Analysis of Cross-sectional and Longitudinal HLA and Anti-viral Responses After COVID Infection in Renal Allograft Recipients: Differences and Correlates.

BACKGROUND: Characterization of anti-HLA versus anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immune globulin isotypes in organ transplant recipients after coronavirus disease 2019 (COVID-19) infection has not been reported. We aimed to determine changes in anti-HLA antibodies in renal transplant patients with COVID-19 and compare the immunoglobulin and epitope-binding pattern versus anti-SARS-CoV-2 antibodies. METHODS: This is a cross-sectional study of 46 kidney transplant recipients including 21 with longitudinal sampling. Using a semi-quantitative multiplex assay, we determined immunoglobulin (Ig) M, IgA, IgG, and IgG1-2-3-4 antibodies against Class I and Class II HLA, and 5 SARS-CoV-2 epitopes including the nucleocapsid protein and multiple regions of the spike protein. RESULTS: Fourteen of 46 (30%) patients had donor-specific anti-HLA antibodies (donor-specific antibody [DSA]), 12 (26%) had non-DSA anti-HLA antibodies and 45 (98%) had anti-SARS-CoV-2 antibodies. Most DSAs targeted HLA-DQ (71%), with a dominant IgG isotype and IgG1 subtype prevalence (93%), and/or IgG3 (64%), followed by IgG2 (36%). Comparatively, there was a higher prevalence of IgA (85% versus 14%, P = 0.0001) and IgM (87%, versus 36%, P = 0.001) in the anti-SARS-CoV-2 antibody profile, when compared to DSAs, respectively. Anti-SARS-CoV-2 antibody profile was characterized by increased prevalence of IgM and IgA, when compared to DSAs. The median calculated panel reactive antibody before COVID-19 diagnosis (24%) tended to decrease after COVID-19 diagnosis (10%) but it was not statistically significant ( P = 0.1). CONCLUSIONS: Anti-HLA antibody strength and calculated panel reactive antibody in kidney transplant recipients after COVID-19 do not significantly increase after infection. Although the IgG isotype was the dominant form in both HLA and SARS-CoV-2 antigens, the alloimmune response had a low IgA pattern, whereas anti-SARS-CoV-2 antibodies were high IgA/IgM.

Multifactorial expression of IL-6 with update on COVID-19 and the therapeutic strategies of its blockade (Review).

Interleukin 6 (IL-6), a cytokine produced by various cells of the human body (macrophages, lymphocytes, astrocytes, ischemic myocytes, endothelial cells) has both pro-inflammatory and anti-inflammatory properties, being a key component in regulating various physiologic and pathological processes. The structure of this molecule and the receptor system it possesses are important due to the different activities that IL-6 can exert; through trans-signaling pro-inflammatory activities are mediated, while through classic signaling, IL-6 is responsible for anti-inflammatory and regenerative activities. IL-6 signaling is involved in coronary artery disease and the global COVID-19 pandemic. This proatherogenic cytokine reaches elevated serum levels in the cytokine storm generated by SARS-CoV-2, and is also associated with smoking or obesity-classic cardiovascular risk factors which promote inflammatory states. IL-6 levels are proportionally correlated with dyslipidemia, hypertension and glucose dysregulation, and they are associated with poor outcomes in patients with unstable angina or acute myocardial infarction. IL-6 targeting for treatment development (not only) in cardiovascular disease and COVID-19 is still a matter of ongoing research, although tocilizumab has proven to be effective in reducing the proatherogenic effects of IL-6 and is suggested to improve COVID-19 patient survival.

Neurodevelopmental impairment at 2 years of age in children born before 29 weeks' gestation with bronchopulmonary dysplasia.

