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1.  Global Mortality Estimates for the 2009 Influenza Pandemic from the GLaMOR Project: A Modeling Study 
PLoS Medicine  2013;10(11):e1001558.
Lone Simonsen and colleagues use a two-stage statistical modeling approach to estimate the global mortality burden of the 2009 influenza pandemic from mortality data obtained from multiple countries.
Please see later in the article for the Editors' Summary
Background
Assessing the mortality impact of the 2009 influenza A H1N1 virus (H1N1pdm09) is essential for optimizing public health responses to future pandemics. The World Health Organization reported 18,631 laboratory-confirmed pandemic deaths, but the total pandemic mortality burden was substantially higher. We estimated the 2009 pandemic mortality burden through statistical modeling of mortality data from multiple countries.
Methods and Findings
We obtained weekly virology and underlying cause-of-death mortality time series for 2005–2009 for 20 countries covering ∼35% of the world population. We applied a multivariate linear regression model to estimate pandemic respiratory mortality in each collaborating country. We then used these results plus ten country indicators in a multiple imputation model to project the mortality burden in all world countries. Between 123,000 and 203,000 pandemic respiratory deaths were estimated globally for the last 9 mo of 2009. The majority (62%–85%) were attributed to persons under 65 y of age. We observed a striking regional heterogeneity, with almost 20-fold higher mortality in some countries in the Americas than in Europe. The model attributed 148,000–249,000 respiratory deaths to influenza in an average pre-pandemic season, with only 19% in persons <65 y. Limitations include lack of representation of low-income countries among single-country estimates and an inability to study subsequent pandemic waves (2010–2012).
Conclusions
We estimate that 2009 global pandemic respiratory mortality was ∼10-fold higher than the World Health Organization's laboratory-confirmed mortality count. Although the pandemic mortality estimate was similar in magnitude to that of seasonal influenza, a marked shift toward mortality among persons <65 y of age occurred, so that many more life-years were lost. The burden varied greatly among countries, corroborating early reports of far greater pandemic severity in the Americas than in Australia, New Zealand, and Europe. A collaborative network to collect and analyze mortality and hospitalization surveillance data is needed to rapidly establish the severity of future pandemics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza—a viral infection of the airways—and hundreds of thousands of people (mainly elderly individuals) die as a result. These seasonal epidemics occur because small but frequent changes in the influenza virus mean that the immune response produced by infection with one year's virus provides only partial protection against the next year's virus. Influenza viruses also occasionally emerge that are very different. Human populations have virtually no immunity to these new viruses, which can start global epidemics (pandemics) that kill millions of people. The most recent influenza pandemic, which was first recognized in Mexico in March 2009, was caused by the 2009 influenza A H1N1 pandemic (H1N1pdm09) virus. This virus spread rapidly, and on 11 June 2009, the World Health Organization (WHO) declared that an influenza pandemic was underway. H1N1pdm09 caused a mild disease in most people it infected, but by the time WHO announced that the pandemic was over (10 August 2010), there had been 18,632 laboratory-confirmed deaths from H1N1pdm09.
Why Was This Study Done?
The modest number of laboratory-confirmed H1N1pdm09 deaths has caused commentators to wonder whether the public health response to H1N1pdm09 was excessive. However, as is the case with all influenza epidemics, the true mortality (death) burden from H1N1pdm09 is substantially higher than these figures indicate because only a minority of influenza-related deaths are definitively diagnosed by being confirmed in laboratory. Many influenza-related deaths result from secondary bacterial infections or from exacerbation of preexisting chronic conditions, and are not recorded as related to influenza infection. A more complete assessment of the impact of H1N1pdm09 on mortality is essential for the optimization of public health responses to future pandemics. In this modeling study (the Global Pandemic Mortality [GLaMOR] project), researchers use a two-stage statistical modeling approach to estimate the global mortality burden of the 2009 influenza pandemic from mortality data obtained from multiple countries.
What Did the Researchers Do and Find?
The researchers obtained weekly virology data from the World Health Organization FluNet database and national influenza centers to identify influenza active periods, and obtained weekly national underlying cause-of-death time series for 2005–2009 from collaborators in more than 20 countries (35% of the world's population). They used a multivariate linear regression model to measure the numbers and rates of pandemic influenza respiratory deaths in each of these countries. Then, in the second stage of their analysis, they used a multiple imputation model that took into account country-specific geographical, economic, and health indicators to project the single-country estimates to all world countries. The researchers estimated that between 123,000 and 203,000 pandemic influenza respiratory deaths occurred globally from 1 April through 31 December 2009. Most of these deaths (62%–85%) occurred in people younger than 65 years old. There was a striking regional heterogeneity in deaths, with up to 20-fold higher mortality in Central and South American countries than in European countries. Finally, the model attributed 148,000–249,000 respiratory deaths to influenza in an average pre-pandemic season. Notably, only 19% of these deaths occurred in people younger than 65 years old.
What Do These Findings Mean?
These findings suggest that respiratory mortality from the 2009 influenza pandemic was about 10-fold higher than laboratory-confirmed mortality. The true total mortality burden is likely to be even higher because deaths that occurred late in the winter of 2009–2010 and in later pandemic waves were missed in this analysis, and only pandemic influenza deaths that were recorded as respiratory deaths were included. The lack of single-country estimates from low-income countries may also limit the accuracy of these findings. Importantly, although the researchers' estimates of mortality from H1N1pdm09 and from seasonal influenza were of similar magnitude, the shift towards mortality among younger people means that more life-years were lost during the 2009 influenza pandemic than during an average pre-pandemic influenza season. Although the methods developed by the GLaMOR project can be used to make robust and comparable mortality estimates in future influenza pandemics, the lack of timeliness of such estimates needs to be remedied. One potential remedy, suggest the researchers, would be to establish a collaborative network that analyzes timely hospitalization and/or mortality data provided by sentinel countries. Such a network should be able to provide the rapid and reliable data about the severity of pandemic threats that is needed to guide public health policy decisions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001558.
The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including archived information on H1N1pdm09
Flu.gov, a US government website, provides access to information on seasonal and pandemic influenza H1N1pdm09
The World Health Organization provides information on influenza and on the global response to H1N1pdm09, including a publication on the evolution of H1N1pdm09 (some information in several languages). Information on FluNet, a global tool for influenza surveillance, is also available
Public Health England provides information on pandemic influenza and archived information on H1N1pdm09
More information for patients about H1N1pdm09 is available through Choices, an information resource provided by the UK National Health Service
More information about the GLaMOR project is available
doi:10.1371/journal.pmed.1001558
PMCID: PMC3841239  PMID: 24302890
2.  Association between the 2008–09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada 
PLoS Medicine  2010;7(4):e1000258.
In three case-control studies and a household transmission cohort, Danuta Skowronski and colleagues find an association between prior seasonal flu vaccination and increased risk of 2009 pandemic H1N1 flu.
Background
In late spring 2009, concern was raised in Canada that prior vaccination with the 2008–09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association.
Methods and Findings
Studies included: (1) test-negative case-control design based on Canada's sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. Logistic regression was used to estimate odds ratios for TIV effect on community- or hospital-based laboratory-confirmed seasonal or pH1N1 influenza cases compared to controls with restriction, stratification, and adjustment for covariates including combinations of age, sex, comorbidity, timeliness of medical visit, prior physician visits, and/or health care worker (HCW) status. For the prospective study risk ratios were computed. Based on the sentinel study of 672 cases and 857 controls, 2008–09 TIV was associated with statistically significant protection against seasonal influenza (odds ratio 0.44, 95% CI 0.33–0.59). In contrast, estimates from the sentinel and three other observational studies, involving a total of 1,226 laboratory-confirmed pH1N1 cases and 1,505 controls, indicated that prior receipt of 2008–09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring–summer 2009, with estimated risk or odds ratios ranging from 1.4 to 2.5. Risk of pH1N1 hospitalization was not further increased among vaccinated people when comparing hospitalized to community cases.
Conclusions
Prior receipt of 2008–09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring–summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza—a viral infection of the airways—and hundreds of thousands of people die as a result. These seasonal epidemics occur because small but frequent changes in the influenza virus mean that an immune response produced one year through infection or vaccination provides only partial protection against influenza the next year. Annual vaccination with killed influenza viruses of the major circulating strains can greatly reduce a person's risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. In most of Canada, vaccination with a mixture of three inactivated viruses (a trivalent inactivated vaccine or TIV) is provided free to children aged 6–23 months, to elderly people, to people with long-term conditions that increase their risk of influenza-related complications, and those who provide care for them; in Ontario, free vaccination is offered to everyone older than 6 months.
In addition, influenza viruses occasionally emerge that are very different and to which human populations have virtually no immunity. These viruses can start global epidemics (pandemics) that can kill millions of people. Experts have been warning for some time that an influenza pandemic is long overdue and, in March 2009, the first cases of influenza caused by a new virus called pandemic A/H1N1 2009 (pH1N1; swine flu) occurred in Mexico. The virus spread rapidly and on 11 June 2009, the World Health Organization declared that a global pandemic of pH1N1 influenza was underway. By the end of February 2010, more than 16,000 people around the world had died from pH1N1.
Why Was This Study Done?
During an investigation of a school outbreak of pH1N1 in the late spring 2009 in Canada, investigators noted that people with illness characterized by fever and coughing had been vaccinated against seasonal influenza more often than individuals without such illness. To assess whether this association between prior vaccination with seasonal 2008–09 TIV and subsequent pH1N1 illness was evident in other settings, researchers in Canada therefore conducted additional studies using different methods. In this paper, the researchers report the results of four additional studies conducted in Canada during the summer of 2009 to assess this possible association.
What Did the Researchers Do and Find?
The researchers conducted four epidemiologic studies. Epidemiology is the study of the causes, distribution, and control of diseases in populations.
Three of the four studies were case-control studies in which the researchers assessed the frequency of prior vaccination with the 2008–09 TIV in people with pH1N1 influenza compared to the frequency among healthy members of the general population or among individuals who had an influenza-like illness but no sign of infection with an influenza virus. The researchers also did a household transmission study in which they collected information about vaccination with TIV among the additional cases of influenza that were identified in 47 households in which a case of laboratory-confirmed pH1N1 influenza had occurred. The first of the case-control studies, which was based on Canada's vaccine effectiveness monitoring system, showed that, as expected, the 2008–09 TIV provided protection against seasonal influenza. However, estimates from all four studies (which included about 1,200 laboratory-confirmed pH1N1 cases and 1,500 controls) showed that prior recipients of the 2008–09 TIV had approximately 1.4–2.5 times increased chances of developing pH1N1 illness that needed medical attention during the spring–summer of 2009 compared to people who had not received the TIV. Prior seasonal vaccination was not associated with an increase in the severity of pH1N1 illness, however. That is, it did not increase the risk of being hospitalized among those with pH1N1 illness.
