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BCG vaccination in children protects against heterologous infections and improves survival independently of tuberculosis prevention. The phase III ACTIVATE trial assessed whether BCG has similar effects in the elderly. In this double-blind, randomized trial, elderly patients (n = 198) received BCG or placebo vaccine at hospital discharge and were followed for 12 months for new infections. At interim analysis, BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% (95% CIs 31.9%-53.4%) after placebo vaccination and 25.0% (95% CIs 16.4%-36.1%) after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin (hazard ratio 0.21, p = 0.013). No difference in the frequency of adverse effects was found. Data show that BCG vaccination is safe and can protect the elderly against infections. Larger studies are needed to assess protection against respiratory infections, including COVID-19 (ClinicalTrials.gov NCT03296423).
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Vacina BCG/efeitos adversos , Vacina BCG/imunologia , Infecções Respiratórias/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Vacina BCG/administração & dosagem , Método Duplo-Cego , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias/imunologia , Viroses/imunologia , Viroses/prevenção & controleRESUMO
BACKGROUND: Sepsis guidelines suggest immediate start of resuscitation for patients with quick Sequential Organ Failure Assessment (qSOFA) 2 or 3. However, the interpretation of qSOFA 1 remains controversial. We investigated whether measurements of soluble urokinase plasminogen activator receptor (suPAR) may improve risk detection when qSOFA is 1. METHODS: The study had two parts. At the first part, the combination of suPAR with qSOFA was analyzed in a prospective cohort for early risk detection. At the second part, the double-blind, randomized controlled trial (RCT) SUPERIOR evaluated the efficacy of the suPAR-guided medical intervention. SUPERIOR took place between November 2018 and December 2020. Multivariate stepwise Cox regression was used for the prospective cohort, while univariate and multivariate logistic regression was used for the RCT. Consecutive admissions at the emergency department (ED) with suspected infection, qSOFA 1 and suPAR ≥ 12 ng/mL were allocated to single infusion of placebo or meropenem. The primary endpoint was early deterioration, defined as at least one-point increase of admission Sequential Organ Failure Assessment (SOFA) score the first 24 h. RESULTS: Most of the mortality risk was for patients with qSOFA 2 and 3. Taking the hazard ratio (HR) for death of patients with qSOFA = 1 and suPAR < 12 ng/mL as reference, the HR of qSOFA = 1 and suPAR ≥ 12 ng/mL for 28-day mortality was 2.98 (95% CI 2.11-3.96). The prospective RCT was prematurely ended due to pandemia-related ED re-allocations, with 91 patients enrolled: 47 in the placebo and 44 in the meropenem arm. The primary endpoint was met in 40.4% (n = 19) and 15.9% (n = 7), respectively (difference 24.5% [5.9-40.8]; odds ratio 0.14 [0.04-0.50]). One post hoc analysis showed significant median changes of SOFA score after 72 and 96 h equal to 0 and - 1, respectively. CONCLUSIONS: Combining qSOFA 1 with the biomarker suPAR improves its prognostic performance for unfavorable outcome and can help decision for earlier treatment. Trial registration EU Clinical Trials Register (EudraCT, 2018-001008-13) and Clinical-Trials.gov (NCT03717350). Registered 24 October 2018.
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Escores de Disfunção Orgânica , Sepse , Humanos , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Meropeném , Prognóstico , Antibacterianos , Serviço Hospitalar de Emergência , Mortalidade Hospitalar , Curva ROC , Estudos RetrospectivosRESUMO
Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.
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Antígeno CTLA-4 , Diagnóstico Tardio , Humanos , Grécia/epidemiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Criança , Idoso , Diagnóstico Tardio/estatística & dados numéricos , Adolescente , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/epidemiologia , Adulto Jovem , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/epidemiologia , Agamaglobulinemia/imunologia , Agamaglobulinemia/complicaçõesRESUMO
We used unsupervised immunophenotyping of blood leukocytes and measured cytokine production by innate immune cell exposed to LPS and R848. We show that COVID-19 induces a rapid, transient upregulation of myeloid-derived suppressor cells (MDSCs) accompanied by a rapid, sustained (up to 3 months) hyporesponsiveness of dendritic cells and monocytes. Blood MDSCs may represent biomarkers and targets for intervention strategies in COVID-19 patients.
