The MMR-Autism Claim and Bad Science: Part I

Recently, some participants on Dr. Bob Sears The Vaccine Book Discussion Forum asked about the validity of his references that show a possible link between the MMR vaccine and autism. The list appears in The Vaccine Book: Resources pp. 257-259 (2007). So why would Dr. Bob believe that these studies support Wakefield's findings? Well, if you just read abstracts and conclusions, then you could easily make that mistake. But the devil's in the details and in this case, the details are extremely shoddy methods and scientific dishonesty. There are 7 'studies' and we will discuss these in a 2-part series, as they appear in the book and closely examine the methods.

The first is the original article by Wakefield et al. (1998) and this is Dr. Sears' summary:

This is the landmark study that began the whole debate. Wakefield found twelve children who developed regressive autism during the second year of life (after the MMR vaccine was given) who also had intestinal inflammatory disease consistent with a viral infection, probably measles related. See page 94 for further discussion.

The information on this paper is exhaustive and you can start by reading the numerous comments from the original Wakefield paper. Ten of the original 13 authors listed a Retraction of the Wakefield et al. paper and this is an excerpt:

We wish to make it clear that in this paper no causal link was established between MMR vaccine and autism as the data were insufficient. However, the possibility of such a link was raised and consequent events have had major implications for public health. In view of this, we consider now is the appropriate time that we should together formally retract the interpretation placed upon these findings in the paper, according to precedent (Zhang et al.).

So several things happened prior to and after that retraction and the most comprehensive explanation can be found on the website of journalist Brian Deer. While he is a journalist, his reports have held up to scrutiny and are, in part, the foundation for the General Medical Council's (GMC) disciplinary proceedings against Dr. Andrew Wakefield and Professors Simon Murch and John Walker-Smith. It is also a plain-English summary. Additionally, compelling evidence of both scientific fraud and abysmal methodologies came to light during the Omnibus Autism Proceedings (OAP), specifically by the testimonies of Dr. Nicholas Chadwick and Dr. Stephen Bustin. Dr. Chadwick was Andrew Wakefield's graduate student at the time of the now infamous MMR-autism study and could not find measles virus in some samples from work prior to the MMR-autism study. He notified Dr. Wakefield of this, who proceeded to report them as positive anyhow via a paper co-authored with Kawashima et al.; Dr. Chadwick asked that his name be removed from any publication that included these results. Incidentally, Dr. Wakefield was not asked to testify at the OAP.

An explanation of Dr. Bustin's testimony can be found here which also discusses the difficulties with the results found in the next paper to be discussed. In short, Wakefield et al. and subsequent studies seemingly supporting Dr. Wakefield's findings did not find what they claim they found. The researchers didn't take any of the simple measures to ensure the quality of their work and verify their findings. This was a scientific fraud shot-heard-around-the-world.

The next paper is by Uhlmann et al. (2002), which includes Wakefield as a co-author and this is Dr. Sears' summary:

This eleven-doctor group in Ireland did intestinal biopsies on a large group of children with autism and found that of the ninety-one who showed ileal lymphonodular hyperplasia and enterocolitis, seventy-five had confirmed measles virus infecting their intestinal linings. Only five of the seventy healthy control patients tested showed the measles virus. This study offers more support for Dr. Wakefield's claim of a link between measles virus, inflammatory bowel disease and autism.

Before we get to the methods, let's briefly jump to the conclusions. O'Leary's lab found that 82.4% of the children with developmental disorders had measles vaccine virus in their guts. This, by itself is astonishing and should be questioned. By these reported numbers, an investigator that wishes to verify these study results would only have to have a sample size of 6 autistic children (95% confidence interval) to detect a significant number of children with measles vaccine virus as compared to controls; this will become more relevant later.

Now for the methods; there was a control group and a developmentally delayed group but no effort was made to actually match the groups or describe their differences other than developmental status. But one of the most important and fatal flaws with the study, was the molecular tests that they carried out. Again, the full testimony of Dr. Stephen Bustin is available. The Uhlmann group, working in Dr. John O'Leary's now-defunct Unigenetics laboratory in Ireland did not describe their controls in a manner that could control for contamination or other investigators could parse. They also used source material that would have been degraded, and thus rendered useless by the methods they were using to detect measles vaccine virus sequences. The primers that are used to detect a particular sequence of interest, in this case, measles vaccine virus, were mismatched which increases the likelihood that a non-target sequence could be detected. But the most crucial flaw in this methodology is that the investigators never sequenced their results. Sequencing maps out the nucleotide arrangement for the target that was amplified; you then compare that to a DNA library such as GenBank which is a repository for millions of sequences. This would have told them (as it did Dr. Chadwick) that what they were getting was not measles vaccine virus but something else.