INTRODUCTION: Very preterm children are at a high risk for neurological impairment, especially those with bronchopulmonary dysplasia (BPD). The main goal of this study was to describe the neurodevelopmental impairment (NDI) at 2 years of corrected age in children born before 29 weeks' gestation between 2010 and 2015 and affected by BPD at 28 days of life. We also searched for risk factors associated with NDI, especially postnatal steroid (PNS) administration. MATERIAL AND METHODS: This was a retrospective study comprising a cohort of children hospitalized at the university hospital in Grenoble, born before 29 weeks' gestation between 2010 and 2015, and included in the monitoring network "Naitre et Devenir" (RND). Infants at 2 years of corrected age were classified as having NDI if they had at least one of the following outcomes: a global developmental quotient (DQ) on the revised Brunet-Lézine scale of<85, blindness, deafness, or cerebral palsy (CP) graded as level 3 or more according to the Gross Motor Function Classification System. RESULTS: A total of 129 children were included, of whom 99 were monitored at the age of 2 years: 31.3% of the population had NDI and 4% had CP. The median DQ test result was 90 (interquartile 82-97). Factors associated with NDI in univariate analysis were low gestational age, low birth weight, a cord pH<7.2, chorioamnionitis, treatment for persistent ductus arteriosus, longer oxygen therapy, and outborn status, which almost reached statistical significance. In multivariate analysis, low gestational age and outborn status remained statistically significant, while chorioamnionitis was found to have some association with NDI. While 13.1% of the followed-up population was treated with PNS, this risk factor was not associated with NDI. CONCLUSION: In a population of very preterm children, one third had NDI at 2 years of corrected age. Low gestational age, outborn status, and perinatal inflammation are associated with this unfavorable outcome. The frequency of sequelae confirms the importance of following up these children.

Glucocorticoid-Induced Skin Atrophy: The Old and the New.

Glucocorticoids are major therapeutic agents highly used in the medical field. Topical glucocorticoids have biologic activities which make them useful in dermatology - anti-inflammatory, vasoconstrictive, immune suppressive and antiproliferative, in treating inflammatory skin disorders (allergic contact eczema, atopic hand eczema, nummular eczema, psoriasis vulgaris or toxic-irritative eczema). Unfortunately, the beneficial effects of topical glucocorticoids are shadowed by their potential for adverse effects - muscle or skin atrophy, striae distensae, rubeosis or acne. Skin atrophy is one of the most prevalent side-effects, with changes found in all skin compartments - marked hypoplasia, elasticity loss with tearing, increased fragility, telangiectasia, bruising, cutaneous transparency, or a dysfunctional skin barrier. The structure and function of the epidermis is altered even in the short-term topical glucocorticoid treatment; it affects stratum corneum components, subsequently affecting skin barrier integrity. The dermis is altered by directly inhibiting fibroblast proliferation, reducing mast cell numbers, and loss of support; there is depletion of mucopolysaccharides, elastin fibers, matrix metalloproteases and inhibition of collagen synthesis. Atrophogenic changes can be found also in hair follicles, sebaceous glands or dermal adipose tissue. Attention should be paid to topical glucocorticoid treatment prescription, to the beneficial/adverse effects ratio of the chosen agent, and studies should be oriented on the development of newer, innovative targeted (gene or receptor) therapies.

A prospective, iterative, adaptive trial of carfilzomib-based desensitization.

Proteasome inhibitor-based strategies hold promise in transplant but have yielded varying results. Carfilzomib, a second-generation proteasome inhibitor, may possess advantages over bortezomib, the first-generation proteasome inhibitors. The purpose of this study was to evaluate the safety, toxicity, and preliminary efficacy of carfilzomib in highly HLA-sensitized kidney transplant candidates. Renal transplant candidates received escalating doses of carfilzomib followed by plasmapheresis (group A) or an identical regimen with additional plasmapheresis once weekly before carfilzomib dosing. Thirteen participants received carfilzomib, which was well tolerated with most adverse events classified as low grade. The safety profile was similar to bortezomib desensitization; however, neurotoxicity was not observed with carfilzomib. Toxicity resulted in permanent dose reduction in 1 participant but caused no withdrawals or deaths. HLA antibodies were substantially reduced with carfilzomib alone, and median maximal immunodominant antibody reduction was 72.8% (69.8% for group A, P = .031, 80.1% for group B, P = .938). After depletion, rebound occurred rapidly and antibody levels returned to baseline between days 81 and 141. Bone marrow studies revealed that approximately 69.2% of plasma cells were depleted after carfilzomib monotherapy. Carfilzomib monotherapy-based desensitization provides an acceptable safety and toxicity profile while leading to significant bone marrow plasma cell depletion and anti-HLA antibody reduction.

IGG3 anti-HLA donor-specific antibodies and graft function in pediatric kidney transplant recipients.

