RESUMEN
BACKGROUND: Hyponatremia and delirium are frequent problems in older hospitalized patients. Although confusional states are considered to be a possible complication of hyponatremia, there has been no systematic study to date of the precise prevalence of delirium among patients with hyponatremia and its effect on long-term outcomes. METHODS: In a 13-month period in 2009/2010, all patients with a serum sodium level less than or equal to 130 mmol/L (the hyponatremia group) in a cohort of hospitalized older patients were studied and compared to a normonatremic control group of patients who were matched for age, sex, and diagnosis group. The prevalence of delirium was determined by two-stage examination. Inhospital mortality, mortality six months after initial examination, and functional status were prospectively analyzed. RESULTS: 179 patients were identified whose serum sodium level was less than or equal to 130 mmol/L (7.9% of all treated patients), of whom 141 were included in the hyponatremia group. The mean age of the participants was 83 (range, 63-102), and 84% were women. Patients with hyponatremia suffered more often from delirium (22.7% versus 8.5%; p = 0.002) and had a higher inhospital mortality (10.6% versus 2.1%; p = 0.005). The mortality six months after initial examination was 31.9% versus 22.7% (p = 0.080). 59.7% of patients in the hyponatremia group and 49% in the control group (p = 0.146) needed a higher level of chronic care after discharge than they had needed before the hospitalization. CONCLUSION: Hyponatremia in hospitalized older patients is associated with a higher likelihood of delirium and an elevated in-hospital mortality.
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Confusión , Mortalidad Hospitalaria , Hiponatremia/complicaciones , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Among Shigella serotypes Shigella dysenteriae type 1 produces the most severe disease, including cases of hemolytic-uremic syndrome and pandemic outbreaks. WRSd1 is a live S. dysenteriae 1 strain attenuated by deletion of the virG(icsA) gene, which encodes a protein that mediates intercellular spread, and stxA and stxB, which encode the Shiga toxin. In this Phase I trial five groups of eight subjects ingested escalating doses of WRSd1 ranging from 10(3) to 10(7)CFU. No subject experienced fever or shigellosis, but 20% had diarrhea. Approximately two-thirds of subjects developed an IgA-ASC response to LPS. Days of fecal shedding of the vaccine strain, but not dose ingested, correlated with stronger immune responses. These results suggest that to be effective an attenuated Shigella vaccine must colonize well.
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Vacunas contra la Shigella/efectos adversos , Vacunas contra la Shigella/inmunología , Shigella dysenteriae/inmunología , Adolescente , Adulto , Anticuerpos Antibacterianos/análisis , Proteínas Bacterianas/genética , Proteínas de Unión al ADN/genética , Diarrea/microbiología , Femenino , Eliminación de Gen , Humanos , Inmunoglobulina A/análisis , Masculino , Persona de Mediana Edad , Toxina Shiga/genética , Factores de Transcripción/genética , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunologíaRESUMEN
We describe the first community-based evaluation of Shigella sonnei strain WRSS1, a live, oral candidate vaccine attenuated by a 212-bp deletion in the virG (or icsA) plasmid virulence gene. Three single-dose regimens of WRSS1 (5 x 10(3) CFU, 2 x 10(4) CFU, and 4 x 10(5) CFU) were tested with cohorts of 15 adult volunteers. The vaccine was generally well tolerated at the 10(3)- and 10(4)-CFU doses. There were no fevers and there was one report of moderate diarrhea in 30 vaccinees; five additional vaccinees reported mild diarrhea. At the 10(5)-CFU dose, there were two reports of low-grade fevers and four reports of moderate diarrhea. The geometric means for immunoglobulin A (IgA) antibody-secreting cells (ASC) against lipopolysaccharide (LPS) were 30, 75, and 193 ASC per 10(6) peripheral blood mononuclear cells (PBMC) for the 10(3)-, 10(4)-, and 10(5)-CFU doses, respectively. The IgG means were 40, 46, and 135 ASC per 10(6) PBMC, respectively. The 10(4)-CFU dose of WRSS1 gave the best balance of safety and immunogenicity, since all vaccinees had a significant IgA ASC response and 73% had a response of more than 50 ASC. The anti-LPS seroconversion rate (threefold) for IgA was 60% and the IgG rate was 27% for the 10(4)-CFU cohort. Each vaccinee and a cohabitating household contact delivered daily perianal stool swabs for bacteriological culture. WRSS1 colonized vaccinees for a median of 5 days, and one individual excreted WRSS1 intermittently for 23 days. None of the 45 household contacts were colonized with WRSS1 after a cumulative 192 days of cohabitation with colonized vaccinees, suggesting that adventitious vaccine spread was not common in the community setting.