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COVID-19 , Doenças do Sistema Imunitário , Células Supressoras Mieloides , Biomarcadores , Citocinas/farmacologia , Humanos , Imunidade Inata , LipopolissacarídeosRESUMO
Hydrogen sulfide (H2S) has recently been recognized as a novel gaseous transmitter with several anti-inflammatory properties. The role of host- derived H2S in infections by Pseudomonas aeruginosa was investigated in clinical and mouse models. H2S concentrations and survival was assessed in septic patients with lung infection. Animal experiments using a model of severe systemic multidrug-resistant P. aeruginosa infection were performed using mice with a constitutive knock-out of cystathionine-γ lyase (Cse) gene (Cse-/-) and wild-type mice with a physiological expression (Cse+/+). Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bone marrow transplantation (BMT) from a Cse+/+ donor; c) treatment with H2S synthesis inhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H2S donor sodium thiosulfate (STS) or GYY3147. Bacterial loads and myeloperoxidase activity were measured in tissue samples. The expression of quorum sensing genes (QS) was determined in vivo and in vitro. Cytokine concentration was measured in serum and incubated splenocytes. Patients survivors at day 28 had significantly higher serum H2S compared to non-survivors. A cut- off point of 5.3 µΜ discriminated survivors with sensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H2S higher and less than 5.3 µΜ (p = 7 x 10-6). In mice expression of Cse and application of STS afforded protection against infection with multidrug-resistant P. aeruginosa. Cyclophosphamide pretreatment eliminated the survival benefit of Cse+/+ mice, whereas BMT increased the survival of Cse-/- mice. Cse-/- mice had increased pathogen loads compared to Cse+/+ mice. Phagocytic activity of leukocytes from Cse-/- mice was reduced but was restored after H2S supplementation. An H2S dependent down- regulation of quorum sensing genes of P.aeruginosa could be demonstrated in vivo and in vitro. Endogenous H2S is a potential independent parameter correlating with the outcome of P. aeruginosa. H2S provides resistance to infection by MDR bacterial pathogens.
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Cistationina gama-Liase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Infecções por Pseudomonas/metabolismo , Sepse/metabolismo , Animais , Humanos , Camundongos , Camundongos Knockout , Infecções por Pseudomonas/complicações , Pseudomonas aeruginosa , Sepse/microbiologiaRESUMO
Oral iron supplementation is the cornerstone for the management of iron-deficiency anemia. A new oral formulation of iron conjugated with N-aspartyl-casein (Fe-ASP) (Omalin®, Uni-Pharma) is studied in the ACCESS double-blind, double-dummy randomized clinical trial; 60 patients were randomized to 12-week oral treatment twice every day either with oral ferrous sulfate (FeSO4) delivering 47 mg elementary iron or oral Fe-ASP delivering 40 mg elementary iron. Participants had hemoglobin less than 10 g/dl, decreased red blood cell (RBC) count, and ferritin lower than 30 ng/ml; patients with a medical history of malignancy were excluded. The primary endpoint was the increase of Hb in the first 4 weeks of treatment, and the study was powered for non-inferiority. A new score of global improvement was introduced where all participants were given one point for any at least 10% increase of Hb, RBC, and reticulocytes. At week 4, the mean (SE) change of Hb was 0.76 g/dl in the FeSO4 group and 0.83 g/dl in the Fe-ASP group (p: 0.876). The odds for worse allocation of the global score were 0.35 in the Fe-ASP group compared to the FeSO4 group. Patients in the Fe-ASP group experienced a significant decrease in the number of IDA-related physical signs by week 4. No differences were found between the two groups in any of the patient-reported outcomes of fatigue and of gastrointestinal adverse events either at week 4 or at week 12. ACCESS is the most recent clinical trial showing the non-inferiority of Fe-ASP to FeSO4 for the primary endpoint of the Hb change.
