TNFA and IL10 Polymorphisms and IL-6 and IL-10 Levels Influence Disease Severity in Influenza A(H1N1)pdm09 Virus Infected Patients

Cytokines are key modulators of immune response, and dysregulated production of proinflammatory and anti-inflammatory cytokines contributes to the pathogenesis of influenza A(H1N1)pdm09 virus infection. Cytokine production is impacted by single nucleotide polymorphisms (SNPs) in the genes coding for them. In the present study, SNPs in the IL6, TNFA, IFNG, IL17A, IL10, and TGFB were investigated for their association with disease severity and fatality in influenza A(H1N1)pdm09-affected patients with mild disease (n = 293) and severe disease (n = 86). Among those with severe disease, 41 patients had fatal outcomes. In a subset of the patients, levels of IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17 were assayed in the plasma for their association with severe disease. The frequency of TNFA rs1800629 G/A allele was significantly higher in severe cases and survived severe cases group compared to that of those with mild infection (OR with 95% for mild vs. severe cases 2.95 (1.52–5.73); mild vs. survived severe cases 4.02 (1.84–8.82)). IL10 rs1800896-rs1800872 G-C haplotype was significantly lower (OR with 95% 0.34 (0.12–0.95)), while IL10 rs1800896-rs1800872 G-A haplotype was significantly higher (OR with 95% 12.11 (2.23–76.96)) in fatal cases group compared to that of the mild group. IL-6 and IL-10 levels were significantly higher in fatal cases compared to that of survived severe cases. IL-6 levels had greater discriminatory power than IL-10 to predict progression to fatal outcome in influenza A(H1N1)pdm09 virus-infected patients. To conclude, the present study reports the association of TNFA and IL10 SNPs with severe disease in Influenza A(H1N1)pdm09 virus-infected subjects. Furthermore, IL-6 levels can be a potential biomarker for predicting fatal outcomes in Influenza A(H1N1)pdm09 virus infected subjects.

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Polymorphisms in Processing and Antigen Presentation-Related Genes and Their Association with Host Susceptibility to Influenza A/H1N1 2009 Pandemic in a Mexican Mestizo Population

Viruses ◽

10.3390/v12111224 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1224

Author(s):

Marco Antonio Ponce-Gallegos ◽

Aseneth Ruiz-Celis ◽

Enrique Ambrocio-Ortiz ◽

Gloria Pérez-Rubio ◽

Alejandra Ramírez-Venegas ◽

...

Keyword(s):

Influenza A ◽

Host Susceptibility ◽

Nucleotide Polymorphisms ◽

H1n1 Infection ◽

Single Nucleotide ◽

Mexican Mestizo ◽

Influenza A H1n1 ◽

Mexican Mestizo Population ◽

Reduced Risk

(1) Background: The influenza A/H1N1 pdm09 virus rapidly spread throughout the world. Despite the inflammatory and virus-degradation pathways described in the pathogenesis of influenza A virus (IAV) infection, little is known about the role of the single nucleotide polymorphisms (SNPs) in the genes involved in the processing and antigenic presentation-related mechanisms. (2) Methods: In this case-control study, we evaluated 17 SNPs in five genes (TAP1, TAP2, TAPBP, PSMB8, and PSMB9). One hundred and twenty-eight patients with influenza A/H1N1 infection (INF-P) and 111 healthy contacts (HC) were included; all of them are Mexican mestizo. (3) Results: In allele and genotype comparison, the rs241433/C allele (TAP2), as well as AG haplotype (rs3763365 and rs4148882), are associated with reduced risk for influenza A/H1N1 infection (p < 0.05). On the other hand, the rs2071888G allele (TAPBP) and GG haplotype (rs3763365 and rs9276810) are associated with a higher risk for influenza A/H1N1 infection. In addition, after adjustment for covariates, the association to a reduced risk for influenza A/H1N1 infection remains with rs241433/C allele (p < 0.0001, OR = 0.24, 95% CI = 0.13–0.43), and the association with TAPBP is also maintained with the G allele (p = 0.0095, OR = 1.89, 95% CI = 1.17–3.06) and GG genotype models (p < 0.05, OR = 2.18, 95% CI = 1.27–3.74). (4) Conclusion: The rs241433/C allele and AC genotype (TAP2) and the AG haplotype are associated with a reduced risk for influenza A/H1N1 infection. In addition, the rs2071888/G allele and GG genotype (TAPBP) and the GG haplotype are associated with a higher risk for developing influenza A/H1N1 infection in a Mexican mestizo population.

