Estimated epidemiologic parameters and morbidity associated with pandemic H1N1 influenza

Background

In the face of an influenza pandemic, accurate estimates of epidemiologic parameters are required to help guide decision-making. We sought to estimate epidemiologic parameters for pandemic H1N1 influenza using data from initial reports of laboratory-confirmed cases.

Methods

We obtained data on laboratory-confirmed cases of pandemic H1N1 influenza reported in the province of Ontario, Canada, with dates of symptom onset between Apr. 13 and June 20, 2009. Incubation periods and duration of symptoms were estimated and fit to parametric distributions. We used competing-risk models to estimate risk of hospital admission and case-fatality rates. We used a Markov Chain Monte Carlo model to simulate disease transmission.

Results

The median incubation period was 4 days and the duration of symptoms was 7 days. Recovery was faster among patients less than 18 years old than among older patients (hazard ratio 1.23, 95% confidence interval 1.06–1.44). The risk of hospital admission was 4.5% (95% CI 3.8%–5.2%) and the case-fatality rate was 0.3% (95% CI 0.1%–0.5%). The risk of hospital admission was highest among patients less than 1 year old and those 65 years or older. Adults more than 50 years old comprised 7% of cases but accounted for 7 of 10 initial deaths (odds ratio 28.6, 95% confidence interval 7.3–111.2). From the simulation models, we estimated the following values (and 95% credible intervals): a mean basic reproductive number (R₀, the number of new cases created by a single primary case in a susceptible population) of 1.31 (1.25–1.38), a mean latent period of 2.62 (2.28–3.12) days and a mean duration of infectiousness of 3.38 (2.06–4.69) days. From these values we estimated a serial interval (the average time from onset of infectiousness in a case to the onset of infectiousness in a person infected by that case) of 4–5 days.

Interpretation

The low estimates for R₀ indicate that effective mitigation strategies may reduce the final epidemic impact of pandemic H1N1 influenza.The emergence and global spread of pandemic H1N1 influenza led the World Health Organization to declare a pandemic on June 11, 2009. As the pandemic spreads, countries will need to make decisions about strategies to mitigate and control disease in the face of uncertainty.For novel infectious diseases, accurate estimates of epidemiologic parameters can help guide decision-making. A key parameter for any new disease is the basic reproductive number (R₀), defined as the average number of new cases created by a single primary case in a susceptible population. R₀ affects the growth rate of an epidemic and the final number of infected people. It also informs the optimal choice of control strategies. Other key parameters that affect use of resources, disease burden and societal costs during a pandemic are duration of illness, rate of hospital admission and case-fatality rate. Early in an epidemic, the case-fatality rate may be underestimated because of the temporal lag between onset of infection and death; the delay between initial identification of a new case and death may lead to an apparent increase in deaths several weeks into an epidemic that is an artifact of the natural history of the disease.We used data from initial reports of laboratory-confirmed pandemic H1N1 influenza to estimate epidemiologic parameters for pandemic H1N1 influenza. The parameters included R₀, incubation period and duration of illness. We also estimated risk of hospital admission and case-fatality rates, which can be used to estimate the burden of illness likely to be associated with this disease.     

Spreading patterns of the influenza A (H1N1) pandemic

We investigate the dynamics of the 2009 influenza A (H1N1/S-OIV) pandemic by analyzing data obtained from World Health Organization containing the total number of laboratory-confirmed cases of infections--by country--in a period of 69 days, from 26 April to 3 July, 2009. Specifically, we find evidence of exponential growth in the total number of confirmed cases and linear growth in the number of countries with confirmed cases. We also find that, i) at early stages, the cumulative distribution of cases among countries exhibits linear behavior on log-log scale, being well approximated by a power law decay; ii) for larger times, the cumulative distribution presents a systematic curvature on log-log scale, indicating a gradual change to lognormal behavior. Finally, we compare these empirical findings with the predictions of a simple stochastic model. Our results could help to select more realistic models of the dynamics of influenza-type pandemics.     

