ABSTRACT: In response to publicity about an alleged but erroneous link between vaccination and autism, the number of children who are being immunized has decreased. This is of concern because many vaccine-preventable diseases have potentially devastating and even lethal consequenses. Numerous studies have negated the role of vaccines in the environmental causation of autism. Most compelling are those studies that show no relation between vaccination status and autism. The evidence for a genetic etiology is strong. There si a 60% to 90% chance for an identical twin and a 5% chance for a sibling to have autism if a relative is affected. Studies of familial cases highlight particular chromosome regions and predisposing genes. The evidence implies that multiple variant genes and the environment interact to cross a threshold and produce autism. Pediatricians can reassure worried parents that medical science has domonstrated that there is no link between autism and vaccines, and that parents can feel safe in immunizing their children.
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Case 1. An older attending physician listens during morning report to the details of the case of a child with suspected croup and decreased oxygen saturation. The resident mentions that he inspected the child’s mouth and pharynx as part of the routine examination. The attending recalls a case 20 years ago when a 2-year-old girl came to the emergency department with fever and stridor so severe that she was forced to sit erect to breathe. How different the examination was then—with observation for drooling, lateral neck radiographs for evidence of a dilated hypopharynx, and careful inspection of the throat when personnel expert at intubation were available. Examination under these conditions might demonstrate a cherry-red mass in the posterior pharynx projecting above the tongue.
Case 2. A newborn, born at full term, presents with a “to and fro” heart murmur at the upper left sternal border. The baby’s length and weight are at the 50th percentile for his age, but his head circumference is below the third percentile for age. Subsequent follow-up reveals that the infant has profound sensorineural deafness.
Case 3. A young girl presents with a peripheral vesicular rash accompanied by high fever and cough. Her health improves somewhat on the third day of illness with fluid therapy, and then worsens with increased fever, respiratory distress, and lethargy. Admission studies demonstrate hypovolemic shock and increased coagulation times, and the child is transferred to the pediatric ICU and placed on mechanical ventilation.
What is the diagnosis in each case—and how could these disorders have been prevented?
Answers and discussion on next page
Answers:
Case 1. Acute epiglottitis caused by Haemophilus influenzae infection (A).
Case 2. Congenital rubella syndrome with patent ductus arteriosus, microcephaly, and deafness (B).
Case 3. Varicella with secondary bacterial infection and septic shock (C).
(This vignette is based on a real case described in a Wall Street Journal article in 2007 in which the child succumbed to cardiac arrest.1)
Because timely vaccination can prevent each of these infections, these presentations should remain only as nightmares in the minds of older pediatricians. We present these cases to illustrate the increased probability that they will occur because vaccination rates have decreased. This decrease is a response to publicity regarding the erroneous association between vaccines (measles-mumpsrubella [MMR] vaccine in particular) and autism.
Here we review the basic characteristics of autism disorder, its causation by genetic-environmental interaction and, most important, evidence proving that past and present vaccines have no relation to autism.
WHAT IS AUTISM?
Autism disorder is a combination of behavioral symptoms that fall into the category of pervasive developmental disorders (PDDs) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).2 In 1943, Kanner described children with 3 types of behavioral problems3:
•Impaired verbal as well as nonverbal communication.
•Impaired social interactions.
•Repetitive movements and routines.
Autism disorder and the relatively mild Asperger disorder comprise autism spectrum disorder; these 2 conditions share features with the other 3 members of the PDD category: Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified. Autistic behaviors can occur in most disorders that manifest with cognitive disability—including genetic syndromes such as Down or fragile X and environmental disorders such as fetal alcohol(Drug information on alcohol) or thalidomide(Drug information on thalidomide) syndromes or rubella. In this discussion, the term “autism” includes all members of the PDD category except for Rett syndrome and excludes other known genetic-developmental conditions. Most studies of autistic children adopt this definition, which accounts, in part, for the bias toward environmental factors. Those who blame vaccines for autism also focus mainly on the childhood disintegrative disorder category of PDD with its developmental stasis and regression after 1 to 2 years of normal development.
Even when children with known genetic-developmental conditions are excluded from studies of autism, evidence for genetic factors is compelling. There is a 60% to 90% chance for an identical twin and a 5% chance for a sibling to have autism if a relative is affected. Studies of familial cases have highlighted particular chromosome regions and predisposing genes.3 Risks for siblings are analogous to those for disorders such as diabetes, mental illness, cleft palate, and other isolated birth defects that follow the model of multifactorial determination. Such risks imply that multiple variant genes and the environment interact to cross a threshold and produce autism. Those with a family history of autism or with underlying genetic-developmental disorders require lower amounts of environmental exposure (lower thresholds) to produce autism.
Baseline genetic testing is usually considered when autism is diagnosed. This includes routine and high-resolution chromosomes that employ fluorescent DNA probes to multiple chromosome regions (subtelomere fluorescent in situ hybridization [FISH]). Recently, novel microarray analysis or DNA chip technology can search for very small extra or missing chromosome material (equivalent to 1 million bases or several genes) as exemplified by changes within chromosome 16.4 Among the genes suspected to cause autism, only that for fragile X syndrome is amenable to routine analysis.3
Although relaxed diagnostic criteria, justifications for therapy, and physician awareness undoubtedly contribute to the increase in autism prevalence (currently said to be 1 in 125 children), recent increases would necessarily point to environmental changes rather than to genetic factors.
