Friday, November 13, 2009

WHO stresses antiviral use in high-risk H1N1 patients

Nov 12, 2009 (CIDRAP News) – Citing reports that hospitals and clinics in some countries are being overwhelmed by pandemic influenza cases, the World Health Organization (WHO) today put an exclamation on its advice about the importance of prompt antiviral treatment for high-risk patients.

Dr. Nikki Shindo said growing clinical experience has given the WHO more confidence about the safety and effectiveness of antiviral drugs, primarily oseltamivir, in patients at risk for severe disease, especially pregnant women, small children, and people with chronic medical conditions.

"In some countries hospitals and clinics are overwhelmed with the number of patients they are treating," Shindo said. "One way to lighten the burden on the healthcare system is to prevent severe disease."

Shindo spoke at a news teleconference today that followed the WHO's release of updated clinical management guidelines this week. Like the current advice from the US Centers for Disease Control and Prevention, the guidelines urge doctors not to wait for flu test results before treating at-risk patients with antivirals.

Shindo said the WHO has received reports of overwhelming numbers of pandemic flu cases in Ukraine, Afghanistan, and Mongolia in particular. The agency is sending antiviral supplies to several poor countries but doesn't have enough to meet their needs, she reported.

The agency recently shipped antivirals to Afghanistan, Mongolia, Belarus, and Ukraine and will soon be sending some to Azerbaijan and Kyrgyzstan, she reported. "We'll use the stockpile to support countries which are likely to be hard hit this winter and unable to meet their needs," she said.

With the addition of about 5 million treatment courses expected soon, the WHO will have up to 10 million courses in its stockpile, Shindo said, adding, "We don't think this is enough to meet the needs of the countries. So we've been working with our partners and other countries who have enough supplies to meet the global need."

She didn't give an estimate of how big a supply will be needed, but said, "We calculate the at-risk groups in developing countries at more or less about 4% of the population."

The WHO is recommending that countries "decentralize the distribution of antivirals and ensure that general practitioners have access to these medications for their patients," Shindo said. "Patients should not have to visit a hospital in order to get antivirals prescribed. This should ensure that individuals get the care they need faster and the burden on hospitals will be reduced."

Three recommendations
Shindo highlighted three WHO recommendations about treatment in H1N1 cases:

  • People in high-risk groups, especially pregnant women, children less than 2 years old, and those with chronic medical conditions, should receive antiviral treatment as soon as possible if they have flu symptoms.
  • People who are not in those groups but have persistent or rapidly worsening symptoms also should get antiviral medication. Particular danger signs include difficult breathing and high fever lasting longer than 3 days.
  • Those who already have pneumonia should be given both antiviral and antibiotic treatment.

"We have heard that doctors in caring for very sick patients in intensive care units report that patients arrived too late and even sophisticated medical procedures couldn't save their lives," Shindo said. "We asked doctors what could've been done differently; all of them answered that things may have been different if they'd been treated with antiviral medication early."

The WHO does not recommend antivirals for otherwise healthy people with mild illness or as preventive measure for healthy people, she noted.

She said the main reason for updating the clinical guidelines now is that experts are more confident about the safety and effectiveness of antiviral treatment than they were earlier in the pandemic. Increased experience with use of the drugs in young children and pregnant women has been particularly helpful.

In response to questions about risk factors, Shindo said children under age 2 have the highest hospitalization rate, with pregnant women second and those with chronic medical conditions, especially chronic lung disease, third.

The median age for hospitalized patients is between 20 and 35, but the median age for the most severe cases is about 10 years older, in the range of 35 to 40, she added.

She also commented that the proportion of severe cases in Ukraine is somewhat lower than what the Southern Hemisphere experienced in its recent winter flu season. "It seems a lot of patients are being admitted with rather milder symptoms than those requiring ICU care," she said.

Clinical guidelines
The new WHO guidelines say that on average, about half of hospitalized H1N1 patients have at least one underlying medical condition, but about a third of patients who end up in ICUs were healthy before they got the virus.

The document says that risk factors for severe disease in previously healthy people remain unclear. It warns that patients can deteriorate quickly, with warning signs such as shortness of breath, altered mental status, persistent high fever, and severe dehydration.

The WHO lists oseltamivir as the first choice for antiviral treatment in all patient groups, including breastfeeding mothers, with zanamivir as the backup if oseltamivir is unavailable or there are signs of resistance to it. Although starting treatment within 48 hours of illness onset is best, an antiviral "may be used at any stage of active disease when ongoing viral replication is anticipated or documented."

For hospital patients, the guidelines stress the importance of monitoring oxygen saturation by pulse oximetry and providing supplemental oxygen when needed. The WHO advises against the use of high-dose cortiocosteroids except in clinical trials.

See also:

Summary of WHO H1N1 clinical management guidelines

Full text of guidelines

Thursday, November 12, 2009

CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April – October 17, 2009

November 12, 2009, 1:00 PM ET


Estimating the number of individual flu cases in the United States is very challenging because many people with flu don’t seek medical care and only a small number of those that do seek care are tested. More people who are hospitalized or die of flu-related causes are tested and reported, but under-reporting of hospitalizations and deaths occurs as well. For this reason CDC monitors influenza activity levels and trends and virus characteristics through a nationwide surveillance system and uses statistical modeling to estimate the burden of flu illness (including hospitalizations and deaths) in the United States.

When the 2009 H1N1 flu outbreak began in April 2009, CDC began reporting the number of laboratory-confirmed cases, hospitalizations and deaths associated with 2009 H1N1 flu in the United States that were reported by states to CDC. These initial case counts, and subsequent ongoing laboratory-confirmed reports of hospitalizations and deaths, are thought to represent a significant undercount of the actual number of 2009 H1N1 flu cases in the United States. A paper in Emerging Infectious Diseases authored by CDC staff entitled “Estimates of the Prevalence of Pandemic (H1N1) 2009, United States, April–July 2009” Adobe PDF file reported on a study to estimate the prevalence of 2009 H1N1 based on the number of laboratory-confirmed cases reported to CDC. Correcting for under-ascertainment, the study found that every case of 2009 H1N1 reported from April – July represented an estimated 79 total cases, and every hospitalized case reported may have represented an average of 2.7 total hospitalized people. Since that time, CDC has been working to develop a way to estimate, in an ongoing way, the impact of the 2009 H1N1 pandemic on the U.S. in terms of 2009 H1N1 cases, hospitalizations and deaths.

