Inflammatory and cytotoxic mediators in COVID-19 patients and in ChAdOx1 nCoV-19 (AZD1222) vaccine recipients.

Immunological and cytotoxic mediators are induced in natural infection and are essential for the effectiveness of vaccination. Vaccination is useful to prevent the spread of SARS-CoV-2 and limit the morbidity/mortality of COVID-19. ChAdOx1 nCoV-19 is one of the most widespread vaccines in the world. We compared the detection of anti-S1 SARS-CoV2 IgG and the profile of inflammatory and cytotoxic responses of patients who developed different clinical outcomes of COVID-19 with individuals previously exposed or not to the virus received the first and booster doses of ChAdOx1 nCoV-19. Plasma from 35 patients with COVID-19 and 11 vaccinated were evaluated by multiplex assay. Here, no vaccinated subjects had serious adverse effects. Those vaccinated with a booster dose had higher anti-S1 IgG than mild/moderate and recovered patients. Critically ill and deceased patients had IgG levels like those immunized. By univariate analysis, IL-2, IL-17, and perforin do not differentiate between patients and vaccinated individuals. Granzyme A increased at dose 1, while patients had their levels reduced. High levels of granulysin, sFas, and IL-6 were detected in the deaths, but after vaccination, all were declined. The multivariate analysis supports the role of IL-6 and granulysin as associated and non-confounding variables related to the worst clinical outcome of COVID-19, but not sFas. Our data confirm the ability of the ChAdOx1 vaccine to produce specific antibody levels up to booster time. Furthermore, our data suggest that the vaccine can regulate both the hyper-production and the kinetics of the production of inflammatory and cytotoxic mediators involved in the cytokine storm, such as granulysin and IL-6.

The Role of Growth Factors in the Pathogenesis of Dengue: A Scoping Review.

Growth factors (GFs) have a role in tissue repair and in the modulation of the expression of inflammatory cells in damage caused by pathogens. This study aims to systematize the evidence on the role of GFs in the pathogenesis of dengue. This scoping review considered all published peer-reviewed studies in the MEDLINE and Embase databases. Ultimately, 58 studies that analyzed GFs in dengue patients, published between 1998 and 2021, were included. DENV-2 infection and secondary infection were more frequent in the patients studied. ELISA and multiplex immunoassay (Luminex) were the most used measurement techniques. Increased levels of vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, transforming growth factor beta, and hepatocyte growth factor as well as reduced levels of platelet-derived growth factor and epidermal growth factor were observed in severe dengue in most studies. Vascular endothelial growth factor and hepatocyte growth factor were identified as biomarkers of severity. In addition, there is evidence that the dengue virus can use the growth factor pathway to facilitate its entry into the cell and promote its viral replication. The use of tyrosine kinase inhibitors is an alternative treatment for dengue that is being studied.

Subsets of Cytokines and Chemokines from DENV-4-Infected Patients Could Regulate the Endothelial Integrity of Cultured Microvascular Endothelial Cells.

Introduction: It is a consensus that inflammatory mediators produced by immune cells contribute to changes in endothelial permeability in dengue. We propose to relate inflammatory mediators seen in dengue patients with the in vitro alteration of endothelial cells (ECs) cultured with serum from these patients. Methods: Patients with mild (DF) to moderate and severe dengue (DFWS/Sev) were selected. ELISA quantified inflammatory mediators. Expression of adhesion molecules and CD147 were evaluated in the ECs cultured with the patient's serum by flow cytometry. We assessed endothelial permeability by measuring transendothelial electrical resistance in cocultures of ECs with patient serum. Results: Dengue infection led to an increase in inflammatory mediators-the IL-10 distinguished DF from DFWS/Sev. There were no changes in CD31, CD54, and CD106 but decreased CD147 expression in ECs. DFWS/Sev sera induced a greater difference in endothelial permeability than DF sera. Correlation statistical test indicated that low IL-10 and IFN-γ and high CCL5 maintain the integrity of ECs in DF patients. In contrast, increased TNF, IFN-γ, CXCL8, and CCL2 maintain EC integrity in DFWS/Sev patients. Conclusions: Our preliminary data suggest that a subset of inflammatory mediators may be related to the maintenance or loss of endothelial integrity, reflecting the clinical prognosis.

Increased Indoleamine 2,3-Dioxygenase 1 (IDO-1) Activity and Inflammatory Responses during Chikungunya Virus Infection.