Age distribution of cases of 2009 (H1N1) pandemic influenza in comparison with seasonal influenza

Introduction

Several aspects of the epidemiology of 2009 (H1N1) pandemic influenza have not been accurately determined. We sought to study whether the age distribution of cases differs in comparison with seasonal influenza.

Methods

We searched for official, publicly available data through the internet from different countries worldwide on the age distribution of cases of influenza during the 2009 (H1N1) pandemic influenza period and most recent seasonal influenza periods. Data had to be recorded through the same surveillance system for both compared periods.

Results

For 2009 pandemic influenza versus recent influenza seasons, in USA, visits for influenza-like illness to sentinel providers were more likely to involve the age groups of 5–24, 25–64 and 0–4 years compared with the reference group of >64 years [odds ratio (OR) (95% confidence interval (CI)): 2.43 (2.39–2.47), 1.66 (1.64–1.69), and 1.51 (1.48–1.54), respectively]. Pediatric deaths were less likely in the age groups of 2–4 and <2 years than the reference group of 5–17 years [OR (95% CI): 0.46 (0.25–0.85) and 0.49 (0.30–0.81), respectively]. In Australia, notifications for laboratory-confirmed influenza were more likely in the age groups of 10–19, 5–9, 20–44, 45–64 and 0–4 years than the reference group of >65 years [OR (95% CI): 7.19 (6.67–7.75), 5.33 (4.90–5.79), 5.04 (4.70–5.41), 3.12 (2.89–3.36) and 1.89 (1.75–2.05), respectively]. In New Zealand, consultations for influenza-like illness by sentinel providers were more likely in the age groups of <1, 1–4, 35–49, 5–19, 20–34 and 50–64 years than the reference group of >65 years [OR (95% CI): 2.38 (1.74–3.26), 1.99 (1.62–2.45), 1.57 (1.30–1.89), 1.57 (1.30–1.88), 1.40 (1.17–1.69) and 1.39 (1.14–1.70), respectively].

Conclusions

The greatest increase in influenza cases during 2009 (H1N1) pandemic influenza period, in comparison with most recent seasonal influenza periods, was seen for school-aged children, adolescents, and younger adults.     

Risk factors and outcomes among children admitted to hospital with pandemic H1N1 influenza

Background

Limited data are available on disease characteristics and outcomes of children with 2009 pandemic influenza A(H1N1) virus infection (pandemic H1N1 influenza) who have required hospital admission.

Methods

We reviewed the charts of 58 children with pandemic H1N1 influenza admitted to a large pediatric hospital in Ontario, Canada, between May 8 and July 22, 2009. We compared risk factors, severity indicators and outcomes of these children with those of 200 children admitted with seasonal influenza A during the previous 5 years (2004/05 to 2008/09).

Results

Children with pandemic H1N1 influenza were significantly older than those with seasonal influenza (median age 6.4 years v. 3.3 years). Forty-six (79%) of the children with pandemic H1N1 influenza had underlying medical conditions; of the other 12 who were previously healthy, 42% were under 2 years of age. Children admitted with pandemic H1N1 influenza were significantly more likely to have asthma than those with seasonal influenza (22% v. 6%). Two children had poorly controlled asthma, and 6 used inhaled medications only intermittently. The median length of stay in hospital was 4 days in both groups of children. Similar proportions of children required admission to the intensive care unit (21% of those with pandemic H1N1 influenza and 14% of those with seasonal influenza) and mechanical ventilation (12% and 10% respectively). None of the children admitted with pandemic H1N1 influenza died, as compared with 1 (0.4%) of those admitted with seasonal influenza.