What Do These Findings Mean?
Because all the investigations in this study are “observational,” the people who had been vaccinated might share another unknown characteristic that is actually responsible for increasing their risk of developing pH1N1 illness (“confounding”). Furthermore, the results reported in this study might have arisen by chance, although the consistency of results across the studies makes this unlikely. Thus, the finding of an association between prior receipt of 2008–09 TIV and an increased risk of pH1N1 illness is not conclusive and needs to be investigated further, particularly since some other observational studies conducted in other countries have reported that seasonal vaccination had no influence or may have been associated with reduced chances of pH1N1 illness. If the findings in the current study are real, however, they raise important questions about the biological interactions between seasonal and pandemic influenza strains and vaccines, and about the best way to prevent and control both types of influenza in future.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000258.
This article is further discussed in a PLoS Medicine Perspective by Cécile Viboud and Lone Simonsen
FightFlu.ca, a Canadian government Web site, provides access to information on pH1N1 influenza
The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including specific information on H1N1 influenza
Flu.gov, a US government website, provides access to information on H1N1, avian and pandemic influenza
The World Health Organization provides information on seasonal influenza and has detailed information on pH1N1 influenza (in several languages)
The UK Health Protection Agency provides information on pandemic influenza and on pH1N1 influenza
doi:10.1371/journal.pmed.1000258
PMCID: PMC2850386  PMID: 20386731
3.  Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study 
PLoS Medicine  2011;8(1):e1000388.
Results from a European multicentre case-control study reported by Marta Valenciano and colleagues suggest good protection by the pandemic monovalent H1N1 vaccine against pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine on H1N1.
Background
A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1).
Methods and Findings
Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9).
Conclusions
Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine. However, the late availability of the pandemic vaccine and subsequent limited coverage with this vaccine hampered our ability to study vaccine benefits during the outbreak period. Future studies should include estimation of the effectiveness of the new trivalent vaccine in the upcoming 2010–2011 season, when vaccination will occur before the influenza season starts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Following the World Health Organization's declaration of pandemic phase six in June 2009, manufacturers developed vaccines against pandemic influenza A 2009 (pH1N1). On the basis of the scientific opinion of the European Medicines Agency, the European Commission initially granted marketing authorization to three pandemic vaccines for use in European countries. During the autumn of 2009, most European countries included the 2009–2010 seasonal influenza vaccine and the pandemic vaccine in their influenza vaccination programs.
The Influenza Monitoring Vaccine Effectiveness in Europe network (established to monitor seasonal and pandemic influenza vaccine effectiveness) conducted seven case-control and three cohort studies in seven European countries in 2009–2010 to estimate the effectiveness of the pandemic and seasonal vaccines. Data from the seven pilot case-control studies were pooled to provide overall adjusted estimates of vaccine effectiveness.
Why Was This Study Done?
After seasonal and pandemic vaccines are made available to populations, it is necessary to estimate the effectiveness of the vaccines at the population level during every influenza season. Therefore, this study was conducted in European countries to estimate the pandemic influenza vaccine effectiveness and seasonal influenza vaccine effectiveness against people presenting to their doctor with influenza-like illness who were confirmed (by laboratory tests) to be infected with pH1N1.
What Did the Researchers Do and Find?
The researchers conducted a multicenter case-control study on the basis of practitioner surveillance networks from seven countries—France, Hungary, Ireland, Italy, Romania, Portugal, and Spain. Patients consulting a participating practitioner for influenza-like illness had a nasal or throat swab taken within 8 days of symptom onset. Cases were swabbed patients who tested positive for pH1N1. Patients presenting with influenza-like illness whose swab tested negative for any influenza virus were controls.
Individuals were considered vaccinated if they had received a dose of the vaccine more than 14 days before the date of onset of influenza-like illness and unvaccinated if they were not vaccinated at all, or if the vaccine was given less than 15 days before the onset of symptoms. The researchers analyzed pandemic influenza vaccination effectiveness in those vaccinated less than 8 days, those vaccinated between and including 8 and 14 days, and those vaccinated more than 14 days before onset of symptoms compared to those who had never been vaccinated.
The researchers used modeling (taking account of all potential confounding factors) to estimate adjusted vaccine effectiveness and stratified the adjusted pandemic influenza vaccine effectiveness and the adjusted seasonal influenza vaccine effectiveness in three age groups (<15, 15–64, and ≥65 years of age).
The adjusted results suggest that the 2009–2010 seasonal influenza vaccine did not protect against pH1N1 illness. However, one dose of the pandemic vaccines used in the participating countries conferred good protection (65.5%–100% according to various stratifications performed) against pH1N1 in people who attended their practitioner with influenza-like illness, especially in people aged <65 years and in those without any chronic disease. Furthermore, good pandemic influenza vaccine effectiveness was observed as early as 8 days after vaccination.
What Do These Findings Mean?
The results of this study provide early estimates of the pandemic influenza vaccine effectiveness suggesting that the monovalent pandemic vaccines have been effective. The findings also give an indication of the vaccine effectiveness for the Influenza A (H1N1) 2009 strain included in the 2010–2011 seasonal vaccines, although specific vaccine effectiveness studies will have to be conducted to verify if similar good effectiveness are observed with 2010–2011 trivalent vaccines. However, the results of this study should be interpreted with caution because of limitations in the pandemic context (late timing of the studies, low incidence, low vaccine coverage leading to imprecise estimates) and potential biases due the study design, confounding factors, and missing values. The researchers recommend that in future season studies, the sample size per country should be enlarged in order to allow for precise pooled and stratified analyses.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000388.
The World Health Organization has information on H1N1 vaccination
The US Centers for Disease Control and Prevention provides a fact sheet on the 2009 H1N1 influenza virus
The US Department of Health and Human services has a comprehensive website on flu
The European Centre for Disease Prevention and Control provides information on 2009 H1N1 pandemic
The European Centre for Disease Prevention and Control presents a summary of the 2009 H1N1 pandemic in Europe and elsewhere
doi:10.1371/journal.pmed.1000388
PMCID: PMC3019108  PMID: 21379316
4.  Comparison of five influenza surveillance systems during the 2009 pandemic and their association with media attention 
BMC Public Health  2013;13:881.
Background
During the 2009 influenza pandemic period, routine surveillance of influenza-like-illness (ILI) was conducted in The Netherlands by a network of sentinel general practitioners (GPs). In addition during the pandemic period, four other ILI/influenza surveillance systems existed. For pandemic preparedness, we evaluated the performance of the sentinel system and the others to assess which of the four could be useful additions in the future. We also assessed whether performance of the five systems was influenced by media reports during the pandemic period.
Methods
The trends in ILI consultation rates reported by sentinel GPs from 20 April 2009 through 3 January 2010 were compared with trends in data from the other systems: ILI cases self-reported through the web-based Great Influenza Survey (GIS); influenza-related web searches through Google Flu Trends (GFT); patients admitted to hospital with laboratory-confirmed pandemic influenza, and detections of influenza virus by laboratories. In addition, correlations were determined between ILI consultation rates of the sentinel GPs and data from the four other systems. We also compared the trends of the five surveillance systems with trends in pandemic-related newspaper and television coverage and determined correlation coefficients with and without time lags.
Results
The four other systems showed similar trends and had strong correlations with the ILI consultation rates reported by sentinel GPs. The number of influenza virus detections was the only system to register a summer peak. Increases in the number of newspaper articles and television broadcasts did not precede increases in activity among the five surveillance systems.
Conclusions
The sentinel general practice network should remain the basis of influenza surveillance, as it integrates epidemiological and virological information and was able to maintain stability and continuity under pandemic pressure. Hospital and virological data are important during a pandemic, tracking the severity, molecular and phenotypic characterization of the viruses and confirming whether ILI incidence is truly related to influenza virus infections. GIS showed that web-based, self-reported ILI can be a useful addition, especially if virological self-sampling is added and an epidemic threshold could be determined. GFT showed negligible added value.
doi:10.1186/1471-2458-13-881
PMCID: PMC3849360  PMID: 24063523
Influenza virus; Pandemic; Surveillance; Influenza-like illness; Media attention
5.  Characterizing the Epidemiology of the 2009 Influenza A/H1N1 Pandemic in Mexico 
PLoS Medicine  2011;8(5):e1000436.
Gerardo Chowell and colleagues address whether school closures and other social distancing strategies were successful in reducing pandemic flu transmission in Mexico by analyzing the age- and state-specific incidence of influenza morbidity and mortality in 32 Mexican states.
Background
Mexico's local and national authorities initiated an intense public health response during the early stages of the 2009 A/H1N1 pandemic. In this study we analyzed the epidemiological patterns of the pandemic during April–December 2009 in Mexico and evaluated the impact of nonmedical interventions, school cycles, and demographic factors on influenza transmission.
Methods and Findings
We used influenza surveillance data compiled by the Mexican Institute for Social Security, representing 40% of the population, to study patterns in influenza-like illness (ILIs) hospitalizations, deaths, and case-fatality rate by pandemic wave and geographical region. We also estimated the reproduction number (R) on the basis of the growth rate of daily cases, and used a transmission model to evaluate the effectiveness of mitigation strategies initiated during the spring pandemic wave. A total of 117,626 ILI cases were identified during April–December 2009, of which 30.6% were tested for influenza, and 23.3% were positive for the influenza A/H1N1 pandemic virus. A three-wave pandemic profile was identified, with an initial wave in April–May (Mexico City area), a second wave in June–July (southeastern states), and a geographically widespread third wave in August–December. The median age of laboratory confirmed ILI cases was ∼18 years overall and increased to ∼31 years during autumn (p<0.0001). The case-fatality ratio among ILI cases was 1.2% overall, and highest (5.5%) among people over 60 years. The regional R estimates were 1.8–2.1, 1.6–1.9, and 1.2–1.3 for the spring, summer, and fall waves, respectively. We estimate that the 18-day period of mandatory school closures and other social distancing measures implemented in the greater Mexico City area was associated with a 29%–37% reduction in influenza transmission in spring 2009. In addition, an increase in R was observed in late May and early June in the southeast states, after mandatory school suspension resumed and before summer vacation started. State-specific fall pandemic waves began 2–5 weeks after school reopened for the fall term, coinciding with an age shift in influenza cases.
