Immunological Complications Research Articles

Streptococcus pneumoniae associated hemolytic uremic syndrome in children.

Previous small-scale, single-center investigations of Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) have shown increased disease severity among SpHUS relative to non-SpHUS patients. Our study compares the impact of S. pneumoniae on patient outcomes between SpHUS cases and non-SpHUS controls using the national, multicenter retrospective Pediatric Health Information Systems (PHIS) Database. Children <18 years of age with a diagnosis of HUS were included. Univariate analyses and multivariable linear and logistic regressions were utilized to assess the impact of S. pneumoniae on mortality, length of stay (LOS), intensive care unit admission (ICU), and mechanical ventilation use. Models were adjusted for demographic and clinical characteristics, including cardiac, neurologic, pulmonary, gastrointestinal, immunologic and renal clinical complications. Of 3,952 index HUS hospitalizations, 231 (5.8%) were due to SpHUS. SpHUS patients had worse outcomes, including longer hospital stays, increased rate of ICU admission, and increased use of mechanical ventilation (p < 0.001 for all). There was a strong positive relationship between clinical complications and adverse outcomes. After adjusting for covariates, SpHUS was associated with an increase in hospital LOS by 3.47 days (p = 0.009) and overall ICU-LOS by 4.21 days (p < 0.001). SpHUS was also associated with increased likelihood of mechanical ventilation (OR: 3.08; p < 0.001), with no increase in ICU admission (p = 0.070) and in-hospital mortality (p = 0.3874). Our study highlights that SpHUS patients are at increased risk of multiple adverse outcomes likely due to the summative impact of pneumococcal infection and HUS as well as more frequent clinical complications.

Immunological Nuances and Complications of Pediatric Organ Transplant: A Narrative Review.

Organ transplantation is considered an exaggerated immune state in which the body reacts in an elaborate cascade of reactions against the lifesaving graft transplanted. Unrepairable organ damage is the main indication for a pediatric patient to undergo a transplant. The host and the donor must fulfill the criteria for a successful transplant to have as few side effects as possible. There has been much-needed research in the domain of surgery of organ transplantation, thereby extending into the pediatric age group. This article elaborates on the post-transplant management, the immuno-biochemistry aspect, and its post-surgery treatment. The post-surgery period requires great emphasis as morbidity and mortality are highest. There is much to understand about managing transplant patients to avoid complications such as infections, hypertension, or side effects of immunosuppressive drugs. The treating clinician faces the challenges of managing the dose and frequency of immuno-suppressive medicines to prevent complications in the patients. If the dose is inadequate, there are chances of graft rejection. If the immuno-suppression is prolonged, there may be chances of infections in the patient. This article aims to summarize the mechanism of graft rejection and put forth the need for further research about creating a universal protocol for managing a patient's immune system post-transplant. The authors hope this protocol will help the clinician better understand the patient's current state and help in appropriately using immuno-suppressive drugs. It calls upon the need for a reliable and easily repeatable battery of investigations that will help solve this dilemma.

Analysis of interleukin 7 and platelet-derived growth factor-BB mRNA expression as potential markers in erythema nodosum leprosum.

Erythema nodosum leprosum (ENL) is an immunological complication of leprosy characterized by acute inflammation of the skin, nerves, and other organs. Identifying laboratory parameters is important for early diagnosis of leprosy reactions. Various cytokine biomarkers have been examined and only a few studies have reported on angiogenesis in leprosy. This study aims to understand the pathomechanism of ENL by examining IL-7 and platelet-derived growth factor (PDGF)-BB mRNA expression that can be the development and consideration of new effective therapies to prevent reactions, recurrences, and defects in leprosy. The study used a cross-sectional analytic design. Sampling was done by peripheral blood from the patient and measuring mRNA expression with specific primers RT-PCR. The expression of mRNA IL-7 and PDGF-BB was significantly different between multibasilar patients without reaction and with ENL reaction, where there was an increased expression in ENL patients. This could be used as the development of potential biomarkers in ENL and development of new therapeutic intervention pathways in ENL.

Chemical Epigenetic Regulation of Adeno-Associated Virus Delivered Transgenes.