Interpretation

Pandemic H1N1 influenza did not appear to cause more severe disease than seasonal influenza A. Asthma appears to be a significant risk factor for severe disease, with no clear relation to severity of asthma. This finding should influence strategies for vaccination and pre-emptive antiviral therapy.Influenza causes significant morbidity and mortality in childhood.¹ Infants, young children and people 65 years of age and older account for the highest rates of influenza-related hospital admission.² Earlier case series of 2009 pandemic influenza A(H1N1) virus infection (pandemic H1N1 influenza) reported small numbers of children^3,4 or did not present data on children separately.⁵ A recently published series that included 122 children confirmed typical influenza-like presentation, reported a high prevalence of underlying medical conditions (60%, including asthma in 29%) and described the need for intensive care in 20% and mechanical ventilation in 10%.⁶ A previous comparison of children with pandemic H1N1 influenza and those in previous years with seasonal influenza included only children considered to have died of influenza.⁷In this article, we present our experience with children admitted to hospital with pandemic H1N1 influenza. Our primary goal was to describe the demographic characteristics, clinical features and markers of severity of illness of these children. Our secondary goal was to identify risk factors for severe disease or poor outcome by comparing these children with those who had been admitted in previous years with seasonal influenza.     

The seroprevalence of pandemic influenza H1N1 (2009) virus in China

Background

Mainland China experienced pandemic influenza H1N1 (2009) virus (pH1N1) with peak activity during November-December 2009. To understand the geographic extent, risk factors, and attack rate of pH1N1 infection in China we conducted a nationwide serological survey to determine the prevalence of antibodies to pH1N1.

Methodology/Principal Findings

Stored serum samples (n = 2,379) collected during 2006-2008 were used to estimate baseline serum reactogenicity to pH1N1. In January 2010, we used a multistage-stratified random sampling method to select 50,111 subjects who met eligibility criteria and collected serum samples and administered a standardized questionnaire. Antibody response to pH1N1 was measured using haemagglutination inhibition (HI) assay and the weighted seroprevalence was calculated using the Taylor series linearization method. Multivariable logistic regression analyses were used to examine risk factors for pH1N1 seropositivity. Baseline seroprevalence of pH1N1 antibody (HI titer ≥40) was 1.2%. The weighted seroprevalence of pH1N1 among the Chinese population was 21.5%(vaccinated: 62.0%; unvaccinated: 17.1%). Among unvaccinated participants, those aged 6-15 years (32.9%) and 16-24 years (30.3%) had higher seroprevalence compared with participants aged 25–59 years (10.7%) and ≥60 years (9.9%, P<0.0001). Children in kindergarten and students had higher odds of seropositivity than children in family care (OR: 1.36 and 2.05, respectively). We estimated that 207.7 million individuals (15.9%) experienced pH1N1 infection in China.

Conclusions/Significance

The Chinese population had low pre-existing immunity to pH1N1 and experienced a relatively high attack rate in 2009 of this virus. We recommend routine control measures such as vaccination to reduce transmission and spread of seasonal and pandemic influenza viruses.     

Age-matched comparison of children hospitalized for 2009 pandemic H1N1 influenza with those hospitalized for seasonal H1N1 and H3N2

BACKGROUND: A wide spectrum of clinical manifestation ranging from deaths to a mild course of disease has been reported in children infected with the 2009 pandemic H1N1 (pH1N1) influenza. METHODOLOGY/MAJOR FINDINGS: We conducted an age-matched control study comparing children hospitalized for pH1N1 with historic controls infected with seasonal H1N1 and H3N2 influenza to correct for the effect of age on disease susceptibility and clinical manifestations. We also compared children with pH1N1 to children concurrently admitted for seasonal influenza during the pandemic period to adjust for differences in health-seeking behavior during the pandemic or other potential bias associated with historic controls. There was no death or intensive care admission. Children with pH1N1 were more likely to have at least one risk condition for influenza, an underlying chronic pulmonary condition, more likely to have asthma exacerbation and to be treated with oseltamivir. There was no difference in other aspects of the clinical course or outcome. CONCLUSION: Disease manifestation of children hospitalized for pH1N1 infection was mild in our patient population.     

