sábado, 12 de junio de 2010
WHO supports fair access to influenza A (H1N1) vaccine
An interview with Marie-Paule Kieny
he vast majority of cases of pandemic influenza A (H1N1) have been mild so far with few deaths. It remains to be seen whether the virus will mutate into a more virulent strain. Marie-Paule Kieny explains how WHO is supporting countries’ efforts to protect their populations with vaccines that should become available as of this month.
Q: When will the first doses of vaccine for the pandemic influenza A (H1N1) be ready?
A: Some manufacturers announced in July that vaccine is available, but that doesn’t mean it’s ready for use, as it needs regulatory approval. Regulatory authorities are considering the best way to register these vaccines as quickly as possible. The consensus is that the first doses will be available to governments for use in September.
Q: Who will get vaccinated first? Who decides this?
A: Vaccine will not be available on the private market and governments will decide who gets vaccinated first. WHO recommends that health workers be the first, to protect the health system and allow them to care for influenza and other patients. The strategy a country takes will depend on its policy objectives and the availability of vaccine. For example, if a country decides to concentrate on protecting essential infrastructure, it may target different people, such as truck drivers, if they are critical for food delivery. Others may try to reduce transmission of the virus. For example, the United States of America decided to immunize children before or at school entry who are in closer physical contact than adults and can amplify infection rates. Countries may also try to reduce morbidity and mortality and target specific groups, such as pregnant women. Some high-income countries have ordered enough vaccine for the whole population. Nevertheless, no countries will have vaccine for everyone from the first day it is available for use, so that each country will need to prioritize. Some middle-income countries have also placed contracts with pharmaceutical companies and have been purchasing vaccine for between 1% and 10–20% of the population. WHO is working hard with manufacturers, governments and donors to ensure that developing countries can access vaccine as soon as possible to immunize their health workers, and when more vaccine becomes available, other groups will be immunized.
Q: How are influenza vaccines produced?
A: The main method is by injecting seed virus into embryonic chicken eggs and harvesting the fluid after several days and purifying it. There are two technologies. More than 90% of influenza vaccines available are known as “inactivated vaccines”, which means you kill the virus to produce the vaccine. Less common are “live attenuated vaccines”, which are derived from a weakened form of the virus that is not killed.
Q: How many different vaccine candidates will be available for A (H1N1)?
A: About 30. Most will be inactivated virus vaccines made in eggs, some will be killed virus vaccines made in cell cultures and a few will be live attenuated virus vaccines. Then you have a lot of variation in the way vaccine is purified and in whether or not it is mixed with an additive, called an adjuvant, which is a booster of immunogenicity (which is the capacity of a vaccine to evoke an immune response) and which is used with killed virus vaccine. All vaccines create antibodies to fight the virus; some will produce a local response, such as attenuated vaccine administered in the nose to give more immunity at the port of entry of the virus. The industry will use tiered pricing, so high-income countries might pay between US$ 10–20 per dose, middle-income countries may pay about half that and low-income half that price again. These are ballpark figures but this is the order of magnitude.
Q: Isn’t it too early to produce vaccines because the pandemic virus could mutate?
A: Although the virus can mutate, we hope that there will be enough cross-protection through recognition of the new virus. But if the virus changes too much, we will need new vaccines.
Q: WHO has recommended the use of adjuvant in pandemic vaccines, but some countries don’t plan to follow this guidance.
A: Many countries, including the USA, have not licensed vaccines with adjuvants of any kind yet. Other vaccines with the same type of adjuvant as planned for pandemic influenza A (H1N1) vaccines have, however, been licensed in European countries. Countries that intend to use vaccine with adjuvant will find that there is a large body of safety data for adults and some for children. In any case, all countries will need to carry out good post-marketing surveillance to make sure that they pick up any early sign of a safety problem with a particular vaccine.
Q: These must be the fastest vaccines ever produced. Given their fast-tracking, what is the guarantee of safety and efficacy?
A: The testing of influenza vaccines is different from that of other vaccines, because the rabies and measles vaccines for example do not change. Since influenza viruses evolve constantly, it is impossible to carry out a complete clinical analysis of seasonal influenza vaccines yearly because the composition changes each year to adapt to the virus and so you are always a year behind. A complete clinical evaluation is not needed also because manufacturers produce seasonal influenza vaccines using the same procedure and equipment, but for a different virus each year. In the USA, vaccines for seasonal influenza are licensed without clinical trials on the basis of a “strain change”. The US regulatory authorities consider the change from seasonal to pandemic H1N1 influenza vaccine production (using the same procedure) as a change in the strain and therefore will not request clinical trials before registration. Having said that, all manufacturers will perform clinical trials to find out whether one or two doses are necessary, to test it in special populations and to administer it jointly with other vaccines. In Europe, a strain change is accompanied by a small clinical trial requested by the European Medicines Agency. In the last couple of years, manufacturers in the European Union registered “mock-up” or prototype H5N1 bird flu vaccines as nobody knows which H5N1 strain might become a pandemic strain. Manufacturers made clinical batches of an H5N1 vaccine with virus stocks from China, Indonesia and Viet Nam. They carried out clinical trials and submitted the results to the regulatory authorities who said the vaccines were fine. They are not allowed to sell H5N1 vaccines, since there is no H5N1 pandemic, but they can use the same procedure to make H1N1 pandemic vaccine. That way they can get a licence in a few days. This is another way vaccines can be licensed without clinical trials, while still ensuring safety on the basis of what is known about influenza vaccines. Based on the extensive knowledge available on seasonal vaccines and the results obtained through evaluation of H5N1 avian influenza vaccines, there is no doubt that it will be possible to make effective H1N1 pandemic vaccines.
Q: What’s been done to ensure that developing countries get enough vaccine?
A: It depends on what we mean by “enough”. Some countries want to vaccinate every member of the population, but there is no way we can do this for the whole world. WHO has a cross-organizational operation that is in place to secure vaccines for developing countries. This is spearheaded by the Director-General’s Office and the legal and vaccine departments. We are engaged in three types of activities. The first is to negotiate donations with manufacturers. Two have been announced: 100 million doses by sanofi-aventis and 50 million doses from GlaxoSmithKline. Second, we are working with other manufacturers to reserve a portion of their vaccine production for WHO at a reduced price. Third, we are working with governments to raise funds to purchase vaccines. We are also working with 11 vaccine manufacturers based in developing countries, providing them with seed financing and technical expertise to help them produce influenza vaccine domestically. We have also helped them access technology and given them sub-licences to use technology for producing live attenuated vaccine. These 11 companies will be manufacturing some of the 30 different expected vaccines.
Q: What happens if developing countries have only partial coverage?
A: Coverage will be partial and not only in developing countries. But we should not be “hypnotized” by vaccines. There are other measures, such as social distancing, school closure, avoidance of large gatherings, antibiotics and personal hygiene. This is not like rabies, which is 100% fatal: we are talking about a disease from which most people recover very well. We will try to help countries to gain access to as much vaccine as possible, at least to preserve their health systems functioning, but there is just not enough vaccine for every country in the world to vaccinate every member of the population twice. ■
LINK: http://www.who.int/bulletin/volumes/87/9/09-030909/en/
he vast majority of cases of pandemic influenza A (H1N1) have been mild so far with few deaths. It remains to be seen whether the virus will mutate into a more virulent strain. Marie-Paule Kieny explains how WHO is supporting countries’ efforts to protect their populations with vaccines that should become available as of this month.
Q: When will the first doses of vaccine for the pandemic influenza A (H1N1) be ready?
A: Some manufacturers announced in July that vaccine is available, but that doesn’t mean it’s ready for use, as it needs regulatory approval. Regulatory authorities are considering the best way to register these vaccines as quickly as possible. The consensus is that the first doses will be available to governments for use in September.
Q: Who will get vaccinated first? Who decides this?
