Results tagged “influenza” from Pathophilia

The 2009 H1N1 (or swine flu) vaccination campaign began in earnest in mid-October of last year, and approximately 100 million vaccinations were administered in the United States. Consequently the rate of GBS associated with vaccination was 3.5 per 10 million. All but 1 case occurred within 6 months of vaccination; 23 cases occurred within 2 weeks of inoculation. The annual background rate of GBS is about 1-4 cases per 100,000. (The 2009 H1N1 vaccine protects against GBS, anyone?)

Original worries about a vaccine-associated increase in GBS stemmed from the observed rise in the condition during the 1976 swine-flu vaccination program.

VAERS = Vaccine Adverse Event Reporting System.

Cases: 57 million; range, 41-84 million. Most cases were among 18-64-year-olds (58%) and children (33%).

Hospitalizations: 257,000; range, 183,000-378,000 (calculated mid-level hospitalization rate, 0.45%). Most hospitalizations were for 18-64-year-olds (58%) and children (32%).

Deaths: 11,690; range, 8330-17,160 (calculated mid-level death rate, 0.02%). Most deaths affected 18-64-year-olds (77%).

Although H1N1 activity has been relatively low during the last 5 weeks of assessment (from mid-December to mid-January), the CDC isn't ready to call the pandemic over.

[T]here are still uncertainties surrounding the rest of this flu season, including the possibility of increases in circulation of seasonal influenza viruses and increases in circulation of 2009 H1N1 viruses. In past pandemics, flu activity has occurred in waves and it’s possible that the United States could experience another wave of flu activity.

The CDC continues to urge vaccination against pandemic influenza and reports that supplies are abundant for all eligible comers—including the elderly. A recent interim report of vaccination coverage indicates that nearly 90% of nonelderly adults with medical conditions (an original at-risk target group) remain unvaccinated.

Depiction of H1N1 virus from Wikipedia.

Investigators from the California Pandemic (H1N1) Working Group collected data from 239 pregnant, postpartum, or nonpregnant women of reproductive age who were hospitalized with or died of probable or confirmed* pandemic flu between April 23 and August 11, 2009. Most (~78%) acquired infection in June or July.

Underlying chronic conditions, specifically asthma, were observed in substantial percentages of all women and particularly nonpregnant women—confirming that pregnancy itself is a risk factor for severe infection with the 2009 H1N1 virus.

a. Percentages based on pregnant women for whom data were available.
b. Pregnant women vs nonpregnant women.
c. Related to cancer or transplantation.

Notable among pregnant women was a rapid clinical deterioration that looked qualitatively different from typical seasonal influenza. About 25% of pregnant women who required mechanical ventilation were intubated at the time of hospitalization, and several deliveries were made in intensive care units. ICU admission and death were about 4 times more likely in pregnant women who received antiviral treatment after 48 hours of symptom onset. Delay of antiviral treatment appeared to be associated with false-negative rapid-antigen test results.

During the 4-month period, the mortality ratio for pandemic flu in pregnant women was estimated at 4.3. Previous mortality ratios for all-cause death among pregnant women in California (2005) and in the United States (2006) were 19.3 and 13.3, respectively.

The authors urge pregnant women to be vaccinated against pandemic flu on the basis of their findings and preliminary vaccine-trial results.

RT-PCT = reverse-transcriptase polymerase chain reaction.

* Probable disease was defined as a positive result by real-time RT-PCR for influenza A that could not be subtyped H1 or H3. Confirmed disease was defined as a positive result by real-time RT-PCR that was specific of 2009 H1N1 influenza.

Depiction of H1N1 virus from Wikipedia.

No. 1: Pandemic H1N1

You were expecting something else?

Coming out of left field (ie, Mexico)* in April, the novel 2009 H1N1 ("swine flu") virus caused an official global pandemic in June, according to the World Health Organization. Cases mounted rapidly, but fear of disease was mitigated by its relatively low mortality rate.** Drawing on their experience from the swine-flu epidemic of 1976, leading US neurologists first believed that a government-led vaccination campaign would be unlikely because of 1) low mortality and 2) the possibility of vaccine-associated Guillain-Barre syndrome (GBS). Boy, were they wrong.

In August, the CDC released its recommendations for the administration of developing H1N1 vaccines to 5 groups. The surprise: Instead of the historically targeted elderly, the CDC prioritized vaccination for children, young adults, and pregnant women because of their emerging risks of disease-related complications and death. Consequently vaccination was recommended for an estimated 159 million Americans as soon as vaccines became available, sometime in mid-October.

In May, the DHHS had contracted with 5 companies—CSL Biotherapies, GSK, MedImmune, Novartis, and sanofi-pasteur—to produce either injectable or nasally administered vaccines for pandemic H1N1 to the tune of $932 million. Government orders for another $883,977,920 and $438,143,025 were placed in July and September, respectively. The total amounted to about 9 bucks per vaccine, which was being produced by the traditional method of viral incubation in fertilized chicken eggs.

This tried-and-true method ultimately led to a delay in vaccine production for 2 primary reasons: the fastidious nature of the 2009 H1N1 virus (when compared with seasonal influenza viruses) and limited chicken eggs. Turns out the pandemic virus required 2 eggs to create a single vaccine dose, instead of the usual one. By October, the federally contracted companies had only cranked out about 10% of the promised 120 million vaccine doses for US residents. Time was a-wastin'.

In October, the CDC investigators estimated that about 3 million citizens had already experienced symptomatic pandemic flu between April and July, on the basis of a probabilistic model. Confirming previous assessments, the incidence of disease and disease-related hospitalizations were considerably higher in children and young adults. Pandemic flu, overall, had necessitated about 14,000 hospitalizations and had caused about 800 deaths in the United States.

The following month, the CDC estimated that up to 34 million Americans had been infected between April and mid-October. Respective hospitalizations and deaths now ranged from 63,000 to 153,000 and from 2500 to 6000. Another age breakdown revealed that disproportionate numbers of younger adults (and to a lesser extent, children) remained susceptible to pandemic flu generally and severe disease specifically. About 45% of Americans who had died from pandemic flu had been healthy.

And then disease began to wane. Earlier this month, only 25 states reported widespread activity. At the same time, data showed that the pandemic flu vaccines (the supplies of which were up) remained effective and were comparably safe. Specifically the risk of GBS appeared no higher than the typical background rate.

The latest recommendations: More than 30 "major health care provider organizations," including the American Medical Association, the American Academy of Pediatrics, and the American Red Cross, are encouraging all US residents to receive a pandemic flu vaccine in anticipation of another wave of infection. An "open letter" to the American people states,

The H1N1 flu vaccine is safe, effective, and the best way to protect yourself and your family from the H1N1 flu. Over 110 million doses...are now available, with more coming every day. Now is the time to protect yourself and those around you by getting vaccinated against the H1N1 flu.

Links to selected Pathophilia posts on pandemic flu (and a few on seasonal flu) are provided here in chronological order.

• WHO: Not-So-Deadly Swine Flu Now Pandemic
• Caution for Today: GBS Risk With Old Swine-Flu Vaccine
• Rapid H1N1 Test Relatively Insensitive
• CDC Recommends Novel H1N1 Vaccine for Certain Groups
• Novel H1N1 Mortality Rate: Pitfalls in Calculation
• Novel H1N1 Infection in Chicago: Children Preferentially Vulnerable
• Novel H1N1 Vaccine Approval for 4 of 5 Companies
• Harvard Expert Estimates Very Low Mortality Rate for 2009 H1N1 Pandemic
• Vaccinations for Seasonal and Pandemic Flu
• Strep Pneumoniae Most Likely Bacterial Pathogen in Fatal H1N1
• H1N1 Vaccine Table
• ...And Furthermore, Bill Maher Needs a Haircut
• H1N1 Vaccine Shortage: Blame Chickens
• The Solace of Illusion
• Influenza: Moms' Reasons for Not Vaccinating
• Millions of Americans Infected With Pandemic Flu
• Reanalysis Negates Recommendation for N95 Respirators
• Seasonal Flu Vaccine: High Demand Leads to Short Supply
• After Delay, FDA Approves GSK's Pandemic Flu Vaccine
• Seasonal Flu Vaccine and Protection Against Pandemic Flu
• CDC: Up to 34 Million Americans With Pandemic Flu
• CDC: Modest Decline in H1N1 Activity
• Norwegian H1N1 Mutation Not New
• Pandemic H1N1: Activity Down; Vaccine Supplies Up
• Pandemic Flu Vaccines Comparably Safe
• Overall H1N1 Mortality in England Comparable to US Estimates

* Instead of the historically expected East Asia.

