Recently in Infectious diseases Category

Released yesterday, the FDA's inspection report of facilities at Wright Company and Quality Egg, ground zero for the recent egg-borne salmonella outbreak, is either an outing of a filthy outlier in the business of mass agriculture or a revelation of the filthy business of mass agriculture. How much chicken shit is acceptable in and around hen houses is virtually unknowable for the 99% of Americans who don't farm. But 4-to-8-feet piles seem excessive.

According to the FDA, the laying facilities in north-central Iowa, managed by Austin "Jack" DeCoster's son, Peter, were plagued with the following:

• Massive and escalating amounts of chicken excrement.

Inspectors reported that "outside access to the manure pits...had been pushed out by the weight of the manure, leaving open access to wildlife or domesticated animals." Manure, aka "dark liquid," was also observed to be seeping through the concrete foundation of the outside of the laying houses. Uncaged birds were seen using the piled-up manure to access laying areas.

• Standing water near manure pits.
• Live rodents, namely mice, who evidently had free access into and out of the laying houses.
• And lots and lots of flies and maggots. "The live flies were on and around egg belts, feed, shell eggs and walkways in different sections of each egg laying area," the inspectors wrote. "In addition, live and dead maggots too numerous to count were observed on the manure pit floor..."

Most important, perhaps, was the fact that the FDA found evidence of Salmonella enteritidis in multiple locations, including in manure and chicken feed.

The FDA's inspection took place from August 12 to August 30, longer than 2 weeks. Given the duration of the inspection (and the possibility that facility managers knew that the FDA was coming), it seems that officers at Wright County and Quality Egg actually had the opportunity to clean up their facilities. If so, the conditions of these businesses may have been, in reality, considerably worse.

At the heart of Cedillo v. US DHHS was the claim that thimerosal-containing vaccines damaged Michelle Cedillo's immune system, which then allowed attenuated measles virus in the MMR vaccine to injure her brain, thereby causing autism. It's a convoluted (and medically illogical) argument, but one that was ostensibly supported, at least in part, by data from a questionable Dublin-based laboratory, Unigenetics.

In the original 2009 decision against the petitioner in the Omnibus Autism Proceeding,* Special Master George Hastings found the detection of vaccine-derived measles virus by Unigenetics in an intestinal sample from Cedillo "not reliable." The decision was based partly on expert testimony from Stephen Bustin, PhD, a UK-based molecular biologist who, as part of UK vaccine litigation, had obtained access to the Unigenetics laboratory and some of its relevant data. On the basis of a number of procedural flaws at Unigenetics, Bustin testified both in the UK and US courts that the company's work was plagued with potentially contaminating errors. Bustin also suggested that results from Unigenetics might even be fraudulent, after reviewing some of the laboratory's altered notebooks.

Access to documents from Unigenetics, on which Bustin based his expert opinion, was the crux of a recent appeal by Cedillo's parents to the US Court of Appeals for the Federal Circuit. This appeal was denied Friday, August 27th. And while the appeal court ruled that Special Master Hastings "erred in permitting the government to introduce the expert reports and testimony of Dr. Bustin because the government did not make available the underlying Unigenetics documents upon which Dr. Bustin relied," the court also noted that Hastings had given the petitioners virtually every opportunity to obtain this information from the UK court themselves, which they apparently did not try to do. (It should be noted that the government argued against the reliability of Unigenetics with other expert testimony. It is presumed on this basis that the Special Master's error was not a reversible one.)

In 2007, the government, in its case preparation, successfully petitioned the UK court to release the Bustin reports, but it did not request the laboratory notebooks or other data on which Bustin relied. The appellate decision further describes the background facts, 

The government explained at oral argument that UK counsel informed them that an application to the UK court requesting "everything" from the UK litigation would be denied as overbroad, and as a result, they needed to narrow their request to the most essential items. The government therefore subsequently "honed down" their request to cover solely the three reports, two of which were filed by Dr. Bustin, that they eventually obtained.

The upshot: Cedillo v. US DHHS has been put to bed.

In a coda to this case, it can be said that life, outside the courtroom, moves relatively quickly and in curious directions. Unigenetics dissolved as a company 5 years ago, although its former director, pathologist John O'Leary, is evidently still working in Dublin at Trinity College. In 2008, O'Leary, in an apparent effort to regain academic credibility, was coauthor of a multi-institutional study ("Lack of association between measles virus vaccine and autism with enteropathy: a case-control study" in PLoS One) that essentially negated the results produced by his own company for Cedillo.

