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.     

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.     

The responses of Aboriginal Canadians to adjuvanted pandemic (H1N1) 2009 influenza vaccine

Background:

Because many Aboriginal Canadians had severe cases of pandemic (H1N1) 2009 influenza, they were given priority access to vaccine. However, it was not known if the single recommended dose would adequately protect people at high risk, prompting our study to assess responses to the vaccine among Aboriginal Canadians.

Methods:

We enrolled First Nations and Métis adults aged 20–59 years in our prospective cohort study. Participants were given one 0.5-mL dose of ASO3-adjuvanted pandemic (H1N1) 2009 vaccine (Arepanrix, GlaxoSmithKline Canada). Blood samples were taken at baseline and 21–28 days after vaccination. Paired sera were tested for hemagglutination-inhibiting antibodies at a reference laboratory. To assess vaccine safety, we monitored the injection site symptoms of each participant for seven days. We also monitored patients for general symptoms within 7 days of vaccination and any use of the health care system for 21–28 days after vaccination.

Results:

We enrolled 138 participants in the study (95 First Nations, 43 Métis), 137 of whom provided all safety data and 136 of whom provided both blood samples. First Nations and Métis participants had similar characteristics, including high rates of chronic health conditions (74.4%–76.8%). Pre-existing antibody to the virus was detected in 34.3% of the participants, all of whom boosted strongly with vaccination (seroprotection rate [titre ≥ 40] 100%, geometric mean titre 531–667). Particpants with no pre-existing antibody also responded well. Fifty-eight of 59 (98.3%) First Nations participants showed seroprotection and a geometric mean titre of 353.6; all 30 Métis participants with no pre-existing antibody showed seroprotection and a geometric mean titre of 376.2. Pain at the injection site and general symptoms frequently occurred but were short-lived and generally not severe, although three participants (2.2%) sought medical attention for general symptoms.

Interpretation:

First Nations and Métis adults responded robustly to ASO3-adjuvanted pandemic (H1N1) 2009 vaccine. Virtually all participants showed protective titres, including those with chronic health conditions.

Trial registration:

ClinicalTrials.gov trial register no. NCT.01001026.During the first wave of the H1N1 pandemic in Canada in 2009, some First Nations communities were severely affected, with younger adults and children most at risk for severe disease.^1,2 Whereas Aboriginal Canadians make up 3.4% of the population (with 1.14 million people), they accounted for 16% of admissions to hospital during the first wave of the pandemic, and 43% of Aboriginal patients had underlying medical conditions.³ The increased rate of severe disease might have resulted from residential crowding, prevalence of chronic health conditions, delayed access to health care or suboptimal immune responses to infection.⁴ When a federally funded, ASO3-adjuvanted (squalene/tocopherol) pandemic vaccine became available for Canadians later in 2009,⁵ Aboriginal people were given priority access to it.³ However, dosing requirements at the time were tentative. Previous studies of an ASO3-adjuvanted influenza A (H5N1) vaccine established that two doses were needed for immunity in adults.⁶ Because the 2009 influenza (H1N1) pandemic occurred without warning, no prepandemic studies had been done with vaccines based on this novel swine-derived virus.⁷The ASO3-adjuvanted pandemic (H1N1) 2009 vaccine manufactured in Canada (Arepanrix, GlaxoSmithKline, Laval, Quebec) was released for public use as soon as it was available, unstudied, to mitigate morbidity during the pandemic’s second wave, which was already in progress. A single 3.75-μg dose of hemagglutinin was recommended for adults using the preliminary results of a European trial of another ASO3-adjuvanted vaccine (Pandemrix, GlaxoSmithKline, Rixensart, Belgium) given to 65 adults aged 18–60 years.⁸ The European product was believed to be equivalent to the Canadian-made vaccine, but this had not yet been shown.We wondered if the recommended single dose would be adequate for Aboriginal Canadian adults given their heightened risk of severe influenza during the first wave. We were unable to identify any previous studies of influenza vaccines involving Aboriginal Canadians to determine if their responses would be similar to other Canadians or to the healthy European study participants on whom the dosing recommendation was based. Consequently, we undertook a study involving First Nations and Métis adults to assess their responses to the pandemic vaccine.     

Estimated cumulative incidence of pandemic (H1N1) influenza among pregnant women during the first wave of the 2009 pandemic

Background

Hospitalization and lab confirmed cases of H1N1 have been reported during the first wave of the 2009 pandemic but these are not accurate measures of influenza incidence in the population. We estimated the cumulative incidence of pandemic (H1N1) influenza among pregnant women in the province of Manitoba during the first wave of the 2009 pandemic.

Methods

Two panels of stored frozen serum specimens collected for routine prenatal screening were randomly selected for testing before (March 2009, n = 252) and after (August 2009, n = 296) the first wave of the pandemic. A standard hemagglutination inhibition assay was used to detect the presence of IgG antibodies against the pandemic (H1N1) 2009 virus. The cumulative incidence of pandemic (H1N1) influenza was calculated as the difference between the point prevalence rates in the first and second panels.

Results

Of the specimens collected in March, 7.1% were positive for the IgG antibodies (serum antibody titre ≥ 1:40). The corresponding prevalence was 15.7% among the specimens collected in August. The difference indicated a cumulative incidence of 8.6% (95% confidence interval [CI] 3.2%–13.7%). The rate differed geographically, the highest being in the northern regions (20.8%, 95% CI 7.9%–31.8%), as compared with 4.0% (95% CI 0.0%–11.9%) in Winnipeg and 8.9% (95% CI 0.0%–18.8%) in the rest of the province.

Interpretation

We estimated that the cumulative incidence of pandemic (H1N1) influenza among pregnant women in Manitoba during the first wave of the 2009 pandemic was 8.6%. It was 20.8% in the northern regions of the province.During the first wave of the pandemic (H1N1) 2009, the province of Manitoba was more severely affected than almost any other Canadian province.¹ Pregnant women in particular had higher rates of laboratory-confirmed infection and of severe illness.² However, the number of laboratory-confirmed cases is not an accurate measure of the incidence of influenza in the population. The number and geographic distribution of confirmed cases are influenced by differences in access to medical care, physicians’ practices and other factors.³We estimated the cumulative incidence of pandemic (H1N1) influenza among pregnant women in the province of Manitoba during the first wave of the 2009 pandemic. We did this by measuring the point seroprevalence in random samples of pregnant women presenting for routine prenatal screening before and after the first wave.     

Rates and determinants of seasonal influenza vaccination in pregnancy and association with neonatal outcomes

Background:

There is growing evidence that seasonal influenza vaccination in pregnancy has benefits for mother and baby. We determined influenza vaccination rates among pregnant women during the 2 nonpandemic influenza seasons following the 2009 H1N1 pandemic, explored maternal factors as predictors of influenza vaccination status and evaluated the association between maternal influenza vaccination and neonatal outcomes.

Methods:

We used a population-based perinatal database in the province of Nova Scotia, Canada, to examine maternal vaccination rates, determinants of vaccination status and neonatal outcomes. Our cohort included women who gave birth between Nov. 1, 2010, and Mar. 31, 2012. We compared neonatal outcomes between vaccinated and unvaccinated women using logistic regression analysis.

Results:

Overall, 1958 (16.0%) of 12 223 women in our cohort received the influenza vaccine during their pregnancy. Marital status, parity, location of residence (rural v. urban), smoking during pregnancy and maternal influenza risk status were determinants of maternal vaccine receipt. The odds of preterm birth was lower among infants of vaccinated women than among those of nonvaccinated women (adjusted odds ratio [OR] 0.75, 95% confidence interval [CI] 0.60–0.94). The rate of low-birth-weight infants was also lower among vaccinated women (adjusted OR 0.73, 95% CI 0.56–0.95).

Interpretation:

Despite current guidelines advising all pregnant women to receive the seasonal influenza vaccine, influenza vaccination rates among pregnant women in our cohort were low in the aftermath of the 2009 H1N1 pandemic. This study and others have shown an association between maternal influenza vaccination and improved neonatal outcomes, which supports stronger initiatives to promote vaccination during pregnancy.Influenza viruses are the leading cause of serious wintertime respiratory morbidity worldwide. Several studies investigating the effects of influenza-related illness during pregnancy have shown a strong impact on the health of pregnant women in terms of increased rates of hospital admission because of respiratory illness.^1–3 Schanzer and colleagues² found that pregnant women in Canada were at increased risk of influenza-related hospital admission when compared with nonpregnant women of similar age and health status. In addition, influenza-related illness during pregnancy may have a negative impact on neonatal outcomes. A study in Nova Scotia, Canada, showed that infants whose mothers were admitted to hospital because of respiratory illness during influenza season while pregnant were more likely to be small for gestational age and to have lower mean birth weight.⁴By 2007, the cumulative evidence from these and other studies was compelling enough for advisory boards in Canada to recommend routine influenza vaccination for all pregnant women, including those without medical comorbidities.⁵ Despite these recommendations, seasonal vaccination rates among pregnant women have remained low. In a cohort of pregnant women who delivered at the IWK Health Centre, Halifax, from 2006 to 2009, only 20% had received the vaccine during their pregnancy.⁶ Increased vaccination rates among pregnant women were reported for the 2009 H1N1 pandemic year,⁷ but it is unknown whether this has translated into higher rates of seasonal influenza vaccination since then. Studies have shown that concern about vaccine safety is the most commonly cited reason for refusing the vaccine,^8,9 despite much evidence showing it to be safe in pregnancy.¹⁰ A recommendation from a maternity care provider has been shown to be a key factor in increasing vaccination rates.^11,12In light of the growing evidence that influenza vaccination during pregnancy has benefits for both the mother and the infant,^13–18 we evaluated rates of seasonal influenza vaccination among pregnant women in the 2 nonpandemic influenza seasons (2010/11 and 2011/12) following the 2009 H1N1 pandemic. We also assessed whether neonatal outcomes differed between women who received the vaccine during pregnancy and those who did not.     

