Chronic Hepatitis: A spectrum of disorders between acute hepatitis and cirrhosis.. The Merck Manual is

• Mad Hatters
• Macrophagic myofasciitis lesions assess long term persistence of vaccine-derived aluminum hydroxide in muscle
• Chronic adverse reactions associated with hepatitis B vaccination
• History and overview
• Ounce of Prevention, Pound of Misery?
• HHS Flagrant Disregard of 'Acceptable' Heavy Metals Exposures

Mad Hatters

'A Mad Hatter Tea-Party' from the book, Alice in Wonderland by Lewis Carroll, illustrated by John Tenniel.

excerpt- The felting process began with camel hair in what is now a part of Turkey. The hair of camels was made into tough felt material for tents.

It was discovered that the felting process was accelerated with the urine of the camel. The art was brought back to Western Europe by the followers of the Crusades. It become the habit for the workers to urinate on the fibres before felting them. The story goes that one particular workman (probably in France!) was being treated with mercury for a venereal disease. It was noticed that his fibres, after the treatment mentioned above, felted quicker and better than that of his more healthy comrades. This was the secret which gave the process the name of 'le secretage' in France. This may be an old wives tale, but it has been passed down in the Felt-hat Industry as the origin of the use of mercury.

excerpt- The mercury from carroting was what caused "Mad Hatters". This was actually heavy metal poisoning from mercury. The mercury attacked the nervous system of those involved in the felting and fulling of the hats. The mercury was airborne in the steam coming off the felt.

By 1800, Philadelphia led all cities in the manufacture of hats. There were 68 working hatters in the city. The annual manufacture value of hats in the United States in 1810 was estimated at ten million dollars.

Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle

ABSTRACT
Macrophagic myofasciitis (MMF) is an emerging condition of unknown cause, detected in patients with diffuse arthromyalgias and fatigue, and characterized by muscle infiltration by granular periodic acid-Schiff's reagent-positive macrophages and lymphocytes. Intracytoplasmic inclusions have been observed in macrophages of some patients. To assess their significance, electron microscopy was performed in 40 consecutive cases and chemical analysis was done by microanalysis and atomic absorption spectrometry. Inclusions were constantly detected and corresponded to aluminium hydroxide, an immunostimulatory compound frequently used as a vaccine adjuvant. A lymphocytic component was constantly observed in MMF lesions. Serological tests were compatible with exposure to aluminium hydroxide-containing vaccines. History analysis revealed that 50 out of 50 patients had received vaccines against hepatitis B virus (86%), hepatitis A virus (19%) or tetanus toxoid (58%), 3-96 months (median 36 months) before biopsy. Diffuse myalgias were more frequent in patients with than without an MMF lesion at deltoid muscle biopsy (P < 0.0001). Myalgia onset was subsequent to the vaccination (median 11 months) in 94% of patients. MMF lesion was experimentally reproduced in rats. We conclude that the MMF lesion is secondary to intramuscular injection of aluminium hydroxide-containing vaccines, shows both long-term persistence of aluminium hydroxide and an ongoing local immune reaction, and is detected in patients with systemic symptoms which appeared subsequently to vaccination.

Key Words: inflammatory myopathy; drug adverse effect; macrophage; vaccine; aluminium hydroxide

Abbreviations: HAV = hepatitis A virus; HBV = hepatitis B virus; MMF = macrophagic myofasciitis; PAS = periodic acid-Schiff reagent; TT = tetanus toxoid

In the present study, intracytoplasmic inclusions were constantly detected in macrophages of the MMF lesion, and were shown to contain aluminium by three different methods. Their crystalline structure was suggestive of aluminium oxyhydroxide (boehmite) rather than aluminium phosphate (Shirodkar et al., 1990). However, high levels of phosphorus were found in aluminium-loaded macrophages. Since phosphate anions generated by acid phosphatase activity in lysosomes are potent complexors of ionized aluminium, it is likely that a proportion of aluminium phosphate or hydroxyphosphate was formed in situ.

Old advertisement for magma medicine used to manage colitis. It contained aluminum hydroxide.