** Estimated in the United States at 0.007%-0.032%.

Depiction of H1N1 virus from Wikipedia.

Approximately 540,000 people (range, 240,000-1,100,000) have sustained symptomatic infection with pandemic influenza in England between June 1 and November 8 of this year, with 138 deaths meeting the described H1N1 case definition. Death rates appear to be highest for individuals aged 65 years or older and lowest for school-aged children and young adults. (By using midlevel estimates from the CDC, the case fatality rate for US individuals aged 65 years or older is substantially lower, at 32 per 100,000.)

As in the United States, there was no or only mild preexisting illness in about one third of England's fatal cases of pandemic flu. Most (78%) of these patients were prescribed antiviral drugs, but three quarters did not receive them within 48 hours of illness onset.

Despite England's relatively low mortality rate, the authors conclude that it "is not a justification for public health inaction." On the contrary, they argue, their data support expansion of the vaccination program to lower-risk groups [blogger's note: which evidently should include England's elderly] and the timely use of antiviral treatment.

* Deaths per 100,000 cases of pandemic influenza.

Depiction of H1N1 virus from Wikipedia.

What do we want? Raw data! When do we want it? Now!

In the midst of the 2009 pandemic influenza epidemic, BMJ editor Fiona Godlee takes Roche to task for not supplying the necessary data to confirm or refute the benefits of oseltamivir (Tamiflu) in otherwise healthy people with influenza. In one of 2 BMJ editorials, Godlee chides Roche for not supplying unconditional access to raw data from a pooled analysis of 10 company-sponsored trials (Kaiser et al; PubMed link here) to Cochrane reviewers Jefferson et al. Consequently the reviewers were "obliged to disregard" the bulk of these data (8 of the 10 trials) and were unable to verify that oseltamivir prevents lower-respiratory-tract complications (eg, pneumonia) due to influenza.

In their previous 2006 Cochrane review, Jefferson et al had concluded that oseltamivir 150 mg daily prevents such complications on the basis of the Kaiser article. However, the authors were criticized through a public feedback mechanism for using the 10-trial analysis without having access to the raw data. Prompted by this criticism, Jefferson et al then conducted another review, published this week in the BMJ, in which they affirmed their critic's perspective:

Data on the effectiveness of oseltamivir against complications of influenza principally came from one study...This was a meta-analysis of 10 trials containing a mixture of published and unpublished data, two of which are reported in this update and the remainder inaccessible to proper scrutiny, so that we are now obliged to disregard them. The remaining data showed no benefit for oseltamivir against complications.

In her editorial, Godlee asks, "Where does this leave oseltamivir, on which governments around the world have spent billions of pounds?" She, moreover, emphasizes that the Cochrane review data apply only to healthy adults with influenza, but they "say nothing about [oseltamivir's] use in patients judged to be at high risk of complications—pregnant women, children under 5, and those with underlying medical conditions." Even the drug's ability to reduce influenza-related symptoms (which Jefferson et al reconfirmed) are doubted, because there are no head-to-head studies with oseltamivir and NSAIDs, for instance.

In another BMJ editorial (with Cochrane director Mike Clarke), Godlee concludes that the latest Cochrane review and a "linked investigation undertaken jointly by the BMJ and Channel 4 News cast doubt not only on the effectiveness and safety of oseltamivir (Tamiflu) but on the system by which drugs are evaluated, regulated, and promoted." In their investigation, Cochrane reviewers became concerned about the actual involvement of listed authors on the Kaiser analysis, the possibility of ghostwriting, the high rates of influenza in the trials, and the low rates of serious adverse events.

Initial responses from Roche employees, who first declined to provide the data and then offered selected files, were less than satisfactory to the reviewers. The latest response from the company: it is "committed to making the 'full study reports' available on a password protected site soon."

On the basis of this experience, Godlee and Clarke conclude that the current system for reporting drug research "isn't working" and offer a number of potential remedies—including government-mandated access to raw data that are used to license and market a drug (eg, something in the spirit of the FDA Amendments Act of 2007).

News sources are all over this story (eg, Bloomberg), and the BMJ offers full-text access to the following relevant articles, including a response from a Roche employee—who chastises Jefferson et al for enlisting the investigative help of a TV news station.**

• Godlee F. We want raw data, now.
• Godlee F, Clarke M. Why don't we have all the evidence on oseltamivir?
• Smith J, on behalf of Roche. Roche replies to the authors of the Cochrane Review on oseltamivir.
• Cohen D. Complications: tracking down the data on oseltamivir.
• Doshi P. Neuraminidase inhibitors--the story behind the Cochrane review.
• Freemantle N, Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?
• Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.
• Web extra (including the criticism that got the ball rolling).

* And I mean that in the nicest possible way.

** Roche's Smith writes, "It is unclear to us why Dr Jefferson would adopt this approach, particularly given that he was a paid ad hoc consultant to Roche working on flu and oseltamivir between 1997 and 1999. During that period he worked closely with Roche experts, many of whom are still in the company, and he would therefore not have had difficulty in contacting them directly to discuss his requirements."

Photo from Vermin Inc at Flickr.

Data from VAERS*—which includes publicly volunteered information—reveal overall adverse-event (AE) rates of 82 per 1 million doses of pandemic flu vaccine (0.0082%) and 47 per 1 million doses of seasonal flu vaccine (0.0047%). Respective rates of serious AEs (eg, death, life-threatening illness, hospitalization, prolonged hospitalization, persistent or significant disability, congenital anomaly) are 4.4 and 2.9 per 1 million vaccine doses each. However, the percentage of serious AEs among all reports is slightly higher with seasonal flu vaccines (6.1% vs 5.4%). No substantial differences are noted between pandemic and seasonal flu vaccines in the types of serious AEs reported, and no AE differences between injectable and intranasal vaccines are apparent.

Among the 13 reported deaths of those who received the pandemic flu vaccine, 9 were associated with a "significant" underlying illness; 1 was the result of a motor vehicle accident; and 3 cases are under review by the CDC. There are 12 reports of Guillain-Barre syndrome (GBS), 4 of which currently meet diagnostic criteria, and 19 reports of possible anaphylaxis. (The background incidence of GBS is 1-2 per 100,000.)

In the VSD**—which includes data from more than 400,000 vaccinated individuals among 8 managed-care organizations—there are no reports of GBS and only 1 case of anaphylaxis. Increased rates of other neurologic or allergic conditions have not been detected.

Historically higher rates of GBS associated with the swine-flu vaccination in the mid-1970s may be related to contemporary methods of vaccine production, the CDC speculates. The Center reports that it continues to monitor vaccine-associated AE data and advises that the number of vaccines administered in the VSD population, in particular, may be too small as yet to detect an increased risk of vaccine-associated GBS.

As of December 3rd, more than 72 million doses of pandemic flu vaccine have been allocated in the United States.

N.B. The CDC states that it used a number of methods (eg, advertising in medical journals) to enhance the reporting of vaccine-associated AEs to VAERS this season.

* As of November 24, 2009.

** From October 1 to November 21, 2009.

Only 25 US states are reporting widespread activity of pandemic influenza, according to the latest update from the CDC. During the previous 3 consecutive weeks, widespread activity was reported in 46, 43, and 32 states. The CDC advises, nevertheless, that most indicators for flu activity remain higher than normal for this time of year.

As of December 3rd, more than 72 million doses of pandemic flu vaccine have been allocated (ie, ready for distribution) in the United States; more than 63 million have been shipped to ordering states or US territories. Approximately one half of the supplies have been allocated for 10 states.

* Including New York City.

