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1.  Frequency of Adverse Events after Vaccination with Different Vaccinia Strains 
PLoS Medicine  2006;3(8):e272.
Background
Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH) strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus.
Methods and Findings
We analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect that showed decreasing incidences of adverse events over several decades. To estimate death rates, we then restricted our analysis to more-recent studies. We estimated that vaccination with the NYCBH strain leads to an average of 1.4 deaths per million vaccinations (95% credible interval, 0–6) and that vaccination with Lister vaccine leads to an average of 8.4 deaths per million vaccinations (95% credible interval, 0–31). We combined age-dependent estimates of the frequency of death after vaccination and revaccination with demographic data to obtain estimates of the expected number of deaths in present societies due to vaccination with the NYCBH and Lister vaccinia strains.
Conclusions
Previous analyses of smallpox vaccination policies, which rely on the commonly assumed value of one death per million vaccinations, may give serious underestimates of the number of deaths resulting from vaccination. Moreover, because there are large, strain-dependent differences in the frequency of adverse events due to smallpox vaccination, it is difficult to extrapolate from predictions for the NYCBH-derived vaccines (stockpiled in countries such as the US) to predictions for the Lister-derived vaccines (stockpiled in countries such as Germany). In planning for an effective response to a possible smallpox outbreak, public-health decision makers should reconsider their strategies of when to opt for ring vaccination and when to opt for mass vaccination.
Analysis of historical data for adverse events suggests that the commonly assumed number of one death per million vaccinations is inaccurate. Large differences between different vaccinia strains used should be taken into account when mass vaccinations are considered.
Editors' Summary
Background.
For thousands of years, smallpox was one of the world's most-feared diseases. This contagious disease, caused by the variola virus, historically killed about 30 percent of the people it infected. Over the centuries, it probably killed more people than all other infectious diseases combined, but it was also the first disease to be prevented by vaccination. In 1796, the English physician Edward Jenner rubbed pus from the spots of a milkmaid with cowpox into scratches on a young boy's arm; according to folklore, people who caught cowpox, a related but mild disease of cows, were protected against smallpox. Six weeks later, after a mild bout of cowpox, when the boy was challenged with pus from a smallpox patient, he did not develop smallpox. This vaccination procedure was later refined so that people were inoculated with pure preparations of live vaccinia virus, which is closely related to the smallpox and cowpox viruses, and by 1979 a global vaccination campaign had totally eradicated the disease.
Why Was This Study Done?
Smallpox vaccination has some adverse effects. In particular, vaccinia virus occasionally infects the brain. This so-called post-vaccination encephalitis can cause permanent brain damage and, it has been estimated, kills one vaccinee in every million. Consequently, as smallpox became rarer, the dangers of vaccination began to outweigh its benefits. Routine smallpox vaccination stopped in the US in 1972, and in 1980 the World Health Organization recommended that all countries stop vaccination. Now, however, there are fears that smallpox may be used for bioterrorism. If this did happen, exposed individuals and their contacts, possibly even whole populations, would have to be vaccinated as quickly as possible (very few people now have strong immunity to smallpox). Many countries have stockpiles of smallpox vaccines for this eventuality, but these contain different vaccinia virus strains. In this study, the researchers examined historical data to discover whether these strains differ in their potential to cause encephalitis and death. This information should help public-health officials plan their vaccination strategies in response to a bioterrorism attack with smallpox.
What Did the Researchers Do and Find?
The researchers collected data from published studies on smallpox vaccination and adverse events from several countries from the late 1950s onwards. They then used these data to extrapolate how often the different vaccinia strains might cause encephalitis and death if they were used today in vaccination programs. They estimate that vaccinating with the New York City Board of Health (NYCBH) strain, which is stockpiled in the US, might cause 2.9 cases of post-vaccination encephalitis and 1.4 deaths per million vaccinated individuals. In contrast, the Lister strain, which is stockpiled in many European countries, might cause 26.2 cases of post-vaccination encephalitis and 2.5 deaths per million vaccinees. For both strains, vaccination of children younger than 1 year old would cause the highest death rate, and individuals being re-vaccinated would be less likely to die than those being vaccinated for the first time. Finally, the researchers use their figures to estimate that about ten people would die if mass vaccination with the NYCBH strain were used in the Netherlands (population 16 million), whereas 55 people would die if the Lister strain were used.
What Do These Findings Mean?
The data used in this study are of variable quality, so the figures calculated by the researchers are only estimates. For instance, given the scatter of the original data, mass vaccination in the Netherlands with the Lister strain might cause anywhere between seven and nearly 200 deaths. However, the study clearly suggests that more serious adverse events would occur after vaccination with the Lister strain than after vaccination with the NYCBH strain. It also indicates that even in the US, where the NYCBH vaccine strain is stockpiled, previous analyses of the effects of vaccination in response to a bioterrorist attack have probably underestimated how many people might die from post-vaccination encephalitis. Public-health decision makers should incorporate these new estimates into their planning for a smallpox outbreak. These increased estimates of adverse events after vaccination might, for example, make mass vaccination with the Lister strain of vaccinia virus less acceptable. Instead, public-health officials might decide to rely on vaccination of only the people directly exposed to released smallpox virus and their close contacts (ring vaccination) to contain a smallpox outbreak.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030272.
World Health Organization, information on smallpox and preparedness in the event of a smallpox outbreak
MedlinePlus encyclopedia entry on smallpox
US National Institute of Allergy and Infectious Diseases, patient fact sheet on smallpox
US Centers for Disease Control and Prevention, information for patients and professionals on smallpox
Wikipedia page on smallpox (note that Wikipedia is a free online encyclopedia that anyone can edit)
Wellcome Library MedHist, links to information on the history of smallpox vaccination
doi:10.1371/journal.pmed.0030272
PMCID: PMC1551910  PMID: 16933957
2.  Optimizing the Dose of Pre-Pandemic Influenza Vaccines to Reduce the Infection Attack Rate 
PLoS Medicine  2007;4(6):e218.
Background
The recent spread of avian influenza in wild birds and poultry may be a precursor to the emergence of a 1918-like human pandemic. Therefore, stockpiles of human pre-pandemic vaccine (targeted at avian strains) are being considered. For many countries, the principal constraint for these vaccine stockpiles will be the total mass of antigen maintained. We tested the hypothesis that lower individual doses (i.e., less than the recommended dose for maximum protection) may provide substantial extra community-level benefits because they would permit wider vaccine coverage for a given total size of antigen stockpile.
Methods and Findings
We used a mathematical model to predict infection attack rates under different policies. The model incorporated both an individual's response to vaccination at different doses and the process of person-to-person transmission of pandemic influenza. We found that substantial reductions in the attack rate are likely if vaccines are given to more people at lower doses. These results are applicable to all three vaccine candidates for which data are available. As a guide to the magnitude of the effect, we simulated epidemics based on historical studies of immunogenicity. For example, for one of the vaccines for which data are available, the attack rate would drop from 67.6% to 58.7% if 160 out of the total US population of 300 million were given an optimal dose rather than 20 out of 300 million given the maximally protective dose (as promulgated in the US National Pandemic Preparedness Plan). Our results are conservative with respect to a number of alternative assumptions about the precise nature of vaccine protection. We also considered a model variant that includes a single high-risk subgroup representing children. For smaller stockpile sizes that allow vaccine to be offered only to the high-risk group at the optimal dose, the predicted benefits of using the homogenous model formed a lower bound in the presence of a risk group, even when the high-risk group was twice as infective and twice as susceptible.
Conclusions
In addition to individual-level protection (i.e., vaccine efficacy), the population-level implications of pre-pandemic vaccine programs should be considered when deciding on stockpile size and dose. Our results suggest that a lower vaccine dose may be justified in order to increase population coverage, thereby reducing the infection attack rate overall.
Steven Riley and colleagues examine the potential benefits of "stretching" a limited supply of vaccine and suggest that substantial reductions in the attack rate are possible if vaccines are given to more people at lower doses.
Editors' Summary
Background.
Every winter, millions of people catch influenza, a viral infection of the nose, throat, and airways. Most recover quickly, but the disease can be deadly. In the US, seasonal influenza outbreaks (epidemics) cause 36,000 excess deaths annually. And now there are fears that an avian (bird) influenza virus might trigger a human influenza pandemic—a global epidemic that could kill millions. Seasonal epidemics occur because flu viruses continually make small changes to their hemagglutinin and neuraminidase molecules, the viral proteins (antigens) that the immune system recognizes. Because of this “antigenic drift,” an immune system response (which can be induced by catching flu or by vaccination with disabled circulating influenza strains) that combats flu one year may provide only partial protection the next year. “Antigenic shift” (large changes in flu antigens) can cause pandemics because communities have no immunity to the changed virus.
Why Was This Study Done?
Although avian influenza virus, which contains a hemagglutinin type that differs from currently circulating human flu viruses, has caused a few cases of human influenza, it has not started a human pandemic yet because it cannot move easily between people. If it acquires this property, which will probably involve further small antigenic changes, it could kill millions of people before scientists can develop an effective vaccine against it. To provide some interim protection, many countries are preparing stockpiles of “pre-pandemic” vaccines targeted against the avian virus. The US, for example, plans to store enough pre-pandemic vaccine to provide maximum protection to 20 million people (including key health workers) out of its population of 300 million. But, given a limited stockpile of pre-pandemic vaccine, might giving more people a lower dose of vaccine, which might reduce the number of people susceptible to infection and induce herd immunity by preventing efficient transmission of the flu virus, be a better way to limit the spread of pandemic influenza? In this study, the researchers have used mathematical modeling to investigate this question.
What Did the Researchers Do and Find?
To predict the infection rates associated with different vaccination policies, the researchers developed a mathematical model that incorporates data on human immune responses induced with three experimental vaccines against the avian virus and historical data on the person–person transmission of previous pandemic influenza viruses. For all the vaccines, the model predicts that giving more people a low dose of the vaccine would limit the spread of influenza better than giving fewer people the high dose needed for full individual protection. For example, the researchers estimate that dividing the planned US stockpile of one experimental vaccine equally between 160 million people instead of giving it at the fully protective dose to 20 million people might avert about 27 million influenza cases in less than year. However, giving the maximally protective dose to the 9 million US health-care workers and using the remaining vaccine at a lower dose to optimize protection within the general population might avert only 14 million infections.
What Do These Findings Mean?