Conclusions
We documented three spatially heterogeneous waves of the 2009 A/H1N1 pandemic virus in Mexico, which were characterized by a relatively young age distribution of cases. Our study highlights the importance of school cycles on the transmission dynamics of this pandemic influenza strain and suggests that school closure and other mitigation measures could be useful to mitigate future influenza pandemics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
From June 2009 to August 2010, the world was officially (according to specific World Health Organization [WHO] criteria—WHO phase 6 pandemic alert) in the grip of an Influenza A pandemic with a new strain of the H1N1 virus. The epidemic in Mexico, which had the second confirmed global case of H1N1 virus was first noted in early April 2009, when reports of respiratory hospitalizations and deaths among 62 young adults in Mexico alerted local health officials to the occurrence of atypical rates of respiratory illness. In line with its inter-institutional National Pandemic Influenza Preparedness and Response Plan, the Ministry of Health cancelled school attendance in the greater Mexico City area on April 24 and expanded these measures to the rest the country three days later. The Ministry of Health then implemented in Mexico City other “social distancing” strategies such as closing cinemas and restaurants and cancelling large public gatherings.
Why Was This Study Done?
School closures and other intense social distancing strategies can be very disruptive to the population, but as yet it is uncertain whether these measures were successful in reducing disease transmission. In addition, there have been no studies concentrating on recurrent pandemic waves in Mexico. So in this study the authors addressed these issues by analyzing the age- and state-specific incidence of influenza morbidity and mortality in 32 Mexican States and quantified the association between local influenza transmission rates, school cycles, and demographic factors.
What Did the Researchers Do and Find?
The researchers used the epidemiological surveillance system of the Mexican Institute for Social Security—a Mexican health system that covers private sector workers and their families, a group representative of the general population, that comprises roughly 40% of the Mexican population (107 million individuals), with a network of 1,099 primary health care units and 259 hospitals nationwide. Then the researchers compiled state- and age-specific time series of incident influenza-like illness and H1N1 influenza cases by day of symptom onset to analyze the geographic dissemination patterns of the pandemic across Mexico and defined three temporally distinct pandemic waves in 2009: spring (April 1–May 20), summer (May 21–August 1), and fall (August 2–December 31). The researchers then applied a mathematical model of influenza transmission to daily case data to assess the effectiveness of mandatory school closures and other social distancing measures implemented during April 24–May 11, in reducing influenza transmission rates.
The Mexican Institute for Social Security reported a total of 117,626 people with influenza-like illness from April 1 to December 31, 2009, of which 36,044 were laboratory tested (30.6%) and 27,440 (23.3%) were confirmed with H1N1 influenza. During this period, 1,370 people with influenza-like illness died of which 585 (1.5 per 100,000) were confirmed to have H1N1 influenza. The median age of people with laboratory confirmed influenza like illness (H1N1) was 18 years overall but increased to 31 years during the autumn wave. The overall case-fatality ratio among people with influenza like illness was 1.2%, but highest (5.5%) among people over 60 years. The researchers found that the 18-day period of mandatory school closures and other social distancing measures implemented in the greater Mexico City area was associated with a substantial (29%–37%) reduction in influenza transmission in spring 2009 but increased in late May and early June in the southeast states, after mandatory school suspension resumed and before summer vacation started. State-specific pandemic waves began 2–5 weeks after school reopened for the fall term, coinciding with an age shift in influenza cases.
What Do These Findings Mean?
These findings show that the age distribution of pandemic influenza morbidity was greater in younger age groups, while the risk of severe disease was skewed towards older age groups, and that there were substantial geographical variation in pandemic patterns across Mexico, in part related to population size. But most importantly, these findings support the effectiveness of early mitigation efforts including mandatory school closures and cancellation of large public gatherings, reinforcing the importance of school cycles in the transmission of pandemic influenza. This analysis increases understanding of the age and transmission patterns of the Mexican 2009 influenza pandemic at various geographic scales, which is crucial for designing more efficient public health interventions against future influenza pandemics.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000436.
The World Health Organization provides information about the global response to the 2009 H1N1 pandemic
doi:10.1371/journal.pmed.1000436
PMCID: PMC3101203  PMID: 21629683
6.  Characterization of Regional Influenza Seasonality Patterns in China and Implications for Vaccination Strategies: Spatio-Temporal Modeling of Surveillance Data 
PLoS Medicine  2013;10(11):e1001552.
Cécile Viboud and colleagues describe epidemiological patterns of influenza incidence across China to support the design of a national vaccination program.
Please see later in the article for the Editors' Summary
Background
The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs.
Methods and Findings
We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005–2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%–151%] in the north versus 37% [95% CI 27%–47%] in the south, p<0.0001). Epidemics peaked in January–February in Northern China (latitude ≥33°N) and April–June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January–February and June–August (periodicity ratio >0.6 in provinces located within 27.4°N–31.3°N, slope of latitudinal gradient with latitude −0.016 [95% CI −0.025 to −0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces.
Conclusions
Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4–6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, millions of people worldwide catch influenza, a viral disease of the airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. These epidemics occur because antigenic drift—frequent small changes in the viral proteins to which the immune system responds—means that an immune response produced one year provides only partial protection against influenza the next year. Annual vaccination with a mixture of killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces the risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. Because the immune response induced by vaccination decays within 4–8 months of vaccination and because of antigenic drift, it is important that these programs are initiated only a few weeks before the onset of local influenza activity. Thus, vaccination starts in early autumn in temperate zones (regions of the world that have a mild climate, part way between a tropical and a polar climate), because seasonal influenza outbreaks occur in the winter months when low humidity and low temperatures favor the transmission of the influenza virus.
Why Was This Study Done?
Unlike temperate regions, seasonal influenza patterns are very diverse in tropical countries, which lie between latitudes 23.5°N and 23.5°S, and in the subtropical countries slightly north and south of these latitudes. In some of these countries, there is year-round influenza activity, in others influenza epidemics occur annually or semi-annually (twice yearly). This complexity, which is perhaps driven by rainfall fluctuations, complicates the establishment of effective routine immunization programs in tropical and subtropical countries. Take China as an example. Before a national influenza vaccination program can be established in this large, climatologically diverse country, public-health experts need a clear picture of influenza seasonality across the country. Here, the researchers use spatio-temporal modeling of influenza surveillance data to characterize the seasonality of influenza A and B (the two types of influenza that usually cause epidemics) in China, to assess the role of putative drivers of seasonality, and to identify broad epidemiological regions (areas with specific patterns of disease) that could be used as a basis to optimize the timing of future Chinese vaccination programs.
What Did the Researchers Do and Find?
The researchers collected together the weekly reports of laboratory-confirmed influenza prepared by the Chinese national sentinel hospital-based surveillance network between 2005 and 2011, data on population size and density, mobility patterns, and socio-economic factors, and daily meteorological data for the cities participating in the surveillance network. They then used various statistical modeling approaches to estimate influenza seasonal characteristics, to assess predictors of influenza seasonal characteristics, and to identify epidemiologically relevant regions. These analyses indicate that, over the study period, northern provinces (latitudes greater than 33°N) experienced winter epidemics of influenza A in January–February, southern provinces (latitudes less than 27°N) experienced peak viral activity in the spring (April–June), and provinces at intermediate latitudes experienced semi-annual epidemic cycles with infection peaks in January–February and June–August. By contrast, influenza B activity predominated in the colder months throughout China. The researchers also report that minimum temperatures, hours of sunshine, and maximum rainfall were the strongest predictors of influenza seasonality.
What Do These Findings Mean?
These findings show that influenza seasonality in China varies between regions and between influenza virus types and suggest that, as in other settings, some of these variations might be associated with specific climatic factors. The accuracy of these findings is limited by the short surveillance period, by sparse surveillance data from some southern and mid-latitude provinces, and by some aspects of the modeling approach used in the study. Further surveillance studies need to be undertaken to confirm influenza seasonality patterns in China. Overall, these findings suggest that, to optimize routine influenza vaccination in China, it will be necessary to stagger the timing of vaccination over three broad geographical regions. More generally, given that there is growing interest in rolling out national influenza immunization programs in low- and middle-income countries, these findings highlight the importance of ensuring that vaccination strategies are optimized by taking into account local disease patterns.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001552.
This study is further discussed in a PLOS Medicine Perspective by Steven Riley
The UK National Health Service Choices website provides information for patients about seasonal influenza and about influenza vaccination
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza surveillance and monitoring
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination; its website contains a short video about personal experiences of influenza.
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
Information about the Chinese National Influenza Center, which is part of the Chinese Center for Disease Control and Prevention: and which runs influenza surveillance in China, is available (in English and Chinese)
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
A recent PLOS Pathogens Research Article by James D. Tamerius et al. investigates environmental predictors of seasonal influenza epidemics across temperate and tropical climates
A study published in PLOS ONE by Wyller Alencar de Mello et al. indicates that Brazil, like China, requires staggered timing of vaccination from Northern to Southern states to account for different timings of influenza activity.
doi:10.1371/journal.pmed.1001552
PMCID: PMC3864611  PMID: 24348203
7.  Clinical and epidemiological profile of patients with severe H1N1/09 pandemic influenza in Australia and New Zealand: an observational cohort study 
BMJ Open  2011;1(1):e000100.
Background
Pandemic influenza H1N1/09 emerged in April 2009 and spread widely in Australia and New Zealand. Although an unprecedented number of cases required intensive care, comparative community-based studies with seasonal influenza strains have not shown any significant differences in clinical symptoms or severity.
Methods
The authors performed active surveillance on confirmed influenza-related admissions and compared the clinical profile of patients with pandemic H1N1/09 influenza and patients with seasonal influenza at eight hospitals in Australia and one hospital in New Zealand.
Results
During the 1 July and 30 November 2009, 560 patients with confirmed influenza were admitted, of which 478 had H1N1/09, and 82 had other seasonal strains. Patients with H1N1/09 influenza were younger, were more likely to have fever and were more likely to be pregnant but less likely to have chronic obstructive pulmonary disease and ischaemic heart disease than patients with seasonal strains. Other clinical features and comorbidities were reported in similar proportions. Admission to intensive care was required in 22% of patients with H1N1/09 influenza and 12% in patients with other strains. Hospital mortality was 5% in patients with H1N1 influenza.