Aluminium intoxication causing encephalopathy, osteomalacia and anaemia has been mainly reported in patients with chronic renal failure undergoing haemodialysis (Salusky et al., 1991). Our patients had normal renal function tests (Gherardi et al., 1998), and their aluminium plasma levels were normal. This was inconsistent with passive aluminium deposition from blood, since aluminium tissue concentrations can usually be inferred from blood concentrations (Salusky et al., 1991; Flarend et al., 1997). Macrophage infiltrates were not observed anywhere else, other than in muscle (Gherardi et al., 1998), and the MMF lesion was exclusively detected in the deltoid muscle in adults. This reminded us that deltoid muscle is an elective site for vaccine injection, and that some vaccines may contain aluminium, an adjuvant frequently used to potentiate the immune response to vaccine antigens (Glenny et al., 1926).

In France, aluminium hydroxide is found in HBV, HAV and most TT vaccines. Elsewhere, it may be found in additional vaccines, such as the six-shot anthrax vaccine administered to the US military personnel (Product Insert for Anthrax Vaccine, 2001). Retrospective serological analysis was either consistent or compatible with previous HBV, HAV or TT immunization in all tested MMF patients. Prevalence of HBV immunization was much higher in these patients (65%) than in the French population of similar age (16-22% in 1996).

History revealed that all MMF patients (50 out of 50) had been immunized 3 months to 8 years before muscle biopsy by aluminium-containing vaccines, including HBV (26%), TT (16%) or combinations of HBV, TT and HAV (58%) vaccines. Rats injected intramuscularly with an aluminium hydroxide-containing vaccine developed infiltrates of macrophages with intracytoplasmic crystalline inclusions very similar to those of MMF. Taken together with previous reports on granulomas induced by various aluminium-containing compounds in humans and animals (Balouet et al., 1977; Gotto and Akama, 1982; Mrak, 1982; Miliauskas et al., 1993; Garcia-Patos et al., 1995), these results firmly establish that aluminium hydroxide-containing vaccines represent the direct cause of the MMF lesion.

The onset of MMF detection was probably related to introduction of the intramuscular route of vaccination in the early 1990s. The striking number of cases detected in France, compared with other countries, is more puzzling. A local pharmaceutical cause linked to manufacturing practices seems unlikely (WHO Vaccine Safety Advisory Committee, 1999). Three combined factors might explain why MMF has been mainly detected in France: (i) MMF probably came to medical attention in France because of extensive immunization programs carried out in this country; (ii) a large number of French people have been primovaccinated at adulthood against hepatitis B which is not the case in other countries, where HBV immunization is restricted to children and risk groups; and (iii) deltoid muscle is a biopsy site more commonly used in France than in other countries (WHO Vaccine Safety Advisory Committee, 1999).

Once injected into tissues, aluminium hydroxide forms a deposit, damages the injected tissue, elicits danger signals from stressed cells, attracts inflammatory and antigen-presenting cells and is subjected to phagocytosis (World Health Organization, 1976; Balouet et al., 1977; Schijns, 2000). Phagocytosed aluminium hydroxide increases survival of macrophages and synergizes the effects of M-CSF (monocyte-colony stimulating factor) and GM-CSF (granulocyte/monocyte colony stimulating factor) (Hamilton et al., 2000). A number of aluminium-loaded macrophages accumulate locally while others migrate to the regional lymph node (World Health Organization, 1976). Aluminium hydroxide induces monocyte-derived cells to acquire the phenotype and APC (antigen presenting cell) functions of dendritic cells (Ulanova et al., 2001). Antigen presentation at the injection site is assessed by the presence of lymphoplasmacytic infiltrates in the vicinity of macrophages, defining the so-called immunogenic granuloma that is not formed when the adjuvant is used alone, and that increases when polyantigens are added to the aluminium-adjuvanted vaccine (Balouet et al., 1977). It is currently believed that the injected aluminium adjuvant is progressively solubilized into blood, redistributed to tissues and gradually secreted into urine (Flarend et al., 1997). Using 26Al-labelled adjuvants, Flarend and colleagues showed that 17% of a full human dose of aluminium hydroxide, and 51% of asimilar dose of aluminium phosphate are eliminated in urine within 28 days after intramuscular injection into rabbits (Flarend et al., 1997). Residence time of aluminium hydroxide in muscle has not been established in spite of its long use in vaccines. A recent study in rabbits showed that macrophage accumulation develops in all injected sites, decreases by day 30, anddisappears from most sites within 3 months post-injection (Franciois Verdier, Aventis-Pasteur, France, presentation at the `Aluminium in vaccines' CDC symposium held in San Juan, Puerto Rico, May 11 and 12, 2000; personal communication). In our laboratory, a residence time longer than 6 months has been observed in rats (Authier et al., 2001a). Further investigations on this important topic are desirable.