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Anemia Ferropriva , Ferro , Humanos , Ferro/uso terapêutico , Anemia Ferropriva/tratamento farmacológico , Caseínas/uso terapêutico , Ferritinas , Hemoglobinas/análiseRESUMO
Sepsis is defined as organ failure caused by dysregulated host response to infection. While early antibiotic treatment in patients with acute infection is essential, treating non-infectious patients must be avoided. Current guidelines recommend procalcitonin (PCT) to guide discontinuation of antibiotic treatment. For initiation of therapy, there is currently no recommended biomarker. In this study, we evaluated Host-Derived Delta-like Canonical Notch Ligand 1 (DLL1), a monocyte membrane ligand that has shown promising results in differentiating infectious from non-infectious critically ill patients. Soluble DLL1 levels were measured in plasma samples of six different cohorts. The six cohorts comprise two cohorts with non-infectious inflammatory auto-immune diseases (Hidradenitis Suppurativa, Inflammatory Bowel Disease), one cohort of bacterial skin infection, and three cohorts of suspected systemic infection or sepsis. In total, soluble DLL1 plasma levels of 405 patients were analyzed. Patients were divided into three groups: inflammatory disease, infection, and sepsis (defined according to the Sepsis-3 definition), followed by the evaluation of its diagnostic performance via Area Under the Receiver Operating Characteristics (AUROC) analyses. Patients of the sepsis group showed significantly elevated plasma DLL1 levels compared to patients with uncomplicated infections and sterile inflammation. However, patients with infections had significantly higher DLL1 levels than patients with inflammatory diseases. Diagnostic performance was evaluated and showed better performance for DLL1 for the recognition of sepsis (AUC: 0.823; CI 0.731-0.914) than C-reactive protein (AUC 0.758; CI 0.658-0.857), PCT (AUC 0.593; CI 0.474-0.711) and White Blood Cell count (AUC 0.577; CI 0.46-0.694). DLL1 demonstrated promising results for diagnosing sepsis and was able to differentiate sepsis from other infectious and inflammatory diseases.
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Doenças Transmissíveis , Sepse , Humanos , Ligantes , Calcitonina , Biomarcadores , Sepse/diagnóstico , Pró-CalcitoninaRESUMO
BACKGROUND: The accuracy of a new optical biosensor (OB) point-of-care device for the detection of severe infections is studied. METHODS: The OB emits different wavelengths and outputs information associated with heart rate, pulse oximetry, levels of nitric oxide and kidney function. At the first phase, recordings were done every two hours for three consecutive days after hospital admission in 142 patients at high-risk for sepsis by placing the OB on the forefinger. At the second phase, single recordings were done in 54 patients with symptoms of viral infection; 38 were diagnosed with COVID-19. RESULTS: At the first phase, the cutoff value of positive likelihood of 18 provided 100% specificity and 100% positive predictive value for the diagnosis of sepsis. These were 87.5 and 91.7% respectively at the second phase. OB diagnosed severe COVID-19 with 83.3% sensitivity and 87.5% negative predictive value. CONCLUSIONS: The studied OB seems valuable for the discrimination of infection severity.
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Técnicas Biossensoriais/métodos , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Sepse/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Área Sob a Curva , Betacoronavirus/isolamento & purificação , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Curva ROC , SARS-CoV-2 , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Failure of circulating monocytes for adequate cytokine production is a trait of sepsis-induced immunosuppression; however, its duration and association with final outcome are poorly understood. METHODS: We conducted a substudy of a large randomised clinical trial. Peripheral blood mononuclear cells (PBMCs) were isolated within the first 24 h from the onset of systemic inflammatory response syndrome in 95 patients with microbiologically confirmed or clinically suspected gram-negative infections. Isolation was repeated on days 3, 7 and 10. PBMCs were stimulated for cytokine production. The study endpoints were the differences between survivors and non-survivors, the persistence of immunosuppression, and determination of admission clinical signs that can lead to early identification of the likelihood of immunosuppression. RESULTS: PBMCs of survivors produced significantly greater concentrations of tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, IL-10, interferon-γ and granulocyte-macrophage colony-stimulating factor after day 3. Using ROC analysis, we found that TNF-α production less than 250 pg/ml after lipopolysaccharide stimulation on day 3 could discriminate patients from healthy control subjects; this was associated with a 5.18 OR of having an unfavourable outcome (p = 0.046). This trait persisted as long as day 10. Logistic regression analysis showed that cardiovascular failure on admission was the only independent predictor of defective TNF-α production on day 3. CONCLUSIONS: Defective TNF-α production is a major trait of sepsis-induced immunosuppression. It is associated with significant risk for unfavourable outcome and persists until day 10. Cardiovascular failure on admission is predictive of defective TNF-α production during follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01223690 . Registered on 18 October 2010.