A "potentially significant" mutation of the 2009 H1N1 virus has been detected in 3 severe cases (including 2 fatalities) of pandemic flu in Norway; however, the mutated virus is nothing new, according to the World Health Organization. The spontaneous mutation—which does not confer resistance to the antiviral drugs oseltamivir (Tamiflu; Roche) or zanamivir (Relenza; GSK)—was detected as early as April and has been found sporadically in both severe and mild flu cases in other countries,* reports WHO.

The 2009 H1N1 mutation has not been described or labeled explicitly in news reports. But according to a quoted Norwegian health official, the mutation "makes it possible for the virus to fasten itself or infect deeper into the bronchioles, and therefore provide for a more serious progress of the disease." This description suggests that the mutation lies in the gene encoding the viral binding protein, hemagglutinin.

WHO maintains that the current pandemic flu vaccine does produce immunity against the mutated virus.

* Namely Brazil, China, Japan, the Ukraine, and the United States.

Depiction of H1N1 virus from Wikipedia.

Pandemic influenza activity has declined during the last week in the United States, according to today's CDC briefing from Anne Schuchat, MD, Director of the National Center for Immunization and Respiratory Diseases. A total of 43 states are now reporting "widespread" activity, Schuchat said, which is down from 46 states last week.

However, Schuchat advised, flu activity at this time is much greater than activity during the same time last year. She further cautioned that flu activity, particularly during this season, is unpredictable.

In addition, there have been a cumulative 171 laboratory-confirmed pediatric deaths due to pandemic flu; about two thirds of these fatalities were children with underlying conditions (eg, cerebral palsy, muscular dystrophy). But the CDC estimates a far greater number of pediatric deaths due to H1N1. The Center will provide new mortality estimates in the near future.

The supply and distribution of pandemic flu vaccine continues to increase. Schuchat reported that a cumulative number of 54.1 million doses have been made available, which is 11 million more doses than 1 week ago. And 93% of the available supplies have been ordered by states. A total of 94.5 million doses of seasonal flu vaccine, the distribution of which is managed by the private sector, have been disseminated.

Schuchat also provided 4 tips for holiday travel:

1. Travel "well"—meaning, if possible, travel only when you're well.
2. Wash your hands.
3. Cover your coughs.
4. Get vaccinated—particularly if you're in a targeted population.

Statements from the media included comments about "potentially significant" viral mutations discovered in 3 H1N1-related cases (2 fatalities and 1 seriously ill patient) in Norway. Schuchat responded that these mutated viruses, although possibly concerning, have been seen in mild cases as well. 

Using a model to account for the underascertainment of cases, the CDC now estimates that 14-34 million Americans were infected with the pandemic influenza virus between April and October 17, 2009. The Center previously estimated the number of US cases between April and July 23rd of this year at 1.8-5.7 million.

A breakdown by age (years) shows that pandemic flu has preferentially affected younger adults and children. (The graph provides midlevel estimates of cases [horizontal bars] and estimated ranges [vertical bars].)

By using the CDC's midlevel estimates, the mortality rate of pandemic flu is 0.018%—which is consistent with the range of mortality rates provided by Harvard epidemiologist Marc Lipstich (0.007%-0.045%).

One of the latest apparent victims of pandemic flu is University of Ottawa chemistry professor Keith Fagnou, 38, an otherwise healthy father of 3 children. Fagnou died of suspected H1N1 disease on November 11, 3 days after being hospitalized.

HT: In the Pipeline.

Brief answer: None.

Longer answer: Recent surveillance data from 356 adults in 8 states indicate that the likelihood of contracting pandemic flu is unaffected by receiving a seasonal flu vaccine. Results of the data analysis are available in the latest issue of MMWR.

After adjusting for age and chronic medical conditions,* the CDC found that the overall effectiveness of the seasonal flu vaccines against contracting pandemic flu was -10%, with a wide 95% confidence interval (CI) straddling zero (-43%, +15%). Data were obtained during the period from May to June of this year.

These epidemiologic data complement known serologic (laboratory) data, which suggest that the trivalent seasonal flu vaccines are unlikely to provide meaningful cross-protection against pandemic flu. Likewise a recent Australian study showed that, in children or adults who received seasonal flu vaccines, cross-reactive antibodies against pandemic flu were not produced. The overall age-adjusted effectiveness of the seasonal flu vaccines against pandemic flu in this study was 3% (CI: -56%, +40%). An unpublished study of high schoolers in New York City also suggests no protective benefit of seasonal flu vaccines against pandemic flu.

However, these data are at odds with those from a recently published Mexican study, which reported a seasonal flu vaccine effectiveness rate of 73% against pandemic flu. But control patients in this study were more likely to have chronic medical conditions—making seasonal flu vaccine coverage more likely in this group. Unpublished data from Canada suggest that "medically attended" pandemic flu may actually be more likely in recipients of the seasonal flu vaccine.

The MMWR editors advise that studies with more rigorous designs and methods are currently under way to evaluate any immunity conferred by seasonal flu vaccines against pandemic flu.

* Which increase the risk of influenza-related complications (eg, heart disease, asthma, diabetes, cancer).

Forever brainstorming, Google is now helping Americans find a flu shot (either against seasonal or pandemic influenza) through the company's beloved Maps feature. The new tool (found here) is the product of a collaboration between Google and the US DHSS, the CDC (flu.gov), and the American Lung Assocation.

For example, here's where residents of the White House can possibly get a seasonal (blue) or pandemic (red) flu shot. (To the left of the map would be a list of the locations, ordered by proximity to the entered address and labeled "A" through whatever.)

For more information about the tool's development, go here.

HT: Mashable by way of attentionusa.com.

The pandemic flu vaccines of 4 companies—CSL, MedImmune, Novartis, and sanofi pasteur—were approved by the FDA in mid-September. GSK's vaccine was delayed by a US government decision to omit immunity-boosting adjuvant (eg, aluminum salts) from all available pandemic flu vaccines, reports the LA Times. (GSK also announced yesterday that it will be donating 50 million doses of its adjuvant-containing pandemic flu vaccine to WHO for use in developing countries.) 

As of November 4, more than 26 million doses of pandemic flu vaccine have been shipped throughout the United States and its territories, according to the CDC. The top 10 recipients have received about half of the supply.

DHHS = Department of Health and Human Services.

N.B.--GSK also makes Relenza (zanamivir), an anti-influenza treatment.

The number of doses of seasonal flu vaccine that were manufactured for this year, 114 million, is slightly higher than the number made last year, and about 90 million doses have been shipped so far, reports the NYT. But the shipped supply has nearly been consumed, with an estimated 85 million shots administered to date (which is about 24 million more than the number given out by this time last year). Manufacturers cannot make more seasonal flu vaccine, because they are committed to producing the pandemic flu vaccine.

Among the 5 FDA-approved vaccines for seasonal flu, a total of 248 lots have been released. (But how many packages or doses in a lot is unclear. The numbers may also vary, depending on the manufacturer or distributor. If lot numbers are uniform, then 1 lot represents about 46,000 doses [114 million divided by 248].)

1 dose = 0.5 mL, unless otherwise indicated.

Except in the case of Flumist,* the seasonal flu vaccines contain the following inactivated viruses:

• A/South Dakota/6/2007 (H1N1) (an A/Brisbane/59/2007-like virus)
• A/Uruguay/716/2007 (H3N2) (an A/Brisbane/10/2007-like virus)
• B/Brisbane/60/2008

* Flumist contains the attenuated viruses.

N.B.--The NDC contains an initial 5-digit labeler code, which is assigned by the FDA, and a 3- or 4-digit product code, which is assigned by the drug firm.

A reanalysis of the Australian study was prompted by initial criticism of the study's design, which did not use randomly selected hospitals as a control group. Follow-up statistical adjustments, to compensate for "clustering" and "multiple testing," revealed nonsignificant differences between infection rates with N95 respirators and those with surgical face masks, reported the authors at the meeting. The reanalysis triggered a retraction of the original conclusions, which had favored the preferential use of N95 respirators. The new, nonsignificant findings are consistent with results of a recent Canadian study, which showed no added, protective benefit from N95 respirators among hospital nurses.

