Characterizing the Countrywide Epidemic Spread of Influenza A(H1N1)pdm09 Virus in Kenya between 2009 and 2018

The spatiotemporal patterns of spread of influenza A(H1N1)pdm09 viruses on a countrywide scale are unclear in many tropical/subtropical regions mainly because spatiotemporally representative sequence data are lacking. We isolated, sequenced, and analyzed 383 A(H1N1)pdm09 viral genomes from hospitalized patients between 2009 and 2018 from seven locations across Kenya. Using these genomes and contemporaneously sampled global sequences, we characterized the spread of the virus in Kenya over several seasons using phylodynamic methods. The transmission dynamics of A(H1N1)pdm09 virus in Kenya were characterized by (i) multiple virus introductions into Kenya over the study period, although only a few of those introductions instigated local seasonal epidemics that then established local transmission clusters, (ii) persistence of transmission clusters over several epidemic seasons across the country, (iii) seasonal fluctuations in effective reproduction number (R_e) associated with lower number of infections and seasonal fluctuations in relative genetic diversity after an initial rapid increase during the early pandemic phase, which broadly corresponded to epidemic peaks in the northern and southern hemispheres, (iv) high virus genetic diversity with greater frequency of seasonal fluctuations in 2009–2011 and 2018 and low virus genetic diversity with relatively weaker seasonal fluctuations in 2012–2017, and (v) virus spread across Kenya. Considerable influenza virus diversity circulated within Kenya, including persistent viral lineages that were unique to the country, which may have been capable of dissemination to other continents through a globally migrating virus population. Further knowledge of the viral lineages that circulate within understudied low-to-middle-income tropical and subtropical regions is required to understand the full diversity and global ecology of influenza viruses in humans and to inform vaccination strategies within these regions.     

Neurological events related to influenza A (H1N1) pdm09

Objectives

To review neurological complications after the influenza A (H1N1) pdm09, highlighting the clinical differences between patients with post-vaccine or viral infection.

Design

A search on Medline, Ovid, EMBASE, and PubMed databases using the keywords “neurological complications of Influenza AH1N1” or “post-vaccine Influenza AH1N1.”

Setting

Only papers written in English, Spanish, German, French, Portuguese, and Italian published from March 2009 to December 2012 were included.

Sample

We included 104 articles presenting a total of 1636 patient cases. In addition, two cases of influenza vaccine-related neurological events from our neurological care center, arising during the period of study, were also included.

Main outcome measures

Demographic data and clinical diagnosis of neurological complications and outcomes: death, neurological sequelae or recovery after influenza A (H1N1) pdm09 vaccine or infection.

Results

The retrieved cases were divided into two groups: the post-vaccination group, with 287 patients, and the viral infection group, with 1349 patients. Most patients in the first group were adults. The main neurological complications were Guillain-Barre syndrome (GBS) or polyneuropathy (125), and seizures (23). All patients survived. Pediatric patients were predominant in the viral infection group. In this group, 60 patients (4.7%) died and 52 (30.1%) developed permanent sequelae. A wide spectrum of neurological complications was observed.

Conclusions

Fatal cases and severe, permanent, neurological sequelae were observed in the infection group only. Clinical outcome was more favorable in the post-vaccination group. In this context, the relevance of an accurate neurological evaluation is demonstrated for all suspicious cases, as well as the need of an appropriate long-term clinical and imaging follow-up of infection and post-vaccination events related to influenza A (H1N1) pdm09, to clearly estimate the magnitude of neurological complications leading to permanent disability.     