Ethical reasons prevented us from performing muscle biopsies in healthy individuals to estimate the residence time of aluminium hydroxide in the human muscle. However, a prospective evaluation showed that MMF detection at deltoid muscle biopsy is rare among aluminium hydroxide-containing vaccine recipients with neuromuscular disorders. Time elapsed from vaccination to histological detection of MMF could be very long, i.e. up to 8 years, the mean delay being 36 months. Both findings, and the previously reported intersubject variability in elimination of aluminium (Balouet et al., 1977; Talbot et al., 1995; Flarend et al., 1997), led the WHO Vaccine Safety Advisory Committee to propose as a working hypothesis that MMF could occur in `a predisposed subset of individuals with impaired ability to clear aluminium from the deltoid muscle' (WHO Vaccine Safety Advisory Committee, 1999).

Clinical manifestations of patients with MMF mainly include steroid responsive diffuse myalgias, arthralgias and chronic fatigue (Gherardi et al., 1998; Chérin et al., 2000). Typically, patients have myalgias of a localized onset, most often in lower limbs, with subsequent extension leading to diffuse muscle pain (Institut de Veille Sanitaire, 2001). Prevalence of myalgias was much higher in MMF patients than in the other 1252 patients who had a deltoid muscle biopsy at the same time in the same centres. Myalgia onset was subsequent to vaccination in 94% of MMF patients and, as a rule, other causes of myalgia were not detected. Taken together, these data make fortuitous association of MMF with chronic myalgias very unlikely. Myalgias, arthralgias and fatigue are among the most common post-vaccinal symptoms reported to passive surveillance systems (Vaccine Adverse Reaction Searchable Database, 2000). Myalgias and arthralgias already have been recognized as adverse effects of HBV vaccination (McMahon et al., 1992), and a possible association between chronic fatigue and HBV vaccination has been debated (Working Group on the Possible Relationship between Hepatitis B Vaccination and the Chronic Fatigue Syndrome, 1993). Most MMF patients had their first myalgias several months after vaccination, and would have not been considered to have an adverse reaction to vaccine using standard criteria (Tourbah et al., 1999). In light of the possible occurrence of long-term persistence of vaccine compounds in the injected tissues, we feel that the short post-exposure period during which imputability of symptoms to an adverse drug reaction is usually accepted might be inappropriate in the setting of vaccines.

Most chronic myalgia and fatigue syndromes remain poorly understood. Patients with MMF had a myopathic electromyogram (42%), CK (creatine kinase) elevation (50%) and abnormal 67Ga scintigraphy (100%) showing increased gallium global uptake predominating in painful areas along limb muscle fascias and in para-articular tissues (Chérin et al., 2000). Significance of such a gallium uptake in MMF patients is at present unclear. A few patients had a second muscle biopsy remote from the MMF detection site, showing poorly specific inflammatory infiltrates and no evidence of MMF diffusion (data not shown). It is not unprecedented that a focal muscle stimulus may elicit diffuse myalgias of an unknown cause: in a recent experimental study, bilateral, long-lasting hyperalgesia was induced by unilateral intramuscular injections of acidic saline, in the absence of histological muscle lesions (Sluka et al., 2001).

