Association of Polymorphisms of IL-6 Pathway Genes (IL6, IL6R and IL6ST) with COVID-19 Severity in an Amazonian Population.

Interleukin-6 has been recognized as a major role player in COVID-19 severity, being an important regulator of the cytokine storm. Hence, the evaluation of the influence of polymorphisms in key genes of the IL-6 pathway, namely IL6, IL6R, and IL6ST, may provide valuable prognostic/predictive markers for COVID-19. The present cross-sectional study genotyped three SNPs (rs1800795, rs2228145, and rs7730934) at IL6. IL6R and IL6ST genes, respectively, in 227 COVID-19 patients (132 hospitalized and 95 non-hospitalized). Genotype frequencies were compared between these groups. As a control group, published data on gene and genotype frequencies were gathered from published studies before the pandemic started. Our major results point to an association of the IL6 C allele with COVID-19 severity. Moreover, IL-6 plasmatic levels were higher among IL6 CC genotype carriers. Additionally, the frequency of symptoms was higher at IL6 CC and IL6R CC genotypes. In conclusion, the data suggest an important role of IL6 C allele and IL6R CC genotype on COVID-19 severity, in agreement with indirect evidence from the literature about the association of these genotypes with mortality rates, pneumonia, and heightening of protein plasmatic levels pro-inflammatory driven effects.

Polymorphisms in the MBL2 gene are associated with the plasma levels of MBL and the cytokines IL-6 and TNF-α in severe COVID-19.

Introduction: Mannose-binding lectin (MBL) promotes opsonization, favoring phagocytosis and activation of the complement system in response to different microorganisms, and may influence the synthesis of inflammatory cytokines. This study investigated the association of MBL2 gene polymorphisms with the plasma levels of MBL and inflammatory cytokines in COVID-19. Methods: Blood samples from 385 individuals (208 with acute COVID-19 and 117 post-COVID-19) were subjected to real-time PCR genotyping. Plasma measurements of MBL and cytokines were performed by enzyme-linked immunosorbent assay and flow cytometry, respectively. Results: The frequencies of the polymorphic MBL2 genotype (OO) and allele (O) were higher in patients with severe COVID-19 (p< 0.05). The polymorphic genotypes (AO and OO) were associated with lower MBL levels (p< 0.05). IL-6 and TNF-α were higher in patients with low MBL and severe COVID-19 (p< 0.05). No association of polymorphisms, MBL levels, or cytokine levels with long COVID was observed. Discussion: The results suggest that, besides MBL2 polymorphisms promoting a reduction in MBL levels and therefore in its function, they may also contribute to the development of a more intense inflammatory process responsible for the severity of COVID-19.

Antibody Response to the SARS-CoV-2 Spike and Nucleocapsid Proteins in Patients with Different COVID-19 Clinical Profiles.

The first case of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in Brazil was diagnosed on February 26, 2020. Due to the important epidemiological impact of COVID-19, the present study aimed to analyze the specificity of IgG antibody responses to the S1, S2 and N proteins of SARS-CoV-2 in different COVID-19 clinical profiles. This study enrolled 136 individuals who were diagnosed with or without COVID-19 based on clinical findings and laboratory results and classified as asymptomatic or as having mild, moderate or severe disease. Data collection was performed through a semistructured questionnaire to obtain demographic information and main clinical manifestations. IgG antibody responses to the S1 and S2 subunits of the spike (S) protein and the nucleocapsid (N) protein were evaluated using an enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. The results showed that among the participants, 87.5% (119/136) exhibited IgG responses to the S1 subunit and 88.25% (120/136) to N. Conversely, only 14.44% of the subjects (21/136) displayed S2 subunit responses. When analyzing the IgG antibody response while considering the different proteins of the virus, patients with severe disease had significantly higher antibody responses to N and S1 than asymptomatic individuals (p ≤ 0.0001), whereas most of the participants had low antibody titers against the S2 subunit. In addition, individuals with long COVID-19 showed a greater IgG response profile than those with symptomatology of a short duration. Based on the results of this study, it is concluded that levels of IgG antibodies may be related to the clinical evolution of COVID-19, with high levels of IgG antibodies against S1 and N in severe cases and in individuals with long COVID-19.

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome.

