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1.
J Infect Dis ; 225(4): 661-674, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33216130

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV)-infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce. METHODS: We investigated circulating markers of mucosal dysfunction, immune activation, mucosal Th17 and Th22 cells, and mucosa-adherent microbiota signatures in gut mucosal specimens from sigmoid colon and terminal ileum of 19 INRs and 20 IRs in addition to 20 HIV-negative individuals. RESULTS: INRs had higher blood levels of the enterocyte damage marker intestinal fatty acid-binding protein than IRs. In gut mucosal biopsies, INRs had lower fractions of CD4+ T cells, higher fractions of interleukin 22, and a tendency to higher fractions of interleukin 17-producing CD4+ T cells. These findings were all restricted to the colon and correlated to circulating markers of enterocyte damage. There were no observed differences in gut microbial composition between INRs and IRs. CONCLUSIONS: Restricted to the colon, enterocyte damage and mucosal immune dysfunction play a role for insufficient immune reconstitution in HIV infection independent of the gut microbiota.


Asunto(s)
Infecciones por VIH , Inmunidad Mucosa , Linfocitos T CD4-Positivos , Colon , VIH , Infecciones por VIH/tratamiento farmacológico , Humanos , Mucosa Intestinal
2.
BMC Infect Dis ; 17(1): 228, 2017 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-28340570

RESUMEN

BACKGROUND: Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related to progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based therapeutic vaccine candidate corresponding to C5/gp41732-744 as well as the effects on pre-existing AB levels to C5/gp41732-744, immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T cell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to several of its HLA-like features and that enhancement of non-neutralising anti-C5 AB by vaccination could reduce C5 exposure and thereby chronic immune activation. METHODS: Thirty-six HIV patients on effective antiretroviral therapy were randomised to one of three dose levels of Vacc-C5 administered intramuscularly with Alhydrogel or intradermally with GM-CSF as adjuvant through initial immunisation and two booster periods over 26 weeks. Vacc-C5-specific AB were measured by ELISA and T cell responses by both IFN-γ ELISPOT and proliferative assays analysed by flow cytometry. Immune regulation was assessed by functional blockade of the two inhibitory cytokines IL-10 and TGF-ß in parallel cultures. Non-parametric statistical tests were applied. RESULTS: Vacc-C5 was found safe and well tolerated in all patients. Only marginal changes in humoral and cellular responses were induced, without any effect on immune activation. Overall, anti-Vacc-C5 AB levels seemed to decrease compared to pre-existing levels. Whereas Vacc-C5-specific CD8+ T cell proliferative responses increased after the first booster period (p = 0.020; CD4+, p = 0.057), they were reduced after the second. In contrast, Vacc-C5-induced T cell regulation increased after completed vaccination (p ≤ 0.027) and was lower at baseline in the few AB responders identified (p = 0.027). CONCLUSIONS: The therapeutic HIV vaccine candidate Vacc-C5 safely induced only marginal immune responses, whereas Vacc-C5-induced T cell regulation markedly increased. Our data support further attention on immune regulation during therapeutic HIV vaccination studies. TRIAL REGISTRATION: NCT01627678 .


Asunto(s)
Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Citocinas/sangre , Citocinas/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Humanos , Linfocitos T/inmunología
3.
BMC Infect Dis ; 16(1): 599, 2016 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-27776487

RESUMEN

BACKGROUND: Tuberculosis (TB) causes a major burden on global health with long and cumbersome TB treatment regimens. Host-directed immune modulating therapies have been suggested as adjunctive treatment to TB antibiotics. Upregulated cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) signaling pathway may cause a dysfunctional immune response that favors survival and replication of Mycobacterium tuberculosis (Mtb). METHODS: Blood samples were obtained from patients with latent TB (n = 9) and active TB (n = 33) before initiation of anti-TB chemotherapy. COX-2 expression in monocytes and ESAT-6 and Ag85 specific T cell cytokine responses (TNF-α, IFN-γ, IL-2), proliferation (carboxyfluorescein succinimidyl ester staining) and regulation (FOXP3+ T regulatory cells) were analysed by flow cytometry and the in vitro effects of the COX-1/2 inhibitor indomethacin were measured. RESULTS: We demonstrate that indomethacin significantly down-regulates the fraction of Mtb specific FOXP3+ T regulatory cells (ESAT-6; p = 0.004 and Ag85; p < 0.001) with a concomitant reduction of Mtb specific cytokine responses and T cell proliferation in active TB. Although active TB tend to have higher levels, there are no significant differences in COX-2 expression between unstimulated monocytes from patients with active TB compared to latent infection. Monocytes in both TB groups respond with a significant upregulation of COX-2 after in vitro stimulation. CONCLUSIONS: Taken together, our in vitro data indicate a modulation of the Th1 effector and T regulatory cells in Mtb infection in response to the COX-1/2 inhibitor indomethacin. The potential role as adjunctive host-directed therapy in TB disease should be further evaluated in both animal studies and in human clinical trials.


Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Indometacina/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antígenos Bacterianos/metabolismo , Ciclooxigenasa 2/sangre , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Tuberculosis Latente/tratamiento farmacológico , Tuberculosis Latente/microbiología , Tuberculosis Latente/patología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Linfocitos T Reguladores/microbiología , Células TH1/efectos de los fármacos , Tuberculosis/microbiología , Tuberculosis/patología , Factor de Necrosis Tumoral alfa/farmacología , Adulto Joven
5.
AIDS Care ; 26(9): 1080-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24359563

RESUMEN

The current study examined the efficacy of a web-based intervention (WBI; Avanti) on symptoms of depression and well-being for patients diagnosed with HIV. A two-armed randomized trial recruited patients on antiretroviral therapy (ART) at an outpatient clinic. Thirty-six patients were allocated to Avanti and 31 patients to a control group. Primary outcomes were symptoms of depression and subjective well-being (SWB), and secondary outcomes included life satisfaction and affect balance. Paired tests showed that only patients following Avanti had significant improvements in SWB by 3 months as well as affect balance. No significant differences between groups were detected in any of the outcome parameters at baseline after 3 months, as expected from group size and variability in the parameters. However, time since HIV diagnosis and ART initiation moderated the effects of Avanti. In conclusion, our data show that patients with HIV infection may benefit from a WBI in adjunct to medical treatment.


Asunto(s)
Depresión/prevención & control , Depresión/psicología , Infecciones por VIH/psicología , Internet , Afecto , Fármacos Anti-VIH/uso terapéutico , Enfermedad Crónica , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Satisfacción Personal , Resultado del Tratamiento
6.
Crit Care Explor ; 5(2): e0865, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36844375

RESUMEN

The Sequential Organ Failure Assessment (SOFA) was chosen in the definition of sepsis due to superior validity in predicting mortality. However, few studies have assessed the contributions of acute versus chronic organ failures to SOFA for mortality prediction. OBJECTIVES: The main objective in this study was to assess the relative importance of chronic and acute organ failures in mortality prediction in patients with suspected sepsis at hospital admission. We also evaluated how the presence of infection influenced the ability of SOFA to predict 30-day mortality. DESIGN SETTING AND PARTICIPANTS: Single-center prospective cohort study including 1,313 adult patients with suspected sepsis in rapid response teams in the emergency department. MAIN OUTCOMES AND MEASURES: The main outcome was 30-day mortality. We measured the maximum total SOFA score during admission (SOFATotal), whereas preexisting chronic organ failure SOFA (SOFAChronic) score was assessed by chart review, allowing calculation of the corresponding acute SOFA (SOFAAcute) score. Likelihood of infection was determined post hoc as "No infection" or "Infection." RESULTS: SOFAAcute and SOFAChronic were both associated with 30-day mortality, adjusted for age and sex (adjusted odds ratios [AORs], 1.3; 95% CI, 1.3-14 and 1.3; 1.2-1.7), respectively. Presence of infection was associated with lower 30-day mortality (AOR, 0.4; 95% CI, 0.2-0.6), even when corrected for SOFA. In "No infection" patients, SOFAAcute was not associated with mortality (AOR, 1.1; 95% CI, 1.0-1.2), and in this subgroup, neither SOFAAcute greater than or equal to 2 (relative risk [RR], 1.1; 95% CI, 0.6-1.8) nor SOFATotal greater than or equal to 2 (RR, 3.6; 95% CI, 0.9-14.1) was associated with higher mortality. CONCLUSIONS AND RELEVANCE: Chronic and acute organ failures were equally associated with 30-day mortality in suspected sepsis. A substantial part of the total SOFA score was due to chronic organ failure, calling for caution when using total SOFA in defining sepsis and as an outcome in intervention studies. SOFA's mortality prediction ability was highly dependent on actual presence of infection.

