Severe Infectious Complications Research Articles

High-Voltage, Pulsed Electric Fields Eliminate Pseudomonas aeruginosa Stable Infection in a Mouse Burn Model.

Objective: The incidence of severe infectious complications after burn injury increases mortality by 40%. However, traditional approaches for managing burn infections are not always effective. High-voltage, pulsed electric field (PEF) treatment shortly after a burn injury has demonstrated an antimicrobial effect in vivo; however, the working parameters and long-term effects of PEF treatment have not yet been investigated. Approach: Nine sets of PEF parameters were investigated to optimize the applied voltage, pulse duration, and frequency or pulse repetition for disinfection of Pseudomonas aeruginosa infection in a stable mouse burn wound model. The bacterial load after PEF administration was monitored for 3 days through bioluminescence imaging. Histological assessments and inflammation response analyses were performed at 1 and 24 h after the therapy. Results: Among all tested PEF parameters, the best disinfection efficacy of P. aeruginosa infection was achieved with a combination of 500 V, 100 μs, and 200 pulses delivered at 3 Hz through two plate electrodes positioned 1 mm apart for up to 3 days after the injury. Histological examinations revealed fewer inflammatory signs in PEF-treated wounds compared with untreated infected burns. Moreover, the expression levels of multiple inflammatory-related cytokines (interleukin [IL]-1α/β, IL-6, IL-10, leukemia inhibitory factor [LIF], and tumor necrosis factor-alpha [TNF-α]), chemokines (macrophage inflammatory protein [MIP]-1α/β and monocyte chemoattractant protein-1 [MCP-1]), and inflammation-related factors (vascular endothelial growth factor [VEGF], macrophage colony-stimulating factor [M-CSF], and granulocyte-macrophage colony-stimulating factor [G-CSF]) were significantly decreased in the infected burn wound after PEF treatment. Innovation: We showed that PEF treatment on infected wounds reduces the P. aeruginosa load and modulates inflammatory responses. Conclusion: The data presented in this study suggest that PEF treatment is a potent candidate for antimicrobial therapy for P. aeruginosa burn infections.

Antibiotic prophylaxis in dentistry and oral surgery: use and misuse

Antibiotic prophylaxis (AP) still represents a common but often misused procedure in dental practice, thus aggravating the risk for antimicrobial resistance and adverse effects occurrence. Our primary objective is to review the available scientific evidence regarding AP in dentistry both among healthy subjects and medically compromised patients. Additionally, the latest available guidelines provided by some of the most authoritative associations are here discussed. AP is advisable only in a small percentage of patients where a risk of severe infective complications (i.e. infective endocarditis and prosthetic joint infection, septicaemia in severely immuno-compromised patients, bisphosphonate-related osteonecrosis of the jaw) exists. On the contrary, little or no scientific evidence exists for AP in subjects with other systemic diseases as well as in healthy individuals. This pioneering recommendation is strongly evidence-based, since a consistent association between any dental procedure and the development of local and distant infective complications is still lacking. In addition, the daily bacteraemia secondary to routine habits has been thought to be robustly associated with a greater risk of systemic disease bacterial-related than a single dental procedure exposure. Compliance of general dental or family practitioners to the current recommendations seems not to be optimal, thus, efforts to improve it should be planned and undertaken.

Translocation of Clostridial Infection as a Complication of Hip Arthroplasty in the Early Postoperative Period: Case Report

Background. Periprosthetic joint infection in the early postoperative period is a severe infectious complication. Its development, as a rule, is associated with the exogenous surgical wound infection, with the iatrogenic factor at the forefront. Clinical case description. A 73-years-old female with left-sided idiopathic 3rd stage hip osteoarthritis and concomitant pathology with a high degree of comorbidity underwent left hip arthroplasty with a cement-fixed “Endoservice” endoprosthesis. In the early postoperative period (4th to 6th days), against the background of chronic calculous cholecystitis exacerbation and gastrointestinal dysfunction, clostridial septicemia developed as a result of bacterial translocation. The timely diagnosis of the endogenous nature of this infection and the targeted antibiotic therapy prevented the surgical wound and endoprosthesis infection. The Harris score for the function of the left hip at discharge was 78 points. Conclusion. The presented clinical case demonstrates the importance of careful preoperative planning, especially in the patient with identifying somatic pathology of infectious nature, the need to detail the organ-specific microbiota as a mandatory procedure, as well as the prevention of periprosthetic joint infection during orthopedic operations, taking into account the data obtained.

Five Predictors Affecting the Prognosis of Patients with Severe Odontogenic Infections.