Both HBV and TT vaccines were implicated in our patients, suggesting a role of the adjuvant in the vaccine-associated systemic effects (McMahon et al., 1992). In addition to deposit formation, aluminium hydroxide potently stimulates the immune system (Brewer et al., 1999). Aluminium hydroxide has been reported to induce IL-1 (interleukin-1) production by monocytes, complement activation, eosinophilia, increased specific and non-specific IgG1 and IgE antibody responses and delayed-type hypersensitivity (Gupta et al., 1995). In the present series, MMF lesions constantly included a lymphoid component, ranging from lymphoplasmacytic infiltrates to organized tertiary lymphoid tissue, assessing an ongoing immunological process at time of biopsy. Persistent systemic immune activation that fails to `switch off' previously has been regarded as the possible cause of chronic fatigue and arthromyalgias (Landay et al., 1991; Hassan et al., 1998), through sustained release of inflammatory cytokines and production of autotoxic T cells and autoantibodies (Konstantinov et al., 1996). Consistently, we have observed that MMF patients have B-cell hyperlymphocytosis, higher IL-6 circulatory levels than healthy vaccinated controls and detectable circulating antinuclear and anti-phospholipid autoantibodies (50%) (Gherardi et al., 2001). These data indicate that MMF is associated with a shift of immune responses towards a Th-2 profile, which is typically induced by aluminium hydroxide (Brewer et al., 1999), and probably contributes to emergence of chronic fatigue and associated manifestations (Rook and Zumla, 1997).

Patients with MMF may also have co-existent autoimmune diseases (Authier et al., 2001b). The significance of this remains uncertain, but aluminium potently induces oxidative stress and lipid peroxidation (Gutteridge et al., 1985; Xie et al., 1996; Yoshino et al., 1999; Campbell and Bondy, 2000), which may reveal cryptic immunogenic epitopes (Horkko et al., 1996; Casciola-Rosen et al., 1997; Petrovas et al., 1999; Kalluri et al., 2000). Metals in a suitable microenvironment could also favour activation of autoreactive T cells that exist in healthy individuals (Fournie et al., 2001). Whether such mechanisms of autoimmunity are involved in MMF patients deserves further investigation.

At this point, an epidemiological survey aimed at evaluating the putative link between long-term persistence of MMF lesions at sites of vaccine injection and systemic symptoms is required. Meanwhile, there is no basis for recommending a change in HBV vaccination practices (WHO Vaccine Safety Advisory Committee, 1999).

We conclude that: (i) intracytoplasmic inclusions are constantly detected in MMF lesions and correspond to aluminium hydroxide crystals; (ii) MMF lesions are secondary to intramuscular injections of aluminium hydroxide-containing vaccines and should be regarded as a post-vaccinal immunogenic granuloma; and (iii) MMF lesions are usually detected in the deltoid muscle of patients with diffuse myalgias appearing subsequently to aluminium hydroxide-containing vaccine administration.

ACKNOWLEDGEMENTS
We are most indebted to Dr Philippe Malfait and to Dr Daniel Levy-Bruhl from the Institut de Veille Sanitaire (Saint-Maurice, France) for their help in the design of the study, and for their kind cooperation for extraction of vaccination data. Data and conclusions of the present paper have been analysed by the Safety of Vaccines Standing Committee of the World Health Organization (Geneva, Switzerland), by the Institut de Veille Sanitaire (Saint-Maurice, France) and Agence Franciaise de Sécurité Sanitaire des Produits de Santé (Saint-Denis, France) and by experts from the Centres of Disease Control (Atlanta, USA). This work was supported by the Association Franciaise contre les Myopathies (AFM).

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Chronic adverse reactions associated with hepatitis B vaccination

Photo is meeting of two hepatitis B vaccine-injured adults (website author on right)

We analyzed adult hepatitis B vaccine (HBV) serious reactions, showing statistical increases in arthritic, neurologic, immunologic, and gastrointestinal reactions. However, some reactions analyzed may have been acute self-limited reactions that did not lead to chronic problems. In order to study this problem, the purpose of this analysis was to examine chronic adverse reactions reported to the Vaccine Adverse Events Reporting System (VAERS) data base following adult HBV from 1997 through 2000. We hypothesized that chronic conditions occurred similarly following adult HBV and adult vaccine control group. The scientific literature contains few studies briefly examining chronic reactions following adult HBV.2, 3

The VAERS is an epidemiologic database maintained by the Centers for Disease Control and Prevention (CDC) since 1990. All vaccine reactions are to be reported to this database as mandated by US law. The CDC requires written and telephonic confirmation of serious reactions and follows up serious reactions 1 year after they occur to determine whether the patient recovered. The VAERS Working Group of the CDC analyzes and publishes epidemiologic studies based on examination of the VAERS.4

