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Frontiers in Immunology 2023Patients with septic shock caused by have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of...
Monoclonal antibodies neutralizing alpha-hemolysin, bicomponent leukocidins, and clumping factor A protected against -induced acute circulatory failure in a mechanically ventilated rabbit model of hyperdynamic septic shock.
BACKGROUND
Patients with septic shock caused by have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of septic shock and to determine whether a novel immunotherapy can prevent or halt its natural disease progression.
METHODS
Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with .
RESULTS
Rabbits challenged with , but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury.
CONCLUSION
These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting virulence factors for the prevention of staphylococcal septic shock.
Topics: Humans; Animals; Rabbits; Staphylococcus aureus; Antibodies, Monoclonal; Hemolysin Proteins; Leukocidins; Shock, Septic; Respiration, Artificial; Stroke Volume; Ventricular Function, Left; Staphylococcal Infections; Shock; Immunoglobulin G
PubMed: 37781371
DOI: 10.3389/fimmu.2023.1260627 -
Yonsei Medical Journal Oct 2023Disseminated nontuberculous mycobacterial (D-NTM) disease occurs primarily in immunocompromised hosts. However, these cases have rarely been reported in South Korea.... (Observational Study)
Observational Study
PURPOSE
Disseminated nontuberculous mycobacterial (D-NTM) disease occurs primarily in immunocompromised hosts. However, these cases have rarely been reported in South Korea. This study aimed to describe the clinical manifestations, disease course, and underlying immune deficiencies of patients with D-NTM disease.
MATERIALS AND METHODS
We retrospectively reviewed the cases of D-NTM disease from January 2005 to December 2019 at a tertiary referral hospital in South Korea. D-NTM disease was defined as a bloodstream infection or infection of two or more non-contiguous body organs with species identification.
RESULTS
Of the 53342 mycobacterial samples from 23338 patients, extrapulmonary NTM was detected in 104 patients, and 3 (2.9%) were diagnosed with D-NTM disease. was isolated from two patients, while subspecies was identified in one. The patients were aged between 18 and 25 years, and two patients were male. All patients were immunocompromised - one received lung transplantation, one was diagnosed with anhidrotic ectodermal dysplasia with T-cell immune deficiency, and one had monocytopenia and mycobacterial infection syndrome associated with mutations. All patients underwent a standard macrolide-based regimen for >5 months, and their sputum tested negative. However, one patient died of bacterial sepsis, while the other two survived.
CONCLUSION
D-NTM disease is rare in a tertiary referral center in South Korea. They occur primarily in immunocompromised patients at a relatively young age. Careful investigation of the underlying immune status is required when treating patients with D-NTM disease.
Topics: Humans; Male; Adolescent; Young Adult; Adult; Female; Tertiary Care Centers; Retrospective Studies; Republic of Korea; Anti-Bacterial Agents
PubMed: 37727920
DOI: 10.3349/ymj.2023.0046 -
The Journal of Clinical Investigation Oct 2023BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.
Topics: Humans; Immunologic Deficiency Syndromes; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Cross-Over Studies; Quality of Life; Heterocyclic Compounds; Primary Immunodeficiency Diseases; Warts; Receptors, CXCR4
PubMed: 37561579
DOI: 10.1172/JCI164918 -
Cancers Jul 2023The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well...
The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well studied. Therefore, we investigated its potential prognostic value in a cohort from the Düsseldorf MDS registry in relationship to the revised international prognostic scoring system (IPSS-R). An AMC below the population's median (<0.2 × 10/L) was associated with several adverse disease features such as lower haemoglobin levels, lower count of neutrophils and platelets, and a higher percentage of blasts in the bone marrow. MDS patients with an AMC < 0.2 × 10/L had a significantly higher risk of progression into acute myeloid leukemia (AML). In a univariate, proportional hazards model the effect of the AMC as a continuous variable was modelled via p-splines. We found a U-shaped effect with the lowest hazard around 0.3 × 10/L. Accordingly, an AMC within the last quartile of the population (0.4 × 10/L) was associated with a reduced overall survival independently of IPSS-R, but not with the risk of secondary AML. Considering monocytopenia as a risk factor for AML progression in MDS may provide an additional argument for allogeneic transplantation or the use of hypomethylating agents in patients who are not clear candidates for those treatments according to current prognostic scoring systems and/or recommendations. Further studies are needed to assess the prognostic impact of the AMC in the context of prognostic scoring systems, considering the molecular risk profile, and to identify the mechanisms responsible for the higher mortality in MDS patients with a subtle monocytosis.