Background: Dental cellulitis management is no longer a simple procedure, as more and more patients are needing long-time hospitalization, several surgeries and intensive care follow-up. This prospective study seeks to highlight criteria that can split patients with severe odontogenic infection into two groups: those with simple evolution and those for whom complex management is necessary. Methods: In this observational study, all patients considered with a severe odontogenic infection (which necessitated hospital admission, intravenous antibiotics and general anaesthesia) were enrolled between January 2004 and December 2014 from Clermont-Ferrand University Hospital (France). They were split into two groups: those who needed one surgical intervention with tooth extraction and collection drainage combined with probabilistic antibiotic to treat infection and those who need several surgeries, intensive care unit follow-up or tracheotomy to achieve healing. Results: 653 patients were included, of which 611 (94%) had one surgery, 42 (6%) had more than one surgery before healing. Penicillin allergy (p < 0.001), psychiatric disorders (p = 0.005), oropharyngeal oedema (p = 0.008), floor oedema (p = 0.004), fever (p = 0.04) and trismus (p = 0.018) on admission were the most relevant predictors of complex evolution. A conditional inference tree (CTREE) illustrated the association of prognostic factors and the need of multiple surgery. Conclusions: Besides clinical symptoms of severity, complications of severe odontogenic infection are predicted by measurables and objectives criteria as penicillin allergy, mandibular molar, C-reactive protein level, psychiatric disorders and alcohol abuse. Their specific association potentialize the risks. IRB number: CE-CIC-GREN-12-08.

Glucocorticoid maintenance therapy and severe infectious complications in ANCA-associated vasculitis: a retrospective analysis

To study the impact of glucocorticoid maintenance dose and treatment duration on outcomes in patients with AAV (ANCA-associated vasculitis) with emphasis on infectious complications. A total of 130 AAV patients from two German vasculitis centers diagnosed between August 2004 and January 2019 treated with cyclophosphamide and glucocorticoids for induction therapy and glucocorticoids for maintenance therapy were retrospectively enrolled. We investigated the influence of glucocorticoid maintenance therapy on patient survival, time to relapse, kidney function, infectious complications and irreversible physical damage. The patients were divided into the following groups: patients treated according to the predefined reduction scheme (< 7.5 mg) or patients treated with glucocorticoids ≥ 7.5 mg after 6 months. Compared to patients receiving < 7.5 mg glucocorticoids after 6 months, patients receiving ge 7.5 mg had an increased rate of infectious episodes per patient (1.7 vs. 0.6; p < 0.001), including urinary tract infection (p = 0.007), pneumonia (p = 0.003), opportunistic pneumonia (p = 0.022) and sepsis (p = 0.008). Especially pneumonia during the first 24 months after disease onset [hazard ratio, 3.0 (95% CI 1.5 − 6.1)] led to more deaths from infection (p = 0.034). Glucocorticoid maintenance therapy after 6 months had no impact on relapse rate or patient survival and decline in kidney function was comparable. Glucocorticoid maintenance therapy with ge 7.5 mg after 6 months is associated with more severe infectious complications leading to an increased frequency of deaths from infection. Glucocorticoid maintenance therapy has no effect on time to relapse or patient survival and should therefore be critically revised throughout the aftercare of AAV patients.

The problem of global development of antibiotic resistant nosocomial pathogens

The problem of global expansion of multidrug-resistant nosocomial infections pathogens is under special attention at the moment. Antibiotic resistance increasing give us the limited treatment options. This problem is particularly acute for transplant clinics, because of patients need lifelong immunosuppressive therapy. From the one hand this ensures stable allograft functioning, but from the other increases the risk of severe infectious complications in the postoperative period. The purpose of this article is analysis carbapenem resistance dynamics of Klebsiella spp., Acinetobacter spp., Pseudomonas spp. and Staphylococcus spp. isolated from the blood of recipients of donor organs from 2009 to 2019 in the Shumakov National Medical Research Center of Transplantology and Artificial Organs. A significant annual decrease of carbapenem-sensitive strains of Klebsiella spp. and Acinetobacter spp. are shown. The study of a distinctive pathogen resistance profile specific to each institution can help one in selecting an adequate antimicrobial strategy and is an effective predictive tool for controlling the growth of multidrug-resistant microorganisms.

COVID-19 and Stem Cell Transplantation; Results from the Prospective Survey By the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT) and the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH)