By advocating the more expensive N95 respirator, the originally reported Australian study had considerable cost implications. To provide a rough idea of the price differential between the 2 mask options: At labsafety.com, a 20-pack of 3M N95 respirator/surgical masks costs $24.90 ($1.25/mask), and a 50-pack of run-of-the-mill surgical masks will set you back $9.70 ($0.20/mask).

From 1.8 to 5.7 million Americans experienced symptomatic swine flu (2009 H1N1 pandemic influenza) between April and July 23rd of this year. This estimate is based on a "probabilistic multiplier model" that adjusts for the underascertainment of pandemic flu cases in the United States. The results of the model, which was created and applied by investigators at the CDC and the Harvard School of Public Health, are available in an expedited article in the journal Emerging and Infectious Diseases.

The probabilistic multiplier model was used to adjust for the underascertainment of pandemic flu cases at each of the following steps (as diagrammed in the provided figures): the pursuit of medical care; the collection of specimens from persons seeking medical care; the submission of specimens for confirmatory testing (ie, RT-PCR); the laboratory detection of the 2009 H1N1 virus; and the reporting of confirmed cases. The model was adjusted separately for hospitalized patients (B)—who, by definition, had already sought medical care.

On the basis of the model, investigators conclude the following for the time period between April and July of this year:

• Every reported case of pandemic flu represents 79 total cases (90% probability range, 47-148).
• The estimated median number of symptomatic cases is 3.0 million.
• The estimated incidence of pandemic flu in persons ≥65 years of age is 107/100,000.
• The estimated incidence of pandemic flu in persons 5-24 years of age is 2196/100,000.
• Every hospitalized case of pandemic flu represents 2.7 total hospitalized cases (90% range, 1.9-4.3)
• The estimated median number of hospitalizations is 14,000 (range, 9000-21,000).
• The estimated ratio of hospitalizations to total symptomatic cases is 0.45% (90% range, 0.16%-1.2%).
• The estimated median incidence of hospitalizations in persons <5 years of age is 13.0/100,000.
• The ratio of deaths to hospitalizations was 6%.* (Note: This value was not derived from the model).
• The estimated median number of deaths is therefore 800 (90% range, 550-1300).

"Because this [death] assumption has several limitations," the authors conclude, "more sophisticated models are also being developed to better understand the severity of the US epidemic in the spring of 2009, including intensive care unit admissions and deaths."

RT-PCR = reverse transcriptase polymerase chain reaction.

* Therefore the overall estimated death rate (although this value is not provided in the article) is 0.027%—which is within the range provided by one of the authors, Harvard epidemiologist Marc Lipsitch, to Reuters in September.

Update: From the AP by way of the CDC—At least 114 American children have now died of complications due to the 2009 H1N1 virus. 

Among the reasons for not vaccinating their children against the seasonal or 2009 H1N1 flu, 52% of moms indicated that their pediatrician "left it up to them." Other reasons for not vaccinating included the misperception that 1) healthy children do not need to be vaccinated (63%) and 2) there are other similarly effective ways to avoid influenza (57%).

Carol Baker, MD, chair of NFID's Childhood Influenza Immunization Coalition and professor of pediatrics at Baylor, called this kind of thinking among parents "magical" or "wishful" and concluded, "[T]he survey reveals the need for more disease education and for health care providers to emphasize to parents that immunization is the best way to prevent flu."

Notably a minority of respondents expressed reservations about the effectiveness (11%) or safety (7%) of influenza vaccinations and their capacity to cause disease (5%).

The survey of 500 US mothers was conducted by telephone during August 19-25 of this year. Respondents were required to have children from 6 months to 18 years of age living with them. The reported margin of error for the survey is 4.4%.

A nonprofit organization, the NFID established the Childhood Influenza Immunization Coalition in 2007 to increase awareness of pediatric influenza and the benefits of immunization. The Coalition is funded by an unrestricted, educational grant from sanofi pasteur, one manufacturer of both seasonal and 2009 H1N1 vaccinations.

* 91% of mothers were concerned that their whole family would become ill if a child contracted seasonal flu.

Bill Maher, put this in your glass pipe and smoke it.

A total of 86 children have now died of H1N1 illness in the United States, according to the latest data from the CDC. Nearly half (47%) of the deaths were reported to the CDC after August 30th, and 11 of these deaths occurred during the last week. Among the most recent deaths (n = 43), 19 (44%) occurred in preteens or teenagers (12-17 years of age).

For all practical purposes, H1N1 activity is now widespread in the United States.

Like white on rice, rational bloggers have been all over Bill Maher's goofy ideas about vaccines and vaccination. It's too bad, though, that the man has a nationally televised show, HBO's "Real Time With Bill Maher," which affords Maher an opportunity to influence potentially gullible viewers in front of (like many a talk/variety/comedy show) an audibly fawning studio audience.

Nevertheless, begrudging props may be given to Maher for inviting retired Republican Senator and physician Bill Frist on Friday to discuss vaccination. In this segment, it's not entirely clear that Maher "gets schooled" by Frist about vaccines (despite the clip's title). Schooling requires that Maher's thick skull be penetrable. And schooling requires time—much more time than television typically allows.

But a blog provides an enduring, leisurely format for dissecting and refuting some of the utterly fallible anti-vaccine statements that Maher made on Friday and that Frist didn't have the chance to challenge.

Maher comment #1: Conservatives always say, about healthcare especially: You gonna let the government run healthcare? They screw everything up. So why would you let them stick a disease into your arm? I would never get a swine flu vaccine or any vaccine. I don't trust the government, especially with my health. [Applause.] And that seems to be a conservative opinion: not to trust the government.

Dissection: The usually liberal Maher tries to create a bit of oh-gosh irony here by aligning himself with traditionally government-distrusting conservatives. He then jumps to make a very broad and loose association between government incompetence and government-recommended vaccination. However, if Maher were familiar with the monumental benefits of historical vaccination programs (eg, against smallpox and polio), the association actually supports organized intervention into healthcare (whether instigated by a government or some other authoritative entity, like the World Health Organization).

At the same time, Maher indicates that vaccination is a process whereby "disease" is injected into the body. First "disease" is a clinical manifestation of bodily dysfunction; it is not something that can be confined in a syringe. But we sort of know what Maher's means here, so we'll give him a pass on this semantic point. What Maher is really implying is that disease-causing virus is injected during vaccination. But that idea is also false.

With respect to the injected 2009 H1N1 (swine flu) vaccine, the inoculant is a killed (actually chemically "split") virus—which is incapable of causing infection (but is capable of inducing protective immunity). The nasal-spray vaccine from MedImmune contains live, attenuated H1N1 virus. The attenuated virus is engineered (ie, cold adapted and temperature sensitive) so that it can replicate in the cooler confines of the nose to induce immunity, without causing influenza-like illness.

Maher indicates that he would never get the swine flu vaccine, which is fine (assuming that Maher isn't at baseline risk for influenza complications and doesn't care for an infant younger than 6 months of age*). The 53-year-old isn't a CDC-recommended candidate for the 2009 H1N1 vaccine (although he should get a seasonal flu shot).

Maher comment #2 (in response to a Frist anecdote about a patient dying of swine flu): I cannot believe that a perfectly healthy person died of swine flu. That person was not perfectly healthy. Medical—Western medicine misses a lot.

Dissection: Maher's just flat-out wrong here. Regardless of what he believes, serious H1N1-related disease preferentially affects persons younger than 65 years of age, and about 45% of Americans who have died of swine flu were healthy, according to the CDC. With his last sentence, Maher also betrays a broad, inherent distrust of Western (really, allopathic) medicine. 

Maher comment #3: Let me read you a quote from the former control officer at the US FDA. His name is Dr. J. Anthony Morris. He said, "There is no evidence that any influenza vaccine thus far developed is effective in preventing or mitigating any attack of influenza. The producers of these vaccines know they are worthless, but they go on selling them anyway."

Dissection: By quoting J. Anthony Morris, Maher reveals a lazy reliance on an ostensibly authoritative source, about which he probably knows nothing. 