A: Vaccine will not be available on the private market and governments will decide who gets vaccinated first. WHO recommends that health workers be the first, to protect the health system and allow them to care for influenza and other patients. The strategy a country takes will depend on its policy objectives and the availability of vaccine. For example, if a country decides to concentrate on protecting essential infrastructure, it may target different people, such as truck drivers, if they are critical for food delivery. Others may try to reduce transmission of the virus. For example, the United States of America decided to immunize children before or at school entry who are in closer physical contact than adults and can amplify infection rates. Countries may also try to reduce morbidity and mortality and target specific groups, such as pregnant women. Some high-income countries have ordered enough vaccine for the whole population. Nevertheless, no countries will have vaccine for everyone from the first day it is available for use, so that each country will need to prioritize. Some middle-income countries have also placed contracts with pharmaceutical companies and have been purchasing vaccine for between 1% and 10–20% of the population. WHO is working hard with manufacturers, governments and donors to ensure that developing countries can access vaccine as soon as possible to immunize their health workers, and when more vaccine becomes available, other groups will be immunized.
Q: How are influenza vaccines produced?
A: The main method is by injecting seed virus into embryonic chicken eggs and harvesting the fluid after several days and purifying it. There are two technologies. More than 90% of influenza vaccines available are known as “inactivated vaccines”, which means you kill the virus to produce the vaccine. Less common are “live attenuated vaccines”, which are derived from a weakened form of the virus that is not killed.
Q: How many different vaccine candidates will be available for A (H1N1)?
A: About 30. Most will be inactivated virus vaccines made in eggs, some will be killed virus vaccines made in cell cultures and a few will be live attenuated virus vaccines. Then you have a lot of variation in the way vaccine is purified and in whether or not it is mixed with an additive, called an adjuvant, which is a booster of immunogenicity (which is the capacity of a vaccine to evoke an immune response) and which is used with killed virus vaccine. All vaccines create antibodies to fight the virus; some will produce a local response, such as attenuated vaccine administered in the nose to give more immunity at the port of entry of the virus. The industry will use tiered pricing, so high-income countries might pay between US$ 10–20 per dose, middle-income countries may pay about half that and low-income half that price again. These are ballpark figures but this is the order of magnitude.
Q: Isn’t it too early to produce vaccines because the pandemic virus could mutate?
A: Although the virus can mutate, we hope that there will be enough cross-protection through recognition of the new virus. But if the virus changes too much, we will need new vaccines.
Q: WHO has recommended the use of adjuvant in pandemic vaccines, but some countries don’t plan to follow this guidance.
A: Many countries, including the USA, have not licensed vaccines with adjuvants of any kind yet. Other vaccines with the same type of adjuvant as planned for pandemic influenza A (H1N1) vaccines have, however, been licensed in European countries. Countries that intend to use vaccine with adjuvant will find that there is a large body of safety data for adults and some for children. In any case, all countries will need to carry out good post-marketing surveillance to make sure that they pick up any early sign of a safety problem with a particular vaccine.
Q: These must be the fastest vaccines ever produced. Given their fast-tracking, what is the guarantee of safety and efficacy?
A: The testing of influenza vaccines is different from that of other vaccines, because the rabies and measles vaccines for example do not change. Since influenza viruses evolve constantly, it is impossible to carry out a complete clinical analysis of seasonal influenza vaccines yearly because the composition changes each year to adapt to the virus and so you are always a year behind. A complete clinical evaluation is not needed also because manufacturers produce seasonal influenza vaccines using the same procedure and equipment, but for a different virus each year. In the USA, vaccines for seasonal influenza are licensed without clinical trials on the basis of a “strain change”. The US regulatory authorities consider the change from seasonal to pandemic H1N1 influenza vaccine production (using the same procedure) as a change in the strain and therefore will not request clinical trials before registration. Having said that, all manufacturers will perform clinical trials to find out whether one or two doses are necessary, to test it in special populations and to administer it jointly with other vaccines. In Europe, a strain change is accompanied by a small clinical trial requested by the European Medicines Agency. In the last couple of years, manufacturers in the European Union registered “mock-up” or prototype H5N1 bird flu vaccines as nobody knows which H5N1 strain might become a pandemic strain. Manufacturers made clinical batches of an H5N1 vaccine with virus stocks from China, Indonesia and Viet Nam. They carried out clinical trials and submitted the results to the regulatory authorities who said the vaccines were fine. They are not allowed to sell H5N1 vaccines, since there is no H5N1 pandemic, but they can use the same procedure to make H1N1 pandemic vaccine. That way they can get a licence in a few days. This is another way vaccines can be licensed without clinical trials, while still ensuring safety on the basis of what is known about influenza vaccines. Based on the extensive knowledge available on seasonal vaccines and the results obtained through evaluation of H5N1 avian influenza vaccines, there is no doubt that it will be possible to make effective H1N1 pandemic vaccines.
Q: What’s been done to ensure that developing countries get enough vaccine?
A: It depends on what we mean by “enough”. Some countries want to vaccinate every member of the population, but there is no way we can do this for the whole world. WHO has a cross-organizational operation that is in place to secure vaccines for developing countries. This is spearheaded by the Director-General’s Office and the legal and vaccine departments. We are engaged in three types of activities. The first is to negotiate donations with manufacturers. Two have been announced: 100 million doses by sanofi-aventis and 50 million doses from GlaxoSmithKline. Second, we are working with other manufacturers to reserve a portion of their vaccine production for WHO at a reduced price. Third, we are working with governments to raise funds to purchase vaccines. We are also working with 11 vaccine manufacturers based in developing countries, providing them with seed financing and technical expertise to help them produce influenza vaccine domestically. We have also helped them access technology and given them sub-licences to use technology for producing live attenuated vaccine. These 11 companies will be manufacturing some of the 30 different expected vaccines.
Q: What happens if developing countries have only partial coverage?
A: Coverage will be partial and not only in developing countries. But we should not be “hypnotized” by vaccines. There are other measures, such as social distancing, school closure, avoidance of large gatherings, antibiotics and personal hygiene. This is not like rabies, which is 100% fatal: we are talking about a disease from which most people recover very well. We will try to help countries to gain access to as much vaccine as possible, at least to preserve their health systems functioning, but there is just not enough vaccine for every country in the world to vaccinate every member of the population twice. ■
LINK: http://www.who.int/bulletin/volumes/87/9/09-030909/en/
Economic Appraisal of Ontario's Universal Influenza Immunization Program: A Cost-Utility Analysis
Abstract
In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP).
Methods and Findings
A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted.
Conclusions
Universal immunization against seasonal influenza was estimated to be an economically attractive intervention.
Cost Influenza
LINK: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850382/?tool=pubmed
In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP).
Methods and Findings
A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted.
Conclusions
Universal immunization against seasonal influenza was estimated to be an economically attractive intervention.
Cost Influenza
LINK: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850382/?tool=pubmed
The invariant NKT cell subset in anti-viral defenses: a dark horse in anti-influenza immunity?
Abstract
iNKT cells, a small subset of alphabeta TCR(+) T cells, are capable of producing large amounts of cytokines upon activation through their TCR. Unlike conventional T cells that express highly diverse TCRs, iNKT cells express a glycolipid-reactive invariant TCR-alpha chain paired with a limited number of beta chain(s). These cells recognize glycolipid antigens when presented on CD1d molecules found on APC or other cells. Although the immunoregulatory roles of iNKT cells in the context of autoimmune disease are fairly well characterized, several lines of evidence highlight the importance of this cell type in immune responses against microbial insults caused by bacterial, viral, and parasitic pathogens. Recent studies that have investigated the role of iNKT cells in immune responses against influenza virus have suggested an important role for these cells in innate defense mechanisms as well as antibody- and cell-mediated responses. This review highlights the important contributions of iNKT cells to immune responses against viral pathogens with particular emphasis on immunity to influenza infections.
Review
LINK: http://www.ncbi.nlm.nih.gov/pubmed/20519638
iNKT cells, a small subset of alphabeta TCR(+) T cells, are capable of producing large amounts of cytokines upon activation through their TCR. Unlike conventional T cells that express highly diverse TCRs, iNKT cells express a glycolipid-reactive invariant TCR-alpha chain paired with a limited number of beta chain(s). These cells recognize glycolipid antigens when presented on CD1d molecules found on APC or other cells. Although the immunoregulatory roles of iNKT cells in the context of autoimmune disease are fairly well characterized, several lines of evidence highlight the importance of this cell type in immune responses against microbial insults caused by bacterial, viral, and parasitic pathogens. Recent studies that have investigated the role of iNKT cells in immune responses against influenza virus have suggested an important role for these cells in innate defense mechanisms as well as antibody- and cell-mediated responses. This review highlights the important contributions of iNKT cells to immune responses against viral pathogens with particular emphasis on immunity to influenza infections.