DHHS = Department of Health and Human Services; MMR = measles-mumps-rubella.

* Which was affirmed by Judge Thomas Wheeler in the US Court of Federal Claims.

Gird yer loins, Austin "Jack" DeCoster. You're about to receive uncompromising media and Congressional attention. And the metaphoric (and partially ironic) tarring and feathering may long be overdue, if archived news stories are any indication.

The growing recall of Salmonella-tainted eggs is focusing widespread attention on DeCoster (photos here and here), who is the owner of Wright County Egg in Galt, Iowa, and Quality Egg, a supplier of chicks and feed to Hillendale Farms in New Hampton, Iowa. On August 13, Wright County recalled 380 million eggs that it had shipped since May 19. Hillandale recalled 170 million eggs on Friday, according to USA Today.

The FDA says that the Wright County eggs had been distributed to "food wholesalers, distribution centers and food service companies in California, Illinois, Missouri, Colorado, Nebraska, Minnesota, Wisconsin and Iowa." These companies distribute eggs nationwide. The recalled eggs were packaged under the brand names of Lucerne, Albertson, Mountain Dairy, Ralph’s, Boomsma’s, Sunshine, Hillandale, Trafficanda, Farm Fresh, Shoreland, Lund, Dutch Farms  and Kemps. [Writer's note: Because Lucerne consistently provides the least expensive dairy products in Chicago-area Dominick's stores, I've always been skeptical of their origin. BTW, Lucerne's cheese is absolutely tasteless.]

DeCoster, who also has a history in hog farming, is reportedly no stranger to alleged health, safety, or labor violations, which date back to at least the mid-1990s.

Reports USA Today,

• In 1997, DeCoster Egg Farms of Turner, Maine, agreed to pay $2 million to settle health and safety citations. Employment conditions at DeCoster's farm were publicly denounced by Labor secretaries Robert Reich (he called them "dangerous and oppressive") and Alexis Herman (who said they were "simply atrocious"). See the NYT's "In Maine, Egg Empire Is Under Fire."
• In 2000, Iowa (as in the state of) called DeCoster a "habitual violator" of environmental regulations. One infraction: allowing hog manure to run off into waterways. DeCoster was prohibited from building new farms. See a 2000 statement from the Iowa Attorney General.
• In 2002, DeCoster paid more than $1.5 million in a settlement with the EEOC regarding sexual harassment claims (including rape) from Mexican women who worked at Wright County.

Other violations, including those of animal mistreatment, are reported by the Washington Post and detailed by Mercy for Animals here and here. DeCoster's heavy use of battery cages to house chickens has been linked to the spread of Salmonella on egg farms.

More than 1000 Americans have been sickened by Salmonella-tainted eggs in the current recall, according to the latest news reports, and the obligatory litigation is in the works. This may be one case in which it is reasonable to root for personal-injury attorneys. 

Last week's report

of a beta-lactam-resistant superbug in the United Kingdom,* which was likely imported from India, highlights the infectious risks associated with medical tourism, according to an accompanying editorial. The growing trend of traveling to get medical care in non-Western countries—particularly for procedures not covered by insurance (eg, gastric bypass)—is expected to grow in India at an annual rate of 30%, says a 2009 news report. By 2015, medical tourism in India will be a 95-billion-rupee or $2-billion industry (if I'm calculating correctly).

At least one Indian doctor is accusing the report's corresponding author, who happens to be from the UK, of fear mongering and racism (despite the fact that multiple nationalities are represented by the listed investigators).

* Specifically Klebsiella pneumoniae and E. coli containing New Delhi metallo-beta-lactamase 1.

Scanning electron micrograph of E. coli bacterium from CDC/Janice Haney Carr.

While most of us are consumed with the Avandia vote or diverted by the umpteenth procedure on Dick Cheney's failing heart, Wayne Koff and Seth Berkley of the International AIDS Vaccine Initiative promise the existence of an effective HIV vaccine...in the not-too-distant future. Their perspective on vaccine development, in the context of the upcoming International AIDS Conference in Vienna, is available in this week's NEJM.

The reasons for their enthusiasm:

• Encouraging results from the large vaccine trial (RV144) in Thailand, which was reported last year.
• The prevention or control of infection with simian immunodefiency virus (a monkey correlate of HIV) in preclinical studies by using "new vaccine approaches."
• The identification of "vulnerable" HIV targets by using broadly neutralizing mAbs.