These findings suggest that, given a limited stockpile of pre-pandemic vaccine, increasing the population coverage of vaccination by using low doses of vaccine might reduce the overall influenza infection rate more effectively than vaccinating fewer people with fully protective doses of vaccine. However, because the researchers' model includes many assumptions, it can only give an indication of how different strategies might perform, not firm numbers for how many influenza cases each strategy is likely to avert. Before public-health officials use this or a similar model to help them decide the best way to use pre-pandemic vaccines to control a human influenza pandemic, they will need more information about the efficacy of these vaccines and about transmission rates of currently circulating viruses. They will also need to know whether pre-pandemic vaccines actually provide good protection against the pandemic virus, as assumed in this study, before they can recommend mass immunization with low doses of pre-pandemic vaccine, selective vaccination with high doses, or a mixed strategy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040218.
US Centers for Disease Control and Prevention provide information on influenza and influenza vaccination for patients and health professionals (in English, Spanish, Filipino, Chinese, and Vietnamese)
The World Health Organization has a fact sheet on influenza and on the global response to avian influenza (in English, Spanish, French, Russian, Arabic, and Chinese)
The MedlinePlus online encyclopedia devotes a page to flu (in English and Spanish)
The UK Health Protection Agency information on avian, pandemic, and seasonal influenza
The US National Institute of Allergy and Infectious Diseases has a comprehensive feature called “focus on the flu”
doi:10.1371/journal.pmed.0040218
PMCID: PMC1892041  PMID: 17579511
3.  CDC's strategic plan for bioterrorism preparedness and response. 
Public Health Reports  2001;116(Suppl 2):9-16.
The Department of Health and Human Services (DHHS) has played a critical lead role over the past two years in fostering activities associated with the medical and public health response to bioterrorism. Based on a charge from Secretary Donna Shalala in 1998, the Centers for Disease Control and Prevention (CDC) is leading public health efforts to strengthen the nation's capacity to detect and respond to a bioterrorist event. As a result of our efforts, federal, state, and local communities are improving their public health capacities to respond to these types of emergencies. For many of us in public health, developing plans and capacities to respond to acts of bioterrorism is an extension of our long-standing roles and responsibilities. These are stated in the CDC Mission Statement: to promote health and quality of life by preventing and controlling disease, injury, and disability, and the Bioterrorism Mission: to lead the public health effort in enhancing readiness to detect and respond to bioterrorism. CDC's infectious diseases control efforts are summarized below: --Initially formed to address malaria control in 1946; --Established the epidemic Intelligence Service in 1951; --Participated in global smallpox eradication and other immunization programs; --Estimated 800-1,000 + field investigations/year since late 1990s; --New diseases: Legionnaire's Disease, toxic shock syndrome, Lyme disease, HIV, hantavirus pulmonary syndrome, West Nile, etc. -- Today: focus on emerging infections and bioterrorism. Over the past 50 years, CDC has seen a decline in the incidence of some infectious diseases and an increase in some, whereas others continue to present on a more unpredictable basis (i.e., hantavirus). Outbreak identification, investigation, and control have been an integral part of what we do for more than 50 years. We estimate that 800 to 1,000 field investigations have occurred every year since the late 1990s. Today, however, we have a new focus on emerging infectious diseases and bioterrorism.
PMCID: PMC1497264  PMID: 11880662
4.  Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Infected Women Receiving Cotrimoxazole Prophylaxis: A Multicenter Randomized Placebo-Controlled Trial 
PLoS Medicine  2014;11(9):e1001735.
Clara Menéndez and colleagues conducted a randomized controlled trial among HIV-positive pregnant women in Kenya, Mozambique, and Tanzania to investigate the safety and efficacy of mefloquine as intermittent preventative therapy for malaria in women receiving cotrimoxazole prophylaxis and long-lasting insecticide treated nets.
Please see later in the article for the Editors' Summary
Background
Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs).
Methods and Findings
A total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27–0.82]; p = 0.008), placental malaria (RR, 0.52 [95% CI 0.29–0.90]; p = 0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37–0.95]; p = 0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p = 0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14–3.33]; p = 0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis.
Conclusions
An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs.
Trial registration
ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, kills about 600,000 people every year. Most of these deaths occur among young children living in sub-Saharan Africa but pregnant women living in Africa are also very vulnerable to malaria. Infection with malaria during pregnancy can cause severe maternal anemia (reduced red blood cell numbers), stillbirths, and pre-term and low-birthweight babies, and is responsible for the deaths of many African women and their babies. To reduce the loss of life from malaria in pregnancy, the World Health Organization (WHO) recommends that pregnant women living in Africa receive the antimalarial drug sulfadoxine-pyrimethamine (SP) at each scheduled antenatal care visit given at least a month apart (intermittent preventive treatment in pregnancy [IPTp]). In addition, WHO advises pregnant women to sleep under insecticide-treated bed nets to protect themselves from the bites of infected mosquitoes and recommends effective case management of pregnant women with malarial illness.
Why Was This Study Done?
Pregnant women living in Africa are often infected with HIV, the virus that causes AIDS. HIV infection increases both the risk and severity of malaria infection during pregnancy, and at least one million pregnancies are complicated by co-infection with malaria and HIV in sub-Saharan Africa every year. WHO recommends that HIV-positive pregnant women take cotrimoxazole (CTX) daily to prevent opportunistic infections (CTX prophylaxis [CTXp]). Unfortunately, both CTX and SP are antifolate drugs and taking two drugs of this type increases a woman's risk of developing a severe skin reaction. Moreover, although CTXp protects children and HIV-infected adults against malaria, it is not known whether CTXp alone protects HIV-infected pregnant women adequately against malaria. Thus, evaluations of alternative drugs for use in IPTp in HIV-positive pregnant women are needed. In this randomized placebo-controlled trial, the researchers study the safety and efficacy of the antimalarial drug mefloquine (MQ) in HIV-infected women receiving CTXp. A randomized, placebo-controlled trial compares outcomes among people chosen through the play of chance to receive either the drug under investigation or a “dummy” (placebo) drug.
What Did the Researchers Do and Find?
The researchers allocated 1,071 HIV-infected pregnant women from Kenya, Mozambique, and Tanzania to receive three doses of MQ (IPTp-MQ), given at least one month apart, or three doses of placebo. All the women received CTXp and were given an insecticide-treated bed net. In an intention-to-treat analysis (an analysis that considers the outcomes of all trial participants irrespective of whether they receive their allocated treatment), the prevalence of parasitemia (parasites in the blood) at delivery among women given IPTp-MQ was 3.5% whereas the prevalence among women given the placebo was 6.9%. In other words, compared to placebo, IPTp-MQ was associated with a reduced risk of maternal parasitemia. IPTp-MQ was also associated with a reduced rate of placental malaria (parasites in the placenta) and a reduced incidence of hospital admissions for non-pregnancy related causes. There was no difference in adverse pregnancy outcomes such as stillbirth between the intervention groups but drug tolerability was poorer in the MQ group than in the placebo group. Finally, in an exploratory (unplanned) according-to-protocol analysis (an analysis that only considers outcomes in trial participants who receive their allocated intervention), women in the MQ group had a higher HIV viral load at delivery than women in the control group and were nearly twice as likely to transmit HIV to their child around the time of birth.
What Do These Findings Mean?
These findings suggest that the addition of IPTp-MQ to CTXp and the use of insecticide-treated bed nets can improve malaria prevention and maternal health in HIV-infected pregnant women in Africa. However, the poor tolerability of MQ and the association of MQ treatment with both an increased HIV viral load at delivery and a higher frequency of mother-to-child-transmission of HIV when compared to placebo raise concerns about the use of MQ in IPTp. Because these last two findings came from an exploratory analysis, which is more likely to throw up a chance finding than a pre-planned analysis further studies are needed to confirm these unexpected but potentially important findings. Nevertheless, overall, the findings of this study suggest that MQ should not be recommended for IPTp in HIV-infected pregnant women in Africa and highlight the need to find alternative drugs for malaria prevention in this group of women who are particularly vulnerable to malaria.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001735.
This study is further discussed in a PLOS Medicine Perspective by Richard Steketee.
A related PLOS Medicine Research Article by González et al. compares the efficacy of IPTp-MQ and IPTp-SP in HIV-negative women
Information is available from the World Health Organization on malaria (in several languages) and on malaria in pregnancy; information on IPTp and the current WHO policy recommendation on IPTp with SP are available; the 2013 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention also provides information on malaria; a personal story about malaria in pregnancy is available
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy
MedlinePlus provides links to additional information on malaria (in English and Spanish)
More information about the trial protocol is available
doi:10.1371/journal.pmed.1001735
PMCID: PMC4172537  PMID: 25247995
5.  Modeling the Worldwide Spread of Pandemic Influenza: Baseline Case and Containment Interventions 
PLoS Medicine  2007;4(1):e13.
Background
The highly pathogenic H5N1 avian influenza virus, which is now widespread in Southeast Asia and which diffused recently in some areas of the Balkans region and Western Europe, has raised a public alert toward the potential occurrence of a new severe influenza pandemic. Here we study the worldwide spread of a pandemic and its possible containment at a global level taking into account all available information on air travel.
Methods and Findings
We studied a metapopulation stochastic epidemic model on a global scale that considers airline travel flow data among urban areas. We provided a temporal and spatial evolution of the pandemic with a sensitivity analysis of different levels of infectiousness of the virus and initial outbreak conditions (both geographical and seasonal). For each spreading scenario we provided the timeline and the geographical impact of the pandemic in 3,100 urban areas, located in 220 different countries. We compared the baseline cases with different containment strategies, including travel restrictions and the therapeutic use of antiviral (AV) drugs. We investigated the effect of the use of AV drugs in the event that therapeutic protocols can be carried out with maximal coverage for the populations in all countries. In view of the wide diversity of AV stockpiles in different regions of the world, we also studied scenarios in which only a limited number of countries are prepared (i.e., have considerable AV supplies). In particular, we compared different plans in which, on the one hand, only prepared and wealthy countries benefit from large AV resources, with, on the other hand, cooperative containment scenarios in which countries with large AV stockpiles make a small portion of their supplies available worldwide.
Conclusions
We show that the inclusion of air transportation is crucial in the assessment of the occurrence probability of global outbreaks. The large-scale therapeutic usage of AV drugs in all hit countries would be able to mitigate a pandemic effect with a reproductive rate as high as 1.9 during the first year; with AV supply use sufficient to treat approximately 2% to 6% of the population, in conjunction with efficient case detection and timely drug distribution. For highly contagious viruses (i.e., a reproductive rate as high as 2.3), even the unrealistic use of supplies corresponding to the treatment of approximately 20% of the population leaves 30%–50% of the population infected. In the case of limited AV supplies and pandemics with a reproductive rate as high as 1.9, we demonstrate that the more cooperative the strategy, the more effective are the containment results in all regions of the world, including those countries that made part of their resources available for global use.