It was also noted in Dr. Bustin's audit of Unigenetics operating procedure for the Uhlmann et al. paper, that measles is an RNA virus and there was no RNA in many of their samples yet they used them and counted them as positives. Also, in some cases, they skipped the reverse-transcription (RT) step which converts the RNA to DNA and miraculously still found positives, which would be impossible and is therefore yet another crucial flaw in this experiment. The laboratory was located adjacent to a plasmid room. Since PCR is prone to contamination, all measures must be taken to ensure clean runs and control for contaminants. Plasmids are a source of this and since many people were walking in and out of the rooms, plasmids could easily make their way into reaction vessels. Again, sequencing would have shown them that, yet they refused to utilise this very basic (and inexpensive) technique. Unigenetics gave their samples to another investigator to replicate (as part of an investigation that was going on in the U.K.) and he could not get the same results with the proper extraction and PCR methods. Now Dr. Bustin was under oath to provide his professional observations of his audit of Unigenetics and accordingly, did not speculate about the Uhlmann et al. study. We are not under those constraints and will daresay the extraordinary lopsidedness of their results, does point to scientific fraud.

Two groups of investigators attempted to replicate Uhlmann et al.'s study and could not get the same results. The first study is by Afzal et al. (2006) who replicated the parameters of Uhlmann et al. BUT with more sensitive molecular methods, proper controls and quantification of starting RNA. They took blood samples from 15 children with autistic disorders that had the MMR jab, 10 of them reportedly regressed in the second year of life and after the MMR jab. They specifically examined leukocytes (white blood cells) because if there is measles virus replicating in their guts as Wakefield et al. contends, then evidence of the virus is going to be found elsewhere. Incidentally, Dr. Afzal asked Wakefield/Uhlmann/O'Leary for their samples to be tested but were refused, which in itself is highly unusual in the scientific community. Afzal et al. did not detect any measles virus, vaccine or wild-type in the children. Although their sample size was small (n=15), given the 82.4% of children with measles vaccine virus present that Uhlmann et al. claimed to have found, they should have detected 6 positives.

A relatively small number of patients was examined in this study. However the reported frequency of positive samples in the largest positive study is about 82% (Uhlmann et al., 2002). While it is impossible to prove a negative, it is clear that this figure is not consistent with zero positive from 15 as here. In fact if the null hypothesis is that 82% of patients have measles sequences, it would be inconsistent with fewer than 6 positives from 15 samples at the 95% confidence level. The failure to find any positives means that the incidence is far lower than this, and possibly zero.

The second study is by D'Souza et al. 2006 and followed the Uhlmann et al. and Kawashima et al. protocols even more closely but with, again, better precision and optimisation of their methods. They used peripheral blood mononuclear cells (PBMCs) which are a perfectly acceptable surrogate for gut biopsies or cerebral spinal fluid. They also had a larger study group with controls and their characteristics included gastrointestinal complaints and the majority receiving 2 doses of MMR:

Fifty-one of 54 children from the ASD group and 31 of 34 from the control group had received MMR vaccine. From the ASD group, 2 children had not been vaccinated, and 1 child’s status was unknown. From the control group, vaccination status was unknown for 3 children. The majority of children with ASD (n = 43; 84%) and the developmentally normal children (n = 28; 90%) had received 2 doses. The Quebec immunization schedule recommends a 2-dose MMR schedule at ages 12 and 18 months.¹⁴ Only 1 (control) child had received 3 doses. Gastrointestinal symptoms, including constipation, cramping, diarrhea, and abnormal stools, were reported in 43 (79.6%) of 54 children from the ASD group and 11 (32.3%) of 34 children from the control group. Regression was reported in 20 (37%) of 54 subjects in the ASD group. The time between vaccination and blood analysis was similar between the 2 groups. The mean time (±SD) between vaccination and blood sampling for the ASD group was 30.4 (±15.9) months and 26.6 (±15.3) months for the control group (2-tailed t test, p = 1.056, not significant).

And their results:

The majority of samples generated positive results in the Uhlmann assays. However, melting curve analyses revealed that only a proportion of these PCR products had the correct melting temperature (ie, identical to the positive MV control). Furthermore, only 2 products generated by the Uhlmann nucleoprotein assay, 3 by the Uhlmann fusion assay, and 4 by the Uhlmann hemagglutinin assay had the correct amplicon size when separated by gel electrophoresis. We successfully obtained sequences for 7 of these 9 products, but none were MV RNA. No specimen was positive using the Kawashima primer-based assays or our own probe-based fusion gene assay.

This is in line with Afzal et al.'s results and again, since almost 80% of the children had gastrointestinal complaints, a minimum of 6 positives should have been detectable if present.

The third paper in the first part of this series is by Thompson et al. (1995) also includes Wakefield as a co-author and this is Dr. Sears' summary:

This group of doctors studied thirty-five hundred adult patients with inflammatory bowel disease and other chronic intestinal conditions who had received the single measles vaccine in 1964 as part of the vaccine safety trials. When compared to a control group of eleven thousand adults who didn't get the measles vaccine, the vaccinated people were three times more likely to develop inflammatory bowel disease. This study predates Dr. Wakefield's work and is consistent with his concern about a link between the measles vaccine and inflammatory bowel disease.

