A Multicenter, Controlled Human Infection Study of Influenza A(H1N1)pdm09 in Healthy Adults.

BACKGROUND: We evaluated the associations between baseline influenza virus-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers and subsequent symptomatic influenza virus infection in a controlled human infection study. METHODS: We inoculated unvaccinated healthy adults aged 18-49 years with an influenza A/California/04/2009/H1N1pdm-like virus (NCT04044352). We collected serial safety labs, serum for HAI and MN, and nasopharyngeal swabs for reverse-transcription polymerase chain reaction (RT-PCR) testing. Analyses used the putative seroprotective titer of ≥40 for HAI and MN. The primary clinical outcome was mild-to-moderate influenza disease (MMID), defined as ≥1 postchallenge positive qualitative RT-PCR test with a qualifying symptom/clinical finding. RESULTS: Of 76 participants given influenza virus challenge, 54 (71.1%) experienced MMID. Clinical illness was generally very mild. MMID attack rates among participants with baseline titers ≥40 by HAI and MN were 64.9% and 67.9%, respectively, while MMID attack rates among participants with baseline titers <40 by HAI and MN were 76.9% and 78.3%, respectively. The estimated odds of developing MMID decreased by 19% (odds ratio, 0.81 [95% confidence interval, .62-1.06]; P = .126) for every 2-fold increase in baseline HAI. There were no significant adverse events. CONCLUSIONS: We achieved a 71.1% attack rate of MMID. High baseline HAI and MN were associated with protection from illness. Clinical Trials Registration. NCT04044352.

The Immunosuppressive Roles of PD-L1 during Influenza A Virus Infection.

The clinical benefits of targeting programmed death-ligand 1 (PD-L1) in various cancers represent a strategy for the treatment of immunosuppressive diseases. Here, it was demonstrated that the expression levels of PD-L1 in cells were greatly upregulated in response to H1N1 influenza A virus (IAV) infection. Overexpression of PD-L1 promoted viral replication and downregulated type-I and type-III interferons and interferon-stimulated genes. Moreover, the association between PD-L1 and Src homology region-2, containing protein tyrosine phosphatase (SHP2), during IAV/H1N1 infection was analyzed by employing the SHP2 inhibitor (SHP099), siSHP2, and pNL-SHP2. The results showed that the expressions of PD-L1 mRNA and protein were decreased under SHP099 or siSHP2 treatment, whereas the cells overexpressing SHP2 exhibited the opposite effects. Additionally, the effects of PD-L1 on the expression of p-ERK and p-SHP2 were investigated in PD-L1-overexpressed cells following WSN or PR8 infection, determining that the PD-L1 overexpression led to the decreased expression of p-SHP2 and p-ERK induced by WSN or PR8 infection. Taken together, these data reveal that PD-L1 could play an important role in immunosuppression during IAV/H1N1 infection; thus, it may serve as a promising therapeutic target for development of novel anti-IAV drugs.

Influenza A(H1N1)pdm09 But Not A(H3N2) Virus Infection Induces Durable Seroprotection: Results From the Ha Nam Cohort.

BACKGROUND: The extent to which influenza recurrence depends upon waning immunity from prior infection is undefined. We used antibody titers of Ha-Nam cohort participants to estimate protection curves and decay trajectories. METHODS: Households (270) participated in influenza-like-illness (ILI) surveillance and provided blood at intervals spanning laboratory-confirmed virus transmission. Sera were tested in hemagglutination inhibition assay. Infection was defined as influenza virus-positive ILI and/or seroconversion. Median protective titers were estimated using scaled-logistic regression to model pretransmission titer against infection status in that season, limiting analysis to households with infection(s). Titers were modelled against month since infection using mixed-effects linear regression to estimate decay and when titers fell below protection thresholds. RESULTS: From December 2008-2012, 295 and 314 participants were infected with H1N1pdm09-like and A/Perth/16/09-like (H3N2Pe09) viruses, respectively. The proportion protected rose more steeply with titer for H1N1pdm09 than for H3N2Pe09, and estimated 50% protection titers were 19.6 and 37.3, respectively. Postinfection titers started higher against H3N2Pe09 but decayed more steeply than against H1N1pdm09. Seroprotection was estimated to be sustained against H1N1pdm09 but to wane by 8-months for H3N2Pe09. CONCLUSIONS: Estimates indicate that infection induces durable seroprotection against H1N1pdm09 but not H3N2Pe09, which could in part account for the younger age of A(H1N1) versus A(H3N2) cases.