Adeno-associated virus (AAV) is a powerful gene therapy vector that has been used in several FDA-approved therapies as well as in multiple clinical trials. This vector has high therapeutic versatility with the ability to deliver genetic payloads to a variety of human tissue types, yet there is currently a lack of transgene expression control once the virus is administered. There are also times when transgene expression is too low for the desired therapeutic outcome, necessitating high viral dose administration resulting in possible immunological complications. Herein, we validate a chemically controllable AAV transgene expression technology in vitro that utilizes bifunctional molecules known as chemical epigenetic modifiers (CEMs). These compounds employ endogenous epigenetic machinery to specifically enhance transgene expression of episomal DNA. A recombinant AAV (rAAV) was designed to both deliver the reporter transgene as well as deliver a synthetic zinc finger (ZFs) protein fused to FK506 binding protein (FKBP). These synthetic ZFs target a DNA-binding array sequence upstream of the promoter expressing the AAV transgene to specifically enhance AAV transgene expression in the presence of a CEM. The transcriptional activating compound CEM87 functions by recruiting the epigenetic transcription activator bromodomain-containing protein 4 (BRD4), increasing AAV transgene activity up to fivefold in a dose-dependent manner in HEK293T cells. The highest levels of transgene product activity are seen 24 h following CEM87 treatment. Additionally, the CEM87-mediated enhancement of different transgene products with either Luciferase or green fluorescent protein (GFP) was observed in multiple cell lines and enhancement of transgene expression was capsid serotype independent. The impact of CEM87 activity can be disrupted through drug removal or chemical recruitment site competition with FK506, thus demonstrating the reversibility of the impact of CEM87 on transgene expression. Collectively, this chemically controllable rAAV transgene technology provides temporal gene expression control that could increase the safety and efficiency of AAV-based research and therapies.

COVID-19 vaccination and leprosy-A UK hospital-based retrospective cohort study.

Individuals with leprosy are at risk of leprosy reactions, T-cell mediated immunological complications, which lead to nerve function impairment. Leprosy reactions require systemic immunosuppression which is a risk factor for severe COVID-19. Vaccination for SARS-CoV-2 infection is recommended in the UK and became widely available in 2021 with individuals at increased risk of severe disease, including the immunosuppressed, prioritised. Vaccines for SARS-CoV-2 may provoke a T cell response. The latter poses a theoretical risk of provoking an immunological response to latent Mycobacterium leprae infection leading to clinical disease or in those with clinical disease triggering a leprosy reaction. BCG vaccination is associated with the development of leprosy in a small proportion of healthy contacts of people with leprosy within twelve weeks of administration. BCG causes a Th1 immune response. We performed a retrospective cohort study to determine the SARS-CoV-2 vaccination status of individuals diagnosed with leprosy attending the Leprosy Clinic in 2021 and whether any had developed leprosy or experienced a new leprosy reaction within twelve weeks of receiving a dose of a SARS-CoV-2 vaccine. The electronic patient records were used to retrieve data. Fifty-two individuals with leprosy attended the clinic in 2021 of which five people were newly diagnosed with leprosy. Thirty-seven (71%) were male and the median age was 48.5 years old (Range 27-85 years). Eight (15.4%) individuals were taking multi-drug therapy (MDT) and eight (15.4%) had completed MDT within three years of the study. Twenty-two (41.5%) individuals were prescribed a systemic immunosuppressant drug during 2021. Ten (18.9%) individuals have one or more risk factors for severe COVID-19. The SARS-CoV-2 vaccination status of fifty (96%) were recorded of which forty-nine were vaccinated (98%). One individual had declined vaccination. One individual was diagnosed with borderline tuberculoid (BT) leprosy having developed red skin lesions with reduced sensation (which increased in size and number) and thickened peripheral nerves one week after a second dose of BNT162b2 vaccine. Another individual who had completed MDT more than three years earlier developed red plaques and tender thickened nerves consistent with a leprosy Type 1 reaction eight weeks after a single dose of BNT162b2 vaccine (having received two doses of CoronaVac vaccine three months earlier). The development of BT leprosy and a Type 1 reaction in another individual shortly after a dose of BNT162b2 vaccine may be associated with vaccine mediated T cell responses. The benefits of vaccination to reduce the risk of severe COVID-19 outweigh these unwanted events but data from leprosy endemic countries may provide further information about potential adverse effects of augmented T cell responses in individuals with leprosy or latent M. leprae infection.

