Recently in Infectious diseases Category
The CDC provides the latest tally for pandemic H1N1 in the United States, from April 2009 through January 16, 2010:
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.
The continuing mumps outbreak in New York and New Jersey—which has affected more than 1500 individuals, most of them Orthodox Jewish boys—is traced to an 11-year-old who visited Britain in June of last year, reports the CDC.
More than 7400 laboratory-confirmed cases of mumps were recorded in the United Kingdom in 2009. The case number is lower than those seen during the epidemic of 2004 and 2005, the UK Health Protection Agency reports, but greater than cases reported during 2007 and 2008.*
The US mumps outbreak continues despite the relatively high rate of vaccination among the infected—88% had received at least 1 vaccine dose; 75%, 2 doses. However, the mumps component of the MMR vaccine provides less protection than the measles or rubella components. The CDC provides an estimated mumps-vaccine efficacy of 73%-91% after 1 dose and 79%-95% after 2 doses.
Among the most common symptoms of mumps among boys is orchitis, or testicular inflammation. According to one source, about 20% of prepubertal boys will develop this painful condition. Consequent risks include testicular atrophy and sterility.
* A resurgence of mumps and measles cases in the United Kingdom is blamed on reduced vaccination rates--which are believed to be (at least partly) the result of the 1998 study of Andrew Wakefield et al linking the MMR vaccine with autism. The discredited study was recently retracted by The Lancet.
Photo of child with parotid gland swelling due to mumps from the CDC/NIP/Barbara Rice.
That rang 12 years ago.
Yesterday, editors of The Lancet officially retracted publication of a 12-year-old debunked study that linked the MMR vaccine to autism, according to the journal's web site, numerous news sources, and countless blogs. The study is believed to be responsible for declining vaccination rates among children in the United Kingdom and the resurgence of measles.
The journal's decision comes on the heels of an announcement last week from the UK's General Medical Council, which found that 3 of the article's authors—Andrew Wakefield, John Walker-Smith, and Simon Murch—did not act in the best interests of the study's 12 pediatric enrollees. Wakefield, in particular, was cited for "callous disregard" toward his subjects, by plying them with a few pounds in exchange for blood samples at a birthday party. The GMC's report is provided courtesy of Kathleen Siedel at her neurodiversity blog.
The Council's investigation of Wakefield and others was prompted by the investigative reporting of Brian Deer from The Sunday Times. Beginning in 2004, Deer alleged that Wakefield not only held significant financial conflicts of interest, but that he actually manufactured data. Responding to Deer's initial investigation, 10 of the study's 13 authors (including Walker-Smith and Murch) retracted their "interpretation" in a letter to The Lancet.
So where does a discredited UK doctor go? Austin, Texas, evidently. Wakefield is Executive Director of The Thoughtful House Center for Children, a questionable research and treatment center for children with autism. However, Wakefield does not have a license to practice medicine in the state, according to the online database of the Texas Medical Board.
In an apparent effort to atone for every Microsoft error message, the Gateses are committing $10 billion USD over the next 10 years for the research, development, and delivery of mortality-reducing vaccines to "the world's poorest countries." Some details of the financial pledge are available in today's press release from the couple's philanthropic foundation. The donated money is in addition to the foundation's already committed $4.5 billion for vaccine R&D.
The foundation's new support is motivated by recent data from the Johns Hopkins Bloomberg School of Public Health, which showed that a 90% vaccination-coverage level* in developing countries would prevent the deaths of about 7.6 million young children during the next decade. The number of lives saved could be ramped up to 8.7 million, if a malaria vaccine is introduced in the year 2014.
Another inspiration for the Gateses' pledge is the success of the rotavirus vaccine. In this week's NEJM, pooled results of a randomized, multicenter trial in South Africa (n = 3166 infants) and Malawi (n = 1733 infants) showed that a live, oral rotavirus vaccine (Rotarix; GSK) reduced cases of severe gastroenteritis due to the organism by 61% (4.9% vs 1.9%).**
Also reported in this week's issue, the recent introduction of rotavirus vaccines in Mexico reduced diarrhea-related deaths by 35% among children younger than 5 years of age (18.1 vs 11.8 deaths per 100,000 children). The life-saving benefit of vaccination was even more apparent among infants younger than 11 months (41% mortality reduction).
Vaccine researchers looking for a chunk of the Gateses' big money can start here. But the foundation only accepts letters of inquiry (LOIs) from 501(c)(3) organizations and other nonprofits. Individuals need not apply.
* Which would include new vaccines for diarrheal illnesses and pneumonia.
** Although there was no significant difference in mortality, 2.5% vs 2.6%.
Pandemic influenza may "notably increase" the overall death rate for pregnant American women in 2009. The prediction is based on data from pregnant or postpartum women who died of infection with the 2009 H1N1 virus in California during a 4-month period. An assessment of flu-related hospitalizations and deaths in this population is available in the latest issue of the NEJM.