COVID-19 is a severe infectious complication in patients with underlying medical conditions such as having undergone hematopoietic stem cell transplantation (HCT). This prospective survey reports outcome on 272 COVID-19 patients from 19 countries having undergone allogeneic (n = 175) or autologous (n = 97) HCT reported to the EBMT registry or to the GETH. All patients had the diagnosis of SARS-CoV-2 documented by PCR. Patients were included in this analysis if COVID-19 diagnosis was before April 10, 2020. The overall survival was estimate by using the Kaplan Meier methods, considering the death due to any cause as an event and the time from COVID-19 infection to the latest follow-up as survival time; difference between groups were tested by the log-rank test. Univariate and multivariate risk factor analysis for overall survival were performed with the Cox regression model.The median age was 54.4 years (1.0 - 80.3) for allogeneic and 60.9 years (7.7 - 73.4) for autologous HCT patients. 20 patients were children (< 18 years of age; median age 11.3 (1.0 - 16.9)). The median time from HCT to diagnosis of COVID-19 was 13.7 months (0.2 - 254.3) in allogeneic and 25.0 months (-0.9 - 350.3) in autologous recipients. Lower respiratory tract disease (LRTD) developed in 84.8% and 21.5% were admitted to an intensive care unit (ICU). At the time of analysis, 68/238 (28.6%) patients had died (47/155 allogeneic patients; 21/83 autologous patients). No follow-up had been received on 34 patients. The median time from infection to death was 19 days (0-102). Five patients were reported to have other primary causes of death than COVID-19. Of the patients reported to be alive, the median follow-up was 44 days. 144 (84.7%) patients (93 allogeneic; 51 autologous) had virologic resolution of the COVID-19 infection having at least one negative PCR. 26 patients were alive and known to be still COVID-19 positive (15 allogeneic; 11 autologous). For 34 patients the resolution status was unknown. Factors influencing the likelihood of resolution in multivariate analysis were underlying diagnosis (p=.01) and longer time from transplant to diagnosis of COVID-19 (p=.035).Overall survival at 6 weeks from COVID-19 diagnosis was 76.8% and 83.8% in allogeneic and autologous HCT recipients (p =ns), respectively (figure 1). Children (n=20) tended to do better with a 6-week survival of 95.0% although the difference was not significantly different (p =.12). In multivariate analysis of the total population older age (HR 1.26; 95% CI 1.05 - 1.51; p = .01) increased the risk and better performance status decreased the risk for fatal outcome (HR 0.79; 95% CI 0.69 - 0.90; p = .0003). The same factors had significant impact on overall survival in allogeneic HCT recipients (age HR 1.28; 95% CI 1.05 - 1.55; p=.01; performance status HR 0.79; 95% CI 0.68 - 0.92); p=.002) while only age impacted survival among autologous HCT patients (data not shown). Other transplant factors such as underlying diagnosis, time from HCT to diagnosis of COVID-19, graft-vs-host disease, or ongoing immunosuppression did not have a significant impact on overall survival.We conclude that HCT patients are at an increased risk compared to the general population to develop LRTD, require admission to ICU, and have increased mortality in COVID-19.Figure 1DisclosuresDuarte:Incyte Corporation: Other: Has received speaker and advisor fees. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mielke:Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau. López Jiménez:MSD: Speakers Bureau; Roche: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau.

Outcomes of GCSF and Pre-Emptive Plerixafor Based Peripheral Blood Stem Cell Mobilization Among Patients with Multiple Myeloma-Experience from Newly Established Transplant Unit in Eastern Mediterranean Area

Introduction Granulocyte Colony Stimulating Factor (GCSF) with cyclophosphamide based peripheral blood stem cell (PBSC) mobilization is a widely used strategy among patients with multiple myeloma (MM), however, it is associated with toxicity and morbidity including severe infectious complications needing hospitalization. Plerixafor with GCSF has been widely used for mobilization as a preemptive strategy or during second attempt at collection with encouraging results. Methods We describe our experience from a newly established transplant unit in the Eastern Mediterranean region. A retrospective chart review was done and all consecutive patients of MM who underwent PBSC mobilization by GCSF and plerixafor between 2017 to 2020 were included in the study. Patients received GCSF (filgrastim, 10 µg/kg/day) and if peripheral blood CD34 count was less than 20/µl on day 4, patients received the first dose of plerixafor (240 µg/kg/day) on the evening of Day 4. Daily apheresis started on Day 5 for a maximum of 4 days, or until enough stem cells collected for one or two transplants at physician's discretion. Results A total of seventeen PBSC collections were carried out among patients with myeloma (n=17). There were 10 males and 7 females. The median age was 53 years (range 38-71), and 8/17 were less than 50 years of age. 14/ 17 were of IgG myeloma subtype, 2/17 were light chain myeloma, 1/17 was IgA myeloma type. 6/17 patients had R-ISS stage 3 disease while rest (11/17) had R-ISS stage 2 disease. 15/17 patients were in first remission. Only 1/17 patients had high-risk cytogenetics. 12/17 patients had bortezomib based therapy while 5/17 had lenalidomide based therapy. 13/17 patients had GCSF alone mobilization while 4/17 had GCSF plus pre-emptive plerixafor. 9/17 had a single collection while 8/17 had 2 collections. All patients on plerixafor needed two collections. Median CD34 stem cell dose was 8.6 x10^6 cells/kg (range 3.4-20 x 10^6 cells/kg). No grade 2-4 adverse events were recorded with this strategy post-collection and none required hospitalization for any adverse events. All patients underwent melphalan based conditioning and autologous stem cell transplant, although only 12/17 received a full dose of 200 mg/m2. 13/17 patients had fresh stem cells infused while the rest had cryopreserved stem cells. Median time to neutrophil recovery was 11 days (range 9-27) while median time to platelet recovery was 12 days (range 10-37). Day 100 mortality was zero percent. Conclusions Our study demonstrates successful collection with high stem cell yield enough for two stem cell transplants with GCSF and preemptive plerixafor strategy, in patients with MM, thus saving patients toxic effects of cyclophosphamide including cytopenias, infections which at times are severe causing morbidity and mortality. Over two-thirds of patients collected with GCSF alone. No major adverse events post stem cell collection were noted and all our patients engrafted early thus reducing hospital stay. Although the use of plerixafor increases cost but failure of mobilization, second mobilization, and infections (at times severe), delayed engraftment have their own costs and implications. Our study at our new transplant unit confirms that this pre-emptive strategy is safe, effective and reasonable chemo free first line option with no major adverse events as demonstrated by other studies. Disclosures No relevant conflicts of interest to declare.