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Association of Single Nucleotide Polymorphisms inTNFAandIL10Genes with Disease Severity in Influenza A/H1N1pdm09 Virus Infections: A Study from Western India

Viral Immunology ◽

10.1089/vim.2018.0120 ◽

2018 ◽

Vol 31 (10) ◽

pp. 683-688 ◽

Cited By ~ 2

Author(s):

Manohar Lal Choudhary ◽

Kalichamy Alagarasu ◽

Urmila Chaudhary ◽

Samruddhi Kawale ◽

Prachi Malasane ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Disease Severity ◽

Influenza A ◽

Western India ◽

Nucleotide Polymorphisms ◽

Virus Infections ◽

Single Nucleotide

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Next-Generation Sequencing Analysis of the Within-Host Genetic Diversity of Influenza A(H1N1)pdm09 Viruses in the Upper and Lower Respiratory Tracts of Patients with Severe Influenza

mSphere ◽

10.1128/msphere.01043-20 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Ikuyo Takayama ◽

Binh Gia Nguyen ◽

Co Xuan Dao ◽

Thach The Pham ◽

Tuan Quoc Dang ◽

...

Keyword(s):

Genetic Diversity ◽

Next Generation Sequencing ◽

Lower Respiratory Tract ◽

Influenza A ◽

Severe Disease ◽

Pdm09 Virus ◽

Influenza A H1n1 ◽

Host Genetic ◽

Ha Protein ◽

Generation Sequencing

ABSTRACT The influenza A(H1N1)pdm09 virus emerged in April 2009 with an unusual incidence of severe disease and mortality, and currently circulates as a seasonal influenza virus. Previous studies using consensus viral genome sequencing data have overlooked the viral genomic and phenotypic diversity. Next-generation sequencing (NGS) may instead be used to characterize viral populations in an unbiased manner and to measure within-host genetic diversity. In this study, we used NGS analysis to investigate the within-host genetic diversity of influenza A(H1N1)pdm09 virus in the upper and lower respiratory samples from nine patients who were admitted to the intensive care unit (ICU). A total of 47 amino acid substitution positions were found to differ between the upper and lower respiratory tract samples from all patients. However, the D222G/N substitution in hemagglutinin (HA) protein was the only amino acid substitution common to multiple patients. Furthermore, the substitution was detected only in the six samples from the lower respiratory tract. Therefore, it is important to investigate influenza A(H1N1)pdm09 virus populations using multiple paired samples from the upper and lower respiratory tract to avoid overlooking potentially important substitutions, especially in patients with severe disease. IMPORTANCE The D222G/N substitution in the hemagglutinin (HA) protein of influenza A(H1N1)pdm09 virus has been reported to be associated with disease severity and mortality in numerous previous studies. In the present study, 75% of lower respiratory samples contained heterogeneous influenza populations that carried different amino acids at position 222 of the HA protein, whereas all upper respiratory samples only contained the wild-type 222D. These results suggest the influenza A(H1N1)pdm09 virus has diversified inside the host owing to differences in tissue specificity. In this study, the within-host genetic diversity of influenza A(H1N1)pdm09 virus was investigated for the first time using next-generation sequencing analysis of the viral whole-genome in samples extracted from the upper and lower respiratory tracts of patients with severe disease.

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Detection of H275Y Mutation Conferring Oseltamivir Drug Resistance in Influenza A (H1N1) pdm09 Virus

Journal of Pure and Applied Microbiology ◽

10.22207/jpam.15.3.34 ◽

2021 ◽

Author(s):

Khushbu Trivedi ◽

Bharti Malhotra ◽

Widhi Dubey ◽

Pratibha Sharma ◽

Farah Deeba ◽

...