Immunogenetic characteristics of hematopoietic stem cell donors representing the most numerous ethnic groups in Russia

Development of criteria for the optimal donor selection based on the analysis of the allo-HSCT results, high-resolution HLA typing for the donor and recipient resulted in decreased incidence of immunological complications, primarily an acute «graft-versus-host reaction». However, due to the pronounced allelic polymorphism of the main histocompatibility complex (MHC) genes, the search for an optimal donor is ineffective in a number of patients. To increase the chances of selecting a donor for patients with rare HLA genotypes, the hematopoietic stem cell donor registries recruit the persons of various nationalities. An increased number of donors from different ethnic groups provide a broader immunogenetic diversity of the donor cohort. Currently, the registry of hematopoietic stem cell donors at the Russian Research Institute of Hematology and Transfusiology includes representatives of 49 nationalities, most of which, are considered themselves Russians. The third largest ethnic group in the registry comprises Tatars. The purpose of this study is a comparative analysis of immunogenetic characteristics of potential hematopoietic stem cells donors in the registry, who have self-identified as Russians and Tatars. As a result of the study, we have not found significant differences in frequencies of HLA allelic groups in the compared cohorts, a trend for higher frequency of the HLA-B*27 group was noted in Tatars. However, significant differences have been revealed for the distribution of HLA haplotypes in Russians and Tatars. The most common HLA haplotype among Tatars was A*02-B*44-DRB1*07, being much less common in Russians (4.61% vs 0.55%, p = 0.002). HLA haplotype A*03-B*13-DRB1*07, belonging to the ten most common among Tatars, was significantly less frequently detected in Russians (1.62% vs 0.08%, p = 0.026). HLA haplotype A*03-B*08-DRB1*03 was also significantly more common in Tatars compared to Russians (1.42% vs 0.06%, p = 0.026). HLA haplotypes A*02-B*18-DRB1*11, A*02-B*15-DRB1*04, A*02-B*15-DRB1*13, presented in Russians at a frequency of &gt; 1%, were not determined among the tested Tatars. HLA haplotypes A*31-B*58-DRB1*04, A*24-B*44-DRB1*01, presented in Tatars at a frequency of &gt; 1%, were not detectable in Russians. The results of our study indicate a need for recruiting more representatives of the Tatar ethnicity to the registry, thus increasing immunogenetic diversity of the donor pool and resulting into increased chances of compatible unrelated donor selection for the patients with HLA haplotypes, which are now underrepresented in our registry.

Circulating microbial cell–free DNA is increased during neutropenia after hematopoietic stem cell transplantation

AbstractWe used a next-generation sequencing platform to characterize microbial cell–free DNA (mcfDNA) in plasma samples from patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). In this observational study, we sought to characterize plasma mcfDNA in order to explore its potential association with the immunologic complications of transplantation. We compared serially collected patient samples with plasma collected from healthy control subjects. We observed changes in total mcfDNA burden in the plasma after transplantation, which was most striking during the early posttransplant neutropenic phase. This elevation could be attributed to a number of specific bacterial taxa, including Veillonella, Bacteroides, and Prevotella (genus level). For an additional cohort of patients, we compared the data of mcfDNA from plasma with 16s-ribosomal RNA sequencing data from stool samples collected at matched time points. In a number of patients, we confirmed that mcfDNA derived from specific microbial taxa (eg, Enterococcus) could also be observed in the matched stool sample. Quantification of mcfDNA may generate novel insights into mechanisms by which the intestinal microbiome influences systemic cell populations and, thus, has been associated with outcomes for patients with cancer.

Histoid leprosy complicated by erythema nodosum leprosum mimicking connective tissue disease.

Erythema nodosum leprosum (ENL) is an immunological complication of leprosy seen in 50% of lepromatous and 10% of borderline lepromatous leprosy. It usually presents as a multisystem disease with papulo-nodular skin lesions and fever. Arthralgia or arthritis is a common initial presentation of erythema nodosum leprosum. Pure rheumatologic presentation of lepromatous leprosy complicated by erythema nodosum leprosum is extremely rare, mimics connective tissue disease and is treated with steroids.