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.
|
Patient Feature |
Pregnant |
Postpartum |
Not Pregnant |
P Value [b] |
|
Chronic illness, % |
34 |
25 |
60 |
<.001 |
|
Asthma, % |
16 |
0 |
28 |
.04 |
|
Nongestational diabetes, % |
2 |
0 |
15 |
.002 |
|
Immunosuppression, % [c] |
3 |
0 |
15 |
.006 |
|
Neurologic disorder, % |
1 |
12 |
10 |
.009 |
|
Hypertension, % |
5 |
12 |
17 |
.009 |
|
Gastrointestinal disease, % |
2 |
0 |
14 |
.006 |
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.
* Instead of the historically expected East Asia.
** Estimated in the United States at 0.007%-0.032%.
Depiction of H1N1 virus from Wikipedia.
No. 4: Medical Science Crawls Toward an HIV Vaccine
In October, peer-reviewed results of a mammoth Thai trial (>16,000) showed modest (and possibly statistically significant) protection against HIV infection after a series of shots in moderate-risk adults. The trial results, although only marginally positive, are generating optimism after 2 decades of failure and, specifically, 3 negative trials (published in 2005, 2006, and 2008) of assorted vaccine regimens in high-risk adults.
In the latest placebo-controlled Thai study, vaccine efficacy—defined as the percentage reduction of HIV infection—climbed to a significant 31.2% in the modified intent-to-treat analysis.* Compare this value with the highest estimated vaccine efficacy in the previous large-scale studies, only 6%, and you get an idea of why some investigators believe that we're actually getting somewhere.
The trial's vaccine regimen consisted of 4 "priming" injections of a recombinant canarypox-vector vaccine (Alvac-HIV; sanofi-pasteur) and 2 booster shots of a recombinant glycoprotein-120 subunit vaccine (AIDSVAX B/E; VaxGen). The prime-boost vaccination series was chosen on the basis of previous trials (Belshe et al, 1994; Russell et al, 2007; and AIDS Vaccine Evaluation Group 022 Protocol Team, 2001), wrote the study investigators. Previously unsuccessful vaccine regimens in high-risk adults consisted of 7 injections of VaxGen's AIDSVAX B/B vaccine; 7 injections of VaxGen's AIDSVAX B/E vaccine; and 3 injections of Merck's trivalent adenovirus-vector vaccine.
The next steps are to determine the immune mechanisms that conferred protection in the Thai trial and to create a vaccine that will maximize those responses.
HIV = human immunodeficiency virus.
* Which excluded 7 individuals who were discovered to have HIV infection at baseline.
The estimated mortality rate of pandemic influenza in England is 0.026% (case fatality rate, 26 per 100,000), according to a report in this week's BMJ. This rate is similar to the mid-level US mortality rate that has been estimated by CDC officials.
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.)
|
Age Group, y |
Case Fatality Rate* |
Mortality Rate, |
|
<1 |
30 (2-260) |
0.030 |
|
1-4 |
27 (3-120) |
0.027 |
|
5-14 |
11 (3-36) |
0.011 |
|
15-24 |
12 (3-40) |
0.012 |
|
25-44 |
30 (10-88) |
0.030 |
|
45-64 |
64 (21-200) |
0.064 |
|
≥65 |
980 (300-3200) |
0.980 |
|
All |
26 (11-66) |
0.026 |
|
Age Group, y |
US Case Fatality Rate* |
US Mortality Rate, |
|
0-17 |
7 |
0.007 |
|
18-64 |
28 |
0.028 |
|
≥65 |
32 |
0.032 |
|
All |
21 |
0.021 |
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.
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.
Lack of funds may stall the Measles Initiative, a multi-organization program designed to reduce the worldwide mortality of measles. Despite the fact that all regions, except for Southeast Asia, have achieved the United Nations goal of reducing measles mortality by 90% from 2000 to 2010 (and have, thereby, prevented 12.7 million measles deaths), the reduction in measles mortality has leveled off since 2007, and the Initiative is facing a funding gap of $59 million, reports the World Health Organization. (WHO's complementary report on the progress toward reducing measles-related deaths can be found in the latest issue of the MMWR.)
Lack of financial resources could suspend the Initiative's pivotal vaccination efforts next year in densely populated regions like China, Indonesia, Pakistan, Bangladesh, Vietnam, Nigeria, and Ethiopia. And because measles is highly contagious, the disease can flourish rapidly if immunity is lacking, report WHO officials.
Although measles-related deaths fell 78% globally, from 733,000 in 2000 to 164,000 in 2008, 77% of last year's deaths (126,000) occurred in Southeast Asia. Experts fear that there could be a significant uptick in measles-related deaths, to an estimated 1.7 million between 2010 and 2013, if vaccination efforts do not continue.
Estimated No. Measles Deaths, 2000-2008, and Projected Deaths, 2009-2013
§ 95% uncertainty intervals.
