RESUMO
Influenza A virus (IAV) is the most common infectious agent in humans, and infects approximately 10-20% of the world's population, resulting in 3-5 million hospitalizations per year. A scientific literature search was performed using the PubMed database and the Medical Subject Headings (MeSH) "Influenza A H1N1" and "Genetic susceptibility". Due to the amount of information and evidence about genetic susceptibility generated from the studies carried out in the last influenza A H1N1 pandemic, studies published between January 2009 to May 2020 were considered; 119 papers were found. Several pathways are involved in the host defense against IAV infection (innate immune response, pro-inflammatory cytokines, chemokines, complement activation, and HLA molecules participating in viral antigen presentation). On the other hand, single nucleotide polymorphisms (SNPs) are a type of variation involving the change of a single base pair that can mean that encoded proteins do not carry out their functions properly, allowing higher viral replication and abnormal host response to infection, such as a cytokine storm. Some of the most studied SNPs associated with IAV infection genetic susceptibility are located in the FCGR2A, C1QBP, CD55, and RPAIN genes, affecting host immune responses through abnormal complement activation. Also, SNPs in IFITM3 (which participates in endosomes and lysosomes fusion) represent some of the most critical polymorphisms associated with IAV infection, suggesting an ineffective virus clearance. Regarding inflammatory response genes, single nucleotide variants in IL1B, TNF, LTA IL17A, IL8, IL6, IRAK2, PIK3CG, and HLA complex are associated with altered phenotype in pro-inflammatory molecules, participating in IAV infection and the severest form of the disease.
Assuntos
Predisposição Genética para Doença , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/genética , Animais , Humanos , Imunidade Inata , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Replicação ViralRESUMO
BACKGROUND: Hypercytokinemia is the main immunopathological mechanism contributing to a more severe clinical course in influenza A (H1N1) virus infections. Most patients infected with the influenza A (H1N1) pdm09 virus had increased systemic levels of pro-inflammatory cytokines; including interleukin IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α). We propose that single-nucleotide polymorphisms (SNPs) in the promoter regions of pro-inflammatory genes are associated with the severity of influenza A (H1N1) pdm09 virus infection. METHODS: 145 patients with influenza A (H1N1) (pA/H1N1), 133 patients with influenza-like illness (ILI), and 360 asymptomatic healthy contacts (AHCs) were included. Eleven SNPs were genotyped in six genes (TNF, LT, IL1B, IL6, CCL1, and IL8) using real-time PCR; the ancestral genotype was used for comparison. Genotypes were correlated with 27 clinical severity variables. Ten cytokines (GM-CSF, TNF-α, IL-2, IL-1ß, IL-6, IL-8, IFN-γ, IL-10, IL-5, and IL-4) were measured on a Luminex 100. RESULTS: The IL6 rs1818879 (GA) heterozygous genotype was associated with severe influenza A (H1N1) virus infection (odds ratio [OR] = 5.94, 95% confidence interval [CI] 3.05-11.56), and two IL1B SNPs, rs16944 AG and rs3136558 TC, were associated with a decreased risk of infection (OR = 0.52 and OR = 0.51, respectively). Genetic susceptibility was determined (pA/H1N1 vs. AHC): the LTA rs909253 TC heterozygous genotype conferred greater risk (OR = 1.9), and a similar association was observed with the IL1B rs3136558 CC genotype (OR = 1.89). Additionally, severely ill patients were compared with moderately ill patients. The TNF-238 GA genotype was associated with an increased risk of disease severity (OR = 16.06, p = 0.007). Compared with ILIs, patients with severe pA/H1N1 infections exhibited increased serum IL-5 (pâ<0.001) and IL-6 (pâ = â0.007) levels. CONCLUSIONS: The TNF gene was associated with disease severity, whereas IL1B and IL6 SNPs were associated with influenza A (H1N1) virus infection.