Influenza A(H1N1)pdm09 Virus but Not Respiratory Syncytial Virus Interferes with SARS-CoV-2 Replication during Sequential Infections in Human Nasal Epithelial Cells

The types of interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses are not well-characterized due to the low number of co-infection cases described since the onset of the pandemic. We have evaluated the interactions between SARS-CoV-2 (D614G mutant) and influenza A(H1N1)pdm09 or respiratory syncytial virus (RSV) in the nasal human airway epithelium (HAE) infected simultaneously or sequentially (24 h apart) with virus combinations. The replication kinetics of each virus were determined by RT-qPCR at different post-infection times. Our results showed that during simultaneous infection, SARS-CoV-2 interferes with RSV-A2 but not with A(H1N1)pdm09 replication. The prior infection of nasal HAE with SARS-CoV-2 reduces the replication kinetics of both respiratory viruses. SARS-CoV-2 replication is decreased by a prior infection with A(H1N1)pdm09 but not with RSV-A2. The pretreatment of nasal HAE with BX795, a TANK-binding kinase 1 inhibitor, partially alleviates the reduced replication of SARS-CoV-2 or influenza A(H1N1)pdm09 during sequential infection with both virus combinations. Thus, a prior infection of nasal HAE with SARS-CoV-2 interferes with the replication kinetics of A(H1N1)pdm09 and RSV-A2, whereas only A(H1N1)pdm09 reduces the subsequent infection with SARS-CoV-2. The mechanism involved in the viral interference between SARS-CoV-2 and A(H1N1)pdm09 is mediated by the production of interferon.     

Influenza surveillance from November 2008 to 2011; including pandemic influenza A(H1N1)pdm09 in Bhutan

Objective Describe the influenza A(H1N1) pandemic in Bhutan. Design Observational study from sentinel surveillance sites. Setting Bhutan remains isolated, with only one to two flights a day at the lone airport, no trains, and only three major roads that enter from India. Main outcome measures PCR positive human respiratory samples Results The first case of A(H1N1)pdm09 infection was detected in Bhutan in July 2009, 3 months after the virus was first reported in Mexico in April 2009. During the official WHO pandemic period (11 June 2009 to 8 August 2010), a total of 2149 samples were collected and tested by RT‐PCR of which 22.7% (487) were confirmed A(H1N1)pdm09; H3N2, H1N1, and B were positive in 2.2%, 1.1%, and 7.2%, respectively. The highest rate of A(H1N1)pdm09 cases (57.4%) was detected in the 6‐20 year‐old age group. Importantly, Bhutan increased from 3 sentinel sites in April 2009 to 11 a year later, and in April 2010 established PCR capability for influenza. Conclusions Despite relative isolation, the A(H1N1)pdm09 reached Bhutan within 3 months of identification in Mexico. The H1N1 pandemic has made Bhutan more prepared for epidemics in the future.     

Epidemiological study of A (H1N1) pdm09 in Iki Island, Nagasaki

An epidemic situation of pandemic (H1N1) 2009 was investigated from August 1 to March 31 in Iki City, an isolated island with a population of about 30,000. All members of the Iki Physicians' Association participated in the investigation. Daily reports of patients with influenza were made to the local health center. During the outbreak, 2,024 individuals were clinically diagnosed as having influenza, or with the rapid diagnostic test. The prevalence was highest among patients 10-19 years of age (26.8%), followed by patients 9 years and under (21.3%). The prevalence was lowest in patients over 60 years (0.4%). Of the 2,024 patients, 1,443 (71.3%) were 19 years of age or younger. Only seven of the 2,024 were admitted to the hospital, and there were no deaths. When the first outbreak occurred, many individual classes and some schools were closed, and subsequently the number of cases rapidly decreased. A second outbreak occurred three weeks later. The same procedures were taken and the outbreak came to an end. A vaccination program for A (H1N1) pdm09 virus was implemented according to the Japanese National Ministry of Health guidelines, one time for persons aged 13 years or over and twice for those 12 years or younger. To test for antibodies to pandemic A (H1N1) pdm09 after the outbreak, 358 serum samples were collected from Aug to Nov 2009, and the HI titer was measured. 205 (57.3%) were HI titer > or = 1:40. The factor most closely related to a 40 HI titer > or = 1:40 was A (H1N1) pdm09 vaccination, followed by symptomatic influenza. Asymptomatic influenza accounted for 11%. In conclusion, 71.3% of 2,024 A (H1N1) pdm09 patients were 19 years of age or younger. From an epidemiological perspective, school and class closures were considered to be very effective in controlling the spread of the disease.     

