Recently in Epidemiology Category
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.
About 16% of people with mild cognitive impairment (MCI) progress to Alzheimer disease during the course of a year, according to new data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Progression from MCI to AD, which correlated with baseline CSF levels of amyloid beta-42, occurred despite the prevalent use of available antidementia therapies (~50% of subjects).
ADNI investigators followed up more than 800 elderly subjects (mean age, ~75 years) with normal cognition, MCI, or AD. Baseline data were notable for remarkably high mean verbal IQ scores and education levels among all 3 groups and relatively high percentages of APOEε4 carriers among individuals with MCI or AD.
|
Baseline Feature |
Normal |
MCI |
AD |
P Value |
|
Mean education, y |
16 ± 2.9 |
15.7 ± 3.0 |
14.7 ± 3.1 |
<.001* |
|
Estimated mean premorbid verbal IQ |
120 |
116 |
114 |
— |
|
APOEε4 carriers, % |
26.6 |
53.3 |
66.1 |
<.001* |
|
Mean MMSE score |
29.1 ± 1.0 |
27.0 ± 1.8 |
23.3 ± 2.1 |
<.001** |
|
Mean ADAS-cog score |
6.2 ± 2.9 |
11.5 ± 4.4 |
18.6 ± 6.3 |
<.001** |
|
AChEI, % |
0 |
43.7 |
84.9 |
— |
|
Memantine, % |
0 |
10.8 |
47.4 |
— |
|
Combined therapy, % |
0 |
8.8 |
40.6 |
— |
|
Mean CSF Aβ-42 level, pg/mL |
206 ± 5 |
164 ± 4 |
143 ± 4 |
<.001** |
* Control vs MCI amd MCI vs AD.
** Control vs MCI; control vs AD; and MCI vs AD.
On the basis of a battery of cognitive and neuropsychological tests, the estimated rate of conversion from normal cognition to MCI was 1.4% during 12 months, and that from MCI to AD was 16.5%. Eight individuals with MCI reverted to normal cognition, and 2 subjects with AD reverted to MCI at 1 year.
Among individuals with MCI, scores on a range of assessments (eg, MMSE, ADAS-cog, clock drawing) could be used to predict progression to AD. Lower CSF levels of amyloid beta-42, which did (and are known to) correlate with higher ADAS-cog scores, were also associated with cognitive decline in normal people and those with MCI.
In July, the ADNI reported that structural abnormalities on MR images are more useful than known CSF biomarkers for discriminating among people with AD, amnestic MCI, or normal cognition, but that the use of MR imaging and CSF analysis is more diagnostically helpful than each measure individually.
AChEI = acetylcholinesterase inhbitor; ADAS-cog = Alzheimer's Disease Assessment Scale, Cognitive Subscale; APOE = apolipoprotein E; CSF = cerebrospinal fluid; MMSE = Mini-Mental State Examination; MR = magnetic resonance.
Photograph: Atrophied brain of person with AD from National Institute on Alcohol Abuse and Alcoholism.
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. 7: Pinning Down the Risk of PML With Tysabri
So do the benefits of Tysabri (natalizumab; Biogen Idec/Elan) in MS still outweigh the potentially deadly risk of progressive multifocal leukoencephalopathy (PML)?
Uh, probably. But as they say: Axe your doctor.
Head-to-head data with the standard treatment of interferon beta don't exist; but if we're using the common benchmark of placebo treatment,* the monoclonal antibody reduces the risk of clinical relapses by about 70% at 1 year. The interferon betas are about half as good.
At last count (October), there were 24 cases of PML linked to Tysabri since the drug's reintroduction into the marketplace in 2006, said the European Medicines Agency. But the risk of PML appears to depend on the length of therapy—an issue addressed in September by Shirley Wang of the WSJ.
According to Biogen Idec, the absolute risk of PML with Tysabri is 0.01%. However, the risk appears to increase with prolonged therapy (eg, >12 months)—which necessitates the use of an actuarial calculation, argued Wang and Cleveland Clinic neurologist Robert Fox in the WSJ. Wang calculated the actuarial risk of Tysabri-related PML at about 0.08%, and Fox reported a PML risk of more than 0.1%, when therapy extends beyond 30 months. The increased risk of PML with prolonged therapy has led some neurologists to advocate the use of so-called drug holidays; although data to support their use are lacking.
