RESUMEN
For decades, intravenous immunoglobulin (IVIg) has provided safe and effective therapy for immunodeficient patients. This proof-of-principle study describes a novel approach to generate personalized IVIg for chronic, antibiotic-resistant infection in real time.
Asunto(s)
Antibacterianos/uso terapéutico , Terapia Biológica , Inmunoglobulinas Intravenosas/uso terapéutico , Infecciones por Mycoplasma/terapia , Medicina de Precisión , Infección de la Herida Quirúrgica/terapia , Anciano , Animales , Bovinos , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Síndromes de Inmunodeficiencia/terapia , Masculino , Infecciones por Mycoplasma/diagnóstico , Mycoplasma hominis/efectos de los fármacos , Prueba de Estudio Conceptual , Infección de la Herida Quirúrgica/microbiologíaRESUMEN
BACKGROUND: Powassan virus (POWV) is a rarely diagnosed cause of encephalitis in the United States. In the Northeast, it is transmitted by Ixodes scapularis, the same vector that transmits Lyme disease. The prevalence of POWV among animal hosts and vectors has been increasing. We present 8 cases of POWV encephalitis from Massachusetts and New Hampshire in 2013-2015. METHODS: We abstracted clinical and epidemiological information for patients with POWV encephalitis diagnosed at 2 hospitals in Massachusetts from 2013 to 2015. We compared their brain imaging with those in published findings from Powassan and other viral encephalitides. RESULTS: The patients ranged in age from 21 to 82 years, were, for the most part, previously healthy, and presented with syndromes of fever, headache, and altered consciousness. Infections occurred from May to September and were often associated with known tick exposures. In all patients, cerebrospinal fluid analyses showed pleocytosis with elevated protein. In 7 of 8 patients, brain magnetic resonance imaging demonstrated deep foci of increased T2/fluid-attenuation inversion recovery signal intensity. CONCLUSIONS: We describe 8 cases of POWV encephalitis in Massachusetts and New Hampshire in 2013-2015. Prior to this, there had been only 2 cases of POWV encephalitis identified in Massachusetts. These cases may represent emergence of this virus in a region where its vector, I. scapularis, is known to be prevalent or may represent the emerging diagnosis of an underappreciated pathogen. We recommend testing for POWV in patients who present with encephalitis in the spring to fall in New England.
Asunto(s)
Virus de la Encefalitis Transmitidos por Garrapatas , Encefalitis Transmitida por Garrapatas/diagnóstico por imagen , Encefalitis Transmitida por Garrapatas/epidemiología , Flavivirus , Aciclovir/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Antivirales/líquido cefalorraquídeo , Antivirales/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/virología , Virus de la Encefalitis Transmitidos por Garrapatas/efectos de los fármacos , Virus de la Encefalitis Transmitidos por Garrapatas/inmunología , Virus de la Encefalitis Transmitidos por Garrapatas/patogenicidad , Encefalitis Transmitida por Garrapatas/diagnóstico , Encefalitis Transmitida por Garrapatas/virología , Femenino , Flavivirus/efectos de los fármacos , Flavivirus/inmunología , Flavivirus/patogenicidad , Humanos , Ixodes/virología , Imagen por Resonancia Magnética , Masculino , Massachusetts/epidemiología , Meningitis Bacterianas/tratamiento farmacológico , Persona de Mediana Edad , New Hampshire/epidemiología , Prevalencia , Estaciones del Año , Estados Unidos/epidemiología , Adulto JovenRESUMEN
OBJECTIVES: We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline. METHODS: We retrospectively identified adult patients who received ceftaroline for ≥7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia. RESULTS: The overall rate of incident neutropenia was 10%-14% with ≥2 weeks and 21% with ≥3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22-44; range 13-68) in patients who developed neutropenia and 15 days (IQR 9-29; range 7-64) in patients without neutropenia] was associated with incident neutropenia (Pâ=â0.048). The median total number of ceftaroline doses received [63 (IQR 44-126; range 36-198) by neutropenic patients and 32 (IQR 22-63; range 14-180) by non-neutropenic patients] was also associated with incident neutropenia (Pâ=â0.023). CONCLUSIONS: The overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use.