Conclusions
The clinical features of H1N1/09 influenza and seasonal strains were similar in hospitalised patients. A higher proportion of patients had comorbidities than had been reported in community-based studies. Although the overall mortality was similar, the authors found evidence that H1N1/09 caused severe disease in a higher proportion of hospitalised patients.
Article summary
Article focus
We performed an observational study of patients with H1N1/09 and seasonal strains of influenza in 2009, based on active surveillance at nine sentinel hospitals.
We explored differences between patients with H1N1/09 influenza infection and those with seasonal influenza infections.
Key messages
This study found that the clinical features of H1N1/09 influenza were similar in hospitalised patients, similar to previous community-based studies.
The finding that H1N1/09 influenza was associated with more severe disease reconciles apparently contradictory data suggesting no differences in community studies, but unprecedented use of critical care services.
Strengths and limitations of this study
This surveillance system was rapidly established, and initial data collection was retrospective from the medical record where symptoms were not always well documented. Despite high levels of awareness in medical staff, clinical testing criteria were operating during the period of the study and were likely to bias the proportion of patients reporting fever and respiratory symptoms. Nucleic-acid detection using PCR is regarded as the gold standard for diagnosis, but our experience with discordant results on repeated testing suggested that it may not be completely sensitive. This study does not encompass the full duration of the epidemic which was waning in several states (notably Victoria and New South Wales) at the commencement of the study period. Although several hospitals provided maternity and paediatric services, these patient groups are likely to be under-represented in this series. The population served by the sentinel hospitals is not known, and thus we were not able to establish a disease incidence rate.
This large study captured all admissions with influenza at multiple hospitals across Australia and New Zealand. All cases were confirmed by nucleic acid detection with clinical details collected by research staff.
doi:10.1136/bmjopen-2011-000100
PMCID: PMC3191436  PMID: 22021761
Infectious diseases; epidemiology; infection control; emergency medicine; toxinology; prehospital; evenoming; anaphylaxis; asthma; television; respiratory; patient reported outcomes airways disease; COPD
8.  Early Pandemic Influenza (2009 H1N1) in Ho Chi Minh City, Vietnam: A Clinical Virological and Epidemiological Analysis 
PLoS Medicine  2010;7(5):e1000277.
Rogier van Doorn and colleagues analyze the initial outbreak, attempts at containment, and establishment of community transmission of pandemic H1N1 influenza in Ho Chi Minh City, Vietnam.
Background
To date, little is known about the initial spread and response to the 2009 pandemic of novel influenza A (“2009 H1N1”) in tropical countries. Here, we analyse the early progression of the epidemic from 26 May 2009 until the establishment of community transmission in the second half of July 2009 in Ho Chi Minh City (HCMC), Vietnam. In addition, we present detailed systematic viral clearance data on 292 isolated and treated patients and the first three cases of selection of resistant virus during treatment in Vietnam.
Methods and Findings
Data sources included all available health reports from the Ministry of Health and relevant health authorities as well as clinical and laboratory data from the first confirmed cases isolated at the Hospital for Tropical Diseases in HCMC. Extensive reverse transcription (RT)-PCR diagnostics on serial samples, viral culture, neuraminidase-inhibition testing, and sequencing were performed on a subset of 2009 H1N1 confirmed cases. Virological (PCR status, shedding) and epidemiological (incidence, isolation, discharge) data were combined to reconstruct the initial outbreak and the establishment of community transmission. From 27 April to 24 July 2009, approximately 760,000 passengers who entered HCMC on international flights were screened at the airport by a body temperature scan and symptom questionnaire. Approximately 0.15% of incoming passengers were intercepted, 200 of whom tested positive for 2009 H1N1 by RT-PCR. An additional 121 out of 169 nontravelers tested positive after self-reporting or contact tracing. These 321 patients spent 79% of their PCR-positive days in isolation; 60% of PCR-positive days were spent treated and in isolation. Influenza-like illness was noted in 61% of patients and no patients experienced pneumonia or severe outcomes. Viral clearance times were similar among patient groups with differing time intervals from illness onset to treatment, with estimated median clearance times between 2.6 and 2.8 d post-treatment for illness-to-treatment intervals of 1–4 d, and 2.0 d (95% confidence interval 1.5–2.5) when treatment was started on the first day of illness.
Conclusions
The patients described here represent a cross-section of infected individuals that were identified by temperature screening and symptom questionnaires at the airport, as well as mildly symptomatic to moderately ill patients who self-reported to hospitals. Data are observational and, although they are suggestive, it is not possible to be certain whether the containment efforts delayed community transmission in Vietnam. Viral clearance data assessed by RT-PCR showed a rapid therapeutic response to oseltamivir.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, millions of people catch influenza—a viral infection of the airways—and about half a million people die as a result. These yearly seasonal epidemics occur because small but frequent changes in the influenza virus mean that the immune response produced by infection with one year's virus provides only partial protection against the next year's virus. Sometimes, however, a very different influenza virus emerges to which people have virtually no immunity. Such viruses can start global epidemics (pandemics) and can kill millions of people. Consequently, when the first case of influenza caused by a new virus called pandemic A/H1N1 2009 (2009 H1N1, swine flu) occurred in March 2009 in Mexico, alarm bells rang. National and international public health agencies quickly issued advice about how the public could help to control the spread of the virus and, as the virus spread, some countries banned flights from affected regions and instigated screening for influenza-like illness at airports. However, despite everyone's efforts, the virus spread rapidly and on June 11, 2009 the World Health Organization (WHO) declared that an influenza pandemic was underway.
Why Was This Study Done?
To date, little is known about the spread of and response to 2009 H1N1 in tropical countries. In this study, therefore, the researchers investigate the early progression of the 2009 H1N1 pandemic in Ho Chi Minh City, Vietnam, and the treatment of infected patients. On April 27, 2009, when WHO announced that human-to-human transmission of 2009 H1N1 was occurring, the Vietnamese Ministry of Health mandated airport body temperature scans and symptom questionnaire screening of travelers arriving in Vietnam's international airports. Suspected cases were immediately transferred to in-hospital isolation, screened for virus using a sensitive test called PCR, and treated with the anti-influenza drug oseltamivir if positive. The first case of 2009 H1N1 infection in Vietnam was reported on May 31, 2009 in a student who had returned from the US on May 26, 2009, and, despite these efforts to contain the infection, by the second half of July the virus was circulating in Ho Chi Minh City (community transmission).
What Did the Researchers Do and Find?
The researchers used reports from the Ministry of Health and relevant health authorities and clinical and laboratory data for people infected with 2009 H1N1 and isolated in hospital to reconstruct the initial outbreak and the establishment of community transmission in Ho Chi Minh City. Between April 27 and July 24 2009, three-quarters of a million passengers arriving in the city on international flights were screened at the airport. 200 passenger tested positive for 2009 H1N1 as did 121 nontravelers who were identified during this period after self-reporting illness or through contact tracing. The infected individuals spent 79% of the days when they tested positive for 2009 H1N1 by PCR (days when they were infectious) in isolation; 60% of their PCR-positive days were spent in isolation and treatment. Importantly, travelers and nontravelers spent 10% and 42.2%, respectively, of their potentially infectious time in the community. None of the patients became severely ill but 61% experienced an influenza-like illness. Finally, the average time from starting treatment to clearance of the virus was between 2.6 and 2.8 days for patients who began treatment 1 to 4 days after becoming ill; for those who started treatment on the first day of illness, the average virus clearance time was 2.0 days.
What Do These Findings Mean?
These findings, although limited by missing data, suggest that the strict containment measures introduced early in the 2009 H1N1 pandemic in Ho Chi Minh City may have reduced the circulation of infected people in the community. This reduction in circulation might have delayed the onset of community transmission, suggest the researchers, but because the study was observational, this possibility cannot be proven. However, importantly, these findings show that the containment measures were unable to prevent the eventual establishment of pandemic influenza in Vietnam, presumably because many imported cases were not detected by airport screening. Finally, these findings suggest that in Vietnam, as in other countries, 2009 H1N1 causes a mild disease and that this disease responds quickly to treatment with oseltamivir whenever treatment is started in relation to the onset of illness.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000277.
The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including specific information on H1N1 influenza and how to prevent its spread
Flu.gov, a US government website, provides information on H1N1, avian, and pandemic influenza
The World Health Organization provides information on seasonal influenza and has detailed information on H1N1 influenza (in several languages); the WHO Representative Office in Vietnam provides an overview of the current 2009 H1N1 situation in Vietnam
The UK Health Protection Agency provides information on pandemic influenza and on H1N1 influenza
Wikipedia has a timeline of the 2009 H1N1 pandemic (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000277
PMCID: PMC2872648  PMID: 20502525
9.  The Spread of Influenza A(H1N1)pdm09 Virus in Madagascar Described by a Sentinel Surveillance Network 
PLoS ONE  2012;7(5):e37067.
Background
The influenza A(H1N1)pdm09 virus has been a challenge for public health surveillance systems in all countries. In Antananarivo, the first imported case was reported on August 12, 2009. This work describes the spread of A(H1N1)pdm09 in Madagascar.
Methods
The diffusion of influenza A(H1N1)pdm09 in Madagascar was explored using notification data from a sentinel network. Clinical data were charted to identify peaks at each sentinel site and virological data was used to confirm viral circulation.
Results
From August 1, 2009 to February 28, 2010, 7,427 patients with influenza-like illness were reported. Most patients were aged 7 to 14 years. Laboratory tests confirmed infection with A(H1N1)pdm09 in 237 (33.2%) of 750 specimens. The incidence of patients differed between regions. By determining the epidemic peaks we traced the diffusion of the epidemic through locations and time in Madagascar. The first peak was detected during the epidemiological week 47-2009 in Antananarivo and the last one occurred in week 07-2010 in Tsiroanomandidy.
Conclusion
Sentinel surveillance data can be used for describing epidemic trends, facilitating the development of interventions at the local level to mitigate disease spread and impact.
doi:10.1371/journal.pone.0037067
PMCID: PMC3353907  PMID: 22615893
10.  Surveillance and Vaccine Effectiveness of an Influenza Epidemic Predominated by Vaccine-Mismatched Influenza B/Yamagata-Lineage Viruses in Taiwan, 2011−12 Season 
PLoS ONE  2013;8(3):e58222.