Review
LINK: http://www.ncbi.nlm.nih.gov/pubmed/20519638
Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.
Abstract
OBJECTIVES: To update a 2005 Cochrane review that assessed the effects of neuraminidase inhibitors in preventing or ameliorating the symptoms of influenza, the transmission of influenza, and complications from influenza in healthy adults, and to estimate the frequency of adverse effects. Search strategy An updated search of the Cochrane central register of controlled trials (Cochrane Library 2009, issue 2), which contains the Acute Respiratory Infections Group's specialised register, Medline (1950-Aug 2009), Embase (1980-Aug 2009), and post-marketing pharmacovigilance data and comparative safety cohorts. Selection criteria Randomised placebo controlled studies of neuraminidase inhibitors in otherwise healthy adults exposed to naturally occurring influenza. MAIN OUTCOME MEASURES: Duration and incidence of symptoms; incidence of lower respiratory tract infections, or their proxies; and adverse events. DATA EXTRACTION: Two reviewers applied inclusion criteria, assessed trial quality, and extracted data. Data analysis Comparisons were structured into prophylaxis, treatment, and adverse events, with further subdivision by outcome and dose. RESULTS: 20 trials were included: four on prophylaxis, 12 on treatment, and four on postexposure prophylaxis. For prophylaxis, neuraminidase inhibitors had no effect against influenza-like illness or asymptomatic influenza. The efficacy of oral oseltamivir against symptomatic laboratory confirmed influenza was 61% (risk ratio 0.39, 95% confidence interval 0.18 to 0.85) at 75 mg daily and 73% (0.27, 0.11 to 0.67) at 150 mg daily. Inhaled zanamivir 10 mg daily was 62% efficacious (0.38, 0.17 to 0.85). Oseltamivir for postexposure prophylaxis had an efficacy of 58% (95% confidence interval 15% to 79%) and 84% (49% to 95%) in two trials of households. Zanamivir performed similarly. The hazard ratios for time to alleviation of influenza-like illness symptoms were in favour of treatment: 1.20 (95% confidence interval 1.06 to 1.35) for oseltamivir and 1.24 (1.13 to 1.36) for zanamivir. Eight unpublished studies on complications were ineligible and therefore excluded. The remaining evidence suggests oseltamivir did not reduce influenza related lower respiratory tract complications (risk ratio 0.55, 95% confidence interval 0.22 to 1.35). From trial evidence, oseltamivir induced nausea (odds ratio 1.79, 95% confidence interval 1.10 to 2.93). Evidence of rarer adverse events from pharmacovigilance was of poor quality or possibly under-reported. CONCLUSION: Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective. Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir's prevention of complications from influenza. Independent randomised trials to resolve these uncertainties are needed.
Meta Analysis
LINK: http://www.ncbi.nlm.nih.gov/pubmed/19995812
OBJECTIVES: To update a 2005 Cochrane review that assessed the effects of neuraminidase inhibitors in preventing or ameliorating the symptoms of influenza, the transmission of influenza, and complications from influenza in healthy adults, and to estimate the frequency of adverse effects. Search strategy An updated search of the Cochrane central register of controlled trials (Cochrane Library 2009, issue 2), which contains the Acute Respiratory Infections Group's specialised register, Medline (1950-Aug 2009), Embase (1980-Aug 2009), and post-marketing pharmacovigilance data and comparative safety cohorts. Selection criteria Randomised placebo controlled studies of neuraminidase inhibitors in otherwise healthy adults exposed to naturally occurring influenza. MAIN OUTCOME MEASURES: Duration and incidence of symptoms; incidence of lower respiratory tract infections, or their proxies; and adverse events. DATA EXTRACTION: Two reviewers applied inclusion criteria, assessed trial quality, and extracted data. Data analysis Comparisons were structured into prophylaxis, treatment, and adverse events, with further subdivision by outcome and dose. RESULTS: 20 trials were included: four on prophylaxis, 12 on treatment, and four on postexposure prophylaxis. For prophylaxis, neuraminidase inhibitors had no effect against influenza-like illness or asymptomatic influenza. The efficacy of oral oseltamivir against symptomatic laboratory confirmed influenza was 61% (risk ratio 0.39, 95% confidence interval 0.18 to 0.85) at 75 mg daily and 73% (0.27, 0.11 to 0.67) at 150 mg daily. Inhaled zanamivir 10 mg daily was 62% efficacious (0.38, 0.17 to 0.85). Oseltamivir for postexposure prophylaxis had an efficacy of 58% (95% confidence interval 15% to 79%) and 84% (49% to 95%) in two trials of households. Zanamivir performed similarly. The hazard ratios for time to alleviation of influenza-like illness symptoms were in favour of treatment: 1.20 (95% confidence interval 1.06 to 1.35) for oseltamivir and 1.24 (1.13 to 1.36) for zanamivir. Eight unpublished studies on complications were ineligible and therefore excluded. The remaining evidence suggests oseltamivir did not reduce influenza related lower respiratory tract complications (risk ratio 0.55, 95% confidence interval 0.22 to 1.35). From trial evidence, oseltamivir induced nausea (odds ratio 1.79, 95% confidence interval 1.10 to 2.93). Evidence of rarer adverse events from pharmacovigilance was of poor quality or possibly under-reported. CONCLUSION: Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective. Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir's prevention of complications from influenza. Independent randomised trials to resolve these uncertainties are needed.
Meta Analysis
LINK: http://www.ncbi.nlm.nih.gov/pubmed/19995812
PREVENTION
Instructions
First, get a flu shot. Before each flu season, the influenza vaccine is created by companies that are designated by the US government. The vaccine is then distributed all across the United States, and priority is given to people who are older and those who are sick and those who are hospitalized. If you are one of those people, please make sure to get your flu shot.
Second, stay healthy and take your vitamins. Exercising, not smoking, eating healthy, and taking multivitamins will keep your immune system healthy and make it harder for the influenza virus to infect you.
Third, wash your hands and stay away from sick people. This cannot be overstated. Washing your hands is the best way to keep from getting many infections, and staying away from sick people is also important. This means staying away from public places where you might be exposed to the influenza virus.
LINK: http://www.ehow.com/how_5177082_prevent-influenza-virus.html
First, get a flu shot. Before each flu season, the influenza vaccine is created by companies that are designated by the US government. The vaccine is then distributed all across the United States, and priority is given to people who are older and those who are sick and those who are hospitalized. If you are one of those people, please make sure to get your flu shot.
Second, stay healthy and take your vitamins. Exercising, not smoking, eating healthy, and taking multivitamins will keep your immune system healthy and make it harder for the influenza virus to infect you.
Third, wash your hands and stay away from sick people. This cannot be overstated. Washing your hands is the best way to keep from getting many infections, and staying away from sick people is also important. This means staying away from public places where you might be exposed to the influenza virus.
LINK: http://www.ehow.com/how_5177082_prevent-influenza-virus.html
A Community Cluster of Oseltamivir-Resistant Cases of 2009 H1N1 Influenza
To the Editor: Oseltamivir-resistant infection with the 2009 pandemic influenza A (H1N1) virus has so far been described only rarely and is conferred by the H275Y substitution in the neuraminidase enzyme.1 Only 3 of the 32 patients with oseltamivir-resistantinfection reported on as of this writing were not receiving oseltamivir when the resistant viruses were detected, and ongoingcommunity transmission has not yet been shown.1 However, the emergence of oseltamivir-resistant 2009 H1N1 influenza remains a grave concern, since widespread oseltamivir resistance has been observed in seasonal H1N1. This resistance was unrelated to selective drug pressure, and the H275Y substitution did not appear to reduce transmissibility or severity.2,3 We report on a cluster of seven cases of oseltamivir-resistant 2009 H1N1 infection in Vietnam.