Method to Estimate 2009 H1N1 Cases, Hospitalizations and Deaths

CDC has developed a method to provide an estimated range of the total number of 2009 H1N1 cases, hospitalizations and deaths in the United States since April, 2009, as well as a breakdown of these estimates by age groups. This method uses data on influenza-associated hospitalizations collected through CDC’s Emerging Infections Program (EIP), which conducts surveillance for laboratory-confirmed influenza-related hospitalizations in children and adults in 62 counties covering 13 metropolitan areas of 10 states. To determine an estimated number of 2009 H1N1 hospitalizations nationwide, the EIP hospitalization data are extrapolated to the entire U.S. population and then corrected for factors that may result in under-reporting using a multiplier from “Estimates of the Prevalence of Pandemic (H1N1) 2009, United States, April–July 2009.”. Adobe PDF file The lower and upper hospitalization estimates also are calculated using the EIP hospitalization data. The national hospitalization estimates are then used to calculate deaths and cases. Deaths are calculated by using the proportion of laboratory-confirmed deaths to hospitalizations reported through CDC’s web-based Aggregate Hospitalization and Death Reporting Activity (AHDRA). Cases are estimated using multipliers derived from “Estimates of the Prevalence of Pandemic (H1N1) 2009, United States, April–July 2009.” Adobe PDF file The lower and upper end of the ranges for deaths and cases are derived from the lower and upper hospitalization estimates. The methods used to estimate impact may be modified as more information becomes available. More information about this methodology is available. Adobe PDF file

Throughout the remainder of the 2009 H1N1 pandemic CDC will update the range of estimated 2009 H1N1 cases, hospitalizations and deaths every three or four weeks. While EIP data is reported weekly during influenza season, because the system is based on reviews of patients medical charts there are sometimes delays in reporting and it can take some time for all the data to fill in. CDC will continue to provide weekly reports of influenza activity each Friday in FluView and will update the 2009 H1N1 Situation Update each Friday as well.

The estimated ranges of cases, hospitalizations and deaths generated by this method provide a sense of scale in terms of the burden of disease caused by 2009 H1N1. It may never be possible to validate the accuracy of these figures. The true number of cases, hospitalizations and deaths may lie within the range provided or it’s also possible that it may lie outside the range. The underlying assumption in this method is that the level of influenza activity (based on hospitalization rates) in EIP sites matches the level of influenza like illness (ILI) activity across the states.

This methodology is not a predictive tool and cannot be used to forecast the number of cases, hospitalizations and deaths that will occur going forward over the course of the pandemic because they are based on actual surveillance data.

The Numbers

  • CDC estimates that between 14 million and 34 million cases of 2009 H1N1 occurred between April and October 17, 2009. The mid-level in this range is about 22 million people infected with 2009 H1N1.
  • CDC estimates that between about 63,000 and 153,000 2009 H1N1-related hospitalizations occurred between April and October 17, 2009. The mid-level in this range is about 98,000 H1N1-related hospitalizations.
  • CDC estimates that between about 2,500 and 6,000 2009 H1N1-related deaths occurred between April and October 17, 2009. The mid-level in this range is about 3,900 2009 H1N1-related deaths.

CDC Estimates of 2009 H1N1 Cases and Related Hospitalizations and Deaths from April-October 17, 2009, By Age Group

2009 H1N1

Mid-Level Range*

Estimated Range *


0-17 years ~8 million ~5 million to ~13 million
18-64 years ~12 million ~7 million to ~18 million
65 years and older ~2 million ~1 million to ~3 million
Cases Total ~22 million ~14 million to ~34 million
0-17 years ~36,000 ~23,000 to ~57,000
18-64 years ~53,000 ~34,000 to ~83,000
65 years and older ~9,000 ~6,000 to ~14,000
Hospitalizations Total ~98,000 ~63,000 to ~153,000
0-17 years ~540 ~300 to ~800
18-64 years ~2,920 ~1,900 to ~4,600
65 years and older ~440 ~300 to ~700
Deaths Total ~3,900 ~2,500 to ~6,100

* Deaths have been rounded to the nearest ten. Hospitalizations have been rounded to the nearest thousand and cases have been rounded to the nearest million. Exact numbers also are available. Adobe PDF file

The results of this method confirm previous epidemiological data indicating that this disease primarily affects people younger than 65 year old, with the number of cases, hospitalizations and deaths overwhelmingly occurring in people 64 years and younger. This is very different from seasonal influenza, where about 60 percent of seasonal flu-related hospitalizations and 90 percent of flu-related deaths occur in people 65 years and older. The proportion of younger people being impacted by 2009 H1N1 is much greater than what occurs during seasonal flu and people 65 and older are much less affected by this virus than what routinely occurs with seasonal influenza. The results generated by this method also underscore the continued importance of the 2009 H1N1 vaccination program and support the recommended target groups for vaccination.

This methodology and the resulting estimates also underscore the substantial under-reporting that occurs when laboratory-confirmed outcomes are the sole method used to capture hospitalizations and deaths. Since the outbreak began in April, states have reported 2009 H1N1 hospitalizations and deaths to CDC. Cumulative reports of laboratory-confirmed 2009 H1N1 hospitalizations and deaths for the same period used in this analysis (April through October 17, 2009), are 17,283 hospitalizations and 1,004 deaths. CDC has maintained since the beginning of this outbreak that laboratory-confirmed data on hospitalizations and deaths reported to CDC is an underestimation of the true number that have occurred because of incomplete testing, inaccurate test results, or diagnosis that attribute hospitalizations and deaths to other causes, for example, secondary complications to influenza. (Information about surveillance and reporting for 2009 H1N1 is available at Questions and Answers: Monitoring Influenza Activity, Including 2009 H1N1.)

The estimates derived from this methodology provide the public, public health officials and policy makers a sense of the health impact of the 2009 H1N1 pandemic. While these numbers are an estimate, CDC feels that they present a fuller picture of the burden of 2009 H1N1 disease on the United States.

CDC will continue to use weekly data from systems that comprise the National Influenza Surveillance System to monitor geographic, temporal and virologic trends in influenza in the nation.

Background Emerging Infections Program

The Emerging Infections Program (EIP) Influenza Project conducts surveillance for laboratory-confirmed influenza-related hospitalizations in children and adults in 62 counties covering 13 metropolitan areas of 10 states. (This includes San Francisco, CA; Denver, CO; New Haven, CT; Atlanta, GA; Baltimore, MD; Minneapolis/St. Paul, MN; Albuquerque, NM; Santa Fe, NM, Las Cruces, NM; Albany, NY; Rochester, NY; Portland, OR; and Nashville, TN.) Cases are identified by reviewing hospital laboratory and admission databases and infection control logs for children and adults with a documented positive influenza test conducted as a part of routine patient care. EIP estimated hospitalization rates are reported every week during the flu season. More information about the Emerging Infections Program is available at

Seasonal Influenza-Associated Hospitalizations in the United States

An average estimated 200,000 flu-related hospitalizations occur in the United States each year, with about 60 percent of these hospitalizations occurring in people 65 years and older.

Background: A study conducted by CDC and published in the Journal of American Medical Association (JAMA) in September 2004External Web Site Icon provided information on the number of people in the United States that are hospitalized from seasonal influenza-related complications each year. The study concluded that, on average, more than 200,000 people in the United States are hospitalized each year for respiratory and heart conditions illnesses associated with seasonal influenza virus infections. The study looked at hospital records from 1979 to 2001. In 1979, there were 120,929 flu-related hospitalizations. The number was lower in some years after that, but there was an overall upward trend. During the 1990s, the average number of people hospitalized was more than 200,000 but individual seasons ranged from a low of 157,911 in 1990-91 to a high of 430,960 in 1997-98.
For more information about seasonal flu-related hospitalizations, visit

Seasonal Influenza-Associated Deaths

Flu-associated mortality varies by season because flu seasons often fluctuate in length and severity. CDC estimates that about 36,000 people died of flu-related causes each year, on average, during the 1990s in the United States with 90 percent of these deaths occurring in people 65 years and older. This includes people dying from secondary complications of the flu.