The Role of Neutrophil-to-Lymphocyte Ratio as A Potential Biomarker of Erythema Nodosum Leprosum Disease Severity: A Retrospective Study

Background: Erythema nodosum leprosum (ENL) is an acute immunologic complication of multibacillary leprosy (MB) that causes systemic inflammation in various organs. It is a major factor contributing to morbidity, mortality, and financial hardship. ENL is diagnosed clinically, and objective indicators for severe conditions remain unexplored. Simple blood biomarkers that differentiate between different ENL disease severity levels are required. Neutrophilto-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been widely studied as severity biomarkers of numerous neoplastic and inflammatory disorders. Objective: We examined NLR and PLR values at various ENL severities and their role as severe disease indicators for ENL. Methods: This cross-sectional retrospective study examined 246 patients with multibacillary leprosy—with and without ENL reactions and aged 18 and above—and calculated their NLR and PLR values. Then, we compared patients with mild and severe disease states to those without ENL. The severity classification was based on the ENLIST ENL Severity Score (EESS). To determine the NLR and PLR cutoff points of mild and severe ENL, a receiver operating characteristic (ROC) curve was constructed. Results: The NLR value for severe ENL was significantly higher than that for mild ENL (p &lt; 0.05), with a severe disease cutoff point of 5.71 (95.7% sensitivity, 68.7% specificity). No significant differences were found in PLR between patients with mild and severe ENL. Conclusion: While PLR is not an effective assay for evaluating ENL severity, NLR is a potential biomarker for severe ENL reactions in patients with multibacillary leprosy.

Treatment of epilepsy with mesenchymal stem cells: literature review

In the past few years, results from experimental and clinical studies have shown that inflammation can be both a consequence and a cause of epilepsy. Distinctive features of mesenchymal stem cells (MSCs) are their immunomodulatory and anti-inflammatory properties, which indicate promise in the field of epilepsy treatment.The article presents a review on the preclinical and clinical use of MSCs in the treatment of epilepsy, and outlines the mechanism of MSCs therapeutic action of in this disease. The authors focused on the analysis of all available in the literature clinical cases of MSCs use in the treatment of epilepsy, as well as the effectiveness and undesirable effects of therapy. The use of MSCs indeed has a significant effect in reducing the number of seizures and has a positive effect on mental functions, however, at present, this method of therapy is not ready for widespread clinical use due to the short period of observation in clinical trials and increased risks of developing immunological and oncological complications in patients.

#3727 REAL LIFE SINGLE-CENTRE EXPERIENCE IN PATIENTS WITH LONG-SURVIVAL RENAL TRANSPLANTATION

Abstract Background and Aims Kidney transplantation is the gold standard treatment for ESRD. Although the short-term results of kidney transplantation have improved significantly in the last 20 years, the increase in survival rates and the improvement of long-term graft outcomes represent a main challenge. Therefore, clinical data on patients with a long history of kidney transplantation are lacking and open field of research. The target of the study is to describe the outcomes in terms of renal function, immunological, infectious and neoplastic complications, and immunosuppressive therapy schemes, in a peculiar population of patients with long-lasting renal transplants. Method This is a retrospective, monocentric and observational cohort study. The study population consists of patients that underwent kidney transplantation in a single Kidney Transplant Unit from 1978 to 2012 and still in follow-up within the same Unit with a functioning graft. Data were extracted from the Hospital digital medical records after informed consent has been obtained. We analysed renal function at 5-year intervals from discharge to the last evaluation using eGFR calculated with the CKD-EPI formula. Data on demographic characteristics, comorbidities, immunosuppressive therapies and complication (divided as infectious, immunological and malignancy) has also been evaluated. Results We enrolled 332 patients with a mean follow-up of 17.9± 6.5 years, of whom 101 (30.4%) with a follow-up &amp;gt;20 years. Figure 1 shows the trend of renal function during the follow-up years. In Table 1 are reported the comorbidities and immunological, infectious and neoplastic complications. 46 (14.5 %) patients underwent a “for cause” kidney biopsy. The main finding, with 62% was transplant glomerulopathy/interstitial fibrosis and tubular atrophy (TG/IFTA) with a mean post-transplant onset of 12.8 years (± 6.1), 9% of rejection findings with a mean time to onset of chronic rejection of 18 years (±8) and 1.3% of biopsied patients received a diagnosis of recurrence with a mean onset of 10.8 years (±4.4). 36.1% of the patients experienced at least one neoplasm with an average post-transplant onset time of 13.4 (±7.7). Infectious complications occurred in 36.1% of the transplanted patients. Conclusion This study provides an exhaustive overview of the characteristics and clinical complications in a “real life” experience with long survivor kidney transplants with the aim to better understand the needs and problems of this peculiar population in order to guide clinician in a more targeted management.