Introduction
The 2011−12 trivalent influenza vaccine contains a strain of influenza B/Victoria-lineage viruses. Despite free provision of influenza vaccine among target populations, an epidemic predominated by influenza B/Yamagata-lineage viruses occurred during the 2011−12 season in Taiwan. We characterized this vaccine-mismatched epidemic and estimated influenza vaccine effectiveness (VE).
Methods
Influenza activity was monitored through sentinel viral surveillance, emergency department (ED) and outpatient influenza-like illness (ILI) syndromic surveillance, and case-based surveillance of influenza with complications and deaths. VE against laboratory-confirmed influenza was evaluated through a case-control study on ILI patients enrolled into sentinel viral surveillance. Logistic regression was used to estimate VE adjusted for confounding factors.
Results
During July 2011−June 2012, influenza B accounted for 2,382 (72.5%) of 3,285 influenza-positive respiratory specimens. Of 329 influenza B viral isolates with antigen characterization, 287 (87.2%) were B/Yamagata-lineage viruses. Proportions of ED and outpatient visits being ILI-related increased from November 2011 to January 2012. Of 1,704 confirmed cases of influenza with complications, including 154 (9.0%) deaths, influenza B accounted for 1,034 (60.7%) of the confirmed cases and 103 (66.9%) of the deaths. Reporting rates of confirmed influenza with complications and deaths were 73.5 and 6.6 per 1,000,000, respectively, highest among those aged ≥65 years, 50−64 years, 3−6 years, and 0−2 years. Adjusted VE was −31% (95% CI: −80, 4) against all influenza, 54% (95% CI: 3, 78) against influenza A, and −66% (95% CI: −132, −18) against influenza B.
Conclusions
This influenza epidemic in Taiwan was predominated by B/Yamagata-lineage viruses unprotected by the 2011−12 trivalent vaccine. The morbidity and mortality of this vaccine-mismatched epidemic warrants careful consideration of introducing a quadrivalent influenza vaccine that includes strains of both B lineages.
doi:10.1371/journal.pone.0058222
PMCID: PMC3589334  PMID: 23472161
11.  Timeliness of syndromic influenza surveillance through work and school absenteeism 
Archives of Public Health  2010;68(3):115-120.
In this paper, we investigate the usefulness of work and school absenteeism surveillance as an early warning system for influenza. In particular, time trends in daily absenteeism rates collected during the A(H1N1)2009 pandemic are compared with weekly incidence rates of influenza-like illness (ILI) obtained from the Belgian Sentinel General Practitioner (SGP) network. The results indicate a rise in absenteeism rates prior to the onset of the influenza epidemic, suggesting that absenteeism surveillance is a promising tool for early warning of influenza epidemics. To convincingly conclude on the usefulness of absenteeism data for early warning, additional data covering several influenza seasons is needed.
doi:10.1186/0778-7367-68-3-115
PMCID: PMC3463027
School absenteeism; worker absenteeism; influenza; influenza A virus; H1N1 subtype
12.  Monitoring the Impact of Influenza by Age: Emergency Department Fever and Respiratory Complaint Surveillance in New York City 
PLoS Medicine  2007;4(8):e247.
Background
The importance of understanding age when estimating the impact of influenza on hospitalizations and deaths has been well described, yet existing surveillance systems have not made adequate use of age-specific data. Monitoring influenza-related morbidity using electronic health data may provide timely and detailed insight into the age-specific course, impact and epidemiology of seasonal drift and reassortment epidemic viruses. The purpose of this study was to evaluate the use of emergency department (ED) chief complaint data for measuring influenza-attributable morbidity by age and by predominant circulating virus.
Methods and Findings
We analyzed electronically reported ED fever and respiratory chief complaint and viral surveillance data in New York City (NYC) during the 2001–2002 through 2005–2006 influenza seasons, and inferred dominant circulating viruses from national surveillance reports. We estimated influenza-attributable impact as observed visits in excess of a model-predicted baseline during influenza periods, and epidemic timing by threshold and cross correlation. We found excess fever and respiratory ED visits occurred predominantly among school-aged children (8.5 excess ED visits per 1,000 children aged 5–17 y) with little or no impact on adults during the early-2002 B/Victoria-lineage epidemic; increased fever and respiratory ED visits among children younger than 5 y during respiratory syncytial virus-predominant periods preceding epidemic influenza; and excess ED visits across all ages during the 2003–2004 (9.2 excess visits per 1,000 population) and 2004–2005 (5.2 excess visits per 1,000 population) A/H3N2 Fujian-lineage epidemics, with the relative impact shifted within and between seasons from younger to older ages. During each influenza epidemic period in the study, ED visits were increased among school-aged children, and each epidemic peaked among school-aged children before other impacted age groups.
Conclusions
Influenza-related morbidity in NYC was highly age- and strain-specific. The impact of reemerging B/Victoria-lineage influenza was focused primarily on school-aged children born since the virus was last widespread in the US, while epidemic A/Fujian-lineage influenza affected all age groups, consistent with a novel antigenic variant. The correspondence between predominant circulating viruses and excess ED visits, hospitalizations, and deaths shows that excess fever and respiratory ED visits provide a reliable surrogate measure of incident influenza-attributable morbidity. The highly age-specific impact of influenza by subtype and strain suggests that greater age detail be incorporated into ongoing surveillance. Influenza morbidity surveillance using electronic data currently available in many jurisdictions can provide timely and representative information about the age-specific epidemiology of circulating influenza viruses.
Don Olson and colleagues report that influenza-related morbidity in NYC from 2001 to 2006 was highly age- and strain-specific and conclude that surveillance using electronic data can provide timely and representative information about the epidemiology of circulating influenza viruses.
Editors' Summary
Background.
Seasonal outbreaks (epidemics) of influenza (a viral infection of the nose, throat, and airways) send millions of people to their beds every winter. Most recover quickly, but flu epidemics often disrupt daily life and can cause many deaths. Seasonal epidemics occur because influenza viruses continually make small changes to the viral proteins (antigens) that the human immune system recognizes. Consequently, an immune response that combats influenza one year may provide partial or no protection the following year. Occasionally, an influenza virus with large antigenic changes emerges that triggers an influenza pandemic, or global epidemic. To help prepare for both seasonal epidemics and pandemics, public-health officials monitor influenza-related illness and death, investigate unusual outbreaks of respiratory diseases, and characterize circulating strains of the influenza virus. While traditional influenza-related illness surveillance systems rely on relatively slow voluntary clinician reporting of cases with influenza-like illness symptoms, some jurisdictions have also started to use “syndromic” surveillance systems. These use electronic health-related data rather than clinical impression to track illness in the community. For example, increased visits to emergency departments for fever or respiratory (breathing) problems can provide an early warning of an influenza outbreak.
Why Was This Study Done?
Rapid illness surveillance systems have been shown to detect flu outbreaks earlier than is possible through monitoring deaths from pneumonia or influenza. Increases in visits to emergency departments by children for fever or respiratory problems can provide an even earlier indicator. Researchers have not previously examined in detail how fever and respiratory problems by age group correlate with the predominant circulating respiratory viruses. Knowing details like this would help public-health officials detect and respond to influenza epidemics and pandemics. In this study, the researchers have used data collected between 2001 and 2006 in New York City emergency departments to investigate these aspects of syndromic surveillance for influenza.
What Did the Researchers Do and Find?
The researchers analyzed emergency department visits categorized broadly into a fever and respiratory syndrome (which provides an estimate of the total visits attributable to influenza) or more narrowly into an influenza-like illness syndrome (which specifically indicates fever with cough and/or sore throat) with laboratory-confirmed influenza surveillance data. They found that emergency department visits were highest during peak influenza periods, and that the affect on different age groups varied depending on the predominant circulating viruses. In early 2002, an epidemic reemergence of B/Victoria-lineage influenza viruses caused increased visits among school-aged children, while adult visits did not increase. By contrast, during the 2003–2004 season, when the predominant virus was an A/H3N2 Fujian-lineage influenza virus, excess visits occurred in all age groups, though the relative increase was greatest and earliest among school-aged children. During periods of documented respiratory syncytial virus (RSV) circulation, increases in fever and respiratory emergency department visits occurred in children under five years of age regardless of influenza circulation. Finally, the researchers found that excess visits to emergency departments for fever and respiratory symptoms preceded deaths from pneumonia or influenza by about two weeks.
What Do These Findings Mean?
These findings indicate that excess emergency department visits for fever and respiratory symptoms can provide a reliable and timely surrogate measure of illness due to influenza. They also provide new insights into how different influenza viruses affect people of different ages and how the timing and progression of each influenza season differs. These results, based on data collected over only five years in one city, might not be generalizable to other settings or years, warn the researchers. However, the present results strongly suggest that the routine monitoring of influenza might be improved by using electronic health-related data, such as emergency department visit data, and by examining it specifically by age group. Furthermore, by showing that school-aged children can be the first people to be affected by seasonal influenza, these results highlight the important role this age group plays in community-wide transmission of influenza, an observation that could influence the implementation of public-health strategies such as vaccination that aim to protect communities during influenza epidemics and pandemics.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040247.
• US Centers for Disease Control and Prevention provides information on influenza for patients and health professionals and on influenza surveillance in the US (in English, Spanish, and several other languages)
• World Health Organization has a fact sheet on influenza and on global surveillance for influenza (in English, Spanish, French, Russian, Arabic, and Chinese)
• The MedlinePlus encyclopedia contains a page on flu (in English and Spanish)
• US National Institute of Allergy and Infectious Diseases has a feature called “focus on flu”
• A detailed report from the US Centers for Disease Control and Prevention titled “Framework for Evaluating Public Health Surveillance Systems for Early Detection of Outbreaks” includes a simple description of syndromic surveillance
• The International Society for Disease Surveillance has a collaborative syndromic surveillance public wiki
• The Anthropology of the Contemporary Research Collaboratory includes working papers and discussions by cultural anthropologists studying modern vital systems security and syndromic surveillance
doi:10.1371/journal.pmed.0040247
PMCID: PMC1939858  PMID: 17683196
13.  Using surveillance data to estimate pandemic vaccine effectiveness against laboratory confirmed influenza A(H1N1)2009 infection: two case-control studies, Spain, season 2009-2010 
BMC Public Health  2011;11:899.
Background
Physicians of the Spanish Influenza Sentinel Surveillance System report and systematically swab patients attended to their practices for influenza-like illness (ILI). Within the surveillance system, some Spanish regions also participated in an observational study aiming at estimating influenza vaccine effectiveness (cycEVA study). During the season 2009-2010, we estimated pandemic influenza vaccine effectiveness using both the influenza surveillance data and the cycEVA study.