A metapopulation stochastic epidemic model for influenza shows the need to include air transportation when assessing the occurrence probability of global outbreaks. The impact of the use of antiviral drugs is also measured.
Editors' Summary
Background.
Seasonal outbreaks (epidemics) of influenza—a viral infection of the nose, throat, and airways—affect millions of people and kill about 500,000 individuals every year. Regular epidemics occur because flu viruses frequently make small changes in the viral proteins (antigens) recognized by the human immune system. Consequently, a person's immune-system response that combats influenza one year provides incomplete protection the next year. Occasionally, a human influenza virus appears that contains large antigenic changes. People have little immunity to such viruses (which often originate in birds or animals), so they can start a global epidemic (pandemic) that kills millions of people. Experts fear that a human influenza pandemic could be triggered by the avian H5N1 influenza virus, which is present in bird flocks around the world. So far, fewer than 300 people have caught this virus but more than 150 people have died.
Why Was This Study Done?
Avian H5N1 influenza has not yet triggered a human pandemic, because it rarely passes between people. If it does acquire this ability, it would take 6–8 months to develop a vaccine to provide protection against this new, potentially pandemic virus. Public health officials therefore need other strategies to protect people during the first few months of a pandemic. These could include international travel restrictions and the use of antiviral drugs. However, to get the most benefit from these interventions, public-health officials need to understand how influenza pandemics spread, both over time and geographically. In this study, the researchers have used detailed information on air travel to model the global spread of an emerging influenza pandemic and its containment.
What Did the Researchers Do and Find?
The researchers incorporated data on worldwide air travel and census data from urban centers near airports into a mathematical model of the spread of an influenza pandemic. They then used this model to investigate how the spread and health effects of a pandemic flu virus depend on the season in which it emerges (influenza virus thrives best in winter), where it emerges, and how infectious it is. Their model predicts, for example, that a flu virus originating in Hanoi, Vietnam, with a reproductive number (R0) of 1.1 (a measure of how many people an infectious individual infects on average) poses a very mild global threat. However, epidemics initiated by a virus with an R0 of more than 1.5 would often infect half the population in more than 100 countries. Next, the researchers used their model to show that strict travel restrictions would have little effect on pandemic evolution. More encouragingly, their model predicts that antiviral drugs would mitigate pandemics of a virus with an R0 up to 1.9 if every country had an antiviral drug stockpile sufficient to treat 5% of its population; if the R0 was 2.3 or higher, the pandemic would not be contained even if 20% of the population could be treated. Finally, the researchers considered a realistic scenario in which only a few countries possess antiviral stockpiles. In these circumstances, compared with a “selfish” strategy in which countries only use their antiviral drugs within their borders, limited worldwide sharing of antiviral drugs would slow down the spread of a flu virus with an R0 of 1.9 by more than a year and would benefit both drug donors and recipients.
What Do These Findings Mean?
Like all mathematical models, this model for the global spread of an emerging pandemic influenza virus contains many assumptions (for example, about viral behavior) that might affect the accuracy of its predictions. The model also does not consider variations in travel frequency between individuals or viral spread in rural areas. Nevertheless, the model provides the most extensive global simulation of pandemic influenza spread to date. Reassuringly, it suggests that an emerging virus with a low R0 would not pose a major public-health threat, since its attack rate would be limited and would not peak for more than a year, by which time a vaccine could be developed. Most importantly, the model suggests that cooperative sharing of antiviral drugs, which could be organized by the World Health Organization, might be the best way to deal with an emerging influenza pandemic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040013.
The US Centers for Disease Control and Prevention has information about influenza for patients and professionals, including key facts about avian influenza and antiviral drugs
The US National Institute of Allergy and Infectious Disease features information on seasonal, avian, and pandemic flu
The US Department of Health and Human Services provides information on pandemic flu and avian flu, including advice to travelers
World Health Organization has fact sheets on influenza and avian influenza, including advice to travelers and current pandemic flu threat
The UK Health Protection Agency has information on seasonal, avian, and pandemic influenza
The UK Department of Health has a feature article on bird flu and pandemic influenza
doi:10.1371/journal.pmed.0040013
PMCID: PMC1779816  PMID: 17253899
6.  Reducing the Impact of the Next Influenza Pandemic Using Household-Based Public Health Interventions 
PLoS Medicine  2006;3(9):e361.
Background
The outbreak of highly pathogenic H5N1 influenza in domestic poultry and wild birds has caused global concern over the possible evolution of a novel human strain [1]. If such a strain emerges, and is not controlled at source [2,3], a pandemic is likely to result. Health policy in most countries will then be focused on reducing morbidity and mortality.
Methods and Findings
We estimate the expected reduction in primary attack rates for different household-based interventions using a mathematical model of influenza transmission within and between households. We show that, for lower transmissibility strains [2,4], the combination of household-based quarantine, isolation of cases outside the household, and targeted prophylactic use of anti-virals will be highly effective and likely feasible across a range of plausible transmission scenarios. For example, for a basic reproductive number (the average number of people infected by a typically infectious individual in an otherwise susceptible population) of 1.8, assuming only 50% compliance, this combination could reduce the infection (symptomatic) attack rate from 74% (49%) to 40% (27%), requiring peak quarantine and isolation levels of 6.2% and 0.8% of the population, respectively, and an overall anti-viral stockpile of 3.9 doses per member of the population. Although contact tracing may be additionally effective, the resources required make it impractical in most scenarios.
Conclusions
National influenza pandemic preparedness plans currently focus on reducing the impact associated with a constant attack rate, rather than on reducing transmission. Our findings suggest that the additional benefits and resource requirements of household-based interventions in reducing average levels of transmission should also be considered, even when expected levels of compliance are only moderate.
Voluntary household-based quarantine and external isolation are likely to be effective in limiting the morbidity and mortality of an influenza pandemic, even if such a pandemic cannot be entirely prevented, and even if compliance with these interventions is moderate.
Editors' Summary
Background.
Naturally occurring variation in the influenza virus can lead both to localized annual epidemics and to less frequent global pandemics of catastrophic proportions. The most destructive of the three influenza pandemics of the 20th century, the so-called Spanish flu of 1918–1919, is estimated to have caused 20 million deaths. As evidenced by ongoing tracking efforts and news media coverage of H5N1 avian influenza, contemporary approaches to monitoring and communications can be expected to alert health officials and the general public of the emergence of new, potentially pandemic strains before they spread globally.
Why Was This Study Done?
In order to act most effectively on advance notice of an approaching influenza pandemic, public health workers need to know which available interventions are likely to be most effective. This study was done to estimate the effectiveness of specific preventive measures that communities might implement to reduce the impact of pandemic flu. In particular, the study evaluates methods to reduce person-to-person transmission of influenza, in the likely scenario that complete control cannot be achieved by mass vaccination and anti-viral treatment alone.
What Did the Researchers Do and Find?
The researchers developed a mathematical model—essentially a computer simulation—to simulate the course of pandemic influenza in a hypothetical population at risk for infection at home, through external peer networks such as schools and workplaces, and through general community transmission. Parameters such as the distribution of household sizes, the rate at which individuals develop symptoms from nonpandemic viruses, and the risk of infection within households were derived from demographic and epidemiologic data from Hong Kong, as well as empirical studies of influenza transmission. A model based on these parameters was then used to calculate the effects of interventions including voluntary household quarantine, voluntary individual isolation in a facility outside the home, and contact tracing (that is, asking infectious individuals to identify people whom they may have infected and then warning those people) on the spread of pandemic influenza through the population. The model also took into account the anti-viral treatment of exposed, asymptomatic household members and of individuals in isolation, and assumed that all intervention strategies were put into place before the arrival of individuals infected with the pandemic virus.
  Using this model, the authors predicted that even if only half of the population were to comply with public health interventions, the proportion infected during the first year of an influenza pandemic could be substantially reduced by a combination of household-based quarantine, isolation of actively infected individuals in a location outside the household, and targeted prophylactic treatment of exposed individuals with anti-viral drugs. Based on an influenza-associated mortality rate of 0.5% (as has been estimated for New York City in the 1918–1919 pandemic), the magnitude of the predicted benefit of these interventions is a reduction from 49% to 27% in the proportion of the population who become ill in the first year of the pandemic, which would correspond to 16,000 fewer deaths in a city the size of Hong Kong (6.8 million people). In the model, anti-viral treatment appeared to be about as effective as isolation when each was used in combination with household quarantine, but would require stockpiling 3.9 doses of anti-viral for each member of the population. Contact tracing was predicted to provide a modest additional benefit over quarantine and isolation, but also to increase considerably the proportion of the population in quarantine.
What Do These Findings Mean?
This study predicts that voluntary household-based quarantine and external isolation can be effective in limiting the morbidity and mortality of an influenza pandemic, even if such a pandemic cannot be entirely prevented, and even if compliance with these interventions is far from uniform. These simulations can therefore inform preparedness plans in the absence of data from actual intervention trials, which would be impossible outside (and impractical within) the context of an actual pandemic. Like all mathematical models, however, the one presented in this study relies on a number of assumptions regarding the characteristics and circumstances of the situation that it is intended to represent. For example, the authors found that the efficacy of policies to reduce the rate of infection vary according to the ease with which a given virus spreads from person to person. Because this parameter (known as the basic reproductive ratio, R0) cannot be reliably predicted for a new viral strain based on past epidemics, the authors note that in an actual influenza pandemic rapid determinations of R0 in areas already involved would be necessary to finalize public health responses in threatened areas. Further, the implementation of the interventions that appear beneficial in this model would require devoting attention and resources to practical considerations, such as how to staff isolation centers and provide food and water to those in household quarantine. However accurate the scientific data and predictive models may be, their effectiveness can only be realized through well-coordinated local, as well as international, efforts.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030361.
• World Health Organization influenza pandemic preparedness page
• US Department of Health and Human Services avian and pandemic flu information site
• Pandemic influenza page from the Public Health Agency of Canada
• Emergency planning page on pandemic flu from the England Department of Health
• Wikipedia entry on pandemic influenza with links to individual country resources (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030361
PMCID: PMC1526768  PMID: 16881729
7.  Antiviral Resistance and the Control of Pandemic Influenza 
PLoS Medicine  2007;4(1):e15.
Background
The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir), combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness). Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans.
Methods and Findings
We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing) that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains.