Chikungunya virus (CHIKV) infection causes intense cytokine/chemokine inflammatory responses and debilitating joint pain. Indoleamine2,3-dioxygenase 1 (IDO-1) is an enzyme that initiates the tryptophan degradation that is important in initial host innate immune defense against infectious pathogens. Besides that, IDO-1 activation acts as a regulatory mechanism to prevent overactive host immune responses. In this study, we evaluated IDO-1 activity and cytokine/chemokine patterns in CHIKV patients. Higher IDO-1 (Kyn/Trp ratio) activation was observed during the early acute phase of CHIKV infection and declined in the chronic phase. Importantly, increased concentrations of Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Interferon γ (IFN-γ), C-C motif chemokine ligand 2/Monocyte Chemoattractant Protein-1 (CCL2/MCP-1) and C-X-C motif chemokine ligand 10/Interferon Protein-10 (CXCL10/IP-10) were found in the acute phase of infection, while C-C motif chemokine ligand 4/Macrophage Inflammatory Protein 1 ß (CCL4/MIP-1ß) was found at increased concentrations in the chronic phase. Likewise, CHIKV patients with arthritis had significantly higher concentrations of CCL4/MIP-1ß compared to patients without arthritis. Taken together, these data demonstrated increased IDO-1 activity, possibly exerting both antiviral effects and regulating exacerbated inflammatory responses. CCL4/MIP-1ß may have an important role in the persistent inflammation and arthritic symptoms following chikungunya infection.

Comparative Analysis of Circulating Levels of SARS-CoV-2 Antibodies and Inflammatory Mediators in Healthcare Workers and COVID-19 Patients.

Advances in knowledge of the pathophysiology of COVID-19 have been acquired; however, the host factors that could explain the mild and severe forms of the disease are not fully understood. Thus, we proposed to evaluate anti-SARS-CoV-2 antibodies and the inflammatory response of different groups of individuals, including healthcare workers (HCW), sick and dead COVID-19 patients and also recovered patients to contribute to this knowledge gap. Our objective is to relate the clinical evolution of these individuals with the level of detection and functionality of specific antibodies and with the production of inflammatory mediators. As main findings, IgA and IgG anti-SARS-CoV-2 were detected in asymptomatic HCW. IFN-γ and TNF-α levels were higher in symptomatic HCWs than patients with COVID-19 and those who died. Patients who died had higher levels of IL-6, IL-10, and CCL2/MCP-1. We found an imbalance between antiviral and pro-inflammatory mediators in the groups, in which IFN-γ and TNF-α seem to be more associated with protection and IL-6 and CCL2/MCP-1 with pathology. Our work is pioneering the Brazilian population and corroborates data from people from other countries.

Different Profiles of Cytokines, Chemokines and Coagulation Mediators Associated with Severity in Brazilian Patients Infected with Dengue Virus.

The incidence of dengue in Latin America has increased dramatically during the last decade. Understanding the pathogenic mechanisms in dengue is crucial for the identification of biomarkers for the triage of patients. We aimed to characterize the profile of cytokines (IFN-γ, TNF-α, IL-1ß, IL-6, IL-18 and IL-10), chemokines (CXCL8/IL-8, CCL2/MCP-1 and CXCL10/IP-10) and coagulation mediators (Fibrinogen, D-dimer, Tissue factor-TF, Tissue factor pathway inhibitor-TFPI and Thrombomodulin) during the dengue-4 epidemic in Brazil. Laboratory-confirmed dengue cases had higher levels of TNF-α (p < 0.001), IL-6 (p = 0.005), IL-10 (p < 0.001), IL-18 (p = 0.001), CXCL8/IL-8 (p < 0.001), CCL2/MCP-1 (p < 0.001), CXCL10/IP-10 (p = 0.001), fibrinogen (p = 0.037), D-dimer (p = 0.01) and TFPI (p = 0.042) and lower levels of TF (p = 0.042) compared to healthy controls. A principal component analysis (PCA) distinguished between two profiles of mediators of inflammation and coagulation: protective (TNF-α, IL-1ß and CXCL8/IL-8) and pathological (IL-6, TF and TFPI). Lastly, multivariate logistic regression analysis identified high aspartate aminotransferase-to-platelet ratio index (APRI) as independent risk factors associated with severity (adjusted OR: 1.33; 95% CI 1.03-1.71; p = 0.027), the area under the receiver operating characteristics curve (AUC) was 0.775 (95% CI 0.681-0.869) and an optimal cutoff value was 1.4 (sensitivity: 76%; specificity: 79%), so it could be a useful marker for the triage of patients attending primary care centers.