Methods
We conducted two case-control studies using the test-negative design, between weeks 48/2009 and 8/2010 of the pandemic season. The surveillance-based study included all swabbed patients in the sentinel surveillance system. The cycEVA study included swabbed patients from seven Spanish regions. Cases were laboratory-confirmed pandemic influenza A(H1N1)2009. Controls were ILI patients testing negative for any type of influenza. Variables collected in both studies included demographic data, vaccination status, laboratory results, chronic conditions, and pregnancy. Additionally, cycEVA questionnaire collected data on previous influenza vaccination, smoking, functional status, hospitalisations, visits to the general practitioners, and obesity. We used logistic regression to calculate adjusted odds ratios (OR), computing pandemic influenza vaccine effectiveness as (1-OR)*100.
Results
We included 331 cases and 995 controls in the surveillance-based study and 85 cases and 351 controls in the cycEVA study. We detected nine (2.7%) and two (2.4%) vaccine failures in the surveillance-based and cycEVA studies, respectively. Adjusting for variables collected in surveillance database and swabbing month, pandemic influenza vaccine effectiveness was 62% (95% confidence interval (CI): -5; 87). The cycEVA vaccine effectiveness was 64% (95%CI: -225; 96) when adjusting for common variables with the surveillance system and 75% (95%CI: -293; 98) adjusting for all variables collected.
Conclusion
Point estimates of the pandemic influenza vaccine effectiveness suggested a protective effect of the pandemic vaccine against laboratory-confirmed influenza A(H1N1)2009 in the season 2009-2010. Both studies were limited by the low vaccine coverage and the late start of the vaccination campaign. Routine influenza surveillance provides reliable estimates and could be used for influenza vaccine effectiveness studies in future seasons taken into account the surveillance system limitations.
doi:10.1186/1471-2458-11-899
PMCID: PMC3262832  PMID: 22129083
14.  Clinical prediction rules combining signs, symptoms and epidemiological context to distinguish influenza from influenza-like illnesses in primary care: a cross sectional study 
BMC Family Practice  2011;12:4.
Background
During an influenza epidemic prompt diagnosis of influenza is important. This diagnosis however is still essentially based on the interpretation of symptoms and signs by general practitioners. No single symptom is specific enough to be useful in differentiating influenza from other respiratory infections. Our objective is to formulate prediction rules for the diagnosis of influenza with the best diagnostic performance, combining symptoms, signs and context among patients with influenza-like illness.
Methods
During five consecutive winter periods (2002-2007) 138 sentinel general practitioners sampled (naso- and oropharyngeal swabs) 4597 patients with an influenza-like illness (ILI) and registered their symptoms and signs, general characteristics and contextual information. The samples were analysed by a DirectigenFlu-A&B and RT-PCR tests. 4584 records were useful for further analysis.
Starting from the most relevant variables in a Generalized Estimating Equations (GEE) model, we calculated the area under the Receiver Operating Characteristic curve (ROC AUC), sensitivity, specificity and likelihood ratios for positive (LR+) and negative test results (LR-) of single and combined signs, symptoms and context taking into account pre-test and post-test odds.
Results
In total 52.6% (2409/4584) of the samples were positive for influenza virus: 64% (2066/3212) during and 25% (343/1372) pre/post an influenza epidemic. During and pre/post an influenza epidemic the LR+ of 'previous flu-like contacts', 'coughing', 'expectoration on the first day of illness' and 'body temperature above 37.8°C' is 3.35 (95%CI 2.67-4.03) and 1.34 (95%CI 0.97-1.72), respectively. During and pre/post an influenza epidemic the LR- of 'coughing' and 'a body temperature above 37.8°C' is 0.34 (95%CI 0.27-0.41) and 0.07 (95%CI 0.05-0.08), respectively.
Conclusions
Ruling out influenza using clinical and contextual information is easier than ruling it in. Outside an influenza epidemic the absence of cough and fever (> 37,8°C) makes influenza 14 times less likely in ILI patients. During an epidemic the presence of 'previous flu-like contacts', cough, 'expectoration on the first day of illness' and fever (>37,8°C) increases the likelihood for influenza threefold. The additional diagnostic value of rapid point of care tests especially for confirming influenza still has to be established.
doi:10.1186/1471-2296-12-4
PMCID: PMC3045895  PMID: 21306610
15.  Usefulness of Syndromic Surveillance for Early Outbreak Detection in Small Islands: The Case of Mayotte 
Objective
To present the usefulness of syndromic surveillance for the detection of infectious diseases outbreak in small islands, based on the experience of Mayotte.
Introduction
Mayotte Island, a French overseas department of around 374 km2 and 200 000 inhabitants is located in the North of Mozambique Channel in the Indian Ocean (Figure 1).
In response to the threat of the pandemic influenza A(H1N1)2009 virus emergence, a syndromic surveillance system has been implemented in order to monitor its spread and its impact on public health (1). This surveillance system which proved to be useful during the influenza pandemic, has been maintained in order to detect infection diseases outbreaks.
Methods
Data are collected daily directly from patients’ computerized medical files that are filled in during medical consultations at the emergency department (ED) of the hospital Center of Mayotte (2). Among the collected variables, the diagnosis coded according to ICD-10 is used to categorize the syndromes. Several syndromes are monitored including the syndromic grouping for conjunctivitis and unexplained fever.
For early outbreak detection, a control chart is used based on an adaptation of the Cusum methods developed by the CDC within the framework of the EARS program (3).
Results
Each week, about 700 patients attend the ED of the hospital. The syndromic surveillance system allowed to detect an outbreak of conjunctivitis from week 10 (Figure 2). During the epidemic peak on week 12, conjunctivitis consultations represented 5% of all consultations. The data of the sentinel practitioner network confirmed this epidemic and the laboratory isolated Enterovirus (4). At the same time, an unusual increase of unexplained fever was detected.
Conclusions
Due to its geographical and socio-demographical situation, the population of Mayotte is widely exposed to infectious diseases. Even on a small island, syndromic surveillance can be useful to detect outbreak early leading to alerts and to mobilize a rapid response in addition to others systems.
PMCID: PMC3692797
Syndromic surveillance; Early outbreak detection; Mayotte Island
16.  Risk factors associated with fatal influenza, Romania, October 2009 – May 2011 
Background
Limited data are available from Central and Eastern Europe on risk factors for severe complications of influenza. Such data are essential to prioritize prevention and treatment resources and to adapt influenza vaccination recommendations.
Objectives
To use sentinel surveillance data to identify risk factors for fatal outcomes among hospitalized patients with severe acute respiratory infections (SARI) and among hospitalized patients with laboratory-confirmed influenza.
Methods
Retrospective analysis of case-based surveillance data collected from sentinel hospitals in Romania during the 2009/2010 and 2010/2011 winter influenza seasons was performed to evaluate risk factors for fatal outcomes using multivariate logistic regression.
Results
During 2009/2010 and 2010/2011, sentinel hospitals reported 661 SARI patients of which 230 (35%) tested positive for influenza. In the multivariate analyses, infection with influenza A(H1N1)pdm09 was the strongest risk factor for death among hospitalized SARI patients (OR: 6·6; 95% CI: 3·3–13·1). Among patients positive for influenza A(H1N1)pdm09 virus infection (n = 148), being pregnant (OR: 7·1; 95% CI: 1·6–31·2), clinically obese (OR: 2·9;95% CI: 1·6–31·2), and having an immunocompromising condition (OR: 3·7;95% CI: 1·1–13·4) were significantly associated with fatal outcomes.
Conclusion
These findings are consistent with several other investigations of risk factors associated with influenza A(H1N1)pdm09 virus infections. They also support the more recent 2012 recommendations by the WHO Strategic Advisory Group of Experts on Immunization (SAGE) that pregnant women are an important risk group for influenza vaccination. Ongoing sentinel surveillance can be useful tool to monitor risk factors for complications of influenza virus infections during each influenza season, and pandemics as well.
doi:10.1111/irv.12209
PMCID: PMC4177790  PMID: 24251915
Influenza; risk factors; Romania; severe acute respiratory illness; surveillance
17.  Teacher led school-based surveillance can allow accurate tracking of emerging infectious diseases - evidence from serial cross-sectional surveys of febrile respiratory illness during the H1N1 2009 influenza pandemic in Singapore 
BMC Infectious Diseases  2012;12:336.
Background
Schools are important foci of influenza transmission and potential targets for surveillance and interventions. We compared several school-based influenza monitoring systems with clinic-based influenza-like illness (ILI) surveillance, and assessed the variation in illness rates between and within schools.
Methods
During the initial wave of pandemic H1N1 (pdmH1N1) infections from June to Sept 2009 in Singapore, we collected data on nation-wide laboratory confirmed cases (Sch-LCC) and daily temperature monitoring (Sch-DTM), and teacher-led febrile respiratory illness reporting in 6 sentinel schools (Sch-FRI). Comparisons were made against age-stratified clinic-based influenza-like illness (ILI) data from 23 primary care clinics (GP-ILI) and proportions of ILI testing positive for pdmH1N1 (Lab-ILI) by computing the fraction of cumulative incidence occurring by epidemiological week 30 (when GP-ILI incidence peaked); and cumulative incidence rates between school-based indicators and sero-epidemiological pdmH1N1 incidence (estimated from changes in prevalence of A/California/7/2009 H1N1 hemagglutination inhibition titers ≥ 40 between pre-epidemic and post-epidemic sera). Variation in Sch-FRI rates in the 6 schools was also investigated through a Bayesian hierarchical model.
Results
By week 30, for primary and secondary school children respectively, 63% and 79% of incidence for Sch-LCC had occurred, compared with 50% and 52% for GP-ILI data, and 48% and 53% for Sch-FRI. There were 1,187 notified cases and 7,588 episodes in the Sch-LCC and Sch-DTM systems; given school enrollment of 485,723 children, this represented 0.24 cases and 1.6 episodes per 100 children respectively. Mean Sch-FRI rate was 28.8 per 100 children (95% CI: 27.7 to 29.9) in the 6 schools. We estimate from serology that 41.8% (95% CI: 30.2% to 55.9%) of primary and 43.2% (95% CI: 28.2% to 60.8%) of secondary school-aged children were infected. Sch-FRI rates were similar across the 6 schools (23 to 34 episodes per 100 children), but there was widespread variation by classrooms; in the hierarchical model, omitting age and school effects was inconsequential but neglecting classroom level effects led to highly significant reductions in goodness of fit.