Background: This estimate came from a 2003 Journal of the American Medical Association (JAMA) studyExternal Web Site Icon, which looked at the 1990-91 through the 1998-99 flu seasons and is based on the number of people whose underlying cause of death on their death certificate was listed as a respiratory or circulatory disease. During these years, the number of estimated deaths ranged from 17,000 to 52,000. This number was corroborated in 2009, when a CDC-authored study was published in the journal Influenza and Other Respiratory VirusesExternal Web Site Icon. This study estimated seasonal flu-related deaths comparing different methods, including the methods used in the 2003 JAMA study but using more recent data. Results from this study showed that during this time period, 36,171 flu-related deaths occurred per year, on average. For more information about how CDC estimates seasonal flu-related deaths, visit

Under-Counting of Flu-Related Deaths

CDC does not know exactly how many people die from seasonal flu each year. There are several reasons for this:

    • First, states are not required to report individual seasonal flu cases or deaths of people older than 18 years of age to CDC.
    • Second, seasonal influenza is infrequently listed on death certificates of people who die from flu-related complications.
    • Third, many seasonal flu-related deaths occur one or two weeks after a person’s initial infection, either because the person may develop a secondary bacterial co-infection (such as a staph infection) or because seasonal influenza can aggravate an existing chronic illness (such as congestive heart failure or chronic obstructive pulmonary disease).
    • Also, most people who die from seasonal flu-related complications are not tested for flu, or they seek medical care later in their illness when seasonal influenza can no longer be detected from respiratory samples. Influenza tests are most likely to detect influenza if performed soon after onset of illness.
    • For these reasons, many flu-related deaths may not be recorded on death certificates.

These are some of the reasons that CDC and other public health agencies in the United States and other countries use statistical models to estimate the annual number of seasonal flu-related deaths. (Flu deaths in children were made a nationally notifiable condition in 2004, and since then, states have reported flu-related child deaths in the United States through the Influenza Associated Pediatric Mortality Surveillance System).

Related Links (-snip)

Swine flu: One killer virus, three key questions

Published online 11 November 2009 | Nature 462, 154-157 (2009) | doi:10.1038/462154a

Nature reports from three laboratories scrutinizing the pandemic flu virus.
Brendan Maher & Declan Butler

As the world mobilizes against the H1N1 flu pandemic, researchers are working to answer pressing questions about the virus. Brendan Maher visited pathologists at the US Centers for Disease Control and Prevention who are looking at how the virus kills, and a New York laboratory that is testing how it spreads. Declan Butler spent time at a French biosafety level-4 facility where researchers are working out the chances that the pandemic virus will reassort with the H5N1 avian flu virus.

1. How does it kill?

There are five sets of eyepieces on the microscope, and Sherif Zaki is looking down one of them. Looking down the other four are members of the team he leads at the infectious-disease pathology branch at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. Other researchers trained in epidemiology, microbiology and electron microscopy watch a large, flat-screen monitor at the end of the narrow conference room that shows an image projected from the microscope.

Dianna Blau, an epidemiologist, reveals the source of the tissue: an 11-year-old girl who died in September, probably from H1N1 influenza. The team had already detected viral RNA in the girl's samples. But observing the presence of the H1N1 virus, especially in this tissue from deep down in the lungs, provides a more accurate and detailed diagnosis. The tissue seems messy, and is flooded with blue-stained Staphylococcus aureus. Zaki scans back and forth across the slide, seeking the hint of red staining that would indicate the presence of antibodies bound to the H1N1 virus. He finds it on one slide, where a red blob indicates a profusion of virus being released from a rupturing cell. They mark her as positive.

“H1N1 looks like avian flu on steroids.” Sherif Zaki

Zaki's lab holds these 'sign out' meetings every afternoon, examining autopsy and other tissues that have been sent to the CDC from doctors and medical examiners around the world to find, confirm or rule out any number of diseases. Since April, their case load has doubled thanks to H1N1. So far, the group has received samples from more than 300 suspect cases, and it has confirmed swine flu in more than a third of them.

In addition to providing a diagnosis, the group's analyses are helping to build up a picture of how the virus kills. Pathological studies can show what tissues are affected and to what extent, adding detail to the worldwide monitoring and surveillance efforts.

The profile emerging is of a distinctive virus. Although seasonal flu tends to infect just the cells high in the upper airway, H1N1 penetrates down into the terminal air sacs called alveoli. "This is not an area of the lung where you would usually see seasonal flu," Zaki says. He has seen such behaviour before, though — in the few samples of lung tissue he has examined from humans killed by the H5N1 avian flu virus. But the virus is much more prevalent in the tissues from the severe H1N1 cases he has examined — "like avian flu on steroids" as Zaki puts it.

Zaki says that his observations fit well with recent research looking at the mechanism of infection. A group led by Mikhail Matrosovich at Philipps University Marburg in Germany and Ten Feizi at Imperial College London studied sialyl glycans, glycoproteins that the flu virus binds to in order to gain entry to human cells1. Although seasonal strains of H1N1 bind mostly to versions of the glycoproteins known as α2-6, the researchers found that the new pandemic H1N1 can also bind to a version called α2-3, which is found in greater proportion in the lower respiratory tract.

Co-infection is common with pandemic H1N1, at least in those who have died. Zaki's group has observed infection with bacteria such as S. aureus or Streptococcus pneumoniae in about a third of the fatal swine-flu cases it has examined. In the rest, the virus seems to be lethal on its own. Zaki slots onto the microscope stage a slide from a 38-year-old male who died without bacterial co-infection. This one is filled with the red staining; also the walls of the alveoli are ruptured and blood cells and fluid fill the spaces normally reserved for gas exchange. Scar-like pink ribbons, called hyaline membranes, arc through the tissue. Pathologists call this state 'diffuse alveolar damage', and it tells them that the man had respiratory distress syndrome. "It's very difficult to treat a patient once they get to this state," Zaki says. He points out that the man was obese and had a history of hypertension and heart problems. Some 90% of the cases his team has reviewed have had some underlying medical condition.

Zaki says that they plan to publish some of their observations soon, and he has been sharing them with others at the CDC and with the public-health community at large. Although pathology can't predict what the virus will do in the future, it can help to identify those most at risk of severe disease. "We've really learned a lot with the lab pathology," says Anne Schuchat, director of the CDC's National Center for Immunization and Respiratory Diseases. "Both the prominence of the pneumonia in some infections and bacterial co-infection have important clinical implications," she says, explaining that pathology results have led the CDC to recommend pneumococcal vaccination for people in at-risk groups.