Data from these investigations can and/or will be used to tweak (for lack of a better word) candidate vaccine regimens against HIV. Specifically in the short term, investigators will attempt to define the immune mechanisms that conferred protection in the Thai trial and then create a vaccine regimen (eg, multiple prime and boost shots) to maximize those responses. Koff and Berkley predict follow-up clinical trials to be under way by 2013. (That's sooner that the legislated kick-off of ObamaCare.)

Successful vaccine development will necessitate the cooperation of government, academia, and industry and will demand, of course, lots of money. Koff and Berkley advise that the global financial crisis should not thwart the forward movement of vaccine development at this promising stage. One visible backer is Bill Gates, who recognizes the big hurdles to a successful HIV vaccine and is scheduled to speak at the Conference, says the WSJ Health Blog.

Let's make no mistake: Disclosing potential pharma-related conflicts of interest among healthcare professionals, when possible, is desirable. But the idea that a few thousand pounds, Euros, or whatever from Roche or GSK led any WHO-advising expert to recommend the government stockpiling of Tamiflu and Relenza (the only drugs that exist to treat influenza symptoms), stretches credulity.

Nevertheless, that's what Deborah Cohen and Philip Carter would evidently like us to entertain in their BMJ "investigative" piece of last week. The writers also float the idea that WHO-advising physicians should have no industry ties whatsoever—a both unrealistic and unwise proposal. In such cases, WHO would be basing its recommendations for the planet on the thoughts of physicians who are actually less knowledgeable about proprietary drugs.

In an ABCNews report on the BMJ article, John Treanor, a vaccine expert from the University of Rochester essentially concurred: "[I]ndividuals with the greatest experience and insight into these interventions will almost always either be employees of industry or individuals paid by industry to conduct studies."* Likewise, John Bartlett of Johns Hopkins said, "[T]he people in medicine who know most about flu are often conflicted because they also are advisors to pharma and often do the big trials that are funded by pharma."

Let's also remember that Cohen and Carter are in the cushy position of being able to make their anti-WHO criticisms in the aftermath of what was a mild influenza pandemic.** Would they have had any problem lambasting WHO for a lack of preparedness if the pandemic had been far worse and the supplies of anti-influenza drugs had been limited? Probably not.

This specter of journalistic duplicity was echoed by ABC's quoted experts:

Treanor: "I think even [Cohen and Carter] would have to agree that there really was no choice here but to prepare for a pandemic. If there had been a severe pandemic and there had been no preparations, the outcome (and the outcry) would have been far worse."

John Barry, author of The Great Influenza: "This is a classic case of 20-20 hindsight, with some witch hunting thrown in." 

Last, biosecurity expert Donald A. Henderson concluded about Cohen's and Carter's angle: "WHO is a handy whipping post. I would characterize this focus on WHO as a 'cheap shot.'" 

* Treanor also acknowledged that a lack of industry ties doesn't necessarily remove bias. Researchers "will always view the product they do work on in a positive light, even if they weren't paid by industry," he said.

** At least as of now.

06/09/10 addendum: Responding to the BMJ accusations, WHO Director-General, Margaret Chan, denies that commercial interests were considered in WHO's decision-making process "for one second," reports Canada's Globe and Mail. "The bottom line...is that decisions to raise the level of pandemic alert were based on clearly defined virological and epidemiological criteria. It is hard to bend these criteria, no matter what the motive," Chan rebutted. (The full text of Chan's letter to the BMJ can be found here.) 

Chan also responded that the continued anonymity of 3 members of WHO's "emergency" committee is to protect them from undue influence, including undue commercial influence. It is reported that their identities will be revealed once their service is complete.

In the meantime, an independent committee is reviewing WHO's handling of the 2009 H1N1 pandemic.

Preliminary data

from the CDC's Emerging Infections Program* (EIP) suggest a small, but statistically significant, increased risk of Guillain-Barre syndrome (GBS) with receipt of the 2009 pandemic H1N1 vaccine. However, the risk, 0.8 excess cases per 1 million vaccinations, is comparable to that seen with other seasonal flu vaccines and is much lower than the observed risk of GBS during the 1976 swine-flu vaccination program (~10 excess cases per 1 million vaccinations). The excess risk of GBS with the 2009 pandemic H1N1 vaccine is also much lower than the risk of hospitalization or death due to illness with the virus itself (222 and 9.7 per 1 million).