Assuntos
Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/genética , Influenza Humana/virologia , Interleucina-1beta/genética , Interleucina-6/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
INTRODUCTION: The frequency and mortality of the pandemic caused by influenza A(H1N1)pdm09 might have been underestimated, especially in developing countries. This study was designed to quantify the possible underestimation of pandemic influenza mortality and evaluate the concordance between the data reported for A(H1N1)pdm09 mortality and the causes of death reported during the pandemic period of April 2009 to February 2010. METHODOLOGY: The death certificates of 754 confirmed cases of A(H1N1)pdm09 infection were included in the study. Data was analyzed using the United States Centers for Disease Control and Prevention's statistical model accounts for the variability in the proportion at each step using the Monte Carlo probabilistic model sampled from a uniform probability distribution. RESULTS: A total of 1,969 deaths were estimated, with an estimated lethality of 5.53 per 100,000 (range, 3.5-8.76 per 100,000) in contrast with the 754 deaths and a lethality of 1.98 per 100,000 infected patients officially reported. In 631 of 754 (83.7%) death certificates from A(H1N1)pdm09 influenza-positive patients, influenza was not mentioned as a cause of death. CONCLUSIONS: It is possible that the mortality of the pandemic was three times higher than officially reported in Mexico. One source of error that could explain this underestimation is in the completion of death certificates, because in > 80% of confirmed cases of infection with influenza virus, it was not reported as the cause of death.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana/mortalidade , Pandemias , Adolescente , Adulto , Idoso , Causas de Morte , Criança , Pré-Escolar , Comorbidade , Atestado de Óbito , Países em Desenvolvimento , Feminino , Humanos , Lactente , Recém-Nascido , Influenza Humana/virologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Some patients have a greater response to viral infection than do others having a similar level of viral replication. Hypercytokinemia is the principal immunopathological mechanism that contributes to a severer clinical course in cases of influenza A/H1N1. The benefit produced, or damage caused, by these cytokines in severe disease is not known. The genes that code for these molecules are polymorphic and certain alleles have been associated with susceptibility to various diseases. The objective of the present study was to determine whether there was an association between polymorphisms of TNF, LTA, IL1B, IL6, IL8, and CCL1 and the infection and severity of the illness caused by the pandemic A/H1N1 in Mexico in 2009. METHODS: Case-control study. The cases were patients confirmed with real time PCR with infection by the A/H1N1 pandemic virus. The controls were patients with infection like to influenza and non-familial healthy contacts of the patients with influenza. Medical history and outcome of the disease was registered. The DNA samples were genotyped for polymorphisms TNF rs361525, rs1800629, and rs1800750; LTA rs909253; IL1B rs16944; IL6 rs1818879; IL8 rs4073; and CCL1 rs2282691. Odds ratio (OR) and the 95% confidence interval (95% CI) were calculated. The logistic regression model was adjusted by age and severity of the illness in cases. RESULTS: Infection with the pandemic A/H1N1 virus was associated with the following genotypes: TNF rs361525 AA, OR = 27.00; 95% CI = 3.07-1248.77); LTA rs909253 AG (OR = 4.33, 95% CI = 1.82-10.32); TNF rs1800750 AA (OR = 4.33, 95% CI = 1.48-12.64); additionally, LTA rs909253 AG showed a limited statistically significant association with mortality (p = 0.06, OR = 3.13). Carriers of the TNF rs1800629 GA genotype were associated with high levels of blood urea nitrogen (p = 0.05); those of the TNF rs1800750 AA genotype, with high levels of creatine phosphokinase (p=0.05). The IL1B rs16944 AA genotype was associated with an elevated number of leukocytes (p <0.001) and the IL8 rs4073 AA genotype, with a higher value for PaO2 mm Hg. CONCLUSION: The polymorphisms of genes involved in the inflammatory process contributed to the severity of the clinical behavior of infection by the pandemic influenza A/H1N1 virus.