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Bactérias Gram-Negativas/metabolismo , Infecções/complicações , Leucócitos Mononucleares/classificação , Idoso , Idoso de 80 Anos ou mais , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Técnicas de Apoio para a Decisão , Feminino , Bactérias Gram-Negativas/patogenicidade , Fator Estimulador de Colônias de Granulócitos e Macrófagos/análise , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Grécia , Humanos , Infecções/sangue , Interferon gama/análise , Interferon gama/sangue , Interleucina-10/análise , Interleucina-10/sangue , Interleucina-6/análise , Interleucina-6/sangue , Interleucina-8/análise , Interleucina-8/sangue , Leucócitos Mononucleares/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos , Curva ROC , Proteínas Recombinantes/análise , Proteínas Recombinantes/sangue , Estatísticas não Paramétricas , Sobreviventes/estatística & dados numéricos , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: TREM-1 (triggering receptor expressed on myeloid cells), a receptor expressed on neutrophils and monocytes, is upregulated in sepsis and seems to tune the inflammatory response. We explored the expression of TREM-1 at the gene level and on cell membranes of monocytes and association with clinical outcome. METHODS: Peripheral venous blood was sampled from 75 septic patients (39 patients with sepsis, 25 with severe sepsis and 11 with septic shock) on sepsis days 1, 3 and 7. TREM-1 on monocytes was measured by flow cytometry; gene expression of TREM-1 in circulating mononuclear cells was assessed by real-time PCR. sTREM-1 was measured in serum by an enzyme immunoassay. RESULTS: Although surface TREM-1, sTREM-1 and TREM-1 gene expression did not differ between sepsis, severe sepsis and septic shock on day 1, survivors had greater expression of surface TREM-1 on days 3 and 7 compared to non-survivors. sTREM-1 on non-survivors decreased on day 3 compared to baseline. Patients with increase of monocyte gene expression of TREM-1 from day 1 to day 3 had prolonged survival compared to patients with decrease of gene expression of TREM-1 from day 1 to day 3 (p: 0.031). CONCLUSIONS: Early decrease of gene expression of TREM-1 in monocytes is associated with poor outcome. A reciprocal decrease of the pro-inflammatory surface receptor TREM-1 linked with sepsis-induced immunosuppression may be part of the explanation.
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Regulação da Expressão Gênica/imunologia , Glicoproteínas de Membrana , Monócitos , Receptores Imunológicos , Sepse , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cinética , Masculino , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Receptores Imunológicos/sangue , Receptores Imunológicos/imunologia , Sepse/sangue , Sepse/imunologia , Sepse/mortalidade , Taxa de Sobrevida , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
BACKGROUND: Choice of empirically prescribed antimicrobials for sepsis management depends on epidemiological factors. The epidemiology of sepsis in Greece was studied in two large-periods. METHODS: Sepsis due to bloodstream infections (BSI) from July 2006 until March 2013 was recorded in a multicenter study in 46 departments. Patients were divided into sepsis admitted in the emergencies and hospitalized in the general ward (GW) and sepsis developing after admission in the Intensive Care Unit (ICU). The primary endpoints were the changes of epidemiology and the factors related with BSIs by multidrug-resistant (MDR) pathogens; the secondary endpoint was the impact of de-escalation on antimicrobial therapy. RESULTS: 754 patients were studied; 378 from 2006-2009 and 376 from 2010-2013. Major differences were recorded between periods in the GW. They involved increase of: sepsis severity; the incidence of underlying diseases; the incidence of polymicrobial infections; the emergence of Klebsiella pneumoniae as a pathogen; and mortality. Factors independently related with BSI by MDR pathogens were chronic hemofiltration, intake of antibiotics the last three months and residence into long-term care facilities. De-escalation in BSIs by fully susceptible Gram-negatives did not affect final outcome. Similar epidemiological differences were not found in the ICU; MDR Gram-negatives predominated in both periods. CONCLUSIONS: The epidemiology of sepsis in Greece differs in the GW and in the ICU. De-escalation in the GW is a safe strategy.