Within EIP's surveillance area, there were 326 cases of GBS (meeting case criteria) between October 1, 2009, and May 10, 2010. Among these patients, 27 received documented vaccination against the 2009 pandemic H1N1 virus during the 42 days preceding their illness, and 274 did not (the vaccine status of 25 was unknown or "pending ascertainment"). Consequently the estimated age-adjusted rates of GBS were 1.92 and 1.21 per 100,000 person-years among vaccinated and unvaccinated persons, respectively. These data led to an attributable excess risk of GBS with vaccination of 0.8 per 1 million vaccinations.

Once again, it's important to remember that association does not mean causation. For instance, many of the vaccinated persons (59%) also reported illness symptoms during the 42 days before GBS onset, which is consistent with many cases of non-vaccine-related cases of GBS. Vaccination, in these cases, could have been completely incidental to the development of neuropathy. Moreover, there was no temporal clustering of GBS onset after vaccination (eg, at 2 weeks), suggesting that vaccine was not causally related to illness. Vaccinated persons with GBS were not sicker, nor did they suffer worse outcomes, than unvaccinated individuals with GBS.

The CDC advises that the final assessment of the EIP data will be available in the fall of this year. Other safety databases, like the Vaccine Safety Datalink, have not shown an association between GBS and receipt of the 2009 pandemic H1N1 vaccine.

* A collaboration among the CDC, state health departments, and academic centers in 10 states. Surveillance covers about 45 million individuals.

While the NYT may have a story in the charge that OSHA isn't in lockstep with biotech safety, throwing up ex-Pfizer scientist Becky McClain as an example is simply irresponsible. By all reports, McClain was diagnosed with hypokalemic periodic paralysis, a genetically determined illness—which she, nevertheless, dubiously claimed was caused by a lentivirus from a Pfizer laboratory. (For background on this story, go here.)

Tossing McClain's case into the OSHA-biosafety mix also does a disservice to those very few scientists who probably did acquire disease in the workplace, like...

• Ru-ching Hsia, a Department of Agriculture scientist who developed coma-inducing hemolytic uremic syndrome after becoming infected in 2003 with laboratory-derived E. coli O157:H7;
• Jeannette Adu-Bobie, who contracted meningococcal septicemia in 2005 while working in a New Zealand vaccine laboratory; and
• Malcolm Casadaban, a U of C researcher who died September 13, 2009, of infection caused by a weakened version of Yersinia pestis.

According to Wikipedia, "[t]he last known case of a scientist dying from a pathogen he was studying was Howard Taylor Ricketts, who died of typhus in 1910."*

* The Rickettsiaceae guy!

OSHA = Occupational Safety Health Administration (which reportedly denied McClain's claim).

A recent, independent search for viral DNA in certain vaccines* revealed nucleic acids of a common pig virus (PCV1) in GSK's Rotarix but not in Merck's Rotateq. The results of the California-based study, which were published online last month in the Journal of Virology, led the FDA to suspend the use of Rotarix in March—despite the fact that 1) the DNA fragments were present from the vaccine's inception** and 2) PCV1, a ubiquitous virus, is not known to cause disease in humans or pigs. (For more background on this story, start here.)

Now the FDA is reporting that Merck's vaccine contains DNA fragments of PCV1 and PCV2. Merck evidently detected the nucleic acids in its product with a more sensitive assay, reports the WSJ. PCV2, like PCV1, does not cause human disease; however, it may sicken pigs. Merck and the FDA speculate that the source of the DNA fragments may be trypsin, a protease which is used in the cell-culture growth of the attenuated vaccine virus.

Commercial trypsin may be obtained from bovine or porcine pancreas. According to one commercial pamphlet, the enzyme can be contaminated with porcine viruses, especially porcine parvovirus (which is not known to cause human disease). There is evidently some give and take when using methods (eg, chemical or filtering) to inactivate or remove contaminating viruses during trypsin manufacture. Gamma irradiation and heat inactivation, while "officially recognized," are "aggressive" and affect trypsin yield, says PAA. Short wave-length UV light is advocated by the company to destroy viral nucleic acids, without compromising the biologic activity of trypsin.