In July 2009, during a 42-hour journey, 10 students socialized together in the same train carriage. None of the students knew each other before the journey, none had contact with a person with suspected influenza in the week before the trip, none weresymptomatic during the journey, and none were previously or currently receiving oseltamivir. Fever developed in four of the students within 12 hours after arrival and in two more students within 48 hours after arrival (Fig. 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). An additional case was identified in a traveler in a different carriage (Patient G). Nasal swabs, throat swabs, or both from all seven persons were positive for 2009 H1N1 RNA when tested with reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays, and viruses were successfully cultured from specimens obtained from three of the persons. The H275Y substitution was detected retrospectively in diagnostic specimens obtained from all seven subjects before any oseltamivir treatment. The concentrations of oseltamivir carboxylate required for a 50% inhibition ofneuraminidase activity of the isolated viruses in a fluorometric neuraminidase-inhibition assay were 323.6, 429.5, and 889.2 nM; these concentrations confirmed resistance4 (see the Supplementary Appendix).
Six patients were admitted to a hospital for isolation, one patient was isolated at home, and all were treated with oseltamivir phosphate at a dose of 75 mg twice daily (Fig. 1 in the Supplementary Appendix), since resistance testing had not yet been performed. All patients recovered uneventfully, although one patient (Patient F), with the highest 50% inhibitory concentration, continued to test positive on RT-PCR until day 9, despite receiving oseltamivir from the day of the onset of illness. An extensive public health investigation did not identify additional patients or the index patient.
In this cluster, infection developed in at least 6 of the 10 people who were probably exposed to the index patient; this shows that resistant 2009 H1N1 viruses are transmissible and can replicate and cause illness in healthy people in the absence of selective drug pressure. Ongoing transmission from the cluster was not detected, but the tracing of all contacts was not possible, so ongoing transmission cannot be ruled out. However, only three other resistant cases have been detected in Vietnam as of this writing, and all were due to selection of resistant viruses during treatment rather than person-to-person transmission. Although data are limited, it is likely that the detected levels of oseltamivir resistance are clinically relevant.5 The loss of oseltamivir as a treatment option for severe 2009 H1N1 infection could have profound consequences. To minimize this risk, the use of oseltamivir should be restricted to prophylaxis and treatment in high-risk persons or the treatment of people with severe or deteriorating illness, antiviral stockpiles should be diversified and optimal dosages and combination therapies should be urgently studied. Close monitoring and reporting of resistance to neuraminidase inhibitors are essential.
Le Quynh Mai, M.D., Ph.D.
National Institute of Hygiene and Epidemiology
Hanoi, Vietnam
Heiman F.L. Wertheim, M.D., Ph.D.
Oxford University Clinical Research Unit
Hanoi, Vietnam
Tran Nhu Duong, M.D., Ph.D.
National Institute of Hygiene and Epidemiology
Hanoi, Vietnam
H. Rogier van Doorn, M.D., Ph.D.
Oxford University Clinical Research Unit
Ho Chi Minh City, Vietnam
Nguyen Tran Hien, M.D., Ph.D.
National Institute of Hygiene and Epidemiology
Hanoi, Vietnam
Peter Horby, M.B., B.S., F.F.P.H.
Oxford University Clinical Research Unit
Hanoi, Vietnam
peter.horby@gmail.com
for the Vietnam H1N1 Investigation Team
Supported by grants from the Wellcome Trust United Kingdom (081613/Z/06/Z and 077078/Z/05/Z, to Drs. Wertheim, van Doorn, and Horby) and the South East Asia Infectious Disease Clinical Research Network (N01-A0-50042, to Drs. Wertheim, van Doorn, and Horby).
Financial and other disclosures provided by the authors are available with the full text of this letter at NEJM.org.
This letter (10.1056/NEJMc0910448) was published on December 9, 2009, at NEJM.org.
References
1. Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. Wkly Epidemiol Rec 2009;84:453-459. [Medline]
2. Moscona A. Global transmission of oseltamivir-resistant influenza. N Engl J Med 2009;360:953-956. [Free Full Text]
3. Cianco B, Meerhoff T, Kramarz P, et al. Oseltamivir-resistant influenza A(H1N1) viruses detected in Europe during season 2007-8 had epidemiological and clinical characteristics similar to co-circulating susceptible A(H1N1) viruses. Euro Surveill 2009;14:pii=19412-pii=19412.
4. Wetherall NT, Trivedi T, Zeller J, et al. Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza virus clinical isolates to neuraminidase inhibitors: report of the Neuraminidase Inhibitor Susceptibility Network. J Clin Microbiol 2003;41:742-750. [Free Full Text]
5. Wattanagoon Y, Stepniewska K, Lindegårdh N, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother 2009;53:945-952. [Free Full Text]
LINK: http://content.nejm.org/cgi/content/full/362/1/86-a
In July 2009, during a 42-hour journey, 10 students socialized together in the same train carriage. None of the students knew each other before the journey, none had contact with a person with suspected influenza in the week before the trip, none weresymptomatic during the journey, and none were previously or currently receiving oseltamivir. Fever developed in four of the students within 12 hours after arrival and in two more students within 48 hours after arrival (Fig. 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). An additional case was identified in a traveler in a different carriage (Patient G). Nasal swabs, throat swabs, or both from all seven persons were positive for 2009 H1N1 RNA when tested with reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays, and viruses were successfully cultured from specimens obtained from three of the persons. The H275Y substitution was detected retrospectively in diagnostic specimens obtained from all seven subjects before any oseltamivir treatment. The concentrations of oseltamivir carboxylate required for a 50% inhibition ofneuraminidase activity of the isolated viruses in a fluorometric neuraminidase-inhibition assay were 323.6, 429.5, and 889.2 nM; these concentrations confirmed resistance4 (see the Supplementary Appendix).
Six patients were admitted to a hospital for isolation, one patient was isolated at home, and all were treated with oseltamivir phosphate at a dose of 75 mg twice daily (Fig. 1 in the Supplementary Appendix), since resistance testing had not yet been performed. All patients recovered uneventfully, although one patient (Patient F), with the highest 50% inhibitory concentration, continued to test positive on RT-PCR until day 9, despite receiving oseltamivir from the day of the onset of illness. An extensive public health investigation did not identify additional patients or the index patient.
In this cluster, infection developed in at least 6 of the 10 people who were probably exposed to the index patient; this shows that resistant 2009 H1N1 viruses are transmissible and can replicate and cause illness in healthy people in the absence of selective drug pressure. Ongoing transmission from the cluster was not detected, but the tracing of all contacts was not possible, so ongoing transmission cannot be ruled out. However, only three other resistant cases have been detected in Vietnam as of this writing, and all were due to selection of resistant viruses during treatment rather than person-to-person transmission. Although data are limited, it is likely that the detected levels of oseltamivir resistance are clinically relevant.5 The loss of oseltamivir as a treatment option for severe 2009 H1N1 infection could have profound consequences. To minimize this risk, the use of oseltamivir should be restricted to prophylaxis and treatment in high-risk persons or the treatment of people with severe or deteriorating illness, antiviral stockpiles should be diversified and optimal dosages and combination therapies should be urgently studied. Close monitoring and reporting of resistance to neuraminidase inhibitors are essential.
Le Quynh Mai, M.D., Ph.D.
National Institute of Hygiene and Epidemiology
Hanoi, Vietnam
Heiman F.L. Wertheim, M.D., Ph.D.
Oxford University Clinical Research Unit
Hanoi, Vietnam
Tran Nhu Duong, M.D., Ph.D.
National Institute of Hygiene and Epidemiology
Hanoi, Vietnam
H. Rogier van Doorn, M.D., Ph.D.
Oxford University Clinical Research Unit
Ho Chi Minh City, Vietnam
Nguyen Tran Hien, M.D., Ph.D.
National Institute of Hygiene and Epidemiology
Hanoi, Vietnam
Peter Horby, M.B., B.S., F.F.P.H.