The risk of subclinical PML with Tysabri therapy appears to be substantially higher. In September, the NEJM published a study by Chen et al, who detected a significant rise in titers of JC virus, the cause of PML, among 19 MS patients after 1 year or longer of therapy. (The same NEJM issue also offered 2 case reports of attempted, and reasonably successful, therapy for PML.)
A quantitative risk-benefit analysis, published last year in Neurology, indicated that the "actual" risk of PML with Tysabri would have to increase more than 7 times to reduce the relative benefit of therapy below that of interferon beta. (The authors used an annual PML risk that was based on the published risk estimate of 1 per 1000 patients treated for an average of 17.9 months.)
The flagship organization for US neurologists, the American Academy of Neurology, provided its most recent recommendations for the use of Tysabri in MS last year. Because of the associated risk of PML, the AAN recommended that the drug be reserved for selected patients who are intolerant of other therapies (eg, interferon beta or glatiramer acetate [Copaxone; Teva]) or whose disease is unresponsive to other therapies.
This month, the journal Multiple Sclerosis printed a company-sponsored supplement, defining "best practice recommendations" for the use of Tysabri. The 6-member panel, which was selected by Biogen Idec and led by neurologist Patricia Coyle, encouraged the "earlier and more rapid transition from first-line treatment to Tysabri." Editorial support for the supplement was provided by The Falk Group, LLC, a pharmaceutical marketing and advertising agency—a fact that doesn't necessarily negate the supplement's recommendations but makes their objectivity suspect.
In the meantime, the SEC is investigating Elan for its filing dated July 31, 2008, in which the company described 2 European patients with MS who developed PML after prolonged Tysabri monotherapy. The reason for the SEC's investigation of this particular filing remains unclear.
* Which is, admittedly, problematic.
From 2002 to 2006, the prevalence of autism spectrum disorders (ASDs) increased significantly among 8-year-old American boys and girls.* This conclusion is based on a newly published, retrospective review from the CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. The CDC investigators ascribe the increased prevalence of ASDs to improved recognition and documentation, but they cannot dismiss a concomitant "true" increase in ASDs.
On the basis of an examination of health and education records at 11 US sites participating in the ADDM Network, the average prevalence of ASDs among 8-year-olds in 2006 was 9.0 per 1000 children (range, 4.2-12.1), or nearly 1%. Among the 10 US sites that provided data for both 2002 and 2006, the overall prevalence of ASDs increased significantly, by 57%. This finding contrasts with a comparison of data from 2000 and 2002, which revealed no significant increase in the overall prevalence of ASDs.
Below are the tabulated prevalence values for ASD at the 10 common sites, stratified by sex, ethnicity, and IQ. These data show consistent across-the-board increases in ASD among the assessed pediatric subgroups.
|
Group |
ASD Prevalence, |
Statistically Significant Increase, % | |
|
2002 |
2006 | ||
|
Overall |
6.0 |
9.4 |
57 |
|
Boys |
9.5 |
15.2 |
60 |
|
Girls |
2.3 |
3.4 |
48 |
|
Non-Hispanic white children |
6.6 |
10.2 |
55 |
|
Non-Hispanic black children |
5.4 |
7.6 |
41 |
|
Hispanic children |
3.2 |
6.1 |
91** |
|
IQ ≤70 |
2.6 |
3.5 |
35 |
|
IQ 71-85 |
1.0 |
1.4 |
90 |
|
IQ >85 |
1.8 |
3.1 |
72 |
The CDC investigators note that the average prevalence of ASDs was higher at sites that had access to health and education records (10.0) than at sites with only health records (7.5). This observation suggests that more opportunities for ASD documentation increase the prevalence of the condition (artificially). Investigators also found that, generally, ASDs were recognized at younger ages in 2006 than in 2002. (And if I'm correctly reading the CDC data, they indicate that significantly more children with below-normal IQs are being classified as having ASDs—a phenomenon that may also explain an increased prevalence of ASDs.)
Most of the children identified as having ASDs in 2006 (70%-90%) displayed developmental problems (eg, language delay) before the age of 3 years; however, the average age at diagnosis was considerably later, at about 4½ years (suggesting lost time for crucial behavioral interventions). In 2006 assessment, most 8-year-olds with ASDs (76%-96%) were receiving special education through public-school programs, under a wide variety of rationales (eg, autism, emotional disturbance, learning disability, language impairment, etc).
The CDC advises that the ADDM Network surveillance sites were selected "on the basis of their ability to conduct active ASD records-based surveillance," and were not intended to be a nationally representative sample. However, the Network accessed the records of more than 300,000 children, representing nearly 8% of all 8-year-olds in the United States.