According to the FDA by way of the WSJ, both Rotarix and Rotateq have been given to millions of babies to reduce the risk of gastrointestinal disease due to rotavirus. However, given that trypsin may be the source of the PCV DNA fragments and is used widely in the biotech industry, contamination may extend well beyond mere vaccine production.

My speculation: Vast potential for the contamination of products with viral nucleic acids with negligible or no risk of illness.

Today's FDA meeting, which was already scheduled to discuss the potential safety issues of PCV1 DNA in Rotarix, will also address the newly found DNA fragments in Rotateq.

* Live, attenuated.

** Meaning that the safety of the contaminated Rotarix vaccine was assessed in approval-required clinical studies.

Image of commercial trypsin from PAA.

05/08/10 update: Yesterday an FDA advisory panel recommended the continued use of Rotarix and Rotateq, according to the WSJ and other news sources. It should be stressed that, while some coverage (I'm talking about you, MedPage Today) indicates that the actual viruses PCV1 or PCV2 are present in the vaccines, only DNA fragments of the viruses have been detected. This fact substantially reduces, if not eliminates, any infectious possibility. Moreover, neither virus is known to cause human disease.

05/15/10 update: Yesterday the FDA sanctioned the continued use of both the Rotarix and Rotateq vaccines. The decision was "[b]ased on a careful review of a variety of scientific information." In hindsight, FDA officials—in a pervasive, overly cautious frame of mind—jumped the gun when it first suspended the use of Rotarix in March.

Recently detected DNA fragments of a common pig virus, circovirus type 1 (PCV1), in GSK's Rotarix vaccine have been present since the early development of the vaccine, says the FDA. The agency reported that GSK found the PCV1 DNA fragments in the "working cell bank" and viral "seed" that was used to produce the oral vaccine. Consequently the contaminated Rotarix vaccine was assessed in clinical studies, which were the basis for FDA approval. The detection of PCV1 DNA fragments does not necessarily mean that intact virus was or is present in the vaccine; moreover, the virus itself is not known to cause human disease.

How GSK learned of the presence of PCV1 DNA fragments in Rotarix is somewhat sketchy in detail. According to the FDA, an "independent US academic research team," while assessing a number of vaccines with a "new technology," detected the PCV1 DNA fragments. After finding the DNA fragments in 2 lots of Rotarix vaccine, the researchers alerted GSK on February 9th. Follow-up tests by the company confirmed the presence of the DNA fragments in the 2 tested lots, as well as samples leading back to the seed virus. GSK notified the FDA on March 10th, and the agency, as a precautionary measure, suspended the use of Rotarix yesterday.

The GSK press release provides 2 references on PCV1:

Li L, Kapoor A, Slikas B, et al. Multiple diverse circoviruses infect farm animals and are commonly found in human and chimpanzee feces. J Virol. 2010;84:1674-1682. (From the Blood Systems Research Institute in San Francisco.)

Hatterman K, Roedner C, Schmitt C, Finsterbusch T, Steinfeldt T, Mankertz A. Infection studies on human cell lines with porcine circovirus type 1 and porcine circovirus type 2. Xenotransplantation. 2004;11:284;294. (From the Robert Koch Institut in Berlin.)

Li et al used something called viral metagenomics to identify "circovirus-like" DNA sequences in stool samples of humans and wild chimpanzees. Viral metagenomics is apparently a relative new field, in which researchers attempt to recover viral DNA from environmental samples (as opposed to laboratory cell lines).* In US adults, the detection of circovirus was limited to the discovery of porcine circovirus (which is also found in most US pork products, according to the authors).

Hatterman et al reported on their infection of human cell lines with PCV1, which did not cause "any visible changes," unlike the type 2 PCV strain.

For children who require rotavirus vaccination, the FDA recommends the use of Merck's Rotateq vaccine—which is evidently not contaminated with PCV1 DNA.

* The technique may (may) be the method by which PCV1 DNA fragments were detected in GSK's Rotarix vaccine.

Image of Rotarix administration from Rotarix Prescribing Information.

03/26/10 addendum: Relying on reason and common sense, the European Medicines Agency reported today that it "sees no safety concerns with the Rotarix oral vaccine" and that the DNA of a virus that does not cause human disease "does not present a risk to public health." The EMA stressed that PCV1 is commonly found in meat and other food products.

The agency, however, requested that 1) GSK identify how the DNA fragments got into Rotarix and 2) produce a vaccine that is free of PCV1 DNA. The agency also reported that other GSK vaccines do not contain PCV1 DNA.