Receptor recognition mechanism of human influenza A H1N1 (1918), avian influenza A H5N1 (2004), and pandemic H1N1 (2009) neuraminidase

Influenza A neuraminidase (NA) is a target for anti-influenza drugs. The function of this enzyme is to cleave a glycosidic linkage of a host cell receptor that links sialic acid (Sia) to galactose (Gal), to allow the virus to leave an infected cell and propagate. The receptor is an oligosaccharide on the host cell surface. There are two types of oligosaccharide receptor; the first, which is found mainly on avian epithelial cell surfaces, links Sia with Gal by an α2,3 glycosidic linkage; in the second, found mainly on human epithelial cell surfaces, linkage is via an α2,6 linkage. Some researchers believe that NAs from different viruses show selectivity for each type of linkage, but there is limited information available to confirm this hypothesis. To see if the linkage type is more specific to any particular NA, a number of NA-receptor complexes of human influenza A H1N1 (1918), avian influenza A H5N1 (2004), and a pandemic strain of H1N1 (2009) were constructed using homology modeling and molecular dynamics simulation. The results show that the two types of receptor analogues bound to NAs use different mechanisms. Moreover, it was found that a residue unique to avian virus NA is responsible for the recognition of the Siaα2,3Gal receptor, and a residue unique to human virus NA is responsible for the recognition of Siaα2,6Gal. We believe that this finding could explain how NAs of different virus origins always possess some unique residues.     

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Background

Whether the enteric absorption of the neuraminidase inhibitor oseltamivir is impaired in critically ill patients is unknown. We documented the pharmacokinetic profile of oseltamivir in patients admitted to intensive care units (ICUs) with suspected or confirmed pandemic (H1N1) influenza.

Methods

We included 41 patients 18 years of age and older with suspected or confirmed pandemic (H1N1) influenza who were admitted for ventilatory support to nine ICUs in three cities in Canada and Spain. Using tandem mass spectrometry, we assessed plasma levels of oseltamivir free base and its active metabolite carboxylate at baseline (before gastric administration of the drug) and at 2, 4, 6, 9 and 12 hours after the fourth or later dose.

Results

Among the 36 patients who did not require dialysis, the median concentration of oseltamivir free base was 10.4 (interquartile range [IQR] 4.8–14.9) μg/L; the median concentration of the carboxylate metabolite was 404 (IQR 257–900) μg/L. The volume of distribution of the carboxylate metabolite did not increase with increasing body weight (R² = 0.00, p = 0.87). The rate of elimination of oseltamivir carboxylate was modestly correlated with estimations of creatinine clearance (R² = 0.27, p < 0.001). Drug clearance in the five patients who required continuous renal replacement therapy was about one-sixth that in the 36 patients with relatively normal renal function.

Interpretation

Oseltamivir was well absorbed enterically in critically ill patients admitted to the ICU with suspected or confirmed pandemic (H1N1) influenza. The dosage of 75 mg twice daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. Adjustment of the dosage in patients with renal dysfunction requiring continuous renal replacement therapy is appropriate; adjustment for obesity does not appear to be necessary.A substantial number of cases of pandemic (H1N1) influenza have involved young adults and adolescents without serious comorbidities who present with severe viral pneumonia complicated by acute respiratory distress syndrome, rhabdomyolysis, renal failure and, occasionally, shock.^1,2 Antiviral therapy in such critically ill patients typically requires oral or nasogastric administration of the neuraminidase inhibitor oseltamivir. Current guidelines from the World Health Organization for the pharmacologic management of progressive or severe pandemic (H1N1) influenza recommend the consideration of high-dose therapy (≥ 150 mg twice daily).^3,4 Critically ill patients exhibit defects in gastrointestinal absorption because of impaired gut perfusion, edema of the bowel wall and ileus as a consequence of critical illness and shock.⁵ Whether the enteric absorption of oseltamivir is impaired in such patients is unknown.We undertook this study to document the pharmacokinetic profile of oseltamivir administered orally or by nasogastric tube in patients admitted to intensive care units (ICUs) with respiratory failure due to suspected or confirmed pandemic (H1N1) influenza.     

Correlates of severe disease in patients with 2009 pandemic influenza (H1N1) virus infection

Background

In the context of 2009 pandemic influenza (H1N1) virus infection (pandemic H1N1 influenza), identifying correlates of the severity of disease is critical to guiding the implementation of antiviral strategies, prioritization of vaccination efforts and planning of health infrastructure. The objective of this study was to identify factors correlated with severity of disease in confirmed cases of pandemic H1N1 influenza.