PubMed: 37509235
DOI: 10.3390/cancers15143572 -
Scientific Reports Jul 2023Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants...
Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients' CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients' age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.
Topics: Humans; Child; Female; Child, Preschool; Infant; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cyclophosphamide; Neuroblastoma; Drug-Related Side Effects and Adverse Reactions
PubMed: 37479763
DOI: 10.1038/s41598-023-38983-0 -
Cureus Jun 2023Background Enteric fever is a systemic infection in humans caused by the Gram-negative bacilli serovars Typhi and Paratyphi Although the diagnosis typically involves...
Background Enteric fever is a systemic infection in humans caused by the Gram-negative bacilli serovars Typhi and Paratyphi Although the diagnosis typically involves the isolation of serovars, it is often determined based on laboratory findings and clinical observations. However, due to the wide variety and the non-specific character of clinical features, making a definitive diagnosis presents numerous challenges. Therefore, the aim of this study was to find the predictive hematological and biochemical parameters which would serve in the diagnosis, prognosis, and treatment of typhoid fever cases. Methodology A cross-sectional study was conducted from November 2020 to September 2021 on1076consented volunteerparticipants. Stool culture and identification tests enabled us to distinguish three groups including 423 Typhi positive patients, 115 Paratyphi positive patients, and 538 negative participants. Biochemical and hematological parameters were evaluated using standard methods from commercial kits and Sysmex KX-21N automated hematology analyzer, respectively. A multiple logistic regression analysis was performed to identify the validity of the hematological and biochemical characteristics for enteric fever diagnosis. Results Multiple logistic regression showed hyper creatininemia, hypoalbuminemia, hyper total proteinemia, hyper alkaline phosphatase (ALP), hyper alanine aminotransferase (ALT), hyper total bilirubinemia, hyper conjugated bilirubinemia, hyper triglyceridemia, hyper C-reactive protein (CRP), leukopenia, thrombocytopenia, lymphopenia, monocytopenia, low hemoglobin, low hematocrit, low mean corpuscular volume (MCV), low mean corpuscular hemoglobin (MCH), low platelet, low platelet crit level, high platelet distribution width (PDW) level, high erythrocyte sedimentation rate 1 (ESR1) level as significant biological abnormalities associated (odds ratio {OR} > 1; p < 0.05) with enteric fever infection. Similarly, hyper ESR2 was an independent predictor (OR > 1; p < 0.05) of Typhi infection. However, a negative and significant association (OR < 1; p < 0.05) was recorded between enteric fever infection and high mean platelet volume (MPV). Conclusion Overall the results of the biochemical and hematological profiles can serve as potential diagnostic markers for typhoid fever. These markers can also be useful in the appropriate management of those with enteric fever, preventing severity and limiting outcomes of mortality.
PubMed: 37461754
DOI: 10.7759/cureus.40498 -
Children (Basel, Switzerland) Jun 2023Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection caused by hyperactivation of the immune system.
BACKGROUND
Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection caused by hyperactivation of the immune system.
METHODS
this is a retrospective analysis of clinical data, biochemical parameters, and immune cell subsets in 40 MIS-C patients from hospital admission to outpatient long-term follow-up.
RESULTS
MIS-C patients had elevated inflammatory markers, associated with T- and NK-cell lymphopenia, a profound depletion of dendritic cells, and altered monocyte phenotype at disease onset, while the subacute phase of the disease was characterized by a significant increase in T- and B-cell counts and a rapid decline in activated T cells and terminally differentiated B cells. Most of the immunological parameters returned to values close to the normal range during the remission phase (20-60 days after hospital admission). Nevertheless, we observed a significantly reduced ratio between recently generated and more differentiated CD8+ T- and B-cell subsets, which partially settled at longer-term follow-up determinations.
CONCLUSIONS
The characterization of lymphocyte distribution in different phases of MIS-C may help to understand the course of diseases that are associated with dysregulated immune responses and to calibrate prompt and targeted treatments.