At the end of the sign-out meeting, Zaki walks back to his office through a quiet lab; the technicians have gone home for the day and the machines used to prepare and stain slides are silent. Six fresh case studies in purple folders sit in a neat row along one of the lab benches ready for processing and examination. They contain slides or tissue embedded in paraffin: one still has lumps of formalin-soaked flesh sitting in a plastic specimen jar.

As the flu season ramps up, Zaki says, he suspects the number of flu cases will increase dramatically. Still, his lab sees only a small slice of what's happening worldwide. "We're looking at the tip of the iceberg in terms of these cases," he says. It's a grim job, reading the tales of the dead, but he adds "that information is important for the living".

Brendan Maher

2. How does it spread?

In a cramped locker room high above the streets of upper Manhattan, laboratory personnel take a visiting journalist into the emerging pathogens facility, an enhanced biosafety level 3 (BSL-3) laboratory on the New York campus of Mount Sinai School of Medicine.

The suiting-up procedure is complicated. Rubber-soled booties must be tucked under a jumpsuit to ensure that spilled fluids don't drip into them. Purple latex gloves are layered underneath green ones; the different colours are used to ensure that rips in the outer layer are visible. Black N95 face masks pinch off the nostrils, forcing the wearer to breathe noisily through his or her mouth. The staff call them Darth Vader masks. They also wear papery mesh scrubs and white 'bunny suit' coveralls made from the material used to insulate houses. Biosafety officer Philip Hauck quotes Dante as he prepares to go in: "Abandon all hope ye who enter here."

In another preparatory room, they add heavy, belted, battery-powered air filters with a hose that hooks into the back of a white head-covering. Once it's adjusted, air begins rushing up over the face, puffing up the suit. The positive pressure in the suit, combined with the negative air pressure in the lab, ensures that the flow of air will carry any airborne pathogens away from the body.

This is the procedure that researchers at Mount Sinai go through every day to carry out their animal studies on deadly pathogens. Since May, pandemic H1N1 has been one of those pathogens. As the pandemic was emerging, John Steel and Anice Lowen secured strains of novel H1N1 from California and the Netherlands, and made plans to include them in their work modelling the transmission of influenza in guinea pigs. BSL-3 facilities are not required to work with H1N1, but Steel and Lowen's institutional review boards wanted the work to be carried out under the most stringent conditions on site.

Many labs use ferrets to model the transmission and pathology of human viruses, but the animals can be difficult to work with. Peter Palese, the head of microbiology at Mount Sinai, came up with the idea to work with guinea pigs a few years ago after reading an article published after the 1918 influenza pandemic, in which researchers in New Mexico noted that the infection had killed off a number of laboratory guinea pigs2. He convinced Lowen and Steel, assistant professors in his lab, to test whether the creatures would transmit human influenza. They did. In 2006, the group showed that the guinea pigs pass the virus between them with about the same efficiency as humans3, and the researchers still use them as a model of transmission even though their animals, purchased from a lab supplier, do not show symptoms or die from the disease.

The first thing the researchers did with the samples of pandemic H1N1 was to compare its transmissibility with that of seasonal flu. They squirted about 10,000 infectious H1N1 particles up the noses of four guinea pigs and, a day later, placed these animals in cages next to uninfected animals, separated by wire-mesh walls that allow respiratory droplets to pass through. Within five days all the exposed animals tested positive for the virus. The team's paper, published last month in the Journal of Virology, suggests that the H1N1 swine flu virus transmits just as efficiently as seasonal flu4. This is contrary to some work on transmission done at the start of the pandemic5 but mirrors real-world data showing that H1N1 spreads rapidly. "The pandemic sort of scooped us," says Lowen. Palese's group also found that previous exposure to the H1N1 and H3N2 subtypes of seasonal influenza limits the ability of exposed animals to become infected with the pandemic H1N1, which supports the idea that a seasonal flu infection or vaccine might offer some cross-protection against swine flu.

Inside the facility are the huge steel ferret cages that Steel and Lowen have adapted for their guinea-pig work so that two animals can fit inside each. They are now planning new experiments, hoping to find the sequences within the genome that enable the virus to transmit so well between humans compared with other swine-adapted influenza strains. They may create reassortments of the virus and then test how well they are transmitted by the guinea pigs. The results might aid in surveillance efforts aimed at identifying other strains from animals that could make the leap to humans.

Everything that goes into the BSL-3 lab must be decontaminated before coming out. This involves spraying down the bodysuit with ethanol, carefully peeling it off and then leaving the facility by way of a shower room. A pen and notepad won't survive the caustic chemical dunk by the exit, so the pages are scanned and put onto a CD that can be sprayed down.

Outside again on the Manhattan streets, H1N1 could be encountered in any cough or sneeze. Without all the protective gear, one feels rather vulnerable.

Brendan Maher

3. What could it turn into?

A deadly line-up of viruses is locked up in the computer-controlled safes at the Jean Mérieux/INSERM biosecurity level four (BSL-4) facility in Lyon, France, including Ebola, Nipah, Lassa, Hendra and Marburg. And in the next few weeks, scientists working there are planning to manufacture a new resident. They hope to test whether the highly transmissible pandemic H1N1 virus could reassort with its deadlier cousin, the H5N1 avian flu, to make a virus with the worst properties of both.

Classed as a national high-security facility, the laboratory is a three-storey shoebox made from armoured glass, perched above a biology research centre of INSERM, the national biomedical agency. The edifice is built to withstand earthquakes, bullets and explosives. It is also smack in the city centre, its entrance just metres from mothers pushing prams along the pavement on avenue Tony Garnier.

Suited up: extensive precautionary measures have to be followed in biosafety level-4 labs.Suited up: extensive precautionary measures have to be followed in biosafety level-4 labs.P. LATRON/INSERM

The lab itself is surrounded by empty corridors and a spartan decor of steel staircases, trusses, raised walkways and ventilation pipes. The air hums from the air-ultrafiltration and other support machinery that take up entire floors above and below. Under negative air pressure to stop viruses escaping in the event of a breach, the lab is split into three zones, with the airstream flowing towards the 'hottest' exposure risk zone, the animal house at the back.

When the current H1N1 pandemic began in April, priority lab time here was allocated to Bruno Lina, a virologist and flu researcher at the CNRS, France's basic-research agency, who works at the University of Claude Bernard Lyon-1. Pandemic H1N1 influenza is not itself a BSL-4 agent — a BSL-2 facility is adequate. But in France, the health ministry classes viral reassortment experiments of the sort Lina is performing as requiring BSL-4 precautions.

The ability to predict which reassortments might take place, and what type of flu viruses might result, could be key to predicting the behaviour of this and future pandemics. The eight genes in the influenza virus's segmented genome are easily swapped between strains. But to be viable, new gene combinations must also be able to work together to package themselves into a virus particle. Viruses within a subtype tend to reassort with one another more easily and generate more viable reassortants than do those from different subtypes.