Methods

This cumulative case–control study included all laboratory-confirmed cases of pandemic H1N1 influenza among residents of the province of Manitoba, Canada, for whom the final location of treatment was known. Severe cases were defined by admission to a provincial intensive care unit (ICU). Factors associated with severe disease necessitating admission to the ICU were determined by comparing ICU cases with two control groups: patients who were admitted to hospital but not to an ICU and those who remained in the community.

Results

As of Sept. 5, 2009, there had been 795 confirmed cases of pandemic H1N1 influenza in Manitoba for which the final treatment location could be determined. The mean age of individuals with laboratory-confirmed infection was 25.3 (standard deviation 18.8) years. More than half of the patients (417 or 52%) were female, and 215 (37%) of 588 confirmed infections for which ethnicity was known occurred in First Nations residents. The proportion of First Nations residents increased with increasing severity of disease (116 [28%] of 410 community cases, 74 [54%] of 136 admitted to hospital and 25 [60%] of 42 admitted to an ICU; p < 0.001), as did the presence of an underlying comorbidity (201 [35%] of 569 community cases, 103 [57%] of 181 admitted to hospital and 34 [76%] of 45 admitted to an ICU; p < 0.001). The median interval from onset of symptoms to initiation of antiviral therapy was 2 days (interquartile range, IQR 1–3) for community cases, 4 days (IQR 2–6) for patients admitted to hospital and 6 days (IQR 4–9) for those admitted to an ICU (p < 0.001). In a multivariable logistic model, the interval from onset of symptoms to initiation of antiviral therapy (odds ratio [OR] 8.24, 95% confidence interval [CI] 2.82–24.1), First Nations ethnicity (OR 6.52, 95% CI 2.04–20.8) and presence of an underlying comorbidity (OR 3.19, 95% CI 1.07–9.52) were associated with increased odds of admission to the ICU (i.e., severe disease) relative to community cases. In an analysis of ICU cases compared with patients admitted to hospital, First Nations ethnicity (OR 3.23, 95% CI 1.04–10.1) was associated with increased severity of disease.

Interpretation

Severe pandemic H1N1 influenza necessitating admission to the ICU was associated with a longer interval from onset of symptoms to treatment with antiviral therapy and with the presence of an underlying comorbidity. First Nations ethnicity appeared to be an independent determinant of severe infection. Despite these associations, the cause and outcomes of pandemic HINI influenza may involve many complex and interrelated factors, all of which require further research and analysis.In April 2009, Canada’s first wave of pandemic influenza (H1N1) virus infections (pandemic H1N1 influenza) began. The highest burden of severe illness in Canada occurred in the province of Manitoba, where 45 Manitobans and 9 out-of-province patients were admitted to an intensive care unit (ICU). In this first wave, ICU staff and equipment were mobilized to expand bed capacity and ventilator capabilities to accommodate clinical need.Although many individuals presented with mild, self-limited symptoms and no sign of pulmonary involvement, some people required admission to an ICU and received maximal life support measures.^1–3 Predicting disease and mitigating hazard in at-risk populations is an important aim of public heath epidemiology, and in preparation for future waves of pandemic H1N1 influenza, determining correlates of the severity of disease may be very important. Initial reports have suggested that, in addition to many of the previously known risk factors for complications of seasonal influenza, obesity⁴ and other underlying comorbidities^3,5 may be risk factors for severe disease. The interval from onset of symptoms to initiation of antiviral therapy or other treatment and supportive care was also associated with adverse outcome in a recent case series.⁶ In a Canadian study of severe pandemic H1N1 influenza, First Nations people were proportionally overrepresented among patients in the ICU.² However, it is unclear if this association was independent of potential confounding factors. The ability to determine correlates of severe pandemic H1N1 disease and subsequent need for ICU resources in at-risk populations would provide opportunities for public and population health analysis and action, public education, strategic prioritization of vaccination efforts, efficient and equitable allocation and use of antiviral drugs, and development of infrastructure within the health system.The objectives of this study were to identify factors that were correlated with severity of disease in confirmed cases of pandemic H1N1 influenza. Our hypothesis, which was based on existing literature, was that obesity, First Nations ethnicity and longer interval from onset of symptoms to treatment would be important determinants of the severity of disease.     

