, there has been a 21% reduction in demand between 2012 and 2015. In contrast, the demand for the "universal" group O D- RBC units is in fact proportionally increasing. STUDY DESIGN AND METHODS: The clinical use of the entire O D- RBC distribution for a 5-week period throughout Australia was reviewed. Fate data on each unit issued (n = 9733) were collected that included the indication and urgency of transfusion, reason for discard, component age, and patient demographics. RESULTS: A total of 74% of audit forms were returned (n = 7143). The national discard rate of issued units was 7.9%. A total of 6387 units were transfused into an estimated total of 3008 patients (55% males) with median patient age of 67 years and median RBC age of 21 days. Forty-seven percent were transfused to group O D- patients. A total of 17.4% were chosen for specific phenotype requirements, 24.5% of units were transfused close to expiry, and 24.5% were transfused into patients of other ABO groups. CONCLUSION: The data appear broadly representative of the current transfusion and inventory management practices surrounding the use of group O D- RBC units. Strategies to reduce O D RBC demand include reevaluation of inventory holdings particularly at smaller centers, increasing the panel of phenotyped RBC units across all ABO groups, more regular rotation of units between hospitals to minimize time expiry, and continuing education for promoting transfusion of ABO-identical RBC units.

Immunomodulation of inflammatory leukocyte markers during intravenous immunoglobulin treatment associated with clinical efficacy in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: The objective of the study was to profile leukocyte markers modulated during intravenous immunoglobulin (IVIg) treatment, and to identify markers and immune pathways associated with clinical efficacy of IVIg for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with potential for monitoring treatment efficacy. METHODS: Response to IVIg treatment in newly diagnosed IVIg-naïve and established IVIg-experienced patients was assessed by changes in expression of inflammatory leukocyte markers by flow cytometry. The adjusted INCAT disability and Medical Research Council sum scores defined clinical response. RESULTS: Intravenous immunoglobulin modulated immunopathogenic pathways associated with inflammatory disease in CIDP. Leukocyte markers of clinical efficacy included reduced CD185+ follicular helper T cells, increased regulatory markers (CD23 and CD72) on B cells, and reduction in the circulating inflammatory CD16+ myeloid dendritic cell (mDC) population and concomitant increase in CD62L and CD195 defining a less inflammatory lymphoid homing mDC phenotype. A decline in inflammatory CD16+ dendritic cells was associated with clinical improvement or stability, and correlated with magnitude of improvement in neurological assessment scores, but did not predict relapse. IVIg also induced a nonspecific improvement in regulatory and reduced inflammatory markers not associated with clinical response. CONCLUSIONS: Clinically effective IVIg modulated inflammatory and regulatory pathways associated with ongoing control or resolution of CIDP disease. Some of these markers have potential for monitoring outcome.

Serum eye drop preparation in Australia: Current manufacturing practice.

Serum eye drops are used to treat diseases such as dry eye syndrome (keratoconjunctivitis sicca), a disease of the surface of the eye that results in an unstable tear film. Patients are referred to the Australian Red Cross Blood Service by ophthalmologists for autologous serum eye drops when other therapies such as artificial tears or topical immunosuppressive agents have failed. In order to manufacture autologous serum eye drops, whole blood is collected from the patients using standard blood collection procedures. The blood is then allowed to clot to produce serum and processed into 20% serum eye drops, which are then returned to the patient for their own use. The eye drops are packaged into a long length of tubing, which is then heat-sealed to produce single-use segments. The demand for serum eye drops in Australia is increasing every year, with a 30% increase in the past 12 months.

Recurrent HLA-B56 mediated neonatal alloimmune thrombocytopenia with fatal outcomes.

Neonatal alloimmune thrombocytopenia is caused by maternal antibodies against paternally-inherited alloantigens present on foetal platelets and is a significant cause of morbidity and mortality in neonates. While generally thought of as a human platelet antibody mediated phenomenon, cases of HLA mediated NAIT have been reported. We document the investigation of a patient with two pregnancies affected by HLA-B56 mediated NAIT and a proposal for management of future pregnancies.

The use of intravenous immunoglobulin for treatment of dermatological conditions in Australia: A review.

Intravenous immunoglobulin has been used in the treatment of various dermatological conditions, including toxic epidermal necrolysis, bullous pemphigoid and pemphigus vulgaris. From March 2008, the National Blood Authority has implemented the 'Criteria for the clinical use of intravenous immunoglobulins in Australia'. The new criteria have formalized the eligibility requirements for several dermatological conditions. This may increase access to intravenous immunoglobulin for treatment for these conditions. However, there remain stringent eligibility criteria with which dermatologists need to be acquainted. In some conditions, dermatology review is mandated by these criteria while in other conditions with skin manifestations, referral to other specialists is required. The following article provides a summary of the salient points in relation to the clinical use of intravenous immunoglobulin in dermatology, as well as its production and supply in Australia.