Modelling mitigation strategies for pandemic (H1N1) 2009

Background

The 2009 influenza A (H1N1) pandemic has required decision-makers to act in the face of substantial uncertainties. Simulation models can be used to project the effectiveness of mitigation strategies, but the choice of the best scenario may change depending on model assumptions and uncertainties.

Methods

We developed a simulation model of a pandemic (H1N1) 2009 outbreak in a structured population using demographic data from a medium-sized city in Ontario and epidemiologic influenza pandemic data. We projected the attack rate under different combinations of vaccination, school closure and antiviral drug strategies (with corresponding “trigger” conditions). To assess the impact of epidemiologic and program uncertainty, we used “combinatorial uncertainty analysis.” This permitted us to identify the general features of public health response programs that resulted in the lowest attack rates.

Results

Delays in vaccination of 30 days or more reduced the effectiveness of vaccination in lowering the attack rate. However, pre-existing immunity in 15% or more of the population kept the attack rates low, even if the whole population was not vaccinated or vaccination was delayed. School closure was effective in reducing the attack rate, especially if applied early in the outbreak, but this is not necessary if vaccine is available early or if pre-existing immunity is strong.

Interpretation

Early action, especially rapid vaccine deployment, is disproportionately effective in reducing the attack rate. This finding is particularly important given the early appearance of pandemic (H1N1) 2009 in many schools in September 2009.Jurisdictions in the northern hemisphere are bracing for a “fall wave” of pandemic (H1N1) 2009.^1–3 Decision-makers face uncertainty, not just with respect to epidemiologic characteristics of the virus,⁴ but also program uncertainties related to feasibility, timeliness and effectiveness of mitigation strategies.⁵ Policy decisions must be made against this backdrop of uncertainty. However, the effectiveness of any mitigation strategy generally depends on the epidemiologic characteristics of the pathogen as well as the other mitigation strategies adopted. Mathematical models can project strategy effectiveness under hypothetical epidemiologic and program scenarios.^6–12 In the case of pandemic influenza, models have been used to assess the effectiveness of school closure⁷ and optimal use of antiviral drug^6,9,10 and vaccination strategies.⁸ However, model projections can be sensitive to input parameter values; thus, data uncertainty is an issue.¹³ Uncertainty analysis can help address the impact of uncertainties on model predictions but is often underutilized.¹³In this article, we present a simulation model of pandemic influenza transmission and mitigation in a population. This model projects the overall attack rate (percentage of people infected) during an outbreak. We introduce a formal method of uncertainty analysis that has not previously been applied to pandemic influenza, and we use this method to assess the impact of epidemiologic and program uncertainties. The model is intended to address the following policy questions that have been raised during the 2009 influenza pandemic: What is the impact of delayed vaccine delivery on attack rates? Can attack rates be substantially reduced without closing schools? What is the impact of pre-existing immunity from spring and summer 2009? We addressed these questions using a simulation model that projects the impact of vaccination, school closure and antiviral drug treatment strategies on attack rates.     

Likelihood of coronary angiography among First Nations patients with acute myocardial infarction

Background:

Morbidity due to cardiovascular disease is high among First Nations people. The extent to which this may be related to the likelihood of coronary angiography is unclear. We examined the likelihood of coronary angiography after acute myocardial infarction (MI) among First Nations and non–First Nations patients.

Methods:

Our study included adults with incident acute MI between 1997 and 2008 in Alberta. We determined the likelihood of angiography among First Nations and non–First Nations patients, adjusted for important confounders, using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database.

Results:

Of the 46 764 people with acute MI, 1043 (2.2%) were First Nations. First Nations patients were less likely to receive angiography within 1 day after acute MI (adjusted odds ratio [OR] 0.73, 95% confidence interval [CI] 0.62–0.87). Among First Nations and non–First Nations patients who underwent angiography (64.9%), there was no difference in the likelihood of percutaneous coronary intervention (PCI) (adjusted hazard ratio [HR] 0.92, 95% CI 0.83–1.02) or coronary artery bypass grafting (CABG) (adjusted HR 1.03, 95% CI 0.85–1.25). First Nations people had worse survival if they received medical management alone (adjusted HR 1.38, 95% CI 1.07–1.77) or if they underwent PCI (adjusted HR 1.38, 95% CI 1.06–1.80), whereas survival was similar among First Nations and non–First Nations patients who received CABG.

Interpretation:

First Nations people were less likely to undergo angiography after acute MI and experienced worse long-term survival compared with non–First Nations people. Efforts to improve access to angiography for First Nations people may improve outcomes.Although cardiovascular disease has been decreasing in Canada,¹ First Nations people have a disproportionate burden of the disease. First Nations people in Canada have a 2.5-fold higher prevalence of cardiovascular disease than non–First Nations people,² with hospital admissions for cardiovascular-related events also increasing.³The prevalence of cardiovascular disease in First Nations populations is presumed to be reflective of the prevalence of cardiovascular risk factors.^4–7 However, the disproportionate increase in rates of hospital admission suggests that suboptimal management of cardiovascular disease or its risk factors may also influence patient outcomes.^2,3 Racial disparities in the quality of cardiovascular care resulting in adverse outcomes have been documented, although most studies have focused on African-American, Hispanic and Asian populations.^8,9 As a result, it is unclear whether suboptimal delivery of guideline-recommended treatment contributes to increased cardiovascular morbidity and mortality among First Nations people.^10–12We undertook a population-based study involving adults with incident acute myocardial infarction (MI) to examine the receipt of guideline-recommended coronary angiography among First Nations and non–First Nations patients.^10–12 Among patients who underwent angiography, we sought to determine whether there were differences between First Nations and non–First Nations patients in the likelihood of revascularization and long-term survival.     

Prevalence of seroprotection against the pandemic (H1N1) virus after the 2009 pandemic

Background

Before pandemic (H1N1) 2009, less than 10% of serum samples collected from all age groups in the Lower Mainland of British Columbia, Canada, showed seroprotection against the pandemic (H1N1) 2009 virus, except those from very elderly people. We reassessed this profile of seroprotection by age in the same region six months after the fall 2009 pandemic and vaccination campaign.

Methods

We evaluated 100 anonymized serum samples per 10-year age group based on convenience sampling. We measured levels of antibody against the pandemic virus by hemagglutination inhibition and microneutralization assays. We assessed geometric mean titres and the proportion of people with seroprotective antibody levels (hemagglutination inhibition titre ≥ 40). We performed sensitivity analyses to evaluate titre thresholds of 80, 20 and 10.

Results

Serum samples from 1127 people aged 9 months to 101 years were obtained. The overall age-standardized proportion of people with seroprotective antibody levels was 46%. A U-shaped age distribution was identified regardless of assay or titre threshold applied. Among those less than 20 years old and those 80 years and older, the prevalence of seroprotection was comparably high at about 70%. Seroprotection was 44% among those aged 20–49 and 30% among those 50–79 years. It was lowest among people aged 70–79 years (21%) and highest among those 90 years and older (88%).

Interpretation

We measured much higher levels of seroprotection after the 2009 pandemic compared than before the pandemic, with a U-shaped age distribution now evident. These findings, particularly the low levels of seroprotection among people aged 50–79 years, should be confirmed in other settings and closer to the influenza season.In a previous age-based survey of about 1000 anonymized serum samples collected before substantial pandemic (H1N1) 2009 activity in the Lower Mainland of the province of British Columbia, Canada, we found that less than 10% of children and adults under 70 years of age had seroprotective levels of antibody against the pandemic (H1N1) virus.¹ This proportion was slightly higher among people aged 70–79 years (27%) and substantially higher among those above 80 years of age (77%).¹The 2009 influenza pandemic and the broad and effective vaccination campaign introduced major changes to this population’s immune status. The first wave in the province, in the spring and summer months, was of limited activity and was followed by a second, more substantial and widespread wave in the fall that peaked during the last week of October and resolved by the end of 2009.² Meanwhile, a highly immunogenic adjuvanted vaccine was provided free of charge through a universal vaccination campaign that targeted all Canadians.³ Supply was limited initially, requiring sequenced rollout of the vaccine, starting with children under five years of age, pregnant women, and people under 65 years who had comorbidities.⁴ The uptake of the vaccine of about 35%–45% in the province overall^4–6 and 44% in the Lower Mainland (Dr. Monika Naus, BC Centre for Disease Control, Vancouver, BC: personal communication, 2010) was estimated to be moderate compared with rates of uptake in other provinces.To assess seroprotective antibody levels after the 2009 pandemic, we repeated our age-based survey of antibody levels against the pandemic (H1N1) 2009 virus in a further 1000 serum samples collected from people in the Lower Mainland in May and June 2010, more than six months after the last peak of the epidemic.     

