Risk factors for fatal and nonfatal reactions to immunotherapy (2008-2018): postinjection monitoring and severe asthma.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) is highly effective but risks exist. OBJECTIVE: To identify practices that influence systemic allergic reactions (SRs) to SCIT and SCIT-associated infections. METHODS: Members of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology completed an annual survey of SCIT-related SRs of varying severity (2008-2018). Injection-related infections were queried (2014-2018). Strategies to enforce postinjection waiting times and to reduce risks from asthma/severe asthma were queried (2016-2018). RESULTS: Data were gathered on 64.5 million injection visits. Ten confirmed fatalities occurred since 2008, including 3 new fatalities since 2017. One fatal reaction occurred per 7.2 million injection visits (2008-2018). No infections occurred. Practices that tracked the time after injections, and required checking out with office personnel, had significantly lower total (P < .001), grade 3 (severe) (P < .001), and grade 4 (very severe) SRs (P < .001). Having more individuals with asthma on SCIT was associated with more grade 3 SRs (P < .02). Not prescribing SCIT in individuals with uncontrolled asthma was associated with fewer grade 3 SRs (P = .02). Having individuals with more severe asthma on SCIT was associated with more total, grade 1, and grade 2 SRs (P < .001); 50% of grade 3 and 4 SRs occurred in individuals with severe asthma. CONCLUSION: SCIT-related fatalities have declined since 2008, with a slight increase in recent years. SCIT is not associated with an increased risk of infections. Tracking the time after injections and checking out with office staff confer significantly lower risks of severe SRs. Asthma, especially severe asthma, is a major risk factor for severe and fatal SRs. Strategies that reduce risks for individuals with asthma, such as not prescribing SCIT to patients with uncontrolled asthma, may lower the risks.

ABO-Incompatible Living-Donor Kidney Transplantation in a Developing Country: A Multicenter Experience in Malaysia.

Malaysia has a low deceased-donor donation rate and has not embarked on a paired kidney exchange program; therefore, ABO-incompatible and HLA-incompatible transplantation remain the main contributor to the sustainability of the national kidney transplantation (KT) program. There were 26 cases of ABO-incompatible KTs performed from 2011 to 2018 in 3 major transplant centers, namely, Hospital Kuala Lumpur, University Malaya Medical Centre, and Prince Court Medical Centre. We collected perioperative and follow-up data through June 2019. The desensitization protocol varies and is center specific: the localized Japanese protocol and Swedish protocol with a target anti-A/B isoagglutinin titer of 16 or 32 on the day of transplant. The induction and tacrolimus-based maintenance protocol was nearly identical. The median follow-up time was 62.3 months (interquartile range, 37.0-79.7). Fifteen subjects had the highest predesensitization anti-A/B titer of ≥32 (57.7%). The acute cellular rejection and antibody-mediated rejection incidence were 12.5% (3 cases) and 8.3% (2 cases), respectively. Patient, graft, and death-censored graft survival rates were 96.2%, 92.3%, and 96.0%, respectively, 1 year post-living-donor KT (LDKT) and 96.2%, 87.2%, and 90.7%, respectively, 5 years post-LDKT. Our experience shows that ABO-incompatible LDKT using a suitable desensitization technique could be a safe and feasible choice for LDKT even with varied desensitization regimens for recipients with relatively high baseline isoagglutinin titers.

Rituximab protects against development of atherosclerotic cardiovascular disease after kidney transplantation: a propensity-matched study.

Recent studies have implicated B cells in atherosclerosis and have verified the atheroprotective effect of rituximab. Rituximab is widely used for desensitization in ABO-incompatible or crossmatch-positive kidney transplantation (KT). Using a single-center KT database, we performed propensity-matched analysis to investigate the association between rituximab and posttransplant atherosclerotic cardiovascular disease (ASCVD). Among 1299 eligible patients, 239 given rituximab induction were matched with 401 controls in a 1:2 propensity score matching process. The cumulative rate of ASCVD during 8 years of follow-up was significantly lower in rituximab-treated patients, compared with matched controls (3.7% vs. 11.2%; P = 0.012). However, all-cause mortality did not differ by group (2.9% vs. 4%; P = 0.943). In multivariable Cox analysis, rituximab proved independently protective of ASCVD (hazard ratio = 0.34, 95% confidence interval: 0.14-0.83). The lower risk of ASCVD seen with rituximab induction reached significance only in patient subsets of diabetes mellitus, pretransplant dialysis, or older age (>50 years). Rituximab induction confers a lower risk of ASCVD during the posttransplant period. This atheroprotective effect appears particularly beneficial in patients whose risk of ASCVD is heightened.

