RESUMEN
BACKGROUND: Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS. METHODS: Effects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 µg of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 µg) in HLA-DR4 transgenic mice. RESULTS: Despite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNγ, failed to improve survival in experimental TSS. CONCLUSIONS: Our results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.
Asunto(s)
Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Choque Séptico/inmunología , Choque Séptico/metabolismo , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/metabolismo , Adipocitos/citología , Animales , Diferenciación Celular , Citocinas/sangre , Modelos Animales de Enfermedad , Enterotoxinas/inmunología , Enterotoxinas/metabolismo , Humanos , Mediadores de Inflamación/sangre , Masculino , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Ratones , Choque Séptico/mortalidad , Infecciones Estafilocócicas/mortalidadRESUMEN
BACKGROUND: Clostridium difficile infection (CDI) is the most common cause of health care-associated diarrhea in children and adults. Although serious complications of CDI have been reported to be increasing in adults, this trend has not yet been demonstrated in children. The purpose of this study was to examine the features of CDI in a pediatric population, with special attention to the occurrence of CDI-related severe outcomes. METHODS: A chart review was conducted for patients with C. difficile infection detected by cytotoxin assay between August, 2008 and July, 2012. Basic demographics, mode of acquisition (nosocomial versus community), laboratory and clinical features, treatment, and outcome data were collected. Pulsed-field gel electrophoresis and polymerase chain reaction detection of toxin A (tcdA), toxin B (tcdB), binary toxin (cdtB) and tcdC genes were performed on isolates from nosocomial cases by the National Microbiology Laboratory, Winnipeg, Manitoba. RESULTS: Ninety percent of children with CDI experienced resolution of symptoms by 30 days after disease onset and 2% experienced a severe outcome. There were no cases where colectomy was performed for CDI, and only one case where CDI contributed to death. Various combinations of clinical and laboratory features were not predictive of a severe outcome. Seventy-four percent of cases were nosocomial-associated. Among all cultured strains, the NAP4 strain occurred most frequently (24%), followed by NAP1 (11%). There was no association between strain type and clinical outcome; however, relapses were significantly more frequent in NAP4-infected children. CONCLUSIONS: Severe outcomes due to CDI are uncommon in children compared to adults. Further prospective pediatric studies on CDI in community and hospital settings are required to better understand risk factors, optimal treatment and the significance of NAP4 in pediatric CDI.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Adolescente , Niño , Preescolar , Infecciones por Clostridium/complicaciones , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/terapia , Estudios de Cohortes , Infección Hospitalaria/complicaciones , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/terapia , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
In vitro, nitric oxide (NO) has been shown to have antimicrobial activity against a wide range of viruses, including influenza A virus. Therefore, we hypothesized that inhaled nitric oxide (iNO) would increase survival in vivo by reducing the viral load in C57Bl/6 mice infected with a lethal dose of influenza A/WSN/33 (H1N1; WSN/33) virus. NO was delivered to influenza-infected mice either continuously or intermittently at 80 or 160 ppm, respectively, using both prophylactic and post-infection treatment strategies. Murine survival and weight loss were assessed, and lung viral load was quantified via plaque assay. Here, we report that iNO administered prophylactically or post-influenza infection failed to improve survival of infected mice. No difference in lung viral load was observed between experimental groups. Although NO has antiviral activity against influenza A virus in vitro, iNO therapy provided no apparent benefit when used for treatment of influenza A virus infection in vivo.