Hospitalized children with 2009 pandemic influenza A (H1N1): comparison to seasonal influenza and risk factors for admission to the ICU

Background

Limited data are available describing the clinical presentation and risk factors for admission to the intensive care unit for children with 2009 H1N1 infection.

Methods

We conducted a retrospective chart review of all hospitalized children with 2009 influenza A (H1N1) and 2008–09 seasonal influenza at The Children''s Hospital, Denver, Colorado.

Results

Of the 307 children identified with 2009 H1N1 infections, the median age was 6 years, 61% were male, and 66% had underlying medical conditions. Eighty children (26%) were admitted to the ICU. Thirty-two (40%) of the ICU patients required intubation and 17 (53%) of the intubated patients developed acute respiratory distress syndrome (ARDS). Four patients required extracorporeal membrane oxygenation. Eight (3%) of the hospitalized children died. Admission to the ICU was significantly associated with older age and underlying neurological condition. Compared to the 90 children admitted during the 2008–09 season, children admitted with 2009 H1N1 influenza were significantly older, had a shorter length of hospitalization, more use of antivirals, and a higher incidence of ARDS.

Conclusions

Compared to the 2008–09 season, hospitalized children with 2009 H1N1 influenza were much older and had more severe respiratory disease. Among children hospitalized with 2009 H1N1 influenza, risk factors for admission to the ICU included older age and having an underlying neurological condition. Children under the age of 2 hospitalized with 2009 H1N1 influenza were significantly less likely to require ICU care compared to older hospitalized children.     

Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza

Background

We describe the disease characteristics and outcomes, including risk factors for admission to intensive care unit (ICU) and death, of all patients in Canada admitted to hospital with pandemic (H1N1) influenza during the first five months of the pandemic.

Methods

We obtained data for all patients admitted to hospital with laboratory-confirmed pandemic (H1N1) influenza reported to the Public Health Agency of Canada from Apr. 26 to Sept. 26, 2009. We compared inpatients who had nonsevere disease with those who had severe disease, as indicated by admission to ICU or death.

Results

A total of 1479 patients were admitted to hospital with confirmed pandemic (H1N1) influenza during the study period. Of these, 1171 (79.2%) did not have a severe outcome, 236 (16.0%) were admitted to ICU and survived, and 72 (4.9%) died. The median age was 23 years for all of the patients, 18 years for those with a nonsevere outcome, 34 years for those admitted to ICU who survived and 51 years for those who died. The risk of a severe outcome was elevated among those who had an underlying medical condition and those 20 years of age and older. A delay of one day in the median time between the onset of symptoms and admission to hospital increased the risk of death by 5.5%. The risk of a severe outcome remained relatively constant over the five-month period.

Interpretation

The population-based incidence of admission to hospital with laboratory-confirmed pandemic (H1N1) influenza was low in the first five months of the pandemic in Canada. The risk of a severe outcome was associated with the presence of one or more underlying medical conditions, age of 20 years or more and a delay in hospital admission.The first cases of pandemic (H1N1) influenza in Canada were reported on Apr. 26, 2009. Retrospective case-finding determined that the onset of symptoms in the first Canadian case, involving a traveller returning from Mexico, occurred on Apr. 12, 2009. The first patient admitted to hospital began to experience symptoms on Apr. 18.During the first few weeks of the outbreak, in-depth follow-up and reporting of cases was conducted in keeping with the World Health Organization’s pandemic plans for each country to comprehensively assess its first 100 cases.¹ By mid-May, many Canadian jurisdictions moved away from this approach because it became increasingly taxing on both public health human resources and laboratory capacity. It was decided that reporting of individual cases would continue nationally only for patients who were admitted to hospital or who died. We provide a detailed review of the disease characteristics and outcomes, including risk factors for admission to intensive care unit (ICU) and death, of patients admitted to hospital in Canada during the first five months of the pandemic.     

