Inferior outcomes in lung transplant recipients with serum Pseudomonas aeruginosa specific cloaking antibodies.

BACKGROUND: Chronic Lung Allograft Dysfunction (CLAD) limits long-term survival following lung transplantation. Colonization of the allograft by Pseudomonas aeruginosa is associated with an increased risk of CLAD and inferior overall survival. Recent experimental data suggests that 'cloaking' antibodies targeting the O-antigen of the P. aeruginosa lipopolysaccharide cell wall (cAbs) attenuate complement-mediated bacteriolysis in suppurative lung disease. METHODS: In this retrospective cohort analysis of 123 lung transplant recipients, we evaluated the prevalence, risk factors and clinical impact of serum cAbs following transplantation. RESULTS: cAbs were detected in the sera of 40.7% of lung transplant recipients. Cystic fibrosis and younger age were associated with increased risk of serum cAbs (CF diagnosis, OR 6.62, 95% CI 2.83-15.46, p < .001; age at transplant, OR 0.69, 95% CI 0.59-0.81, p < .001). Serum cAbs and CMV mismatch were both independently associated with increased risk of CLAD (cAb, HR 4.34, 95% CI 1.91-9.83, p < .001; CMV mismatch (D+/R-), HR 5.40, 95% CI 2.36-12.32, p < .001) and all-cause mortality (cAb, HR 2.75, 95% CI 1.27-5.95, p = .010, CMV mismatch, HR 3.53, 95% CI 1.62-7.70, p = .002) in multivariable regression analyses. CONCLUSIONS: Taken together, these findings suggest a potential role for 'cloaking' antibodies targeting P. aeruginosa LPS O-antigen in the immunopathogenesis of CLAD.

Pretransplant Cytomegalovirus-Specific Cellular Immunity and Risk of Viral Reactivation Following Lung Transplantation: A Prospective Cohort Study.

Cytomegalovirus (CMV) remains a significant burden in lung transplant recipients. Deficiencies in T-cell immunity posttransplant increase the risk of CMV-associated complications. However, it is not clear if underlying poor pretransplant immunity increases risk. To assess this, we recruited 39 prospective lung transplant patients and performed QuantiFERON-CMV on their peripheral blood. More than a third of prospective CMV-seropositive transplant recipients were CMV non-immune reactive (CMV-NIR) pretransplant. CMV-NIR status was associated with a significantly higher incidence of CMV reactivation posttransplant, demonstrating that dysfunctional CMV immunity in prospective lung transplant recipients is associated with an increased risk of viral reactivation posttransplant.

Anaplasmosis Presenting With Respiratory Symptoms and Pneumonitis.

Anaplasmosis is a now common tick-borne illness that is characterized by the presence of fever, myalgias, thrombocytopenia, and elevated liver function tests. We report 4 cases with an atypical presentation with pulmonary symptoms and imaging findings, along with the characteristics of each patient, clinical course, and response to therapy.

Case Report of Immuno-Oncotherapy (IO) Provoked Encephalitis Mimicking Brain Metastasis in a Patient with History of Traumatic Brain Injury.

BACKGROUND: Immuno-oncotherapy (IO) has revolutionized systemic cancer care but remains experimental in brain tumors. IO treatment risks multiorgan autoimmune inflammatory responses that limit its use. The central nervous system (CNS) is an immune-specialized compartment with restricted cellular access, thus fewer cases are reported for immune-mediated encephalitis. Interestingly, patients with history of blood-brain barrier compromise are potentially at higher risk for immune cell trafficking to the CNS. CASE DESCRIPTION: We report the first case, to our knowledge, of a 70-year-old man with clear cell renal cell carcinoma with pulmonary metastases treated with lung irradiation, nephrectomy, and chemotherapy prior to switching to single-agent nivolumab IO. The patient presented with new-onset generalized tonic-clonic seizure and left visual field-cut. Review of patient history revealed remote traumatic brain injury (TBI). Brain imaging noted a solid-enhancing right occipital mass that was presumed metastasis versus lymphoma. Cerebrospinal fluid cytology was negative for malignancy but concerning for lymphoproliferative process not determined to be malignant. The patient started steroids and anti-epileptic therapy. After negative systemic cancer re-staging, IO was discontinued and steroids were initiated with demonstrated patient clinical improvement. CONCLUSIONS: We concluded the diagnosis of immune-mediated encephalitis secondary to IO with collection of reactive T-cells within the area of encephalomalacia. The area of encephalomalacia from prior TBI served to compartmentalize the reactive lymphocytes, giving the appearance of a mass. Taken together, new onset seizure in patients on IO might signal encephalitis and CNS metastatic mimicry should be considered in patients with a prior history of TBI and encephalomalacia.

Endothelial Glycocalyx Shedding Predicts Donor Organ Acceptability and Is Associated With Primary Graft Dysfunction in Lung Transplant Recipients.