No, it isn't Dr. Sears and this is why. This paper is merely an attempt to validate results from a previous paper by Lewin et al. (1995) of which (surprise surprise) Wakefield is a co-author of.

Groups were recruited from different study populations with no attempt to match or control for differences that would also contribute to or explain prevalence of intestinal bowel disorders (IBD). Information obtained, such as measles vaccine history and IBD history from the control group (not supposedly vaccinated for measles) was sloppy and relied heavily upon self-reporting. Essentially comparing apples to oranges. This introduces considerable bias potential because there is no standardisation of data collection regarding exposures and disease outcomes so the investigators didn't have all of the information that could be potential confounders for the measles jab. And this is the case as you will see.

Their methods for measles detection (as explained in the Lewin et al. paper) were prone to cross-reactivity with other antigens so they couldn't actually claim that they found measles without other molecular detection methods for viral presence. Other investigators had failed to find evidence of measles virus in gut biopsy samples of IBD patients using much better detection methods, if one could be bothered to read the comments published in the Lancet about this paper. They are really quite helpful, particularly if one is unsure of how to read and understand the methods of a controversial study. We highly recommend doing this.

Another problem with this study is that the authors postulated that measles infection, therefore attenuated, live, measles vaccine is a risk factor for IBD (which includes Crohn's disease and ulcerative colitis). Thompson et al. found a significantly lower risk of IBD in the unvaccinated control group as compared to the vaccinated group. This is incongruous with their hypothesis because 85% of the unvaccinated control group reportedly had natural measles infections versus no natural measles infections in the vaccinated group. If measles infection is associated with a higher risk of IBD you would expect to see higher numbers in the control group. This just further demonstrates the selection bias and slipshod methodology used to ascertain this association. A criticism of this study (published in the comments) deigned to point out that:

The relative risk of measles vaccinees developing inflammatory bowel disease compared with unvaccinated individuals (relative risk 2.5-3.0) should be in perspective: Crohn’s disease is more common in subjects whose first house had a hot water tap (odds ratio 5.0).

In other words, there is a stronger association between those that had hot water in their house as children and IBD, than those that received the single measles jab. It is interesting to note that even Wakefield himself has backed away from this work (Chadwick et al. 1998).

These papers are not independent replications of Wakefield's 1998 Lancet paper other than all being slapdash works that range from appalling incompetence to seemingly outright fraud. They and their supporting works all have Wakefield as a co-author on them. We will review the next 4 studies Dr. Sears claims 'support' Wakefield's work listed in The Vaccine Book in the next coming weeks.

ETA 07.19.09 for accuracy.

Measles in Brooklyn

I don't know why they waited so long with the health alert, but here it is:

http://tinyurl.com/nnel9k

A measles alert was issued yesterday by the city's Health Department after an outbreak of 11 confirmed cases and one suspected case, all in the Williamsburg and Borough Park sections of Brooklyn.

The 12 cases identified over the past two months involve 10 children, between the ages of 8 months and 4 years, and two adults, according to the Health Department.

The alert sent to physicians and other health-care providers states that "most of the cases have had a close contact with each other" and that "in one instance, transmission may have occurred in a physician's waiting room." None of the 12 had been vaccinated.

The cases are still under investigation and officials were sketchy on details.

/...snip.../

Dr. Jane Zucker, an assistant health commissioner with the bureau of immunization, acknowledged that some parents have expressed concern about the measles vaccine and want to wait until their children are 3 or 4 years old. But she cautioned against such delays.

The advisory urges doctors to be alert for measles symptoms and immediately report clinically suspect cases to the department.

My bold: this is why I think that delaying MMR until the age of 3 or 4 is dangerous.

Note that once again measles appear to have spread in a doctor's waiting room - if I was a pediatrician, unvaccinated patients would make me nervous, too (see my earlier blog on SSPE in children who caught measles as babies in their pediatrician's waiting room - that fate is still looming over the children in Brooklyn).

The Toxin Gambit Part 1: Formaldehyde

We will be conducting a multiple-part series describing some of the vaccine constituents that many consider 'toxins' or just have what the actual chemical is, just plain wrong. The first part of our series will be dedicated to information regarding formaldehyde, what it is, why it is in vaccines and any health implications. So thank you to Valo for your suggestion.

For the purpose of this series, it is important to understand the metric scale, not so much the actual measurements but their relationship to one another. For example, if a microgram (mcg) is a grain of sand, then a milligram (mg) is a slice of American cheese, so a gram (g) is an average 5.5 year-old boy and a kilogram (kg) would be 7 H2 Hummers. Again, these aren't actual weights, volumes or measurements, but rather, their differences on a visual scale.