Anti-HLA DSAs are associated with ABMR and graft loss in KT recipients, yet the influence of DSA IgG subclass on outcomes in pediatric KT recipients is not completely understood. We performed a single-center retrospective chart review of pediatric KT recipients with anti-HLA DSAs, aiming to study the association between specific DSA IgG subclasses and graft outcomes, including ABMR and significant graft dysfunction (graft loss or 50% decrease in eGFR). Thirty-six patients (mean age 15.4y) with DSAs initially detected 1 month-14.3 years post-transplantation were followed for a median of 2.8 years. Rates of IgG1, 2, 3, and 4 subclass detection were 92%, 33%, 58%, and 25%, respectively. Twenty-two patients (61%) had clinical ABMR, whereas 19% had subclinical ABMR, and 13 (36%) experienced significant graft dysfunction. Patients with IgG3+ DSAs had a higher risk of graft dysfunction compared with IgG3- patients (52% vs 13%, P = .03). In a multiple Cox proportional regression analysis, the presence of IgG3+ DSA was independently associated with significant graft dysfunction (HR 10.45, 95% CI 1.97-55.55, P = .006). In conclusion, IgG3 subclass DSAs are associated with graft dysfunction and may be useful for risk stratification and treatment decisions in DSA-positive pediatric KT recipients.

Hyperandrogenism Accompanies Increased Intra-Abdominal Fat Storage in Normal Weight Polycystic Ovary Syndrome Women.

CONTEXT: Normal weight polycystic ovary syndrome (PCOS) women may have altered adipose structure-function underlying metabolic dysfunction. OBJECTIVE: This study examines whether adipose structure-functional changes exist in normal weight PCOS women and correlate with hyperandrogenism and/or hyperinsulinemia. DESIGN: This is a prospective cohort study. SETTING: The setting was an academic medical center. PATIENTS: Six normal weight PCOS women and 14 age- and body mass index-matched normoandrogenic ovulatory (NL) women were included. INTERVENTION(S): All women underwent circulating hormone and metabolic measurements; frequently sampled intravenous glucose tolerance testing; total body dual-energy x-ray absorptiometry; abdominal magnetic resonance imaging; and SC abdominal fat biopsy. MAIN OUTCOME MEASURE(S): Circulating hormones and metabolites, body fat and its distribution, and adipocyte size were compared between PCOS and NL women, and were correlated with each other in all women. RESULTS: Circulating LH and androgen levels were significantly greater in PCOS than NL women, as were fasting insulin levels, pancreatic ß-cell responsiveness to glucose, and total abdominal fat mass. Intra-abdominal fat mass also was significantly increased in PCOS women and was positively correlated with circulating androgen, fasting insulin, triglyceride, and non-high-density lipoprotein cholesterol levels in all women. SC abdominal fat mass was not significantly increased in PCOS women, but contained a greater proportion of small SC abdominal adipocytes that positively correlated with serum androgen levels in all women. CONCLUSION: Hyperandrogenism in normal weight PCOS women is associated with preferential intra-abdominal fat deposition and an increased population of small SC abdominal adipocytes that could constrain SC adipose storage and promote metabolic dysfunction.

Vulvodynia: The Role of Inflammation in the Etiology of Localized Provoked Pain of the Vulvar Vestibule (Vestibulodynia).

Vulvar pain affecting the vestibule (vestibulodynia) is an enigmatic pain disorder that greatly affects quality of life and sexual functioning. The most common form of the disorder (localized provoked vulvodynia) is initiated by genital contact but is otherwise asymptomatic. Findings on examination are limited to excessive tenderness of the vestibule with light touch with cotton swab but may also include localized erythema and pelvic floor muscle tightness and tenderness. This review will summarize the literature regarding the role of inflammation in the genesis of the disorder. Some evidence exists for altered histology consisting of increased numbers of mast cells and nerve endings. Immunological abnormalities that have been reported include altered cytokines and neurokines. Abnormal inflammatory response and heightened sensitivity of the vaginal opening has been documented in a murine model of vaginal infection with Candida albicans. In vitro studies of fibroblasts from the vestibule of affected women with vestibulodynia demonstrate a proinflammatory response to C albicans that may be important in the initiation of pain. However, thus far none of the findings have led to adequate treatments.

The Role of Inflammatory Pathways in Implantation Failure: Chronic Endometritis and Hydrosalpinges.

The process of implantation is highly complex and involves a delicate interplay between the embryo and the appropriate maternal environment. The failure to implant is thought to be due to maternal factors or embryonic factors. Inflammation can be a part of the normal physiologic process during implantation; however, there are also pathologic entities that adversely affect uterine receptivity. This review will focus on chronic endometritis and hydrosalpinges as two specific inflammatory processes that contribute to implantation failure. For both chronic endometritis and hydrosalpinges, we will review the diagnosis, pathophysiology, and effect on implantation following treatment. The existing literature conclusively demonstrates that hydrosalpinges should be addressed by either laparoscopic salpingectomy or proximal tubal occlusion prior to in vitro fertilization. The picture for chronic endometritis is less clear since the diagnosis and treatment of chronic endometritis are not standardized, and there are no available randomized controlled trials on this topic. Future studies may target gene expression arrays as a method for further elucidating the role of inflammatory markers in normal and abnormal implantation processes.