Conclusions
The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Therefore, the risk of resistance should be considered in pandemic planning and monitored closely during a pandemic.
Emergence of oseltamivir-resistant influenza strains during a pandemic is likely given the heightened selective pressure if the drug is widely used. Marc Lipsitch and colleagues suggest that resistance would reduce but not completely offset the drug's benefits for pandemic control.
Editors' Summary
Background.
Governments and health authorities worldwide are planning how they would best prepare for and deal with a future influenza pandemic. Seasonal influenza is thought to affect between 5% and 15% of the population worldwide each year. Most people who get influenza recover within a couple of weeks without lasting effects, but a small proportion of patients, mostly young children and elderly people, experience serious complications that can be fatal. An influenza pandemic happens when new variants of the influenza virus emerge against which little immunity exists in the general population. Pandemic influenza strains are transmitted more rapidly than seasonal strains, often sweep across several countries or continents, and make more people ill. There are drugs that can treat and prevent influenza. One of them, oseltamivir (Tamiflu) is an antiviral drug that works by preventing viral particles from being released by infected human cells. Stockpiling large amounts of oseltamivir and related drugs with the intent to treat a large fraction of the population is a key part of pandemic preparedness of many countries. However, it is known that influenza viruses can develop resistance to these drugs.
Why Was This Study Done?
It is not clear how the emergence of oseltamivir-resistant influenza strains would affect the course of any future influenza pandemic. Much research in this area has focused on how likely the new strains are to emerge in the first place, rather than on how they might spread once they had emerged. In the context of an influenza pandemic, antiviral drugs would be used in a large proportion of the population, likely driving the selection and spread of resistant viruses. For this study, the researchers wanted to estimate the likely impact of resistant strains during an influenza pandemic.
What Did the Researchers Do and Find?
These researchers set up a mathematical model (i.e., simulations done on a computer) to mimic the spread of influenza. They then fed a set of assumptions into the computer. These included information about the rate of transmission of influenza from one person to another; what proportion of people would receive antiviral drugs for prophylaxis or treatment; how likely the drugs would be to successfully treat or prevent infection; and in what proportion of people the virus might become resistant to drugs. The modeling led to three main predictions. First, it predicted that widespread use of antiviral drugs such as oseltamivir could quickly lead to the spread of resistant viruses, even if resistant strains emerged only rarely. Second, even with resistant strains circulating, prophylaxis and treatment with oseltamivir would still delay the spread of the pandemic and reduce its total size. Third, nondrug interventions (such as social isolation and school closures) would further reduce the number of cases, but a higher proportion of cases would be caused by resistant strains if these control measures were used.
What Do These Findings Mean?
These findings suggest that, in the event of a future influenza pandemic for which antiviral drugs are used, there is a risk of resistance emerging and resistant strains causing illness in a substantial number of people. This would counteract the benefits of antiviral drugs but not eliminate those benefits entirely. Like all modeling studies, this one relies on realistic assumptions being entered into the model, and it is hard to know closely the model will mimic a real-life situation until the properties of an actual pandemic strain are known. Most studies, including this one, suggest that in the event of a pandemic, antiviral drugs will have an overall beneficial impact on reducing death rates and adverse health outcomes. However, given the sizeable effects of resistance suggested here, its role should be considered in pandemic planning. This includes surveillance that can detect emergence and spread of resistant strains.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0040015.
World Health Organization: information on pandemic preparedness
World Health Organization: fact sheets on influenza
Information from the UK Health Protection Agency on pandemic influenza
US government website on both pandemic flu and avian flu (information provided by the US Department of Health and Human Services)
doi:10.1371/journal.pmed.0040015
PMCID: PMC1779817  PMID: 17253900
8.  Live, Attenuated Influenza A H5N1 Candidate Vaccines Provide Broad Cross-Protection in Mice and Ferrets 
PLoS Medicine  2006;3(9):e360.
Background
Recent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic.
Methods and Findings
Live, attenuated candidate vaccines possessing genes encoding a modified H5 hemagglutinin (HA) and a wild-type (wt) N1 neuraminidase from influenza A H5N1 viruses isolated in Hong Kong and Vietnam in 1997, 2003, and 2004, and remaining gene segments derived from the cold-adapted (ca) influenza A vaccine donor strain, influenza A/Ann Arbor/6/60 ca (H2N2), were generated by reverse genetics. The H5N1 ca vaccine viruses required trypsin for efficient growth in vitro, as predicted by the modification engineered in the gene encoding the HA, and possessed the temperature-sensitive and attenuation phenotypes specified by the internal protein genes of the ca vaccine donor strain. More importantly, the candidate vaccines were immunogenic in mice. Four weeks after receiving a single dose of 106 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages (clades 1, 2, and 3) that were isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses.
Conclusions
The promising findings in these preclinical studies of safety, immunogenicity, and efficacy of the H5N1 ca vaccines against antigenically diverse H5N1 vaccines provide support for their careful evaluation in Phase 1 clinical trials in humans.
Promising preclinical results on safety, immunogenicity, and efficacy against diverse H5N1 strains provide support for careful evaluation of live, attenuated H5N1 vaccines in clinical trials in humans.
Editors' Summary
Background.
Influenza A viruses are classified into subtypes according to two of the proteins from the virus surface, the hemagglutinin (HA) and neuraminidase (NA) proteins, each of which occurs naturally in several different versions. For example, the global epidemic (pandemic) of 1918–1919 was caused by an influenza virus containing subtype 1 hemagglutinin and subtype 1 neuraminidase (H1N1), the 1957–1958 pandemic involved an H2N2 virus, and the 1969 pandemic, H3N2. Since 1997, several serious outbreaks of H5N1 infection have occurred in poultry and in humans, raising concerns that H5N1 “bird flu” may cause the next human influenza pandemic. Although human-to-human transmission of H5N1 viruses appears limited, mortality rates in human outbreaks of the disease have been alarmingly high—approximately 50%. A protective vaccine against H5N1 influenza might not only benefit regions where transmission from poultry to humans occurs, but could conceivably avert global catastrophe in the event that H5N1 evolves such that human-to-human spread becomes more frequent.
Why Was This Study Done?
Several approaches are in progress to develop vaccines against H5N1 viruses. To date, the products that have been tested in humans have not been very effective in producing a strong immune response. To be optimal for human use, a vaccine would have to be very safe, remain stable in storage, and provide protection against influenza caused by naturally occurring H5N1 viruses that are not precisely identical to the ones used to make the vaccine. This study was done to develop a new H5N1 vaccine and to test it in animals.
What Did the Researchers Do and Find?
The researchers developed vaccines using three artificially constructed, weakened forms of the H5N1 influenza virus. The three vaccine viruses were constructed using flu virus proteins other than HA and NA from an artificially weakened (attenuated) strain of influenza. These were combined in laboratory-grown cells with HA and NA proteins from H5N1 viruses isolated from human cases during three different years: 2004, 2003, and 1997. They grew larger quantities of the resulting viruses in hen's eggs, and tested the vaccines in chickens, ferrets, and mice.
In tests of safety, the study found that, unlike the natural viruses from which they were derived, the vaccine strains did not cause death when injected into the bloodstream of chickens, and did not even cause infection when given through the birds' breathing passages. Similarly, while the natural viruses were lethal in mice at various doses, the vaccine strains did not cause death even at the highest dose. In ferrets, infection with the vaccine strains was limited to the upper respiratory tract, while the natural viruses spread to the lungs and other organs.
In tests of protection, all mice that had received any of the three vaccines survived following infection with any of the natural viruses (so-called viral challenge), while unvaccinated mice died following viral challenge. This occurred even though standard blood tests could not detect a strong immune responses following a single dose of vaccine. Challenge virus was detected in the lungs of the immunized mice, but at lower levels than in the unvaccinated mice. Mice given two doses of a vaccine showed stronger immunity on blood tests, and almost complete protection from respiratory infection following challenge. In addition, mice and ferrets that had received two doses of vaccine were protected against challenge with H5N1 strains from more recent outbreaks in Asia that differed substantially from the strains that were used for the vaccine.
What Do These Findings Mean?
This study shows that it is possible to create a live, attenuated vaccine based on a single H5N1 virus that can provide protection (in mice and ferrets, at least) against different H5N1 viruses that emerge years later. Attenuated influenza virus vaccines of this sort are unlikely to be useful to protect fowl because they do not infect or induce an immune response in chickens. However, while the safety and protection found in small animals are encouraging, it is not possible to know without human testing whether a vaccine that protects mice and ferrets will work in humans, or how this type of vaccine may compare with others being developed for use in humans against H5N1 influenza. Tests of one of the vaccines in human volunteers in carefully conducted clinical trials are currently under way.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030360.
WHO Influenza Pandemic Preparedness page
US Department of Health and Human Services Avian and Pandemic flu information site
Wikipedia entry on H5N1 (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
CDC Avian Influenza Web page
doi:10.1371/journal.pmed.0030360
PMCID: PMC1564176  PMID: 16968127
9.  Estimating Infection Attack Rates and Severity in Real Time during an Influenza Pandemic: Analysis of Serial Cross-Sectional Serologic Surveillance Data 
PLoS Medicine  2011;8(10):e1001103.
This study reports that using serological data coupled with clinical surveillance data can provide real-time estimates of the infection attack rates and severity in an emerging influenza pandemic.
Background
In an emerging influenza pandemic, estimating severity (the probability of a severe outcome, such as hospitalization, if infected) is a public health priority. As many influenza infections are subclinical, sero-surveillance is needed to allow reliable real-time estimates of infection attack rate (IAR) and severity.
Methods and Findings
We tested 14,766 sera collected during the first wave of the 2009 pandemic in Hong Kong using viral microneutralization. We estimated IAR and infection-hospitalization probability (IHP) from the serial cross-sectional serologic data and hospitalization data. Had our serologic data been available weekly in real time, we would have obtained reliable IHP estimates 1 wk after, 1–2 wk before, and 3 wk after epidemic peak for individuals aged 5–14 y, 15–29 y, and 30–59 y. The ratio of IAR to pre-existing seroprevalence, which decreased with age, was a major determinant for the timeliness of reliable estimates. If we began sero-surveillance 3 wk after community transmission was confirmed, with 150, 350, and 500 specimens per week for individuals aged 5–14 y, 15–19 y, and 20–29 y, respectively, we would have obtained reliable IHP estimates for these age groups 4 wk before the peak. For 30–59 y olds, even 800 specimens per week would not have generated reliable estimates until the peak because the ratio of IAR to pre-existing seroprevalence for this age group was low. The performance of serial cross-sectional sero-surveillance substantially deteriorates if test specificity is not near 100% or pre-existing seroprevalence is not near zero. These potential limitations could be mitigated by choosing a higher titer cutoff for seropositivity. If the epidemic doubling time is longer than 6 d, then serial cross-sectional sero-surveillance with 300 specimens per week would yield reliable estimates when IAR reaches around 6%–10%.