Pandemic H1N1 2009 Influenza A Virus Induces Weak Cytokine Responses in Human Macrophages and Dendritic Cells and Is Highly Sensitive to the Antiviral Actions of Interferons

In less than 3 months after the first cases of swine origin 2009 influenza A (H1N1) virus infections were reported from Mexico, WHO declared a pandemic. The pandemic virus is antigenically distinct from seasonal influenza viruses, and the majority of human population lacks immunity against this virus. We have studied the activation of innate immune responses in pandemic virus-infected human monocyte-derived dendritic cells (DC) and macrophages. Pandemic A/Finland/553/2009 virus, representing a typical North American/European lineage virus, replicated very well in these cells. The pandemic virus, as well as the seasonal A/Brisbane/59/07 (H1N1) and A/New Caledonia/20/99 (H1N1) viruses, induced type I (alpha/beta interferon [IFN-α/β]) and type III (IFN-λ1 to -λ3) IFN, CXCL10, and tumor necrosis factor alpha (TNF-α) gene expression weakly in DCs. Mouse-adapted A/WSN/33 (H1N1) and human A/Udorn/72 (H3N2) viruses, instead, induced efficiently the expression of antiviral and proinflammatory genes. Both IFN-α and IFN-β inhibited the replication of the pandemic (H1N1) virus. The potential of IFN-λ3 to inhibit viral replication was lower than that of type I IFNs. However, the pandemic virus was more sensitive to the antiviral IFN-λ3 than the seasonal A/Brisbane/59/07 (H1N1) virus. The present study demonstrates that the novel pandemic (H1N1) influenza A virus can readily replicate in human primary DCs and macrophages and efficiently avoid the activation of innate antiviral responses. It is, however, highly sensitive to the antiviral actions of IFNs, which may provide us an additional means to treat severe cases of infection especially if significant drug resistance emerges.The novel swine origin 2009 influenza A (H1N1) virus was identified in April 2009, and it is currently causing the first influenza pandemic of the 21st century. The virus is a completely new reassortant virus (8, 38), and the majority of the human population does not have preexisting immunity against it. The case fatality rate of the current pandemic virus infection is still unclear, but it is estimated to be somewhat higher than that of seasonal influenza virus infections (8). In most cases, the pandemic 2009 A (H1N1) virus causes an uncomplicated respiratory tract illness with symptoms similar to those caused by seasonal influenza viruses. However, gastrointestinal symptoms atypical to seasonal influenza have been detected in a significant proportion of cases (4, 7, 35).The pandemic 2009 (H1N1) influenza A virus originates from a swine influenza A virus strain. It underwent multiple reassortment events in pigs and then transferred into the human population (8, 38). The new virus has gene segments from the North American triple-reassortant and Eurasian swine H1N1 viruses (8, 38). Sequence analysis of this new pandemic virus revealed that hemagglutinin (HA), NP, and NS gene segments are derived from the classical swine viruses, PB1 from human H3N2, and PB2 and PA from avian viruses within the triple-reassortant virus (8). In addition, the NA and M segments originate from the Eurasian swine virus lineage. The pandemic 2009 (H1N1) virus is genetically and antigenically distinct from previous seasonal human influenza A (H1N1) viruses. Thus, the current seasonal influenza vaccines are likely to give little, if any, protection against pandemic 2009 A (H1N1) virus infection (12, 14). However, some evidence indicates that people born early in the 20th century have cross-neutralizing antibodies against the pandemic 2009 A (H1N1) viruses (12, 14).At present, relatively little is known about the pathogenesis and transmission of the pandemic 2009 A (H1N1) virus in humans. Studies with ferrets revealed that the pandemic virus replicated better than seasonal H1N1 viruses in the respiratory tracts of the animals. This suggests that the virus is more pathogenic in ferrets than seasonal influenza viruses (19, 24). The respiratory tract is the primary infection site of all mammalian influenza viruses, and, indeed, the specific glycan receptors on the apical surface of the upper respiratory tract have been reported to bind HA of the 2009 A (H1N1) virus (19). In human lung tissue binding assays, 2009 A (H1N1) HA showed a glycan binding pattern similar to that of the HA from the pandemic 1918 A (H1N1) virus though its affinity to α2,6 glycans was much lower than that of the 1918 virus HA. The lower glycan binding properties of the pandemic 2009 A (H1N1) virus seemed to correlate with less-efficient transmission in ferrets compared to seasonal H1N1 viruses (19). According to another study with ferrets, the transmission of the pandemic 2009 A (H1N1) virus via respiratory droplets was as efficient as that of a seasonal A (H1N1) virus (24). It is clear that, besides experimental infections in animal models, analyses of the characters and pathogenesis of the pandemic 2009 A (H1N1) virus infection in humans are urgently needed.In the present study, we have focused on analyzing innate immune responses in primary human dendritic cells (DCs) and macrophages in response to an infection with one of the Finnish isolates of the pandemic 2009 A (H1N1) virus. DCs and macrophages reside beneath the epithelium of the respiratory organs, and these cells are thus potential targets for influenza viruses. From the epithelial cells influenza viruses spread in DCs and macrophages, which coordinate the development of an effective innate immune response against the virus (22, 34, 41). During influenza virus infection, DCs and macrophages secrete antiviral cytokines such as interferons (IFNs) and tumor necrosis factor alpha (TNF-α) (3, 13, 26). Moreover, DCs and macrophages activate virus-destroying NK cells and T cells with the cytokines they secrete and via direct cell-to-cell contacts (9, 29, 33, 37). Here we show that the pandemic (H1N1) virus infects and replicates very well in human monocyte-derived DCs and macrophages. The pandemic virus as well as two recent seasonal H1N1 viruses induced a relatively weak innate immune response in these cells, as evidenced by a poor expression of antiviral and proinflammatory cytokine genes. However, like seasonal influenza A viruses, the pandemic 2009 (H1N1) virus was extremely sensitive to the antiviral actions of type I IFNs (IFN-α/β). Interestingly, the pandemic 2009 (H1N1) virus was even more sensitive to antiviral IFN-λ3 than a seasonal A (H1N1) virus. Thus, IFNs may provide us with an additional means to combat severe pandemic influenza virus infections, especially if viral resistance against neuraminidase (NA) inhibitors begins to emerge.     

Association between First Nations ethnicity and progression to kidney failure by presence and severity of albuminuria

Background:

Despite a low prevalence of chronic kidney disease (estimated glomerular filtration rate [GFR] < 60 mL/min per 1.73 m²), First Nations people have high rates of kidney failure requiring chronic dialysis or kidney transplantation. We sought to examine whether the presence and severity of albuminuria contributes to the progression of chronic kidney disease to kidney failure among First Nations people.

Methods:

We identified all adult residents of Alberta (age ≥ 18 yr) for whom an outpatient serum creatinine measurement was available from May 1, 2002, to Mar. 31, 2008. We determined albuminuria using urine dipsticks and categorized results as normal (i.e., no albuminuria), mild, heavy or unmeasured. Our primary outcome was progression to kidney failure (defined as the need for chronic dialysis or kidney transplantation, or a sustained doubling of serum creatinine levels). We calculated rates of progression to kidney failure by First Nations status, by estimated GFR and by albuminuria category. We determined the relative hazard of progression to kidney failure for First Nations compared with non–First Nations participants by level of albuminuria and estimated GFR.

Results:

Of the 1 816 824 participants we identified, 48 669 (2.7%) were First Nations. First Nations people were less likely to have normal albuminuria compared with non–First Nations people (38.7% v. 56.4%). Rates of progression to kidney failure were consistently 2- to 3-fold higher among First Nations people than among non–First Nations people, across all levels of albuminuria and estimated GFRs. Compared with non–First Nations people, First Nations people with an estimated GFR of 15.0–29.9 mL/min per 1.73 m² had the highest risk of progression to kidney failure, with similar hazard ratios for those with normal and heavy albuminuria.

Interpretation:

Albuminuria confers a similar risk of progression to kidney failure for First Nations and non–First Nations people.Severe chronic kidney disease (estimated glomerular filtration rate [GFR] < 30 mL/min per 1.73 m²) is almost 2-fold higher, and rates of end-stage kidney disease (defined as the need for chronic dialysis or kidney transplantation) are 4-fold higher, among First Nations people compared with non–First Nations people in Canada.^1,2 The reasons for the higher rate of end-stage kidney disease when there is a lower prevalence of earlier stages of chronic kidney disease in First Nations people (estimated GFR 30–60 mL/min per 1.73 m²) are unclear. The rising incidence of diabetes is seen as the major cause of kidney failure among First Nations people;³ however, First Nations people without diabetes are also 2–3 times more likely to eventually have kidney failure.⁴ These observations suggest that diabetes is not the sole determinant of risk for kidney failure and that there are yet undefined factors that may accelerate the progression of chronic kidney disease in the First Nations population.⁵Recent studies have highlighted the prognostic importance of albuminuria as a risk factor for kidney failure.⁶ Although ethnic variations in the prevalence and severity of albuminuria and their association with renal outcomes have been reported, these studies are primarily limited to non–First Nations populations.⁷ A limited number of studies have reported an increased prevalence of albuminuria among First Nations people, suggesting the potential association between albuminuria and risk of kidney failure.^8,9 We sought to measure the presence and severity of albuminuria and estimate the risk of progression to kidney failure for First Nations people compared with non–First Nations people using a community-based cohort.     