2019年广州市甲型H1N1流感病毒全基因组序列的遗传特征分析

目的 对甲型H1N1流感病毒进行基因组全序列遗传特征分析,为流感的科学防控提供新数据.方法 选取7株2019年广州市甲型H1N1流感病毒进行全基因组序列测定,分析其遗传特征.结果 7株病毒的核苷酸同源性最高为PB2基因(98.8％～99.9％),最低为NA基因(97.3％～99.2％).总体上,不同月份的H1N1流感分...     

Hospitalizations from pandemic Influenza [A(H1N1)pdm09] infections among type 1 and 2 diabetes patients in Spain

Objectives To describe and analyze the clinical characteristics and outcomes for all patients with diabetes who were hospitalized with laboratory‐confirmed A(H1N1)pdm09 infections in Spain during 2009. Methods Observational retrospective study using data collected by the Spanish National Hospital Discharge Database. We selected all admissions with diagnosis ICD‐9‐CM code 488·1 [A(H1N1)pdm09]. Discharges were grouped as follows: no diabetes, Type1 and Type 2 diabetes. Underlying medical conditions and risk factors included all those that constitute an indication for annual influenza vaccination, pregnancy, and obesity. The outcome variables analyzed were in‐hospital case fatality risk, length of hospital stay, and costs. Results The total number of persons hospitalized with A(H1N1)pdm09 was 11 499. Of those, 97 suffered Type 1 and 936 Type 2, giving an overall prevalence of diabetes of 9%. The most common underlying medical condition among Type 2 subjects was obesity (26·8%), and for Type 1 renal disease (10·3%). In‐hospital mortality was 2·1% among Type 1 patients, 3·8% among Type 2 patients, and 2·3% among non‐diabetics; after multivariate analysis, diabetes was not a factor independently associated with dying during hospitalization for A(H1N1)pdm09. Independent factors increasing the risk of death among diabetic patients included age (OR 1·03; 95% CI1·01–1·05), hematological disorders (OR 3·49; 95% CI, 1·46–8·37), and obesity (OR 1·88; 95% CI1·07–3·92). Conclusions Among individuals hospitalized in Spain with A(H1N1)pdm09 infections, the age‐specific prevalence of diabetes was higher than the general population in most age groups. The results of multivariate analysis suggest that possibly concomitant conditions such as obesity increase the risk of dying from the infection, but not diabetes itself.     

Rapid Detection and Differentiation of Swine-Origin Influenza A Virus (H1N1/2009) from Other Seasonal Influenza A Viruses

We previously developed a rapid and simple gold nanoparticle(NP)-based genomic microarray assay for identification of the avian H5N1 virus and its discrimination from other influenza A virus strains (H1N1, H3N2). In this study, we expanded the platform to detect the 2009 swine-origin influenza A virus (H1N1/2009). Multiple specific capture and intermediate oligonucleotides were designed for the matrix (M), hemagglutinin (HA), and neuraminidase (NA) genes of the H1N1/2009 virus. The H1N1/2009 microarrays were printed in the same format as those of the seasonal influenza H1N1 and H3N2 for the HA, NA, and M genes. Viral RNA was tested using capture-target-intermediate oligonucleotide hybridization and gold NP-mediated silver staining. The signal from the 4 capture-target-intermediates of the HA and NA genes was specific for H1N1/2009 virus and showed no cross hybridization with viral RNA from other influenza strains H1N1, H3N2, and H5N1. All of the 3 M gene captures showed strong affinity with H1N1/2009 viral RNA, with 2 out of the 3 M gene captures showing cross hybridization with the H1N1, H3N2, and H5N1 samples tested. The current assay was able to detect H1N1/2009 and distinguish it from other influenza A viruses. This new method may be useful for simultaneous detection and subtyping of influenza A viruses and can be rapidly modified to detect other emerging influenza strains in public health settings.     