Keyword(s):

Drug Resistance ◽

Influenza A ◽

Sanger Sequencing ◽

World Health ◽

Western India ◽

Nucleotide Polymorphisms ◽

Allelic Discrimination ◽

Pdm09 Virus ◽

Influenza A H1n1 ◽

H275y Mutation

In the treatment of influenza, Neuraminidase inhibitors (NAIs) (Oseltamivir and Zanamivir) play a major role. The emergence of variants of influenza A (H1N1) pdm09 virus resistant to Oseltamivir is a matter of great concern as it limits its usage. Therefore, vigilant monitoring for Oseltamivir-resistant viruses has been recommended by the World Health Organization (WHO). Our study aimed to screen the influenza A (H1N1) pdm09 virus for NAI drug resistance during the outbreak of 2015-16 in North-Western India. A total of 640 H1N1pdm09 virus-positive samples were screened for drug resistance to Oseltamivir by WHO allelic discrimination real-time RT-PCR protocol. The allelic discrimination PCR protocol can detect the presence of single nucleotide polymorphisms (SNPs), the H275Y mutation is detected by this method which causes resistance to Oseltamivir. Sanger sequencing of partial fragment of NA gene (fragment IV), of 90 samples were performed to confirm the presence of NA-H275Y mutation. Neuraminidase susceptibility of 20 randomly selected isolates to Oseltamivir was tested using NA inhibition chemiluminiscence based assay. Among 640 H1N1pdm09 positive samples tested, H275Y mutation was detected in one sample (0.15%) by PCR and confirmed by Sanger sequencing also. All the 20 isolates tested for NAI susceptibility by NA star assay were found to be sensitive to Oseltamivir. WHO allelic discrimination PCR is an easy, rapid and sensitive method for high-throughput detection of resistance to Oseltamivir. Systematic regular drug resistance surveillance of Influenza A is essential to monitor the emergence and spread of drug-resistant strains.

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Respiratory microbes detected in hospitalized adults with acute respiratory infections: associations between influenza A(H1N1)pdm09 virus and intensive care unit admission or fatal outcome in Vietnam (2015–2017)

BMC Infectious Diseases ◽

10.1186/s12879-021-05988-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Phuong Thai Truong ◽

Shinji Saito ◽

Ikuyo Takayama ◽

Hiroyuki Furuya ◽

Binh Gia Nguyen ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Influenza A ◽

Respiratory Infections ◽

Fatal Outcome ◽

H3n2 Virus ◽

Significance Level ◽

Icu Admission ◽

Pdm09 Virus ◽

Influenza A H1n1

Abstract Background Acute respiratory tract infection (ARI) is a leading cause of hospitalization, morbidity, and mortality worldwide. Respiratory microbes that were simultaneously detected in the respiratory tracts of hospitalized adult ARI patients were investigated. Associations between influenza A(H1N1)pdm09 virus (H1N1pdm) detection and intensive care unit (ICU) admission or fatal outcome were determined. Methods This prospective observational study was conducted between September 2015 and June 2017 at Bach Mai Hospital, Hanoi, Vietnam. Inclusion criteria were hospitalized patients aged ≥15 years; one or more of symptoms including shortness of breath, sore throat, runny nose, headache, and muscle pain/arthralgia in addition to cough and fever > 37.5 °C; and ≤ 10 days from the onset of symptoms. Twenty-two viruses, 11 bacteria, and one fungus in airway specimens were examined using a commercial multiplex real-time PCR assay. Associations between H1N1pdm detection and ICU admission or fatal outcome were investigated by univariate and multivariate logistic regression analyses. Results The total of 269 patients (57.6% male; median age, 51 years) included 69 ICU patients. One or more microbes were detected in the airways of 214 patients (79.6%). Single and multiple microbes were detected in 41.3 and 38.3% of patients, respectively. Influenza A(H3N2) virus was the most frequently detected (35 cases; 13.0%), followed by H1N1pdm (29 cases; 10.8%). Hematological disease was associated with ICU admission (p < 0.001) and fatal outcomes (p < 0.001) using the corrected significance level (p = 0.0033). Sex, age, duration from onset to sampling, or number of detected microbes were not significantly associated with ICU admission or fatal outcomes. H1N1pdm detection was associated with ICU admission (odds ratio [OR] 3.911; 95% confidence interval [CI] 1.671–9.154) and fatal outcome (OR 5.496; 95% CI 1.814–16.653) after adjusting for the confounding factors of comorbidities, bacteria/Pneumocystis jirovecii co-detection, and age. Conclusions H1N1pdm was associated with severe morbidity and death in adult patients hospitalized with respiratory symptoms. The diagnosis of subtype of influenza virus may be epidemiologically important.