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Vacunas contra la Shigella/efectos adversos , Vacunas contra la Shigella/inmunología , Shigella sonnei/inmunología , Administración Oral , Adulto , Células Productoras de Anticuerpos/inmunología , Proteínas Bacterianas/genética , Estudios de Cohortes , Disentería Bacilar/prevención & control , Femenino , Eliminación de Gen , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Israel , Lipopolisacáridos/inmunología , Masculino , Vacunas contra la Shigella/administración & dosificación , Shigella sonnei/genética , Shigella sonnei/patogenicidad , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunología , Virulencia/genéticaRESUMEN
We report the first community-based evaluation of Shigella flexneri 2a strain SC602, a live, oral vaccine strain attenuated by deletion of the icsA (virG) plasmid virulence gene, given at 10(4) CFU. The primary objectives of this trial were to determine the safety and immunogenicity of the vaccine and to determine the duration of colonization. Four of 34 volunteers experienced transient fevers, and three reported diarrhea during the first 3 days of the study. Half of the volunteers mounted a positive serum immunoglobulin A (IgA) response to S. flexneri lipopolysaccharide. All but one of the volunteers excreted the vaccine in their stools for 1 to 33 days, and this excretion was often intermittent. Data from the community-based study were supplemented with an inpatient trial in which three volunteers received 10(3) and nine received 10(4) CFU. All volunteers who received 10(3) CFU excreted SC602 and had an IgA antibody-secreting cell response. Two of these had a serum IgA response. Six of the nine volunteers who received 10(4) CFU excreted SC602. One vaccinee had a transient fever and two met the definition of diarrhea. Six volunteers that received 10(4) CFU had an antibody-secreting cell response, and four had a serum IgA response. SC602 has now been tested at 10(4) CFU in a total of 58 volunteers. The cumulative results of these clinical trials, reported here and previously (Coster et al., Infect. Immun. 67:3437-3443, 1999), have demonstrated that SC602 is a substantially attenuated candidate vaccine that can evoke protection against the most severe symptoms of shigellosis in a stringent human challenge model of disease.
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Vacunas contra la Shigella/inmunología , Shigella flexneri/inmunología , Adolescente , Adulto , Anticuerpos Antibacterianos/sangre , Proteínas Bacterianas , Proteínas de Unión al ADN/genética , Heces/microbiología , Humanos , Persona de Mediana Edad , Vacunas contra la Shigella/efectos adversos , Shigella flexneri/aislamiento & purificación , Factores de Transcripción/genética , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunologíaRESUMEN
As a step in the development of an oral vaccine against ETEC, we evaluated the safety and immunogenicity of CS6, a polymeric protein commonly found on the surface of ETEC. Formulations included 1 and 5mg doses of CS6, either encapsulated in biodegradable polymer poly(D, L)-lactide-co-glycolide (PLG), or as free protein, administered orally in a solution of either normal saline or a rice-based buffer. Three doses of CS6 were given at 2-week intervals. Blood was collected immediately before and 7 days after each dose. All formulations were well tolerated. Four of five volunteers who received 1mg CS6 in PLG microspheres with buffer had significant IgA ASC responses (median=30 ASC per 10(6) PBMC) and significant serum IgG responses (median=3.5-fold increase). Oral administration of these prototype ETEC vaccine formulations are safe and can elicit immune responses. The ASC, serum IgA, and serum IgG responses to CS6 are similar in magnitude to the responses after challenge with wild-type ETEC [Coster et al., unpublished data]. Further studies are underway to determine whether these immune responses are sufficient for protection.
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Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/inmunología , Toxinas Bacterianas/administración & dosificación , Toxinas Bacterianas/inmunología , Enterotoxinas/administración & dosificación , Enterotoxinas/inmunología , Proteínas de Escherichia coli/administración & dosificación , Proteínas de Escherichia coli/inmunología , Vacunas contra Escherichia coli/administración & dosificación , Vacunas contra Escherichia coli/inmunología , Escherichia coli/inmunología , Administración Oral , Adolescente , Adulto , Anticuerpos Antibacterianos/análisis , Antígenos Bacterianos/efectos adversos , Cápsulas , Escherichia coli/metabolismo , Proteínas de Escherichia coli/efectos adversos , Vacunas contra Escherichia coli/efectos adversos , Femenino , Humanos , Inmunidad Celular , Inmunización , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéuticoRESUMEN
Transcutaneous immunization (TCI) is a new method for vaccine delivery that has been shown to induce immunity relevant to enteric disease vaccines. We evaluated the clinical safety and immunogenicity of a recombinant subunit vaccine against enterotoxigenic Escherichia coli (ETEC) delivered by TCI. Adult volunteers received patches containing the recombinant ETEC colonization factor CS6, either with heat-labile enterotoxin (LT) or patches containing CS6 alone. The vaccine was administered at 0, 1, and 3 months, and serum antibodies and antibody-secreting cells (ASCs) were assessed. Among the 26 volunteers that completed the trial, there were no responses to CS6 in the absence of LT. In the groups receiving both CS6 and LT, 68 and 53% were found to have serum anti-CS6 immunoglobulin G (IgG) and IgA, respectively; 37 and 42% had IgG and IgA anti-CS6 ASCs. All of the volunteers receiving LT had anti-LT IgG, and 90% had serum anti-LT IgA; 79 and 37% had anti-LT IgG and IgA ASCs. Delayed-type hypersensitivity (DTH), suggesting T-cell responses, was seen in 14 of 19 volunteers receiving LT and CS6; no DTH was seen in subjects receiving CS6 alone. This study demonstrated that protein antigens delivered by a simple patch could induce significant systemic immune responses but only in the presence of an adjuvant such as LT. The data suggest that an ETEC vaccine for travelers delivered by a patch may be a viable approach worthy of further evaluation.