Differential Activation of NK Cells by Influenza A Pseudotype H5N1 and 1918 and 2009 Pandemic H1N1 Viruses

Natural killer (NK) cells are the effectors of innate immunity and are recruited into the lung 48 h after influenza virus infection. Functional NK cell activation can be triggered by the interaction between viral hemagglutinin (HA) and natural cytotoxicity receptors NKp46 and NKp44 on the cell surface. Recently, novel subtypes of influenza viruses, such as H5N1 and 2009 pandemic H1N1, transmitted directly to the human population, with unusual mortality and morbidity rates. Here, the human NK cell responses to these viruses were studied. Differential activation of heterogeneous NK cells (upregulation of CD69 and CD107a and gamma interferon [IFN-γ] production as well as downregulation of NKp46) was observed following interactions with H5N1, 1918 H1N1, and 2009 H1N1 pseudotyped particles (pps), respectively, and the responses of the CD56^dim subset predominated. Much stronger NK activation was triggered by H5N1 and 1918 H1N1 pps than by 2009 H1N1 pps. The interaction of pps with NK cells and subsequent internalization were mediated by NKp46 partially. The NK cell activation by pps showed a dosage-dependent manner, while an increasing viral HA titer attenuated NK activation phenotypes, cytotoxicity, and IFN-γ production. The various host innate immune responses to different influenza virus subtypes or HA titers may be associated with disease severity.Influenza is a contagious, acute respiratory disease caused by influenza viruses and has caused substantial human morbidity and mortality over the past century (24, 27). The 1918-1919 pandemic caused by influenza virus type A H1N1 was responsible for an estimated 50 million deaths (21). In recent years, novel subtype influenza viruses, such as H5N1 and the 2009 pandemic H1N1, have been transmitted directly from animals to the human population. These infections were characterized by unusually high rates of severe respiratory disease and mortality among young patients (8, 18). Various genetic shifts have occurred in these viruses, allowing them to evade the host protective effects of specific antihemagglutinin (HA) or antineuraminidase (NA) antibodies (27). Therefore, host innate immunity in the early phase of infection, which includes a variety of pattern recognition molecules, inflammatory cytokines, and immune cells, such as macrophages and natural killer (NK) cells, plays a critical role in host defense.NK cells are bone marrow-derived, large, granular lymphocytes and are key effector cells in innate immunity for host defense against invading infectious pathogens and malignant transformation through cytolytic activity and production of cytokines, such as gamma interferon (IFN-γ) (10, 28, 43, 51). In humans, NK cells account for approximately 10% of all blood lymphocytes and are identified by their expression of the CD56 surface antigen and their lack of CD3. Two distinct subsets of human NK cells have been defined according to the cell surface density of CD56 expression (10). The majority (∼90% in blood) of human NK cells are CD56^dim, and a minor population (∼10% in blood) is CD56^bright. These NK subsets are functionally distinct, with the immunoregulatory CD56^bright cells producing abundant cytokines and the cytotoxic CD56^dim cells probably functioning as efficient effectors of natural and antibody-dependent target cell lysis (11).Many lines of evidence suggest that NK cells can be functionally activated by the interaction between natural cytotoxicity receptors (NCRs) on the cell surface and influenza virus HA protein or stress-induced proteins from infected cells (2, 13, 33, 44, 46). On the other hand, influenza virus is able to evade host immunity by infecting NK cells and triggering cell apoptosis or by attenuating NK cell lysis of H3N2-infected cells, owing to alterations in HA binding properties (35, 39). The infiltration of macrophages and lymphocytes into the lung and strong inflammatory responses were detected in H5N1 and the 1918 and 2009 pandemic H1N1 infections. Nevertheless, little is known about the precise roles of NK cells in these infections.In this study, the responses of NK cells to 1918 H1N1, 2009 H1N1, and H5N1 influenza A viruses were evaluated using three strains of influenza A virus pseudotyped particles (pps). Our findings may aid in understanding the pathogenicity of influenza viruses and its correlation with clinical severity.     

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.     

Swine Influenza H1N1 Virus Induces Acute Inflammatory Immune Responses in Pig Lungs: a Potential Animal Model for Human H1N1 Influenza Virus

Pigs are capable of generating reassortant influenza viruses of pandemic potential, as both the avian and mammalian influenza viruses can infect pig epithelial cells in the respiratory tract. The source of the current influenza pandemic is H1N1 influenza A virus, possibly of swine origin. This study was conducted to understand better the pathogenesis of H1N1 influenza virus and associated host mucosal immune responses during acute infection in humans. Therefore, we chose a H1N1 swine influenza virus, Sw/OH/24366/07 (SwIV), which has a history of transmission to humans. Clinically, inoculated pigs had nasal discharge and fever and shed virus through nasal secretions. Like pandemic H1N1, SwIV also replicated extensively in both the upper and lower respiratory tracts, and lung lesions were typical of H1N1 infection. We detected innate, proinflammatory, Th1, Th2, and Th3 cytokines, as well as SwIV-specific IgA antibody in lungs of the virus-inoculated pigs. Production of IFN-γ by lymphocytes of the tracheobronchial lymph nodes was also detected. Higher frequencies of cytotoxic T lymphocytes, γδ T cells, dendritic cells, activated T cells, and CD4⁺ and CD8⁺ T cells were detected in SwIV-infected pig lungs. Concomitantly, higher frequencies of the immunosuppressive T regulatory cells were also detected in the virus-infected pig lungs. The findings of this study have relevance to pathogenesis of the pandemic H1N1 influenza virus in humans; thus, pigs may serve as a useful animal model to design and test effective mucosal vaccines and therapeutics against influenza virus.Swine influenza is a highly contagious, acute respiratory viral disease of swine. The causative agent, swine influenza virus (SwIV), is a strain of influenza virus A in the Orthomyxoviridae family. Clinical disease in pigs is characterized by sudden onset of anorexia, weight loss, dyspnea, pyrexia, cough, fever, and nasal discharge (21). Porcine respiratory tract epithelial cells express sialic acid receptors utilized by both avian (α-2,3 SA-galactose) and mammalian (α-2,6 SA-galactose) influenza viruses. Thus, pigs can serve as “mixing vessels” for the generation of new reassortant strains of influenza A virus that may contain RNA elements of both mammalian and avian viruses. These “newly generated” and reassorted viruses may have the potential to cause pandemics in humans and enzootics in animals (52).Occasional transmission of SwIV to humans has been reported (34, 43, 52), and a few of these cases resulted in human deaths. In April 2009, a previously undescribed H1N1 influenza virus was isolated from humans in Mexico. This virus has spread efficiently among humans and resulted in the current human influenza pandemic. Pandemic H1N1 virus is a triple reassortant (TR) virus of swine origin that contains gene segments from swine, human, and avian influenza viruses. Considering the pandemic potential of swine H1N1 viruses, it is important to understand the pathogenesis and mucosal immune responses of these viruses in their natural host. Swine can serve as an excellent animal model for the influenza virus pathogenesis studies. The clinical manifestations and pathogenesis of influenza in pigs closely resemble those observed in humans. Like humans, pigs are also outbred species, and they are physiologically, anatomically, and immunologically similar to humans (9, 23, 39, 40). In contrast to the mouse lung, the porcine lung has marked similarities to its human counterpart in terms of its tracheobronchial tree structure, lung physiology, airway morphology, abundance of airway submucosal glands, and patterns of glycoprotein synthesis (8, 10, 17). Furthermore, the cytokine responses in bronchoalveolar lavage (BAL) fluid from SwIV-infected pigs are also identical to those observed for nasal lavage fluids of experimentally infected humans (20). These observations support the idea that the pig can serve as an excellent animal model to study the pathogenesis of influenza virus.Swine influenza virus causes an acute respiratory tract infection. Virus replicates extensively in epithelial cells of the bronchi and alveoli for 5 to 6 days followed by clearance of viremia by 1 week postinfection (48). During the acute phase of the disease, cytokines such as alpha interferon (IFN-α), tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-12, and gamma interferon (IFN-γ) are produced. These immune responses mediate both the clinical signs and pulmonary lesions (2). In acute SwIV-infected pigs, a positive correlation between cytokines in BAL fluid, lung viral titers, inflammatory cell infiltrates, and clinical signs has been detected (2, 48).Infection of pigs with SwIV of one subtype may confer complete protection from subsequent infections by homologous viruses and also partial protection against heterologous subtypes, but the nature of the immune responses generated in the swine are not fully delineated. Importantly, knowledge related to host mucosal immune responses in the SwIV-infected pigs is limited. So far only the protective virus-specific IgA and IgG responses in nasal washes and BAL fluid, as well as IgA, IgG, and IgM responses in the sera of infected pigs, have been reported (28). Pigs infected with H3N2 and H1N1 viruses have an increased frequency of neutrophils, NK cells, and CD4 and CD8 T cells in the BAL fluid (21). Pigs infected with the pandemic H1N1 virus showed activated CD4 and CD8 T cells in the peripheral blood on postinfection day (PID) 6 (27). Proliferating lymphocytes in BAL fluid and blood and virus-specific IFN-γ-secreting cells in the tracheobronchial lymph nodes (TBLN) and spleen were detected in SwIV-infected pigs (7). Limited information is available on the mucosal immune responses in pig lungs infected with SwIV, which has a history of transmission to humans.In this study, we examined the acute infection of SwIV (strain SwIV OH07) in pigs with respect to viral replication, pathology, and innate and adaptive immune responses in the respiratory tract of these pigs. This virus was isolated from pigs which suffered from respiratory disease in Ohio, and the same virus was also transmitted to humans and caused clinical disease (43, 55). Interestingly, like pandemic H1N1 influenza virus, SwIV also infects the lower respiratory tract of pigs. Delineation of detailed mucosal immune responses generated in pig lungs during acute SwIV OH07 infection may provide new insights for the development of therapeutic strategies for better control of virus-induced inflammation and for the design and testing of effective vaccines.     