Favorable Outcome of an Exclusively Posttransplant Prophylactic Strategy After Heart Transplantation in Recipients With High Immunological Risk.

BACKGROUND: Management of the increasing number of sensitized heart transplant candidates has become a recurrent issue. Rather than using pretransplant desensitization therapies, we used a posttransplant prophylactic strategy. Our aim was to describe outcomes in transplant recipients with preformed donor-specific anti-HLA antibodies (pfDSA) managed with this strategy. METHODS: A posttransplant protocol was applied to patients transplanted with pfDSA, consisting of perioperative management of DSA (polyvalent immunoglobulins +/- perioperative plasmapheresis sessions, according to DSA level, as well as induction therapy) and systematic treatment of subsequent antibody-mediated rejection (AMR), even when subclinical. We performed a retrospective analysis of this prospective protocol. The study included all consecutive first recipients of a noncombined heart transplant performed between 2009 and 2015 at our center. The primary endpoint was all-cause mortality. Secondary endpoints included primary graft dysfunction, early posttransplant bleeding, rejection, and cardiac allograft vasculopathy-free survival. RESULTS: A total of 523 patients were studied, including 88 (17%) and 194 (37%) transplanted with DSA mean fluorescence intensity (MFI) of 500 to 1000 and greater than 1000, respectively. The median follow-up period was 4.06 years. Survival was not significantly different between groups. Rejection-free survival was worse in patients with pfDSA MFI >1000, evidenced by a fourfold increase in the risk of antibody-mediated rejection. The incidence of primary graft dysfunction and cardiac allograft vasculopathy-free survival did not significantly differ between groups. Perioperative plasmapheresis increased the risk for transfusion of packed red blood cells. CONCLUSIONS: This exclusively posttransplant prophylactic strategy achieved favorable outcomes in heart transplant recipients with pfDSA.

A comparison of desensitization methods: Rituximab with/without plasmapheresis in ABO-incompatible living donor liver transplantation.

BACKGROUND: Plasmapheresis is a desensitization method used prior to ABO-incompatible (ABO-I) living donor liver transplantation. However, studies on its usefulness in the rituximab era are lacking. METHODS: Fifty-six adult patients underwent ABO-I living donor liver transplantation between January 2012 and October 2015. A single dose of rituximab (300 mg/m2) was administered 2 weeks before surgery with plasmapheresis in all patients until February 2014 (RP group, n = 26). Patients were administered rituximab only, without plasmapheresis between March 2014 and October 2015 (RO group, n = 30). RESULTS: The 6-, 12- and 18-month overall survival rates were 92.3%, 80.8% and 76.9% in the RP group and 96.6%, 85.4% and 85.4% in the RO group, respectively (P = 0.574). When the initial isoagglutinin titers < 16, neither group showed a rebound rise of isoagglutinin titers. For patients with initial isoagglutinin titers ≥ 16, the rebound rise of isoagglutinin titers was more prominent in the RP group. There was no difference in time-dependent changes in B cell subpopulations and ABO-I-related complications. CONCLUSIONS: Sufficient desensitization for ABO-I living donor liver transplantation can be achieved using rituximab alone. This desensitization strategy does not affect the isoagglutinin titers, ABO-I-related complications and patient survival.

Results of a multicenter prospective clinical study in Japan for evaluating efficacy and safety of desensitization protocol based on rituximab in ABO-incompatible kidney transplantation.

BACKGROUND: Deceased organ donations are rare in Japan, with most kidney transplants performed from a limited number of living donors. Researchers have thus developed highly successful ABO-incompatible transplantation procedures, emphasizing preoperative desensitization and postoperative immunosuppression. A recent open-label, single-arm, multicenter clinical study prospectively examined the efficacy and safety of rituximab/mycophenolate mofetil desensitization in ABO-incompatible kidney transplantation without splenectomy. METHODS: Mycophenolate mofetil and low dose steroid were started 28 days pretransplant, followed by two doses of rituximab 375 mg/m2 at day -14 and day -1, and postoperative immunosuppression with tacrolimus or ciclosporin and basiliximab. The primary endpoint was the non-occurrence rate of acute antibody-mediated rejection. Patient survival and graft survival were monitored for 1 year posttransplant. RESULTS: Eighteen patients received rituximab and underwent ABO-incompatible kidney transplantation. CD19-positive peripheral B cell count decreased rapidly after the first rituximab infusion and recovered gradually after week 36. The desensitization protocol was tolerable, and most rituximab-related infusion reactions were mild. No anti-A/B antibody-mediated rejection occurred with this series. One patient developed anti-HLA antibody-mediated rejection (Banff 07 type II) on day 2, which was successfully managed. Patient and graft survival were both 100 % after 1 year. CONCLUSION: Our desensitization protocol was confirmed to be clinically effective and with acceptable toxicities for ABO-I-KTx (University Hospital Medical Information Network Registration Number: UMIN000006635).