Conclusions
Epidemic curves from Sch-FRI were comparable to GP-ILI data, and Sch-FRI detected substantially more infections than Sch-LCC and Sch-DTM. Variability in classroom attack rates suggests localized class-room transmission.
doi:10.1186/1471-2334-12-336
PMCID: PMC3544582  PMID: 23206689
Respiratory tract infections; Vaccination; Serology
18.  Effectiveness and safety of the A-H1N1 vaccine in children: a hospital-based case–control study 
BMJ Open  2011;1(2):e000167.
Objective
To verify whether vaccination against the A-H1N1 virus in the paediatric population was effective in preventing the occurrence of influenza-like illness (ILI) or was associated with adverse events of special interest.
Design, setting and patients
A case–control analysis was performed as part of surveillance of children hospitalised through the emergency departments of eight paediatric hospitals/wards for ILI, neurological disorders, non-infectious muco-cutaneous diseases and vasculitis, thrombocytopaenia and gastroduodenal lesions.
Results
Among 736 children enrolled from November 2009 to August 2010, only 25 had been vaccinated with the pandemic vaccine. Out of 268 children admitted for a diagnosis compatible with the adverse events of special interest, six had received the A-H1N1 vaccine, although none of the adverse events occurred within the predefined risk windows. Only 35 children out of 244 admitted with a diagnosis of ILI underwent laboratory testing: 11 were positive and 24 negative for the A-H1N1 virus. None of the A-H1N1 positive children had received the pandemic vaccine. The OR of ILI associated with any influenza vaccination was 0.9 (95% CI 0.1 to 5.5).
Conclusions
The study provides additional information on the benefit–risk profile of the pandemic vaccine. No sign of risk associated with the influenza A-H1N1 vaccine used in Italy was found, although several limitations were observed: in Italy, pandemic vaccination coverage was low, the epidemic was almost over by mid December 2009 and the A-H1N1 laboratory test was performed only during the epidemic phase (in <10% of children). This study supports the importance of the existing network of hospitals for the evaluation of signals relevant to new vaccines and drugs.
Article summary
Article focus
To assess the effectiveness of the influenza A-H1N1 vaccine and the occurrence of adverse events of special interest in the paediatric population.
Key messages
During the 2009–2010 influenza season, very limited information was available on the safety and effectiveness of the influenza A-H1N1 vaccine.
Together with other post-marketing studies, our findings provide additional information on the benefit–risk profile of the pandemic vaccine.
Strengths and limitations of this study
The study focused on influenza-like illness and adverse events of special interest that were sufficiently severe to cause hospitalisation in children and provided additional information on the benefit–risk profile of the pandemic vaccine.
A-H1N1 vaccination coverage in Italy during the 2009–2010 influenza season was very low, with around 4% of the general population and only 3.7% of the children included in this study having been vaccinated.
The influenza outbreak was almost over by the first half of December 2009, and both the incidence and severity of the disease were lower than expected.
doi:10.1136/bmjopen-2011-000167
PMCID: PMC3191592  PMID: 22021877
19.  Age Distribution of Influenza Like Illness Cases during Post-Pandemic A(H3N2): Comparison with the Twelve Previous Seasons, in France 
PLoS ONE  2013;8(6):e65919.
In France, the 2011–2012 influenza epidemic was characterized by the circulation of antigenically drifted influenza A(H3N2) viruses and by an increased disease severity and mortality among the elderly, with respect to the A(H1N1)pdm09 pandemic and post-pandemic outbreaks. Whether the epidemiology of influenza in France differed between the 2011–2012 epidemic and the previous outbreaks is unclear. Here, we analyse the age distribution of influenza like illness (ILI) cases attended in general practice during the 2011–2012 epidemic, and compare it with that of the twelve previous epidemic seasons. Influenza like illness data were obtained through a nationwide surveillance system based on sentinel general practitioners. Vaccine effectiveness was also estimated. The estimated number of ILI cases attended in general practice during the 2011–2012 was lower than that of the past twelve epidemics. The age distribution was characteristic of previous A(H3N2)-dominated outbreaks: school-age children were relatively spared compared to epidemics (co-)dominated by A(H1N1) and/or B viruses (including the 2009 pandemic and post-pandemic outbreaks), while the proportion of adults over 30 year-old was higher. The estimated vaccine effectiveness (54%, 95% CI (48, 60)) was in the lower range for A(H3N2) epidemics. In conclusion, the age distribution of ILI cases attended in general practice seems to be not different between the A(H3N2) pre-pandemic and post-pandemic epidemics. Future researches including a more important number of ILI epidemics and confirmed virological data of influenza and other respiratory pathogens are necessary to confirm these results.
doi:10.1371/journal.pone.0065919
PMCID: PMC3673950  PMID: 23755294
20.  Monitoring the emergence of community transmission of influenza A/H1N1 2009 in England: a cross sectional opportunistic survey of self sampled telephone callers to NHS Direct 
Objective To evaluate ascertainment of the onset of community transmission of influenza A/H1N1 2009 (swine flu) in England during the earliest phase of the epidemic through comparing data from two surveillance systems.
Design Cross sectional opportunistic survey.
Study samples Results from self samples by consenting patients who had called the NHS Direct telephone health line with cold or flu symptoms, or both, and results from Health Protection Agency (HPA) regional microbiology laboratories on patients tested according to the clinical algorithm for the management of suspected cases of swine flu.
Setting Six regions of England between 24 May and 30 June 2009.
Main outcome measure Proportion of specimens with laboratory evidence of influenza A/H1N1 2009.
Results Influenza A/H1N1 2009 infections were detected in 91 (7%) of the 1385 self sampled specimens tested. In addition, eight instances of influenza A/H3 infection and two cases of influenza B infection were detected. The weekly rate of change in the proportions of infected individuals according to self obtained samples closely matched the rate of increase in the proportions of infected people reported by HPA regional laboratories. Comparing the data from both systems showed that local community transmission was occurring in London and the West Midlands once HPA regional laboratories began detecting 100 or more influenza A/H1N1 2009 infections, or a proportion positive of over 20% of those tested, each week.
Conclusions Trends in the proportion of patients with influenza A/H1N1 2009 across regions detected through clinical management were mirrored by the proportion of NHS Direct callers with laboratory confirmed infection. The initial concern that information from HPA regional laboratory reports would be too limited because it was based on testing patients with either travel associated risk or who were contacts of other influenza cases was unfounded. Reports from HPA regional laboratories could be used to recognise the extent to which local community transmission was occurring.
doi:10.1136/bmj.b3403
PMCID: PMC2733951  PMID: 19713236
21.  Age Distribution of Cases of 2009 (H1N1) Pandemic Influenza in Comparison with Seasonal Influenza 
PLoS ONE  2011;6(7):e21690.
Introduction
Several aspects of the epidemiology of 2009 (H1N1) pandemic influenza have not been accurately determined. We sought to study whether the age distribution of cases differs in comparison with seasonal influenza.
Methods
We searched for official, publicly available data through the internet from different countries worldwide on the age distribution of cases of influenza during the 2009 (H1N1) pandemic influenza period and most recent seasonal influenza periods. Data had to be recorded through the same surveillance system for both compared periods.
Results
For 2009 pandemic influenza versus recent influenza seasons, in USA, visits for influenza-like illness to sentinel providers were more likely to involve the age groups of 5–24, 25–64 and 0–4 years compared with the reference group of >64 years [odds ratio (OR) (95% confidence interval (CI)): 2.43 (2.39–2.47), 1.66 (1.64–1.69), and 1.51 (1.48–1.54), respectively]. Pediatric deaths were less likely in the age groups of 2–4 and <2 years than the reference group of 5–17 years [OR (95% CI): 0.46 (0.25–0.85) and 0.49 (0.30–0.81), respectively]. In Australia, notifications for laboratory-confirmed influenza were more likely in the age groups of 10–19, 5–9, 20–44, 45–64 and 0–4 years than the reference group of >65 years [OR (95% CI): 7.19 (6.67–7.75), 5.33 (4.90–5.79), 5.04 (4.70–5.41), 3.12 (2.89–3.36) and 1.89 (1.75–2.05), respectively]. In New Zealand, consultations for influenza-like illness by sentinel providers were more likely in the age groups of <1, 1–4, 35–49, 5–19, 20–34 and 50–64 years than the reference group of >65 years [OR (95% CI): 2.38 (1.74–3.26), 1.99 (1.62–2.45), 1.57 (1.30–1.89), 1.57 (1.30–1.88), 1.40 (1.17–1.69) and 1.39 (1.14–1.70), respectively].
Conclusions
The greatest increase in influenza cases during 2009 (H1N1) pandemic influenza period, in comparison with most recent seasonal influenza periods, was seen for school-aged children, adolescents, and younger adults.
doi:10.1371/journal.pone.0021690
PMCID: PMC3128617  PMID: 21747947
22.  Forecasting Influenza Epidemics from Multi-Stream Surveillance Data in a Subtropical City of China 
PLoS ONE  2014;9(3):e92945.
Background
Influenza has been associated with heavy burden of mortality and morbidity in subtropical regions. However, timely forecast of influenza epidemic in these regions has been hindered by unclear seasonality of influenza viruses. In this study, we developed a forecasting model by integrating multiple sentinel surveillance data to predict influenza epidemics in a subtropical city Shenzhen, China.
Methods
Dynamic linear models with the predictors of single or multiple surveillance data for influenza-like illness (ILI) were adopted to forecast influenza epidemics from 2006 to 2012 in Shenzhen. Temporal coherence of these surveillance data with laboratory-confirmed influenza cases was evaluated by wavelet analysis and only the coherent data streams were entered into the model. Timeliness, sensitivity and specificity of these models were also evaluated to compare their performance.
Results
Both influenza virology data and ILI consultation rates in Shenzhen demonstrated a significant annual seasonal cycle (p<0.05) during the entire study period, with occasional deviations observed in some data streams. The forecasting models that combined multi-stream ILI surveillance data generally outperformed the models with single-stream ILI data, by providing more timely, sensitive and specific alerts.
Conclusions
Forecasting models that combine multiple sentinel surveillance data can be considered to generate timely alerts for influenza epidemics in subtropical regions like Shenzhen.
doi:10.1371/journal.pone.0092945
PMCID: PMC3968046  PMID: 24676091
23.  Influenza Surveillance among Outpatients and Inpatients in Morocco, 1996–2009 
PLoS ONE  2011;6(9):e24579.