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Antibacterianos , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Farmacorresistência Bacteriana Múltipla , Idoso , Feminino , Grécia/epidemiologia , Humanos , Incidência , Unidades de Terapia Intensiva , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/epidemiologiaRESUMO
BACKGROUND: Addition of macrolide antibiotics to ß-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a ß-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. METHODS: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of ß-lactam plus ß-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). FINDINGS: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. INTERPRETATION: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to ß-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. FUNDING: Hellenic Institute for the Study of Sepsis and Abbott Products Operations.
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Claritromicina , Pneumonia , Adulto , Humanos , Claritromicina/uso terapêutico , Grécia , Estudos Prospectivos , Pró-Calcitonina , Pneumonia/tratamento farmacológico , Antibacterianos , Anti-Inflamatórios , Método Duplo-Cego , Resultado do TratamentoRESUMO
ABSTRACT: Optimal management of septic patients requires accurate assessment of both current severity status and prognosis. Since the 1990s, substantial advances have been made in the use of circulating biomarkers for such assessments. This summary of the session on "Biomarkers: can they really use guide our daily practice?" presented at the 2021 WEB-CONFERENCE OF THE EUROPEAN SHOCK SOCIETY, 6 November 2021. These biomarkers include ultrasensitive detection of bacteremia, circulating soluble urokina-type plasminogen activator receptor (suPAR), C-reactive protein (CRP) and ferritin and procalcitonin. In addition, the potential application of novel multiwavelength optical biosensor technology allows noninvasive monitoring of multiple metabolites that can be used to assess severity and prognosis in septic patients. The application these biomarkers and improved technologies provide the potential for improved personalized management of septic patients.
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Bacteriemia , Proteína C-Reativa , Humanos , Biomarcadores , Ferritinas , Pró-CalcitoninaRESUMO
Introduction: The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a chronic inflammatory state. Perhaps counterintuitively, obesity is also associated with lower mortality in sepsis patients. We investigated the association between obesity, circulating adipocytokine concentrations, immune dysregulation, and outcome in sepsis patients. Methods In this secondary analysis of a prospective study, plasma concentrations of the adipocytokines leptin, adiponectin, and resistin were assessed in 167 patients at diagnosis of sepsis due to pneumonia, bacteremia, or acute cholangitis. Adipocytokines were compared between patients with normal weight (body mass index [BMI], 18.5-24.9 kg/m 2 ; n = 67), overweight (BMI, 25.0-29.9 kg/m 2 ; n = 56), and obesity (BMI ≥30 kg/m 2 ; n = 42), as well as between immunological endotypes: hyperinflammation (n = 40), immunoparalysis (n = 62), and unclassified (n = 55). Results: Higher circulating concentrations of leptin were observed in patients with obesity compared with patients with normal weight ( P = 0.008) and overweight ( P = 0.02), whereas adiponectin and resistin plasma concentrations were not different ( P = 0.08 and P = 0.85, respectively). Resistin concentrations were associated with immunological endotypes, with the highest levels found in hyperinflammatory patients ( P < 0.001). Furthermore, resistin concentrations were predictive for 28-day mortality (adjusted odds ratio, 1.03 per 10 ng/mL; P = 0.04). These associations were not found for leptin and adiponectin. Conclusion: Obesity and BMI-related adipocytokines are not related to the development of a hyperactive or suppressed immune response as defined by ferritin and mHLA-DR expression in sepsis patients. Although resistin is related to the immune response and an increased risk of adverse clinical outcomes, these associations are similar in patients with normal weight, overweight, and obesity. This implies that the relationship between resistin and clinical outcome is likely driven by the inflammatory response and not by obesity itself. Taken together, although there exists a strong association between inflammation and sepsis mortality, our results do not point toward a role for obesity and BMI-related adipocytokines in immune dysregulation in sepsis patients.