7.
J Virol ; 85(13): 6557-66, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21490090

RESUMEN

Chronic HIV infection is characterized by chronic immune activation and dysfunctional T cells with elevated intracellular cyclic AMP (cAMP), which inhibits the T cell activation capability. cAMP may be induced by prostaglandin E(2) following lipopolysaccharide (LPS)-induced upregulation of cyclooxygenase type 2 (COX-2) in monocytes due to the elevated LPS levels in patients with chronic HIV infection. This hypothesis was tested using celecoxib, a COX-2 inhibitor, for 12 weeks in HIV-infected patients without antiretroviral treatment in a prospective, open, randomized exploratory trial. Thirty-one patients were randomized in the trial; 27 completed the study, including 13 patients on celecoxib. Celecoxib reduced chronic immune activation in terms of CD38 density on CD8(+) T cells (-24%; P = 0.04), IgA levels (P = 0.04), and a combined score for inflammatory markers (P < 0.05). Celecoxib further reduced the inhibitory surface receptor programmed death 1 (PD-1) on CD8(+) T cells (P = 0.01), including PD-1 on the HIV Gag-specific subset (P = 0.02), enhanced the number of CD3(+) CD4(+) CD25(+) CD127(lo/-) Treg or activated cells (P = 0.02), and improved humoral memory recall responses to a T cell-dependent vaccine (P = 0.04). HIV RNA (P = 0.06) and D dimers (P = 0.07) tended to increase in the controls, whereas interleukin-6 (IL-6) possibly decreased in the treatment arm (P = 0.10). In conclusion, celecoxib downmodulated the immune activation related to clinical progression of chronic HIV infection and improved T cell-dependent functions in vivo.


Asunto(s)
Vacunas contra el SIDA/inmunología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéutico , Linfocitos T/inmunología , Vacunas contra el SIDA/administración & dosificación , Adulto , Celecoxib , Enfermedad Crónica , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Resultado del Tratamiento
8.
Scand J Infect Dis ; 44(8): 566-72, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22339485

RESUMEN

BACKGROUND: Vacc-4x contains 4 HIV p24-like short peptides. In a previous phase II trial this immunized 90% of 38 patients on antiretroviral treatment (ART) after intradermal delivery in conjunction with local granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant. In this study, 22 responders were retested for cellular memory at a median 7.3 y after their last immunization. All had resumed effective ART after an interspersed ART-free median interval of 2.2 y. METHODS: Vacc-4x as 15-mer overlapping by 2 amino acid panels and Vacc-4x consensus peptide sequences (4xCP) were used as antigens. Proliferation was determined as percentages of CFSE(dim)HLA-DR(+) 7AAD(-) CD3+ T cells of the CD4+ and CD8+ subsets after 6 days of culture. Frequencies of specific T cells in 6-h cultures were determined by interferon-γ (IFN)(+) CD4+ and IFN(+) CD8+, as well as degranulating bifunctional CD107a + IFN(+) CD8 + subsets. RESULTS: Proliferative CD4+ and CD8+ responses to Vacc-4x as well as 4xCP were still present in 95% and 68%, respectively. Proliferation correlated with the Vacc-4x delayed-type hypersensitivity test (DTH) obtained after completed immunizations (CD4 + r = 0.63 (p = 0.002) and CD8 + r = 0.47 (p = 0.03)), suggesting that they represent T cell memory recall responses. The proliferative CD8+ and possibly CD4 + subset responses to 4xCP peptides correlated with Vacc-4x (r = 0.46 (p = 0.03) and r = 0.38 (p = 0.08), respectively). Forty-one percent still had Vacc-4x-specific IFN + CD4 + T cells, which correlated to corresponding frequencies of 4xCP peptides (r = 0.50, p = 0.02). CD107a(+) IFN(+) CD8 + T cell responses against Vacc-4x were found in 55%. CONCLUSIONS: Evidence of long-lasting T cell memory recall responses to a peptide-based immunotherapeutic candidate for HIV-infected patients should enhance the focus on peptide-based intradermal vaccine delivery.