Conclusions
Serial cross-sectional serologic data together with clinical surveillance data can allow reliable real-time estimates of IAR and severity in an emerging pandemic. Sero-surveillance for pandemics should be 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 about half a million 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. Occasionally, however, a very different influenza virus emerges to which people have virtually no immunity. Such viruses can start global epidemics (pandemics) and kill millions of people. The most recent influenza pandemic began in March 2009 in Mexico, when the first case of influenza caused by a new virus called pandemic A/H1N1 2009 (pdmH1N1) occurred. The virus spread rapidly despite strenuous efforts by national and international public health agencies to contain it, and on 11 June 2009, the World Health Organization (WHO) declared that an influenza pandemic was underway. By the time WHO announced that the pandemic was over (10 August 2010), pdmH1N1 had killed more than 18,000 people.
Why Was This Study Done?
Early in the 2009 influenza pandemic, as in any emerging pandemic, reliable estimates of pdmH1N1's transmissibility (how easily it spreads between people) and severity (the proportion of infected people who needed hospital treatment) were urgently needed to help public health officials plan their response to the pandemic and advise the public about the threat to their health. Because infection with an influenza virus does not always make people ill, the only way to determine the true size and severity of an influenza outbreak is to monitor the occurrence of antibodies (proteins made by the immune system in response to infections) to the influenza virus in the population—so-called serologic surveillance. In this study, the researchers developed a method that uses serologic data to provide real-time estimates of the infection attack rate (IAR; the cumulative occurrence of new infections in a population) and the infection-hospitalization probability (IHP; the proportion of affected individuals that needs to be hospitalized) during an influenza pandemic.
What Did the Researchers Do and Find?
The researchers tested nearly 15,000 serum samples collected in Hong Kong during the first wave of the 2009 pandemic for antibodies to pdmH1N1 and then used a mathematical approach called convolution to estimate IAR and IHP from these serologic data and hospitalization data. They report that if the serological data had been available weekly in real time, they would have been able to obtain reliable estimates of IAR and IHP by one week after, one to two weeks before, and three weeks after the pandemic peak for 5–14 year olds, 15–29 year olds, and 30–59 year olds, respectively. If serologic surveillance had begun three weeks after confirmation of community transmission of pdmH1N1, sample sizes of 150, 350, and 500 specimens per week from 5–14 year olds, 15–19 year olds, and 20–29 year olds, respectively, would have been sufficient to obtain reliable IAR and IHP estimates four weeks before the pandemic peak. However, for 30–59 year olds, even 800 specimens per week would not have generated reliable estimates because of pre-existing antibodies to an H1N1 virus in this age group. Finally, computer simulations of future pandemics indicate that serologic surveillance with 300 serum specimens per week would yield reliable estimates of IAR and IHP as soon as the true IAR reached about 6%.
What Do These Findings Mean?
These findings suggest that serologic data together with clinical surveillance data could be used to provide reliable real-time estimates of IARs and severity in an emerging influenza pandemic. Although the number of samples needed to provide accurate estimates of IAR and IHP in real life may vary somewhat from those reported here because of limitations in the design of this study, these findings nevertheless suggest that the level of testing capacity needed to provide real-time estimates of IAR and IHP during an emerging influenza pandemic should be logistically feasible for most developed countries. Moreover, collection of serologic surveillance data from any major city affected early in an epidemic could potentially provide information of global relevance for public health. Thus, the researchers conclude, serologic monitoring should be included in future plans for influenza pandemic preparedness and response and in planning for other pandemics.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001103.
A recent PLoS Medicine Research Article by Riley et al. provides further information on patterns of infection with the pdmH1N1 virus
The Hong Kong Centre for Health Protection provides information on pandemic H1N1 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 seasonal, pandemic, and H1N1 influenza
WHO provides information on seasonal influenza and has information on the global response to H1N1 influenza (in several languages)
The UK Health Protection Agency provides information on pandemic influenza and on H1N1 influenza
More information for patients about H1N1 influenza is available through Choices, an information resource provided by the UK National Health Service
doi:10.1371/journal.pmed.1001103
PMCID: PMC3186812  PMID: 21990967
10.  Risk management of seasonal influenza during pregnancy: current perspectives 
Influenza poses unique risks to pregnant women, who are particularly susceptible to morbidity and mortality. Historically, pregnant women have been overrepresented among patients with severe illness and complications from influenza, and have been more likely to require hospitalization and intensive care unit admission. An increased risk of adverse outcomes is also present for fetuses/neonates born to women affected by influenza during pregnancy. These risks to mothers and babies have been observed during both nonpandemic and pandemic influenza seasons. During the H1N1 influenza pandemic of 2009–2010, pregnant women were more likely to be hospitalized or admitted to intensive care units, and were at higher risk of death compared to nonpregnant adults. Vaccination remains the most effective intervention to prevent severe illness, and antiviral medications are an important adjunct to ameliorate disease when it occurs. Unfortunately, despite national guidelines recommending universal vaccination for women who are pregnant during influenza season, actual vaccination rates do not achieve desired targets among pregnant women. Pregnant women are also sometimes reluctant to use antiviral medications during pregnancy. Some of the barriers to use of vaccines and medications during pregnancy are a lack of knowledge of recommendations and of safety data. By improving knowledge and understanding of influenza and vaccination recommendations, vaccine acceptance rates among pregnant women can be improved. Currently, the appropriate use of vaccination and antiviral medications is the best line of defense against influenza and its sequelae among pregnant women, and strategies to increase acceptance are crucial. This article will review the importance of influenza in pregnancy, and discuss vaccination and antiviral medications for pregnant women.
doi:10.2147/IJWH.S47235
PMCID: PMC4122531  PMID: 25114593
antiviral medications; knowledge; vaccination
11.  Bioterrorism: Preparing the Plastic Surgeon 
Eplasty  2011;11:e47.
Introduction: Many medical disciplines, such as emergency medicine, trauma surgery, dermatology, psychiatry, family practice, and dentistry have documented attempts at assessing the level of bioterrorism preparedness in their communities. Currently, there is neither such an assessment nor an existing review of potential bioterrorism agents as they relate to plastic surgery. Therefore, the purpose of this article is to present plastic surgeons with a review of potential bioterrorism agents. Methods: A review of the literature on bioterrorism agents and online resources of the Centers for Disease Control and Prevention was conducted. Category A agents were identified and specific attention was paid to the management issues that plastic surgeons might face in the event that these agents are used in an attack. Results: Disease entities reviewed were smallpox, anthrax, plague, viral hemorrhagic fever, tularemia, and botulism. For each agent, we presented the microbiology, pathophysiology, clinical presentation, potential for weaponization, medical management, and surgical issues related to the plastic surgeon. Conclusion: This article is the first attempt at addressing preparedness for bioterrorism in the plastic surgery community. Many other fields have already started a similar process. This article represents a first step in developing evidence-based consensus guidelines and recommendations for the management of biological terrorism for plastic surgeons.
PMCID: PMC3223485  PMID: 22132252
12.  Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis 
PLoS Medicine  2011;8(7):e1001053.
This study analyzes data from 19 countries (from April 2009 to Jan 2010), comprising some 70,000 hospitalized patients with severe H1N1 infection, to reveal risk factors for severe pandemic influenza, which include chronic illness, cardiac disease, chronic respiratory disease, and diabetes.
Background
Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures.
Methods and Findings
Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3).
Conclusions
Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In April 2009, a new strain of influenza A H1N1 was first identified in Mexico and the United States and subsequently spread around the world. In June 2009, the World Health Organization (WHO) declared a pandemic alert phase 6, which continued until August 2010. Throughout the pandemic, WHO and member states gathered information to characterize the patterns of risk associated with the new influenza A H1N1 virus infection and to assess the clinical picture. Although risk factors for severe disease following seasonal influenza infection have been well documented in many countries (for example, pregnancy; chronic medical conditions such as pulmonary, cardiovascular, renal, hepatic, neuromuscular, hematologic, and metabolic disorders; some cognitive conditions; and immunodeficiency), risk factors for severe disease following infection early in the 2009 H1N1 pandemic were largely unknown.
Why Was This Study Done?
Many countries have recently reported data on the association between severe H1N1 influenza and a variety of underlying risk factors, but because these data are presented in different formats, making direct comparisons across countries is difficult, with no clear consensus for some conditions. Therefore, to assess the frequency and distribution of known and new potential risk factors for severe H1N1 infection, this study was conducted to collect data (from 1 April 2009 to 1 January 2010) from surveillance programs of the Ministries of Health or National Public Health Institutes in 19 countries―Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong (special administrative region), Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom.
What Did the Researchers Do and Find?
As part of routine surveillance, countries were asked to provide risk factor data on laboratory-confirmed H1N1 in patients who were admitted to hospital, admitted to the intensive care unit (ICU), or had died because of their infection, using a standardized format. The researchers grouped potential risk conditions into four categories: age, chronic medical illnesses, pregnancy (by trimester), and other conditions that were not previously considered as risk conditions for severe influenza outcomes, such as obesity. For each risk factor (except pregnancy), the researchers calculated the percentage of each group of patients using the total number of cases reported in each severity category (hospitalization, admission to ICU, and death). To evaluate the risk associated with pregnancy, the researchers used the ratio of pregnant women to all women of childbearing age (age 15–49 years) at each level of severity to describe the differences between levels.
The researchers were able to collect data on approximately 70,000 patients requiring hospitalization, 9,700 patients admitted to the ICU, and 2,500 patients who died from H1N1 infection. The proportion of patients with H1N1 with one or more reported chronic conditions increased with severity—the median was 31.1% of hospitalized patients, 52.3% of patients admitted to the ICU, and 61.8% of patients who died. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. The proportion of patients with obesity increased with increasing disease severity—median of 6% of hospitalized patients, 11.3% of patients admitted to the ICU, and 12.0% of all deaths from H1N1.
What Do These Findings Mean?