Asunto(s)
Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Cefalosporinas/efectos adversos , Cefalosporinas/uso terapéutico , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Centros Médicos Académicos , Adulto , Anciano , Anciano de 80 o más Años , Boston/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven , CeftarolinaAsunto(s)
Sangre/parasitología , Fiebre/etiología , Malaria Vivax/diagnóstico , Plasmodium vivax/aislamiento & purificación , Adulto , Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Ritmo Circadiano , Diagnóstico Diferencial , Humanos , Malaria Vivax/complicaciones , Malaria Vivax/tratamiento farmacológico , Masculino , Parasitemia , ViajeRESUMEN
Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, ß-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1ß in response to ß-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1ß and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1ß-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.
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Feohifomicosis , beta-Glucanos , Animales , Humanos , Masculino , Ratones , Proteínas Adaptadoras de Señalización CARD/genética , Lectinas Tipo C/genética , Macrófagos/metabolismo , Feohifomicosis/microbiología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Although the toxicity of streptolysin O (SLO) and streptolysin S (SLS) in purified group A streptococci (GAS) has been established, the effect of these molecules in natural infection is not well understood. To identify whether biologically relevant concentrations of SLO and SLS were cytotoxic to epithelial and phagocytic cells that the bacteria would typically encounter during human infection and to characterize the influence of cell injury on bacterial pathogenesis, we derived GAS strains deficient in SLO or SLS in the background of an invasive GAS M3 isolate and determined their virulence in in vitro and in vivo models of human disease. Whereas bacterial production of SLO resulted in lysis of both human keratinocytes and polymorphonuclear leukocytes, GAS expression of SLS was associated only with keratinocyte injury. Expression of SLO but not SLS impaired polymorphonuclear leukocyte killing of GAS in vitro, but this effect could only be demonstrated in the background of acapsular organisms. In mouse invasive soft-tissue infection, neither SLO or SLS expression significantly influenced mouse survival. By contrast, in a mouse model of bacterial sepsis after intraperitoneal inoculation of GAS, SLO expression enhanced the virulence of both encapsulated and acapsular GAS, whereas SLS expression increased the virulence only of acapsular GAS. We conclude that the cytotoxic effects of SLO protect GAS from phagocytic killing and enhance bacterial virulence, particularly of strains that may be relatively deficient in hyaluronic acid capsule. Compared to SLO, SLS in this strain background has a more modest influence on GAS pathogenicity and the effect does not appear to involve bacterial resistance to phagocytosis.
Asunto(s)
Streptococcus pyogenes/patogenicidad , Estreptolisinas/toxicidad , Animales , Cápsulas Bacterianas/metabolismo , Proteínas Bacterianas , Femenino , Eliminación de Gen , Hemólisis , Humanos , Queratinocitos , Ratones , Neutrófilos/inmunología , Fagocitosis , Sepsis/microbiología , Sepsis/mortalidad , Infecciones de los Tejidos Blandos/microbiología , Infecciones de los Tejidos Blandos/mortalidad , Infecciones Estreptocócicas/microbiología , Infecciones Estreptocócicas/mortalidad , Streptococcus pyogenes/metabolismo , Estreptolisinas/genética , VirulenciaRESUMEN
Group A streptococci (GAS) produce several secreted products that are thought to enhance pathogenicity by facilitating spread of the organisms through host tissues. Two such products, streptolysin O (SLO) and NAD+-glycohydrolase, appear to be functionally linked, in that SLO is required for transfer of NAD+-glycohydrolase into epithelial cells. However, the effects of NAD+-glycohydrolase on host cells are largely unexplored. We now report that SLO-mediated delivery of NAD+-glycohydrolase to the cytoplasm of human keratinocytes results in major changes in host cell biology that enhance GAS pathogenicity. We derived isogenic mutant strains deficient in the expression of SLO, NAD+-glycohydrolase or both proteins in the background of a virulent, M-type 3 strain of GAS. All three mutant strains were internalized by human keratinocytes more rapidly and in higher numbers than were organisms from the wild-type strain. Association of the mutant strains with keratinocytes also resulted in reduced cytotoxicity and reduced keratinocyte apoptosis compared with wild-type GAS. These results support a model in which NAD+-glycohydrolase contributes to GAS pathogenesis by modulating host cell signalling pathways to inhibit GAS internalization, to augment SLO-mediated cytotoxicity and to induce keratinocyte apoptosis. We conclude that NAD+-glycohydrolase is a novel type of bacterial toxin that acts intracellularly in the infected host to enhance the survival and proliferation of an extracellular pathogen.