Asunto(s)
Vacunas contra el SIDA/administración & dosificación , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proteína p24 del Núcleo del VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Vacunas contra el SIDA/inmunología , Antirretrovirales/administración & dosificación , Femenino , Estudios de Seguimiento , Antígeno HLA-A2/inmunología , Humanos , Memoria Inmunológica/inmunología , Inyecciones Intradérmicas , Interferón gamma/inmunología , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Masculino , Péptidos/inmunología
9.
Shock ; 58(4): 251-259, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-36130401

RESUMEN

ABSTRACT: Background: Biomarkers for early recognition of infection are warranted. The hypothesis of this study was that calprotectin, C-reactive protein (CRP), IL-6 and procalcitonin (PCT), alone or in combination, provide clinically useful information to the clinicians for early identification of infection in patients with possible sepsis in the emergency department (ED). Biomarker dynamics in the first week of hospitalization were explored. Methods: Adult patients in rapid response teams in the ED were included in a prospective observational study (n = 391). Patients who received antibiotics after biomarker availability were excluded. The ED clinician (EDC) decision whether to start antibiotics was registered. Calprotectin, CRP, IL-6, and PCT were analyzed in blood samples drawn within 15 min after ED arrival and in a subgroup for 1 week. Infection likelihood was evaluated post hoc . Results: In identifying patients with infection, CRP (area under the receiver operating characteristic curve [AUC], 0.913) and IL-6 (AUC, 0.895) were superior to calprotectin (AUC, 0.777) and PCT (AUC, 0.838). The best regression model predicting infections included EDC, CRP, and IL-6. Using optimal cutoff values, CRP and IL-6 in combination reached 95% positive and 90% negative predictive values for infection. The EDC undertreated or overtreated 65 of 391 patients (17%), and CRP and IL-6 optimal cutoff values could correct this in 32 of 65 patients (49%). Longitudinal samples revealed that IL-6 peaked in the ED, whereas CRP and PCT peaked later. Conclusion: C-reactive protein and IL-6 were superior to calprotectin and PCT for recognizing infection in patients with possible sepsis in the ED. Combining these two biomarkers with different dynamics improved recognition of infection and could aid clinical management in rapid response teams in the ED.


Asunto(s)
Polipéptido alfa Relacionado con Calcitonina , Sepsis , Adulto , Humanos , Proteína C-Reactiva/metabolismo , Interleucina-6 , Sepsis/diagnóstico , Biomarcadores , Curva ROC , Servicio de Urgencia en Hospital , Complejo de Antígeno L1 de Leucocito , Antibacterianos
10.
Infect Dis (Lond) ; 54(5): 367-377, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34983302

RESUMEN

BACKGROUND: Seasonal influenza causes substantial numbers of hospitalizations annually. We have characterized the clinical picture and treatment practice in hospitalized adult influenza patients and assessed whether clinical risk scores on admission or influenza type were associated with severe outcomes. METHODS: Clinical characteristics and risk scores on admission (CRB65, CRB, SIRS and quick Sequential Organ Failure Assessment [qSOFA]), treatment and severe outcomes (defined as: stay in intensive care unit (ICU), receiving oxygen supplementation or staying ≥5 days in hospital), were recorded in patients hospitalized with influenza at Oslo University Hospital, Norway, between 2014 and 2018. RESULTS: Among the 156 included patients, 52.6% had influenza A(H3N2), 32.6% influenza B and 12.8% influenza A(H1N1). Median age was 70 years and 59.6% of patients were ≥65 years. Nine (5.8%) of the patients were treated in ICU, 43.0% received oxygen and 47.4% stayed ≥5 days in hospital. Overall, 34.6% of the patients had a high CRB score on admission which was associated with stay in ICU and oxygen supplementation. Multivariate analyses identified age, and pneumonia (46.8%), but not influenza type, to be associated with severe outcomes. Antiviral treatment was given to 37.2% of the patients, while 77.6% received antibiotics. Only 25.5% of patients with influenza B received antiviral therapy. CONCLUSIONS: The influenza patients were mostly elderly, and few patients were treated in ICU. A high CRB score was associated with severe outcomes with possible implications for patient monitoring. Less than 40% of the patients received antiviral therapy, whereas the majority were treated with antibiotics, indicating potential for optimising treatment strategies.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Adulto , Anciano , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Hospitalización , Humanos , Subtipo H3N2 del Virus de la Influenza A , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Unidades de Cuidados Intensivos
11.
J Acquir Immune Defic Syndr ; 89(1): 77-86, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34878437