Immune Desensitization Allows Pediatric Blood Group Incompatible Kidney Transplantation.

BACKGROUND: Blood group incompatible transplantation (ABOi) in children is rare as pretransplant conditioning remains challenging and concerns persist about the potential increased risk of rejection. METHODS: We describe the results of 11 ABOi pediatric renal transplant recipients in the 2 largest centers in the United Kingdom, sharing the same tailored desensitization protocol. Patients with pretransplant titers of 1 or more in 8 received rituximab 1 month before transplant; tacrolimus and mycophenolate mofetil were started 1 week before surgery. Antibody removal was performed to reduce titers to 1 or less in 8 on the day of the operation. No routine postoperative antibody removal was performed. RESULTS: Death-censored graft survival at last follow-up was 100% in the ABOi and 98% in 50 compatible pediatric transplants. One patient developed grade 2A rejection successfully treated with antithymocyte globulin. Another patient had a titer rise of 2 dilutions treated with 1 immunoadsorption session. There was no histological evidence of rejection in the other 9 patients. One patient developed cytomegalovirus and BK and 2 others EBV and BK viremia. CONCLUSIONS: Tailored desensitization in pediatric blood group incompatible kidney transplantation results in excellent outcomes with graft survival and rejection rates comparable with compatible transplants.

Alternative products to treat allergic rhinitis and alternative routes for allergy immunotherapy.

BACKGROUND: Some alternative products instead of immunotherapy are used in patients with allergic rhinitis (AR). METHODS: In this paper, alternative products to treat allergic rhinitis and alternative routes for allergy immunotherapy are reviewed. RESULTS: Alternative products and methods used instead of immunotherapy are tea therapy, acupuncture, Nigella sativa, cinnamon bark, Spanish needle, acerola, capsaicin (Capsicum annum), allergen-absorbing ointment, and cellulose powder. N. sativa has been used in AR treatment due to its anti-inflammatory effects. N. sativa oil also inhibits the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The beneficial effects of N. sativa seed supplementation on the symptoms of AR may be due to its antihistaminic properties. To improve the efficacy of immunotherapy, some measures are taken regarding known immunotherapy applications and alternative routes of intralymphatic immunotherapy and epicutaneous immunotherapy are used. CONCLUSION: There are alternative routes and products to improve the efficacy of immunotherapy.

Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013).

BACKGROUND: In 2008, an annual surveillance study of systemic reactions (SRs) from subcutaneous immunotherapy (SCIT) injections was initiated in North America. OBJECTIVE: To define the incidence of SRs to SCIT. METHODS: From 2008 to 2013, 27% to 51% of American Academy of Allergy, Asthma, and Immunology and American College of Asthma, Allergy, and Immunology members completed an annual survey of SCIT-related SRs of varying severity. From 2012 to 2013, data were collected regarding SRs with off-label sublingual immunotherapy (SLIT), selection of patients with asthma for SCIT, and strategies for dose adjustment during pollen seasons. RESULTS: From 2008 to 2013, data were gathered on 28.9 million injection visits, including 344,480 patients for 2012 to 2013. Since 2008, a total of 2 confirmed fatalities were directly reported that occurred under the care of allergists. Two additional fatalities occurred under the care of nonallergists. The rate of SRs from SCIT remained stable, occurring in 1.9% of patients, with 0.08% and 0.02% experiencing grade 3 and 4 SRs. SRs occurred in 1.4% of patients receiving off-label SLIT, including 0.03% with grade 3 SRs. There were no SLIT-related grade 4 SRs or fatalities. Practices that never administered SCIT in patients with uncontrolled asthma (Asthma Control Test score <20) had significantly fewer grade 3 and 4 SRs (odds ratio, 0.7; 95% confidence interval, 0.5-1.0, and odds ratio, 0.3; 95% confidence interval, 0.1-0.8, respectively). Lowering doses during pollen seasons for patients with highly positive skin tests reduced SRs of all severity grades (P < .05). CONCLUSIONS: SCIT-related fatality rates may be decreasing, but continued vigilance regarding modifiable risk factors, including careful patient selection, is needed. Dose adjustment during pollen seasons for highly sensitive patients may reduce risks. Potential risk for SRs from off-label SLIT exists.