BACKGROUND: The endothelial glycocalyx, a sieve-like structure located on the luminal surface of all blood vessels, has been found to be integral to regulation of capillary permeability and mechanotransduction. Given this, we investigated the role of endothelial glycocalyx breakdown products in organ donors and recipients in terms of acceptability for transplant and risk of primary graft dysfunction (PGD). METHODS: Endothelial glycocalyx breakdown products were measured in the peripheral blood of 135 intended and actual organ donors. Breakdown product levels were tested for association with donor demographic and clinical data, organ acceptability for transplant along with lung recipient outcomes (n = 35). Liquid chromatography mass spectrometry analysis was performed to confirm glycosaminoglycan levels and sulfation patterns on donor samples (n = 15). In transplant recipients (n = 50), levels were measured pretransplant and daily for 4 days posttransplant. Levels were correlated with PGD severity and intubation time. RESULTS: Decreased hyaluronan levels in peripheral blood independently predicted organ acceptability in intended and actual donors (odds ratio, 0.96; [95% confidence interval, 0.93-0.99] P = 0.026). Furthermore, high donor syndecan-1 levels were associated with PGD in recipients (3142 [1575-4829] versus 6229 [4009-8093] pg/mL; P = 0.045). In recipient blood, levels of syndecan-1 were correlated with severe (grades 2-3) PGD at 72 hours posttransplant (5982 [3016-17191] versus 3060 [2005-4824] pg/mL; P = 0.01). CONCLUSIONS: Endothelial glycocalyx breakdown occurs in lung transplant donors and recipients and predicts organ acceptability and development of PGD. Glycocalyx breakdown products may be useful biomarkers in transplantation, and interventions to protect the glycocalyx could improve transplant outcomes.

Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: A randomized, controlled pilot trial.

BACKGROUND: Lung transplant recipients (LTRs) are at very high risk of skin cancer. Omega-3 fatty acids (FAs) are anti-inflammatory and immune-modulating and could potentially reduce this risk. We assessed the feasibility of omega-3 FA supplementation to reduce skin cancer among these patients. METHODS: LTRs aged 18+ years, at least 1 year post-transplant, were recruited from the outpatient clinic of The Prince Charles Hospital, Brisbane. Participants were randomly allocated to 4-times-daily supplements containing either omega-3 FA (3.36 eicosapentaenoic acid [EPA] + docosahexaenoic acid) or placebo (4 g olive oil) for 12 months. Primary outcomes were rates of recruitment, retention, adherence (assessed by plasma omega-3 FA), and safety. Secondary outcomes were incident skin cancers. RESULTS: Among 106 eligible lung transplant recipients, 49 consented to take part (46%) with 25 allocated to omega-3 FA and 24 to placebo supplements. Of these, 22 (88%) and 20 (83%), respectively, completed the trial. After 12 months, median plasma EPA increased substantially in the intervention group (125.0 to 340.0 µmol/L), but not the placebo group (98.0 to 134.5 µmol/L). In the intervention group, 6 patients developed skin cancers compared with 11 in the placebo group, giving an odds ratio (95% confidence interval) of 0.34 (0.09 to 1.32). There were no serious, active intervention-related adverse events. CONCLUSIONS: This pilot trial among LTRs showed acceptable recruitment and high retention and adherence. We demonstrated a signal for reduction of new skin cancer cases in those taking omega-3 FA supplements, which supports the notion that a larger, more definitive trial is warranted.

Strategies to identify candidates for D variant genotyping.

BACKGROUND: RhD variants have altered D epitopes and/or decreased antigen copies per red cell. Individuals carrying these variants may test antigen negative, weakly positive, or positive by serology, and may or may not be at risk of alloimmunisation after exposure. There have been recommendations to perform RHD genotyping of patients, pregnant women and females of childbearing potential with serological weak D phenotype, to guide prophylactic use of Rh immune globulin (RhIG), and better conserve D-negative blood products. The purpose of this study was to evaluate the performance of a set of empirical criteria to identify such patients. MATERIALS AND METHODS: A two-method strategy of gel testing (GT) and tube testing (TT) was used for Rh typing of patients with no historical blood type in the present institution. A monoclonal-polyclonal blend anti-D was used for Rh typing by TT at immediate spin. Three empirical criteria were used to identify candidates for genotyping: C1: discrepancy between the two test methods and a GT reaction strength >2+ stronger than TT; C2: weak serological reaction, defined as reaction strength ≤2+ regardless of testing method if both GT and TT were performed or reaction strength ≤2+ if only GT was performed, or reaction strength ≤1+ if only TT was performed; C3: presence of anti-D in D-positive patients with no history of RhIG use in the preceding 3 months and in whom alloanti-D is suspected. RESULTS: Overall, 50 patients, ranging from newly born to 93 years old, were identified. Genomic testing confirmed D variants in 49/50 cases with a positive predictive value of 98%. DISCUSSION: This two-method strategy is a powerful screening tool for identifying candidates for RHD genotyping. This strategy meets the current requirements of two blood type determinations/two specimens in pre-transfusion testing while simultaneously identifying candidates for RHD genotyping with a minimal increase in work load and cost.