RESUMEN

BACKGROUND: HIV-infected immunological nonresponders (INRs) have increased risk of non-AIDS morbidity and compromised gut barrier immunity. Probiotics are widely used to improve health. We assessed the effects of probiotics in INRs with a comprehensive analysis of gut immunity and microbiome in terminal ileum and sigmoid colon. METHODS: The study involved clinical intervention with five-strain probiotic capsules (1.2 × 1010 CFUs/d) for 8 weeks in 20 INRs with CD4+ T-cell counts <400 cells/µL and plasma HIV RNA <50 copies/mL for more than 3.5 years. Colonoscopy with sampling of gut biopsies from terminal ileum and sigmoid colon and fecal and blood sampling were performed before and after the intervention. Flow cytometry (cytokine production, immune activation, and exhaustion), ELISA (inflammation, microbial translocation, and enterocyte damage), and 16S rRNA sequencing analyses were applied. RESULTS: In the terminal ileum, increased alpha diversity, increased abundance of Bifidobacterium sp., and decreased frequencies of IL-22+ CD4+ T cells were observed. The increased abundance of Bifidobacterium sp. in the terminal ileum correlated with increased fraction of CD4+ T cells in the same compartment (r = 0.54, P = 0.05) and increased CD4/CD8 ratio in peripheral blood (r = 0.49, P = 0.05). There were no corresponding changes in the sigmoid colon and no changes in fecal microbiome. Probiotic intervention did not affect peripheral blood CD4 count, viral load, or soluble markers of inflammation and microbial translocation. CONCLUSIONS: Probiotics induced segment-specific changes in the terminal ileum but did not affect systemic CD4 counts in INRs. Further clinical studies are warranted to recommend probiotics to INRs.


Asunto(s)
Infecciones por VIH , Probióticos , Linfocitos T CD4-Positivos , Humanos , Íleon , Inmunidad Mucosa , Mucosa Intestinal , Probióticos/uso terapéutico , ARN Ribosómico 16S/genética
12.
Crit Care Explor ; 3(7): e0490, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34291222

RESUMEN

OBJECTIVES: Increase of nucleated RBCs in peripheral blood has been shown to be predictive of mortality in ICU patients. The aim of this study was to explore the prognostic value of nucleated RBCs in the first blood sample taken at admission to the emergency department from patients with suspected sepsis. DESIGN: Single-center prospective cohort study. SETTING: Emergency department. PATIENTS: One-thousand two-hundred thirty-one consecutive adult patients with suspected sepsis were included in a prospective quality register-based cohort study. Inclusion criteria were as follows: patients received in rapid response team with blood cultures taken and immediate antibiotics given in the emergency department. INTERVENTION: Not applicable. MEASUREMENT AND MAIN RESULTS: Nucleated RBCs, Sequential Organ Failure Assessment score, Quick Sequential Organ Failure Assessment, Charlson Comorbidity Index, and commonly used laboratory tests measured in the emergency department were compared with 30-day mortality. Nvaucleated RBC counts were divided into five groups, called "Nucleated RBC score," according to nucleated RBC count levels and analyzed with logistic regression together with the Sequential Organ Failure Assessment score and Charlson Comorbidity Index. Of the 262 patients with nucleated RBCs equal to or higher than the detection limit (0.01 × 109/L), 26% died within 30 days, compared with 12% of the 969 patients with nucleated RBCs below the detection limit (p < 0.0001). Mortality was significantly higher for each increase in Nucleated RBC score, except from score 2 to 3, and was 62% in the highest group. In multivariate logistic regression, odds ratios for 30-day mortality were as follows: Nucleated RBC score: 1.33 (95% CI, 1.13-1.56), Sequential Organ Failure Assessment score: 1.32 (1.29-1.56), and Charlson Comorbidity Index: 1.17 (1.09-1.25). CONCLUSIONS: Most patients with suspected sepsis in emergency department had undetectable nucleated RBCs at admission to the emergency department. However, increased nucleated RBCs significantly predicted 30-day mortality. Nucleated RBCs may provide additional prognostic information to Sequential Organ Failure Assessment score and other laboratory tests.