Human Infection with Eurasian Avian-Like Swine Influenza A(H1N1) Virus, the Netherlands, September 2019.

We report a zoonotic infection of a pig farmer in the Netherlands with a Eurasian avian-like swine influenza A(H1N1) virus that was also detected in the farmed pigs. Both viruses were antigenically and genetically characterized. Continued surveillance of swine influenza A viruses is needed for risk assessment in humans and swine.

Oseltamivir Resistance in Severe Influenza A(H1N1)pdm09 Pneumonia and Acute Respiratory Distress Syndrome: A French Multicenter Observational Cohort Study.

In a multicenter cohort study including 22 oseltamivir-treated patients with influenza A(H1N1)pdm09 acute respiratory distress syndrome, prevalence of the H275Y substitution in the neuraminidase, responsible for highly reduced sensitivity to oseltamivir, was 23%. Patients infected with the H275Y mutant virus had higher day 28 mortality than others (80% vs 12%; P = .011).

Change in risk for narcolepsy over time and impact of definition of onset date following vaccination with AS03 adjuvanted pandemic A/H1N1 influenza vaccine (Pandemrix) during the 2009 H1N1 influenza pandemic.

PURPOSE: To estimate risk for narcolepsy in defined time windows following exposure to adjuvanted A(H1N1) pandemic vaccine (Pandemrix) and impact of different definitions of index date for the narcolepsy diagnosis. METHODS: Vaccine exposure in approximately 30% of the Swedish population in 2009 was linked to information on narcolepsy diagnosis retrieved from the national patient registry. Cases were verified by a systematic chart review. Poisson regression was used to compare incidence in defined time windows following vaccination. RESULTS: Of 266 cases of narcolepsy identified, 25% (66/266) were prevalent cases with symptom onset documented before vaccine exposure. Incident cases had a median time interval between first symptom and the date recorded in the patient registry of 64 weeks (IQR 39-107) when vaccinated (N = 182) and 65 weeks (IQR 51-72) when unvaccinated (N = 16). With first symptom defining index date, the adjusted risk for narcolepsy in younger patients was increased 14 times during the first year after vaccination, three times elevated the second year, but with no detectable increased risk more than 2 years after vaccination exposure. Using the index date from the patient registry, the adjusted increase in risk was about seven times elevated for all three time intervals. CONCLUSIONS: The magnitude of the estimated increased risk for narcolepsy following exposure to the A(H1N1) pandemic vaccine is highly dependent on the method used to determine the index date for disease onset. The sometimes very long and potentially variable interval from first symptom to a health care registry diagnosis complicates estimations of risk.

PANDEMIC INFLUENZA A (H1N1) 2009 PRESENTING AS A MILD DISEASE IN CHILDREN IN A CROATIAN CLINICAL CENTRE.

Pandemic influenza A virus (H1N1) 2009 causes a disease that is epidemiologically and clinically not significantly different from seasonal influenza, but there are differences. The aim of the study was to display and compare epidemiological and clinical characteristics of pandemic influenza in children. At Dr. Fran Mihaljevic University Hospital for Infectious Diseases in Zagreb, in the first two seasons, the incidence of pandemic influenza virus A (H1N1) in particular was exhaustively analyzed only in patients with laboratory-confirmed pandemic influenza A virus (H1N1) 2009. In hospitalized children with documented influenza pandemic, moderate form of the disease predominated, which ultimately meant shorter hospital stay and fewer complications. Otitis media was the rarest complication in children in both seasons. In conclusion, children younger than 5 years, especially boys, were vulnerable groups for pandemic influenza, presenting as a mild disease with low mortality and few complications. Most of the affected children with influenza did not have important risk factors such as asthma and obesity, highlighted by other authors as significant risk factors.

Influenza and risk of later celiac disease: a cohort study of 2.6 million people.