These findings show that risk factors for severe H1N1 infection are similar to those for seasonal influenza, with some notable differences: a substantial proportion of people with severe and fatal cases of H1N1 had pre-existing chronic illness, which indicates that the presence of chronic illness increases the likelihood of death. Cardiac disease, chronic respiratory disease, and diabetes are important risk factors for severe disease that will be especially relevant for countries with high rates of these illnesses. Approximately 2/3 of hospitalized people and 40% of people who died from H1N1 infection did not have any identified pre-existing chronic illness, but this study was not able to comprehensively assess how many of these cases had other risk factors, such as pregnancy, obesity, smoking, and alcohol misuse. Because of large differences between countries, the role of risk factors such as obesity and pregnancy need further study—although there is sufficient evidence to support vaccination and early intervention for pregnant women. Overall, the findings of this study reinforce the need to identify and target high-risk groups for interventions such as immunization, early medical advice, and use of antiviral medications.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001053.
WHO provides a Global Alert and Response (GAR) with updates on a number of influenza-related topics
The US Centers for Disease Control and Prevention provides information on risk factors and H1N1
doi:10.1371/journal.pmed.1001053
PMCID: PMC3130021  PMID: 21750667
13.  Syndromic surveillance using automated collection of computerized discharge diagnoses 
The Syndromic Surveillance Information Collection (SSIC) system aims to facilitate early detection of bioterrorism attacks (with such agents as anthrax, brucellosis, plague, Q fever, tularemia, smallpox, viral encephalitides, hemorrhagic fever, botulism toxins, staphylococcal enterotoxin B, etc.) and early detection of naturally occurring disease outbreaks, including large foodborne disease outbreaks, emerging infections, and pandemic influenza. This is accomplished using automated data collection of visit-level discharge diagnoses from heterogeneous clinical information systems, integrating those data into a common XML (Extensible Markup Language) form, and monitoring the results to detect unusual patterns of illness in the population. The system, operational since January 2001, collects, integrates, and displays data from three emergency department and urgent care (ED/UC) departments and nine primary care clinics by automatically mining data from the information systems of those facilities. With continued development, this system will constitute the foundation of a population-based surveillance system that will facilitate targeted investigation of clinical syndromes under surveillance and allow early detection of unusual clusters of illness compatible with bioterrorism or disease outbreaks.
doi:10.1007/PL00022320
PMCID: PMC3456541  PMID: 12791784
Biological warfare; Bioterrorism; Data collection; Database; Informatics; Information systems; Sentinel surveillance
14.  Prophylactic and Therapeutic Efficacy of Human Monoclonal Antibodies against H5N1 Influenza 
PLoS Medicine  2007;4(5):e178.
Background
New prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza (HPAI) H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies (mAbs) and tested their efficacy for prophylaxis and therapy in a murine model of infection.
Methods and Findings
Using Epstein-Barr virus we immortalized memory B cells from Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. Supernatants from B cell lines were screened in a virus neutralization assay. B cell lines secreting neutralizing antibodies were cloned and the mAbs purified. The cross-reactivity of these antibodies for different strains of H5N1 was tested in vitro by neutralization assays, and their prophylactic and therapeutic efficacy in vivo was tested in mice. In vitro, mAbs FLA3.14 and FLD20.19 neutralized both Clade I and Clade II H5N1 viruses, whilst FLA5.10 and FLD21.140 neutralized Clade I viruses only. In vivo, FLA3.14 and FLA5.10 conferred protection from lethality in mice challenged with A/Vietnam/1203/04 (H5N1) in a dose-dependent manner. mAb prophylaxis provided a statistically significant reduction in pulmonary virus titer, reduced associated inflammation in the lungs, and restricted extrapulmonary dissemination of the virus. Therapeutic doses of FLA3.14, FLA5.10, FLD20.19, and FLD21.140 provided robust protection from lethality at least up to 72 h postinfection with A/Vietnam/1203/04 (H5N1). mAbs FLA3.14, FLD21.140 and FLD20.19, but not FLA5.10, were also therapeutically active in vivo against the Clade II virus A/Indonesia/5/2005 (H5N1).
Conclusions
These studies provide proof of concept that fully human mAbs with neutralizing activity can be rapidly generated from the peripheral blood of convalescent patients and that these mAbs are effective for the prevention and treatment of H5N1 infection in a mouse model. A panel of neutralizing, cross-reactive mAbs might be useful for prophylaxis or adjunctive treatment of human cases of H5N1 influenza.
Cameron Simmons and colleagues provide proof of concept that human monoclonal antibodies with neutralizing activity can be rapidly generated from peripheral blood of convalescent patients and are effective in preventing and treating H5N1 infection in a mouse model.
Editors' Summary
Background.
Every year, millions of people catch influenza, a viral disease of the nose, throat, and airways. Although most recover, influenza outbreaks (epidemics) kill about half a million people annually. Epidemics occur because small but frequent changes in the viral proteins (antigens) to which the immune system responds mean that an immune response produced one year provides only partial protection against influenza the next year. Human flu viruses also occasionally appear that contain major antigenic changes. People have little or no immunity to such viruses (which often originate in animals or birds), so these viruses can start deadly pandemics—global epidemics. The Spanish flu pandemic in 1918/9, Asian flu in 1957, and Hong Kong flu in 1968 all killed millions. Experts believe that another pandemic is overdue and may be triggered by the avian H5N1 influenza virus—the name indicates that this bird virus carries type 5 hemagglutinin and type 1 neuraminidase, the two major flu antigens. H5N1, which rapidly kills infected birds, is now present in flocks around the world and, since 1997, it has caused 258 cases of human flu and 153 deaths. People have caught H5N1 through close contact with infected birds but, luckily, H5N1 rarely passes between people.
Why Was This Study Done?
H5N1 might acquire the ability to move between people and start a human influenza pandemic at any time. Some of the H5N1 viruses are resistant to the antiviral drugs used to treat flu and there will inevitably be a lag of some months between the emergence of a human pandemic H5N1 strain and the bulk production of a vaccine effective against it. Thus, new preventative and therapeutic strategies are needed to combat human infections with H5N1. One possibility is passive immunotherapy—treating people with antibodies (proteins that recognize antigens) that can stop H5N1 from infecting cells (so-called neutralizing antibodies). In this study, the researchers have generated neutralizing human monoclonal antibodies (laboratory-produced preparations that contain one type of human antibody) and tested their ability to halt viral growth in mice infected with H5N1.
What Did the Researchers Do and Find?
Patients who have survived infection with H5N1 make neutralizing antibodies, so the researchers isolated and immortalized the immune cells making these antibodies from the patients' blood. They grew up each cell separately and purified the antibody that the cells made. These monoclonal antibodies were then tested for their ability to neutralize H5N1 and other flu viruses in the laboratory. The researchers identified several that neutralized the H5N1 strain with which the patients were originally infected and chose two for further study. In the test tube, the four antibodies neutralized closely related H5N1 viruses and an H5N1 virus from a different lineage (clade) that has also caused human disease, in addition to the original H5N1 virus, although with different efficacies. In mice, the antibodies provided protection from infection with the original virus when given a day before or one to three days after infection. Three antibodies also partly protected the mice against H5N1 from a different clade. Finally, the researchers showed that the antibodies protected mice by limiting viral replication, by lessening the deleterious effects of the virus in the lungs, and by stopping viral spread out of the lungs.
What Do These Findings Mean?
These results indicate that passive immunotherapy with human monoclonal antibodies could help to combat avian H5N1 if (or when) it starts a human pandemic. Passive immunotherapy is already used to prevent infections with several other viruses. In addition, a crude form of the approach—early treatment of patients with plasma (the liquid portion of blood) from convalescent patients—halved the death rate during the Spanish flu pandemic. Large amounts of pure monoclonal antibodies can be relatively easily made for clinical use, and this study indicates that some monoclonal antibodies neutralize H5N1 viruses from different clades. The researchers sound a note of caution, however: Before passive immunotherapy can help to halt an H5N1 pandemic, they warn, the monoclonal antibodies will have to be tested to see whether they can neutralize not only all the currently circulating H5N1 viruses but also any emerging pandemic versions, which might be antigenically distinct.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040178.
US Centers for Disease Control and Prevention information about influenza for patients and professionals including key facts about avian influenza
US National Institute of Allergy and Infectious Disease feature on seasonal, avian, and pandemic flu
World Health Organization factsheet on influenza and information on avian influenza, including latest figures for confirmed human cases
UK Health Protection Agency information on seasonal, avian, and pandemic influenza
Wikipedia pages on passive immunity and monoclonal antibodies (note: Wikipedia is an online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040178
PMCID: PMC1880850  PMID: 17535101
15.  Patients' request for and emergency physicians' prescription of antimicrobial prophylaxis for anthrax during the 2001 bioterrorism-related outbreak 
BMC Public Health  2005;5:2.
Background
Inappropriate use of antibiotics by individuals worried about biological agent exposures during bioterrorism events is an important public health concern. However, little is documented about the extent to which individuals with self-identified risk of anthrax exposure approached physicians for antimicrobial prophylaxis during the 2001 bioterrorism attacks in the United States.
Methods
We conducted a telephone survey of randomly selected members of the Pennsylvania Chapter of the American College of Emergency Physicians to assess patients' request for and emergency physicians' prescription of antimicrobial agents during the 2001 anthrax attacks.
Results
Ninety-seven physicians completed the survey. Sixty-four (66%) respondents had received requests from patients for anthrax prophylaxis; 16 (25%) of these physicians prescribed antibiotics to a total of 23 patients. Ten physicians prescribed ciprofloxacin while 8 physicians prescribed doxycycline.
Conclusion
During the 2001 bioterrorist attacks, the majority of the emergency physicians we surveyed encountered patients who requested anthrax prophylaxis. Public fears may lead to a high demand for antibiotic prophylaxis during bioterrorism events. Elucidation of the relationship between public health response to outbreaks and outcomes would yield insights to ease burden on frontline clinicians and guide strategies to control inappropriate antibiotic allocation during bioterrorist events.
doi:10.1186/1471-2458-5-2
PMCID: PMC546188  PMID: 15634353
16.  Emerging and Zoonotic Infections in Women 
Synopsis
Emerging infections, many of them zoonotic, are caused by a wide variety of pathogens with global distribution. Their impact on women is similarly diverse. Pathogens that were previously rare are emerging in recent years to cause disease in new populations, and global travel facilitates their rapid spread across continents. Finally, human encroachment on previously remote areas has brought people into contact with zoonotic diseases and vectors never before characterized. Although systematic study of rare outbreaks can be challenging, our knowledge of emerging pathogens and their differential effects on women, including those who are pregnant, has started to accumulate. We discuss the effects on women of lymphocytic choriomeningitis virus, West Nile virus, SARS coronavirus, avian influenza A (H5N1), virus, and the viral hemorrhagic fevers. We also explore the spirochetal illnesses and Chagas disease as they pertain to the pregnant patient. Finally, we review the potential impact of candidate bioterror agents on the female population, and address related issues of prophylaxis and therapy.
doi:10.1016/j.idc.2008.05.007
PMCID: PMC2650502  PMID: 18954762
17.  Bioterrorism – Health emergency preparedness and response 
Paediatrics & Child Health  2003;8(2):93-96.