13.
Front Immunol ; 12: 744155, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34691047

RESUMEN

Immunological non-responders (INR), a subgroup of people living with HIV (PLHIV) who fail to restore CD4+ T cell numbers upon effective antiretroviral treatment, have impaired gut mucosal barrier function and an inferior clinical prognosis compared with immunological responders (IR). The contribution of gut-homing and exhaustion of mucosal T cells to the INR phenotype was previously unknown. Flow cytometry analysis of mononuclear cells from peripheral blood and ileal and colonic lamina propria showed that INR had higher fractions of gut-homing CD4+ T cells in blood compared with IR. In addition, gut-homing cells were more likely to display signs of exhaustion in INR. The increased CD4+ T cell exhaustion in INR was ubiquitous and not restricted to subpopulations defined by activation, differentiation or regulatory T cell markers. In INR, colon CD4+ T cell exhaustion correlated negatively with the fraction of CD4+ T cells in the same compartment, this was not apparent in the ileum. The fraction of exhausted mucosal CD4+ T cells correlated with I-FABP and REG3α, markers of enterocyte damage. We conclude that alterations of gut-homing and exhaustion of T cells may contribute to impaired gut immune and barrier functions associated with immunological non-response in PLHIV.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Resistencia a Medicamentos/inmunología , Infecciones por VIH/inmunología , Inmunosenescencia/inmunología , Mucosa Intestinal/inmunología , Adulto , Anciano , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/patología , Quimiotaxis de Leucocito/inmunología , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad
14.
Nat Commun ; 12(1): 6774, 2021 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-34811370

RESUMEN

Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Vacunas contra la Tuberculosis/inmunología , Tuberculosis/tratamiento farmacológico , Tuberculosis/inmunología , Vacunación , Adolescente , Adulto , Ciclooxigenasa 2 , Etoricoxib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tuberculosis/prevención & control , Adulto Joven
15.
Front Cell Infect Microbiol ; 11: 669623, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34307194

RESUMEN

Introduction: Eicosanoids and intracellular signaling pathways are potential targets for host-directed therapy (HDT) in tuberculosis (TB). We have explored the effect of cyclooxygenase 2 inhibitor (COX-2i) treatment on eicosanoid levels and signaling pathways in monocytes. Methods: Peripheral blood mononuclear cells isolated from TB patients included in a randomized phase I clinical trial of standard TB treatment with (n=21) or without (n=18) adjunctive COX-2i (etoricoxib) were analyzed at baseline, day 14 and day 56. Plasma eicosanoids were analyzed by ELISA and liquid chromatography-mass spectrometry (LC-MS), plasma cytokines by multiplex, and monocyte signaling by phospho-flow with a defined set of phospho-specific antibodies. Results: Lipoxygenase (LOX)-derived products (LXA4 and 12-HETE) and pro-inflammatory cytokines were associated with TB disease severity and were reduced during TB therapy, possibly accelerated by adjunctive COX-2i. Phosphorylation of p38 MAPK, NFkB, Erk1/2, and Akt in monocytes as well as plasma levels of MIG/CXCL9 and procalcitonin were reduced in the COX-2i group compared to controls. Conclusion: COX-2i may reduce excess inflammation in TB via the LOX-pathway in addition to modulation of phosphorylation patterns in monocytes. Immunomodulatory effects of adjunctive COX-2i in TB should be further investigated before recommended for use as a HDT strategy.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Tuberculosis , Eicosanoides , Humanos , Leucocitos Mononucleares , Lipooxigenasa , Monocitos , Tuberculosis/tratamiento farmacológico
16.
Eur J Immunol ; 39(5): 1280-7, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19384871