Over the summer, Lina's team has been using the BSL-4 facility to investigate the likelihood that pandemic H1N1 will acquire resistance to the front-line antiviral drug oseltamivir (Tamiflu) through reassortment, and how easily these reassortants might spread. Resistance can emerge by spontaneous mutation, but given that seasonal H1N1 is already resistant to the drug and spreads easily, reassortment is perhaps the most likely way that pandemic H1N1 will acquire resistance — especially as seasonal H1NI and pandemic H1N1 are the same subtype. Since the start of the pandemic, Tamiflu-resistant strains have sporadically appeared in several countries but none has yet gained a foothold. That they haven't arisen more often or spread more easily may be because there is little seasonal H1N1 circulating, as pandemic H1N1 is outcompeting it — a large number of co-infections are needed for transmissible reassortants to arise.

In his work, Lina co-cultured the two H1N1 viruses in a cell line. He is now testing how pathogenic the reassortants are in mice, before using ferrets to test their capacity to spread. The biggest hazard that the scientists face in the lab is a bite or a scratch from an infected animal, so all manipulations are done on animals that have been anaesthetized remotely.

Lina is also preparing to submit a protocol to the facility's scientific board seeking the green light to try to reassort pandemic H1N1 and the H5N1 avian flu virus. "It's controversial research, but it is basic science that needs to be done," says Lina. H5N1 has killed more than half of the people it has infected since it resurged in 2003, but has rarely spread from one person to another. H1N1, on the other hand, seems to be as transmissible as seasonal flu, but mild in most people, if severe in some. The aim of Lina's proposal is to find out the probability of a reassortant arising that combines the lethality of H5N1 with the transmissibility of H1N1.

“It's controversial research, but it is basic science that needs to be done.” Bruno Lina

In particular, Lina is searching for putative molecular controls of the virus's segmented genome that may determine why some reassortants can package the virus and others can't. s"We don't know which regions in H5N1 are responsible for that control," says Lina. That could have benefits for disease surveillance, he says. If researchers know the key genetic regions that facilitate reassortment, surveillance efforts could watch out for H5N1 or H1N1 viruses with changes in those regions, ones that might be on the verge of dangerous reassortments.

Lina will use reverse genetics to generate a soup of reassortants, test whether any are viable, and if they are, assess their virulence and transmissibility. Because H1N1 and H5N1 are different subtypes, Lina does not expect them to swap genes easily. In 2005, he tried to reassort H5N1 with seasonal H1N1 and H3N2 viruses, without success. "After a year we only had three reassortants, and none was fit," recalls Lina, "they just don't reassort well."

The experiments that Lina's team is carrying out in the BSL-4 lab aren't technically novel or difficult in themselves. But the encumbrance of the safety procedures for getting in and out of the high-security lab make even the most straightforward procedures complicated, says Lina. Looking through the bulletproof window, one can see why. As the researchers move around the lab, they connect and disconnect their blindingly white spacesuits from some 60 yellow air hoses dangling from the ceiling. The hands of the researchers snipping away at tissue samples are wrapped in multiple layers of gloves to avoid accidental pricks. "It's like trying to do surgery wearing boxing gloves," says Hervé Raoul, director of the facility.

Before researchers can even begin to work in the lab, they must pass a three-week training course. It's only after a further 200 hours of practice that they are given any real autonomy in the lab, and they are never allowed inside alone. Users are limited to working a maximum of one four-hour shift a day, so that they are less likely to make mistakes. They are also encouraged to share any concerns about the behaviour of colleagues, or whether they themselves are going through a difficult patch, which might cause distraction and accidents.

Before Lina's experiments get approved, the facility's external scientific board will need to be convinced of the public-health justification, that the science is top-notch and that the experiments can be done safely, says Raoul. It will also need to be approved by government regulatory agencies. If all goes well, he could have his authorization in weeks, Lina says.

"Compared to the big guns in flu research, I'm a little guy," says Lina. "But having access on my doorstep to one of the rare BSL-4 facilities in the world with an animal house is a big advantage."

Declan Butler

  • References

    1. Childs, R. A. et al. Nature Biotechnol. 27, 797-799 (2009). | Article
    2. Lamb, F. H. & Brannin, E. B. J. Am. Med. Assoc. 72, 1056-1062 (1919).
    3. Lowen, A. C., Mubareka, S., Tumpey, T. M., García-Sastre, A. & Palese, P. Proc. Natl Acad. Sci. USA 103, 9988-9992 (2006). | Article | PubMed | ChemPort |
    4. Steel, J. et al. J. Virol. doi:10.1128/JVI.01732-09 (2009).
    5. Maines, T. R. et al. Science 325, 484-487 (2009). | PubMed | ChemPort |

Wednesday, November 11, 2009

Experts warn of possible A/H1N1 mutation

Video (in English) at the link.

2009-11-11 13:25 BJT

Medical experts are warning that the A/H1N1 flu has entered a period of high frequency and easy transmission. And with fresh cases of pigs infected by the virus in Hong Kong and Taiwan, experts say the possibility that the virus will mutate is growing.

Recent monitoring has found several cases of pigs, cats and dogs infected by the human A/H1N1 flu virus. Experts now fear that close contact between people and animals will increase the danger of mutation. China's Ministry of Health reported 30 fatal cases on the mainland as of Monday, out of nearly 60 thousand confirmed cases. It said the increase in infections will inevitably result in additional severe cases. Experts call for a timely response each time a case is confirmed, to prevent the illness from worsening.

Dr. Zhong Nanshan, head of Chinese Medical Association, said, "Because when the virus harms the lungs, there is a high possibility of breathing difficulty. It is different from the usual pneumonia. And there will be great difficulty treating such patients, even though they are young and healthy. The reason for this is unclear yet, but what we can do is get vaccinated, and go to the hospital as soon as possible when suffering from a continuous fever. "
hat-tip Tonka

H1N1 Cases: Healthy to Death's Door in One Week

In 1 Percent of Swine Flu Cases, Doctors Say Virus Attacks Lungs So Viciously That Other Organs Can Fail

Nov. 11, 2009

On one floor of the University Hospital Case Medical Center in Cleveland, the H1N1 virus is showing just how random, powerful and destructive it can be, even for healthy adults in the prime of their lives.

Robert Bradbury, 34, and Walter Savitts, 44, were airlifted from smaller hospitals to University Hospital Case Medical Center in Cleveland, where they arrived in critical condition, barely able to breathe, due to severe cases of the H1N1 virus.
(ABC News)

Walter Savitts, 44, depends on a machine for every breath. His wife, Margaret, is constantly at his side. Nearly three weeks ago, he came down with what seemed an ordinary case of the flu.

"I just figured you're going to get the 24 hour bug or something like that. I never thought that it would turn out to be something like this," Margaret said.

The truck driver had been in excellent health until that October morning.

"Just a fever, small cough. Not a big thing," Margaret told "Nightline." "By Monday, he started saying his chest was hurting so he went to the emergency room. ... They told him he had the flu and sent him home. ... By Thursday, he was in so much pain at 3 a.m. that he went back to the hospital and they said that he had full flown pneumonia ...and by 2 a.m. Monday morning he was in full respiratory failure."

Watch the full story on "Nightline" Wednesday at 11:35 p.m. ET

In the next hospital room, 34-year-old Robert Bradbury floated in and out of consciousness. Except for an asthma attack six years ago, he, too, had been healthy and strong before the virus took hold.