Oxford University Clinical Research Unit
Hanoi, Vietnam
peter.horby@gmail.com
for the Vietnam H1N1 Investigation Team
Supported by grants from the Wellcome Trust United Kingdom (081613/Z/06/Z and 077078/Z/05/Z, to Drs. Wertheim, van Doorn, and Horby) and the South East Asia Infectious Disease Clinical Research Network (N01-A0-50042, to Drs. Wertheim, van Doorn, and Horby).
Financial and other disclosures provided by the authors are available with the full text of this letter at NEJM.org.
This letter (10.1056/NEJMc0910448) was published on December 9, 2009, at NEJM.org.
References
1. Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. Wkly Epidemiol Rec 2009;84:453-459. [Medline]
2. Moscona A. Global transmission of oseltamivir-resistant influenza. N Engl J Med 2009;360:953-956. [Free Full Text]
3. Cianco B, Meerhoff T, Kramarz P, et al. Oseltamivir-resistant influenza A(H1N1) viruses detected in Europe during season 2007-8 had epidemiological and clinical characteristics similar to co-circulating susceptible A(H1N1) viruses. Euro Surveill 2009;14:pii=19412-pii=19412.
4. Wetherall NT, Trivedi T, Zeller J, et al. Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza virus clinical isolates to neuraminidase inhibitors: report of the Neuraminidase Inhibitor Susceptibility Network. J Clin Microbiol 2003;41:742-750. [Free Full Text]
5. Wattanagoon Y, Stepniewska K, Lindegårdh N, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother 2009;53:945-952. [Free Full Text]
LINK: http://content.nejm.org/cgi/content/full/362/1/86-a
EPIDEMIOLOGY
Seasonal variations
Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemispheres have winter at different times of the year, there are actually two different flu seasons each year. This is why the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.
A long-standing puzzle has been why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Increased travel due to the Northern Hemisphere winter holiday season may also play a role. Another factor is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus also survives longer on surfaces at colder temperatures and aerosol transmission of the virus is highest in cold environments (less than 5 °C) with low relative humidity. Indeed, the lower air humidity in winter seems to be the main cause of seasonal influenza transmission in temperate regions.
However, seasonal changes in infection rates also occur in tropical regions, and in some countries these peaks of infection are seen mainly during the rainy season. Seasonal changes in contact rates from school terms, which are a major factor in other childhood diseasessuch as measles and pertussis, may also play a role in the flu. A combination of these small seasonal effects may be amplified by dynamical resonance with the endogenous disease cycles. H5N1 exhibits seasonality in both humans and birds.
An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on immunity to the virus. This idea was first proposed by Robert Edgar Hope-Simpson in 1965. He proposed that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or artificial) UV radiation. This could explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the sun, and their vitamin D levels fall.
Pandemic Influenza Vaccine Policy — Considering the Early Evidence
EDITORIAL
CLICK DOWNLOAD
Influenza Editorial
LINK: http://content.nejm.org/cgi/content/full/361/25/e59
CLICK DOWNLOAD
Influenza Editorial
LINK: http://content.nejm.org/cgi/content/full/361/25/e59
The Emotional Epidemiology of H1N1 Influenza Vaccination
PERSPECTIVES
Danielle Ofri, M.D., Ph.D.
Last spring, when 2009 H1N1 influenza first came to our attention, my patients were in a panic. Our clinic was flooded with callsand walk-in patients, all with the same question: "When will there be a vaccine?"
It was all so new then, and we didn't have an answer. That lack of answer seemed to fuel anxiety to a fever pitch. A substantialcohort of my patients continued calling, almost on a weekly basis, to ask about the vaccine.
These, of course, were the same patients who routinely refused the seasonal flu vaccine. Each year we'd go through the same drill: I'd offer them the flu shot. I'd explain the clinical reasoning behind this recommendation. I'd strongly encourage vaccination.
"No, thanks," they'd say. "The vaccine makes me sick." Or "My brother had a bad reaction." Or, simply, "I don't do flu shots."
The irony was painful. No matter how often I trotted out the statistics of 30,000 to 40,000 annual deaths from influenza, the patients would not be moved. So when they demanded the H1N1 vaccine last spring, I reminded them of their reluctance over the seasonal flu shot. "Oh, that's different," they said.
Six months have passed. Flu season is now here. After repeated delays, H1N1 vaccine finally arrived in our clinic earlier this month to the uniform relief of the medical staff. But my formerly desperate patients were now leery. "It's not tested," they said. "Everyone knows there are problems with the vaccine." "I'm not putting that in my body."
I was unprepared for this response, but maybe I shouldn't have been. For weeks now, in the schoolyard of my children's elementary school, other parents had been sidling up to me, seemingly in need of validation. "You're not giving your kids that swine flu shot, are you?" they'd say, their tone nervous, if a bit derisive.
How to explain this dramatic shift in 6 short months? It certainly isn't related to logic or facts, since few new medical data became available during this period. It seems to reflect a sort of psychological contagion of myth and suspicion.
Just as there are patterns of infection, there seem to be patterns of emotional reaction ("emotional epidemiology") associated with new illnesses. When 2009 H1N1 influenza was first detected, it fit a classic pattern that Priscilla Wald recently outlined in her book Contagious1: It was novel and mysterious; it emerged from a teeming third-world city, and it was now making its insidious — and seemingly unstoppable — way toward the "civilized" world.
This is the story line for most headline-grabbing illnesses — HIV, Ebola virus, SARS, typhoid. These diseases capture our imagination and ignite our fears in ways that more prosaic illnesses do not. These dramatic stakes lend themselves quite naturally to thriller books and movies; Dustin Hoffman hasn't starred in any blockbusters about emphysema or dysentery.
When the inoculum of dramatic illness is first introduced into society, the public psyche rapidly becomes infected. Almost like an IgE-mediated histamine release, there is an immediate flooding of fear, even if the illness — like Ebola — is infinitely less likely to cause death than, say, a run-in with the Second Avenue bus. This immediate fear of the unknown was what had all my patients demanding the as-yet-unproduced H1N1 vaccine last spring.
As the novel disease establishes itself within society, a certain amount of emotional tolerance is created. H1N1 infection waxed and waned over the summer, and my patients grew less anxious. There was, of course, no medical basis for this decreased vigilance. Unusual risk groups and atypical seasonality should, in fact, have raised concern. By late summer, the perceived mysteriousness of H1N1 had receded, and the number of messages on my clinic phone followed suit.
But emotional epidemiology does not remain static. As autumn rolled around, I sensed a peeved expectation from my patients that this swine flu problem should have been solved already. The fact that it wasn't "solved," that the medical profession seemed somehow to be dithering, created an uneasy void. Not knowing whether to succumb to panic or to indifference, patients instead grew suspicious.
No amount of rational explanation — about the natural variety of influenza strains, about the simple issue of outbreak timing that necessitated a separate H1N1 vaccine — could allay this wariness.
Similarly, reassuring fellow parents that I was indeed vaccinating my own children did little to ease their apprehension. When the New York City public school system offered free vaccinations for both students and families, there was an abysmally poor turnout. Less than one quarter of the consent forms sent home in kids' backpacks were returned.
The dramatic shift in public sentiment over the course of this H1N1 epidemic is both fascinating and frustrating. It is clear that there is a distinct emotional epidemiology and that it bears only a faint connection to the actual disease epidemiology of the virus.
We cannot combat H1N1 influenza merely by ensuring adequate supplies of vaccine and oseltamivir. Unless the medical profession confronts the emotional epidemiology of H1N1 with a full-court press, we run the risk of an uncontrollable epidemic.
There is no doubt that we are far behind the curve in terms of public relations. Our science has not been dithering at all, but our articulation of that science has often seemed that way, from the unfortunate initial appellation of swine flu to our inability to clarify distinctions between vaccine-production issues and clinical-risk issues. Suspicion has its own contagion, and we have not been aggressive enough in countering it.
Every practicing clinician is, to some degree, an armchair epidemiologist. We register patterns of disease as they play out among our patients. We are also keen detectives of emotional epidemiology, though we often aren't aware of this as such. Keeping tabs on the emotional epidemiology as well as the disease epidemiology, and treating both with equal urgency, are the essential clinical tools for this influenza season.