RESUMEN

Recent studies have indicated that Treg contribute to the HIV type 1 (HIV-1)-related immune pathogenesis. However, it is not clear whether T cells with suppressive properties reside within the HIV-1-specific T-cell population. Here, PBMC from HIV-1-infected individuals were stimulated with a 15-mer Gag peptide pool, and HIV-1-specific T cells were enriched by virtue of their secretion of IL-10 or IFN-gamma using immunomagnetic cell-sorting. Neither the IL-10-secreting cells nor the IFN-gamma-secreting cells expressed the Treg marker FOXP3, yet the IL-10-secreting cells potently suppressed anti-CD3/CD28-induced CD4(+) as well as CD8(+) T-cell proliferative responses. As shown by intracellular cytokine staining, IL-10- and IFN-gamma-producing T cells represent distinct subsets of the HIV-1-specific T cells. Our data collectively suggest that functionally defined HIV-1-specific T-cell subsets harbor potent immunoregulatory properties that may contribute to HIV-1-associated T-cell dysfunction.


Asunto(s)
Infecciones por VIH/inmunología , VIH-1/inmunología , Interleucina-10/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Proliferación Celular , Citometría de Flujo , Factores de Transcripción Forkhead/sangre , Factores de Transcripción Forkhead/inmunología , Infecciones por VIH/sangre , Humanos , Separación Inmunomagnética , Interferón gamma/sangre , Interferón gamma/inmunología , Interleucina-10/sangre , Leucocitos Mononucleares/inmunología , Estadísticas no Paramétricas , Subgrupos de Linfocitos T/citología , Linfocitos T Reguladores/citología
17.
Nat Commun ; 11(1): 5284, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-33082342

RESUMEN

Here, we randomized 53 patients hospitalized with coronavirus disease 2019 (COVID-19) to hydroxychloroquine therapy (at a dose of 400 mg twice daily for seven days) in addition to standard care or standard care alone (ClinicalTrials.gov Identifier, NCT04316377). All severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients 18 years of age or older were eligible for study inclusion if they had moderately severe COVID-19 at admission. Treatment with hydroxychloroquine did not result in a significantly greater rate of decline in SARS-CoV-2 oropharyngeal viral load compared to standard care alone during the first five days. Our results suggest no important antiviral effect of hydroxychloroquine in humans infected with SARS-CoV-2.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Anciano , COVID-19 , Infecciones por Coronavirus/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/mortalidad , SARS-CoV-2 , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Tratamiento Farmacológico de COVID-19
18.
Trials ; 21(1): 485, 2020 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-32503662