Outcomes Following ABO-Incompatible Kidney Transplantation Performed After Desensitization by Nonantigen-Specific Immunoadsorption.

BACKGROUND: For desensitization of ABO-incompatible kidney transplant recipients we recently proposed nonantigen-specific immunoadsorption (IA) and rituximab. METHODS: We now compared clinical outcomes of 34 ABO-incompatible living-donor kidney recipients who were transplanted using this protocol with that of 68 matched ABO-compatible patients. In addition, we analyzed efficacy and cost of nonantigen-specific as compared to blood group antigen-specific IA. RESULTS: Before desensitization, the median isoagglutinin titer of 34 ABO-incompatible patients was 1:64 (Coombs technique). Patients received a median of 7 preoperative IA treatments. Twenty-four patients had a median of 2 additional plasmapheresis treatments to reach the preoperative target isoagglutinin titer of 1:8 or less. After a median postoperative follow-up of 22 months, overall graft survival in the ABO-incompatible group was not significantly different from that in ABO-compatible patients (log-rank P = 0.20), whereas patient survival tended to be lower (log-rank P = 0.05). The incidence of rejection episodes was 15% in both groups. The ABO-incompatible kidney recipients had a higher incidence of BK virus replication (P = 0.04) and nephropathy (P = 0.01) and showed more often colonization with multidrug resistant bacteria (P = 0.02). In comparison to blood group antigen-specific IA, nonantigen-specific IA showed equal efficacy but was associated with reduction in cost. CONCLUSIONS: Clinical outcomes of ABO-incompatible patients desensitized with a nonantigen-specific IA device and rituximab do not differ from that of matched ABO-compatible patients although a trend toward reduced patient survival was noted. Special attention must be paid to the higher incidence of BK virus infection in recipients of ABO-incompatible grafts.

Factors Predicting Risk for Antibody-mediated Rejection and Graft Loss in Highly Human Leukocyte Antigen Sensitized Patients Transplanted After Desensitization.

BACKGROUND: Desensitization with intravenous immunoglobulin and rituximab (I+R) significantly improves transplant rates in highly sensitized patients, but antibody-mediated rejection (ABMR) remains a concern. PATIENTS AND METHODS: Between July 2006 and December 2012, 226 highly sensitized patients received transplants after desensitization. Most received alemtuzumab induction and standard immunosuppression. Two groups were examined: ABMR (n = 181) and ABMR (n = 45, 20%). Risk factors for ABMR, pathology, and outcomes were assessed. RESULTS: Significant risks for ABMR included previous transplants and pregnancies as sensitizing events, donor-specific antibody (DSA) relative intensity scores greater than 17, presence of both class I and II DSAs at transplant and time on waitlist. The ABMR showed a significant benefit for graft survival and glomerular filtration rate at 5 years (P < 0.0001). Banff pathology characteristics for ABMR patients with or without graft loss did not differ. C4d versus C4d ABMR did not predict graft loss (P = 0.086). Thrombotic microangiopathy (TMA) significantly predicted graft failure (P = 0.045). The ABMR episodes were treated with I+R (n = 25), or, in more severe ABMR, plasma exchange (PLEX)+I+R (n = 20). Graft survival for patients treated with I+R was superior (P = 0.028). Increased mortality was seen in ABMR patients experiencing graft loss after ABMR treatment (P = 0.004). The PLEX + Eculizumab improved graft survival for TMA patients (P = 0.036). CONCLUSION: Patients desensitized with I+R who remain ABMR have long-term graft and patient survival. The ABMR patients have significantly reduced graft survival and glomerular filtration rate at 5 years, especially TMA. Severe ABMR episodes benefit from treatment with PLEX + Eculizumab. The DSA-relative intensity scores at transplant was a strong predictor of ABMR. Donor-specific antibody avoidance and reduction strategies before transplantation are critical to avoiding ABMR and improving long-term outcomes.

Immunotherapy safety: what have we learned from surveillance surveys?

