Hemovigilance and the Notify Library.

Hemovigilance systems allow reporting of adverse occurrences associated with blood transfusion to a central database where events can be reviewed and analyzed for the benefit of patients and donors. Hemolytic and serologic transfusion reactions are among the many types of reactions reported to these systems. The Notify Library, a database of adverse events associated with medical products of human origin, has incorporated hemovigilance into its didactic resources. Students and practitioners are encouraged to use the electronic library and to further enhance this resource through review and recommendation of additional publications in the area of immunohematology.Hemovigilance systems allow reporting of adverse occurrences associated with blood transfusion to a central database where events can be reviewed and analyzed for the benefit of patients and donors. Hemolytic and serologic transfusion reactions are among the many types of reactions reported to these systems. The Notify Library, a database of adverse events associated with medical products of human origin, has incorporated hemovigilance into its didactic resources. Students and practitioners are encouraged to use the electronic library and to further enhance this resource through review and recommendation of additional publications in the area of immunohematology.

Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart-Liver Transplantation.

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.

Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year.

This study examined outcomes beyond 1 year in eculizumab-treated (EC) positive crossmatch kidney transplants (+XMKTx) compared to a historical control group. +XMKTx received desensitization with either plasma exchange (PE) alone (N = 48) or PE and EC (N = 30). EC, given for at least 1 month, was continued in the setting of persistently high DSA (B flow cytometric crossmatch [BFXM] >200) including: 4 weeks (n = 14); 9 weeks (n = 6), 6 months (n = 2), and 12 months (n = 8). All patients had at least 2 years follow-up. The incidence of acute clinical ABMR was lower in the EC group than controls (6.7% vs. 43.8% p < 0.01). Death-censored allograft survival was similar between groups. Chronic ABMR was the main cause of graft loss. On 1-year protocol biopsies, no differences were noted between EC and controls including: cg score >0, 26.7% versus 31.9% (p = 0.62), ptc score ≥ 2, 60.0% versus 60.0% (p = 1.00), or C4d + , 33.8% versus 13.5% (p = 0.08). A persistently high BFXM in EC-treated patients was associated with cg score >0 at 1 year, while EC appeared to protect against cg if the BFXM remained low. We conclude that despite decreasing acute clinical ABMR rates, EC treatment does not prevent chronic ABMR in recipients with persistently high BFXM after +XMKTx.

Anti-phospholipase A2 receptor antibodies in recurrent membranous nephropathy.

About 70% of patients with primary membranous nephropathy (MN) have circulating anti-phospholipase A2 receptor (PLA2R) antibodies that correlate with disease activity, but their predictive value in post-transplant (Tx) recurrent MN is uncertain. We evaluated 26 patients, 18 with recurrent MN and 8 without recurrence, with serial post-Tx serum samples and renal biopsies to determine if patients with pre-Tx anti-PLA2R are at increased risk of recurrence as compared to seronegative patients and to determine if post-Tx changes in anti-PLA2R correspond to the clinical course. In the recurrent group, 10/17 patients had anti-PLA2R at the time of Tx versus 2/7 patients in the nonrecurrent group. The positive predictive value of pre-Tx anti-PLA2R for recurrence was 83%, while the negative predictive value was 42%. Persistence or reappearance of post-Tx anti-PLA2R was associated with increasing proteinuria and resistant disease in 6/18 cases; little or no proteinuria occurred in cases with pre-Tx anti-PLA2R and biopsy evidence of recurrence in which the antibodies resolved with standard immunosuppression. Some cases with positive pre-Tx anti-PLA2R were seronegative at the time of recurrence. In conclusion, patients with positive pre-Tx anti-PLA2R should be monitored closely for recurrent MN. Persistence or reappearance of antibody post-Tx may indicate a more resistant disease.

Who should answer the question: "Can I drive with this plaster cast?".

INTRODUCTION: The application of a plaster cast is known to affect driving ability, but patients continue to drive. The individuals and authorities involved in assessing driving safely include doctors, the Driver and Vehicle Licensing Agency (DVLA), police, insurance companies, and patients, but it is unclear who should take responsibility for the advice given, especially in the event of an accident. METHODS: We contacted senior plaster technicians in 348 hospitals in the UK. We recorded their responses regarding advice given to patients on driving in specific casts. Sixteen motor insurance companies and 40 police forces were also contacted in order to canvass their opinions. RESULTS: 188 technician interviews (response rate 54%) were conducted. Only 10% of respondents offered advice unprompted; an average of 48% of patients asked for advice. 88% of respondents referred patients to their motor insurance companies, and also to the DVLA (11.7%), doctor (10.6%), or police (5.9%). Only 20.2% of plaster rooms provided written information. All insurance companies would insure patients provided the doctor had not explicitly objected to driving, but there was no consensus amongst the responses received from police. In the event of an accident after the treating doctor had advised against driving, insurance companies were likely to invalidate the policy, and the police would seek penalty punishment or prosecution. CONCLUSIONS: Although doctors are not specifically trained to assess the ability of patients to drive, insurance companies and police forces place the responsibility on doctors to advise patients. Since current evidence suggests plaster casts can impair driving ability, we suggest patients should be advised not to drive. Patients accept all responsibility if they continue to drive after receiving this specific advice and understanding its implications.