Zinc(Ⅱ)-induced Neuroimmunological Renal Chronic Kidney Disease Prevention and Suppressive Progression

Zinc(Ⅱ) supplementation with 30 mg/day should become likely therapeutic chronic kidney disease (CKD) prevention implications with immense importance of CKD-associated immunological and neurological complications. Zinc induced neuroimmunological suppressive CKD progression with Stage 2 ～ 3A, 3B, zinc supplementation (30 mg/day) may be beneficial for nutritional status in CKD children and adolescents, and zinc could reduce urinary protein excretion composed of albumin and/or minimize proteinuria excretion in proteinuric CKD. In CKD 4-5 stage, risk of cardiovascular disease (CVD) become higher that zinc supplementation of 25 mg/day in zinc homeostasis has a beneficial effect for CVD in vascular dysfunction. Thus, zinc intake of 30 mg/day and serum zinc level of 60～76 μg/dL could slow down CKD Stage 4 progression. Zinc induced CKD Stage 5 (eGFR &lt; 15) is involved that zinc is actively bound to several proteins that the decrease of circulating zinc levels in CKD is partly caused by renal losses of zinc, becoming zinc-deficiency with advanced stage CKD and ESRD in CKD. Serum zinc and serum albumin levels are 37.4 ± 5.4 and 2.6 ± 0.6 µg/dL, respectively, for as eGFR 6.6 (5.2–8.3). Zn intake of 45-75 mg/day and serum zinc level of ≤78.3 µg/dL are beneficial for HD and maintenance hemodialysis (MHD) patients, in which Zinc 15 mg/day and Selenium 50–70 μg/day that are recommended may be thought to prevent ESRD stage. Zinc induced NAD(P)H oxidase (Nox) activation occurring ROS generation in CKD cell involves assembly that ROS include the superoxide anion (O2•–), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•), and in the kidney. Zinc(Ⅱ) ions-binding protein molecular mechanism is involved that Zn2+ ions-several protein complexes coordinated binding model of ligands of such as albumin, a-macroglobulin and transferrin in several proteins had been found on the binding specificity by Zn2+ ions-centered tetrahedral geometric coordination, in which causing zinc-activated serine, histidine and aspartate hydrogen residues enhance renal function activity and resulting inhibition of CKD progression proceeds.

Immune dysregulation in Kabuki syndrome: a case report of Evans syndrome and hypogammaglobulinemia

Kabuki syndrome (KS) is a rare multisystemic disease due to mutations in the KMT2D or KDM6A genes, which act as epigenetic modulators of different processes, including immune response. The syndrome is characterized by anomalies in multiple organ systems, and it is associated with autoimmune and inflammatory disorders, and an underlying immunological phenotype characterized by immunodeficiency and immune dysregulation. Up to 17% of KS patients present with immune thrombocytopenia characterized by a severe, chronic or relapsing course, and often associated to other hematological autoimmune diseases including autoimmune hemolytic anemia, eventually resulting in Evans syndrome (ES). A 23-year-old woman, clinically diagnosed with KS and presenting from the age of 3 years with ES was referred to the Rare Diseases Centre of our Pediatric Department for corticosteroid-induced hyperglycemia. Several ES relapses and recurrent respiratory infections in the previous years were reported. Severe hypogammaglobulinemia, splenomegaly and signs of chronic lung inflammation were diagnosed only at the time of our observation. Supportive treatment with amoxicillin-clavulanate prophylaxis and recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin replacement were immediately started. In KS patients, the failure of B-cell development and the lack of autoreactive immune cells suppression can lead to immunodeficiency and autoimmunity that may be undiagnosed for a long time. Our patient's case is paradigmatic since she presented with preventable morbidity and severe lung disease years after disease onset. This case emphasizes the importance of suspecting immune dysregulation in KS. Pathogenesis and immunological complications of KS are discussed. Moreover, the need to perform immunologic evaluations is highlighted both at the time of KS diagnosis and during disease follow-up, in order to allow proper treatment while intercepting avoidable morbidity in these patients.