Finding reliable information on Morris (at least on the web) is a challenge; at first blush, he appears to be a quotable favorite among anti-vaccinationists—probably because of the specious appeal-to-authority angle (ie, Morris reportedly has/had a PhD in bacteriology and was an FDA employee). An archived newspaper search reveals that Morris was a virologist in the Division of Biologic Standards, which was part of the NIH until 1972 when the division was transferred to the FDA.

In the fall of 1971, Morris made news by arguing to Congress that influenza vaccines were not just useless, but dangerous (see Lyons RD. Influenza shots held ineffective. NYT. October 15, 1971). He claimed that "not only has there been little or no benefit from the use of influenza vaccine in man, but harm has resulted." However, a federally appointed, 12-person scientific committee rejected Morris's claims of incompetence within his NIH division; although the committee did concede, in ho-hum fashion, that "inactivated influenza vaccines are imperfect instruments for the prevention of influenza." (The committee may have been referring to subpotent lots of influenza vaccine that were distributed in the 1960s.) The committee then proceeded to reject Morris's claims that influenza vaccines are harmful (see Lyons RD. Charges of poor vaccine regulation rejected. NYT. November 30, 1971).

A related news story in June 1972 indicates that Morris had been demoted within his division, which was now (presumably) a part of the FDA. But later news reports indicate that Morris was appointed director of the Slow and Temperate Virus Branch of the agency.

In July 1976, Morris, then 57, was finally fired from the FDA for "insubordination" and "inefficiency." Morris claimed that he was sacked from his $35,000-a-year job because he opposed President Ford's swine flu vaccination program. FDA officials acknowledged, at the time, that it was very unusual for an FDA employee to be fired, but the process that led to Morris's departure began long before anybody recognized the swine flu threat. Later Morris showed up on fear-mongering talk shows like "Phil Donahue" and provided anti-vaccine quotes to news reporters as recently as 1988. 

A phrase search of various archived newspapers fails to return a source for the exact quote cited by Maher, except in 1 instance: Donald Harte, in a November 2007 editorial for the Marin Independent Journal ("Is there a vaccine that protects against non-science?") requotes Morris from a citation in a contemporary issue of Health & Fitness magazine. The quote was described as being 30 years old, but the original source was not identified. 

Morris, if alive this year (and I haven't been able to confirm whether he's alive or dead), would be about 90. 

Maher comment #4: But a virus is always mutating. You would agree with that? [Frist: Yeah.] So, so the vaccine that they produce back in March—that's not really what's gonna prevent what's, what's going on now. Because—I know a lot of people on the conservative side don't believe in evolution—but—and you can't see evolution in advanced species, but you can see—[Frist interrupts: We know this vaccine is 98% effective...]

Dissection: Here Maher tries to discount the efficacy of the swine flu vaccine by implying that the virus has mutated so much since the creation of the vaccine (in March) that it will evade whatever immunity is produced by inoculation. However, on October 9 (the same day that Maher's show aired), the CDC reported that the 2009 H1N1 viruses "have not undergone substantial antigenic change since they were first characterized in April 2009 and should be well-matched to the monovalent vaccine strain." 

Last month, data published in the NEJM indicated that significant antibody titers were generated in 97% of adults after 1 dose of the inactivated vaccine. Rates of antibody production among children aged 6-35 months, 3-9 years, and 10-17 years were 25%, 36%, and 76%, respectively. These data are the foundation for recommending 2 vaccine doses in children younger than 10 years of age. The suboptimal immune response in younger children is probably related to their limited immune experience with influenza viruses and is clearly not the result of viral mutation.

There have been scattered reports of 2009 H1N1 virus that is resistant to oseltamivir (Tamiflu), but all of these isolates were susceptible to zanamivir (Relenza).

Maher comment #5: Dr. Jonas Salk: "Live virus vaccines against influenza and paralytic polio, for example, may in each instance cause the disease it's intended to prevent."

Dissection: Another appeal to authority by Maher. Salk, as everyone knows, was the creator of the inactivated polio vaccine. The quote cannot be confirmed and, again, appears to be a favorite among online anti-vaccinationists. An archived newspaper search fails to return relevant hits, and without context, it's useless to interpret a statement that Salk may or may not have made.

* And don't we all hope that's the case.

A simplified table of the FDA-approved vaccines against the 2009 H1N1 virus is provided here, with a focus on age and dose recommendations. For complete data, see this week's MMWR.

The IM shots contain inactivated virus, and the nasal spray (from MedImmune) contains attenuated virus. Prefilled syringes do not contain mercury (that is, 25 microg Hg per 0.5 mL of vaccine, in the form of thimerosal preservative). When 2 doses are recommended, they are administered approximately 4 weeks apart.

The nasal spray vaccine is indicated for healthy, nonpregnant persons aged 2-49 years and should not be administered to persons with asthma. The dose of the nasal spray is divided equally between each nostril.  

Note: These data are for informational purposes only and should be confirmed by referring to authoritative sources (eg, the CDC) and/or a treating healthcare professional.

* Latter approved by FDA for age group on 11/12/09.

Pneumococcal vaccines, which can protect against influenza complications, are underused. And there is no shortage of these vaccines. These facts were relayed by Thomas Frieden in today's CDC press conference.

The CDC recommends the PCV7 vaccine (Prevnar; Wyeth) routinely for children younger than 2 years of age (1 dose each at 2, 4, 6, and 12-15 months) and older children who have not completed the 4-series vaccination.

The CDC recommends the PPSV23 vaccine (PneumoVax; Merck) for all adults aged 65 years or older and any individual 2-64 years of age with a long-term health problem (eg, diabetes) or a condition that lowers resistance to infection (including therapy). The CDC also recommends the PPSV23 vaccine for adults 19-64 years of age who smoke or have asthma.

Pneumococcal immunization protects against infection with Streptococcus pneumoniae, the most common bacterial pathogen in reported fatal cases of H1N1 infection to date.

For authoritative and comprehensive information on this subject, see the CDC web site.

PCV7 = 7-valent pneumococcal conjugate vaccine; PPSV23 = 23-valent pneumococcal polysaccharide vaccine.

Photomicrograph of S. pneumoniae grown from blood culture from the CDC/Dr. Mike Miller.

According to today's MMWR.

Among the 77 fatal cases of 2009 H1N1 influenza that were reported in the United States from May 1 to August 20, bacterial pathogens were identified in 22 cases (29%). Streptococcus pneumoniae was detected in 10 (45%).

The breakdown:

And no state remains unaffected.

The CDC advises, however, that heightened H1N1 activity does not reflect the severity of disease. At least 99% of all subtyped influenza virus samples (n = 1402) are the 2009 H1N1 virus.

Also according to CDC data, the in-hospital death ratio associated with influenza-like illness (ILI), as of September 19, was 0.093 (mortality rate, 9.3%). US deaths include 49 children.

Multiplying the US hospitalization ratio for April 15 to July 24 (0.114) by the CDC's latest in-hospital death ratio for ILI provides a case-fatality ratio of 0.0106 (mortality rate, ~1%). However, a Harvard epidemiologist recently estimated the H1N1 death rate to be considerably lower—from 0.007% to 0.045%.

Vaccines for the 2009 H1N1 virus are expected to be available next month (that is, in a few days), with the nasal-spray vaccine preceding the shot vaccine in the US marketplace. Candidates for the nasal vaccine are nonpregnant persons 2-49 years of age.

Newly released results from a national survey (N = 1678), performed by the University of Michigan in August, revealed that a minority of parents plan to have their children vaccinated against the pandemic H1N1 virus. (The CDC currently recommends that all individuals from 6 months to 24 years of age undergo H1N1 [swine flu] vaccination.) Surveyed parents reported that they are more likely to have their children receive the seasonal influenza vaccination.

Parents' perception of the risks associated with H1N1 flu were closely linked to the likelihood of opting for the vaccine. Notably Hispanic parents were more likely to report their intention of having their children undergo vaccination—possibly because they perceive a higher threat from the disease than non-Hispanic parents. For instance, Hispanic parents may be more aware of the recent history of H1N1 disease in Mexico.

That's because...

The injected vaccine for seasonal influenza was more effective at inducing immunity than the nasal-spray version in adults, according to a study published yesterday in the NEJM. The results can possibly be applied to vaccine options for pandemic H1N1. (But then again, maybe not. Read on.)