"We are young people, young healthy people, athletic," said Robert's wife, Candice Murton-Bradbury. "He plays volleyball. We are out a lot, we walk, and he's a nonsmoker, you know, all the things that they tell you to take care of yourself."

Slightly more than three weeks ago, after a night of celebrating with his wife and colleagues, the Ohio restaurant manager fell asleep at work.

"I guess he lay down at work and never got up again," Murton-Bradbury said. "And was just very incoherent and not with it."

Co-workers took Bradbury to an emergency room the morning of Tuesday, Oct. 20. Due to the severity of his illness, doctors decided to send him to Case Medical Center for more advanced treatment.

Doctor: 'He Was Pretty Much Dead When He Came In'

Bradbury and Savitts were airlifted from smaller hospitals to Case Medical Center, where they arrived in critical condition, barely able to breathe.

Dr. Arie Blitz, a surgeon and medical professor, treated both men. He said when Bradbury arrived, his vital organs were failing.

"He was pretty much dead when he came in," Blitz said. "He developed something that I have never seen before in medicine ... four things at once. ... He had H1N1 flu. He developed a big pulmonary embolism, which is a clot that was sent off to the lung. He had a heart attack, and he had a stroke all at the same time."

Blitz told Bradbury's wife that her husband had a 1 percent chance of survival. "They pretty much informed all of us that he wasn't going to survive," Murton-Bradbury said. "One of the vascular surgeons came out and gave me his wedding ring, which was terrible, to say the least."

Savitts wasn't doing much better. His lungs were so badly damaged, according to Blitz, that it was as if they'd been torn to pieces. Both men were beyond the help of ventilators, so doctors performed emergency surgery, called extracorporeal membrane oxygenation, or ECMO.

"The goal of ECMO is to do two things. One is to rest the lungs so we can let it repair itself and two, provide the oxygen needs of the body and get rid of the carbon dioxide waste product of the body," Blitz said.

ECMO has become a vital tool in the battle to save critically-ill flu patients when ventilators alone can't help. Blitz has used it on only his most dire cases.

"They were dying, they were all on death's doorstep, would not have survived no matter what," he said. "Some of these patients would not be around today without that technology."

In some cases, ventilators alone can't help patients breathe. Doctors say that ECMO is needed in about a third of the most serious H1N1 cases. At first, the patients must be induced into a coma to let the body rest and the lungs recover.

Strain on Hospital Staff

Patients like Savitts require round the clock nursing care. In his case, the nurse is ex-Marine Madison Edge, who Savitt's wife Margaret calls her "partner in crime."

"I've been doing this nine years, and I've never seen an influx like this year," Edge said. "I've never seen a flu season like this one here."

The flu is straining the hospital staff, with as much as 20 percent of the nurses out sick here. Pregnant doctors and nurses, those most vulnerable to the virus, have been reassigned. To protect themselves and the patients, the staff must constantly don sterile masks and gowns.

Registered nurse Molly Zerbini takes care of infected children in the pediatric intensive care unit.

"These masks are not the most comfortable thing ever. They're very hot, they're very sweaty, but to protect ourselves and [avoid] transmittal to, particularly, other kids, is priority, so we're dealing with the discomfort of them," Zerbini said.

Influx in Adult Cases of H1N1

At first, in mid-October, the emergency room at Case Medical Center, like others across the country, was flooded with infected children. But now, those pediatric cases have tapered off and the hospital is seeing an increase in the number of adults who have the virus.

"H1N1 for most patients is a relatively benign disease and doesn't progress. But a small percentage of patients can have very, very severe disease and can die from this," Blitz said. "The unfortunate thing about it is that it's not in patients that we can predict with any reliability who gets really sick from it. The ones that we've been seeing here are quite young, in their 30s and 40s, and otherwise very healthy and previously healthy, who come down with H1N1, and within a week's time are on death's door."

Most recover quickly, but experts estimate that in 1 percent of H1N1 cases, the virus attacks the lungs so viciously that vital organs are robbed of oxygen.

"Almost every patient that we have put on artificial support has had not only failed lungs but also failed livers, failed kidneys and even strokes and heart attacks," Blitz said.

Next Step: Recovery, Prayer

Walter Savitts is fortunate that only his lungs were damaged. But nine days after his emergency surgery, he remains in a coma, unable to breathe on his own.

"It gets hard. Some days you just want to cry and cry, but I've got to keep telling myself that he's doing well and it could have turned out a lot worse," Margaret Savitts said.

Blitz said that Savitts' prognosis is good. He estimated a 75 percent chance of survival.

"I think when he came in, without having ECMO, he would have died within 24 hours," Blitz said.

Next door, Bradbury emerged from a deep, induced slumber two weeks after doctors told his wife that he had only a one in a hundred chance to make it.

"He looked at me and made real eye contact, and then the look on his face was, first, awe and then it was relief and he slid over in the bed and put his head against my head," she told "Nightline." "That was the day that I knew that he was going to be OK."

Not entirely. A kidney failure has left her husband on dialysis, but he is grateful to be alive.

"I can guarantee they saved my life here. If it wasn't for them, I wouldn't be here right now. That's for sure," Bradbury said.

To the Savitts family in the room next door, Bradbury's case is an inspiration.

"I had a pretty slim chance at survival there," Bradbury said. "I wasn't really supposed to make it. But I guess ... you believe in God now."

On Monday night, Bradbury, his wife and mother prepared for his move out of surgical intensive care to another ward of the hospital. That same night, Savitts suffered a setback: attempts to wean him off mechanical breathing faltered.

In one room, a man fighting for his survival. In the next, another man on the path to recovery. Both struck down, in their prime years, by a fast and furious virus that works in ways so random that no one fully understands it.

Reuters: New U.S. swine flu death estimates will be guess

Wed Nov 11, 2009 6:57pm EST
By Maggie Fox, Health and Science Editor - Analysis

WASHINGTON (Reuters) - U.S. health officials are due to release new estimates of deaths from swine flu on Thursday, but the numbers will be just that -- a rough estimate.

The U.S. Centers for Disease Control and Prevention and the World Health Organization stopped trying to count actual cases months ago, once it became clear that H1N1 was a pandemic that would infect millions.

There are nowhere near enough diagnostic tests to give to everyone with flu-like symptoms to see if they really have swine flu, and autopsies have shown that some people who have died had H1N1 and no one even knew it.

So the death figures will be based on models, calculated by looking intensively at small groups of people, gathering data on overall reports of sickness and death, and reconciling the two.

This is also what happens every year with seasonal influenza, which WHO says kills 250,000 to 500,000 people a year globally and which CDC says kills 36,000 Americans in an average year.

Will this pandemic kill even more?

Not necessarily. Seasonal flu attacks about 20 percent of the population in an average year but it is the elderly who are the most likely to die. These patients often have other conditions and a flu infection can be the last straw that kills them.

H1N1 is hitting a younger population -- adults in their 20s and 30s and children. The latest counts from CDC showed that 1,000 have died so far, including 129 children.

The global count is more than 6,000, according to WHO.