Methods
We retrospectively examined adult HBV reactions reported to VAERS from 1997 through 2000 using Microsoft Access (Redmond, WA). We examined neuropathy, neuritis, myelitis, vasculitis, thrombocytopenia, gastrointestinal disease, multiple sclerosis, and arthritis reactions, where patients, based on a 1-year follow-up, were considered not to have recovered from their reaction. These terms for reactions were based on descriptions by those reporting them. We have examined each of these reactions in previous studies, enabling us to extend and expand our previous findings.

Incidence rates were based on the estimates of the Biological Surveillance Summaries that we obtained from the CDC for the number of doses administered during the study periods examined. The CDC estimates that 20 516 508 adult HBVs were administered from 1997 through 2000. Additionally, as a control, tetanus-diphtheria (Td) vaccine chronic reactions reported to VAERS from 1991 through 2000 in adults were analyzed. The CDC estimates that 141 832 679 adult Td vaccinations were administered from 1991 through 2000. The incidence rates of adult adverse reactions in the Td vaccine recipients provided a background rate to compare against the incidence rates of adverse reactions in adult HBV recipients. We chose our temporal period following adult Td vaccine so as to allow our search of the VAERS to yield as many reactions following our adult Td vaccine control group as possible; this would allow for an increased power in our statistical analyses. Relative risk was determined by dividing the incidence rate of the reaction following adult HBV by the incidence rate of the reaction following adult Td vaccine control group. Attributable risk was determined by subtracting 1 from the relative risk. Percent association was calculated by dividing the relative risk by the relative risk plus 1 and multiplying this computed value by 100. In our statistical analysis, a 2 2 × 2 contingency table was employed. We used the statistical package contained in Corel's Quattro Pro and accepted a p value of 0.05 as statistically significant.

Results
Table 1 summarizes chronic reactions reported following adult HBV in comparison with those reported following adult Td vaccination. The results show even more significant increases in chronic conditions following adult HBV than acute conditions in comparison with adult Td vaccination.

Discussion
In conclusion, our study demonstrates that adult HBV is statistically associated not only with acute neuropathy, neuritis, myelitis, vasculitis, thrombocytopenia, gastrointestinal disease, multiple sclerosis, and arthritis, but some of these patients go on to develop chronic adverse reactions that persist for at least 1 year following HBV. These types of chronic adverse reactions following adult HBV should be discussed with patients contemplating being immunized with HBV and should be included in the differential diagnosis of those who develop them following adult HBV.

REFERENCES

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4. Singleton JA, Lloyd JC, Mootrey GT, Salive ME, Chen RT, the VAERS Working Group. An overview of the Vaccine Adverse Events Reporting System (VAERS) as a surveillance system. Vaccine 1999;17:2908-17. [PubMed Citation]

History and overview

Vaccines
made from new recombinant DNA biotechnology have been touted as the safest ever; this despite that such vaccines, the hepatitis B vaccine for an example, were on the market a decade before the mapping of the human genome.

Cell biologist Bonnie Dunbar, PhD at Baylor College of Medicine has postulated that genetic protein sequences in the vaccines may show molecular mimicry to human nerve tissue in some individuals. The only safety studies performed have been on populations from Alaska and Asia. Most adverse events reported for this vaccine have been from Caucasians.

History:
Viera Scheibner's article about adjuvants that appeared in the February -March 2001 'Nexus' publication discusses a paper written in 1948 by Ayvasian and Badger. They surveyed 750 student nurses in training at a large municipal hospital during the years 1932-1946 who received numerous vaccinations. In a given time period, three in particular (0.4% incidence) developed and died from disseminated lupus erythematosis. One can only imagine how many of the nursing students developed chronic crippling conditions.