Steroid Sparing Maintenance Immunosuppression in Highly Sensitised Patients Receiving Alemtuzumab Induction.

This analysis reports on the outcomes of two different steroid sparing immunosuppression protocols used in the management of 120 highly sensitised patients (HSPs) with cRF>85% receiving Alemtuzumab induction, 53 maintained on tacrolimus (FK) monotherapy and 67 tacrolimus plus mycophenolate mofetil (FK + MMF). There was no difference in the median cRF or mode of sensitisation between the two groups, although the FK + MMF cohort received more poorly matched grafts. There was no difference in one-year patient or allograft survival, however rejection free survival was inferior with FK monotherapy compared with FK + MMF at 65.4% and 91.4% respectively, p < 0.01. DSA-free survival was comparable. Whilst there was no difference in rates of BK between the cohorts, CMV-free survival was inferior in the FK + MMF group at 86.0% compared with 98.1% in the FK group, p = 0.026. One-year post-transplant diabetes free survival was 89.6% and 100.0% in the FK and FK + MMF group respectively, p = 0.027, the difference attributed to the use of prednisolone to treat rejection in the FK cohort, p = 0.006. We report good outcomes in HSPs utilising a steroid sparing protocol with Alemtuzumab induction and FK + MMF maintenance and provide granular data on immunological and infectious complications to inform steroid avoidance in these patient groups.

Racial disparities in the outcomes of allogeneic bone marrow transplant: A 5-year nationwide inpatient study.

e19060 Background: Allogeneic bone marrow transplantation (ABMT) is a life-saving procedure in hematological malignancies and bone marrow failure disorders. Despite advances in the field, literature proposes racial disparities in the outcomes of ABMT. This study aims to investigate this difference among distinct racial cohorts. Methods: We identified patients who underwent ABMT for malignant and nonmalignant hematologic diseases from 2016-2020 using the nationwide inpatient sample (NIS) database. We compared the racial differences in outcomes during the hospitalization, including immunologic and hematologic complications, associated infections, length of stay, and mortality rate. Baseline characteristics were compared using a T-test and Chi-Square. Multivariate regression analysis was applied to estimate differences in outcomes. We used STATA Version 17.0 Software for data analysis. The p-value was set at p &lt; 0.05 for statistical significance. Results: A retrospective study was conducted on a cohort of 14,599 adults who underwent ABMT. Out of which 30% (4,379) developed complications. The mean age for ABMT was 54, and the average length of stay was 29 days. In this cohort, 79.5% (11,325) were whites, 4.2% (610) were blacks, 8.3% (1,185) were Hispanics, and 7.8% (1,125) were others. When comparing the outcomes among racial groups, invasive fungal infections 15.5% (95), mucositis 36% (220), septic shock 9% (55), and respiratory failure 14.7% (90) were more common in blacks (p &lt; 0.05). Neutropenia 41.3% (490) and cytomegalovirus (CMV) infection 12.2% (145) were more common in Hispanics (p &lt; 0.05). However, no significant difference was noted in immunologic complications (graft versus host disease (GVHD), bone marrow rejection (BMR), bone marrow failure (BMF)), pancytopenia, clostridium difficile infection (CDI), and mortality (p &lt; 0.05). Conclusions: Our study shows that blacks had a higher prevalence of invasive fungal infections, mucositis, septic shock, and respiratory failure, while Hispanics reported a higher prevalence of neutropenia and CMV infection. However, no significant differences were noted in GVHD, BMR, BMF, pancytopenia, CDI, and mortality rates. Therefore, it can be concluded that while there are some differences in post-ABMT complications among racial groups, overall, the rates of major complications and mortality do not significantly differ.

Fertility post immune checkpoint blockade.