A(H1N1)pdm09 hemagglutinin D222G and D222N variants are frequently harbored by patients requiring extracorporeal membrane oxygenation and advanced respiratory assistance for severe A(H1N1)pdm09 infection

Background

In patients with A(H1N1)pdm09 infection, severe lung involvement requiring admission to intensive care units (ICU) has been reported. Mutations at the hemagglutinin (HA) receptor binding site (RBS) have been associated with increased virulence and disease severity, representing a potential marker of critical illness.

Objectives

To assess the contribution of HA‐RBS variability in critically ill patients, A(H1N1)pdm09 virus from adult patients with severe infection admitted to ICU for extracorporeal membrane oxygenation support (ECMO) during influenza season 2009–2011 in Piemonte (4·2 million inhabitants), northwestern Italy, was studied.

Patients and methods

We retrospectively analyzed HA‐RBS polymorphisms in ICU patients and compared with those from randomly selected inpatients with mild A(H1N1)pdm09 disease and outpatients with influenza from the local surveillance program.

Results

By HA‐RBS direct sequencing of respiratory specimens, D222G and D222N viral variants were identified in a higher proportion in ICU patients (n = 8/24, 33·3%) than in patients with mild disease (n = 2/34, 6%) or in outpatients (n = 0/44) (Fisher''s exact test P < 0·0001; OR 38·5; CI 95% 4·494–329·9). Eleven ICU patients died (42%), three of them carrying the D222G variant, which was associated with RBS mutation S183P in two. D222G and D222N mutants were identified in upper and lower respiratory samples.

Conclusions

A(H1N1)pdm09 HA substitutions D222G and D222N were harbored in a significantly higher proportion by patients with acute respiratory distress for A(H1N1)pdm09 severe infection requiring ICU admission and ECMO. These data emphasize the importance of monitoring viral evolution for understanding virus–host adaptation aimed at the surveillance of strain circulation and the study of viral correlates of disease severity.     

Relationships between A(H1N1)pdm09 influenza infection and infections with other respiratory viruses

Background

A(H1N1)pdm09, a new influenza pandemic virus emerged in 2009. The A(H1N1)pdm09 infection had several unique characteristics which included rapid transmissibility and high morbidity in obese individuals, pregnant women and individuals suffering from chronic diseases.

Objectives

To study the relationships between A(H1N1)pdm09 influenza infection and infections with other respiratory viruses such as respiratory syncytial virus (RSV), human metapneumo virus (hMPV), adenovirus and seasonal influenza.

Methods

Samples (nasopharyngeal swabs or aspirates) collected between 2007 until 2012 from patients of various ages that were hospitalized due to respiratory virus infections were analyzed for the presence of various respiratory viruses, using qRT-PCR.

Results

In 2009–2010, when the pandemic influenza A(H1N1)pdm09 first appeared, two major infection peaks were noted and individuals of various ages were infected. Following the decline of the A(H1N1)pdm09 virus infection, the percentages of patients infected with adenovirus and hMPV increased, while infection frequency with RSV B and with seasonal influenza virus decreased. Furthermore, RSV infections were delayed and very few percentages of patients were co-infected with more than one virus. Interestingly, the A(H1N1)pdm09 virus lost its dominancy when it reappeared in the winter of 2010–2011, and at this time, only the incidence of RSV infections was affected by the A(H1N1)pdm09 virus.

Conclusions

The A(H1N1)pdm09 virus had distinct effects on other respiratory viruses when it first appeared versus later, when it evolved from being a pandemic to a seasonal virus.     

Tropism and Infectivity of Pandemic Influenza A H1N1/09 Virus in the Human Placenta

Influenza virus infection in pregnant women may put the fetus at higher risk; however, to date, there has been no detailed research about the expression of influenza virus receptors in the human placenta. We employed the lectin staining technique, which is a classic influenza virus receptor research method for studying the distribution of viral receptors in the human placenta. In addition, we examined the susceptibility of the human placenta to H1N1/09, by detecting viral proteins and RNA at different time points post-infection. We found that the human placenta expressed both avian and human influenza A virus receptors (α-2, 3-linked sialic acid and α-2, 6-linked sialic acid). In addition, H1N1/09 did not only infect the human placenta, but also replicated and was released into the culture media. We concluded that the human placenta is susceptible to the 2009 influenza A virus (H1N1/09) infection, and that particular attention should be paid to shielding pregnant women from infection during influenza season.     