It is possible that these younger patients may be more likely to survive their bout of flu, even if they have chronic conditions.

Doctors are comparing information about who is the most likely to die.


A study in The Lancet medical journal released late on Wednesday shows that in Mexico, where the new flu appears to have spread first last March, young people were the most likely to be infected but elderly were most likely to die.

This study matches one published last week in the Journal of the American Medical Association that showed 11 percent of Californians hospitalized for H1N1 died, but among people 50 and older, 18 to 20 percent who went to a hospital died.

A CDC estimate released last month suggested that up to 20,000 people were hospitalized with H1N1 through July and that 6 percent of hospitalized patients died, or about 1,300 people.

Seasonal flu has a death rate of less than 0.1 percent. The worst pandemic, such as the influenza pandemic of 1918, had a mortality rate of 2 percent or more.

The Mexican study also found that infants and people aged 39 years and under were the most likely to get infected, but that far fewer than 1 percent of these patients died.

Ten percent of patients over 70 who were treated in clinics died, they found.

They found that 4.5 percent of patients aged 50 to 59 died, but just 2.7 percent of those in their 40s and 2 percent of patients in their 30s.

These were all people who attended clinics that were part of the Mexican Institute for Social Security network, the Institute's Victor Borja-Aburto and colleagues reported, so milder cases for which patients did not seek treatment were not included in the analysis.

Mexicans who had been vaccinated for seasonal influenza had a 35 percent lower risk of getting H1N1, even though the seasonal flu vaccine offers no protection against the new virus.

Every day of delay in hospital admission after the fourth day of illness raised the risk of death by almost 20 percent, Borja-Aburto's team found.

The study shows hard it is to get a grip on flu deaths, as doctors cannot assess or count people who do not show up for treatment.

And numbers take months to collect. The latest Mexican data includes cases from April to July.

(Editing by Philip Barbara)

AP: CDC now says 4,000 swine flu deaths in US

ATLANTA — Federal health officials now say that 4,000 or more Americans likely have died from swine flu — about four times the estimate they've been using.

The new, higher figure was first reported by The New York Times. It includes deaths caused by complications related to swine flu, including pneumonia and bacterial infections. Until now, the Centers for Disease Control and Prevention had conservatively put the U.S. swine flu death count at more than 1,000. Officials said this week they're working on an even more accurate calculation.

The CDC says "many millions" of Americans have caught the pandemic flu virus since it first appeared in April.

New England Journal of Medicine: Emergence of Oseltamivir-Resistant Pandemic H1N1 Virus during Prophylaxis

Published at November 11, 2009 (10.1056/NEJMc0910060)

To the Editor:
Neuraminidase inhibitors (oseltamivir and zanamivir) are recommended for treatment of severe illness caused by the 2009 pandemic influenza A (H1N1) virus, and their use has also been advocated for postexposure prophylaxis in high-risk persons.1 We report the emergence of an oseltamivir-resistant virus in a familial cluster of infections with the 2009 H1N1 virus.

In a 13-year-old boy with asthma, infection with the 2009 H1N1 virus developed and was confirmed by reverse-transcriptase polymerase-chain-reaction (RT-PCR) testing of a nasopharyngeal aspirate. Administration of oseltamivir (60 mg twice a day for 5 days for this boy who weighed 32 kg) was begun, and the patient was discharged home the same day. Simultaneous with treatment of the index patient, postexposure prophylaxis with oseltamivir (75 mg once a day for 10 days) was prescribed to all household contacts (the boy's 59-year-old father, who had chronic obstructive pulmonary disease and was taking prednisone at a dose of 5 mg daily; 50-year-old mother; and 15-year-old and 18-year-old sisters). Approximately 24 hours after oseltamivir prophylaxis was begun, influenza-like symptoms developed in the father (Figure 1). On day 8 of oseltamivir prophylaxis, the father consulted his general practitioner because of persistent cough. A nasopharyngeal aspirate collected at that time was positive for the 2009 H1N1 virus, according to RT-PCR testing and culture. The father had an uneventful clinical course, and a nasopharyngeal aspirate sampled at the end of his illness was negative for the 2009 H1N1 virus. Influenza-like symptoms did not develop in any other household contacts.

Figure 1
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Figure 1. Symptoms, Antiviral Therapy, and Virologic Results in the Index Patient and His Father.

Timelines are shown for the index patient (the son), who was infected with a wild-type strain of 2009 H1N1 virus, and his father, who was infected with a H275Y mutant strain of 2009 H1N1 virus. NA denotes not applicable, ND not done, R resistant, RT-PCR reverse-transcriptase polymerase chain reaction, S susceptible, + positive, and – negative.

The 2009 H1N1 viral isolate collected from the index patient before oseltamivir therapy was susceptible to oseltamivir (50% inhibitory concentration, 0.27 nM) and zanamivir (50% inhibitory concentration, 0.18 nM), whereas the father's 2009 H1N1 viral isolate was resistant to oseltamivir (50% inhibitory concentration, >400 nM) but susceptible to zanamivir (50% inhibitory concentration, 0.12 nM). Complete 2009 H1N1 virus genomes of the father's virus (GenBank accession number, FN434454 [GenBank] ) differed from the index patient's virus (GenBank accession number, FN434445 [GenBank] ) by only one substitution (H275Y) in the neuraminidase protein. The role of the H275Y substitution was assessed by generating recombinant neuraminidase proteins.2 The mutant neuraminidase protein was more resistant to oseltamivir than was the wild-type protein by a factor of more than 400, confirming the phenotypic results.

Our results indicate that the same neuraminidase mutation (H275Y) is associated with oseltamivir resistance not only in seasonal H1N13 and avian H5N14 viruses but now also in 2009 pandemic H1N1 strains. We hypothesize that the presence of subtherapeutic levels of oseltamivir at a time when viral replication had already begun was an important factor that led to the emergence of the resistant virus in the father of our index patient. Other oseltamivir-resistant strains of 2009 H1N1 virus detected during postexposure prophylaxis have been reported to the World Health Organization.5

These observations support the need for limiting the indications for postexposure prophylaxis. It also seems reasonable to rapidly convert prophylactic (once daily) regimens to therapeutic (twice daily) regimens as soon as influenza-like symptoms develop in a patient receiving prophylactic treatment. Monitoring for the H275Y mutation during outbreaks of 2009 H1N1 virus is important in order to rapidly identify transmission events that could lead to large-scale dissemination of an oseltamivir-resistant 2009 H1N1 virus, similar to what occurred with recent H1N1 virus seasonal strains.3

Mariana Baz, M.Sc.
Yacine Abed, Ph.D.
Jesse Papenburg, M.D.
Xavier Bouhy, B.Sc.
Marie-Ève Hamelin, Ph.D.
Guy Boivin, M.D.
Centre Hospitalier Universitaire de Québec
Quebec, QC, Canada

Financial and other disclosures provided by the authors are available with the full text of this letter at

This letter (10.1056/NEJMc0910060) was published on November 11, 2009, at


  1. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season. Atlanta: Centers for Disease Control and Prevention. (Accessed November 9, 2009, at
  2. Abed Y, Goyette N, Boivin G. A reverse genetics study of resistance to neuraminidase inhibitors in an influenza A/H1N1 virus. Antivir Ther 2004;9:577-581. [Web of Science][Medline]
  3. Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 2009;301:1034-1041. [Free Full Text]
  4. de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005;353:2667-2672. [Free Full Text]
  5. Antiviral use and the risk of drug resistance: pandemic (H1N1) 2009 briefing note 12. Geneva: World Health Organization, September 25, 2009. (Accessed November 9, 2009, at

Recalculating the Tally in Swine Flu Deaths

Published: November 10, 2009
About 4,000 Americans — rather than about 1,200 — have died of swine flu since the disease emerged in April, according to new figures being calculated by epidemiologists for the Centers for Disease Control and Prevention.