Financial and other disclosures provided by the author are available with the full text of this article at NEJM.org.
Source Information
From New York University School of Medicine and Bellevue Hospital, New York.
This article (10.1056/NEJMp0911047) was published on November 25, 2009, at NEJM.org. LINK http://content.nejm.org/cgi/content/full/NEJMp0911047
References
1. Wald P. Contagious: cultures, carriers, and the outbreak narrative. Durham, NC: Duke University Press, 2008.
Danielle Ofri, M.D., Ph.D.
Last spring, when 2009 H1N1 influenza first came to our attention, my patients were in a panic. Our clinic was flooded with callsand walk-in patients, all with the same question: "When will there be a vaccine?"
It was all so new then, and we didn't have an answer. That lack of answer seemed to fuel anxiety to a fever pitch. A substantialcohort of my patients continued calling, almost on a weekly basis, to ask about the vaccine.
These, of course, were the same patients who routinely refused the seasonal flu vaccine. Each year we'd go through the same drill: I'd offer them the flu shot. I'd explain the clinical reasoning behind this recommendation. I'd strongly encourage vaccination.
"No, thanks," they'd say. "The vaccine makes me sick." Or "My brother had a bad reaction." Or, simply, "I don't do flu shots."
The irony was painful. No matter how often I trotted out the statistics of 30,000 to 40,000 annual deaths from influenza, the patients would not be moved. So when they demanded the H1N1 vaccine last spring, I reminded them of their reluctance over the seasonal flu shot. "Oh, that's different," they said.
Six months have passed. Flu season is now here. After repeated delays, H1N1 vaccine finally arrived in our clinic earlier this month to the uniform relief of the medical staff. But my formerly desperate patients were now leery. "It's not tested," they said. "Everyone knows there are problems with the vaccine." "I'm not putting that in my body."
I was unprepared for this response, but maybe I shouldn't have been. For weeks now, in the schoolyard of my children's elementary school, other parents had been sidling up to me, seemingly in need of validation. "You're not giving your kids that swine flu shot, are you?" they'd say, their tone nervous, if a bit derisive.
How to explain this dramatic shift in 6 short months? It certainly isn't related to logic or facts, since few new medical data became available during this period. It seems to reflect a sort of psychological contagion of myth and suspicion.
Just as there are patterns of infection, there seem to be patterns of emotional reaction ("emotional epidemiology") associated with new illnesses. When 2009 H1N1 influenza was first detected, it fit a classic pattern that Priscilla Wald recently outlined in her book Contagious1: It was novel and mysterious; it emerged from a teeming third-world city, and it was now making its insidious — and seemingly unstoppable — way toward the "civilized" world.
This is the story line for most headline-grabbing illnesses — HIV, Ebola virus, SARS, typhoid. These diseases capture our imagination and ignite our fears in ways that more prosaic illnesses do not. These dramatic stakes lend themselves quite naturally to thriller books and movies; Dustin Hoffman hasn't starred in any blockbusters about emphysema or dysentery.
When the inoculum of dramatic illness is first introduced into society, the public psyche rapidly becomes infected. Almost like an IgE-mediated histamine release, there is an immediate flooding of fear, even if the illness — like Ebola — is infinitely less likely to cause death than, say, a run-in with the Second Avenue bus. This immediate fear of the unknown was what had all my patients demanding the as-yet-unproduced H1N1 vaccine last spring.
As the novel disease establishes itself within society, a certain amount of emotional tolerance is created. H1N1 infection waxed and waned over the summer, and my patients grew less anxious. There was, of course, no medical basis for this decreased vigilance. Unusual risk groups and atypical seasonality should, in fact, have raised concern. By late summer, the perceived mysteriousness of H1N1 had receded, and the number of messages on my clinic phone followed suit.
But emotional epidemiology does not remain static. As autumn rolled around, I sensed a peeved expectation from my patients that this swine flu problem should have been solved already. The fact that it wasn't "solved," that the medical profession seemed somehow to be dithering, created an uneasy void. Not knowing whether to succumb to panic or to indifference, patients instead grew suspicious.
No amount of rational explanation — about the natural variety of influenza strains, about the simple issue of outbreak timing that necessitated a separate H1N1 vaccine — could allay this wariness.
Similarly, reassuring fellow parents that I was indeed vaccinating my own children did little to ease their apprehension. When the New York City public school system offered free vaccinations for both students and families, there was an abysmally poor turnout. Less than one quarter of the consent forms sent home in kids' backpacks were returned.
The dramatic shift in public sentiment over the course of this H1N1 epidemic is both fascinating and frustrating. It is clear that there is a distinct emotional epidemiology and that it bears only a faint connection to the actual disease epidemiology of the virus.
We cannot combat H1N1 influenza merely by ensuring adequate supplies of vaccine and oseltamivir. Unless the medical profession confronts the emotional epidemiology of H1N1 with a full-court press, we run the risk of an uncontrollable epidemic.
There is no doubt that we are far behind the curve in terms of public relations. Our science has not been dithering at all, but our articulation of that science has often seemed that way, from the unfortunate initial appellation of swine flu to our inability to clarify distinctions between vaccine-production issues and clinical-risk issues. Suspicion has its own contagion, and we have not been aggressive enough in countering it.
Every practicing clinician is, to some degree, an armchair epidemiologist. We register patterns of disease as they play out among our patients. We are also keen detectives of emotional epidemiology, though we often aren't aware of this as such. Keeping tabs on the emotional epidemiology as well as the disease epidemiology, and treating both with equal urgency, are the essential clinical tools for this influenza season.
Financial and other disclosures provided by the author are available with the full text of this article at NEJM.org.
Source Information
From New York University School of Medicine and Bellevue Hospital, New York.
This article (10.1056/NEJMp0911047) was published on November 25, 2009, at NEJM.org. LINK http://content.nejm.org/cgi/content/full/NEJMp0911047
References
1. Wald P. Contagious: cultures, carriers, and the outbreak narrative. Durham, NC: Duke University Press, 2008.
2009 H1N1 ACIP Vaccination Recommendations
LISTEN AUDIO
In this podcast, Dr. Tony Fiore discusses who should be vaccinated against 2009 H1N1 flu during the 2009-2010 season. He explains the target groups for vaccination, and how these groups differ from those recommended for seasonal flu vaccination. Created: 9/2/2009 by Coordinating Center for Infectious Diseases, National Center for Immunization and Respiratory Diseases, Influenza Division (CCID/NCIRD/ID). Date Released: 9/2/2009. Series Name: CDC Featured Podcasts.
In this podcast, Dr. Tony Fiore discusses who should be vaccinated against 2009 H1N1 flu during the 2009-2010 season. He explains the target groups for vaccination, and how these groups differ from those recommended for seasonal flu vaccination. Created: 9/2/2009 by Coordinating Center for Infectious Diseases, National Center for Immunization and Respiratory Diseases, Influenza Division (CCID/NCIRD/ID). Date Released: 9/2/2009. Series Name: CDC Featured Podcasts.
CASE REPORT - 11 JUNE 2010
Pandemic (H1N1) 2009
Weekly update
11 June 2010 -- As of 6 June, worldwide more than 214 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 18156 deaths.
WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and Member States and through monitoring of multiple sources of information.
Situation update:
Active but declining transmission of pandemic influenza virus persists in limited areas of the tropics, particularly in Southeast Asia and the Caribbean. As countries of the temperate southern hemisphere enter winter, only sporadic influenza activity has been detected so far, except in Chile and Uruguay, both of which have recently reported small numbers of pandemic influenza virus detections. Although seasonal influenza B viruses have been the predominant type of influenza virus circulating worldwide since the end of February 2010, there have been increasing but low level detections of seasonal influenza H3N2 viruses, particularly in South America and in East Africa.