Formaldehyde is a naturally-occurring chemical that can also be synthesised. The chemical formula is CH2O and is also known as methanal (not to be confused with methanol), formal and methyl aldehyde. It is also not to be confused with formalin, which is an aqueous solution of formaldehyde. Numerous isomers of formaldehyde exist but they are not formaldehyde. It is used in the manufacture of resins that are then used for the production of pressed wood products, paper, textile fibres, adhesives and plastics (EPA 2009 and WHO 2006). Of course, those involved with the manufacturing of products with formaldehyde may sustain occupational exposure and subsequent pathologies (EPA, 2009 and WHO, 2006). Formaldehyde is also a by-product of tobacco smoke and combustion reactions from stoves, kerosene space heaters and automobiles (EPA 2009).

Naturally occurring sources of formaldehyde are found in plants, fruits, vegetables, animals (including humans) and seafood (Mason et al. 2004 and Inchem 1989). Table 14 of the Environmental Health Programme on Chemical Safety: Formaldehyde, and Table 95.2, Chapter 95: Formaldehyde, lists some commonly-consumed foods and their formaldehyde concentrations. (Clary and Sullivan 2001 and Inchem 1989). In a study of Shiitake mushrooms, investigators reported formaldehyde concentrations of 100-300 mg/kg; this wide variation is a result of a combination of analysis techniques, naturally-occurring formaldehyde and also possible contamination with exogenous formaldehyde (Mason et al. 2004).

Formaldehyde is a normal, essential human metabolite with a biological half-life of about 1.5 minutes (Clary and Sullivan 2001). It is endogenously produced and is involved with methylation reactions for and biosynthesis of some proteins and nucleic acids. It is also rapidly metabolised to formate and excreted in urine or to carbon dioxide and exhaled (WHO, 2006 and Clary and Sullivan 2001). Some common routes of exposure for exogenous formaldehyde include dermal, from occupational handling, inhalation, from occupational exposure and environment, oral via dietary intake and of course, intramuscularly or subcutaneously from vaccines. (Franks 2005, Clary and Sullivan 2001 and Inchem 1989).

Human normal blood concentrations of formaldehyde are 2.74 +/- 0.14 mg/L (Franks 2005). The average adult male (86 kg) in the U.S. has a blood volume of 5.8 litres; the average adult female (74 kg) has a blood volume of 5.0 litres and an average 2 month old infant (5 kg), 0.43 litres. So this translates to 15.1-16.7 mg of normal formaldehyde range in an adult male, 13.0-14.4 mg in an adult female and 1.1-1.2 mg in a 2 month-old infant which works out to be 0.22-0.24 mg/kg (CHOP 2008 and Franks 2005). Using the visual scale provided earlier for the infant, that would be a little more than 1 slice of American cheese/35 H2 Hummers.

Toxic levels of formaldehyde can induce a variety of illness from localised skin/respiratory tract irritation to cancer (Bosetti et al. 2008, Sundstrom et al. 2001 and Pandley et al. 2000). Inhalation of 1.0-2.0 parts per million or ppm (ppm=mg/kg) is considered mildly irritating, while 3.0 ppm causes moderate eye irritation although there is variation of sensitivity in individuals (Sundstrom et al. 2001 and Inchem 1989). Chronic inhalation studies on rats and mice have resulted in nasal cavity squamous cell carcinomas, when exposed to levels above 6-15 ppm (Bosetti et al. 2008 and Clary and Sullivan 2001). Formaldehyde toxicity resulting in death occurs in humans at a volume of about 60-90ml (Pandey 2000). The CDC conducted a survey of 'travel trailers' used for displaced people from hurricanes Katrina and Rita and found levels ranging from 0.003-0.59 ppm with an average of 0.077 ppm (CDC 2008). Thus far, only symptoms of local irritation have been reported (CDC 2008). A 2005 study of single-family homes in 3 cities detected an average of 0.17 ppm and 0.016-0.025 ppm in travel trailers (Weisel et al. 2005).

Formaldehyde in vaccines is left over from the production process, where it serves a couple of different functions, depending upon the type of antigens used. Essentially, it is used for killing cells and/or inactivating toxins. For example, the diphtheria-tetanus-acellular pertussis vaccine is a toxoid vaccine. The toxins produced by the bacteria are what causes illness in humans and what we need antibodies against. The addition of formaldehyde internally cross-links the toxin and also cross-links it to other toxins, effectively detoxifying to eliminate pathogenicity. Viral vaccines such as influenza and hepatitis A vaccines utilise formaldehyde to inactivate viral activity, allowing the recipient to produce antibodies to the antigens without pathogenicity (Aunins et al. 2000).