Emergence of ciprofloxacin-resistant Neisseria meningitidis B from asymptomatic carriers during an outbreak in Peru, 2017.

Asymptomatic carriers are a likely source of transmission of Neisseria meningitidis to close contacts who are placed at a higher risk for invasive meningococcal disease (IMD). Although N. meningitidis ciprofloxacin-resistance is rare, there have been an increase in the reports of resistant isolates mainly in patients diagnosed with IMD, and little is known about the N. meningitidis ciprofloxacin-resistance in the carrier populations. We performed a pharyngeal carriage study during a 2017 military setting outbreak in Peru, caused by a ciprofloxacin-resistant N. meningitidis B. The isolates analysed came from two hospitalized cases and six asymptomatic carriers. Whole-genome sequence-based analysis was performed and showed that strains carrying the Thr91Ile mutation, in the gene encoding for subunit A of DNA gyrase (gyrA), were responsible for the fluoroquinolone resistance (MICs ≥0.256 µg ml-1) and were closely related to highly virulent strains from France, Norway and the UK. Phylogenetic analysis of the gyrA gene revealed that likely these Peruvian isolates acquired resistance through horizontal gene transfer from Neisseria lactamica. Our study provides evidence for the emergence and propagation of ciprofloxacin-resistant N. meningitidis B from asymptomatic carriers, and recommends the introduction of serogroup B vaccines for high-risk populations.

Evaluación de la seroprotección contra sarampión, rubéola y hepatitis B en niños menores de cinco años del Perú, 2011 / Evaluation of the seroprotection against measles, rubella and hepatitis B in children under 5 years of age in Peru, 2011

Objetivos. Estimar la prevalencia de anticuerpos contra sarampión, rubéola y hepatitis B en niños de 1 a 4 años del Perú. Materiales y métodos. Se realizó una encuesta nacional basada en la aplicación de un cuestionario y obtención de muestra de sangre capilar en papel de filtro para el estudio de anticuerpos contra sarampión, rubéola y hepatitis B en niños de 1 a 4 años. Se utilizó un muestreo probabilístico, estratificado y multietápico con inferencia a nivel nacional y siete ámbitos de estudio: Lima metropolitana, resto de costa urbana, costa rural, sierra urbana, sierra rural, selva urbana y selva rural. Las muestras de sangre capilar fueron procesadas siguiendo protocolos estandarizados para la determinación de anticuerpos mediante técnica de ELISA utilizando reactivos comerciales. Resultados. Se encontró una prevalencia nacional de 91,6% (IC95%: 90,6-92,7%), 91,3% (IC 95%: 90,3-92,4%) y 95,9% (IC 95%: 95,0-96,8%) para anticuerpos contra sarampión, rubéola y hepatitis B respectivamente. No se evidenció diferencias significativas de las prevalencias entre los diferentes ámbitos de estudio y en los diferentes estratos socioeconómicos de los conglomerados. Conclusiones. En niños de 1 a 4 años se ha estimado una prevalencia nacional de anticuerpos contra sarampión y rubéola entre 90-93%, mientras que para anticuerpos contra hepatitis B (anti-HBsAg) entre 95-97%.

Objectives. To estimate the prevalence of antibodies against measles, rubella and hepatitis B in children aged between 1 and 4 years in Peru. Materials and methods. A national survey was conducted based on a questionnaire and capillary blood sample taken on filter paper in order to study antibodies against measles, rubella and hepatitis B in children from 1 to 4 years of age. A stratified, multistage, probability sampling design was used to be representative at the national level and at level of seven ambits, including the Metropolitan Lima Area, the rest of the urban coast, the rural coast, the urban highlands, the rural highlands, the urban jungle and the rural jungle. The capillary blood samples were processed according to the standardized protocols for detection of antibodies using the ELISA technique and commercial reagents. Results. The survey showed a national prevalence of antibodies against measles, rubella and hepatitis B of 91.6% (CI 95%: 90.6%; 92.7%), 91.3% (CI 95%: 90.3%; 92.4%) and 95.9% (CI 95%: 95.0%; 96.8%) respectively. There was no evidence of significant differences in the prevalence among the ambits of study or among the socioeconomic strata of the conglomerates for any of the three types of antibodies. Conclusions. In children from 1 to 4 years of age, the national prevalence of antibodies against measles and Rubella was between 90-93%, while the prevalence of antibodies against Hepatitis B (anti-HBsAg) was between 95-97%.