In the tropics of the Americas, overall pandemic influenza activity is low, however, both seasonal influenza H3N2 and type B viruses are actively circulating in parts of tropical South America. Active but declining transmission of pandemic influenza virus continues to be detected primarily in Cuba. Since early 2010, pandemic influenza virus has circulated at low levels in Costa Rica. Sporadic detections of pandemic influenza virus continue to be reported in Brazil. During the most recent reporting week (last week of May 2010), both Brazil and Venezuela reported regional spread of influenza activity associated with an increasing trend of respiratory diseases. In Venezuela, recent influenza activity (which began during early May 2010) has been predominantly due to circulating seasonal influenza A viruses. In Bolivia, circulation of seasonal influenza viruses, predominantly type B, was observed between March and May 2010 and now appears to be subsiding.
In Asia overall pandemic influenza virus transmission remains low, except in parts of tropical South and Southeast Asia, particularly Singapore, Malaysia, and Bangladesh. In Singapore, overall levels of ARI remained slightly below the epidemic threshold and the proportion of respiratory samples testing positive for pandemic influenza virus increased slightly to 34%. In Malaysia, limited data suggests that pandemic influenza virus transmission has begun to decline since plateauing during May 2010. In Bangladesh, there has been stable persistent low level co-circulation of pandemic and seasonal influenza B viruses since March 2010. Sporadic detections of pandemic influenza virus continued to be reported across other parts of Asia. In East Asia, overall influenza activity remains low, however, seasonal influenza B viruses continue to circulate at low and declining levels.
In Sub-Saharan Africa, pandemic influenza virus continued to circulate at low levels in parts of West Africa, most notably in Ghana. During the most recent reporting week, 13% of all respiratory samples tested positive for pandemic influenza virus in Ghana. Small but significant numbers of seasonal H3N2 viruses have been detected in Kenya and Tanzania since late May 2010.
Overall, in the temperate regions of the northern hemisphere, pandemic influenza viruses have been detected only sporadically during the past month. In the temperate southern hemisphere, only two countries, Chile and Uruguay, have recently reported small numbers of pandemic influenza virus detections. In Chile, there was low level geographically limited circulation of pandemic influenza virus during May 2010; 3.4% of respiratory samples tested positive for pandemic influenza virus during the last week of May 2010. Of note, in Uruguay, 11 (44%) of 25 samples tested positive for pandemic influenza during the most recent reporting week (the last week of May 2010); however, the corresponding intensity of respiratory diseases in the population is not yet known. Other respiratory viruses, most notably RSV, are known to be circulating in Chile and Argentina. There have been no recent detections of pandemic influenza virus in South Africa. In New Zealand and Australia, overall levels of ILI remain low; only sporadic detections of seasonal and pandemic influenza viruses have been recently reported in Australia.
The Global Influenza Surveillance Network (GISN) continues monitoring the global circulation of influenza viruses, including pandemic, seasonal and other influenza viruses infecting, or with the potential to infect, humans including seasonal influenza. For more information on virological surveillance and antiviral resistance please see the weekly virology update (Virological surveillance data, below).
Weekly update
11 June 2010 -- As of 6 June, worldwide more than 214 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 18156 deaths.
WHO is actively monitoring the progress of the pandemic through frequent consultations with the WHO Regional Offices and Member States and through monitoring of multiple sources of information.
Situation update:
Active but declining transmission of pandemic influenza virus persists in limited areas of the tropics, particularly in Southeast Asia and the Caribbean. As countries of the temperate southern hemisphere enter winter, only sporadic influenza activity has been detected so far, except in Chile and Uruguay, both of which have recently reported small numbers of pandemic influenza virus detections. Although seasonal influenza B viruses have been the predominant type of influenza virus circulating worldwide since the end of February 2010, there have been increasing but low level detections of seasonal influenza H3N2 viruses, particularly in South America and in East Africa.
In the tropics of the Americas, overall pandemic influenza activity is low, however, both seasonal influenza H3N2 and type B viruses are actively circulating in parts of tropical South America. Active but declining transmission of pandemic influenza virus continues to be detected primarily in Cuba. Since early 2010, pandemic influenza virus has circulated at low levels in Costa Rica. Sporadic detections of pandemic influenza virus continue to be reported in Brazil. During the most recent reporting week (last week of May 2010), both Brazil and Venezuela reported regional spread of influenza activity associated with an increasing trend of respiratory diseases. In Venezuela, recent influenza activity (which began during early May 2010) has been predominantly due to circulating seasonal influenza A viruses. In Bolivia, circulation of seasonal influenza viruses, predominantly type B, was observed between March and May 2010 and now appears to be subsiding.
In Asia overall pandemic influenza virus transmission remains low, except in parts of tropical South and Southeast Asia, particularly Singapore, Malaysia, and Bangladesh. In Singapore, overall levels of ARI remained slightly below the epidemic threshold and the proportion of respiratory samples testing positive for pandemic influenza virus increased slightly to 34%. In Malaysia, limited data suggests that pandemic influenza virus transmission has begun to decline since plateauing during May 2010. In Bangladesh, there has been stable persistent low level co-circulation of pandemic and seasonal influenza B viruses since March 2010. Sporadic detections of pandemic influenza virus continued to be reported across other parts of Asia. In East Asia, overall influenza activity remains low, however, seasonal influenza B viruses continue to circulate at low and declining levels.
In Sub-Saharan Africa, pandemic influenza virus continued to circulate at low levels in parts of West Africa, most notably in Ghana. During the most recent reporting week, 13% of all respiratory samples tested positive for pandemic influenza virus in Ghana. Small but significant numbers of seasonal H3N2 viruses have been detected in Kenya and Tanzania since late May 2010.
Overall, in the temperate regions of the northern hemisphere, pandemic influenza viruses have been detected only sporadically during the past month. In the temperate southern hemisphere, only two countries, Chile and Uruguay, have recently reported small numbers of pandemic influenza virus detections. In Chile, there was low level geographically limited circulation of pandemic influenza virus during May 2010; 3.4% of respiratory samples tested positive for pandemic influenza virus during the last week of May 2010. Of note, in Uruguay, 11 (44%) of 25 samples tested positive for pandemic influenza during the most recent reporting week (the last week of May 2010); however, the corresponding intensity of respiratory diseases in the population is not yet known. Other respiratory viruses, most notably RSV, are known to be circulating in Chile and Argentina. There have been no recent detections of pandemic influenza virus in South Africa. In New Zealand and Australia, overall levels of ILI remain low; only sporadic detections of seasonal and pandemic influenza viruses have been recently reported in Australia.
The Global Influenza Surveillance Network (GISN) continues monitoring the global circulation of influenza viruses, including pandemic, seasonal and other influenza viruses infecting, or with the potential to infect, humans including seasonal influenza. For more information on virological surveillance and antiviral resistance please see the weekly virology update (Virological surveillance data, below).
History of Influenza
Spanish Flu (1918–1920)
The 1918 flu pandemic, commonly referred to as the Spanish flu, was a category 5 influenza pandemic caused by an unusually severe and deadly Influenza A virus strain of subtype H1N1.
The difference between the influenza mortality age-distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).
The Spanish flu pandemic lasted from 1918 to 1919, although Price-Smith's data suggest it may have begun in Austria in the Spring of 1917. Older estimates say it killed 40–50 million people while current estimates say 50 million to 100 million people worldwide were killed. This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death, although the Black Death is estimated to have killed over a fifth of the world's population at the time, a significantly higher proportion. This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms. Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred." The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.
The Spanish flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old. This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that up to 1% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.
The Manchester Influenza Epidemic of 1937
The Epidemic that never escalated to Pandemic This is an example of an interwar epidemic that public health controls did not allow to develop into a full blown pandemic because of what was already known from 1918, as well as employing very strict patient, contact and family isolation. In 1937 there were 620 claims for sickness benefits made to various insurance companies.
Asian Flu (1957–1958)
The "Asian Flu" was a category 2 flu pandemic outbreak of avian influenza that originated in China in early 1956 lasting until 1958. It originated from mutation in wild ducks combining with a pre-existing human strain. The virus was first identified in Guizhou. It spread toSingapore in February 1957, reached Hong Kong by April, and US by June. Death toll in the US was approximately 69,800. The elderly were particularly vulnerable Estimates of worldwide deaths vary widely depending on source, ranging from 1 million to 4 million.