The actual amount in vaccines is minuscule, even when considering an infant that receives the full CDC schedule. If you look at this table, it contains a list of vaccines and their final formaldehyde content. Not included in this table is Pentacel which contains 0.005mg of formaldehyde. If all vaccines are given as per the CDC recommendation and separately, the most a 2 month old infant would receive is 0.1204 mg of formaldehyde or 120.4 mcg. Going back to what normal formaldehyde levels for a 5kg, 2-month old infant are 1.1-1.2 mg or 0.22-0.24mg/kg so the total formaldehyde exposure from vaccines would raise that to 1.22-1.32 mg or raises the baseline level by less than 1 grain of sand/35 Hummers. Put another way, the amount contained within a vaccine is more than 50 times less than what is in a pear.

Given what is known about human formaldehyde metabolism, excretion and toxic levels, along with what is actually in vaccines, we hope that this gives some perspective about the safety of the amount of formaldehyde that an infant would receive via vaccines. There is simply no valid argument, beyond the scope of fear-mongering that formaldehyde exposure from vaccines is implicated in any health problems, whatsoever.

References:
Aunins JG, Lee AL, Volkin DB. Vaccine Production. In: Bronzino JD, ed. The Biomedical Engineering Handbook 2nd ed. Vol. 2. New York, NY: Springer Publishing; 2000. http://books.google.com/books?id=T2UIoAxcFdIC&pg=PT175&lpg=PT175&dq=&source=bl&ots=J4Skfly-bt&sig=InDm5MbbsfSOztSu5WoeSGAYh7A&hl=en&ei=s938SciZD4TCM6Gi8csE&sa=X&oi=book_result&ct=result&resnum=8. Accessed May 10, 2009:105-8—105-9.

Bosetti C, McLaughlin JK, Tarone RE, Pira E, La Vecchia C. Formaldehyde and cancer risk: a quantitative review of cohort studies through 2006 . Annals of Oncology. 2008; 19:29-43. http://annonc.oxfordjournals.org/cgi/reprint/19/1/29.pdf. Accessed May 10, 2009.

The Children's Hospital of Philadelphia (CHOP). Vaccine Education Center Web site. http://www.chop.edu/consumer/jsp/division/generic.jsp?id=75809. Accessed May 10, 2009.

Clary JJ and Sullivan, Jr. JB. Formaldehyde. In: Sullivan, Jr. JB and Krieger GR, eds. Clinical Environmental and Toxic Exposures. 2nd ed. Philadelphia, PA: Lippincott, Williams and Wilkins; 2001. http://books.google.com/books?id=PyUSgdZUGr4C&pg=PA1008&lpg=PA1008&dq=formaldehyde+human+normal+metabolite&source=bl&ots=IJTP64uYmW&sig=jttT7L4_AseC6hm3eVXzUP56hQI&hl=en&ei=Gmv7SfTkJ46UMrvr3dQE&sa=X&oi=book_result&ct=result&resnum=1#PPP1,M1. Accessed May 10, 2009:1007-1008 and 1010.

Indoor Air Quality. U.S. Environmental Protection Agency (EPA) Web site. http://www.epa.gov/iaq/formaldehyde.html. Accessed and link repaired Aug 1, 2012.

Franks SJ. A mathematical model for the absorption and metabolism of formaldehyde vapour by humans [abstract]. Toxicology and Applied Pharmacology. 2004; 206(3):309-320. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4F7B42G-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=7617394a3010f1b021e3164141aefec1. Accessed May 10, 2009.

Environmental Health Criteria 89: Formaldehyde. International Programme on Chemical Safety (INCHEM) Web site. http://www.inchem.org/documents/ehc/ehc/ehc89.htm#SubSectionNumber:5.1.4. Accessed May 10, 2009.

Mason DJ, Sykes MD, Panton SW, Rippon EH. Determination of naturally-occurring formaldehyde in raw and cooked Shiitake mushrooms by spectrophotometry and liquid chromatography-mass spectrometry [abstract]. Food Additives and Contaminants. 2004; Nov;21(11):1071-1082. http://www.informaworld.com/smpp/content%7Edb=all?content=10.1080/02652030400013326. Accessed May 10, 2009.

Pandey CK, Agarwal A, Baronia A, Singh N. Toxicity of ingested formalin and its management [Abstract]. Human & Experimental Toxicology. 2000;Jun,19(6);360-366. http://www.ncbi.nlm.nih.gov/pubmed/10962510?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor. Accessed May 10, 2009. PMID: 10962510.

CDC Final Report on Formaldehyde Levels in FEMA-Supplied Travel Trailers, Park Models, and Mobile Homes Web site http://www.cdc.gov/nceh/ehhe/trailerstudy/pdfs/FEMAFinalReport.pdf. July 2, 2008. Accessed May 10, 2009.

Weisel CP et al. Relationships of indoor, outdoor, and personal air (RIOPA). Part I. Collection methods and descriptive analyses [abstract]. Research Report (Health Effects Institute). 2005;Nov(130 Pt 1):1-107; discussion 109-127. http://www.ncbi.nlm.nih.gov/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=16454009&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVCitation. Accessed May 10, 2009. PMID: 16454009.