[Evaluation of the seroprotection against measles, rubella and hepatitis B in children under 5 years of age in Peru, 2011]. / Evaluación de la seroprotección contra sarampión, rubéola y hepatitis B en niños menores de cinco años del Perú, 2011.

OBJECTIVES: To estimate the prevalence of antibodies against measles, rubella and hepatitis B in children aged between 1 and 4 years in Peru. MATERIALS AND METHODS: A national survey was conducted based on a questionnaire and capillary blood sample taken on filter paper in order to study antibodies against measles, rubella and hepatitis B in children from 1 to 4 years of age. A stratified, multistage, probability sampling design was used to be representative at the national level and at level of seven ambits, including the Metropolitan Lima Area, the rest of the urban coast, the rural coast, the urban highlands, the rural highlands, the urban jungle and the rural jungle. The capillary blood samples were processed according to the standardized protocols for detection of antibodies using the ELISA technique and commercial reagents. RESULTS: The survey showed a national prevalence of antibodies against measles, rubella and hepatitis B of 91.6% (CI 95%: 90.6%; 92.7%), 91.3% (CI 95%: 90.3%; 92.4%) and 95.9% (CI 95%: 95.0%; 96.8%) respectively. There was no evidence of significant differences in the prevalence among the ambits of study or among the socioeconomic strata of the conglomerates for any of the three types of antibodies. CONCLUSIONS: In children from 1 to 4 years of age, the national prevalence of antibodies against measles and Rubella was between 90-93%, while the prevalence of antibodies against Hepatitis B (anti-HBsAg) was between 95-97%.

[Clinical characteristics of patients admitted to hospital "Cesar Garayar García", Iquitos during the dengue epidemic, January-February 2011]. / Características clínicas de pacientes internados en el Hospital de Apoyo de Iquitos "César Garayar García" durante la epidemia de dengue, enero-febrero de 2011.

We conducted a clinical description of confirmed dengue cases admitted to the Hospital " César Garayar García" in Iquitos from January 25 to February 5, 2011. According to current WHO classification, major warning signs leading to hospitalization were: abdominal pain (28/28) and persistent vomiting (15/28), the causes of severity were: hypotension (9 / 13), severe bleeding (6 / 13) and plasma extravasation with respiratory distress (4 / 13). The median patient age was 22 years, however, 8 / 13 patients classified as severe dengue were under 16 years. In conclusion, unlike previous epidemics, we found a high involvement of young people and severity in the clinical presentation predominating a high frequency of shock (hypotension) and vascular leakage, which could be related to the circulation of an emerging variant DENV-2 which is more virulent.

Características clínicas de pacientes internados en el Hospital de Apoyo de Iquitos "César Garayar García" durante la epidemia de dengue, enero-febrero de 2011 / Clinical characteristics of patients admitted to hospital "Cesar Garayar García", Iquitos during the dengue epidemic, January-February 2011

Se realizó una descripción clínica de pacientes con dengue confirmado internados en el Hospital de Apoyo de Iquitos "César Garayar García" desde el 25 de enero al 05 de febrero de 2011. Según la actual clasificación de la OMS, los principales signos de alarma que motivaron hospitalización fueron: dolor abdominal (28/28) y vómitos persistentes (15/28); las causas de gravedad fueron: hipotensión (9/13), sangrado grave (6/13) y extravasación de plasma con dificultad respiratoria (4/13). La mediana de edad de los pacientes fue 22 años, sin embargo, 8/13 pacientes clasificados como dengue grave fueron menores de 16 años. En conclusión, se evidencia una mayor afectación de la población joven y gravedad en la presentación clínica a diferencia de epidemias anteriores, predominando el shock (hipotensión) por extravasación vascular, lo cual podría estar relacionado con la circulación de una variante emergente del DENV-2 con mayor virulencia.

We conducted a clinical description of confirmed dengue cases admitted to the Hospital " César Garayar García" in Iquitos from January 25 to February 5, 2011. According to current WHO classification, major warning signs leading to hospitalization were: abdominal pain (28/28) and persistent vomiting (15/28), the causes of severity were: hypotension (9 / 13), severe bleeding (6 / 13) and plasma extravasation with respiratory distress (4 / 13). The median patient age was 22 years, however, 8 / 13 patients classified as severe dengue were under 16 years. In conclusion, unlike previous epidemics, we found a high involvement of young people and severity in the clinical presentation predominating a high frequency of shock (hypotension) and vascular leakage, which could be related to the circulation of an emerging variant DENV-2 which is more virulent.