Effect of ambient air pollution on the incidence of appendicitis

Background

The pathogenesis of appendicitis is unclear. We evaluated whether exposure to air pollution was associated with an increased incidence of appendicitis.

Methods

We identified 5191 adults who had been admitted to hospital with appendicitis between Apr. 1, 1999, and Dec. 31, 2006. The air pollutants studied were ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and suspended particulate matter of less than 10 μ and less than 2.5 μ in diameter. We estimated the odds of appendicitis relative to short-term increases in concentrations of selected pollutants, alone and in combination, after controlling for temperature and relative humidity as well as the effects of age, sex and season.

Results

An increase in the interquartile range of the 5-day average of ozone was associated with appendicitis (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.03–1.25). In summer (July–August), the effects were most pronounced for ozone (OR 1.32, 95% CI 1.10–1.57), sulfur dioxide (OR 1.30, 95% CI 1.03–1.63), nitrogen dioxide (OR 1.76, 95% CI 1.20–2.58), carbon monoxide (OR 1.35, 95% CI 1.01–1.80) and particulate matter less than 10 μ in diameter (OR 1.20, 95% CI 1.05–1.38). We observed a significant effect of the air pollutants in the summer months among men but not among women (e.g., OR for increase in the 5-day average of nitrogen dioxide 2.05, 95% CI 1.21–3.47, among men and 1.48, 95% CI 0.85–2.59, among women). The double-pollutant model of exposure to ozone and nitrogen dioxide in the summer months was associated with attenuation of the effects of ozone (OR 1.22, 95% CI 1.01–1.48) and nitrogen dioxide (OR 1.48, 95% CI 0.97–2.24).

Interpretation

Our findings suggest that some cases of appendicitis may be triggered by short-term exposure to air pollution. If these findings are confirmed, measures to improve air quality may help to decrease rates of appendicitis.Appendicitis was introduced into the medical vernacular in 1886.¹ Since then, the prevailing theory of its pathogenesis implicated an obstruction of the appendiceal orifice by a fecalith or lymphoid hyperplasia.² However, this notion does not completely account for variations in incidence observed by age,^3,4 sex,^3,4 ethnic background,^3,4 family history,⁵ temporal–spatial clustering⁶ and seasonality,^3,4 nor does it completely explain the trends in incidence of appendicitis in developed and developing nations.^3,7,8The incidence of appendicitis increased dramatically in industrialized nations in the 19th century and in the early part of the 20th century.¹ Without explanation, it decreased in the middle and latter part of the 20th century.³ The decrease coincided with legislation to improve air quality. For example, after the United States Clean Air Act was passed in 1970,⁹ the incidence of appendicitis decreased by 14.6% from 1970 to 1984.³ Likewise, a 36% drop in incidence was reported in the United Kingdom between 1975 and 1994¹⁰ after legislation was passed in 1956 and 1968 to improve air quality and in the 1970s to control industrial sources of air pollution. Furthermore, appendicitis is less common in developing nations; however, as these countries become more industrialized, the incidence of appendicitis has been increasing.⁷Air pollution is known to be a risk factor for multiple conditions, to exacerbate disease states and to increase all-cause mortality.¹¹ It has a direct effect on pulmonary diseases such as asthma¹¹ and on nonpulmonary diseases including myocardial infarction, stroke and cancer.^11–13 Inflammation induced by exposure to air pollution contributes to some adverse health effects.^14–17 Similar to the effects of air pollution, a proinflammatory response has been associated with appendicitis.^18–20We conducted a case–crossover study involving a population-based cohort of patients admitted to hospital with appendicitis to determine whether short-term increases in concentrations of selected air pollutants were associated with hospital admission because of appendicitis.     

Epidemiology of diabetes mellitus among First Nations and non-First Nations adults

Background

First Nations people in Canada experience a disproportionate burden of type 2 diabetes mellitus. To increase our understanding of this evolving epidemic, we compared the epidemiology of diabetes between First Nations and non-First Nations adults in Saskatchewan from 1980 to 2005.

Methods

We used administrative databases to perform a population-based study of diabetes frequency, incidence and prevalence in adults by ethnic background, year, age and sex.

Results

We identified 8275 First Nations and 82 306 non-First Nations people with diabetes from 1980 to 2005. Overall, the incidence and prevalence of diabetes were more than 4 times higher among First Nations women than among non-First Nations women and more than 2.5 times higher among First Nations men than among non-First Nations men. The number of incident cases of diabetes was highest among First Nations people aged 40–49 , while the number among non-First Nations people was greatest in those aged 70 or more years. The prevalence of diabetes increased over the study period from 9.5% to 20.3% among First Nations women and from 4.9% to 16.0% among First Nations men. Among non-First Nations people, the prevalence increased from 2.0% to 5.5% among women and from 2.0% to 6.2% among men. By 2005, almost 50% of First Nations women and more than 40% of First Nations men aged 60 or older had diabetes, compared with less than 25% of non-First Nations men and less than 20% of non-First Nations women aged 80 or older.

Interpretation

First Nations adults are experiencing a diabetes epidemic that disproportionately affects women during their reproductive years. This ethnicity-based pattern suggests diverse underlying mechanisms that may include differences in the diabetogenic impact of gestational diabetes.The global epidemic of type 2 diabetes mellitus disproportionately affects indigenous and developing populations.¹ Although genotypic variants related to energy balance may underlie this epidemic,² the rapid emergence of type 2 diabetes in genetically diverse populations worldwide is most likely caused by environmental factors. Increasing rates of type 2 diabetes among Canada’s First Nations people, for example, parallel an epidemic of overweight and obesity that has coincided with socio-cultural disruption and a loss of traditional lifestyles.³In Saskatchewan in 1937, diabetes was not detected among the 1500 First Nations people who underwent a tuberculosis survey.⁴ By 1990, almost 10% of the province’s First Nations adults had diabetes;⁵ by 2006, the proportion was over 20%,⁶ while it remained at about 6% in the general population.^5,6 Although an increased prevalence of diabetes among First Nations people has also been documented in other Canadian provinces,³ only recently have consistent diabetes case definitions applied to health care system administrative databases been used to compare differences between large populations of First Nations and non-First Nations people.^7–9We sought to describe the epidemiology of diabetes in Saskatchewan from 1980 to 2005. We reasoned that finding ethnicity-based differences in trends and patterns of type 2 diabetes over the longest period reported for a Canadian jurisdiction would help to clarify the underlying mechanisms behind known disparities and translate into more effective diabetes prevention and management initiatives.     