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization (WHO). Volume 88 Formaldehyde, 2-Butoxyethanol and 1-tert-Butxypropan-2-ol. 2006. Web site. http://monographs.iarc.fr/ENG/Monographs/vol88/volume88.pdf. Accessed May 10, 2009.

Cochrane Collaboration on Influenza

I went to a talk given by Sir Iain Chalmers, cofounder and current director of the Cochrane Collaboration yesterday. He spoke about the various controlled trials that need to be performed to ensure that a new medicine is a) effective and b) not doing more harm than no treatment or previously used treatments. He was taking us through the history of treatments for pneumonia (for the longest time treated with blood letting, as late as 1903), treatment and prevention of diphtheria, and prevention of whooping cough and measles. I am hoping the James Lind Library or Public Health Department of Edinburgh University will publish the lecture eventually. For the moment, Evans, Thornton and Chalmers' book "Testing Treatments" , free for download at the James Lind Library is a suitable alternative. But since everyone is talking about the flu, Sir Iain also pointed to the Cochrane Collaboration's new page on all things infuenza and to Dr Tom Jefferson's pod cast that summarizes the findings of all Cochrane Reviews on influenza in a few minutes. Listen in - you may be surprised:

Special Podcast - summary of Cochrane Reviews on influenza

Play Now! | Download [mp3]

MMR Vaccine, Roseola and Autism

Recently, Dr. Bob Sears made this comment to one of his readers with regards to concerns with a study conducted by Singh et al. in 1998,

What I CAN tell you is that SOME (maybe about 25%) of kids with autism show improvements in some autistic symptoms when they are treated with an anti-viral medication that treats herpes and roseola viruses. I wil [sic] provide more details and research on this issue in the Autism Book next year (so don't ask me to post any more info on that right now). So, roseola virus MAY play a role in some kids' autism.
What we don't know, however, is whether or not getting roseola or another viral illness near the MMR vaccine poses any risk for autism.

Since this scared several moms on the board, we decided to take a look at that and some other papers that infer such an association. Singh et al. had a patient group (with autism) aged 4-12 years old (n=48) with no mention of how these children were selected but blood samples from the autistic group were 'supplied by their parents nationwide'. A 'control' group, if you can even call it that, consisted of serum samples they had from previous studies from non-autistic people aged 5-50 years old (n=34; <12 n="19;">12 years old, n=15).

They did not describe how they set their positive serology criteria, only what they were, nor did they define how many replicates, if any they performed. The information provided is inadequate to reference manufacturers' protocols. Since they were testing for measles IgG and hhv-6 IgG, the former would have, presumably, been acquired via vaccination, the latter by natural infection yet the authors did not ascertain any medical history regarding these parameters. It is also important to note that the brain autoantibody assays were internally validated only, not by any other investigators.

There were no differences between either of the groups in terms of antibodies detected for either measles or hhv-6. In Table 1, there were 6 results in each group left off for the hhv-6 IgG analysis with no explanation as to why. Selection biases were not controlled for since there were no selection criteria to begin with. The anti-MBP and anti-NAFP presences in the autistic group cannot be explained by the mere presence of measles and HHV-6 antibodies without having adequate medical histories on the groups.

Congenital viral illnesses, i.e. in-utero infections, such as rubella, herpes and cytomegalovirus and possibly even transfer of maternal autoantibodies, have been shown to be aetiological agents in the onset of autism in a small subset of children (Yamashita et al. 2003 and Zimmerman et al. 2006). Singh et al. are attempting to establish viral or vaccine-derived autoantibody reactions in children with autism. They say,

This was an excellent rate of seroconversion post-MMR immunisation since virtually all subjects in the study had their MMR immunisations and none had any history of wild-type measles virus infection.

Something is off with this statement since they didn't provide any medical history for any of the subjects and since they didn't detect anti-measles IgG in 18% and 15% of their control and autistic groups, respectively, either something is wrong with the sensitivity of their test and/or virtually all of the subjects were not vaccinated. This is the erroneous conclusion that the authors then make,

As reported here, we found that positive titres of both measles and HHV-6 antibodies are related to brain autoantibodies, I.e., the higher the virus antibody titre the greater the chance of brain autoantibody. Since this chance was higher for measles virus antibody and MBP autoantibody, it is quite possible that the measles infection is an earlier event in autoimmunity to myelin (MBP) whereas HHV-6 infection may exist as a co-infection or reactivation mechanism.

So the authors are inferring a measles infection when they only had antibodies from vaccination and then hhv-6 reacted synergystically with measles vaccination to cause autism. That is quite a leap since they could have found antibodies to anything and correlated those with anti-brain autoantibodies since we don't know the selection criteria and medical histories for the autistic group. Also, they are not presenting any statistical analysis of the relationship between antibody titers. Furthermore, no other clinical findings were reported in the autistic group to support what is nothing more than a hand-waving, free-association.