In a randomized, double-blind, placebo-controlled study of 1952 healthy adults (18-49 years of age) during the 2007-2008 influenza season,* the injected vaccine (which contains inactivated virus) reduced the relative risk of laboratory-confirmed influenza by 50%, when compared with the nasal-spray vaccine (which contains live, attenuated virus). The rates of absolute efficacy against influenza A (predominately the H3N2 virus) were 72% and 29% for the shot and spray vaccines, respectively.

Other data indicate, however, that the spray vaccine is more effective for the prevention of flu than the injection in young, vaccine-naive children (2 doses) and in older children (1 dose).

It is speculated that the nasal-spray vaccine is relatively less effective in adults, because preexisting seasonal flu antibodies thwart the vaccine antigens at their entry point in the nasal passages. But because the pandemic H1N1 virus is new to everybody, the nasal-spray vaccine may work comparably in children and adults.

* According to the CDC, circulating viruses during this season in the United States were influenza A (71%) and influenza B (29%). Early in the season, influenza A H1N1 viruses predominated, followed by an increase in circulating H3N2 viruses. Influenza B viruses were more common during the tail of the season. Circulating H3N2 viruses were most common overall.

********************************

And on a related note...

A high-profile anecdote of confirmed illness with the pandemic H1N1 virus was provided yesterday by CNN's Sanjay Gupta. Gupta's prominent symptoms were similar to those of seasonal flu: a hacking cough, fever, nausea, and body aches. Although Gupta reported, "[T]his was the sickest I have ever been," he recuperated after a couple of days of symptomatic treatment and bed rest. He evidently did not receive antiviral therapy (eg, oseltamivir [Tamiflu]).

Seasonal Influenza Vaccine (available now)

Who should receive the seasonal influenza vaccine?

• Individuals from 6 months to 19 years of age and individuals 50 years of age or older
• Pregnant women
• Persons with certain chronic medical conditions
• Individuals living in nursing-home or long-term care facilities
• Persons living or working with others who are at risk for influenza-related complications (eg, healthcare workers, daycare employees).

Who is a candidate for the intranasal spray vaccine, which contains 3 live, attenuated seasonal influenza viruses?

Healthy, nonpregnant persons 2-49 years of age.

Who is a candidate for the intramuscular vaccine, which contains 3 inactivated seasonal influenza viruses?

Children 6-35 months of age (dose, 0.25 mL) and individuals 3 years of age or older (dose, 0.5 mL).

Who should receive 2 doses of the seasonal influenza vaccine (each separated by 4 weeks)?

Children younger than 9 years of age who 1) are receiving the seasonal influenza vaccine for the first time or 2) received the vaccine for the first time during the previous influenza season and received only 1 dose.

Pandemic H1N1 (Swine Flu) Vaccine (expected in October)

Who should receive the swine flu vaccine?

• Pregnant women
• Persons who live with or care for infants younger than 6 months of age
• Healthcare and emergency medical personnel
• Persons aged from 6 months to 24 years
• Individuals aged 25-64 years who are at risk for influenza-related complications (eg, persons with asthma, diabetes, hypertension, HIV). 

Who is a candidate for the intranasal spray vaccine, which contains the live, attenuated pandemic H1N1 virus?

The same individuals who are candidates for the intranasal seasonal influenza vaccine: healthy, nonpregnant persons 2-49 years of age.

Who is a candidate for the intramuscular vaccine, which contains the inactivated pandemic H1N1 virus?

All individuals who are priority candidates for the pandemic H1N1 vaccine.*

Who should receive 2 doses of the swine flu vaccine (each separated by 3-4 weeks)?

Late-breaking data suggest that 1 vaccine dose will be sufficient to induce a protective immune response in persons 10 years of age or older. Children from 6 months to 9 years of age, however, will likely require 2 doses of vaccine.

* I suspect that doses, like those for the seasonal influenza vaccine, are cut by half for children 6-35 months of age; however, I have not yet confirmed this information.

**********************

The US Department of Health and Human Services (HHS) recently ordered 56 million more doses of the pandemic H1N1 vaccine from MedImmune and sanofi pasteur for an additional $438,143,025. The total US government spend on the pandemic H1N1 vaccine is now $2,255,120,945, which amounts to $8.98 per vaccine dose.

• Estimated, cumulative number of pandemic H1N1 infections in the United States between April and June: more than 1 million. (See yesterday's post, for example, for how the estimated case number affects the estimated mortality rate.)
• Peaks of activity: May and June nationwide; late August in the Southeast.
• Confirmed H1N1 hospitalization rate from April to August: generally lower than that for seasonal influenza but higher than usual for the time period.
• In-hospital death rate from mid-April to August 30th: 6.5% (593/9079); proportion of deaths due to pneumonia and influenza "within the bounds" of summertime expectations.
• Circulating virus: 97% pandemic H1N1 that is sensitive to antiviral treatment.
• Antiviral drug sensitivity: 99.4% of 1372 tested samples are susceptible to oseltamivir (Tamiflu; Roche); oseltamivir-resistant viruses still susceptible to zanamivir (Relenza; GSK); all viruses resistant to amantadine and rimantadine.
• Recommendations for persons with influenza-like illness (ILI): after afebrile (untreated), stay home for another 24 hours.
• Antiviral treatment recommendations: early therapy for persons with severe ILI and those individuals with suspected ILI and risk factors for complications (<5 years of age; >64 years of age; or underlying health conditions, including pregnancy).
• Vaccines for seasonal influenza: available now and urged for all children, persons 50 years of age or older, and those at greater risk for influenza-related complications.
• Vaccines for pandemic H1N1: still expected by mid-October; first in line have already been designated by the CDC.

Depiction of H1N1 virus from Wikipedia.

Lipsitch proposes that the mortality risk due to the 2009 H1N1 virus is comparable to that of a "moderate" influenza season—less than 0.1%.** The epidemiologist bases his calculation on reports of influenza-like illness throughout the world, as well as reports of hospitalizations and confirmed deaths.

Working backward, one can conclude that Lipsitch estimates the number of people infected so far with the 2009 H1N1 virus worldwide at several million.

* Calculated by multiplying the US hospitalization ratio from April 15 to July 24, or 0.114, by a recent in-hospital death ratio (eg, 0.065) and then multiplying by 100.

** Although CDC data suggest a death rate for seasonal flu that is higher than 0.045%. According to the Centers, 5%-20% of the US population is affected each year by seasonal influenza. The US population is approximately 300 million, so that means 15-60 million are infected annually. About 36,000 people die of seasonal flu, for an annual mortality rate of 0.06%-0.24%. About 200,000 are hospitalized, for a hospitalization rate of 0.3%-1.3%.

Depiction of H1N1 virus from Wikipedia.

Last week's late-breaking data indicated that 1 vaccine dose (15 micrograms), instead of the originally anticipated 2, will be sufficient to induce a "robust" immune response in most adult recipients. The optimal dose in children, however, has not been confirmed.

The vaccines are produced by using the same methods as those for seasonal flu vaccines, including viral cultivation in chicken eggs. (WHO nicely explains the vaccine-manufacturing process here.) Consequently people with "severe or life-threatening" allergies to chicken eggs should not receive the vaccine. Vaccines will also be available in preserved (ie, thimerosal containing) and nonpreserved formulations.

Side effects of the injected and nasal-mist vaccines are anticipated to be similar to those seen with the seasonal flu vaccines.

Five companies contracted with the US Department of Health and Human Services (HHS) to create and manufacture a vaccine against the novel H1N1 virus; only GlaxoSmithKline failed to receive vaccine approval yesterday. Reasons for the delayed or deferred approval of GSK's vaccine were not provided by the FDA or the company.

According to a cached version of the web page detailing HHS's contracting activities, the following government orders for novel H1N1 vaccines were made in May and June.

HHS = Health and Human Services.

Addendum: An updated HHS web page reveals that MedImmune received a total of $151,008,000 in contracts for May and June. The cumulative government spend is therefore $1,815,977,920. With an order of 195 million doses, that's $9.31 per vaccine dose.  