OBJECTIVES: Influenza has been linked to autoimmune conditions, but its relationship to subsequent celiac disease (CD) is unknown. Our primary aim was to determine the risk of CD after influenza. A secondary analysis examined the risk of CD following pandemic influenza vaccination. METHODS: This nationwide register-based cohort study included 2,637,746 Norwegians (born between 1967-2013) followed during 2006-2014 with information on influenza diagnosed in primary or non-primary care, pandemic vaccination (Pandemrix), and subsequent CD. Cox regression yielded hazard ratios adjusted (HR) for socio-demographic characteristics and earlier healthcare use. RESULTS: During 13,011,323 person-years of follow-up 7321 individuals were diagnosed with CD (56/100,000 person-years). There were 351,666 individuals diagnosed with influenza, including 82,980 during the 2009-2010 pandemic, and 969,968 individuals were vaccinated. Compared with participants without influenza, who had a CD incidence of 55/100,000 person-years, those diagnosed with seasonal and pandemic influenza had a rate of 68 and 78, per 100,000 person-years, respectively. The HR for CD was 1.29 (95%CI, 1.21-1.38) after seasonal influenza and 1.29 (95%CI, 1.15-1.44) after pandemic influenza; HRs remained significantly increased one year after exposure, when restricted to laboratory-confirmed influenza, and after multivariate adjustments. The reverse association, i.e., risk of influenza after CD, was not significant (HR 1.05; 95%CI, 0.98-1.12). The HR for CD after pandemic vaccination was 1.08 (95%CI, 1.03-1.14). CONCLUSION: A positive association with influenza diagnosis is consistent with the hypothesis that infections may play a role in CD development. We could neither confirm a causal association with pandemic vaccination, nor refute entirely a small excess risk.

Distribution of influenza virus types by age using case-based global surveillance data from twenty-nine countries, 1999-2014.

BACKGROUND: Influenza disease burden varies by age and this has important public health implications. We compared the proportional distribution of different influenza virus types within age strata using surveillance data from twenty-nine countries during 1999-2014 (N=358,796 influenza cases). METHODS: For each virus, we calculated a Relative Illness Ratio (defined as the ratio of the percentage of cases in an age group to the percentage of the country population in the same age group) for young children (0-4 years), older children (5-17 years), young adults (18-39 years), older adults (40-64 years), and the elderly (65+ years). We used random-effects meta-analysis models to obtain summary relative illness ratios (sRIRs), and conducted meta-regression and sub-group analyses to explore causes of between-estimates heterogeneity. RESULTS: The influenza virus with highest sRIR was A(H1N1) for young children, B for older children, A(H1N1)pdm2009 for adults, and (A(H3N2) for the elderly. As expected, considering the diverse nature of the national surveillance datasets included in our analysis, between-estimates heterogeneity was high (I2>90%) for most sRIRs. The variations of countries' geographic, demographic and economic characteristics and the proportion of outpatients among reported influenza cases explained only part of the heterogeneity, suggesting that multiple factors were at play. CONCLUSIONS: These results highlight the importance of presenting burden of disease estimates by age group and virus (sub)type.

Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation.

We explored age-dependent patterns in haemagglutination inhibition (HI) titre to seasonal [1956 A(H1N1), 1977 A(H1N1), 2007 A(H1N1)] and pandemic [A(H1N1)pdm09] influenza strains using serological data collected from an adult French influenza cohort. Subjects were recruited by their general practitioners from 2008 to 2009 and followed until 2010. We explored age-related differences between strain-specific HI titres using 1053 serological samples collected over the study period from 398 unvaccinated subjects. HI titres against the tested seasonal and pandemic strains were determined using the HI technique. Geometric mean titres (GMTs) were estimated using regression models for interval-censored data. Generalized additive mixed models were fit to log-transformed HI estimates to study the relationship between HI titre and age (age at inclusion and/or age at initial strain circulation). GMT against one strain was consistently highest in the birth cohort exposed to that strain during childhood, with peak titres observed in subjects aged 7-8 years at the time of initial strain circulation. Our results complete previous findings on influenza A(H3N2) strains and identify a strain-dependent relationship between HI titre and age at initial strain circulation.

Awareness about swine flu/H1N1 influenza virus among the tertiary population of Lahore, Pakistan.