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Adipocinas , Sepse , Humanos , Leptina , Resistina , Adiponectina/metabolismo , Estudos Prospectivos , Sobrepeso/complicações , Obesidade/complicações , Inflamação , Sepse/complicaçõesRESUMO
Mucormycosis has emerged as a group of severe infections mainly in immunocompromised patients. We analysed the epidemiology of mucormycosis in Greece in a multicentre, nationwide prospective survey of patients of all ages, during 2005-2022. A total of 108 cases were recorded. The annual incidence declined after 2009 and appeared stable thereafter, at 0.54 cases/million population. The most common forms were rhinocerebral (51.8%), cutaneous (32.4%), and pulmonary (11.1%). Main underlying conditions were haematologic malignancy/neutropenia (29.9%), haematopoietic stem cell transplantation (4.7%), diabetes mellitus (DM) (15.9%), other immunodeficiencies (23.4%), while 22.4% of cases involved immunocompetent individuals with cutaneous/soft-tissue infections after motor vehicle accident, surgical/iatrogenic trauma, burns, and injuries associated with natural disasters. Additionally, DM or steroid-induced DM was reported as a comorbidity in 21.5% of cases with various main conditions. Rhizopus (mostly R. arrhizus) predominated (67.1%), followed by Lichtheimia (8.5%) and Mucor (6.1%). Antifungal treatment consisted mainly of liposomal amphotericin B (86.3%), median dose 7 mg/kg/day, range 3-10 mg/kg/day, with or without posaconazole. Crude mortality was 62.8% during 2005-2008 but decreased significantly after 2009, at 34.9% (p = 0.02), with four times fewer haematological cases, fewer iatrogenic infections, and fewer cases with advanced rhinocerebral form. The increased DM prevalence should alert clinicians for timely diagnosis of mucormycosis in this patient population.
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Sepsis is a clinical syndrome defined as a dysregulated host response to infection resulting in life-threatening organ dysfunction. Sepsis is a major public health concern associated with one in five deaths worldwide. Sepsis is characterized by unbalanced inflammation and profound and sustained immunosuppression, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based therapies for sepsis. Yet, the picture is not so straightforward because of the versatile and dynamic features of miRNAs. Clearly, more research is needed to clarify the expression and role of miRNAs in sepsis, and to promote the use of miRNAs for sepsis management.
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MicroRNAs , Sepse , Biomarcadores/metabolismo , Humanos , Tolerância Imunológica , Inflamação , MicroRNAs/metabolismo , Sepse/diagnóstico , Sepse/tratamento farmacológico , Sepse/genéticaRESUMO
INTRODUCTION: Sepsis is a major cause of death among hospitalised patients. Accumulating evidence suggests that immune response during sepsis cascade lies within a spectrum of dysregulated host responses. On the one side of the spectrum there are patients whose response is characterised by fulminant hyperinflammation or macrophage activation-like syndrome (MALS), and on the other side patients whose immune response is characterised by immunoparalysis. A sizeable group of patients are situated between the two extremes. Recognising immune endotype is very important in order to choose the appropriate immunotherapeutic approach for each patient resulting in the best chance to improve the outcome. METHODS AND ANALYSIS: ImmunoSep is a randomised placebo-controlled phase 2 clinical trial with a double-dummy design in which the effect of precision immunotherapy on sepsis phenotypes with MALS and immunoparalysis is studied. Patients are stratified using biomarkers. Specifically, 280 patients will be 1:1 randomly assigned to placebo or active immunotherapy as adjunct to standard-of-care treatment. In the active immunotherapy arm, patients with MALS will receive anakinra (recombinant interleukin-1 receptor antagonist) intravenously, and patients with immunoparalysis will receive subcutaneous recombinant human interferon-gamma. Τhe primary endpoint is the comparative decrease of the mean total Sequential Organ Failure Assessment score by at least 1.4 points by day 9 from randomisation. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices; the National Ethics Committee of Greece and by the National Organization for Medicines of Greece; the Central Committee on Research Involving Human Subjects and METC Oost Netherland for the Netherlands; the National Agency for Medicine and Medical Products of Romania; and the Commission Cantonale d'éthique de la recherche sur l'être human of Switzerland. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04990232.