Ingredients:
Vaccine ingredients are necessarily toxic. Inherent to the design is a balance between a dose that will create an artificial immunity without endangering the host. Ingredients can be considered in the following classifications:

1. Micro-organisms - in general these are the bacterial or viral antigens. They are weakened by having broken cell walls, protein 'envelopes,'or through attenuation, which is the process of weakening the organism to the host cell by growing the cell in the organ of another species. There may also be some micro-organisms that are a result of contamination.
2. Chemical substances / adjuvants - foreign to the body, these are used in vaccines because they stimulate the immune system to mount a defense to the antigen. Aluminum hydroxide is the most commonly used adjuvant in human vaccines. The new synthetic vaccines, such as recombinant hepatitis, have weak immunogenicity and therefore require a powerful adjuvant. There is growing evidence that United States military personnel were injected with vaccines containing squalene, still considered 'experimental' for use in humans. Studies have shown that adjuvants are not always required in a vaccine. The use of adjuvants helps to defray manufacturing costs.
3. Tissue fixatives - these have the purpose of stabilizing the cell, either preventing decay or additional cell proliferation. Formalin is an example of a fixative; it is a 37% solution of gaseous formaldehyde. Formaldehyde may be a residual from the process of weakening an antigen.
4. Preservatives - Since 1940 thimerosal has been used as a preservative in human vaccines. Thimerosal is 49.6% mercury by weight. Mercury is a cytotoxin. It kills cells. One reason the cytotoxin is added is to kill microorganisms that may be introduced with each puncture of the syringe into a multi-dose vial. There are fewer production costs associated with manufacturing multi-dose vials, rather than single dose vials.

Outdated Forms:
The CDC publishes a 'Vaccine Information Statement' to educate patients prior to receiving immunization. The one that informs the patient about the hepatitis B vaccine advises the patient not to take the vaccine if (s)he has ever had a life-threatening allergic reaction to Baker's yeast or prior hepatitis B vaccine. It makes the claim that it the first anti-cancer vaccine because it prevents a type of hepatic malignancy.

As a result of the 1997 FDA Modernization Act, a report released in 1999 revealed that hepatitis B vaccine contains ethylmercury. These forms have not been updated since 1998 and therefore fail to even mention the toxic heavy metals ingredients.

Ounce of Prevention, Pound of Misery?

Thousands have claimed bad reactions to their hepatitis B inoculation. So why isn't the health bureaucracy's mass vaccination policy being investigated by Congress?

When nurses gave her newborn son another injection, the room filled with the sound of his healthy cry. Julienne Jack recalls wondering through the haze of her post-labor exhaustion what that one was for. In fact, it was the hepatitis B vaccine, which Ohio mandated for all its newborns — a safe inoculation without known side effects, according to the Centers for Disease Control and Prevention, or CDC, in Atlanta.

But as she took her tiny firstborn into her arms again, coaxing him to nurse, Jack sensed something disturbing in the sound of his cry, the strange restlessness of his movements, a sudden yellowing of his skin. It was a relief when he seemed to slip into peaceful stillness in her arms. Just 27 hours old, she remembers thinking. She daydreamed of the future for their family of three until the night nurse came to return the baby to his crib. Something in his appearance as the nurse lifted him from her arms, however, tore a cry from her throat: "What's wrong with him?"

The nurse rushed Brandon out of the room and down the hall in search of help. After an hour, bed-bound by the lingering effects of an epidural, Jack faced the news alone: Little more than an hour after receiving the hepatitis B vaccination, her baby was dead.

No explanation was offered. The mystified coroner marked the cause of death unknown. Two years later a death certificate still has not been issued.

In Jack's eyes, the chain of events that day in the hospital implicates the vaccination. Brandon's doctors, though they voluntarily waived the family's medical bills, deny any such connection. The lawyer whose help the family enlisted to obtain copies of the medical records sent a letter saying the Jacks had no case against any of the medical professionals involved because he could find "no reports of any serious reaction to the vaccination."

In fact, "no confirmed reactions" is the standard line of federal officials in most cases, although since 1990 more than 24,000 reports of possible adverse reactions to the hepatitis B vaccine have been registered with the Food and Drug Administration's Vaccine Adverse Event Reporting System, or VAERS, including a significant number of severe injuries and deaths.

Federal guidelines issued in 1991 recommending three doses of the vaccine for health professionals coming into contact with blood, at-risk groups including intravenous drug users and people with multiple sex partners -- and every child born after 1990 -- remain unchanged. At least 35 states mandated the vaccine for entrance to kindergarten by 1996, and in 1977 the Advisory Commission on Immunization Programs reported vaccination of 84 percent of America's 19- to 35-month-olds.