Evolution and control of H5N1

The evolutionary dynamics of the H5N1 virus present a challenge for conventional control measures. Efforts must consider the regional aspects of endemic H5N1.The H5N1 virus has spread across Asia, Europe and Africa, and has infected birds in several endemic areas, including China, Indonesia, Vietnam and Egypt. H5N1 outbreaks pose a massive threat for the poultry industry and, ultimately, for human health [1]. However, the rapid spread of the virus also offers the opportunity to study and learn from its dynamics in the wild. The insights gained should inform new public health policies and preventive actions against a possible pandemic.Progress in influenza research has been impressive. In particular, the application of reverse genetics has led to the identification of mutations and reassortment changes that determine virus virulence. Perhaps the most significant results come from the two now infamous studies, published in Nature and Science, about the generation of recombinant H5N1 viruses that are transmissible in ferrets [2,3]. These advances show that we are steadily elucidating influenza virus at the molecular level. By contrast, our understanding of the dynamics of highly pathogenic influenza virus in the environment remains limited [4,5].Highly pathogenic avian influenza (HPAI) is an important poultry disease. The major reservoir of the virus is wild waterfowl, and infected birds are usually asymptomatic as a result of long-term evolutionary adaptation [1,6]. After transmission from wild waterfowl to poultry, however, avian influenza viruses occasionally become highly pathogenic and can cause mortalities of up to 100% within 48 h of infection. The standard method for controlling an HPAI outbreak is the testing and culling of all infected poultry, and the setting up of a concentric control area around the infected flock.The HPAI H5N1 virus, circulating in Eurasia and Africa, emerged in China around 1997 [1] but it only infected terrestrial birds at the time. Continuous transmission in poultry eventually allowed the virus to evolve, resulting in large outbreaks in China in 2005 with high mortality in wild waterfowl. The virus spread rapidly, probably though migratory birds, to Central Asia, Europe, the Middle East and Africa. Such ‘east to west'' movements of H5N1 viruses over comparably long distances have not since been recorded. Moreover, migrating wildfowl have begun to spread the virus intermittently between Asia and Siberia [7]. This H5N1 lineage is the longest-circulating HPAI virus that has been reported, and it has reached epizootic levels in both domestic and wild bird populations.…the challenge is to understand the evolution of H5N1 to better predict new strains that could become a serious threat for human healthOne of the striking characteristics of the H5N1 lineage, in contrast with other HPAI, is its infectivity toward mammals. H5N1 can be directly transmitted from birds to humans and cause severe disease, although it has a significantly lower transmissibility than seasonal influenza viruses [1]. So far, 608 cases of human H5N1 infections have been reported with 59% mortality [5]. Most human infections have resulted from close contact with H5N1-infected poultry or poultry products, and no sustained human–human transmission has as yet been documented. Nonetheless, a potential H5N1 pandemic remains a great concern for public health.The viruses that caused the five influenza pandemics since 1900 arose by two mechanisms: reassortment among avian, human and swine influenza viruses, and accumulation of mutations in an avian influenza virus [1,8]. Triple reassortment between avian H5N1, swine H3N1 and H1N1 viruses, and double reassortment between avian H5N1 and H9N2 viruses has already been reported in Asia, which raises concerns about new reassortment viruses that could infect humans [9,10]. Meanwhile, research has identified some 80 genetic mutations that could increase infectivity of avian influenza viruses in mammals, and thus potentially facilitate avian influenza evolution to generate a pandemic strain [8,11]. H5N1 strains with some of these mutations have often been found in bird populations [5] and in human H5N1 strains [12]. Indeed, specific mutations that could confer switching in receptor-binding specificity were reported in H5N1-infected patients in Thailand [13]. The two controversial studies published in Nature and Science also showed how a handful of mutations might enable the H5N1 virus to be transmitted between humans [2,3]. Pathogenic variants of the H5N1 virus with a higher pandemic potential could naturally evolve; the challenge is to understand the evolution of H5N1 to better predict new strains that could become a serious threat for human health.…continuous replication of H5N1 virus in Egypt has provided a valuable opportunity to study the impact of genetic evolution on phenotypic variation without reassortmentThe evolutionary dynamics of the Egyptian H5N1 strains provide clues to understanding the pandemic potential of H5N1. The virus was introduced only once in Egypt, in early 2006, and spread among a variety of bird species, including chickens, ducks, turkeys, geese and quail [14]. The virus rapidly evolved to form a phylogenetically distinct clade that has since diverged into multiple sublineages [15]. Thus, continuous replication of H5N1 virus in Egypt has provided a valuable opportunity to study the impact of genetic evolution on phenotypic variation without reassortment.After diversification in local bird populations, some new H5 sublineages have emerged in Egypt with a higher affinity for human-type receptors. Indeed, since their emergence in 2008, almost all human H5N1 strains in Egypt have been phylogenetically grouped into these new sublineages, which can be transmitted to humans with a higher efficacy than other avian influenza viruses. This might explain why, since 2009, Egypt has had the highest number of human cases of H5N1 infection, with more than 50% of the cases worldwide [5]. Fortunately, these Egyptian H5N1 sublineages still do not have binding affinity for receptors in the upper respiratory tract and, therefore, do not sustain transmission in humans. However, it increases the risk of H5N1 variants that are better adapted to humans after viral replication in infected patients.…Egypt is regarded as the country with the highest H5N1 pandemic potential worldwideThe Egyptian H5N1 sublineages are also diversifying antigenically in the field, as some are no longer crossreactive to other co-circulating sublineages [15]. Moreover, faint traces of species-specific evolutionary changes have been detected [16], implying a change in their host species. It shows that the H5N1 virus has undergone significant diversification in Egypt during the past seven years. Of greater concern, however, are Egyptian H5N1 strains that carry mammalian influenza virus type PB2 and have lost the N-linked 158 glycosylation site in the top region of haemagglutinin [15,17], both of which can potentially facilitate viral transmission to humans. The genetic diversification of H5N1 virus in Egypt represents an increasing pandemic potential, and Egypt is regarded as the country with the highest H5N1 pandemic potential worldwide [18].A similar situation exists in other geographical areas. Multiple clades and sublineages of H5N1 are co-circulating in Asia, occasionally enabling reassortment events within and beyond the viral subtypes in the field [19,20]. Several H5N1 strains with enhanced binding affinity to human-type receptors have been reported in Indonesia [12]. Similarly, avian and swine H5N1 strains with an altered receptor-binding preference have been isolated sporadically in Indonesia and Laos [21,22]. As in other areas, distinct groups of H5N1 viruses are circulating amongst themselves and with other avian influenza viruses, generating diverse viral phenotypes in nature. The evolutionary dynamics of H5N1 might even accelerate in the wild. H5N1 viruses diverge genetically in ducks [23]; they can transfer the virus over long distances by migration. Thus, the H5N1 virus has established a complex life cycle in nature with accelerated evolutionary dynamics. The pandemic threat of H5N1 remains a serious concern and might be increasing.Control measures based on isolating and culling are still the gold standard for controlling the early phase of an H5N1 outbreak, and worked against the H5N1 outbreaks in Hong Kong in 1997 and in Thailand in 2004 [4]. However, this measure failed in several countries and made H5N1 endemic. Cross-border circulation of H5N1 further complicates implementation of a classical control strategy based on culling in the infected area.In response, public health officials in several countries, including Egypt and Indonesia, advocate poultry vaccination as a preventive or adjunct control measure [1]. Although vaccination does not completely prevent infections, its proper use can help to control avian influenza outbreaks by reducing virus transmission from infected animals. However, it can also increase vaccine-driven evolution among avian influenza viruses. The endemic status of H5N1, which can cause devastating local epidemics, puts pressure on health officers to use a vaccine or a vaccination strategy that might eventually increase selective pressure and thereby accelerate H5N1 evolution. Given the high mutability and diversity of circulating viruses, it seems best to avoid using a vaccine based on a strain from a different geographical area because there would only be a partial antigen match; such a heterologous vaccine would only be effective in the short term compared with a homologous vaccine. During past control of H5N1 epidemics using imported vaccines, escape mutants have emerged within about a year of the start of vaccination, which made the epidemic even worse [14]. When a vaccination strategy is implemented in an endemic area, the vaccine seed strain should be selected from the same geographical area to try to get the longest possible protection. Vaccine seed virus selection must be periodically revised to produce well-matched and efficacious vaccines.Close communication and workshops hold the greatest potential for controlling the H5N1 virusIn most cases, H5 vaccine for an endemic area comes from a foreign supplier. It would be necessary to enable foreign manufacturers to produce customized H5 vaccines based on epidemic strains from different areas. The best approach might be a plasmid-based reverse genetics system to construct vaccine seed viruses [1]. In egg-based production, which is the basis of flu vaccine production, the seed virus needs to be adapted for high growth. This time-consuming step carries the risk of antigenic changes during vaccine production. Yet, advances in influenza reverse genetics have led to the development of cell culture systems to produce recombinant viruses, which would enable rapid genetic mutagenesis and reassortment. Once reverse genetics generates a virus genome that is well adapted to growth in cell culture, the haemagglutinin and neuraminidase genes can be easily interchanged with those of other influenza viruses. In addition, virus growth in cell culture can shorten production time, which increases the probability of selecting a seed virus antigenically appropriate for the upcoming flu season, and enables a rapid increase in production if necessary [24].A control strategy imposed without consideration of regional customs will not be successfulGiven the zoonotic risks of influenza viruses to both humans and animals, the establishment of a vaccine production system applicable to both human and animal infections is an urgent issue. The capacity of vaccine production needs to be flexible for seasonal, pre-pandemic and pandemic vaccines. Advances in genetic engineering facilitate in vitro control of human- and avian-type receptor expression on cultured cells, which should allow both human and avian influenza viruses to grow in the same system. As vaccine production capacity based on cell culture develops, commercial production of H5N1 vaccines tailored to each geographical area should become possible. In addition, emergency vaccination guidelines, such