PubMed: 37371300
DOI: 10.3390/children10061069 -
Microorganisms May 2023Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1...
Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1 October 2017 to 30 September 2021, at the Department of Pediatric Infectious Diseases and Clinical Immunity of Ibn Rochd University Hospital-Casablanca. During this period, on 591 patients newly diagnosed with a probable IEI, eight of them (1.3%), from six independent families, had isolated or syndromic unusual viral skin infections, which were either profuse, chronic or recurrent infections, and resistant to any treatment. The median age of disease onset was nine years old and all patients were born from a first-degree consanguineous marriage. By combining clinical, immunological and genetic investigations, we identified GATA2 deficiency in one patient with recalcitrant profuse verrucous lesions and monocytopenia (1/8) and STK4 deficiency in two families with HPV lesions, either flat or common warts, and lymphopenia (2/8), as previously reported. We also identified COPA deficiency in twin sisters with chronic profuse Molluscum contagiosum lesions, pulmonary diseases and microcytic hypochromic anemia (2/8). Finally, we also found one patient with chronic profuse MC lesions and hyper IgE syndrome, (1/8) and two patients with either recalcitrant profuse verrucous lesions or recurrent post-herpetic erythema multiforme and a combined immunodeficiency (2/8) with no genetic defect identified yet. Raising clinicians awareness that infectious skin diseases might be the consequence of an inborn error of immunity would allow for optimized diagnosis, prevention and treatment of patients and their families.
PubMed: 37317175
DOI: 10.3390/microorganisms11051202 -
Thrombosis Research Aug 2023Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical,...
INTRODUCTION
Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown.
METHODS
Monocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units.
RESULTS
Contact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes.
CONCLUSION
Tissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.
Topics: Humans; Monocytes; Endotoxemia; Thromboplastin; Thromboinflammation; Lipopolysaccharides; Sepsis
PubMed: 37263122
DOI: 10.1016/j.thromres.2023.05.018 -
Current Hematologic Malignancy Reports Aug 2023GATA2 deficiency is a haploinsufficiency syndrome associated with a wide spectrum of disease, including severe monocytopenia and B and NK lymphopenia, predisposition to... (Review)
Review
PURPOSE OF REVIEW
GATA2 deficiency is a haploinsufficiency syndrome associated with a wide spectrum of disease, including severe monocytopenia and B and NK lymphopenia, predisposition to myeloid malignancies, human papillomavirus infections, and infections with opportunistic organisms, particularly nontuberculous mycobacteria, herpes virus, and certain fungi. GATA2 mutations have variable penetrance and expressivity with imperfect genotype-phenotype correlations. However, approximately 75% of patients will develop a myeloid neoplasm at some point. Allogeneic hematopoietic cell transplantation (HCT) is the only currently available curative therapy. Here, we review the clinical manifestations of GATA2 deficiency, characterization of the hematologic abnormalities and progression to myeloid malignancy, and current HCT practices and outcomes.
RECENT FINDINGS
Cytogenetic abnormalities are common with high rates of trisomy 8, monosomy 7, and unbalanced translocation der(1;7) and may suggest an underlying GATA2 deficiency in patients presenting with myelodysplastic syndrome (MDS). Mutations in ASXL1 and STAG2 are the most frequently encountered somatic mutations and are associated with lower survival probability. A recent report of 59 patients with GATA2 deficiency who underwent allogenic HCT with myeloablative, busulfan-based conditioning and post-transplant cyclophosphamide reported excellent overall and event-free survival of 85% and 82% with reversal of disease phenotype and low rates of graft versus host disease. Allogeneic HCT with myeloablative conditioning results in disease correction and should be considered for patients with a history of recurrent, disfiguring and/or severe infections, organ dysfunction, MDS with cytogenetic abnormalities, high-risk somatic mutations or transfusion dependence, or myeloid progression. Improved genotype/phenotype correlations are needed to allow for greater predictive capabilities.
Topics: Humans; Chromosome Aberrations; Disease Susceptibility; GATA2 Deficiency; GATA2 Transcription Factor; Genotype; Myelodysplastic Syndromes; Myeloproliferative Disorders; Neoplasms
PubMed: 37247092
DOI: 10.1007/s11899-023-00695-7