Data supporting the approximate 1% prevalence of ASDs include a 2007 parent survey and several contemporary international studies, says the CDC.
* ASDs are defined on the basis of documented behaviors consistent with the DSM-IV-TR criteria for autistic disorder; pervasive development disorder, not otherwise specified; and Asperger disorder. The age of 8 years is identified as a "reasonable index age at which to monitor peak prevalence for ASDs." ASD symptoms are usually observed before the age of 3 years.
** The whopping increased prevalence of ASDs in Hispanic children is attributed to the increase in the Hispanic population overall and a prevalence increase of 144% in Arizona. The other Network sites did not reveal an increased prevalence of ASD among Hispanic children.
Unexplained bone-marrow failure (ie, agranulocytosis) in residents of New Mexico, Washington, and Canada led to the discovery of levamisole, an antiparasitic antibiotic, as a prevalent cutting agent in cocaine. A report of the investigation by public health officials, which began last year and identified 21 affected Americans, is available in the latest issue of MMWR.
According to the report, levamisole, as a treatment for rheumatoid arthritis or breast cancer, causes agranulocytosis in 2.5%-13% of patients; however, use of the drug is currently and primarily restricted to veterinary practice (eg, to deworm livestock and aquarium fish).
As of July of this year, about 70% of seized cocaine entering the United States contained levamisole, according to the DEA. The concentration of the additive is approximately 10%, says the agency. Given these statistics, MMWR editors suspect that levamisole-associated agranulocytosis due to cocaine use is vastly underrecognized and underreported.
The reason why levamisole, in particular (versus, say, Italian baby laxative a la Atlantic City) is added to cocaine "remains unclear." Online sources indicate that the antibiotic is a white- to pale cream-colored, odorless or nearly odorless, crystalline powder.
According to the SF Chronicle, by way of Wikipedia, levamisole and cocaine were detected in the body of DJ AM.
Fifty-four of 57 Nigerian children died between October 2008 and January 2009 after receiving a liquid acetaminophen preparation that was tainted with diethylene glycol (DEG). Exposure to the branded teething product, My Pikin,* was determined in 96% of the identified cases of unexplained acute renal failure (ARF) in the 57 children, according to a retrospective surveillance study performed by Nigerian officials, the CDC, and the US FDA. Their report is available in the latest issue of the MMWR.
The surveillance study was prompted by clusters of unexplained ARF cases in very young children (≤3 years of age) among hospitals in Lagos, Kadun, and Osun in the fall of last year. Initial reports led to the identification of the DEG-tainted product, a full product recall, and the shutting down of the responsible manufacturer in Lagos, Barewa Pharmaceuticals. Despite a nationwide recall and a press release in November of last year, which resulted in the confiscation of 7616 of 15,000 bottles of the contaminated drug, more than a quarter of the affected children received the product after the recall was announced.
Among children for whom data were available, the median time from drug exposure to ARF was 5.6 days (range, 0-24 days), and the mean time between the onset of ARF and death was 6.8 days (range, 1-19 days). Treatments with dialysis, received by 24 children, and the ethylene-glycol antidote fomepizole, received by 2 children, did not appear to prolong survival.
The MMWR editors report at least 12 episodes of DEG contamination in oral or topical medications during the last 70 years, which have caused at least 450 deaths. (Most of these episodes are described here and here.) The contamination was almost always due to the intentional economic-driven substitution of DEG for the more expensive solvents of glycerin or propylene glycol. (An account of the US deaths that occurred in 1937 due to a DEG-tainted antibiotic solution has been provided in numerous serial posts at this blog [search for "sulfanilamide" or "Massengill," for example], and the deceased are listed on this page.)
Prevention of DEG-contaminated drugs is easy and cheap, according to the editors. "Simple, rapid, and low-cost assays" that use thin-layer chromatography are available to detect and measure DEG at levels of 2% in liquid acetaminophen products and 6% in glycerin, they report.
* DEG accounted for 17%-21% of the My Pikin liquid medication by weight in sampled bottles. According to the MMWR, another contaminated acetaminophen-based syrup, made by a different manufacturer, was discovered to contain 0.5% DEG.
Photo of My Pikin Baby Teething Formula from Vanguard.
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.
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.
Vaccines for pandemic influenza appear to be as safe as current seasonal influenza vaccines, reports the CDC. The Center's preliminary assessment of safety reports from the US Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) are available in the latest issue of the MMWR.
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.