Acute pancreas allograft rejection is associated with increased risk of graft failure in pancreas transplantation.

The effect of acute allograft rejection (AR) on long-term pancreas allograft function is unclear. We retrospectively studied 227 consecutive pancreas transplants performed at our institution between January 1, 998 and December 31, 2009 including: 56 simultaneous pancreas and kidney (SPK), 69 pancreas transplantation alone (PTA); and 102 pancreas after kidney (PAK) transplants. With a median follow-up of 6.1 (IQR 3-9) years, 57 patients developed 79 episodes of AR, and 19 experienced more than one episode. The cumulative incidence for AR was 14.7%, 19.7%, 26.6% and 29.1% at 1, 2, 5 and 10 years. PTA transplant (hazards ratio [HR]=2.28, p=0.001) and donor age (per 10 years) (HR=1.34, p=0.006) were associated with higher risk for AR. The first AR episode after 3 months post PT was associated with increased risk for complete loss (CL) (HR 3.79, p<0.001), and the first AR episode occurring during 3- to 12-month and 12- to 24-month periods after PT were associated with significantly increased risk for at least partial loss (PL) (HR 2.84, p=0.014; and HR 6.25, p<0.001, respectively). We conclude that AR is associated with increased risk for CL and at least PL. The time that the first AR is observed may influence subsequent graft failure.

Five-year outcomes in living donor kidney transplants with a positive crossmatch.

Renal transplant candidates with high levels of donor-specific anti-HLA antibodies have low transplantation rates and high mortality rates on dialysis. Using desensitization protocols, good short-term outcomes are possible in "positive crossmatch kidney transplants (+XMKTx)", but long-term outcome data are lacking. The aim of the current study was to determine actual 5-year graft outcomes of +XMKTx. We compared graft survival and the functional and histologic status of 102 +XMKTx to 204 -XMKTx matched for age and sex. Actual 5-year death-censored graft survival was lower in the +XMKTx group (70.7% vs. 88.0%, p < 0.01) and chronic injury (glomerulopathy) was present in 54.5% of surviving grafts. Graft survival was higher in recipients with antibody against donor class I only compared with antibody against class II (either alone or in combination with class I) (85.3% vs. 62.6%, p = 0.05) and was similar to -XMKTx (85.3 vs. 88.0%, p = 0.64). Renal function and proteinuria ranged across a wide spectrum in all groups reflecting the different histological findings at 5 years. We conclude that when compared to -XMKTx, +XMKTx have inferior outcomes at 5 years, however, almost half of the surviving grafts do not have glomerulopathy and avoiding antibodies against donor class II may improve outcomes.

Prevalence, course and impact of HLA donor-specific antibodies in liver transplantation in the first year.

The presence of preformed donor-specific HLA antibodies (DSA) in liver transplant recipients is increasingly recognized; however, the prevalence of DSA and their impact on early allograft function remains unknown. We prospectively followed serum DSA levels of 90 consecutive liver transplant recipients from baseline to 4 months. Twenty recipients (22.2%) had preformed DSA. No antibody-targeting treatments were undertaken. Seven days after transplantation, DSA levels decreased markedly in all but three patients. Day 7 protocol biopsies showed diffuse C4d deposition along the portal stroma, central vein, subendothelial and stromal space in the patients with persistent high DSA levels. The rate of acute cellular rejection was not significantly different in patients with DSA. The transaminase and bilirubin levels remained comparable during the first year despite the presence of DSA. The three patients with persistently high DSA levels continue to have normal allograft function. We conclude that in most cases, DSA disappear after liver transplant, however in rare instances where they persist, there is evidence of complement activation in the liver allograft, without significant clinical impact in the first year.

Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.

Sensitized renal transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).

Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation.

Renal transplant candidates with donor-specific alloantibody (DSA) have increased risk of antibody-mediated allograft injury. The goal of this study was to correlate the risk of antibody-mediated rejection (AMR), transplant glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of pretransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (-XM) transplants performed between April 2000 and July 2007. Using a combination of cell-based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and -XM groups. In +XM transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of -XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody-mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long-term allograft survival highlighting the need for improved therapy for these candidates.

Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.

We examined the course of donor-specific alloantibody (DSA) levels early after transplant and their relationship with acute humoral rejection (AHR) in two groups of positive crossmatch (+XM) kidney transplant recipients: High DSA group-41 recipients with a baseline T- or B-cell flow crossmatch (TFXM, BFXM) channel shift >or=300 (molecules of equivalent soluble fluorochrome units (MESF) of approximately 19 300) who underwent pretransplant plasmapheresis (PP), and Low DSA group-29 recipients with a baseline channel shift <300 who did not undergo PP. The incidence of AHR was 39% (16/41) in the High DSA group and 31% (9/29) in the Low DSA group. Overall, mean DSA levels decreased by day 4 posttransplant and remained low in patients who did not develop AHR. By day 10, DSA levels increased in patients developing AHR with 92% (23/25) of patients with a BFXM >359 (MESF of approximately 34 000) developing AHR. The BFXM and the total DSA measured by single antigen beads correlated well across a wide spectrum suggesting that either could be used for monitoring. We conclude that AHR is associated with the development of High DSA levels posttransplant and protocols aimed at maintaining DSA at lower levels may decrease the incidence of AHR.

Identifying a newly discovered HLA-C allele, HLA-C*02:138.

A new allele, now named HLA-C*02:138, was discovered during testing of a registry donor for possible stem cell transplantation.

Identifying a newly discovered HLA-C allele: HLA-C*07:607.

Phased sequencing identified the HLA-C*07:607 allele in an African-American patient and sibling donor.

Undetectable negative tissue transglutaminase IgA antibodies predict mucosal healing in treated coeliac disease patients.

BACKGROUND: Tissue transglutaminase (tTG) immunoglobulin A (IgA) testing is a sensitive adjunct to the diagnosis of coeliac disease. The threshold for positivity was developed for diagnosis, with negative results reported as below the reference value (<4 U/mL). AIM: To investigate if an undetectable (tTG IgA<1.2 U/mL) is more predictive of healing compared to patients with negative but detectable serology (1.2-3.9 U/mL). METHODS: We performed a retrospective study of 402 treated coeliac disease patients seen at the Mayo Clinic with negative tTG IgA values drawn within 1 month of duodenal biopsy between January 2009 and December 2015. The Corazza-Villanacci score was used to assess mucosal healing. The presence of gastrointestinal symptoms was also collected. Logistic regression was used to assess the relationship of clinical variables with a normal biopsy. RESULTS: Patients with undetectable titres more frequently had normal duodenal histology compared to patients with detectable tTG IgA levels (117/240 vs. 53/162; OR=1.96; 1.292, 2.961). Asymptomatic patients more frequently had normal duodenum as compared to symptomatic patients (88/163 vs. 82/239; OR=2.25; CI: 1.494, 3.377). Patients with undetectable serology and on a gluten-free diet for ≥2 years were more likely to have no villous atrophy compared to patients with detectable serology (148/192 vs. 55/88; OR=2.02; CI: 1.17, 3.49). CONCLUSION: In subjects recovering from coeliac disease with negative tTG IgA serology, an undetectable titre is associated with normal histology on follow-up biopsy.

Comparison Between Total IgG, C1q, and C3d Single Antigen Bead Assays in Detecting Class I Complement-Binding Anti-HLA Antibodies.

BACKGROUND: Complement-binding donor-specific antibodies (DSAs) are associated with antibody-mediated rejection and allograft loss. Novel single antigen bead (SAB) assays-that is, complement component 1q (C1q) and complement component 3d (C3d) assays-have been developed to specifically detect complement-binding DSA, but it remains unclear whether these assays have an improved ability to detect complement-binding DSA as compared with using the total IgG SAB assay with a high mean fluorescence intensity (MFI) cutoff. The aim of this study was to compare the ability of the total IgG, C1q, and C3d SAB assays in detecting complement-binding anti-HLA antibodies. METHODS: Twenty sera known to have complement-binding anti-HLA antibodies (serologic class I HLA typing by complement-dependent cytotoxicity method) were tested with 3 different SAB assays: total IgG (undiluted and 1:8 dilution), C1q, and C3d. Serologic anti-HLA specificities were compared with those obtained by IgG, C1q, and C3d SAB assays. RESULTS: IgG SAB was more sensitive in detecting complement-binding antibodies (sensitivity 24 of 24 = 1, odds ratio infinity). Pearson correlation showed the association between (1) C1q and IgG SAB assays (cutoff C1q SAB 1000 MFI, cutoff IgG SAB 5000 MFI: r = 0.347, P < .0001) and (2) C3d and IgG SAB assays (cutoff 500 MFI C3d SAB, 5000 MFI for IgG SAB: r = -0.173, P = .279). CONCLUSIONS: For class I anti-HLA antibodies, IgG SAB (cutoff MFI > 5000) was more sensitive in detecting complement-binding antibodies when compared with C1q and C3d SAB assays.