Subcutaneous allergen immunotherapy (SCIT) is beneficial for the treatment of allergic rhinitis, asthma, and in preventing stinging insect anaphylaxis, but is not without risks. Four retrospective surveillance surveys and one on-going national prospective study have attempted to characterize the incidence and risk factors for fatal and non-fatal SCIT reactions. These studies have contributed significantly to currently recommended SCIT safety guidelines. Recent surveillance studies indicate stable SR rates, and a possible decline in the incidence of fatal reactions since the implementation of evidence-based safety guidelines. This review will provide a detailed summary of the evidence from surveillance studies for risk factors associated with SCIT reactions, including: uncontrolled asthma, prior systemic reactions, dosing during peak pollen seasons, epinephrine being delayed or not given, dosing or administration errors, inadequate waiting times, reactions occurring more than 30 min after injections, injections given in medically unsupervised settings, concomitant beta-blocker and angiotensin-converting enzyme inhibitor (ACEi) use, and accelerated build-up regimens.

Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy.

ABO-incompatible (ABOi) renal transplantation has been increasing, but malignant tumor is a troubling complication of kidney transplantation due to potent immunosuppression. Few previous studies, however, have demonstrated that potent immunosuppression for ABOi living-donor renal transplantation (LDRT) is a risk factor for malignancy. In the present research, data on 252 LDRT patients ftom 2003 to 2008 were retrospectively analyzed to clarify whether ABOi LDRT was associated with malignancy. A potent immunosuppressive regimen for ABOiLDRT consisted of splenectomy, cyclophosphamide, and double-filtration plasmapheresis to minimize the risk of antibody-mediated rejection, in addition to conventional immunosuppresssants including calcineurin inhibitor, prednisolone, and anti-CD25 monoclonal antibody. A total of 11 incidences of malignancy were observed during a median follow-up of 48 months. The incidence rates in ABO-compatible (ABOc; n = 189) and ABOi (n = 63) LDRT groups were 4.2 % (8/189) and 4.8 % (3/63), respectively. Kaplan-Meier survival analysis showed no statistical difference in event-free survival for malignancy between ABOc and ABOiLDRT groups (log-rank P = .73). Multivariable Cox regression analyses identified no associations of malignancy with ABOi LDRT or any immunosuppressant use. In conclusion, our investigation suggested that potent immunosuppression with splenectomy and cyclophosphamide for ABOi LDRT may not be a risk factor for malignancy.

Bridge to transplant experience: factors influencing survival to and after cardiac transplant.

OBJECTIVE: Balancing longer duration of mechanical circulatory support while awaiting functional recovery against the increased risk of adverse events with each day on support is difficult. Therefore, we investigated the complex interplay of duration of mechanical circulatory support and patient and device factors affecting survival on support, as well as survival after transplantation. METHODS: From December 21, 1991, to July 1, 2006, mechanical circulatory support was used in 375 patients as a bridge to transplantation, with 262 surviving to transplant. Implantable pulsatile devices were used in 321 patients, continuous flow was used in 11 patients, a total artificial heart was used in 5 patients, external pulsatile devices were used in 34 patients, and extracorporeal membrane oxygenation was used in 68 patients. Two time-related models were developed: (1) a competing-risks multivariable model of death on mechanical circulatory support, with modulated renewal for each sequential support mode; and (2) a model of death after transplant in which patient factors and duration of mechanical circulatory support were investigated as risk factors. RESULTS: Survival after initiating mechanical circulatory support, irrespective of transplantation, was 86% at 30 days, 55% at 5 years, and 41% at 10 years; survival was 94%, 74%, and 58% at the same time intervals, respectively, after transplantation in those surviving the procedure. Risk factors for death included longer, but not shorter, duration of mechanical circulatory support, use of multiple devices, global sensitization, and poor renal function. CONCLUSION: Initiating mechanical circulatory support early with a single definitive device may improve survival to and after cardiac transplantation. Early transplant, which avoids infection, sensitization, and neurologic complications, may improve bridge and transplant survival.

[Allergy--triggers of life-threatening and fatal anaphylaxis]. / Von Aspirin bis Zanderfilet: Die häufigsten Auslöser tödlicher Anaphylaxien.

Cases of life-threatening and fatal anaphylaxis represent the most extreme forms of acute allergic reactions. They are estimated to have an incidence of 1-3 per 10,000 persons, with an associated death rate of 0.5-2%. Medicinal drugs, insect stings and foods are the most common triggering agents. In particular in the case of drugs, the median time lapse between contact with the triggering agent and death is a very short 5-10 minutes. Fatal anaphylaxis due to foods usually leads first to dyspnea and then to respiratory failure. Allergic bronchial asthma represents a major risk factor. Knowledge of the allergens capable of triggering life-threatening and fatal anaphylaxis makes it easier for the physician to assess the risk potential when confronted by an emergency situation.