Prospective evaluation of the toxicity profile of proteasome inhibitor-based therapy in renal transplant candidates and recipients.

BACKGROUND: A prospective intermediate-term evaluation of toxicities associated with bortezomib therapy for antibody-mediated rejection (AMR) and desensitization was conducted. METHODS: Patients were graded for bortezomib-related toxicities: hematologic and gastrointestinal toxicities by Common Terminology Criteria for Adverse Events and peripheral neuropathy by modified Functional Assessment of Cancer Therapy questionnaire and Common Terminology Criteria for Adverse Events. RESULTS: Fifty-one patients treated for AMR and 19 patients treated for desensitization received 96 bortezomib cycles (1.3 mg/m(2) ×4 doses); mean (SD) follow-up was 16.3 (9.0) months. Patients treated for AMR and patients treated for desensitization were similar in age, gender, ethnicity, and baseline peripheral neuropathy. Patients treated for AMR received a mean (SD) of 4.9 (2.0) bortezomib doses in 1.3 (0.5) cycles; and patients treated for desensitization, a mean of 7.3 (1.6) doses in 1.8 (0.4) cycles. Prevalence of diabetes and anemia were higher at baseline in patients treated for AMR. In the AMR cohort, two cases of cytomegalovirus infection, two cases of BK virus infection, and one case of Epstein-Barr virus infection were observed. No cases of viral infection were observed in the desensitization cohort. Malignancies were not observed. Significant bortezomib toxicities included anemia and peripheral neuropathy, which were manageable. Anemia was more common in patients treated for AMR; and peripheral neuropathy, more common in patients treated for desensitization. CONCLUSIONS: Bortezomib-related toxicities in kidney transplant candidates and recipients are low in incidence and severity and vary based on treatment population.

Pathophysiology of premenstrual syndrome and premenstrual dysphoric disorder.

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder are triggered by hormonal events ensuing after ovulation. The symptoms can begin in the early, mid or late luteal phase and are not associated with defined concentrations of any specific gonadal or non-gonadal hormone. Although evidence for a hormonal abnormality has not been established, the symptoms of the premenstrual disorders are related to the production of progesterone by the ovary. The two best-studied and relevant neurotransmitter systems implicated in the genesis of the symptoms are the GABArgic and the serotonergic systems. Metabolites of progesterone formed by the corpus luteum of the ovary and in the brain bind to a neurosteroid-binding site on the membrane of the gamma-aminobutyric acid (GABA) receptor, changing its configuration, rendering it resistant to further activation and finally decreasing central GABA-mediated inhibition. By a similar mechanism, the progestogens in some hormonal contraceptives are also thought to adversely affect the GABAergic system. The lowering of serotonin can give rise to PMS-like symptoms and serotonergic functioning seems to be deficient by some methods of estimating serotonergic activity in the brain; agents that augment serotonin are efficacious and are as effective even if administered only in the luteal phase. However, similar to the affective disorders, PMS is ultimately not likely to be related to the dysregulation of individual neurotransmitters. Brain imaging studies have begun to shed light on the complex brain circuitry underlying affect and behaviour and may help to explicate the intricate neurophysiological foundation of the syndrome.

Proteasome inhibitor-based therapy for antibody-mediated rejection.

The development of donor-specific anti-human leukocyte antigen antibodies (DSAs) following renal transplantation significantly reduces long-term renal graft function and survival. The traditional therapies for antibody-mediated rejection (AMR) have provided inconsistent results and transient effects that may be due to a failure to deplete mature antibody-producing plasma cells. Proteasome inhibition (PI) is a novel AMR therapy that deletes plasma cells. Initial reports of PI-based AMR treatment in refractory rejection demonstrated the ability of bortezomib to deplete plasma cells producing DSA, reduce DSA levels, provide histological improvement or resolution, and improve renal allograft function. These results have subsequently been confirmed in a multicenter collaborative study. PI has also been shown to provide effective primary AMR therapy in case reports. Recent studies have demonstrated that PI therapy results in differential responses in early and late post-transplant AMR. Additional randomized studies are evaluating the role of PI in transplant induction, acute AMR, and chronic rejection in renal transplantation. An important theoretical advantage of PI-based regimens is derived from several potential strategies for achievement of synergy.