Asunto(s)
Óxido Nítrico/administración & dosificación , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Administración por Inhalación , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Femenino , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Subtipo H1N1 del Virus de la Influenza A/fisiología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/efectos adversos , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Índice de Severidad de la Enfermedad , Insuficiencia del Tratamiento , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: Health care workers (HCW), particularly immigrants and ethnic minorities are at increased risk for SARS-CoV-2 infection. Outcomes during a COVID-19 associated hospitalization are not well described among HCW. We aimed to describe the characteristics of HCW admitted with COVID-19 including immigrant status and ethnicity and the associated risk factors for Intensive Care unit (ICU) admission and death. METHODS: Adults with laboratory-confirmed community-acquired COVID-19 hospitalized from March 1 to June 30, 2020, at four tertiary-care hospitals in Montréal, Canada were included. Demographics, comorbidities, occupation, immigration status, country of birth, ethnicity, workplace exposures, and hospital outcomes (ICU admission and death) were obtained through a chart review and phone survey. A Fine and Gray competing risk proportional hazards model was used to estimate the risk of ICU admission among HCW stratified by immigrant status and region of birth. RESULTS: Among 1104 included persons, 150 (14%) were HCW, with a phone survey participation rate of 68%. HCWs were younger (50 vs 64 years; p<0.001), more likely to be female (61% vs 41%; p<0.001), migrants (68% vs 55%; p<0.01), non-White (65% vs 41%; p<0.001) and healthier (mean Charlson Comorbidity Index of 0.3 vs 1.2; p<0.001) compared to non-HCW. They were as likely to be admitted to the ICU (28% vs 31%; p = 0.40) but were less likely to die (4% vs. 17%; p<0.001). Immigrant HCW accounted for 68% of all HCW cases and, compared to Canadian HCW, were more likely to be personal support workers (PSW) (54% vs. 33%, p<0.01), to be Black (58% vs 4%) and to work in a Residential Care Facility (RCF) (59% vs 33%; p = 0.05). Most HCW believed that they were exposed at work, 55% did not always have access to personal protective equipment (PPE) and 40% did not receive COVID-19-specific Infection Control (IPAC) training. CONCLUSION: Immigrant HCW were particularly exposed to COVID-19 infection in the first wave of the pandemic in Quebec. Despite being young and healthy, one third of all HCW required ICU admission, highlighting the importance of preventing workplace transmission through strong infection prevention and control measures, including high COVID-19 vaccination coverage.
Asunto(s)
COVID-19 , SARS-CoV-2 , Adulto , COVID-19/epidemiología , Vacunas contra la COVID-19 , Canadá/epidemiología , Femenino , Personal de Salud , Hospitales , Humanos , Masculino , Pandemias/prevención & control , Quebec/epidemiologíaRESUMEN
Human herpesvirus-8 (HHV8)-associated multicentric Castleman disease (HHV8-MCD) is a rare nonmalignant lymphoproliferative disorder most commonly observed in PLWH. Herein, we describe an HIV-infected adult male from Cameroon with relapsing HHV8-MCD (HIV+MCD). The patient developed constitutional symptoms, diffuse lymphadenopathy, thrombocytopenia and autoimmune hemolytic anemia. Excisional lymph node biopsy findings were consistent with HHV8-MCD. He was successfully treated with corticosteroids and rituximab. One year later, he developed relapsing disease and was successfully treated again with rituximab. Interestingly, HIV viral load blips correlate with MCD flares, suggesting that low-level viremia is linked with T-cell clonal expansion and/or inflammation, rather than a lack of effective antiretroviral therapy. Rituximab either alone or in combination with chemotherapy for aggressive disease is the standard of care, with approximately 95% of treated patients achieving complete remission. Despite highly effective therapy, HIV+MCD often presents with a relapsing and remitting disease course and carries an increased risk for the development of HHV8-associated lymphoma.
RESUMEN
BACKGROUND: The emergence of novel respiratory viruses such as avian influenza A(H7N9) virus and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) highlights the importance of understanding determinants of transmission to healthcare workers (HCWs) and the public. OBJECTIVES: We aim to determine the viral content of the air emitted by symptomatic inpatients or long-term care residents with laboratory-confirmed influenza virus infection (emitters), and in the breathing zones of healthcare workers who attend to them. DESIGN: A prospective pilot study of patients with laboratory-confirmed influenza virus infection was undertaken. Air within 1m of the patient was sampled using a high volume air sampler. In addition, a lower volume air sampler was placed <1 m from the patient, with another >1 m from the patient. Viral RNA was recovered from the samplers and submitted for quantitative real time PCR. In addition, personal button samplers were provided to HCWs. RESULTS: The air emitted by 15 participants with laboratory-confirmed influenza virus infection was sampled. Of the patients infected with influenza A, viral RNA was recovered from the air emitted by 9/12 patients using the low-volume sampler; no viral RNA was detected from air emitted by patients with influenza B (n=3). Influenza virus RNA was recovered from one HCW's sampler. CONCLUSIONS: Patients with respiratory virus infection emit virus into the air which disperses to >1 m and may reach the breathing zone of a HCW. This pilot study highlights the feasibility and importance of conducting a larger-scale study to identify determinants of exposure and transmission from patient to HCW.
Asunto(s)
Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza B/aislamiento & purificación , Gripe Humana/transmisión , Adulto , Anciano , Anciano de 80 o más Años , Microbiología del Aire , Servicios de Salud Comunitaria , Femenino , Humanos , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Recent evidence suggests that loss of endothelial barrier function and resulting microvascular leak play important mechanistic roles in the pathogenesis of infection-related end-organ dysfunction and failure. Several distinct therapeutic strategies, designed to prevent or limit infection-related microvascular endothelial activation and permeability, thereby mitigating end-organ injury/dysfunction, have recently been investigated in pre-clinical models. In this review, these potential therapeutic strategies, namely, VEGFR2/Src antagonists, sphingosine-1-phosphate agonists, fibrinopeptide Bß 15-42, slit2N, secinH3, angiopoietin-1/tie-2 agonists, angiopoietin-2 antagonists, statins, atrial natriuretic peptide, and mesenchymal stromal (stem) cells, are discussed in terms of their translational potential for the management of clinical infectious diseases.