Identification of Predictive Markers of Severe and Prolonged Neutropenia after CD19-Specific CAR T-Cell Treatment in Patients with Relapsed/Refractory B-Cell Malignancies

Introduction: Genetically engineered CD19-specific CAR T-lymphocytes have emerged as a powerful new class of immunotherapeutic agents in relapsed/refractory B-cell malignancies. However, their utility is hampered by unique toxicities including prolonged cytopenias that can predispose for severe infectious complications. Here, we evaluate predictive markers of hematotoxicity in patients treated in the real-world setting. Methods: To define the incidence and nature of CAR T-cell associated hematotoxicity, we performed a retrospective chart review across three German academic hospitals (LMU Munich, Tübingen, Hamburg-Eppendorf). Between January 2019 and June 2020, a total of 69 patients (58 r/r B-NHL, 11 BCP-ALL) were studied following treatment with the commercial CD19-specific CAR T-cell products Axi-cel (n=43) or Tisa-cel (n=26). The relative impact of baseline (=prior to lymphodepletion) demographic, laboratory and clinical characteristics on hematotoxicity was analyzed by uni- &amp; multivariate analysis using the following primary endpoint: duration of clinically significant neutropenia - defined as an ANC &amp;lt;500/µl - between days 0-60. Results: In this heavily pre-treated cohort, the incidence of severe neutropenia (ANC &amp;lt;500/µl) was 97% with a median duration of 12 days (95% CI: 10-15). Neutropenia followed a bimodal temporal curve with intermittent hematopoietic recovery upon G-CSF support. Profound, protracted (ANC &amp;lt;100/µl for ≥7 days) and prolonged (ANC &amp;lt;1000/µl after day 21) neutropenia was common, occurring in 36% and 78% of patients respectively. The incidence of severe anemia (Hb &amp;lt;7 g/dl or requiring pRBC transfusion) and severe thrombocytopenia (PLT count &amp;lt;50 G/l) was 68% and 71% respectively. Of note, a total of 12 patients (17 %) observed severe, G-CSF-refractory bone marrow aplasia with an ANC &amp;lt; 500/µl greater than 30 days. The following baseline clinical markers were significantly correlated with the duration of neutropenia by univariate or logistic regression analysis (Figure 1): Platelet Count (r = -0.45, P=0.0001), Hemoglobin (r = - 0.33, P=0.006), ANC (r = - 0.28, P=0.02), C-reactive Protein (r = +0.35, P=0.004), Ferritin (r = +0.52, P= &amp;lt;0.0001), and BM Infiltration for lymphoma (LR=6.7, P=0.0096). Interestingly, the following baseline factors were not significantly correlated: LDH, age, prior lines of cytotoxic therapy, and eGFR. On stepwise multivariate analysis using a binary logistic regression for the outcome severe neutropenia ≥ 14 days, baseline ferritin, hemoglobin and platelet count retained significance. In terms of dynamic clinical variables, both peak IL-6 and peak CRP were not associated with increased hematotoxicity, though peak IL-6 exhibited a trend towards significance (r = +0.22, P= 0.077). While peak ferritin was associated with a longer duration of neutropenia (r = +0.37, P=0.025), the peak value was less predictive than the baseline value. Moreover, we observed no nested dependency between hematotoxicity and CRS/ICANS. CRS grade in particular was not associated with prolonged neutropenia in our study cohort. Furthermore, the application of G-CSF was not associated with an increased rate or severity of neurotoxicity. When comparing the duration of neutropenia by CAR product (Axi-cel vs. Tisa-cel) and disease entity (DLBCL vs. BCP-ALL), no statistically significant difference was observed. Conclusions: Profound and prolonged neutropenia was common in our study cohort. This included cases of severe, G-CSF-refractory bone marrow aplasia. The identified predictive markers point toward a multifactorial model of pathogenesis for CAR T-cell associated hematotoxicity. They include markers of impaired hematopoietic reserve (e.g. low baseline PLT count, Hemoglobin, ANC), inflammatory state (e.g. hyperferritinemia, elevated CRP), and tumor microenvironment (e.g. BM infiltration). These findings carry important implications for both risk-stratification and the development of predictive clinical tools. The identified factors are currently being validated in an independent patient cohort and prospective validation is ongoing. Figure 1 Disclosures Blumenberg: Novartis: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Research Funding. Buecklein:Celgene: Research Funding; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Gilead: Consultancy, Research Funding. Ayuk:Celgene: Consultancy, Honoraria; Kite/Gilead: Honoraria; Therakos/Mallinckrodt: Honoraria, Research Funding; Neovii: Research Funding; Novartis: Honoraria. Subklewe:Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding.