The latest WHO update (August 30th) for infections with the novel H1N1 virus indicates more than 254,206 cases globally and at least 2837 deaths, for a crude mortality rate of 1.1%. However, this mortality rate is likely overestimated, because the total number of H1N1 cases is underestimated. Pitfalls in calculating the death rate (or the case-fatality ratio) during the H1N1 pandemic are discussed here.

Dr. Thomas Frieden of the Centers for Disease Control and Prevention (CDC) conducted this week's broadcasted press conference on the status of the novel H1N1 epidemic in the United States.

Points made.

• The bad news: Novel H1N1 virus is here and spreading, and notably, infection didn't abate during the summer ("very usual"). Expect to see more cases in the coming months.
• The good news: The virus has not mutated, as yet, to become more deadly; and so far, antiviral-resistant strains of H1N1 have not been observed. (See Addendum.)
• The caution: But influenza is unpredictable, and readiness for the worst is imperative.
• The verified data:
  a) There have been 36 pediatric deaths in the United States, details of which are in the latest issue of the MMWR; children with special needs appear to be particularly vulnerable to infectious complications, including death.
  b) Recent experience in the Southern Hemisphere (5 countries) is similar to that in the United States (during the Spring); there have been hospitalization challenges but no increase in the H1N1-related death rate.
  c) The Institute of Medicine (IOM) issued a report today recommending fitted N95 respirators, instead of the typical face mask, for healthcare workers who interact with H1N1-infected patients.*
• The unverified data: A 1-dose vaccine, which was recently approved in China.
• The 2-dose vaccine:
  a) Still expected in mid-October.
  b) To induce effective immunity, 2 doses are anticipated to be necessary.
  c) Recommended groups for vaccination remain the same.
  d) The vaccine itself is free, although administration may not be; the government is in the process of releasing $1.5 billion to enable/facilitate vaccine administration.
  e) Vaccination programs will be run on the local level (eg, state). 
• The upcoming surveillance: For possible adverse events (eg, Guillain-Barre syndrome, miscarriages) associated with vaccination.
• The challenge to safeguard healthcare resources:
  a) Most cases of novel H1N1 infection are mild and don't necessitate laboratory testing or antiviral treatment.
  b) Stay home if you're sick.
  c) Cover your face when coughing or sneezing.
  d) Wash your hands.
  e) Don't go to the doctor unless you're severely ill or have an underlying condition (although it's important to be seen promptly in these cases, so that antiviral therapy can be instituted in a timely fashion [ie, within 48 hours of symptom onset]).
  f) To employers: Don't require a permission note from an employee's doctor before the employee can return to work; in general, telecommuting may be a good idea.

* The IOM was not charged with considering cost, when making its recommendation.

Depiction of H1N1 virus from Wikipedia.

09/05/09 addendum: In its August 12th report, WHO indicated knowledge of 12 cases of disease that is resistant to oseltamivir (Tamiflu; Roche). The mutated virus, however, remains sensitive to zanamivir (Relenza; GSK). Oseltamivir-resistant cases occurred sporadically throughout the world and were apparently not connected. 

Children with underlying medical conditions are particularly vulnerable to complications, including death, due to infection with the novel (2009) H1N1 virus. This conclusion is based on a recent analysis of 36 pediatric deaths that have occurred in the United States due to the virus.* Features of these cases are provided in the latest issue of the CDC's MMWR.

Among the 477 deaths associated with laboratory-confirmed novel H1N1 virus in the United States (as of August 8), 36 (7.5%) have occurred in persons younger than 18 years of age. The age breakdown of the pediatric victims is as follows:

Most of the children (67%) had at least 1 "high-risk" medical condition (eg, respiratory, cardiac, or neurologic condition), and 92% of these children had neurodevelopmental conditions (eg, developmental delay, cerebral palsy).

A substantial percentage (43%) with culture or pathologic data (n = 23) had bacterial coinfections; among these 10 children, 6 were 5 years of age or older and had no high-risk comorbidities. Confirmed bacterial pathogens were Staphylococcus aureus (3/5 of which were methicillin resistant), Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus constellatus. All pathogens were community acquired, according to the CDC's Thomas Frieden (at today's broadcasted press conference; see today's follow-up post).

The median duration of illness, from symptom onset to death, was 6 days (range, 1-28 days). One half of pediatric victims were male; one third were Hispanic.

Among 31 children for whom data were available, 19 (61%) received antiviral treatment; but only 4 received treatment within 2 days of symptom onset. Just over half (13/25) of the children had received at least 1 inoculation against the 2008-2009 seasonal H1N1 virus.

The MMWR article also provides pediatric-death data from previous influenza seasons; however, the editors advise caution when comparing seasonal death data because of possible differences in case ascertainment and differing sensitivities of laboratory tests (particularly rapid H1N1 tests). In addition, comparisons of seasonal data are highly limited during an ongoing epidemic/pandemic. 

The CDC editors stress the importance of pneumococcal vaccination in children, particularly in very young children with high-risk medical conditions, and the benefit of antiviral treatment in persons who are hospitalized for novel H1N1 infection, even when treatment is started 48 hours after symptom onset. Empiric antibacterial therapy should be directed at S. aureus, S. pneumoniae, and S. pyogenes. 

* The conclusion is not unexpected, given that complications due to seasonal influenza are increased in very young children (<5 years of age) with certain chronic medical conditions.

The latest WHO update for infection with the novel H1N1 virus indicates more than 209,438 cases of disease globally and at least 2185 deaths, for a crude mortality rate of 1%. However, this mortality rate is likely an overestimate of the actual H1N1-related mortality rate. Pitfalls in calculating the death rate (or the case-fatality ratio) during the H1N1 pandemic are discussed here.

Data from April 24 to July 25 indicate the following overall attack and hospitalization rates (per 100,000) by age group within the city's 77 communities.

Consequently the overall attack rate among children aged 5-14 years is more than 14 times that among adults aged 60 years or older. Hospitalization rates are also considerably higher among the younger pediatric populations. These data support current guidelines for preferentially vaccinating younger age groups against the novel H1N1 virus.

Reasons for the higher attack and hospitalization rates among children may be related to the existence of partial (ie, cross-reactive) immunity to the novel H1N1 virus among the elderly and/or higher virus-transmission/contact rates among children.

Overall attack and hospitalization rates are also higher among minority ethnic groups, for unclear reasons; although the relatively higher prevalence of underlying conditions, like asthma or diabetes, in minority ethnic groups may explain their increased vulnerability to H1N1 infection.

Among those hospitalized, 40 (19.5%) were admitted to an intensive-care unit; 9 (4%) required mechanical ventilation. The rates of preexisting asthma and diabetes in hospitalized patients were 21% and 7%, respectively. Also notable is the fact that 14 (7%) hospitalized patients were pregnant. Among those surviving patients with admission and discharge data (n = 97), the median hospital stay was 2 days (range, 1-11 days).

As of August 24, there were 7 H1N1-related deaths in Chicago (crude mortality rate, 0.45%); all were associated with respiratory compromise.

1. 20-year-old pregnant woman
2. 54-year-old women with acute myeloid leukemia
3. 22-year-old man receiving long-term hemodialysis
4. 32-year-old obese* man with asthma
5. 52-year-old man with lymphoma
6. 26-year-old woman with no reported chronic health conditions
7. 47-year-old woman with no reported chronic health conditions

The CDC editors note that the true hospitalization rate and, particularly, the attack rate associated with the novel H1N1 virus in Chicago might be overestimated, because the number of confirmed cases is underestimated. To alleviate laboratory workloads, H1N1 testing was discouraged for outpatients by the city's Department of Public Health after April 30th.

The most common clinical symptoms among affected Chicagoans are fever (73%), cough (68%), sore throat (29%), and dyspnea (15%).

* Another recent MMWR report from the Michigan Department of Community Health suggests that obese and extremely obese patients may be particularly vulnerable to complications associated with novel H1N1 infection.

Although the crude mortality rate for infection with the novel H1N1 virus has been supplied at this blog (by using raw data from the World Health Organization), there are a number of pitfalls when calculating this value during an epidemic/pandemic. The drawbacks of using the simple equation for the mortality rate—that is, dividing the number of known deaths (the numerator) by the number of known cases (the denominator)*—are outlined in a recent (if somewhat mathematically challenging) article in the BMJ.