Assuntos
COVID-19 , Sepse , Humanos , SARS-CoV-2 , Método Duplo-Cego , Sepse/terapia , Resultado do Tratamento , Imunoterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
The state of immune activation may guide targeted immunotherapy in sepsis. In a double-blind, double-dummy randomized clinical study, 240 patients with sepsis due to lung infection, bacteremia, or acute cholangitis were subjected to measurements of serum ferritin and HLA-DR/CD14. Patients with macrophage activation-like syndrome (MALS) or immunoparalysis were randomized to treatment with anakinra or recombinant interferon-gamma or placebo. Twenty-eight-day mortality was the primary endpoint; sepsis immune classification was the secondary endpoint. Using ferritin >4,420 ng/mL and <5,000 HLA-DR receptors/monocytes as biomarkers, patients were classified into MALS (20.0%), immunoparalysis (42.9%), and intermediate (37.1%). Mortality was 79.1%, 66.9%, and 41.6%, respectively. Survival after 7 days with SOFA score decrease was achieved in 42.9% of patients of the immunotherapy arm and 10.0% of the placebo arm (p = 0.042). Three independent immune classification strata are recognized in sepsis. MALS and immunoparalysis are proposed as stratification for personalized adjuvant immunotherapy. Clinicaltrials.gov registration NCT03332225.
Assuntos
Síndrome de Ativação Macrofágica , Sepse , Humanos , Sepse/terapia , Antígenos HLA-DR/metabolismo , Síndrome de Ativação Macrofágica/complicações , Ferritinas/uso terapêutico , ImunoterapiaRESUMO
Predicting the severity of COVID-19 remains an unmet medical need. Our objective was to develop a blood-based host-gene-expression classifier for the severity of viral infections and validate it in independent data, including COVID-19. We developed a logistic regression-based classifier for the severity of viral infections and validated it in multiple viral infection settings including COVID-19. We used training data (N = 705) from 21 retrospective transcriptomic clinical studies of influenza and other viral illnesses looking at a preselected panel of host immune response messenger RNAs. We selected 6 host RNAs and trained logistic regression classifier with a cross-validation area under curve of 0.90 for predicting 30-day mortality in viral illnesses. Next, in 1417 samples across 21 independent retrospective cohorts the locked 6-RNA classifier had an area under curve of 0.94 for discriminating patients with severe vs. non-severe infection. Next, in independent cohorts of prospectively (N = 97) and retrospectively (N = 100) enrolled patients with confirmed COVID-19, the classifier had an area under curve of 0.89 and 0.87, respectively, for identifying patients with severe respiratory failure or 30-day mortality. Finally, we developed a loop-mediated isothermal gene expression assay for the 6-messenger-RNA panel to facilitate implementation as a rapid assay. With further study, the classifier could assist in the risk assessment of COVID-19 and other acute viral infections patients to determine severity and level of care, thereby improving patient management and reducing healthcare burden.
Assuntos
COVID-19 , Regulação da Expressão Gênica , RNA Mensageiro/sangue , SARS-CoV-2/metabolismo , Doença Aguda , COVID-19/sangue , COVID-19/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Trained immunity refers to the ability of the innate immune system exposed to a first challenge to provide an enhanced response to a secondary homologous or heterologous challenge. We reported that training induced with ß-glucan one week before infection confers protection against a broad-spectrum of lethal bacterial infections. Whether this protection persists over time is unknown. To tackle this question, we analyzed the immune status and the response to Listeria monocytogenes (L. monocytogenes) of mice trained 9 weeks before analysis. The induction of trained immunity increased bone marrow myelopoiesis and blood counts of Ly6Chigh inflammatory monocytes and polymorphonuclear neutrophils (PMNs). Ex vivo, whole blood, PMNs and monocytes from trained mice produced increased levels of cytokines in response to microbial products and limited the growth of L. monocytogenes. In vivo, following challenge with L. monocytogenes, peripheral blood leukocytes were massively depleted in control mice but largely preserved in trained mice. PMNs were reduced also in the spleen from control mice, and increased in the spleen of trained mice. In transwell experiments, PMNs from trained mice showed increased spontaneous migration and CXCL2/MIP2α-induced chemotaxis, suggesting that training promotes the migration of PMNs in peripheral organs targeted by L. monocytogenes. Trained PMNs and monocytes had higher glycolytic activity and mitochondrial respiration than control cells when exposed to L. monocytogenes. Bacterial burden and dissemination in blood, spleen and liver as well as systemic cytokines and inflammation (multiplex bead assay and bioluminescence imaging) were reduced in trained mice. In full agreement with these results, mice trained 9 weeks before infection were powerfully protected from lethal listeriosis. Altogether, these data suggest that training increases the generation and the antimicrobial activity of PMNs and monocytes, which may confer prolonged protection from lethal bacterial infection.