WHY THE CONCERN ABOUT VACCINES AND AUTISM?
Wakefield and colleagues5 published an article in 1998 on the MMR vaccine and autism. These investigators had followed use of this vaccine for 3 decades in the United States and Europe.1,6 The MMR vaccine was initially given to children at age 12 to 15 months: its efficacy was high and the incidence of the vaccine’s component diseases dropped by 99%. A second dose of MMR is now given to children aged 4 to 6 years after some localized outbreaks of measles or mumps in older children suggested incomplete immunity.
Wakefield, a gastroenterologist, described 12 children in whom abdominal pain, diarrhea, and inflammation by endoscopy developed after MMR vaccination. Nine of these children also exhibited developmental regression and autism.5 Wakefield posited a gut-brain interaction in which the MMR vaccine produced persistent measles infection and gut inflammation with increased absorption of CNS toxins.
After realizing that Wakefield’s investigation had been funded by trial lawyers claiming damage from the MMR vaccine, 10 of his 12 coauthors and the journal editors published a retraction in 2004.7 Nevertheless, concerns about MMR and/or mercury in vaccines were inflamed by Wakefield’s article and have led to lower vaccination rates along with the expected disease outbreaks in the United Kingdom, Europe, and the United States.
Much of the scare over vaccines and autism centered on the preservative thimerosal, a compound containing 50% ethyl mercury that has been added to vaccines since the 1930s. Preservatives in vaccines were initially mandated by the FDA to prevent bacterial contamination and skin infections. Legitimate concerns about mercury grew after reports of ingestion of contaminated fish surrounding Minimata Island in Japan and of contaminated grain in Iraq.8 Higher mercury levels caused cerebral dysfunction, ataxias, and potential death in adults. The offspring of exposed women suffered from severe mental deficiency, seizures, impaired hearing and vision (but not autism).
These well-documented cases of mercury toxicity involved very high levels of methyl mercury, a compound that is more toxic than the ethyl mercury in thimerosal. Furthermore, the amounts of mercury from thimerosal preservative in other vaccines ranged from 12.5 to 25 μg per dose. By comparison, a can of tuna contains 11.5 μg of mercury.9 A final irony is that the MMR vaccine dramatized in the Wakefield study never did contain thimerosal.9
In response to increasing media articles and lawsuits relating to vaccines and autism, the FDA Modernization Act of 1997 specifically considered mercury and noted that multiple vaccines exposed children to levels of mercury that could exceed safety limits established by the Environmental Protection Agency.9 The FDA and American Academy of Pediatrics then urged removal of thimerosal from vaccines in 1999 because it would decrease concerns; this took effect in 2001 in the United States. Only certain influenza vaccines now contain small amounts of thimerosal. Most other Western countries have discontinued thimerosal in vaccines. As we will discuss, the discontinuation dates provide good markers for comparing autism among thimerosal-exposed and non-exposed children.
Despite the removal of thimerosal from vaccines, media coverage continues to emphasize this concern— illustrated by this year’s television episode of Eli Stone in which a plaintiff recovered damages for vaccine- related autism.10 The controversy continues in real life as the first of more than 4800 damage claims went to the US Court of Federal Claims and concerned a 12-year-old child with autism and GI symptoms. A special legal design has been formulated with 3 special masters presiding over 9 test cases divided among 3 hypotheses: MMR in combination with other vaccines causes autism; MMR alone causes autism; or combination vaccines cause autism.11 This first case has now been settled and some damages were awarded to the plaintiff. The outcome served to reinforce the disproven association between vaccines and autism.
NO ASSOCIATION BETWEEN VACCINES AND AUTISM
Numerous studies have negated the role of vaccines in the environmental causation of autism.1,6 Most compelling are those that show no relation between vaccination status and autism. Madsen and colleagues12 did a retroactive population study of all children (more than 500,000) born in Denmark between 1991 and 1998. They found no difference in the incidence of autism between those who were and those who were not vaccinated. There was also no correlation between autism and the presence or absence of thimerosal in vaccines.
Other studies have shown that autism rates have continued their general increase since thimerosal was eliminated from vaccines. Schecter and Grether13 analyzed records of children in California born between 1989 and 2003 in whom autism had been diagnosed between 1995 to 2007. Overall, the prevalence of autism increased from 0.3 per 1000 in 1993 to 1.3 per 1000 in 2003 despite removal of thimerosal in 2001. Nield6 summarizes 10 sample studies that refute the link between MMR vaccine and autism—including several showing a constant rate of autism and several showing no link with thimerosal or mercury levels.
Medical science has, therefore, demonstrated that there is no link between autism and vaccines. Parents should feel safe in immunizing their children and realize the far greater risks from contracting disease (as illustrated in the opening cases). Families with members who have autism should also recognize that alternative therapies based on chelation to remove heavy metals have lost their major justification: thimerosal is no longer used in vaccines and never contained the demonstrated toxin methyl mercury. Heavy metals are thus one of many environmental factors to be considered in autism, but there is no compelling evidence for any particular agent as yet. Parents should also avail themselves of the growing ability to detect genetic changes in autism: results may alleviate parental guilt about prenatal or childhood exposures and can help to inform relatives about risks for future children.