Essential role of PET-CT in the management of patients with severe infectious complication CIEDS: multicentre study

Abstract Background With the increasing number of implanted cardiac pacemakers, ICDs and CRTs, the number of serious infectious complications of these procedures increases significantly, especially in the longer term from the primary implantation. The systematic solution is in most cases endovasal extraction of these systems. Methods In a multicenter, prospective, randomized, controlled trial evaluating the benefit of CIEDS infection management in 277 patients, a conventional approach using blood cultures, microbiological examinations and TEE versus innovative management of these patients using PET-CT was compared. PET-CT examination is able to differentiate very well the infection of the implant pocket (Figure A) against bacterial endocarditis (Figure B). Thanks to this, it is possible to individualize the management of the patient and to shorten the dates of hospitalization, resp. time to re-implantation of the new system in patients without the presence of bacterial endocarditis. Results The results of the multicentre study are summarized in Table 1. Conclusions A comprehensive examination of patients with CDRIE using PET-CT significantly shortens hospital stay, time of antibiotic therapy and, as a consequence, leads to a lower incidence of serious complications of extraction procedures. PET-CT in CDRIE patients Funding Acknowledgement Type of funding source: None

NEONATAL SCREENING IN UKRAINE: THE NEW CHALLENGES

Introduction. The priority of modern pediatrics and neonatology is to improve the organizational forms and methods of providing medical care to children, reducing morbidity, mortality and disability prevention. Severe Combined Immunodeficiency (SCID) is a group of primary immunodeficiency conditions with particularly severe dysfunction or absence of T and B cells, and sometimes NK lymphocytes. Late diagnosis of primary immunodeficiency, namely SCID, leads to the development of severe infectious complications, significantly complicates the further treatment and survival of patients, often leading to death from infancy. Today there are results of SCID treatment, with early diagnosis the effectiveness of therapy and survival of children is more than 90% in the world. A number of countries around the world conduct neonatal screening at the state level for early diagnosis of SCID. Modern neonatal screening in Ukraine is provided for 4 nosologies, while in other countries it covers from 8 to 60 genetic pathologies. The aim of our study is the early detection and diagnosis of severe primary immunodeficiency by neonatal screening, prevention of severe infections and complications in this group of patients, timely radical treatment, improving survival and quality of life of children with severe primary immunodeficiency. Materials and methods. For the first time in Ukraine, it is planned to conduct a pilot study of screening of newborns to detect severe primary immunodeficiencies, which will be based on the determination of T- and B-lymphopenia by TRECs and KRECs. The prevalence of T- and B-lymphopenias among 19 newborns, their importance in the diagnosis of severe combined immunodeficiencies and severe antibody disorders will be determined. Based on the results of the study, a protocol for the detection of primary immunodeficiencies by TRECs and KRECs and further tactics for infection prevention, treatment and surveillance of such children will be developed. For the first time, the clinical and economic feasibility of introducing neonatal screening for severe immunodeficiencies in Ukraine will be substantiated. Expected results. After studying the prevalence of T- and B-lymphopenia in infants, their importance in the diagnosis of SCID and severe antibody disorders will be formulated. Conclusions. Early diagnosis of primary immunodeficiency is extremely important to improve the patient's quality of life, as delayed diagnosis leads to a lack of adequate therapy and, consequently, to further serious infections that interfere with daily life, increasing the risk of various non-infectious complications. It is known that these disorders negatively affect the health of the patient, the quality of life of his family and people caring for him. In addition, existing research in the world proves that early diagnosis and bone marrow transplantation is an effective way to reduce the incidence and mortality of patients with SCID and lymphopenia

Administration of intravenous immunoglobulin in patients with chronic lymphocytic leukemia and infectious complications