Asunto(s)
Enfermedades Transmisibles/tratamiento farmacológico , Endotelio Vascular/metabolismo , Microvasos/metabolismo , Animales , Enfermedades Transmisibles/genética , Enfermedades Transmisibles/metabolismo , Enfermedades Transmisibles/fisiopatología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Humanos , Microvasos/efectos de los fármacosRESUMEN
The development of severe influenza has been attributed, in part, to a heightened innate immune response. Recent evidence suggests that endothelial activation, loss of barrier function, and consequent microvascular leak may also serve important mechanistic roles in the pathogenesis of severe influenza. The aim of this review is to summarize the current evidence in support of endothelial activation and dysfunction as a central feature preceding the development of severe influenza. We also discuss the effect of influenza on platelet-endothelial interactions.
Asunto(s)
Endotelio Vascular/fisiopatología , Virus de la Influenza A/fisiología , Gripe Humana/fisiopatología , Animales , Endotelio Vascular/inmunología , Humanos , Virus de la Influenza A/patogenicidad , Gripe Humana/inmunología , Gripe Humana/patología , Gripe Humana/virologíaRESUMEN
RATIONALE: Severe influenza remains a major public health threat and is responsible for thousands of deaths annually. Increasing antiviral resistance and limited effectiveness of current therapies highlight the need for new approaches to influenza treatment. Extensive pre-clinical data have shown that mesenchymal stromal (stem) cell (MSC) therapy can induce anti-inflammatory effects and enhance repair of the injured lung. We hypothesized that MSC therapy would improve survival, dampen lung inflammation and decrease acute lung injury (ALI) in a murine model of severe influenza. METHODS: C57Bl/6 mice were infected with influenza A/PuertoRico/8/34 (mouse-adapted H1N1) or influenza A/Mexico/4108/2009 (swine-origin pandemic H1N1) and administered human or mouse MSCs via the tail vein, either pre- or post- infection. MSC efficacy was evaluated as both an independent and adjunctive treatment strategy in combination with the antiviral agent, oseltamivir. Weight loss and survival were monitored. Inflammatory cells, cytokine/chemokines (IFN-γ, CXCL10, CCL2 and CCL5) and markers of ALI (total protein and IgM), were measured in bronchoalveolar lavage fluid and lung parenchyma. RESULTS: Administration of murine MSCs or human MSCs in a prophylactic or therapeutic regimen failed to improve survival, decrease pulmonary inflammation/inflammatory cell counts or prevent ALI in influenza virus-infected mice. MSCs administered in combination with oseltamivir also failed to improve outcomes. CONCLUSIONS: Despite similarities in the clinical presentation and pathobiology of ALI and severe influenza, our findings suggest that MSC therapy may not be effective for prevention and/or treatment of acute severe influenza.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Subtipo H1N1 del Virus de la Influenza A , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Infecciones por Orthomyxoviridae/terapia , Animales , Antivirales/administración & dosificación , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Infecciones por Orthomyxoviridae/mortalidad , Infecciones por Orthomyxoviridae/virología , Neumonía/patología , Neumonía/virología , Insuficiencia del TratamientoRESUMEN
Influenza A virus is a significant cause of morbidity and mortality worldwide. Severe influenza is recognized as a clinical syndrome, characterized by hyperinduction of proinflammatory cytokine production, otherwise known as hypercytokinemia or a 'cytokine storm'. Research focused on therapeutics to modulate influenza virus-induced inflammation is currently underway. In this review, we discuss the limitations of current antiviral drug treatment strategies, describe the influenza viral and host pathogenicity determinants, and present the evidence supporting the use of immunomodulatory therapy to target the host inflammatory response as a means to improve clinical outcome in severe influenza. We then review the experimental data on investigational immunomodulatory agents targeting the host inflammatory response in severe influenza, including anti-TNF therapy, statins, glucocorticoids, cyclooxygenase-2 inhibitors, macrolides, peroxisome proliferator-activated receptor agonists, AMP-activated protein kinase agonists and high mobility group box 1 antagonists. We then conclude with a rationale for the use of mesenchymal stromal (stem) cells and angiopoietin-1 therapy against deleterious influenza-induced host responses that mediate end-organ injury and dysfunction.