Differential use of antivirals for treatment of patients with influenza A(H1N1)pdm09 in Germany

Background

The World Health Organization recommends early antiviral treatment for patients with severe influenza illness or those at increased risk for severe illness.

Objectives

The aim of this study was to determine the proportion of cases with laboratory‐confirmed A(H1N1)pdm09 infection that have been treated with antivirals in Germany during the pandemic (H1N1) 2009 and to investigate factors associated with the use of antivirals.

Methods

We analyzed cases with laboratory‐confirmed A(H1N1)pdm09 infection notified to national health authorities in Germany between week 29/2009 and week 17/2010 using multivariable logistic regression. Severity of disease was defined by pneumonia or death.

Results and conclusions

Of 160 804 cases with laboratory‐confirmed A(H1N1)pdm09 infection, 22% were treated with antivirals. Cases with severe disease were more likely to be treated with antivirals than cases without severe disease (odds ratio = 1·66; 95% confidence interval: 1·46–1·89). In the group with at least one underlying medical condition, only children aged between 1 and 4 years had significant lower odds for receiving antiviral treatment compared with cases in the age group 15 to 49 years (odds ratio = 0·75; 95% confidence interval: 0·6–0·94). In conclusion, the implementation of international recommendations on use of antivirals differed according to the age of patients in Germany during the pandemic (H1N1) 2009. This indicates that the potential of antivirals to prevent severe influenza might not have been fully exhausted. The reasons leading to the observed differences in patient management need to be investigated.     

Factors influencing infection by pandemic influenza A(H1N1)pdm09 over three epidemic waves in Singapore

Introduction

Previous influenza pandemics had second and on occasion third waves in many countries that were at times more severe than the initial pandemic waves.

Objective

This study aims to determine the seroepidemiology of successive waves of H1N1pdm09 infections in Singapore and the overall risks of infection.

Methods

We performed a cohort study amongst 838 adults, with blood samples provided upon recruitment and at 5 points from 2009 to 2011 and tested by haemagglutination inhibition (HI) with A/California/7/2009 (H1N1pdm09). Surveys on key demographic and clinical information were conducted at regular intervals, and associations between seroconversion and these variables were investigated.

Results

After the initial wave from June to September 2009, second and third waves occurred from November 2009 to February 2010 and April to June 2010, respectively. Seroconversion was 13·5% during the first wave and decreased to 6·2% and 6·8% in subsequent waves. Across the three waves, the elderly and those with higher starting HI titres were at lower risk of seroconversion, while those with larger households were at greater risk. Those with higher starting HI titres were also less likely to have an acute respiratory infection.

Conclusions

The second and third waves in Singapore had lower serological attack rates than the first wave. The elderly and those with higher HI titres had lower risk, while those in larger households had higher risk of seroconversion.     

Differential Influence of Age on the Relationship between Genetic Mismatch and A(H1N1)pdm09 Vaccine Effectiveness

Assessment of influenza vaccine effectiveness (VE) and identification of relevant influencing factors are the current priorities for optimizing vaccines to reduce the impacts of influenza. To date, how the difference between epidemic strains and vaccine strains at genetic scale affects age-specific vaccine performance remains ambiguous. This study investigated the association between genetic mismatch on hemagglutinin and neuraminidase genes and A(H1N1)pdm09 VE in different age groups with a novel computational approach. We found significant linear relationships between VE and genetic mismatch in children, young adults, and middle-aged adults. In the children’s group, each 3-key amino acid mutation was associated with an average of 10% decrease in vaccine effectiveness in a given epidemic season, and genetic mismatch exerted no influence on VE for the elderly group. We demonstrated that present vaccines were most effective for children, while protection for the elderly was reduced and indifferent to vaccine component updates. Modeling such relationships is practical to inform timely evaluation of VE in different groups of populations during mass vaccination and may inform age-specific vaccination regimens.