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Role of tumor necrosis factor gene single nucleotide polymorphisms in the natural course of 2009 influenza A H1N1 virus infection

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2011.11.012 ◽

2012 ◽

Vol 16 (3) ◽

pp. e204-e208 ◽

Cited By ~ 26

Author(s):

Anastasia Antonopoulou ◽

Fotini Baziaka ◽

Thomas Tsaganos ◽

Maria Raftogiannis ◽

Pantelis Koutoukas ◽

...

Keyword(s):

Influenza A ◽

Tumor Necrosis ◽

H1n1 Virus ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Factor Gene ◽

Influenza A H1n1 ◽

Necrosis Factor ◽

H1n1 Virus Infection

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Role of the Host Genetic Susceptibility to 2009 Pandemic Influenza A H1N1

Viruses ◽

10.3390/v13020344 ◽

2021 ◽

Vol 13 (2) ◽

pp. 344

Author(s):

Gloria Pérez-Rubio ◽

Marco Antonio Ponce-Gallegos ◽

Bruno André Domínguez-Mazzocco ◽

Jaime Ponce-Gallegos ◽

Román Alejandro García-Ramírez ◽

...

Keyword(s):

Genetic Susceptibility ◽

Complement Activation ◽

Influenza A ◽

Infectious Agent ◽

Nucleotide Polymorphisms ◽

Medical Subject Headings ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Pubmed Database ◽

Influenza A H1n1

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.

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Observed association between the HA1 mutation D222G in the 2009 pandemic influenza A(H1N1) virus and severe clinical outcome, Norway 2009-2010

Eurosurveillance ◽

10.2807/ese.15.09.19498-en ◽

2010 ◽

Vol 15 (9) ◽

Cited By ~ 133

Author(s):

A Kilander ◽

R Rykkvin ◽

S G Dudman ◽

O Hungnes

Keyword(s):

Clinical Outcome ◽

Causal Relationship ◽

Pandemic Influenza ◽

Influenza A ◽

H1n1 Virus ◽

Severe Disease ◽

Specific Mutation ◽

Mild Disease ◽

Influenza A H1n1

Infection with the recently emerged pandemic influenza A(H1N1) virus causes mild disease in the vast majority of cases, but sporadically also very severe disease. A specific mutation in the viral haemagglutinin (D222G) was found with considerable frequency in fatal and severe cases in Norway, but was virtually absent among clinically mild cases. This difference was statistically significant and our data are consistent with a possible causal relationship between this mutation and the clinical outcome.

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Clinical predictors of disease severity during the 2009–2010 A(HIN1) influenza virus pandemic in a paediatric population

Epidemiology and Infection ◽

10.1017/s0950268815000114 ◽

2015 ◽

Vol 143 (14) ◽

pp. 2939-2949 ◽

Cited By ~ 16

Author(s):

M. N. GARCIA ◽

D. C. PHILPOTT ◽

K. O. MURRAY ◽

A. ONTIVEROS ◽

P. A. REVELL ◽

...

Keyword(s):

Influenza Virus ◽

Disease Severity ◽

Influenza A ◽

Severe Disease ◽

Paediatric Population ◽

The United States ◽

Clinical Predictors ◽

Presenting Symptoms ◽

Severe Influenza ◽

Influenza A H1n1

SUMMARYA novel influenza virus emerged in the United States in spring 2009, rapidly becoming a global pandemic. Children were disproportionally affected by the novel influenza A(H1N1) pandemic virus [A(H1N1)pdm]. This retrospective electronic medical record review study aimed to identify clinical predictors of disease severity of influenza A(HIN1)pdm infection in paediatric patients. Disease severity was defined on an increasing three-level scale from non-hospitalized, hospitalized, and admitted to the intensive care unit (ICU). From April 2009 to June 2010, 696 children presented to Texas Children's Hospital's emergency department, 38% were hospitalized, and 17% were admitted to the ICU. Presenting symptoms associated with severe influenza were dyspnoea [odds ratio (OR) 5·82], tachycardia (OR 2·61) and fatigue (OR 1·96). Pre-existing health conditions associated with disease severity included seizure disorder (OR 4·71), obesity (OR 3·28), lung disease (OR 2·84), premature birth (OR 2·53), haematological disease (OR 2·22), and developmental delay (OR 2·20). According to model fitness tests, presenting symptoms were more likely to predict severe influenza than underlying medical conditions. However, both are important risk factors. Recognition of clinical characteristics associated with severe disease can be used for triaging case management of children during future influenza outbreaks.

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