Briefly, however, the UK authors highlight 2 general sources of potential error: 1) difficulties with case ascertainment; and 2) inevitable delays between infection onset, death, and subsequent reporting.

Case Ascertainment

Particularly as the pandemic advances (for example, in the hot zones of Mexico and the United States), there is the likelihood of underrecognizing (or simply ignoring) mild cases of infection. Consequently the denominator is underestimated, and the mortality rate is overestimated.

But deaths due to H1N1 may also be unrecognized. For instance, some vascular deaths may not be recognized as caused by influenza. Also, at least in developing areas, hospital surveillance may be poor. Consequently the numerator and the mortality rate are underestimated.

The authors' solution (at least for the underrecognition of cases) is to use closely monitored hospitalization data from the early part of the pandemic and in-hospital mortality data later in the pandemic (when total case ascertainment becomes difficult). The overall mortality rate (or really, the case-fatality ratio) is the hospitalization ratio X the fatality ratio among hospitalized cases.

Of course, this calculation requires sufficient sample sizes. For instance, to obtain 95% confidence intervals for a case-fatality ratio ranging from 0.5 to 1.5, you would need ~1100 cases and ~200 hospitalizations. An important assumption with this solution, the authors stress, is that the hospitalization ratio and the in-hospital death ratio remain constant over the course of the pandemic; but guidelines for the hospitalization of H1N1 cases, in particular, may change as the pandemic advances.

Nevertheless, by using numbers from the CDC, the H1N1 case-fatality ratio can be estimated according to the authors' equation. There were 43,771 confirmed or probable cases of novel H1N1 infection in the United States from April 15 to July 24,** resulting in 5011 hospitalizations. Therefore the hospitalization ratio for this time period was 0.114. As of August 20, there have been 522 deaths among 7982 hospitalizations, for an in-hospital death ratio of 0.65 0.065. The case-fatality ratio in the United States is therefore 0.114 X 0.65 0.065, or 0.0075 (and the mortality rate is 0.75%).

Inevitable Delays

The case-fatality ratio may also be underestimated when there is a delay between the onset of infection and knowledge of the final outcome of the case. This effect, the authors note, is known statistically as censoring—which subsides after the pandemic peaks.

The authors' solution is to divide the number of deaths by the number of cases in which the outcome is known; however, this solution may be problematic when there is a relatively long delay between symptom onset and death, as is typical in cases of influenza.

Their second proposed solution is an estimator, which contains a big, fat sigma (a sigma!), to calculate the case-fatality ratio on a particular day. The estimator also requires knowledge of the time from symptom onset to death to approximate the expected number of deaths on the particular day in question.

The estimator is reproduced here for statisticians, epidemiologists, and the otherwise fanatical. Knock yer-selves out (and feel free to post yer calculation).

As of today, the World Health Organization reports 1799 deaths due to the novel H1N1 swine-flu virus among a global total of more than 182,166 cases. By using these numbers, the overall mortality rate is 0.98% (although the actual rate is somewhat lower). The death rate as of August 6th was 0.82%. Again most of the deaths (~87%) have occurred in the Americas.

As of August 6th, the World Health Organization reports 1462 deaths due to the novel H1N1 swine-flu virus among a global total of 177,457 cases, for an overall mortality rate of 0.82%. The death rate as of July 31st, was 0.71%, which is up more than 60% from mid-June. Among the tabulated deaths, a steady 87% (1462) have occurred in the Americas.

Preliminary data from the CDC

The CDC determined the following sensitivities of 3 commercially available RIDTs by using respiratory specimens that were positive for the novel H1N1 virus with rRT-PCR. However, the CDC advises against discriminating among the 3 tests' sensitivities, because of the relatively low number of specimens analyzed.

* n = 34.

The sensitivities of the RIDTs declined in proportion to declining titers of novel H1N1. Factors that affect influenza titers in specimens include the timing of specimen collection during illness, the age of the patient, the type of specimen collected, and the transportation and storage of the specimen.

The overall sensitivities of the RIDTs for seasonal H1N1 (n = 5) or seasonal H3N2 (n = 15) were observed to be 60%-80% and 80%-83%, respectively. (It is important to note that RIDTs do not distinguish among subtypes of influenza A virus.) The CDC advises that the results of RIDTs should be interpreted in the context of known circulating viral strains and provides this link for guidance.

N. B.—The sensitivity and specificity of the rRT-PCR assay, when compared with the reference standard of viral culture, are 99.3% and 92.3%, respectively.

08/13/09 update: RIDT data from the Naval Health Research Center indicate respective sensitivities of 51% for the detection of novel H1N1 (n = 39 patients), 63% for seasonal H1N1 (n = 19), and 31% for H3N2 (n = 19). Specificities for all influenza A virus types were 99%. Values are for the QuickVue Influenza A+B test; the reference standard is rRT-PCR. 

As of July 31st, the World Health Organization reports 1154 deaths due to the H1N1 virus among a global total of 162,380 cases, for an overall mortality rate of 0.71%. Consequently the H1N1 death rate has increased more than 60% after holding steady at about 0.44% since mid-June. The current H1N1 death rate also surpasses the death rate from early June (0.66%). Among the tabulated deaths, 87% (1008) have occurred in North and South America.

WHO reports that the "overwhelming majority" of H1N1 cases have been mild, with spontaneous recovery, despite the fact that the virus has spread with "unprecedented speed." Confirming these cases with laboratory testing, however, is "extremely resource-intensive," WHO writes. "In some countries, this strategy is absorbing most national laboratory and response capacity, leaving little capacity for the monitoring and investigation of severe cases and other exceptional events."

For countries well ensconced in the H1N1 pandemic, surveillance procedures will now mirror those used to assess seasonal influenza activity. Countries with "well-established laboratory-based surveillance systems" will monitor any changes in the H1N1 virus.

According to WHO's most recent (and last) global update, on July 6, a total of 94,512 H1N1 cases had occurred throughout 135 countries or territories. The overall mortality rate remains steady, at 0.45% (429 deaths).

H1N1 cases have now been reported in 120 countries or territories, and related deaths have occurred in 17. Countries disproportionately affected by new cases (where more than 500 cases have occurred) include Thailand, the United Kingdom, Brazil, Peru, and Spain. The number of swine flu deaths in the United States now surpasses those in Mexico.

The World Health Organization reports a total of 52,160 cases of H1N1 disease (up from 27,727) in 99 countries (up from 74), with a large bulk of new cases reported in the United States (3594) and Chile (1190). The number of deaths stands at 231 (up from 141), for an overall mortality rate of 0.44%.* Swine-flu-related deaths have now affected 11 countries.

* Which is slightly less than the previously calculated mortality rate of 0.5%. 

While drugmakers create a vaccine against the currently pandemic swine-flu virus (H1N1 S-OIV 2009), neurologists are advised to monitor the safety of such inoculations, should they be implemented. The caution is founded on a higher-than-expected rate of Guillain-Barre syndrome (GBS) in vaccine recipients during the 1976 immunization campaign against swine flu, reports Neurology Today.

More than 30 years ago, soldiers at Fort Dix, New Jersey, experienced an outbreak of swine flu. Fearing a recurrence of the 1918 influenza epidemic, US government officials implemented a widespread vaccine campaign in which more than 40 million Americans were immunized. However, the drive was aborted after 3 months when reports of GBS in vaccinated individuals emerged. Although GBS surveillance data for the time period are sketchy, evidence suggests that vaccine recipients were significantly more likely to develop the condition within several weeks after inoculation.*

At present, leading neurologists do not anticipate a government-led vaccine campaign against H1N1 S-OIV 2009, given the low mortality rate (0.5%) of the current swine-flu pandemic and the historical risk of GBS with inoculation.

* The typical background rate of GBS is about 1.5 per 100,000 individuals.

As of yesterday, 74 countries had reported a total of 27,727 cases of swine flu, the majority of which have occurred in Mexico and the United States. But the virus has caused only 141 deaths, for an overall mortality rate of about one half of 1%.