Background. Chronic lymphocytic leukemia (CLL) is one of the most frequent malignant blood disorders in adult patients. For the last several decades treatment of CLL made its way from simple chemotherapy agents (chlorambucil, cyclophosphamide, fludarabine) to highly technological innovative medications (monoclonal antibodies, targeted agents, CAR T-cell therapy). Despite quite high rate of remissions induced by the novel treatment methods significant proportion of the patients develop infectious mostly bacterial complications in the long term. Various infections often become the cause of mortality in CLL patients in remission. They develop in about 70 % of the patients and become severe in about 30 % of them (requiring inpatient hospitalization and/or intravenous antibacterial treatment). Novel agents for treatment of CLL influencing the immune B-cells lead to immune suppression (secondary hypogammaglobulinemia, immunoglobulin G (IgG) deficiency), distribution and severity of infectious complications. Substitutive treatment with intravenous IgG changed clinical course of the secondary hypoimmunoglobulinemia reducing significantly incidence of the infectious events in CLL patients as well as in patients undergoing immunochemotherapy (ICT) and immunosuppressive treatment.&#x0D; Objective. To determine the necessity for immunocorrection in patients with CLL requiring ICT.&#x0D; Materials and methods. Patients with the diagnosis of CLL undergoing ICT within hematology department developing infectious complications were observed.&#x0D; Results and discussion. Patients with CLL undergoing ICT were tested and analyzed and according to the results in 31 of these patients hypogammaglobulinemia and reduced levels of IgG were revealed. In 8 of the patients reduction of IgG was detected already at the primary diagnosis of CLL (Binet stages B and C). Depending on the performed treatment of CLL frequency of infectious complications differed and was the highest in subjects with progressive course of leukemia and in those who were treated with RFC (rituximab, fludarabine and cyclophosphamide) ICT. Levels of IgG ranged from 0.86 to 5.55 g/L (median – 3.49 g/L, lower-upper quartile – 2.62-4.76 g/L). Levels of hypogammaglobulinemia in the whole group ranged from 4.49 to 16.87 g/L (median – 12.11 g/L, lower-upper quartile – 11.44-12.88 g/L). Patients underwent the substitutive treatment with intravenous immunoglobulin with the dose of 0.4 g/kg every month. The medication was administered according to standard recommendations. There were no side effects registered within 24 h of infusion. Additionally, patients with infectious complications were treated with antibacterial, antifungal and antiviral agents. After application of intravenous immunoglobulin general condition of the patients improved, body temperature normalization and reduction of recurrent infectious events were observed. The mean time from the diagnosis of persistent hypogammaglobulinemia to complete resolution of infectious complications was 12.5 months (ranging from 3.6 to 27 months). Our results suggested that patients with IgG deficiency without signs of infection responded better to this treatment. Levels of IgG increased from 6.57 to 13.5 g/L (median – 9.35 g/L, lower-upper quartile – 7.57-10.70 g/L) and levels of γ-globulin grew from 14.4 to 17.69 g/L (median – 16.70 g/L, lower-upper quartile – 15.96-17.30 g/L).&#x0D; Conclusions. Secondary hypogammaglobulinemia and deficiency of the serum IgG often develop in patients with blood malignancies, especially in those involving clonal proliferation of the B-cells, like in CLL. According to our study immunocorrection by intravenous immunoglobulin resulted in resolution of infectious complications in all cases of confirmed immunodeficiency. In order to prevent severe infections in CLL patients it is expedient to perform screening of the humoral immunity status before initiation of ICT and in case of development of febrile conditions.

Infusion intravenous IgG replacement therapy for hypogammaglobulinemia after anti-CD20 monoclonal antibodies at patients with non-hodgkin’s malignant lymphomas

Objective. Determining the risk of infectious complications in patients with non-hodgkin’s lymphomas (NМL) who received anti-CD20 monoclonal therapy and the effectiveness of intravenous immunoglobulin G (IgG) replacement therapy.&#x0D; Materials and methods. A prospective analysis of data of 37 persons with NML who were treated in the hematology clinic of the National Military Medical Clinical Center “Main Military Clinical Hospital” from January to December 2019. Statistical data processing was performed using computer programs Microsoft Office Excel (2007) and statistical processing package Statistica 6.0 using the procedure 2×2 Tables (YI/VI/Phil, McNemar, Fisher Exact) module Nonparametric Statistics, which uses the analysis of a four-cell conjugation table.&#x0D; Results and discussion. The mean age of patients was 56.5±1.4 years; 12 (32.43 %) were female patients. Baseline IgG levels before anti-CD20 monoclonal therapy were not determined in 17 (45.94 %) patients. Hypogammaglobulinemia was detected in 20 (54.05 %) subjects who were tested for IgG levels prior to anti-CD20 therapy. After administration of anti-CD20 monoclonal therapy, hypogammaglobulinemia worsened. There was an increase in severe infections after anti-CD20 therapy (from 9.4 to 40.7 %; p&lt;0,001). An analysis of patient survival within 6 months of starting anti-CD20 monoclonal therapy revealed an increased mortality associated with an increase in age (hazard ratio (HR) 1.05; 95 % confidence interval (CI) 1.00-1.02; p&lt;0.005), male (HR 1.12; 95 % CI 1.01-1.18; p&lt;0.005), severe infectious complications (HR 5.18; 95 % CI 3.16-4,72; p&lt;0.001). Only 10 (27.02 %) patients received IgG replacement therapy after anti-CD20 monoclonal therapy. Among these patients, a higher cumulative dose of immunoglobulin replacement therapy was associated with a reduced risk of serious infectious complications (HR 1.00; 95 % CI 0.98-1.02; p&lt;0.005).&#x0D; Conclusions. Monitoring of IgG levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from IgG replacement, which may in turn help to avoid excess morbidity and mortality.