The larger number of deaths does not mean the virus is more dangerous. Rather, it is a new estimate made by combining deaths from laboratory-confirmed cases of the flu and deaths that appear to be brought on by flu, even though the patient may have ultimately died of bacterial pneumonia, other infections or organ failure.

The new estimate of deaths — actually a range both larger and smaller than 4,000 — will not be released until sometime next week because the centers’ consultants are still looking over the figures, said Glen Nowak, a C.D.C. spokesman.

The new estimate will be a more accurate comparison to the 36,000 deaths from seasonal flu each year, he said. That estimate is also based on confirmed cases as well as hospital reports of people who appear to have died after a bout of flu. Over 90 percent of seasonal flu victims are over 65, and many are bedridden or in nursing homes or have serious medical problems like cancer or heart disease that the flu worsens.

The new estimate “does sound much more reasonable,” said Ira M. Longini Jr., a flu epidemiologist at the University of Washington. “It doesn’t surprise me that it’s higher.”

Michael T. Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, said the new estimate was more accurate “but doesn’t change the decisions you’d make from a public health perspective.”

“If it was 40,000 deaths rather than 4,000, that would be different,” Dr. Osterholm said.

A much higher death rate would mean more drastic measures to keep people apart and could mean, for example, adding immune-boosting adjuvants to the vaccine so more people could get it.

Both Dr. Osterholm and Dr. Longini said the new figure does not suggest that the epidemic will eventually kill as many as 90,000 Americans, as was envisioned in one forecast widely publicized in August in a report issued by the President’s Council of Advisers on Science and Technology. That report posited a range of 30,000 to 90,000 deaths.

Dr. Longini said he thought deaths were likely to be in the 30,000-to-40,000 range, and Dr. Osterholm said they would “have a long way to go to even get there.”

The vaccine, Dr. Longini said, should also cut the death rate. About 10 million new doses are shipped each week.

Swine Flu Deaths in Europe Doubling Weekly, Health Agency Says

By Andrea Gerlin

Nov. 11 (Bloomberg) -- Swine flu deaths in Europe doubled in three of the last four weeks, the European Centre for Disease Prevention and Control said.

Eighty-four people in 31 European Union and European Free Trade Association countries died from swine flu last week, compared with 43 the week before, Stockholm-based ECDC said in a bulletin on its Web site. Two weeks ago, 49 people died, up from 24 and 12 the previous weeks, the agency said.

We are globally entering the acceleration phase” of the pandemic, Denis Coulombier, head of the ECDC’s unit of preparedness and response, said in a telephone interview late yesterday. “We are heading toward the peak for sure.”

The region’s swine flu outbreak has been most severe in northern countries such as Ireland, Iceland and the Ural region of Russia, according to the World Health Organization’s regional office in Copenhagen. Norway, Sweden and the Netherlands are also experiencing significant levels of the illness, the WHO said in its Nov. 6 weekly report.

A total of 414 people in Europe have died from swine flu since the outbreak began in Mexico and the U.S. in April, ECDC said. The figure includes 155 deaths in the U.K., 73 in Spain, 31 in Italy and 30 in France since the beginning of the pandemic.

Almost 80 percent of all swine flu cases in Europe have occurred in people under 30 years of age, according to a risk assessment published by ECDC on Nov. 6.

Young People

“In the acceleration phase, it’s not a surprise that the younger ones are the ones who are most contributing to the spread,” Coulombier said. “It doesn’t mean at the end of the wave you will have the same pattern.”

ECDC was established five years ago by the European Union to assist its member states in responding to communicable diseases. Its statistics are probably “gross underestimates” because health-care systems, laboratory testing, surveillance and definitions used to identify cases vary across Europe and affect reporting, the agency said.

The Geneva-based WHO estimated on Nov. 6 that 482,300 people worldwide have been sickened by the H1N1 virus that causes swine flu and 6,000 have died.

Russia has confirmed 4,560 cases of the disease, almost 4,000 of them since Oct. 6, the state public health service Rospotrebnadzor said on Nov. 6. Nineteen people aged 20 years to 53 years had died as of Nov. 2, the majority of them from pneumonia after failing to seek medical attention, the agency said.

Cold Weather

Cold weather and humidity have spurred Russia’s swine flu outbreak, said Oleg Kiselev, head of the Russian Academy of Sciences’ Influenza Institute in St. Petersburg. The pandemic is expected to peak in the country in December, Kiselev said.

“We are planning to vaccinate as many as 20 percent of the population, which will cut the number of swine flu cases by half and significantly reduce the death toll,” Kiselev said in a telephone interview on Nov. 10.

Swine flu immunization programs are under way in most European countries. Risk groups such as pregnant women and people with existing medical conditions are among the first people getting the shots.

An estimated 620,000 people in England, about 1 in 82, had contracted swine flu through last week. About one-fifth of those hospitalized for the illness last week were in intensive care, the highest level since the pandemic began, Chief Medical Officer Liam Donaldson said.

Projected Peak

The pandemic is projected to peak in the U.K. this month, Neil Ferguson, a professor of mathematical biology at Imperial College in London, said through his spokeswoman Emily Lyons on Oct. 29.

Admissions to Dutch hospitals for swine flu doubled over the previous week for the second week in a row, according to the National Institute for Public Health and the Environment. Seven people died from the illness last week, bringing the total number to 17.

Norway had 6,300 confirmed cases of swine flu as of Nov. 4, according to the Norwegian Institute of Public Health. Sixteen people had died from the illness as of Nov. 9 and all but two of them had risk factors, the institute said.

The Norwegian government temporarily removed the requirement for a prescription for Roche Holding AG’s Tamiflu and GlaxoSmithKline Plc’s Relenza last week, enabling pharmacies to directly dispense the antiviral drugs. It also started an intensive-care registry to track severely ill swine flu patients last month.

Sweden had 647 laboratory-confirmed cases of swine flu in the week ended Nov. 1, compared to 350 cases in the week ended Oct. 25 and 197 cases in the week ended Oct. 18, according to the Swedish Institute for Infectious Disease Control. A total of 2,771 cases have been recorded since May, and three people have died, all of them middle-aged and suffering from underlying medical conditions.

The pandemic is at the beginning of its cycle in Sweden, the institute has said.

To contact the reporter responsible for this story: Andrea Gerlin in London at

Last Updated: November 11, 2009 00:50 EST