Double-chambered right ventricle with pulmonary valve endocarditis.

A rare case of isolated pulmonary valve endocarditis associated with a double-chambered right ventricle in a nonaddict, was diagnosed on two-dimensional echocardiography and cardiac catheterization and angiography. The patient was successfully operated and the above findings confirmed on the operation table.

Properties of cyanovirin-N (CV-N): inactivation of HIV-1 by sessile cyanovirin-N (sCV-N).

Cyanovirin-N (CV-N) is a novel anti-HIV protein isolated and characterized from a cyanobacterium Nostoc ellipsosporum. CV-N protein is a single 101 amino acid chain containing two intrachain disulphide bonds and considerable internal sequence duplication, but no significant homology to previously described proteins or to the transcription products of known nucleotide sequences. In solution, CV-N exists largely as a beta-sheet protein with internal two-fold pseudosymmetry. CV-N irreversibly inactivates diverse laboratory strains, primary isolates and clades of HIV-1, as well as strains of HIV-2 and simian immunodeficiency virus (SIV). CV-N binds with extremely high affinity to highly conserved binding site(s) on the viral envelope glycoprotein gp120, preventing virus-to-cell fusion, viral entry and infection of cells. The CV-N binding site appears to overlap, but is not identical with, the unique carbohydrate-dependent epitope 2G12, and may lie predominantly within an immunologically "silent" region of gp120. CV-N is undergoing preclinical development for topical anti-HIV prophylactic (e.g., microbicidal) applications to prevent sexual transmission of HIV. Since CV-N may be immunogenic in humans, methods for using CV-N for ex vivo inactivation of HIV in blood, plasma, or putative vaccines preferably would allow for its exclusion from biologicals for parenteral use. To explore this concept we biotinylated CV-N (bCV-N) and coupled it to streptavidin coated magnetic beads to provide a product which we termed sessile CV-N (sCV-N). When reacted with a laboratory strain and a primary isolate of HIV- 1, the sCV-N completely inactivated 100 TCID50 of the virus. However RT-PCR of the viral extracts indicated that only a fraction of the virus was removed by the sCV-N, leaving behind a relatively larger fraction of non-infectious virus in the supernatant which we designated as replication incompetent virions (RIV). It would be worthwhile investigating the role of RIV as a putative HIV vaccine.

Pulsed Doppler derived indices in predicting noninvasively, pulmonary arterial pressures.

The pulsed doppler (P.D.) signals obtained in RVOT just below the pulmonary leaflets were used to calculate acceleration time (AcT), pre-ejection period (PEP) and their ratios. These indices were correlated in 31 patients (2 1/2-49 yrs. age) having varying cardiac lesions to Pulmonary arterial pressure (P.A.P) measured during cardiac catheterisation. The mean values of AcT for those with normal PAP was 137 +/- 19.9ms, as compared to 105 +/- 37 ms in those in whom PAP greater than 20mm of Hg. (t = 3.0.p less than .01). The P value was less than 0.001 when comparison was between normal PAP and severe PH. The ratios of PEP upon AcT was 0.87 +/- 0.18 for normal PAP, as compared to 1.39 +/- 0.74 in those with PH (t = 0.31, p less than 0.01). The PEP/AcT predicted systolic PAP 35.49 PEP/AcT + 3.22 (r = 0.77, p less than 0.001). The mean PAP was best predicted by 23.94 PEP/AcT + 2.44 (r = 0.75, p less than 0.001). The quantitative assessment showed presence of presystolic 'a' wave in all with normal PAP; this was absent in all the 9 patients with severe PH (MAPA greater than 40mm of Hg.). We conclude that noninvasively obtained P.D. derived indices can help accurately to predict PAP.

Coronary arteriographic findings soon after non Q wave myocardial infarction.

We performed early coronary arteriography in 27 patients (23 males, 4 females) having non Q wave MI. Infarct related vessel (IRV) was totally blocked in 25.9%, whereas 66.7% had severe residual stenosis (greater than or equal to 70%). Left main was involved in 7.5%, and at least 2 major coronary arteries were involved in 51.8%. Visible collaterals were seen in 11%. We feel, as compared to transmural MI, where total occlusion of IRV is common, the higher incidence of subtotal occlusion of IRV with severe residual stenosis, poor collaterals and significant involvement of at least one other major coronary artery may be responsible for observation of early recurrent ischemic episodes in non Q wave MI.