Glucocorticoid Maintenance Therapy and Severe Infectious Complications in ANCA-Associated Vasculitis

Glucocorticoid Maintenance Therapy and Severe Infectious Complications in ANCA-Associated Vasculitis

FATAL INTRACEREBRAL HEMORRHAGE IN A PATIENT WITH SEVERE COVID-19 INFECTION

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Stroke like lesions has been documented in COVID-19 patients. Although the exact stroke-incidence is unknown, it was reported to be around 5 % in a hospitalized cohort in Wuhan and 1.1 % in a study in New York City. CASE PRESENTATION: A 73-year-old male with a past medical history of hypertension and hyperlipidemia presents to ER with fever, cough, myalgia, increasing shortness of breath, and confusion for one day. His daughter is known COVID-19 positive. The patient was noted to be febrile, tachypneic, and hypoxic to 90% at room air. Chest X-ray showed bilateral infiltrates and the COVID-19 test was positive. The patient was immediately intubated due to his significant acute respiratory distress. Inflammatory markers were significantly elevated: Troponin T: 5.86, Lactate dehydrogenase: 542, CRP: 350 mg/l, Ferritin: 1878, D-dimer: >20, fibrinogen: 1094, Total Creatinine kinase: 2260 and creatinine: 5.7. His course was complicated by septic shock requiring three vasopressors; acute kidney injury requiring hemodialysis; Enterococcus Faecalis bacteremia treated with Ampicillin, and Klebsiella pneumonia sensitive to ceftriaxone. EKGs showed new onset of atrial fibrillation without ST changes. Echocardiogram showed normal ejection fraction without wall motion abnormalities. His significant troponin elevation was likely due to myonecrosis related to COVID-19 infection and he was started on heparin drip. The patient respiratory status continued to improve however he remained obtunded. Head CT showed acute right frontal hemorrhage and focal hyperdense foci in the left frontal lobe and basal ganglia. Brain MRI showed a 2.8 x 2.4 cm lesion situated in the right sub-frontal region with appearances of abscess versus necrotic tissue and extensive bilateral scattered deep white matter infarcts. Neurosurgery didn’t recommend any intervention due to poor prognosis. After 27 days of intubation, the family requested comfort measures, and the patient was terminally extubated. DISCUSSION: ‘Sepsis-induced coagulopathy’ is one of the hallmarks of severe COVID-19, usually manifests as a high D-dimer and elevated fibrinogen. It induces a systemic inflammatory response with endothelial dysfunction and microthrombosis predisposing to acute strokes. The risk of developing a cerebrovascular disease is multifactorial and includes cardiovascular risk factors, old age, and severe COVID-19 disease manifestations with sings of hypercoagulability. In this case, the stroke like-lesions could be related to septic emboli with the conversation to hemorrhage due to heparin use in the setting of severe COVID-19 infection. CONCLUSIONS: Ischemic and hemorrhagic stroke has been reported as a complication of severe COVID-19 infection. The definite mechanism is unknown, but these findings can indicate poor prognosis with potential neurological sequelae and increased mortality. Reference #1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202903/ Reference #2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236667/ Reference #3: https://jamanetwork.com/journals/jamaneurology/fullarticle/2766766 DISCLOSURES: No relevant relationships by Karim Anis, source=Web Response No relevant relationships by Anastasia Maltseva, source=Web Response No relevant relationships by Lady Sanchez Fernandez, source=Web Response

Defining the scourge of COVID-19 hyperinflammatory syndrome.

Defining the scourge of COVID-19 hyperinflammatory syndrome.

Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system (CNS) with an autoimmune component. Among the recent disease-modifying treatments available, Natalizumab, a monoclonal antibody directed against the alpha chain of the VLA-4 integrin (CD49d), is a potent inhibitor of cell migration toward the tissues including CNS. It potently reduces relapses and active brain lesions in the relapsing remitting form of the disease. However, it has also been associated with a severe infectious complication, the progressive multifocal leukoencephalitis (PML). Using the standard protocol with an injection every 4 weeks it has been shown by a close monitoring of the drug that trough levels soon reach a plateau with an almost saturation of the target cell receptor as well as a down modulation of this receptor. In this review, mechanisms of action involved in therapeutic efficacy as well as in PML risk will be discussed. Furthermore the interest of a biological monitoring that may be helpful to rapidly adapt treatment is presented. Indeed, development of anti-NAT antibodies, although sometimes unapparent, can be detected indirectly by normalization of CD49d expression on circulating mononuclear cells and might require to switch to another drug. On the other hand a stable modulation of CD49d expression might be useful to follow the circulating NAT levels and apply an extended interval dose scheme that could contribute to limiting the risk of PML.