as pre-pandemic vaccine stockpiling, expanding and accelerating vaccine production and setting vaccination priorities, should be formulated in a business–government partnership, to ensure pandemic preparation. There is no guarantee that the H5N1 virus will be the next pandemic influenza strain. However, exploring options for versatile vaccine manufacturing is a key to controlling zoonotic influenza viruses, including H5N1.The complexity of H5N1 ecology also makes control of endemic H5N1 by vaccination a complex task. The problem is that antigenically different groups of viruses, which are not crossreactive, are often co-circulating in endemic areas. Circulation of viruses in each sublineage is not restricted in terms of geography or host species, which complicates efforts to use a vaccine produced against antigens from a single virus strain [15]. Of greater concern, H5N1 virus infects a variety of bird species [1], which means the vaccination targets have expanded. Bird species differ in their optimal vaccination protocol—for example, the single vaccination used routinely in chickens does not induce an adequate immune response in turkeys, which require multi-dose vaccination at an older age [25]. Furthermore, rearing many bird species and their hybrid breeds in uncontrolled confinement is common in H5N1 endemic countries, especially in rural areas. Therefore, the immunogenicity of existing vaccines is probably inadequate to protect all target species with a single vaccination scheme. Endemic H5N1 already forces public health officials to redefine vaccine development policy to improve both vaccine immunogenicity and vaccination regime.Unfortunately, it is unlikely that science will ever produce a clear answer as to when, where and how the next pandemic influenza virus will emergeToday, there are numerous techniques that could overcome these problems by increasing immunogenic potency and crossreactivity. Innovative vaccine formats—multivalent, universal, nasal and synthetic vaccines—possibly coupled with the use of adjuvants, could improve the global vaccine supply [24]. These new technologies should be applied as soon as possible. Nevertheless, no single technique can probably resolve the underlying complexity of H5N1 dynamics. Over-reliance on vaccination might therefore only worsen the situation. Vaccination can help control endemic H5N1 only when administered as part of an integrated control programme that includes surveillance, culling, restricting host movement and enhanced quarantine and biosecurity.The complex evolutionary dynamics of the H5N1 virus are challenging host species barriers and the ecology brings H5N1 into close proximity to humans [1]. The close link between the virus and humans is a multifaceted phenomenon that can affect health in myriad ways. Thus, we need to redefine control strategies to address the nature of H5N1 dynamics. Surveillance is the basis of infection control in the field. Wild birds and their predators should be included as surveillance targets, thereby expanding the H5N1 host species range. Another drawback is the fact that epidemiological studies focus mainly on virus genotyping. Although genetic data is informative, the diversity of H5N1 viruses makes characterization based only on genetic traits difficult. Characterization of viral phenotypes—antigenicity, receptor-binding preference, pathogenicity and transmissibility—is equally important for investigating the evolutionary dynamics of H5N1 viruses in nature. We would need techniques to determine easily viral phenotype, in particular new rapid diagnostic systems that can be used for timely epidemiological investigations and rapid infection control measures [1]. For example, portable kits that can determine virus receptor specificity would allow field testing of whether a particular avian influenza virus strain has adapted to human-type receptors, thereby adding a new dimension for characterizing and assessing H5N1 outbreaks.Our perception of H5N1 control should change from short-term hunting to long-term controlThe large-scale slaughter of all known and suspected infected birds in H5N1 endemic countries is hugely expensive in terms of execution costs and compensation for lost poultry. Financial assistance from international organizations might be needed to promote the thorough implementation of such a policy. However, H5N1 endemic countries are not all poor nations and some have already built a certain level of technology infrastructure. Thus, transfer of epidemiological skills and concepts to local health officers and scientists is a priority. Overseas collaborations between technologically developed countries and their institutions, and H5N1 endemic countries and their institutions, should be established at a functional level. Close communication and workshops hold the greatest potential for controlling the H5N1 virus. Such projects supported by governments and funding agencies would encourage establishment of bilateral and multilateral relationships between developed countries and the developing countries, which are the epicentres of H5N1 outbreaks. Sharing information about risk and risk management is one of the key methods for reducing the threat of future H5N1 epidemics.Globalization has had major benefits for international travel and trade, and sharing of information. The improvements in information technology have dramatically increased the speed and ease of data flow [26]. Intelligence networks facilitate instantaneous sharing of information and enable global warnings about potential hazards as well as problem-solving. Moreover, collaborative research centres, which have been established on reciprocal bases between scientifically advanced countries and institutes and overseas partner countries and institutes in Asia, Africa and Latin America, are important players in information networking—for instance the Institute Pasteur Network, the Mahidol Oxford Tropical Medicine Research Unit and Japan Initiative for Global Research Network on Infectious Diseases. Linking such laboratory-based networks should be the next step. This would have a profound synergistic effect by maximizing research capacity, human resources and geographic coverage to build a robust global-scale network for infection control.However, regional socio-cultural issues can be a significant concern for virus control wherever accepted values and scientific understanding might differ. Multiple local and regional factors—customs, religion, politics and economics—can affect H5N1 control in an area. Successful implementation of an H5N1 control strategy depends largely on mutual understanding and consideration of local idiosyncrasies.Some examples from Egypt show how regional identity can be closely linked with local public health initiatives. Egypt is an Islamic nation and bird meat is an important source of animal protein, and the only source in some rural areas [14]. A large proportion of Egyptian households in rural areas raise poultry. Although broiler and layer chickens are raised under modern hygienic controls on commercial farms, backyard birds are raised in open uncontrolled farms, leaving them free to interact with other birds (Fig 1A). The poultry meat trade depends mainly on live bird markets in traditional bazaars (Fig 1B), because of a preference for freshly slaughtered poultry. Pigeon towers are built on farms, backyards and roofs throughout villages to raise pigeons for eating. Generally, birds in Egypt are raised in proximity to humans (Fig 1C), which presents an increasing risk of human H5N1 infection in Egypt and establishment of endemic H5N1 in birds nationwide.Open in a separate windowFigure 1Socio-cultural traditions in rearing birds for food in Egypt. (A) Free rearing of backyard birds. (B) Live birds at a downtown market. (C) An example of the intertwined relationship between birds and humans.Such regional identity is inseparable from socio-cultural contexts, making fundamental change virtually impossible. Although there are many scenarios in which a local public health system could be improved by food safety standards and veterinary inspection or short-term closing of live bird markets for virus clearance, H5N1 control measures have to be implemented whilst respecting the intrinsic socio-cultural traditions in the region. A control strategy imposed without consideration of regional customs will not be successful. It is the local health officers and scientists who are best suited to address the enormous complexity and breadth of issues required for H5N1 control. They also experience H5N1 outbreaks in their area on a regular basis and have a great incentive to be involved in infection control. Therefore, it is important to include local expertise in planning and implementing a control strategy.Science in an area such as infectious disease research can no longer be viewed as independent of societal needs…Science is frequently looked at as if it can produce a ‘silver bullet'' to solve every problem. Early success in vaccine and antibiotic development also created a false sense of optimism that scientific methods could eliminate the risk of infection. However, the reality has turned out to be different—some infectious diseases remain uncontrollable and far from eradication. Given the mutable and diversifying nature of avian influenza viruses, there is a significant possibility that different avian influenza subtypes and strains do not follow a single evolutionary pathway. Unfortunately, it is unlikely that science will ever produce a clear answer as to when, where and how the next pandemic influenza virus will emerge. Our perception of H5N1 control should change from short-term hunting to long-term control. The ecology of H5N1 virus brings it into close proximity to humans. The most important strategy is to minimize contact between terrestrial poultry and wild waterfowl to segregate H5N1 in poultry, because H5N1 spread would be uncontrollable if it established a stable equilibrium in waterfowl. For example, H5N1 viruses in Siberia have not been consistently isolated each year from carcasses and faeces of wildfowl migrating from Asia [7]. This implies that H5N1 circulation in the wild still largely depends on occasional introduction from poultry. It is possible that trials to limit H5N1 infection in poultry would lead to a reduction in viral spread and a dwindling evolutionary path in nature. Infection control policy must abandon fixed strategies in favour of flexible ones to keep pace with the evolutionary dynamics of pathogens such as H5N1 (Fig 2).Open in a separate windowFigure 2Changing dynamics of H5N1 virus in the field. Endemic H5N1 virus diversifies in nature, making traditional control measures extremely difficult.Today''s infection control strategy is becoming largely dependent on the reliability and accuracy of information networking. However, the vast flood of scientific information can hide erroneous information and easily mislead the public [26]. Of greater concern, globalization has prompted the centralization of capital and resources, which can lead to an overemphasis on certain research topics. As a consequence, research projects are often short term, without consideration of effects that might have a long-term social impact [27]. This has led to a debate about whether to limit publication of certain types of research or keep scientific information completely accessible. There is probably no easy answer to this. Our global society needs a more mature approach to support research projects that are accurate reflections of societal needs in public health. At the same time, the increasing links between science and society put more pressure on science to play a greater role in society. This is a serious dilemma—how to use science to solve societal problems whilst maintaining its autonomy [27]. Science in an area such as infectious disease research can no longer be viewed as independent of societal needs; we need to establish a balance between the pursuit of independent basic research and its application for solving clinical problems and crises.? Open in a separate windowYohei WatanabeOpen in a separate windowKazuyoshi IkutaOpen in a separate windowMadiha S Ibrahim     