Does therapeutic plasma exchange have a role in the treatment of prosthetic hip-associated cobalt toxicity? A case report and literature review.

BACKGROUND: Prosthetic hip-associated cobalt toxicity (PHACT) is an uncommon, but potentially devastating, complication for patients with metal-on-metal hip implants (MoMs). Clinical management of PHACT is poorly defined, with primary intervention being MoM explant followed by chelation therapy. Therapeutic plasma exchange (TPE) in cobalt toxicity has not been previously described. Given that cobalt is predominantly albumin bound, it should theoretically be removed by TPE. Here we report a case of PHACT and our experience using TPE to lower plasma cobalt levels. CASE REPORT: A 61-year-old woman developed deafness, blindness, ambulatory dysfunction, and endocrinopathies after MoM implant. Cobalt levels on admission were greater than 1500 µg/L. In an attempt to rapidly lower cobalt levels before MoM explant, hemodialysis and TPE were performed. Hemodialysis removed negligible amounts of cobalt. One session of TPE temporarily removed approximately two-thirds of measurable cobalt, but levels rebounded to pre-TPE values after 8 hours. It was only after MoM removal that cobalt levels plateaued below 300 µg/L and clinical symptoms improved. DISCUSSION: TPE removed cobalt from a PHACT patient, but a durable decrease in cobalt was only achieved after MoM explant. These findings are comparable to reports where chelation was employed in PHACT patients before MoM explant. The observed rebound phenomenon is likely from rapid equilibration between the immense extravascular tissue source (the MoM) and the intravascular compartment. CONCLUSION: TPE may serve as adjunctive therapy for PHACT patients whose cobalt levels remain high after explant, especially in patients with renal failure, in whom chelation is contraindicated.

Comparative Evaluation of the BD Phoenix Yeast ID Panel and Remel RapID Yeast Plus System for Yeast Identification.

Becton Dickinson Phoenix Yeast ID Panel was compared to the Remel RapID Yeast Plus System using 150 recent clinical yeast isolates and the API 20C AUX system to resolve discrepant results. The concordance rate between the Yeast ID Panel and the RapID Yeast Plus System (without arbitration) was 93.3% with 97.3% (146/150) and 95.3% (143/150) of the isolates correctly identified by the Becton Dickinson Phoenix and the Remel RapID, respectively, with arbitration.

Env-2dCD4 S60C complexes act as super immunogens and elicit potent, broadly neutralizing antibodies against clinically relevant human immunodeficiency virus type 1 (HIV-1).

The ability to induce a broadly neutralizing antibody (bNAb) response following vaccination is regarded as a crucial aspect in developing an effective vaccine against human immunodeficiency virus type 1 (HIV-1). The bNAbs target the HIV-1 envelope glycoprotein (Env) which is exposed on the virus surface, thereby preventing cell entry. To date, conventional vaccine approaches such as the use of Env-based immunogens have been unsuccessful. We expressed, purified, characterized and evaluated the immunogenicity of several unique HIV-1 subtype C Env immunogens in small animals. Here we report that vaccine immunogens based on Env liganded to a two domain CD4 variant, 2dCD4(S60C) are capable of consistently eliciting potent, broadly neutralizing antibody responses in New Zealand white rabbits against a panel of clinically relevant HIV-1 pseudoviruses. This was irrespective of the Env protein subtype and context. Importantly, depletion of the anti-CD4 antibodies appeared to abrogate the neutralization activity in the rabbit sera. Taken together, this data suggests that the Env-2dCD4(S60C) complexes described here are "super" immunogens, and potentially immunofocus antibody responses to a unique epitope spanning the 2dCD4(60C). Recent data from the two available anti-CD4 monoclonal antibodies, Ibalizumab and CD4-Ig (and bispecific variants thereof) have highlighted that the use of these broad and potent entry inhibitors could circumvent the need for a conventional vaccine targeting HIV-1. Overall, the ability of the unique Env-2dCD4(S60C) complexes to elicit potent bNAb responses has not been described previously, reinforcing that further investigation for their utility in preventing and controlling HIV-1/SIV infection is warranted.

Transfusion-related acute lung injury in an era of TRALI risk mitigation.

Transfusion-related acute lung injury (TRALI) is a rare complication of transfusion, for which the true incidence remains obscure, since there are a number of factors that may lead to misdiagnosis. Despite this, it continues to be the leading cause of transfusion-associated mortality. Here we present a historical case of TRALI in an elderly female who received group AB plasma and discuss how current mitigation strategies would likely have prevented its occurrence. It is important to remember that both immune and non-immune factors play a role in TRALI pathogenesis, and although current preventative strategies may decrease TRALI's incidence, they likely will not eliminate it.