Hong Kong Flu (1968–1969)
The Hong Kong Flu was a category 2 flu pandemic caused by a strain of H3N2 descended from H2N2 by antigenic shift, in which genes from multiple subtypes reassorted to form a new virus. The Hong Kong Flu pandemic of 1968 and 1969 killed an estimated one million people worldwide. Those over 65 had the greatest death rates. In the US, there were about 33,800 deaths.
2009 Flu Pandemic (Since 2009)
In March-April 2009, an epidemic of influenza-like illness of unknown causation occurred in Mexico. On April 24, 2009, following the isolation of an A/H1N1 influenza in 7 ill patients in the southwest US. The WHO issued a statement on the outbreak of "influenza like illness" in the confirmed cases of A/H1N1 influenza had been reported in Mexico, and that 20 confirmed cases of the disease had been reported in the US.The next day, the number of confirmed cases rose to 40 in the US, 26 in Mexico, 6 in Canada, and 1 in Spain.The disease spread rapidly through the rest the spring, and by May 3, 787 confirmed cases of the disease had been reported worldwide. On June 11, 2009, the ongoing outbreak of Influenza A/H1N1, commonly referred to as "swine flu", was officially declared by the WHO to be the first influenza pandemic of the 21st century and a new strain of Influenza A virus subtype H1N1 first identified in April 2009. It is thought to be amutation (reassortment) of four known strains of influenza A virus subtype H1N1: one endemic in humans, one endemic in birds, and two endemic in pigs (swine).
In November 1, 2009 a worldwide update by the U.N.'s World Health Organization (WHO) stated that "199 countries and overseas territories/communities have officially reported a total of over 482,300 laboratory confirmed cases of the influenza pandemic H1N1 infection, that included 6,071 deaths.
The 1918 flu pandemic, commonly referred to as the Spanish flu, was a category 5 influenza pandemic caused by an unusually severe and deadly Influenza A virus strain of subtype H1N1.
The difference between the influenza mortality age-distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).
The Spanish flu pandemic lasted from 1918 to 1919, although Price-Smith's data suggest it may have begun in Austria in the Spring of 1917. Older estimates say it killed 40–50 million people while current estimates say 50 million to 100 million people worldwide were killed. This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death, although the Black Death is estimated to have killed over a fifth of the world's population at the time, a significantly higher proportion. This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms. Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred." The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.
The Spanish flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old. This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that up to 1% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.
The Manchester Influenza Epidemic of 1937
The Epidemic that never escalated to Pandemic This is an example of an interwar epidemic that public health controls did not allow to develop into a full blown pandemic because of what was already known from 1918, as well as employing very strict patient, contact and family isolation. In 1937 there were 620 claims for sickness benefits made to various insurance companies.
Asian Flu (1957–1958)
The "Asian Flu" was a category 2 flu pandemic outbreak of avian influenza that originated in China in early 1956 lasting until 1958. It originated from mutation in wild ducks combining with a pre-existing human strain. The virus was first identified in Guizhou. It spread toSingapore in February 1957, reached Hong Kong by April, and US by June. Death toll in the US was approximately 69,800. The elderly were particularly vulnerable Estimates of worldwide deaths vary widely depending on source, ranging from 1 million to 4 million.
Hong Kong Flu (1968–1969)
The Hong Kong Flu was a category 2 flu pandemic caused by a strain of H3N2 descended from H2N2 by antigenic shift, in which genes from multiple subtypes reassorted to form a new virus. The Hong Kong Flu pandemic of 1968 and 1969 killed an estimated one million people worldwide. Those over 65 had the greatest death rates. In the US, there were about 33,800 deaths.
2009 Flu Pandemic (Since 2009)
In March-April 2009, an epidemic of influenza-like illness of unknown causation occurred in Mexico. On April 24, 2009, following the isolation of an A/H1N1 influenza in 7 ill patients in the southwest US. The WHO issued a statement on the outbreak of "influenza like illness" in the confirmed cases of A/H1N1 influenza had been reported in Mexico, and that 20 confirmed cases of the disease had been reported in the US.The next day, the number of confirmed cases rose to 40 in the US, 26 in Mexico, 6 in Canada, and 1 in Spain.The disease spread rapidly through the rest the spring, and by May 3, 787 confirmed cases of the disease had been reported worldwide. On June 11, 2009, the ongoing outbreak of Influenza A/H1N1, commonly referred to as "swine flu", was officially declared by the WHO to be the first influenza pandemic of the 21st century and a new strain of Influenza A virus subtype H1N1 first identified in April 2009. It is thought to be amutation (reassortment) of four known strains of influenza A virus subtype H1N1: one endemic in humans, one endemic in birds, and two endemic in pigs (swine).
In November 1, 2009 a worldwide update by the U.N.'s World Health Organization (WHO) stated that "199 countries and overseas territories/communities have officially reported a total of over 482,300 laboratory confirmed cases of the influenza pandemic H1N1 infection, that included 6,071 deaths.
ARTICLE
Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus.
Abstract
Influenza A virus is being extensively studied because of its major impact on human and animal health. However, the dynamics of influenza virus infection and the cell types infected in vivo are poorly understood. These characteristics are challenging to determine, partly because there is no efficient replication-competent virus expressing an easily traceable reporter gene. Here, we report the generation of a recombinant influenza virus carrying a GFP reporter gene in the NS segment (NS1-GFP virus). Although attenuated when compared with wild-type virus, the NS1-GFP virus replicates efficiently in murine lungs and shows pathogenicity in mice. Using whole-organ imaging and flow cytometry, we have tracked the dynamics of influenza virus infection progression in mice. Imaging of murine lungs shows that infection starts in the respiratory tract in areas close to large conducting airways and later spreads to deeper sections of the lungs. In addition to epithelial cells, we found GFP-positive antigen-presenting cells, such as CD11b(+)CD11c(-), CD11b(-)CD11c(+), and CD11b(+)CD11c(+), as early as 24 h after intranasal infection. In addition, a significant proportion of NK and B cells were GFP positive, suggesting active infection of these cells. We next tested the effects of the influenza virus inhibitors oseltamivir and amantadine on the kinetics of in vivo infection progression. Treatment with oseltamivir dramatically reduced influenza infection in all cell types, whereas, surprisingly, amantadine treatment more efficiently blocked infection in B and NK cells. Our results demonstrate high levels of immune cells harboring influenza virus antigen during viral infection and cell-type-specific effects upon treatment with antiviral agents, opening additional avenues of research in the influenza virus field.
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Article Influenza
Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus.
Abstract
Influenza A virus is being extensively studied because of its major impact on human and animal health. However, the dynamics of influenza virus infection and the cell types infected in vivo are poorly understood. These characteristics are challenging to determine, partly because there is no efficient replication-competent virus expressing an easily traceable reporter gene. Here, we report the generation of a recombinant influenza virus carrying a GFP reporter gene in the NS segment (NS1-GFP virus). Although attenuated when compared with wild-type virus, the NS1-GFP virus replicates efficiently in murine lungs and shows pathogenicity in mice. Using whole-organ imaging and flow cytometry, we have tracked the dynamics of influenza virus infection progression in mice. Imaging of murine lungs shows that infection starts in the respiratory tract in areas close to large conducting airways and later spreads to deeper sections of the lungs. In addition to epithelial cells, we found GFP-positive antigen-presenting cells, such as CD11b(+)CD11c(-), CD11b(-)CD11c(+), and CD11b(+)CD11c(+), as early as 24 h after intranasal infection. In addition, a significant proportion of NK and B cells were GFP positive, suggesting active infection of these cells. We next tested the effects of the influenza virus inhibitors oseltamivir and amantadine on the kinetics of in vivo infection progression. Treatment with oseltamivir dramatically reduced influenza infection in all cell types, whereas, surprisingly, amantadine treatment more efficiently blocked infection in B and NK cells. Our results demonstrate high levels of immune cells harboring influenza virus antigen during viral infection and cell-type-specific effects upon treatment with antiviral agents, opening additional avenues of research in the influenza virus field.
Double-click to download
Article Influenza
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