In January 1999, the CDC further expanded its goals, calling for universal immunization of children up to age 18. Government agencies and pharmaceutical groups 0categorically deny that the VAERS reports are cause for alarm, explaining that the purpose of the data collection merely is to reveal unexpected patterns, that the adverse-reaction numbers may be inflated due to double reporting and that no scientific data prove the vaccine is the cause of the problems.

"Bad things happen to people all the time. It's unfortunate that we don't know the causes of many of those," says Neal Halsey, a leader in the American Academy of Pediatrics and director of the vaccine safety center at Johns Hopkins University in Baltimore. But Barbara Fisher, founder of the watchdog group National Vaccine Information Center, or NVIC (on the World Wide Web at www.909shot.com), objects. "Why can no one confirm or deny a causal relationship in these tens of thousands of adverse reports?" she asks. "Because the kind of scientific studies that could reveal the link have not been done." And, alas, they haven't.

"When vaccine coverage reaches high levels like they do in the U.S., essentially anyone with a negative medical event will have previously been vaccinated," Robert Chen of the CDC's National Immunization Program tells Insight. His solution to the dilemma raises the eyebrows of privacy advocates. "What is needed is a database with all vaccinations and all medical events linked in a large cohort to see if those vaccinated recently are more likely to develop the adverse event of interest," he says. "The CDC has established such a cohort with 5 million members of four large staff-models [health-maintenance organizations] on the West Coast in the Vaccine Safety Data Link Study."

Other approaches also are being examined. Bonnie Dunbar, a professor of cell biology at Baylor College of Medicine in Texas, is a leader among the growing number of scientists who are joining consumer advocates, parents'-rights groups and undiagnosed patients in searching for answers about adverse reactions to the vaccine.

To Dunbar and her colleagues, preliminary evidence indicates some people might be genetically disposed to an adverse autoimmune or neurological response to the recombinant hepatitis B vaccine. In an open letter last November, Dunbar wrote, "After carrying out extensive literature research on this vaccine, it is apparent that the serious adverse side effects of this vaccine ... may be much more significant than generally known (or admitted)."

Halsey tells Insight he doubts the credibility of people questioning the vaccine. But Dunbar's 25 years as a research scientist and medical-school professor and her National Institutes of Health honors for pioneering work in contraceptive vaccines are sturdy credentials.

Today's recombinant hepatitis B vaccine derives from a surface protein of the virus molecule. Dunbar suggests that similarities between the antigen and proteins in human nerves and tissues could trick the autoimmune systems of the genetically susceptible into attacking themselves. In Science magazine last summer, Halsey scoffed at that theory, asking how a fragment of virus protein used in a vaccine could cause symptoms not even caused by the virus. Dunbar explains that any part of a virus molecule introduced into the human body can be met by a unique immune response. "The same rigorous testing [is required] every time you change the vaccine. The companies don't want to hear that because it is going to cost them a lot of money."

William Hildebrand, an immunogeneticist at the University of Oklahoma, plans to take a close look at the five or six genes that are responsible for controlling the immune response. Three observations lead him to conjecture that an individual's HLA genotype may mediate how he or she responds to the vaccine: Almost all negative responses occur in Caucasians, the number of genes determining autoimmune responses varies from race to race 0and the reported adverse responses are consistently autoimmune in nature. "It justifies asking what are the reactions and how frequent are they," Hildebrand says, "and that's all I would argue needs to be done at this time. If you understand which genes are involved in the adverse response, you can begin to understand the adverse response."

Until the research is done, however, Hildebrand remains skeptical of both sides of the debate. "One side is saying you can't prove [a cause-and-effect relationship]. The other side is saying, ‘You know something is going on here.' I say let's find out. If you say that the world is flat and you don't do research, maybe the world will stay flat."

Denied government grants, funding for this research is being supplied by private donations, often from patients and surviving families. The initiatives of the inquiring scientists are important to bewildered survivors such as the Jacks, who have moved to Pennsylvania where they have been assured they can obtain a medical exemption for a second child they are expecting this summer. For two years they believed they were alone in their suspicions about the vaccine. Then a friend told them about an investigation and televised report by the TV newsmagazine 20/20.