Health emergency planning for preparedness and response against acts of terrorism, including the malfeasant threat or actual release of biological agents designed to harm others, has assumed a higher level of concern for most western nations, including Canada, following the explosive attacks in the United States on September 11, 2001. These terrorist attacks were followed by an outbreak of anthrax infections. The Bacillus anthracis spores in these attacks were dispersed by using regular postal services in the United States. In addition to the unsettling sense of social vulnerability that resulted from these attacks, a greater appreciation that the integration of public health, emergency health and social services with security activities was required to fully address the need to protect the health and other interests of the citizens. Collaborative work among regional, provincial, territorial, federal and international authorities within these domains is emerging as an effective response to the risk management of bioterrorism. The following is a brief description of the health framework for preparedness and response, and the biological agents of major concern in terrorism.
PMCID: PMC2791430  PMID: 20019925
Bioterrorism; Health emergency
18.  Pandemic Influenza and Pregnant Women 
Emerging Infectious Diseases  2008;14(1):95-100.
Planning for a future influenza pandemic should include considerations specific to pregnant women. First, pregnant women are at increased risk for influenza-associated illness and death. The effects on the fetus of maternal influenza infection, associated fever, and agents used for prophylaxis and treatment should be taken into account. Pregnant women might be reluctant to comply with public health recommendations during a pandemic because of concerns regarding effects of vaccines or medications on the fetus. Guidelines regarding nonpharmaceutical interventions (e.g., voluntary quarantine) also might present special challenges because of conflicting recommendations about routine prenatal care and delivery. Finally, healthcare facilities need to develop plans to minimize exposure of pregnant women to ill persons, while ensuring that women receive necessary care.
doi:10.3201/eid1401.070667
PMCID: PMC2600164  PMID: 18258087
pregnancy; women; influenza; H5N1; avian influenza; pandemic influenza; antiviral medications; influenza vaccine; perspective
19.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
20.  Estimating the Location and Spatial Extent of a Covert Anthrax Release 
PLoS Computational Biology  2009;5(1):e1000356.
Rapidly identifying the features of a covert release of an agent such as anthrax could help to inform the planning of public health mitigation strategies. Previous studies have sought to estimate the time and size of a bioterror attack based on the symptomatic onset dates of early cases. We extend the scope of these methods by proposing a method for characterizing the time, strength, and also the location of an aerosolized pathogen release. A back-calculation method is developed allowing the characterization of the release based on the data on the first few observed cases of the subsequent outbreak, meteorological data, population densities, and data on population travel patterns. We evaluate this method on small simulated anthrax outbreaks (about 25–35 cases) and show that it could date and localize a release after a few cases have been observed, although misspecifications of the spore dispersion model, or the within-host dynamics model, on which the method relies can bias the estimates. Our method could also provide an estimate of the outbreak's geographical extent and, as a consequence, could help to identify populations at risk and, therefore, requiring prophylactic treatment. Our analysis demonstrates that while estimates based on the first ten or 15 observed cases were more accurate and less sensitive to model misspecifications than those based on five cases, overall mortality is minimized by targeting prophylactic treatment early on the basis of estimates made using data on the first five cases. The method we propose could provide early estimates of the time, strength, and location of an aerosolized anthrax release and the geographical extent of the subsequent outbreak. In addition, estimates of release features could be used to parameterize more detailed models allowing the simulation of control strategies and intervention logistics.
Author Summary
Releasing highly pathogenic organisms into an urban population is a form of bioterrorism that could result in a large number of casualties. The first indication that a covert open-air release has occurred is quite likely to be individuals reporting for medical attention. If such an attack is suspected, then public health authorities would attempt to identify those individuals who have been infected in order to provide rapid treatment with the aim of reducing the possibility of disease and potential death. Aiming treatment at too small an area might miss individuals infected further down and/or up wind, whereas issues surrounding both treatment resources and serious side effects may rule out mass treatment campaigns of large sections of the population. Our work provides scientific robustness to firstly estimate where and when an aerosolized release has occurred and secondly identify the most critically affected geographic areas. In order to use this statistical tool during an outbreak, public health workers would only need to collect the time of symptomatic onset and the home and work locations of early cases; recent weather information would also be required. Although the accuracy of the estimates is likely to improve as more cases appear, treating individuals based on early estimates might prove more beneficial since time would be of the essence.
doi:10.1371/journal.pcbi.1000356
PMCID: PMC2663800  PMID: 19360099
21.  Insufficient preparedness of primary care practices for pandemic influenza and the effect of a preparedness plan in Japan: a prefecture-wide cross-sectional study 
BMC Family Practice  2013;14:174.
Background
Cases of emerging infectious diseases, including H5N1 influenza, H7N9 influenza, and Middle East Respiratory Syndrome, have been reported in recent years, and the threat of pandemic outbreaks persists. In Japan, primary care is the frontline against emerging infectious diseases in communities. Although the importance of pandemic preparedness in primary care has been highlighted previously, few studies have thus far investigated the preparedness among primary care practices (PCPs) or differences in the preparedness of different institutional settings. We examined PCP preparedness and response to the 2009 influenza pandemic in Japan, and explored the role of a pandemic preparedness plan during the pandemic.
Methods
We used a survey questionnaire to assess how well individual PCPs in Okinawa, Japan, were prepared for the 2009 influenza pandemic. The questionnaire was mailed to all eligible PCPs (N = 465) in Okinawa, regardless of their institutional setting. In addition, we assessed the differences in the preparedness of clinics and hospitals and determined whether the national preparedness plan affected individual preparedness and response. Data were analyzed using descriptive and logistic regression analyses.
Results
A total of 174 (37.4%) PCPs responded to our survey. In general, high-level personal protective equipment (PPE) such as N95 masks (45.4%), gowns (30.5%), and eye protection (21.3%) was stocked at a low rate. Clinic-based PCPs were significantly less prepared than hospital-based PCPs to provide N95 masks (OR 0.34), gowns (OR 0.15), and eye protection (OR 0.18). In addition, only 32.8% of PCPs adopted an adequate business continuity plan (BCP). After controlling for institutional setting, reading the national preparedness plan was significantly associated with establishment of a BCP (OR 5.86), and with knowledge of how to transfer a swab specimen to a local medical laboratory (OR 5.60).
Conclusions
With regard to PPE availability, PCPs (especially clinic-based PCPs) were not adequately prepared for the influenza pandemic. Awareness of the national pandemic preparedness plan is likely to promote prefecture-wide implementation of BCPs and surveillance activity.
doi:10.1186/1471-2296-14-174
PMCID: PMC3840630  PMID: 24252688
Primary care practice; Primary care; Preparedness; Response; Pandemic preparedness plan; Personal protective equipment; Business continuity plan; Pandemic influenza
22.  Incident HIV during Pregnancy and Postpartum and Risk of Mother-to-Child HIV Transmission: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001608.
Alison Drake and colleagues conduct a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy and the postpartum period and to compare mother-to-child HIV transmission risk among women with incident versus chronic infection.
Please see later in the article for the Editors' Summary
Background
Women may have persistent risk of HIV acquisition during pregnancy and postpartum. Estimating risk of HIV during these periods is important to inform optimal prevention approaches. We performed a systematic review and meta-analysis to estimate maternal HIV incidence during pregnancy/postpartum and to compare mother-to-child HIV transmission (MTCT) risk among women with incident versus chronic infection.
Methods and Findings
We searched PubMed, Embase, and AIDS-related conference abstracts between January 1, 1980, and October 31, 2013, for articles and abstracts describing HIV acquisition during pregnancy/postpartum. The inclusion criterion was studies with data on recent HIV during pregnancy/postpartum. Random effects models were constructed to pool HIV incidence rates, cumulative HIV incidence, hazard ratios (HRs), or odds ratios (ORs) summarizing the association between pregnancy/postpartum status and HIV incidence, and MTCT risk and rates. Overall, 1,176 studies met the search criteria, of which 78 met the inclusion criterion, and 47 contributed data. Using data from 19 cohorts representing 22,803 total person-years, the pooled HIV incidence rate during pregnancy/postpartum was 3.8/100 person-years (95% CI 3.0–4.6): 4.7/100 person-years during pregnancy and 2.9/100 person-years postpartum (p = 0.18). Pooled cumulative HIV incidence was significantly higher in African than non-African countries (3.6% versus 0.3%, respectively; p<0.001). Risk of HIV was not significantly higher among pregnant (HR 1.3, 95% CI 0.5–2.1) or postpartum women (HR 1.1, 95% CI 0.6–1.6) than among non-pregnant/non-postpartum women in five studies with available data. In African cohorts, MTCT risk was significantly higher among women with incident versus chronic HIV infection in the postpartum period (OR 2.9, 95% CI 2.2–3.9) or in pregnancy/postpartum periods combined (OR 2.3, 95% CI 1.2–4.4). However, the small number of studies limited power to detect associations and sources of heterogeneity.
Conclusions
Pregnancy and the postpartum period are times of persistent HIV risk, at rates similar to “high risk” cohorts. MTCT risk was elevated among women with incident infections. Detection and prevention of incident HIV in pregnancy/postpartum should be prioritized, and is critical to decrease MTCT.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, about 3.4 million children younger than 15 years old (mostly living in sub-Saharan Africa) are infected with HIV, the virus that causes AIDS by gradually destroying immune system cells, thereby leaving infected individuals susceptible to other serious infections. In 2012 alone, 230,000 children (more than 700 every day) were newly infected with HIV. Most HIV infections among children are the result of mother-to-child HIV transmission (MTCT) during pregnancy, delivery, or breastfeeding. The rate of MTCT (and deaths among HIV-positive pregnant women from complications related to HIV infection) can be greatly reduced by testing women for HIV infection during pregnancy (antenatal HIV testing), treating HIV-positive women with antiretroviral drugs (ARVs, powerful drugs that control HIV replication and allow the immune system to recover) during pregnancy, delivery, and breastfeeding, and giving ARVs to their newborn babies.
Why Was This Study Done?