A related publication by T. Binstock (2001) that appeared in Medical Hypotheses, need we say more? We tried hard to find any science to analyse, but failed. The author just waxes moronically about infections, immune responses and ASD children without a shred, nothing, to support this 'hypothesis'. The author is clearly setting up a post hoc argument using sources that don't support such a conclusion. But to give an example, part of Binstock's hypothesis is predicated upon the observations of wild-type measles infection in monocytes and lymphocytes and of course, the well-known fraudulent and specious report by Wakefield et al. (1998) that measles vaccine virus persists in intestinal M-cells.

The immune impairments associated with autism would, in some individuals, increase the likelihood of significant effects from gastrointestinal pathogens.

What 'immune impairments' associated with autism? The author has leapt over any other aetiologies right to autism is an immune disorder. The author is the founder of 'The Institute for Molecular Introspections', which, unremarkably, has no information about what she does there.

Another related publication by Nicolson et al. (2007), Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and Human Herpes Virus-6 Coinfections in the Blood of Patients With Autistic Spectrum Disorders . also relies upon weak associations and hand-waving. The introduction sets the hypothesis up that infectious organisms are responsible for or exacerbate autism spectrum disorders (ASDs). The authors do this by making tenuous relationships of Mycoplasma spp., Chlamydia pneumoniae and human herpes virus-6 (hhv-6) with ASD children. Their gratuitous use of letters and non-indexed 'studies', along with cherry-picked data from studies describing congenital infections emphasise this grasp to correlate these infections with ASD aetiology and aggravations thereof.

Recruitment was unclear in terms of which support groups they were derived from in addition to how control patients were recruited. They did not perform adequate statistical analyses to determine if the groups were well-matched (more comment on this below). They also mentioned 'routine laboratory test' but did not describe what those were.

No P-value is reported for age analysis between controls and patients. Rural vs. Urban was only examined for patients and there was a high degree of significance ((P<0.05)>Interestingly, though not reported, common diagnoses of illness in the children of Gulf War veterans with mycoplasmal infections included ASD-like illnesses, among others, and we found the same infection, primarily M. fermentans, in both the sick adults and the children in these families. Curiously, this observation is found in their previous work only and don't report what treatments, if any, were offered and subsequent results. Their PCR techniques have only been validated by themselves and there are many other techniques that are far more sensitive and specific. The authors are trying to create a relationship between Gulf War syndrome and ASD via vaccine exposure. They, at least, have the good sense to list some limitations of their study but do not include some of the most glaring ones which is potential exposure. They then go on to make this most interesting statement,

The infections found in ASD patients in the
present and previous studies (Takahashi et al., 2001; Yamashita et al., 2003; Libbey et al., 2005; Nicolson et al., 2003c, 2005b) could have originated from vaccines or from opportunistic infections in immune-suppressed children. Bacterial contamination has been found in commercial vaccines, and in one study 6% of commercial vaccines were contaminated with mycoplasmas (Thornton, 1986). Thus the appearance of infections in children diagnosed with ASD may eventually be linked to the multiple vaccines received during childhood either as a source or from opportunistic infections in immune-suppressed recipients of multiple vaccines.

The paper was published in 2007 and those contaminated vaccines the authors reference were for veterinary, not human use, from over 21 years ago. That is an example of the appalling, inflammatory tactics, inferior investigators must make in order to support their hypotheses. How this paper ever got through peer-review is certainly beyond us. The lead author G.L. Nicolson, refers to himself as professor (I guess PhD is too hackneyed) and is the founder of The Institute for Molecular Medicine which conveniently 'researches' and 'treats' Mycoplasma infections. A closer look at the website shows that according to him, mycoplasma is the cause for almost every illness on the planet and his treatment the cure.

Most children are seropositive to hhv-6, specifically roseola infantum by the age of 2 (Stoekle, M.Y. 2000). It is normally self-limiting but can be associated with febrile seizures in 6-15% during the febrile phase of the illness. Rarely, hhv-6 manifests as encephalitis and fulminant hepatitis (Lewis, 2007). So what does this have to do with the MMR vaccine? Well, it has and will be again, postulated that the MMR vaccine can either 'reactivate' a latent hhv-6 or CMV infection or the MMR vaccine will act synergystically with hhv-6 or CMV infection to cause regressive autism. This is a preposterous notion predicated on the wild assumption that the MMR vaccine causes active measles infection and also that hhv-6 and CMV will somehow exhibit more severe pathology than has been observed. The other postulation is that some autism can be treated with anti-viral therapy. We searched Pubmed and the Cochrane database, but, not surprisingly, there is nothing to support this notion. It is hard to imagine that a therapy that helps 25% of all children should have been missed. It would be dangerous practise to recommend anti-viral therapy be initiated based upon antibody presence alone but rather based upon clinical presentation and confirmation of virus. There is quite clearly no reason to imply hhv-6 in the aetiology of ASDs.