RESUMEN

OBJECTIVES: The hypothesis of the study is that treatment with hydroxychloroquine sulphate in hospitalised patients with coronavirus disease 2019 (Covid-19) is safe and will accelerate the virological clearance rate for patients with moderately severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when compared to standard care. Furthermore, we hypothesize that early treatment with hydroxychloroquine sulphate is associated with more rapid resolve of clinical symptoms as assessed by the National Early Warning Score 2 (NEWS2), decreased admission rate to intensive care units and mortality, and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide). TRIAL DESIGN: The study is a two-arm, open label, pragmatic randomised controlled group sequential adaptive trial designed to assess the effect on viral loads and clinical outcome of hydroxychloroquine sulphate therapy in addition to standard care compared to standard care alone in patients with established Covid-19. By utilizing resources already paid for by the hospitals (physicians and nurses in daily clinical practice), this pragmatic trial can include a larger number of patients over a short period of time and at a lower cost than studies utilizing traditional randomized controlled trial designs with an external study organization. The pragmatic approach will enable swift initiation of randomisation and allocation to treatment. PARTICIPANTS: Patients will be recruited from all inpatients at Akershus University Hospital, Lørenskog, Norway. Electronic real-time surveillance of laboratory reports from the Department of Microbiology will be examined regularly for SARS-CoV-2 positive subjects. All of the following conditions must apply to the prospective patient at screening prior to inclusion: (1) Hospitalisation; (2) Adults 18 years or older; (3) Moderately severe Covid-19 disease (NEWS2 of 6 or less); (4) SARS-CoV-2 positive nasopharyngeal swab; (5) Expected time of hospitalisation > 48 hours; and (6) Signed informed consent must be obtained and documented according to Good Clinical Practice guidelines of the International Conference on Harmonization, and national/local regulations. Patients will be excluded from participation in the study if they meet any of the following criteria: (1) Requiring intensive care unit admission at screening; (2) History of psoriasis; (3) Known adverse reaction to hydroxychloroquine sulphate; (4) Pregnancy; or (5) Prolonged corrected QT interval (>450 ms). Clinical data, including standard hospital biochemistry, medical therapy, vital signs, NEWS2, and microbiology results (including blood culture results and reverse transcriptase polymerase chain reaction [RT-PCR] for other upper airway viruses), will be automatically extracted from the hospital electronic records and merged with the study specific database. INTERVENTION AND COMPARATOR: Included patients will be randomised in a 1:1 ratio to (1) standard care with the addition of 400 mg hydroxychloroquine sulphate (PlaquenilTM) twice daily for seven days or (2) standard care alone. MAIN OUTCOMES: The primary endpoint of the study is the rate of decline in SARS-CoV-2 viral load in oropharyngeal samples as assessed by RT-PCR in samples collected at baseline, 48 and 96 hours after randomization and administration of drug for the intervention arm. Secondary endpoints include change in NEWS2 at 96 hours after randomisation, admission to intensive care unit, mortality (in-hospital, and at 30 and 90 days), duration of hospital admission, clinical status on a 7-point ordinal scale 14 days after randomization ([1] Death [2] Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation [3] Hospitalised, on non-invasive ventilation or high flow oxygen devices [4] Hospitalized, requiring supplemental oxygen [5] Hospitalised, not requiring supplemental oxygen [6] Not hospitalized, but unable to resume normal activities [7] Not hospitalised, with resumption of normal activities), and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide) at 96 hours after randomization. RANDOMISATION: Eligible patients will be allocated in a 1:1 ratio, using a computer randomisation procedure. The allocation sequence has been prepared by an independent statistician. BLINDING (MASKING): Open label randomised controlled pragmatic trial without blinding, no active or placebo control. The virologist assessing viral load in the oropharyngeal samples and the statistician responsible for analysis of the data will be blinded to the treatment allocation for the statistical analyses. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): This is a group sequential adaptive trial where analyses are planned after 51, 101, 151 and 202 completed patients, with a maximum sample size of 202 patients (101 patients allocated to intervention and standard care and 101 patients allocated to standard care alone). TRIAL STATUS: Protocol version 1.3 (March 26, 2020). Recruitment of first patient on March 26, 2020, and 51 patients were included as per April 28, 2020. Study recruitment is anticipated to be completed by July 2020. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT04316377. Trial registered March 20, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Ensayos Clínicos Pragmáticos como Asunto , COVID-19 , Infecciones por Coronavirus/virología , Femenino , Hospitalización , Humanos , Masculino , Noruega , Pandemias , Neumonía Viral/virología , Proyectos de Investigación , SARS-CoV-2 , Carga Viral , Tratamiento Farmacológico de COVID-19
19.
J Antimicrob Chemother ; 64(5): 901-9, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19740910

RESUMEN

Mitochondrial toxicity contributes to serious adverse effects observed in HIV-infected individuals treated with nucleoside reverse transcriptase inhibitors (NRTIs). However, similar mitochondrial abnormalities have recently been found even in treatment-naive patients, suggesting that chronic HIV per se could contribute to the toxicity observed in NRTI-exposed individuals. This review gives a current status of the field, with particular focus on recent observations suggesting that distinct mechanisms might cause such toxicity in both NRTI-exposed individuals and those naive to antiretroviral treatment.


Asunto(s)
Antirretrovirales/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Antirretrovirales/toxicidad , Humanos , Inhibidores de la Transcriptasa Inversa/toxicidad
20.
Scand J Infect Dis ; 41(11-12): 808-17, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19922062

RESUMEN

Antiretroviral treatment (ART) has provided excellent clinical efficacy in HIV infection, and individuals treated for HIV might therefore expect normal duration of life. However, this enthusiasm might be moderated by some devastating long-term adverse effects that are frequently observed in HIV-infected individuals, phenomena that may be even more pronounced as the HIV-infected populations become older and therefore perhaps more susceptible to some of these adverse effects. We here review the clinical impact of mitochondrial toxicity giving rise to many of the adverse effects caused by ART.


Asunto(s)
Mitocondrias/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Humanos , Mitocondrias/metabolismo , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Factores de Tiempo
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