An analysis of 332 fatalities infected with pandemic 2009 influenza A (H1N1) in Argentina

Background

The apparent high number of deaths in Argentina during the 2009 pandemic led to concern that the influenza A H1N1pdm disease was different there. We report the characteristics and risk factors for influenza A H1N1pdm fatalities.

Methods

We identified laboratory-confirmed influenza A H1N1pdm fatalities occurring during June-July 2009. Physicians abstracted data on age, sex, time of onset of illness, medical history, clinical presentation at admission, laboratory, treatment, and outcomes using standardize questionnaires. We explored the characteristics of fatalities according to their age and risk group.

Results

Of 332 influenza A H1N1pdm fatalities, 226 (68%) were among persons aged <50 years. Acute respiratory failure was the leading cause of death. Of all cases, 249 (75%) had at least one comorbidity as defined by Advisory Committee on Immunization Practices. Obesity was reported in 32% with data and chronic pulmonary disease in 28%. Among the 40 deaths in children aged <5 years, chronic pulmonary disease (42%) and neonatal pathologies (35%) were the most common co-morbidities. Twenty (6%) fatalities were among pregnant or postpartum women of which only 47% had diagnosed co-morbidities. Only 13% of patients received antiviral treatment within 48 hours of symptom onset. None of children aged <5 years or the pregnant women received antivirals within 48 h of symptom onset. As the pandemic progressed, the time from symptom-onset to medical care and to antiviral treatment decreased significantly among case-patients who subsequently died (p<0.001).

Conclusion

Persons with co-morbidities, pregnant and who received antivirals late were over-represented among influenza A H1N1pdm deaths in Argentina, though timeliness of antiviral treatment improved during the pandemic.     

Genetic diversity of the 2009 pandemic influenza A(H1N1) viruses in Finland

Background

In Finland, the first infections caused by the 2009 pandemic influenza A(H1N1) virus were identified on May 10. During the next three months almost all infections were found from patients who had recently traveled abroad. In September 2009 the pandemic virus started to spread in the general population, leading to localized outbreaks and peak epidemic activity was reached during weeks 43–48.

Methods/Results

The nucleotide sequences of the hemagglutinin (HA) and neuraminidase (NA) genes from viruses collected from 138 patients were determined. The analyzed viruses represented mild and severe infections and different geographic regions and time periods. Based on HA and NA gene sequences, the Finnish pandemic viruses clustered in four groups. Finnish epidemic viruses and A/California/07/2009 vaccine virus strain varied from 2–8 and 0–5 amino acids in HA and NA molecules, respectively, giving a respective maximal evolution speed of 1.4% and 1.1%. Most amino acid changes in HA and NA molecules accumulated on the surface of the molecule and were partly located in antigenic sites. Three severe infections were detected with a mutation at HA residue 222, in two viruses with a change D222G, and in one virus D222Y. Also viruses with change D222E were identified. All Finnish pandemic viruses were sensitive to oseltamivir having the amino acid histidine at residue 275 of the neuraminidase molecule.

Conclusions

The Finnish pandemic viruses were quite closely related to A/California/07/2009 vaccine virus. Neither in the HA nor in the NA were changes identified that may lead to the selection of a virus with increased epidemic potential or exceptionally high virulence. Continued laboratory-based surveillance of the 2009 pandemic influenza A(H1N1) is important in order to rapidly identify drug resistant viruses and/or virus variants with potential ability to cause severe forms of infection and an ability to circumvent vaccine-induced immunity.     

Cost-effectiveness of 2009 pandemic influenza A(H1N1) vaccination in the United States

Background

Pandemic influenza A(H1N1) (pH1N1) was first identified in North America in April 2009. Vaccination against pH1N1 commenced in the U.S. in October 2009 and continued through January 2010. The objective of this study was to evaluate the cost-effectiveness of pH1N1 vaccination.