References:
AskDr.Sears.com Vaccine Discussion Forum. http://www.askdrsears.com/thevaccinebook/ Accessed April 25, 2009.

Binstock T. Intra-monocyte pathogens delineate autism subgroups [abstract]. Med Hypotheses. 2001 Apr;56(4):523-31. http://www.medical-hypotheses.com/article/S0306-9877(00)91247-7/abstract. Accessed April 25, 2009.

Lewis LS. Pediatrics, Roseola Infantum. Emedicine from WebMD. http://emedicine.medscape.com/article/803804-overview. Accessed April 25, 2009.

Nicolson GL, Gan R, Nicolson NL, Haier J. Evidence for Mycoplasma ssp., Chlamydia
pneunomiae, and Human Herpes Virus-6 Coinfections in the Blood of Patients With Autistic Spectrum Disorders [abstract]. J Neurosci Res. 2007 Apr;85(5):1143-8. http://www3.interscience.wiley.com/journal/114103383/abstract?CRETRY=1&SRETRY=0. Accessed April 25, 2009.

Singh VK, Lin SX, Yang VC. Serological Association of Measles Virus and Human Herpesvirus-6 with Brain Autoantibodies in Autism [abstract]. Clin Immunol Immunopathol. 1998 Oct;89(1):105-8. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WCK-45K0Y05-D&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f419ebcf5a947ce50023ffa1d8399849. Accessed April 25, 2009.

Stoeckle MY. The Spectrum of Human Herpesvirus 6 Infection: From Roseola Infantum to Adult Disease [abstract]. Annu Rev Med. 2000;51:423-30. http://www.ncbi.nlm.nih.gov/pubmed/10774474?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor. Accessed April 25, 2009. PMID: 10774474

Thornton DH. A survey of mycoplasma detection in veterinary vaccines [abstract]. Vaccine. 1986 Dec;4(4):237-40. http://www.ncbi.nlm.nih.gov/pubmed/3799018?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor. Accessed April 25, 2009. PMID: 3799018

Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children [abstract]. Lancet. 1998 Feb 28;351(9103):637-41. http://www.ncbi.nlm.nih.gov/pubmed/9500320?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor. Accessed April 25, 2009. PMID: 9500320

Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T. Possible Association between Congenital Cytomegalovirus Infection and Autistic Disorder [abstract]. J Autism Dev Disord. 2003 Aug;33(4):455-9. http://www.springerlink.com/content/p9q1u6p463126226/. Accessed April 25, 2009.

Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA, Pearce DA. Maternal antibrain antibodies in autism [abstract]. Brain Behav Immun. 2007 Mar;21(3):351-7. Epub 2006 Oct 6. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WC1-4M27X07-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=1bea1a04a11273e2d7f4fc9c1ae485be. Accessed April 25, 2009

Medical care for unvaccinated children

Some anonymous person asked me on Dr Bob's board whether I did not think that unvaccinated children should see a doctor when they are sick (well, anon phrased a bit differently, but I guess this is what s/he meant).

Of course they should. Every child has the right to adequate medical care. However, every parent who has a sick child has to think for a moment, before they haul it to the pediatrician:

Could my child be contagious? Could this be something dangerous to the other kids in the practise?

Parents of unvaccinated children have more dangerous diseases to consider than parents of vaccinated children - some parents do not think first. In the year 2000, an unvaccinated preteen came down with a fever and parents took him to a pediatrician's practise. He infected six children in the waiting room with measles, three of these children were under 12 months old. Two are now dying.
ETA: Two of them developed SSPE as a consequence of their infection on that day and have since died after years of battling SSPE, Micha passed in 2013 and Natalie in 2011.

This is Micha in April 2005, about a year after the onset of his SSPE. He was 5 months old when he contracted measles in that practise (ETA: this movie needs a RealPlayer plugin):



The average survival time after onset of SSPE is 4 years. Micha is still alive. He is not better. He needs to take strong medication to keep the seizures at bay.

This is Natalie - she was 11 months old when she contracted measles from the same unvaccinated preteen. She came down with SSPE in Summer 2007:



The movies are in German, the mothers talk about the healthy children they had, their dreams and aspirations, watch for a minute or two to understand why we think that:

If parents think they know enough about measles not to vaccinate their children, they should recognize the signs of the disease and have a doctor who does home visits for medical care.

Catherina

Edited on 4/2/11 to exchange the Micha and Natalie movies for copies that run.
Edited on Feb 23/15 to add information that both Micha and Natalie have since died.

This week is European Immunzation Week

This week marks the 4th European Immunization Week by the WHO. Even very rich European countries, like Germany, miss the mark and fatal outbreaks of vaccine preventable diseases still occur. Wales, Germany, and Switzerland are currently battling measles outbreaks.