Background
There is limited information about the epidemiology of influenza in Africa. We describe the epidemiology and seasonality of influenza in Morocco from 1996 to 2009 with particular emphasis on the 2007–2008 and 2008–2009 influenza seasons. Successes and challenges of the enhanced surveillance system introduced in 2007 are also discussed.
Methods
Virologic sentinel surveillance for influenza virus was initiated in Morocco in 1996 using a network of private practitioners that collected oro-pharyngeal and naso-pharyngeal swabs from outpatients presenting with influenza-like-illness (ILI). The surveillance network expanded over the years to include inpatients presenting with severe acute respiratory illness (SARI) at hospitals and syndromic surveillance for ILI and acute respiratory infection (ARI). Respiratory samples and structured questionnaires were collected from eligible patients, and samples were tested by immunofluorescence assays and by viral isolation for influenza viruses.
Results
We obtained a total of 6465 respiratory specimens during 1996 to 2009, of which, 3102 were collected during 2007–2009. Of those, 2249 (72%) were from patients with ILI, and 853 (27%) were from patients with SARI. Among the 3,102 patients, 98 (3%) had laboratory-confirmed influenza, of whom, 85 (87%) had ILI and 13 (13%) had SARI. Among ILI patients, the highest proportion of laboratory-confirmed influenza occurred in children less than 5 years of age (3/169; 2% during 2007–2008 and 23/271; 9% during 2008–2009) and patients 25–59 years of age (8/440; 2% during 2007–2009 and 21/483; 4% during 2008–2009). All SARI patients with influenza were less than 14 years of age. During all surveillance years, influenza virus circulation was seasonal with peak circulation during the winter months of October through April.
Conclusion
Influenza results in both mild and severe respiratory infections in Morocco, and accounted for a large proportion of all hospitalizations for severe respiratory illness among children 5 years of age and younger.
doi:10.1371/journal.pone.0024579
PMCID: PMC3169614  PMID: 21931764
24.  Response to the challenges of pandemic H1N1 in a small island state: the Barbadian experience 
BMC Public Health  2010;10(Suppl 1):S10.
Background
Having been overwhelmed by the complexity of the response needed for the severe acute respiratory syndrome (SARS) epidemic, public health professionals in the small island state of Barbados put various measures in place to improve its response in the event of a pandemic
Methods
Data for this study was collected using Barbados’ National Influenza Surveillance System, which was revitalized in 2007. It is comprised of ten sentinel sites which send weekly notifications of acute respiratory illness (ARI) and severe acute respiratory illness (SARI) to the Office of the National Epidemiologist. During the 2009 H1N1 pandemic, meetings of the National Pandemic Planning Committee and the Technical Command Committee were convened. The pharmaceutical and non-pharmaceutical interventions (NPIs) implemented as a result of these meetings form the basis of the results presented in this paper.
Results
On June 3, 2009, Barbados reported its first case of 2009 H1N1. From June until October 2009, there were 155 laboratory confirmed cases of 2009 H1N1, with one additional case occurring in January 2010. For the outbreak period (June-October 2009), the surveillance team received reports of 2,483 ARI cases, compared to 412 cases for the same period in 2008. The total hospitalization rate due to SARIs for the year 2009 was 90.1 per 100,000 people, as compared to 7.3 per 100,000 people for 2008. Barbados’ pandemic response was characterized by a strong surveillance system combining active and passive surveillance, good risk communication strategy, a strengthened public and private sector partnership, and effective regional and international collaborations. Community restriction strategies such as school and workplace closures and cancellation of group events were not utilized as public health measures to delay the spread of the virus. Some health care facilities struggled with providing adequate isolation facilities.
Conclusions
The number of confirmed cases was small but the significant surge in ARI and SARI cases indicate that the impact of the virus on the island was moderate. As a result of 2009 H1N1, virological surveillance has improved significantly and local, regional and international partnerships have been strengthened.
doi:10.1186/1471-2458-10-S1-S10
PMCID: PMC3005570  PMID: 21143820
25.  Efficacy of Oseltamivir-Zanamivir Combination Compared to Each Monotherapy for Seasonal Influenza: A Randomized Placebo-Controlled Trial 
PLoS Medicine  2010;7(11):e1000362.
Analysis of virological and clinical outcomes from a randomized trial that was terminated early suggest that combined treatment of seasonal influenza in adult outpatients with oseltamivir plus zanamivir is no more effective than either oseltamivir or zanamivir monotherapy.
Background
Neuraminidase inhibitors are thought to be efficacious in reducing the time to alleviation of symptoms in outpatients with seasonal influenza. The objective of this study was to compare the short-term virological efficacy of oseltamivir-zanamivir combination versus each monotherapy plus placebo.
Methods and Findings
We conducted a randomized placebo-controlled trial with 145 general practitioners throughout France during the 2008–2009 seasonal influenza epidemic. Patients, general practitioners, and outcome assessors were all blinded to treatment assignment. Adult outpatients presenting influenza-like illness for less than 36 hours and a positive influenza A rapid test diagnosis were randomized to oseltamivir 75 mg orally twice daily plus zanamivir 10 mg by inhalation twice daily (OZ), oseltamivir plus inhaled placebo (O), or zanamivir plus oral placebo (Z). Treatment efficacy was assessed virologically according to the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/µl at day 2 (primary outcome), and clinically to the time to alleviation of symptoms until day 14. Overall 541 patients (of the 900 planned) were included (OZ, n = 192; O, n = 176; Z, n = 173), 49% male, mean age 39 years. In the intention-to-treat analysis conducted in the 447 patients with RT-PCR-confirmed influenza A, 46%, 59%, and 34% in OZ (n = 157), O (n = 141), and Z (n = 149) arms had RT-PCR<200 cgeq/µl (−13.0%, 95% confidence interval [CI] −23.1 to −2.9, p = 0.025; +12.3%, 95% CI 2.39–22.2, p = 0.028 for OZ/O and OZ/Z comparisons). Mean day 0 to day 2 viral load decrease was 2.14, 2.49, and 1.68 log10 cgeq/µl (p = 0.060, p = 0.016 for OZ/O and OZ/Z). Median time to alleviation of symptoms was 4.0, 3.0, and 4.0 days (+1.0, 95% CI 0.0–4.0, p = 0.018; +0.0, 95% CI −3.0 to 3.0, p = 0.960 for OZ/O and OZ/Z). Four severe adverse events were observed. Nausea and/or vomiting tended to be more frequent in the combination arm (OZ, n = 13; O, n = 4; and Z, n = 5 patients, respectively).
Conclusions
In adults with seasonal influenza A mainly H3N2 virus infection, the oseltamivir-zanamivir combination appeared less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy. Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00799760
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In the last few years, use of the neuraminidase inhibitors, oseltamivir and zanamivir, has been considered a key strategy for limiting the impact of influenza both in individuals (by reducing morbidity and mortality) and collectively (by slowing the virus' spread to buy time for vaccine production, the cornerstone of influenza control). However, there are concerns that widespread use of a single antiviral drug may lead to resistant strains, which could dramatically reduce its effectiveness in future. Theoretically, if well tolerated, and if producing at least additive antiviral activity, the combination of two antiviral agents could offer several advantages such as reducing disease severity and reducing the viral shedding period, which in turn could lead to lower infection rates and reduced resistance especially in immunocompromised patients. Importantly, combining two drugs could ensure optimal treatment of all types of circulating influenza virus and subtypes or variants. The combination of two neuraminidase inhibitors is feasible as both oseltamivir and zanamivir are licensed for seasonal influenza and have different key mutations associated with resistance to each drug.
Why Was This Study Done?
As yet, there have been no robust randomized controlled trials that compare the effectiveness of monotherapy with either oseltamivir or zanamivir with the effectiveness of a oseltamivir-zanamivir combination. Such a study would be important for influenza pandemic planning.
What Did the Researchers Do and Find?
The researchers conducted a randomized, placebo-controlled trial within 145 general practitioners throughout France during the seasonal influenza epidemic in 2008–2009. Adults who visited their general practitioner with symptoms of an influenza-like illness for less than 36 hours and who had a positive influenza A rapid test were randomized to one of three arms: (1) oral oseltamivir 75 mg twice daily plus zanamivir 10 mg by inhalation twice daily, (2) oral oseltamivir 75 mg twice daily plus inhaled placebo, or (3) zanamivir 10 mg by inhalation twice daily plus oral placebo. The effects of the drugs or combination of drugs was assessed virologically, by looking at the proportion of patients with nasal influenza reverse transcription (RT)-PCR below a particular level on day 2 of treatment. Clinical measures of effectiveness included the time to resolution of illness, the number of patients with alleviation of symptoms at the end of treatment, and the incidence of secondary complications of influenza such as otitis, bronchitis, sinusitis, and pneumonia. In the study, patients, general practitioners, and outcome assessors were all blinded to treatment assignments. Due to the emergence of the H1N1 pandemic in 2009, the study's independent data-monitoring committee requested that the researchers terminate the trial early and analyze the results earlier than planned.
541 patients (of the 900 planned) were enrolled in the study (192 in group 1; 176 in group 2; and 173 in group 3) of whom 447 were infected with influenza A. Overall the oseltamivir-zanamivir combination was both virologically and clinically significantly less effective than the oseltamivir monotherapy. In addition, the clinical effects of the oseltamivir-zanamivir combination on time to resolution of symptoms were not significantly different from that of zanamivir monotherapy, suggesting that oseltamivir does not add clinical benefit to zanamivir monotherapy.
What Do These Findings Mean?
The results of this study essentially show that in France during the Winter of 2009 prepandemic (of which 85% was due to of H3N2 virus), in adults with seasonal influenza A virus infection, the combination of oseltamivir and zanamivir was less effective than oseltamivir monotherapy and not significantly more effective than zanamivir monotherapy. These results call for caution in the use of the oseltamivir-zanamivir combination in treatment of adult outpatients. In addition, as the clinical and virological effects of oseltamivir monotherapy over zanamivir monotherapy were superior in this trial, oseltamivir should be the recommended treatment during influenza seasons with predominant H3N2 viruses. However, the results of this study should be confirmed in the coming years on future circulating influenza viruses.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000362.
Wikipedia has information on H3N3 influenza A virus (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Health Organization has a global alert and response site on seasonal influenza
Patient UK provides information about antivirals for influenza
Answers.com has information about oseltamivir and about zanamivir
doi:10.1371/journal.pmed.1000362
PMCID: PMC2970549  PMID: 21072246

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