Influenza vaccination,pneumococcal vaccination and risk of acute myocardial infarction: matched case–control study

Background

Previous studies have shown an association between acute myocardial infarction and preceding respiratory infection. Contradictory evidence exists on the influence of influenza vaccination and pneumococcal vaccination in preventing cardiovascular disease. We aimed to investigate the possible association of influenza vaccination and pneumococcal vaccination with acute myocardial infarction.

Methods

We used a matched case–control design with data from the United Kingdom General Practice Research Database. Cases were patients who were at least 40 years of age at diagnosis of first acute myocardial infarction recorded from Nov.1, 2001, to May 31, 2007, and were matched for sex, general practice, age and calendar time (i.e., month corresponding to index date of acute myocardial infarction), with up to four controls each. Data were analyzed using conditional logistic regression, adjusted for vaccination target groups, cardiovascular risk factors, treatment medications and attendances at a general practice.

Results

We included 78 706 patients, of whom 16 012 were cases and 62 694 were matched controls. Influenza vaccination had been received in the previous year by 8472 cases (52.9%) and 32 081 controls (51.2%) and was associated with a 19% reduction in the rate of acute myocardial infarction (adjusted odds ratio [OR] 0.81, 95% confidence interval [CI] 0.77–0.85). Early seasonal influenza vaccination was associated with a lower rate of acute myocardial infarction (adjusted OR 0.79, 95% CI 0.75–0.83) than vaccination after mid-November (adjusted OR 0.88, 95% CI 0.79–0.97). Pneumococcal vaccination was not associated with a reduction in the rate of acute myocardial infarction (adjusted OR 0.96, 95% CI 0.91–1.02).

Interpretation

Influenza vaccination but not pneumococcal vaccination is associated with a reduced rate of first acute myocardial infarction. This association and the potential benefit of early seasonal vaccination need to be considered in future experimental studies.Winter peaks in incidence of acute myocardial infarction have been linked to climate,¹ metabolic factors² and infection.³ Because known risk factors do not fully account for cases of acute myocardial infarction, current interest is focused on the putative link with respiratory infection. Significant increases in acute myocardial infarction occur during peak winter incidence of pneumonia, influenza and influenza-like syndrome,⁴ particularly during years dominated by epidemic rather than nonepidemic influenza A. This association supports the notion that the increase is caused by influenza rather than cold weather.⁵Acute myocardial infarction may increase susceptibility to respiratory illness,⁶ but the association between acute myocardial infarction and respiratory infection occurring within four weeks prior to the acute myocardial infarction^7,8 supports infection as a cause of acute myocardial infarction. Although the exact mechanism is unknown, the favoured hypothesis is that infection triggers plaque rupture.⁹ Although several observational studies, as well as two randomized controlled trials,^10,11 suggest a positive effect of influenza vaccine in preventing acute myocardial infarction, they provide insufficient and conflicting evidence.¹²The aim of this study was to investigate a possible association between influenza or pneumococcal vaccination and acute myocardial infarction.     

Transmission of Pandemic H1N1 Influenza Virus and Impact of Prior Exposure to Seasonal Strains or Interferon Treatment

Novel swine-origin influenza viruses of the H1N1 subtype were first detected in humans in April 2009. As of 12 August 2009, 180,000 cases had been reported globally. Despite the fact that they are of the same antigenic subtype as seasonal influenza viruses circulating in humans since 1977, these viruses continue to spread and have caused the first influenza pandemic since 1968. Here we show that a pandemic H1N1 strain replicates in and transmits among guinea pigs with similar efficiency to that of a seasonal H3N2 influenza virus. This transmission was, however, partially disrupted when guinea pigs had preexisting immunity to recent human isolates of either the H1N1 or H3N2 subtype and was fully blocked through daily intranasal administration of interferon to either inoculated or exposed animals. Our results suggest that partial immunity resulting from prior exposure to conventional human strains may blunt the impact of pandemic H1N1 viruses in the human population. In addition, the use of interferon as an antiviral prophylaxis may be an effective way to limit spread in at-risk populations.A pandemic of novel swine-origin influenza virus (H1N1) is developing rapidly. As of 12 August 2009, nearly 180,000 cases had been reported to the WHO from around the globe (36). Sustained human-to-human transmission has furthermore been observed in multiple countries, prompting the WHO to declare a public health emergency of international concern and to raise the pandemic alert level to phase 6 (7).Swine are a natural host of influenza viruses, and although sporadic incidences of human infection with swine influenza viruses occur (8, 9, 14, 29, 35), human-to-human transmission is rare. H1N1 influenza viruses have likely circulated in swine since shortly after the 1918 human influenza pandemic (38). From the 1930s, when a swine influenza virus was first isolated, to the late 1990s, this classical swine lineage has remained relatively stable antigenically (34). In the late 1990s, however, genetic reassortment between a human H3N2 virus, a North American avian virus, and a classical swine influenza virus produced a triple reassortant virus, which subsequently spread among North American swine (34). Further reassortment events involving human influenza viruses led to the emergence in pigs of triple reassortants of the H1N1 and H1N2 subtypes (34). None of these swine viruses have demonstrated the potential for sustained human-to-human transmission.The swine-origin influenza viruses now emerging in the human population possess a previously uncharacterized constellation of eight genes (28). The NA and M segments derive from a Eurasian swine influenza virus lineage, having entered pigs from the avian reservoir around 1979, while the HA, NP, and NS segments are of the classical swine lineage and the PA, PB1, and PB2 segments derive from the North American triple reassortant swine lineage (13). This unique combination of genetic elements (segments from multiple swine influenza virus lineages, some of them derived from avian and human influenza viruses) may account for the improved fitness of pandemic H1N1 viruses, relative to that of previous swine isolates, in humans.Several uncertainties remain about how this outbreak will develop over time. Although the novel H1N1 virus has spread over a broad geographical area, the number of people known to be infected remains low in many countries, which could be due, at least in part, to the lack of optimal transmission of influenza viruses outside the winter season; thus, it is unclear at this point whether the new virus will become established in the long term. Two major factors will shape the epidemiology of pandemic H1N1 viruses in the coming months and years: the intrinsic transmissibility of the virus and the degree of protection offered by previous exposure to seasonal human strains. Initial estimates of the reproductive number (R₀) have been made based on the epidemiology of the virus to date and suggest that its rate of spread is intermediate between that of seasonal flu and that of previous pandemic strains (3, 11). However, more precise estimates of R₀ will depend on better surveillance data in the future. The transmission phenotype of pandemic H1N1 viruses in a ferret model was also recently reported and was found to be similar to (16, 27) or less efficient (25) than that of seasonal H1N1 strains. The reason for this discrepancy in the ferret model is unclear.Importantly, in considering the human population, the impact of immunity against seasonal strains on the transmission potential of pandemic H1N1 viruses is not clear. According to conventional wisdom, an influenza virus must be of a hemagglutinin (HA) subtype which is novel to the human population in order to cause a pandemic (18, 38). Analysis of human sera collected from individuals with diverse influenza virus exposure histories has indicated that in those born in the early part of the 20th century, neutralizing activity against A/California/04/09 (Cal/04/09) virus is often present (16). Conversely, serological analyses of ferret postinfection sera (13) and human pre- and postvaccination sera (4a) revealed that neutralizing antibodies against recently circulating human H1N1 viruses do not react with pandemic H1N1 isolates. These serological findings may explain the relatively small number of cases seen to date in individuals greater than 65 years of age (6). Even in the absence of neutralizing antibodies, however, a measure of immune protection sufficient to dampen transmission may be present in a host who has recently experienced seasonal influenza (10). If, on the other hand, transmission is high and immunity is low, then pandemic H1N1 strains will likely continue to spread rapidly through the population. In this situation, a range of pharmaceutical interventions will be needed to dampen the public health impact of the pandemic.Herein we used the guinea pig model (4, 21-24, 26, 30) to assess the transmissibility of the pandemic H1N1 strains Cal/04/09 and A/Netherlands/602/09 (NL/602/09) relative to that of previous human and swine influenza viruses. To better mimic the human situation, we then tested whether the efficiency of transmission is decreased by preexisting immunity to recent human H1N1 or H3N2 influenza viruses. Finally, we assessed the efficacy of intranasal treatment with type I interferon (IFN) in limiting the replication and transmission of pandemic H1N1 viruses.     

Pandemic Influenza (H1N1) 2009 Pneumonia: CURB-65 Score for Predicting Severity and Nasopharyngeal Sampling for Diagnosis Are Unreliable

Background

From the first case reports of pandemic influenza (H1N1) 2009 it was clear that a significant proportion of infected individuals suffered a primary viral pneumonia. The objective of this study was twofold; to assess the utility of the CURB-65 community acquired pneumonia (CAP) severity index in predicting pneumonia severity and ICU admission, and to assess the relative sensitivity of nasopharyngeal versus lower respiratory tract sampling for the detection of pandemic influenza (H1N1) CAP.

Methods

A retrospective cohort study of 70 patients hospitalised for pandemic influenza (H1N1) 2009 in an adult tertiary referral hospital. Characteristics evaluated included age, pregnancy status, sex, respiratory signs and symptoms, smoking and alcohol history, CURB-65 score, co-morbidities, disabling sequelae, length of stay and in-hospital mortality outcomes. Laboratory features evaluated included lymphocyte count, C-reactive protein (CRP), nasopharyngeal and lower respiratory tract pandemic influenza (H1N1) 2009 PCR results.

Results

Patients with pandemic (H1N1) 2009 influenza CAP differed significantly from those without pneumonia regarding length of stay, need for ICU admission, CRP and the likelihood of disabling sequelae. The CURB-65 score did not predict CAP severity or the need for ICU admission (only 2/11 patients admitted to ICU had CURB-65 scores of 2 or 3). Nasopharyngeal specimens for PCR were only 62.9% sensitive in CAP patients compared to 97.8% sensitivity for lower respiratory tract specimens.

Conclusions

The CURB-65 score does not predict severe pandemic influenza (H1N1) 2009 CAP or need for ICU admission. Lower respiratory tract specimens should be collected when pandemic (H1N1) 2009 influenza CAP is suspected.