12014 Background: Immune checkpoint blockade (ICB) is radically altering the treatment paradigm for a wide range of malignancies. Consequently, the proportion of ICB exposed pts will expand and the impact of ICB on fertility is of increasing importance. We sought to evaluate fertility outcomes post ICB exposure at our institution. Methods: Pts &lt; 45 years old post ≥ 1 cycles of ICB at MSK who consented to the MSK-IMPACT protocol (NCT01775072) were screened for eligibility (n = 537). Pts in receipt of prior cytotoxic chemotherapy or tyrosine kinase, BRAF or MEK inhibitors were excluded. 96 eligible pts were emailed a 28-question survey; 65% were followed up by phone. Results: 50/96 pts responded to the survey, male to female ratio was 27:23. 5 pts were excluded from final analysis due to additional systemic agent use pre-conception. Median age at ICB exposure was 35 (range 19-44). 53% (25/45) of pts received ICB in the metastatic setting. 40% (17/42) of pts received fertility counseling pre-ICB use. There was no statistically significant difference between rates of fertility counseling in metastatic vs non-metastatic settings (p = 0.14). 7 pts (14%) conceived and 2 pts (4%) are currently trying to conceive children post ICB. 4 pts (3 female, 1 male) conceived children with reproductive technology. 3/4 pts used sperm or embryos frozen prior to ICB and IVF leading to successful pregnancies, 2 of which are currently ongoing. One patient froze embryos 6 months after 2 years of PD1 inhibitor (PD1i) monotherapy and embryo implantation led to a currently ongoing pregnancy. Notably this pt developed hypothyroidism with ICB use, controlled with levothyroxine, and has remained euthyroid during pregnancy to date. 3 pts (2 female, 1 male) receiving single agent PD1i in the localized setting conceived naturally at 2 yrs, 9 months and 2 months respectively post ICB. 4/8 pregnancies are currently ongoing without reported immunological complications. 3 deliveries have resulted in 4 children (including 1 set of twins). 1 of these pts had a 1st trimester miscarriage of unclear cause followed by successful pregnancy complicated by gestational diabetes. First pregnancies occurred a median of 1 year post ICB (range 2-24 months). No autoimmune conditions in progeny were reported. Conclusions: Successful conception occurred both naturally and with reproductive assistance technologies post ICB. Most pts did not receive fertility counseling pre-ICB use, possibly reflective of nascent appreciation of complete and durable ICB responses. There were no definite adverse immunological complications reported in pregnancy or progeny of these pts. As ICB indications expand prospective evaluation of ICB impact on fertility in pts desirous of a family is critical and consequently we are integrating longitudinal fertility analysis in neoadjuvant ICB protocols. [Table: see text]

Human Orf with Immune-Mediated Reactions: A Systematic Review

Background: Orf is a highly contagious zoonosis caused by Orf virus (ORFV), which is endemic in sheep and goats worldwide. Human Orf is usually a self-limiting disease, but potential complications, including immune-mediated reactions, may occur. Methods: We included all articles regarding Orf-associated immunological complications published in peer-reviewed medical journals. We conducted a literature search of the United States National Library of Medicine, PubMed, MEDLINE, PubMed Central, PMC, and the Cochrane Controlled Trials. Results: A total of 16 articles and 44 patients were included, prevalently Caucasian (22, 95.7%) and female (22, 57.9%). The prevailing immunological reaction was erythema multiforme (26, 59.1%), followed by bullous pemphigoid (7, 15.9%). In most cases, the diagnosis was made on the basis of clinical and epidemiological history (29, 65.9%), while a biopsy of secondary lesions was performed in 15 patients (34.1%). A total of 12 (27.3%) patients received a local or systemic treatment for primary lesions. Surgical removal of primary lesion was described in two cases (4.5%). Orf-immune-mediated reactions were treated in 22 cases (50.0%), mostly with topical corticosteroids (12, 70.6%). Clinical improvement was reported for all cases. Conclusions: Orf-related immune reactions can have a varied clinical presentation, and it is important for clinicians to be aware of this in order to make a prompt diagnosis. The main highlight of our work is the presentation of complicated Orf from an infectious diseases specialist’s point of view. A better understanding of the disease and its complications is essential to achieve the correct management of cases.

