Increased circulating levels of High Mobility Group Box 1 (HMGB1) in acute-phase Chikungunya virus infection: Potential disease biomarker.

BACKGROUND: Chikungunya virus (CHIKV) causes a febrile syndrome with intense and debilitating arthralgia that can persist for several months or years after complete virus clearance. As there is no specific antiviral treatment or vaccine against CHIKV, identification of serological markers that help clinical management of CHIKV patients is urgent. The High Mobility Group Box 1 (HMGB1) protein is secreted to extracellular milieu and triggers an intense inflammatory process by inducing the overexpression of pro-inflammatory cytokines. HMGB1 plays an important role in several virus diseases as well as in rheumatoid arthritis. OBJECTIVES: This study focus on the investigation of HMGB1 serum levels in a sera panel from CHIKV-infected patients in an attempt to assess its potential as a biomarker for chikungunya clinical management. STUDY DESIGN: Eighty CHIKV-positive samples and 32 samples from healthy donors were subjected to a quantitative HMGB1 ELISA assay to assess the HMGB1 circulating levels. RESULTS: HMGB1 levels were significantly higher in CHIKV-positive samples (516.12 ng/mL, SEM ± 48.83 ng/mL) compared to negative control (31.20 ng/mL, SEM ± 3.24 ng/mL, p < 0.0001). Circulating levels of HMGB1 persisted elevated during the whole acute-phase of disease and correlated with virus titer (p < 0.05). CONCLUSIONS: The present study is the first to describe increased serum levels of HMGB1 in CHIKV infection and its positive correlation with virus titer, suggesting its potential use as a biomarker for diagnosis and treatment of chikungunya fever.

Timeline analysis of IgA and IgG levels in Covid-19 hospitalized patients according to the clinical outcome / Análise temporal das concentrações de IgA e IgG em pacientes hospitalizados com Covid-19 de acordo com o desfecho clínico

ABSTRACT Introduction: Studies suggest the association between antibody production and the severity of coronavirus disease 2019 (Covid-19). Objectives: To evaluate the concentrations of immunoglobulins class A (IgA) and class G (IgG) during the hospitalization period of Covid-19 patients according to the outcome (survival vs death). Materials and methods: Patients with severe acute respiratory syndrome of coronavirus 2 (Sars-CoV-2) infection confirmed by reverse transcriptase reaction followed by polymerase chain reaction (RT-PCR) were included in this prospective study. Samples were obtained weekly during the follow-up of individuals, considering symptom onset. Titers of anti-Sars-CoV-2 IgA and IgG were measured using a commercial immunoassay. Correlations between IgA/IgG and cycle threshold (Ct) values for N1 and N2 target genes were also assessed. Results: We studied 55 Covid-19 patients (59.7±16.2 years, 63.6% male), of which 28 (50.9%) died. We observed IgA and IgG positivity (IgA+ and IgG+) in 90.9% and 80% of patients, respectively. The highest IgA+ frequency was observed at weeks 2 and 3 and the highest IgG+ at weeks 3 and 4. It is important to note that patients who died presented lower IgA titers in the first two weeks (p < 0.05); however, a significant increase in IgA levels was observed in the subsequent weeks. Lastly, we identified that significant correlations between Ct values and immunoglobulins levels, both IgA and IgG were correlated with Ct N2 in patients who died. Conclusion: Our results suggest that lower IgA titers in early Covid-19, which is associated with lower Ct values, may indicate patients at higher risk for death.

RESUMEN Introducción: Los estudios sugieren una asociación entre la producción de anticuerpos y la gravedad de la enfermedad por coronavirus 2019 (Covid-19). Objetivos: Evaluar las concentraciones de inmunoglobulinas clase A (IgA) y clase G (IgG) durante la hospitalización de pacientes con Covid-19 según el desenlace (supervivencia vs muerte). Materiales y métodos: Se incluyeron en este estudio prospectivo pacientes con síndrome respiratorio agudo severo de infección por coronavirus 2 (Sars-CoV-2) confirmado por la reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR). Las muestras se obtuvieron semanalmente durante el seguimiento de los individuos, considerando la aparición de los síntomas. Los títulos de IgA e IgG anti-Sars-CoV-2 se midieron usando un inmunoensayo comercial. También se evaluaron las correlaciones entre IgA/IgG y los valores de los umbrales de ciclo [cycle threshold (Ct)] para los genes N1 y N2. Resultados: Se estudiaron 55 pacientes Covid-19 (59,7 ± 16,2 años, 63,6% varones), de los cuales 28 (50,9%) fallecieron. Observamos positividad de IgA e IgG (IgA+ e IgG+) en el 90,9% y el 80% de los pacientes, respectivamente. La frecuencia más alta de IgA+ se observó en las semanas dos y tres y la IgG + más alta en las semanas tres y cuatro. Es importante señalar que los pacientes que fallecieron presentaron títulos de IgA más bajos en las dos primeras semanas (p < 0,05); sin embargo, se observó un aumento significativo en los niveles de IgA en las semanas siguientes. Conclusión: Identificamos correlaciones significativas entre los valores de Ct y los niveles de Ig, tanto IgA como IgG se correlacionaron con Ct N2 en los pacientes que fallecieron. Nuestros resultados sugieren que los títulos de IgA más bajos en Covid-19 temprano, que se asocia con valores de Ct más bajos, pueden indicar que los pacientes tienen un mayor riesgo de muerte.

RESUMO Introdução: Estudos sugerem a associação entre a produção de anticorpos e a gravidade da coronavirus disease 2019 (Covid-19). Objetivos: Avaliar as concentrações de imunoglobulinas da classe A (IgA) e da classe G (IgG) durante a internação de pacientes com Covid-19 de acordo com o desfecho (sobrevida vs óbito). Materiais e métodos: Pacientes com infecção pela síndrome respiratória aguda grave do coronavírus 2 (Sars-CoV-2) confirmada por reação da transcriptase reversa seguida de reação em cadeia da polimerase (RT-PCR) foram incluídos neste estudo prospectivo. As amostras foram obtidas semanalmente durante o acompanhamento dos indivíduos, considerando o início dos sintomas. Os títulos de IgA e IgG anti-Sars-CoV-2 foram mensurados por meio de um imunoensaio comercial. Correlações entre IgA/IgG e valores de limiar de detecção [cycle thresholds (Ct)] para os genes alvos N1 e N2 também foram avaliadas. Resultados: Estudamos 55 pacientes com Covid-19 (59,7 ± 6,2 anos; 63,6% do sexo masculino); destes, 28 (50,9%) morreram. Observamos positividade para IgA e IgG (IgA+/IgG+) em 90,9% e 80% dos pacientes, respectivamente. A maior frequência de IgA+ foi verificada nas semanas 2 e 3, e a maior frequência de IgG+, nas semanas 3 e 4. É importante observar que os pacientes que morreram apresentaram títulos de IgA mais baixos nas primeiras duas semanas (p < 0,05); no entanto, um aumento significativo na concentração de IgA foi observado nas semanas subsequentes. Por fim, identificamos correlações significativas entre os valores de Ct e imunoglobulinas; tanto IgA quanto IgG foram correlacionadas com Ct N2 em pacientes que morreram. Conclusão: Nossos resultados sugerem que títulos mais baixos de IgA no início da Covid-19 - que estão associados a valores mais baixos de Ct - podem indicar pacientes com risco elevado de evoluir para óbito.