Methodology

A computer simulation model was developed to predict costs and health outcomes for a pH1N1 vaccination program using inactivated vaccine compared to no vaccination. Probabilities, costs and quality-of-life weights were derived from emerging primary data on pH1N1 infections in the US, published and unpublished data for seasonal and pH1N1 illnesses, supplemented by expert opinion. The modeled target population included hypothetical cohorts of persons aged 6 months and older stratified by age and risk. The analysis used a one-year time horizon for most endpoints but also includes longer-term costs and consequences of long-term sequelae deaths. A societal perspective was used. Indirect effects (i.e., herd effects) were not included in the primary analysis. The main endpoint was the incremental cost-effectiveness ratio in dollars per quality-adjusted life year (QALY) gained. Sensitivity analyses were conducted.

Results

For vaccination initiated prior to the outbreak, pH1N1 vaccination was cost-saving for persons 6 months to 64 years under many assumptions. For those without high risk conditions, incremental cost-effectiveness ratios ranged from $8,000–$52,000/QALY depending on age and risk status. Results were sensitive to the number of vaccine doses needed, costs of vaccination, illness rates, and timing of vaccine delivery.

Conclusions

Vaccination for pH1N1 for children and working-age adults is cost-effective compared to other preventive health interventions under a wide range of scenarios. The economic evidence was consistent with target recommendations that were in place for pH1N1 vaccination. We also found that the delays in vaccine availability had a substantial impact on the cost-effectiveness of vaccination.     

Evolutionary pathways of the pandemic influenza A (H1N1) 2009 in the UK

The emergence of the influenza (H1N1) 2009 virus provided a unique opportunity to study the evolution of a pandemic virus following its introduction into the human population. Virological and clinical surveillance in the UK were comprehensive during the first and second waves of the pandemic in 2009, with extensive laboratory confirmation of infection allowing a detailed sampling of representative circulating viruses. We sequenced the complete coding region of the haemagglutinin (HA) segment of 685 H1N1 pandemic viruses selected without bias during two waves of pandemic in the UK (April-December 2009). Phylogenetic analysis showed that although temporal accumulation of amino acid changes was observed in the HA sequences, the overall diversity was less than that typically seen for seasonal influenza A H1N1 or H3N2. There was co-circulation of multiple variants as characterised by signature amino acid changes in the HA. A specific substitution (S203T) became predominant both in UK and global isolates. No antigenic drift occurred during 2009 as viruses with greater than four-fold reduction in their haemagglutination inhibition (HI) titre ("low reactors") were detected in a low proportion (3%) and occurred sporadically. Although some limited antigenic divergence in viruses with four-fold reduction in HI titre might be related to the presence of 203T, additional studies are needed to test this hypothesis.     

人H7N9禽流感病毒与H1N1流感病毒感染小鼠病理学损伤的比较

目的比较分析H7N9病毒与H1N1病毒感染小鼠病理学损伤特点,初步探讨两种病毒感染致小鼠急性肺损伤的致病机制。方法 H7N9病毒与H1N1病毒分别感染小鼠,观察不同病毒感染后小鼠生存率,并于不同时间点取心、肝、脾、肺、肾、脑、肠等组织,伊红-苏木素染色并进行组织病理学分析,免疫组化检测病毒抗原分布及中性粒细胞浸润。综合分析肺组织病理损伤与病毒复制、宿主免疫反应之间的关系。结果 H7N9病毒感染小鼠肺及脾脏损伤较轻,存活率较高。H1N1病毒感染的小鼠肺及脾脏损伤较重,感染后9 d全部死亡;两种病毒抗原主要分布于支气管上皮细胞、少量间质细胞和肺泡上皮细胞,病毒复制水平无明显差异。但H1N1病毒感染后肺及脾脏中均有大量中性粒细胞浸润,小鼠机体炎症反应明显强于H7N9病毒感染后小鼠炎症反应。结论 H7N9病毒与H1N1病毒感染后小鼠病理学损伤特点及程度均不同,病毒复制是小鼠肺损伤的诱发因素但并非决定因素,宿主针对病毒感染产生的免疫反应程度与急性肺损伤密切相关。