The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have developed a global plan that aims to move towards eliminating new HIV infections among children by 2015 and towards keeping their mothers alive. To ensure the plan's success, the incidence of HIV (the number of new infections) among women and the rate of MTCT must be reduced by increasing ARV uptake by mothers and their infants for the prevention of MTCT. However, the risk of HIV infection among pregnant women and among women who have recently given birth (postpartum women) is poorly understood because, although guidelines recommend repeat HIV testing during late pregnancy or at delivery in settings where HIV infection is common, pregnant women are often tested only once for HIV infection. The lack of retesting represents a missed opportunity to identify pregnant and postpartum women who have recently acquired HIV and to prevent MTCT by initiating ARV therapy. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a study that uses statistical methods to combine the results of several studies), the researchers estimate maternal HIV incidence during pregnancy and the postpartum period, and compare the risk of MTCT among women with incident (new) and chronic (long-standing) HIV infection.
What Did the Researchers Do and Find?
The researchers identified 47 studies (35 undertaken in Africa) that examined recent HIV acquisition by women during pregnancy and the 12-month postpartum period. They used random effects statistical models to estimate the pooled HIV incidence rate and cumulative HIV incidence (the number of new infections per number of people at risk), and the association between pregnancy/postpartum status and HIV incidence and MTCT risk and rates. The pooled HIV incidence rate among pregnant/postpartum women estimated from 19 studies (all from sub-Saharan Africa) that reported HIV incidence rates was 3.8/100 person-years. The pooled cumulative HIV incidence was significantly higher in African countries than in non-African countries (3.6% and 0.3%, respectively; a “significant” difference is one that is unlikely to arise by chance). In the five studies that provided suitable data, the risk of HIV acquisition was similar in pregnant, postpartum, and non-pregnant/non-postpartum women. Finally, among African women, the risk of MTCT was 2.9-fold higher during the postpartum period among those who had recently acquired HIV than among those with chronic HIV infection, and 2.3-fold higher during the pregnancy/postpartum periods combined.
What Do These Findings Mean?
These results suggest that women living in regions where HIV infection is common are at high risk of acquiring HIV infection during pregnancy and the postpartum period and that mothers who acquire HIV during pregnancy or postpartum are more likely to pass the infection on to their offspring than mothers with chronic HIV infections. However, the small number of studies included in this meta-analysis and the use of heterogeneous research methodologies in these studies may limit the accuracy of these findings. Nevertheless, these findings have important implications for the global plan to eliminate HIV infections in children. First, they suggest that women living in regions where HIV infection is common should be offered repeat HIV testing (using sensitive methods to enhance early detection of infection) during pregnancy and in the postpartum period to detect incident HIV infections, and should be promptly referred to HIV care and treatment. Second, they suggest that prevention of HIV transmission during pregnancy and postpartum should be prioritized, for example, by counseling women about the need to use condoms to prevent transmission during this period of their lives.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001608.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children and HIV/AIDS and on the prevention of mother-to-child transmission of HIV (in English and Spanish)
The 2013 UNAIDS World AIDS Day Report provides information about the AIDS epidemic and efforts to halt it; the 2013 UNAIDS Progress Report on the Global Plan provides information on progress towards eliminating new HIV infections among children; the UNAIDS Believe it. Do it website provides information about the campaign to support the UNAIDS global plan
Personal stories about living with HIV/AIDS, including stories from young people infected with HIV, are available through Avert, NAM/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001608
PMCID: PMC3934828  PMID: 24586123
23.  Syndromic Surveillance from a Local Perspective – A Review of the Literature 
Objective
Review of the origins and evolution of the field of syndromic surveillance. Compare the goals and objectives of public health surveillance and syndromic surveillance in particular. Assess the science and practice of syndromic surveillance in the context of public health and national security priorities. Evaluate syndromic surveillance in practice, using case studies from the perspective of a local public health department.
Introduction
Public health disease surveillance is defined as the ongoing systematic collection, analysis and interpretation of health data for use in the planning, implementation and evaluation of public health, with the overarching goal of providing information to government and the public to improve public health actions and guidance [1,2]. Since the 1950s, the goals and objectives of disease surveillance have remained consistent [1]. However, the systems and processes have changed dramatically due to advances in information and communication technology, and the availability of electronic health data [2,3]. At the intersection of public health, national security and health information technology emerged the practice of syndromic surveillance [3].
Methods
To better understand the current state of the field, a review of the literature on syndromic surveillance was conducted: topics and keywords searched through PubMed and Google Scholar included biosurveillance, bioterrorism detection, computerized surveillance, electronic disease surveillance, situational awareness and syndromic surveillance, covering the areas of practice, research, preparedness and policy. This literature was compared with literature on traditional epidemiologic and public health surveillance. Definitions, objectives, methods and evaluation findings presented in the literature were assessed with a focus on their relevance from a local perspective, particularly as related to syndromic surveillance systems and methods used by the New York City Department of Health and Mental Hygiene in the areas of development, implementation, evaluation, public health practice and epidemiological research.
Results
A decade ago, the objective of syndromic surveillance was focused on outbreak and bioterrorism early-event detection (EED). While there have been clear recommendations for evaluation of syndromic surveillance systems and methods, the original detection paradigm for syndromic surveillance has not been adequately evaluated in practice, nor tested by real world events (ie, the systems have largely not ‘detected’ events of public health concern). In the absence of rigorous evaluation, the rationale and objectives for syndromic surveillance have broadened from outbreak and bioterrorism EED, to include all causes and hazards, and to encompass all data and analyses needed to achieve “situational awareness”, not simply detection. To evaluate current practices and provide meaningful guidance for local syndromic surveillance efforts, it is important to understand the emergence of the field in the broader context of public health disease surveillance. And it is important to recognize how the original stated objectives of EED have shifted in relation to actual evaluation, recommendation, standardization and implementation of syndromic systems at the local level.
Conclusions
Since 2001, the field of syndromic surveillance has rapidly expanded, following the dual requirements of national security and public health practice. The original objective of early outbreak or bioterrorism event detection remains a core objective of syndromic surveillance, and systems need to be rigorously evaluated through comparison of consistent methods and metrics, and public health outcomes. The broadened mandate for all-cause situation awareness needs to be focused into measureable public health surveillance outcomes and objectives that are consistent with established public health surveillance objectives and relevant to the local practice of public health [2].
PMCID: PMC3692931
evaluation; biosurveillance; situational awareness; syndromic surveillance; local public health
24.  Effective Post-Exposure Treatment of Ebola Infection  
PLoS Pathogens  2007;3(1):e2.
Ebola viruses are highly lethal human pathogens that have received considerable attention in recent years due to an increasing re-emergence in Central Africa and a potential for use as a biological weapon. There is no vaccine or treatment licensed for human use. In the past, however, important advances have been made in developing preventive vaccines that are protective in animal models. In this regard, we showed that a single injection of a live-attenuated recombinant vesicular stomatitis virus vector expressing the Ebola virus glycoprotein completely protected rodents and nonhuman primates from lethal Ebola challenge. In contrast, progress in developing therapeutic interventions against Ebola virus infections has been much slower and there is clearly an urgent need to develop effective post-exposure strategies to respond to future outbreaks and acts of bioterrorism, as well as to treat laboratory exposures. Here we tested the efficacy of the vesicular stomatitis virus-based Ebola vaccine vector in post-exposure treatment in three relevant animal models. In the guinea pig and mouse models it was possible to protect 50% and 100% of the animals, respectively, following treatment as late as 24 h after lethal challenge. More important, four out of eight rhesus macaques were protected if treated 20 to 30 min following an otherwise uniformly lethal infection. Currently, this approach provides the most effective post-exposure treatment strategy for Ebola infections and is particularly suited for use in accidentally exposed individuals and in the control of secondary transmission during naturally occurring outbreaks or deliberate release.
Author Summary
Being highly pathogenic for humans and monkeys and the subject of former weapons programs makes Ebola virus one of the most feared pathogens worldwide today. Due to a lack of licensed pre- and post-exposure intervention, our current response depends on rapid diagnostics, proper isolation procedures, and supportive care of case patients. Consequently, the development of more specific countermeasures is of high priority for the preparedness of many nations. In this study, we investigated an attenuated vesicular stomatitis virus expressing the Ebola virus surface glycoprotein, which had previously demonstrated convincing efficacy as a vaccine against Ebola infections in rodents and monkeys, for its potential use in the treatment of an Ebola virus infection. Surprisingly, treatment of guinea pigs and mice as late as 24 h after lethal Ebola virus infection resulted in 50% and 100% survival, respectively. More important, 50% of rhesus macaques (4/8) were protected if treated 20 to 30 min after Ebola virus infection. Currently, this approach provides the most effective treatment strategy for Ebola infections and seems particularly suited for the use in accidental exposures and the control of human-to-human transmission during outbreaks.
doi:10.1371/journal.ppat.0030002
PMCID: PMC1779298  PMID: 17238284
25.  Using Social Network Analysis to Understand Missouri's System of Public Health Emergency Planners 
Public Health Reports  2007;122(4):488-498.
SYNOPSIS
Objectives.
Effective response to large-scale public health threats requires well-coordinated efforts among individuals and agencies. While guidance is available to help states put emergency planning programs into place, little has been done to evaluate the human infrastructure that facilitates successful implementation of these programs. This study examined the human infrastructure of the Missouri public health emergency planning system in 2006.
Methods.
The Center for Emergency Response and Terrorism (CERT) at the Missouri Department of Health and Senior Services has responsibility for planning, guiding, and funding statewide emergency response activities. Thirty-two public health emergency planners working primarily in county health departments contract with CERT to support statewide preparedness. We surveyed the planners to determine whom they communicate with, work with, seek expertise from, and exchange guidance with regarding emergency preparedness in Missouri.
Results.
Most planners communicated regularly with planners in their region but seldom with planners outside their region. Planners also reported working with an average of 12 local entities (e.g., emergency management, hospitals/clinics). Planners identified the following leaders in Missouri's public health emergency preparedness system: local public health emergency planners, state epidemiologists, the state vaccine and grant coordinator, regional public health emergency planners, State Emergency Management Agency area coordinators, the state Strategic National Stockpile coordinator, and Federal Bureau of Investigation Weapons of Mass Destruction coordinators. Generally, planners listed few federal-level or private-sector individuals in their emergency preparedness networks.
Conclusions.
While Missouri public health emergency planners maintain large and varied emergency preparedness networks, there are opportunities for strengthening existing ties and seeking additional connections.
PMCID: PMC1888499  PMID: 17639652

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