The present study was designed to assess the Knowledge, Attitude and Practices (KAP) of the parents of b-thalassaemia children (410) selected from public (73.2%) and private (26.8%) thalassaemia centers of Rawalpindi-Islamabad. Qualitative and quantitative approaches were used to collect the data, which was analyzed by using SPSS. Majority of the respondents (70%) were rural young parents with no knowledge of thalassaemia before marriage. However, now 81.2% were aware about this. Majority of the respondents (89%) had the knowledge about premarital screening, 86.1% were opposed to intermarriages of carrier and 57% believed that if carrier got married then prenatal diagnosis or Chorionic villus sampling test is necessary. About 76.8% of the couples were screened and 42.2% had an experience of Chorionic villus sampling among which 20% abortions were reported. Overall 82% parents had received genetic counselling. The present study suggests that parent's regular visits and genetic counseling at thalassaemia centers have played important role about awareness.

Guillain-Barré syndrome following the 2009 pandemic monovalent and seasonal trivalent influenza vaccination campaigns in Spain from 2009 to 2011: outcomes from active surveillance by a neurologist network, and records from a country-wide hospital discharge database.

BACKGROUND: Studies have shown a slight excess risk in Guillain-Barré syndrome (GBS) incidence associated with A(H1N1)pdm09 vaccination campaign and seasonal trivalent influenza vaccine immunisations in 2009-2010. We aimed to assess the incidence of GBS as a potential adverse effect of A(H1N1)pdm09 vaccination. METHODS: A neurologist-led network, active at the neurology departments of ten general hospitals serving an adult population of 4.68 million, conducted GBS surveillance in Spain in 2009-2011. The network, established in 1996, carried out a retrospective and a prospective study to estimate monthly alarm thresholds in GBS incidence and tested them in 1998-1999 in a pilot study. Such incidence thresholds additionally to observation of GBS cases with immunisation antecedent in the 42 days prior to clinical onset were taken as alarm signals for 2009-2011, since November 2009 onwards. For purpose of surveillance, in 2009 we updated both the available centres and the populations served by the network. We also did a retrospective countrywide review of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis from January 2009 to December 2011. RESULTS: Among 141 confirmed of 148 notified cases of GBS or Miller-Fisher syndrome, Brighton 1-2 criteria in 96 %, not a single patient was identified with clinical onset during the 42-day time interval following A(H1N1)pdm09 vaccination. In contrast, seven cases were seen during a similar period after seasonal campaigns. Monthly incidence figures did not, however, exceed the upper 95 % CI limit of expected incidence. A retrospective countrywide review of the registry of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis did not suggest higher admission rates in critical months across the period December 2009-February 2010. CONCLUSIONS: Despite limited power and underlying reporting bias in 2010-2011, an increase in GBS incidence over background GBS, associated with A(H1N1)pdm09 monovalent or trivalent influenza immunisations, appears unlikely.

Severity of influenza A(H1N1) illness and emergence of D225G variant, 2013-14 influenza season, Florida, USA.

Despite a regional decline in influenza A(H1N1)pdm09 virus infections during 2013-14, cases at a Florida hospital were more severe than those during 2009-10. Examined strains had a hemagglutinin polymorphism associated with enhanced binding to lower respiratory tract receptors. Genetic changes in this virus must be monitored to predict the effect of future pandemic viruses.

Non-convulsive seizures in children with infection-related altered mental status.

BACKGROUND: In the intensive care unit, the use of continuous electroencephalography (cEEG) in children with altered mental status often results in the detection of non-convulsive seizures (NCS). Children with influenza can occasionally display altered mental status, but the prevalence of NCS in children with influenza with altered mental status is yet to be determined. This study determined the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection. METHODS: We retrospectively reviewed admissions to the pediatric intensive care unit between September 2009 and February 2010 and confirmed the presence of NCS on cEEG in children with influenza A(H1N1)pdm09 and with altered mental status. RESULTS: Of the 15 patients (aged 41-159 months old), NCS was identified on cEEG in five children (33%). CONCLUSIONS: Approximately one-third of the children infected with influenza A(H1N1)pdm09 with altered mental status had NCS. Further research is needed to determine if the detection and management of NCS improve outcome in these children.