The duration and severity of COVID-19 are related to age, comorbidities, and cytokine synthesis. This study evaluated the impact of these factors on patients with clinical presentations of COVID-19 in a Brazilian cohort. A total of 317 patients diagnosed with COVID-19 were included; cases were distributed according to clinical status as severe (n=91), moderate (n=56) and mild (n=170). Of these patients, 92 had acute COVID-19 at sample collection, 90 had already recovered from COVID-19 without sequelae, and 135 had sequelae (long COVID syndrome). In the acute COVID-19 group, patients with the severe form had higher IL-6 levels (p=0.0260). In the post-COVID-19 group, there was no significant difference in cytokine levels between groups with different clinical conditions. In the acute COVID-19 group, younger patients had higher levels of TNF-α, and patients without comorbidities had higher levels of TNF-α, IL-4 and IL-2 (p<0.05). In contrast, patients over age 60 with comorbidities had higher levels of IL-6. In the post-COVID-19 group, subjects with long COVID-19 had higher levels of IL-17 and IL-2 (p<0.05), and subjects without sequelae had higher levels of IL-10, IL-6 and IL- 4 (p<0.05). Our results suggest that advanced age, comorbidities and elevated serum IL-6 levels are associated with severe COVID-19 and are good markers to differentiate severe from mild cases. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 and IL-10 appear to constitute a cytokine profile of long COVID-19, and these markers are potential targets for COVID-19 treatment and prevention strategies.

Cryptococcosis: Identification of Risk Areas in the Brazilian Amazon.

The Brazilian Amazon has a specific epidemiological profile for cryptococcosis, considering its social and economic inequality, health reality, and low access to health services. Furthermore, Brazil and Colombia have the highest cryptococcosis incidence rates in Latin America. In this study, we identified the areas of risk for cryptococcosis in the state of Pará in the Brazilian Amazon. This was an ecological study of patients admitted to a referral hospital from 2008 to 2018, aged 13 years or older, and of both sexes. The spatial distribution was determined using ArcGis 10.3.1 software. Cryptococcosis was confirmed in 272 cases. The incidence rate was 3.41 cases/100,000 inhabitants. Spatial distribution was concentrated in the Metropolitana de Belém, Nordeste Paraense, and Marajó mesoregions. The sociodemographic profile consisted of 62% men, aged between 24 and 34 years (36%), without completed secondary education (64.7%), and with occupations varying between agricultural activities (13.8%) and household activities (22%). The mean hospitalization time was 39 days; the prevalent clinical form was neurological (89.7%). The mortality rate among patients with cryptococcosis was up to 40%. Knowledge of the real magnitude of the disease in the Brazilian Amazon makes it possible to identify areas with the greatest risks and to propose control and epidemiological surveillance programs.

Cryptococcosis in the Amazon: A current overview and future perspectives.

The Amazon region or regional Amazon complex includes nine states of Brazil with an area of around 5.1 million km, which is almost 60% of the country's territory. The sanitary conditions in this region are reflected by illness resulting from substandard living conditions and limited access to prevention measures and health care, in addition to the epidemiological profile of cryptococcosis. This article aims to provide a comprehensive review of the literature on cryptococcosis in the Amazon region and its future prospects. Thus, the present study searched the Scientific Electronic Library Online, Latin American and Caribbean Health Sciences Literature, Medical Literature Analysis and Retrieval System, Virtual Health Library, PubMed, and CAPES Periodical Portal for studies on cryptococcosis in the Amazon region, with an established search period of 1999 to 2018, using the search terms "Cryptococcus," "cryptococcosis," and "Amazon" with the Boolean operator AND. Out of 275 articles found, 29 were selected according to the inclusion criteria and were categorized into clinical and environmental studies. Analysis of these studies verified the increased occurrence of infection by Cryptococcus gattii at younger ages in the supposedly immunocompetent and the predominance of C. neoformans in HIV-positive patients. No occurrence of Cryptococcus laurentii infection has been identified in the literature. The regional endemic molecular types included VNI, VNII, and VGII. Similarly, the strain sequence type (ST) allelic profiles, including ST5, 7, 20, and 264-268, were identified in C. gattii isolated in Amazonas state. VNI isolates are a genetically monotypic group, with ST93 being highly important in HIV individuals. In urban environments, cryptococcosis agents were isolated in samples collected fromtrees, wooden houses, and dove excrement. Due to the absence of a control program and specific epidemiological surveillance for the primary disease, cryptococcal meningitis has become a failure parameter in the treatment of HIV/AIDS patients. The findings of the present study underscore the need for programs to track cryptococcal antigens and identify high-risk populations in order to reduce the morbimortality of this disease.