Respiratory and other systemic complications of coronavirus disease 2019 in adults: A narrative review

To review and summarize the health complications known to be caused by the coronavirus disease 2019 (COVID-19) and theirpathophysiology. A thorough search was conducted for articles on the complications of COVID-19 from December 30th, 2019through November 20th, 2020. August using the PubMed, Google Scholar, and World Health Organization (WHO) databases.and it was supplemented with inclusion of pertinent articles till May 30th, 2021 Articles that did not have patient data, thosewhich included data of patients &lt; 18 years of age, studies limited to pregnant patients, and studies limited to only specificco-morbidities and organ dysfunctions were excluded to avoid selection bias and heterogeneity in study population. A total of108 studies were included in the narrative review. These studies reported numerous complications of COVID-19 with the mostcommon being acute respiratory acute respiratory distress syndrome (ARDS) (19.5%–72%), myocardial injury (13.6%–36%),cytokine storm (5%–10%), acute kidney injury (AKI) (4%–54.7%), acute liver injury (14%–62.4%), and venous thromboembolism(VTE) (4%–20%). Our review extensively illustrates the incidence, predictors, and pathophysiology of respiratory, cardiovascular,immunological, hepatobiliary, coagulative, neurological, and renal complications of COVID-19. Enhancing the host immuneresponses against viral infection and modulating the inflammatory responses, along with appropriate support of respiratoryfunction; as well as the management of complications involving multiple organ systems potential leading to multi-organ failure,are all important aspects to be considered for the recovery of critically ill patients with COVID-19.

Advances in CRISPR/Cas gene therapy for inborn errors of immunity.

Inborn errors of immunity (IEIs) are a group of inherited disorders caused by mutations in the protein-coding genes involved in innate and/or adaptive immunity. Hematopoietic stem cell transplantation (HSCT) is a mainstay definitive therapy for many severe IEIs. However, the lack of HLA-matched donors increases the risk of developing severe immunological complications. Gene therapy provides long-term clinical benefits and could be an attractive therapeutic strategy for IEIs. In this review, we describe the development and evolution of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) gene-editing systems, including double-strand break (DSB)-based gene editing and DSB-free base editing or prime editing systems. Here, we discuss the advances in and issues associated with CRISPR/Cas gene editing tools and their potential as therapeutic alternatives for IEIs. We also highlight the progress of preclinical studies for the treatment of human genetic diseases, including IEIs, using CRISR/Cas and ongoing clinical trials based on this versatile technology.

Epidemiological and Clinical Features of Leprosy Reactions and Associated Risk Factors in Malagasy People from 2012 to 2021

<i>Introduction</i>: Leprosy is a transmissible infectious disease while cutaneous and neurological manifestations vary according to the patient's immunity. It is a chronic disease with acute immunological complication called leprosy reactions. Leprosy remains endemic in Madagascar. The objective of this study is to characterize the epidemiological and clinical profile of leprosy and leprosy reactions and to determine the risk factors for leprosy reactions. <i>Methods</i>: This was a retrospective, case-control study over a period of 10 years from January 2012 to December 2021 conducted among leprosy patients of the University Hospital Joseph Raseta Befelatanana. Univariate and multivariate logistic regression was used to determine the risk factors for leprosy reactions. <i>Results:</i> Of the 161 patients selected, 53 patients had a leprosy reaction. There were 91 males and 70 females with a mean age of 35.8 years (±15,47). The borderline lepromatous type was the most common clinical form. The prevalence of lepromatous reaction was 33%. Type 1 and type 2 reactions were found in 41.50% and 45.28% of cases respectively. The average time to develop leprosy reactions after the initiation of multidrug therapy was 5.80 months (±3.91). From multivariate analysis, the risk factors identified were: male gender [OR=2.64 (95% CI: 1.80-9.57), p=0.02], positive BI [OR=3.53 (95% CI: 2.41-48.98), p=0.02], MB treatment regimen [OR=8.87 (95% CI: 1.23-3.57), p=0.008)], and poor adherence to treatment [OR=1.97 (95% CI: 1.34-12.95), p=0.0354]. <i>Conclusion: </i>The knowledge of these risk factors allows for early diagnosis and treatment of leprosy reactions to prevent the morbidities due to leprae disease such as amputations and disabilities that are a source of stigma.