Tumefactive acute disseminated encephalomyelitis complicating human swine influenza (H1N1).

This report illustrates an adult patient presenting with tumefactive acute disseminated encephalomyelitis complicating human swine influenza. Its presentation, diagnosis, investigation findings, course, and response to treatment are discussed herein.

Molecular characterization and evolutionary dynamics of influenza A(H1N1) strains isolated from 2015 to 2017 in North India.

Background and Objectives: The influenza A(H1N1) virus is known for large outbreaks, epidemics and pandemics worldwide owing to its genome plasticity which evolves constantly. In the year 2015 and then in 2017, India witnessed an upsurge in cases. Materials and Methods: The study was carried out in this period (2015-2017) with samples from 5 states across north India. The hemagglutinin 1 (HA1) and non-structural 1 (NS1) gene segments of the viral genome were characterised by phylogenetic analysis, selection pressure analysis, prediction of potential glycosylation sites and phylodynamic analysis of the study strains. Results: The study strains belonged to genogroup 6B. A total of 12 mutations were observed, half of which were located on the key receptor binding region of the HA1 protein. Established virulence markers D222G, S183P were observed in 2017 samples. Acquisition of an extra glycosylation site was observed in few strains from 2017 and 2016. Selection pressure analysis found the average dN/dS (v) ratio of 0.2106 and few codon sites in particular showed significant evidence of being under negative selection. Conclusion: The genogroup 6B continues to be the dominant circulating strain in Indian subcontinent region however the presence of pathogenic mutations in the 2017 strains from north India underlines the importance of continued molecular surveillance.

The recommendations and the way forward to fight human infections caused by influenza A (H1N1) in Brazil.

Many recent outbreaks of influenza A (H1N1) in the world, especially in Brazil, it has become clear that the severity of the disease is not known in the same form. On Wednesday, June 7, 2023, Brazil notified the WHO of a fatal case of human infection with a variant of the influenza A(H1N1) virus of swine origin, this case was confirmed in a laboratory in the region of the interior state of Paraná. This is the first human infection caused by an influenza A (H1N1) virus reported in 2023 nationwide in Brazil. To mitigate H1N1 flu in Brazil, we urge the Brazillian government through its Ministry of Health to improve on mass awareness about the signs and symptoms of H1N1 flu among the Brazillians. The Brazillian government should also implement the One Health approach towards the control of H1N1 flu in Brazil, as we believe that these recommendations would go a long way in preventing future cases and the spread of H1N1 flu in Brazil. This article aims to present the clinical presentations of the H1N1 flu and the implications, recommendations and the way forward to protect the Brazilian population against the H1N1 flu.

Novel reassortant influenza A(H1N2) virus derived from A(H1N1)pdm09 virus isolated from swine, Japan, 2012.

We isolated a novel influenza virus A(H1N2) strain from a pig on January 13, 2012, in Gunma Prefecture, Japan. Phylogenetic analysis showed that the strain was a novel type of double-reassortant virus derived from the swine influenza virus strains H1N1pdm09 and H1N2, which were prevalent in Gunma at that time.

Clinical misdiagnosis of influenza infection with a confusing clinical course: A case report.

A 32-year-old woman with a history of hypothyroidism and major depressive disorder was admitted with severe weakness and somnolence. She had tachycardia and hypotension, indicative of severe dehydration, and was treated with a vasopressor and sodium bicarbonate, but her clinical manifestations deteriorated. A high-resolution computed tomography (HRCT) scan showed a patchy ground glass appearance with interlobular septal thickening, suggesting pneumonia. Reverse transcription-polymerase chain reaction (RT-PCR) was requested for the influenza A virus (IAV), which was positive. The patient was treated with oseltamivir and discharged with improved clinical symptoms.

Acute necrotising encephalopathy: A rare complication providing a clue for the outbreak of H1N1 among medical students in Kanpur, India.

Kanpur, India, recently witnessed an outbreak of undifferentiated febrile illness among medical students. Several students developed high-grade fever with altered sensorium within 2-3 days after the index case. Surprisingly, this outbreak coincided with the death of several pigs in the vicinity. Acute necrotising encephalitis, although rare, was noted in some patients. When correlated with each other, all of these incidents were suggestive of an outbreak of H1N1.