A systematic review of orbital apex syndrome of odontogenic origin: Proposed algorithm for treatment.

Orbital apex syndrome (OAS) can be a rare, but severe complication of an odontogenic infection and has high morbidity and mortality. Antibacterial drugs are typically an appropriate treatment choice, but the most severe cases are fungal in nature and pose a tough challenge to the clinician. The aim of this study was to determine the predisposing factors, specific aspects in its management and the appropriate treatment strategy in order to improve patient outcome. A systematic review was conducted using PubMed, PubMed Central, Web of Science, and Scopus up to February 2020, based on the associations between dental extraction or infections and OAS. Of 721 papers found, 18 articles were considered eligible and presented in total 21 cases (13 fungal and eight bacterial infections). The information was organized into a diagnostic and treatment algorithm which included data extracted both from the included cases and updated literature of treatment efficacy studies. Immunosuppression (uncontrolled diabetes mellitus and chemotherapy) was found as an important predisposing factor particularly for fungal infections. In these cases, we suggest that early simultaneous approaches, including aggressive surgical procedures and systemic administration of amphotericin B, result in a better outcome. In conclusion, medical intervention success depends on aggressive treatment and multidisciplinary teamwork.

Primary prophylaxis was associated with lower arthropathy in Colombian men with haemophilia B: A longitudinal analysis (2015‐2019)

The risk of chronic haemophilic arthropathy (CHA) is related to severity. Evidence suggests that primary prophylaxis (PPr) could reduce CHA incidence and its impact on quality of life. To evaluate the association between PPr and CHA in Colombian males with haemophilia B (HB) during 2015 to 2019. A panel-time analysis was performed with data provided by the National Health System to update a nationwide open cohort of people with congenital coagulopathies. The association was evaluated in a logistic random-effect regression model (LRERM), adjusted by age at diagnosis, prophylaxis dose and frequency, severity, haemarthrosis and high-titre inhibitors. During 2015-2019, a total of 362 men with HB and treated with either, primary, secondary or tertiary prophylaxis were identified. At baseline, CHA prevalence in the cohort was 36.84% (n=133), median age was 19.0years (IQR: 10.0-27.0), and median age at diagnosis was 1.0year (IQR: 0.0-4.0). PPr was prescribed in 37.85% (n=137), and median dose (IU/Kg/dose) was almost the same for primary vs. secondary/tertiary prophylaxis. Patients in PPr had a lower frequency of severe HB, CHA, haemarthrosis, infectious complications and high-titre inhibitors than those in secondary or tertiary prophylaxis (STPr). In the LRERM, PPr was associated with a significant reduction of 89.70% in the odds of CHA (aOR=0.103, IC 95%: 0.040, 0.270; P<.001), compared with STPr. PPr decreased the odds of CHA by 89.70% in males with HB in Colombia. Our findings are consistent with previous studies and support the strategy to prescribe PPr to our patients.

Immunosupressive therapy of aplastic anemia patients: successes and failures (single center experiment 2007-2016)

Treatment programs for patients with acquired aplastic anemia include two main therapeutic options: allogeneic bone marrow transplantation and combined immunosuppressive therapy (IST). However, combined IST remains the method of choice for most adult AA patients. This study included 120 AA patients who received IST at the National Research Center for Hematology in 20072016. The analysis was applied to 120 patients. Median age was 25 (1765) years, M/F: 66/54, SAA/NSAA: 66%/34%. Effectiveness of IST was carried out in 120 patients with AA. This group did not include 8 SAA patients who died during the first 3 months from the start of treatment from severe infectious complications (early deaths 6.2%) and 2 AA patients who dropped out of surveillance. The observation time was 55 (6120) months. Paroxysmal nocturnal hemoglobinuria (PNH clone) was detected in 67% of AA patients. The median PNH clone size (granulocytes) was 2.5 (0.0199.5)%. The treatment was according to the classical protocol of combined IST: horse antithymocytic globulin and cyclosporin A. Most of patients (87%) responded to combined immunosuppressive therapy. To achieve a positive response, it was sufficient to conduct one course of ATG to 64% of patients, two courses of ATG 24% of patients and 2% of patients responded only after the third course of ATG. A positive response after the first course was obtained in 64% of patients included in the analysis. Most of the responding patients (93%) achieve a positive response after 36 months from the start of treatment. Therefore, the 3rd6th months after the first course of ATG in the absence of an answer to the first line of therapy can be considered the optimal time for the second course of ATG. This tactic allows to get an answer in another 58% of patients who did not respond to the first course of ATG. The probability of an overall 10-year survival rate was 90% (95% confidence interval 83.696.2).