While searching for the Internet version of the TV report, Jack found contact information for a father who had appeared on the show. That man is Michael Belkin, a New York financial adviser whose search for answers after his 5-week-old daughter died hours after her vaccination led him to apply his statistical training from the University of California at Berkeley to the tangled web of epidemiological studies at the core of the hepatitis B vaccination controversy.

Does the risk/reward ratio for administering the hepatitis B vaccine to the typical American baby justify the national vaccine mandate? Even questions about the incidence of the disease are difficult to answer. For example, 1996 and 1997 issues of the CDC's Morbidity and Mortality Weekly Reports, or MMWR, show only about 10,000 cases of hepatitis B reported in the United States. Yet the CDC estimates the total annual incidence of the disease at 150,000 to 300,000. The CDC believes the vast majority of cases go unreported because the hosts are asymptomatic or mistake the reaction for the flu.

Undoubtedly, asymptomatic chronic infection by the disease (which studies show is more likely to occur the earlier the virus is contracted) can lead to devastating cancers or cirrhosis late in life. Marketing materials for the vaccine produced by the International Task Force on hepatitis B Immunization and the Program for Appropriate Technology in Health begin by warning doctors that three-quarters of the world's population lives in high- or midrange risk areas for hepatitis B and that the virus causes up to 80 percent of the world's liver-cancer deaths.

The materials claim a need for mass vaccination in the United States despite low endemicity in most of the nation: Certain narrow populations, such as Alaska natives, Southeast Asian immigrants, gay men and others experience moderate to high levels of infection.

But according to the CDC's figures, among infants, only those born to mothers infected with the virus are at any measurable risk for the disease. Belkin estimates that his daughter, like other infants of the average American family, had a .001 percent chance of contracting the disease. Of the 279 total reported cases of hepatitis B infection in American children under the age of 14 (as documented in a 1996 issue of MMWR), only 54 of those cases occurred in the newborn to 1-year-old age group in a total of 3.9 million babies born in the United States that year.

The need for American children born to families without the disease to receive the vaccine hinges, in most cases, upon their likelihood of engaging in promiscuous sexual behavior or sharing drug needles later in life. But even if this is satisfactory justification, Belkin notes, no conclusive evidence exists to indicate that immunity lasts beyond 10 years. Therefore, the inoculation would appear to protect only the sexually promiscuous and heroin-addicted under age 10.

Despite the unified rhetoric of government and industry officials, the roar of the victim mice is being picked up by mainstream media. Reports on the possible dangers of hepatitis B vaccinations have appeared not only on 20/20 but in the Washington Post, the Chicago Tribune, Gannet News Service and Science, among others.

Infants are not the only ones in whom adverse events or reactions have been reported. Dunbar began to look into adverse reactions when her adult brother and her lab assistant each experienced autoimmune or neurological dysfunction after they were injected with the vaccine as professional precautions. Dunbar tells Insight that she personally hears each day from an average of four people who believe they were injured as a result of the hepatitis B vaccine.

One of them was Eric Jeffries, a former Fulbright scholar at Cambridge and a young father on his way to the top in the banking industry. He tells Insight that he was vaccinated prior to a tropical vacation but four days later began experiencing severe autoimmune dysfunctions ranging from fever, headaches and extreme pain to rashes and gastrointestinal troubles. He immediately thought of the vaccine, but a phone call to his doctor assured him the vaccine is not associated with adverse reactions. As his condition deteriorated, he was tested for everything from rheumatoid arthritis to fibromyalgia and AIDS. Finally, a doctor seconded his suspicion that, whatever the disorder, it had been triggered by the vaccine. Today, no longer able to work or even to walk, Jeffries still is looking for answers.

Betty Fluck was told that she needed to have the hepatitis B vaccine when she returned to her work as a registered nurse after taking a few years off to raise her three boys. Just hours before the vaccine was administered, she was helping to run her three school-age sons' soccer games with her husband, a coach, and was working on her yellow belt in karate. On Dec. 2, 1997, she received the vaccine. Twelve hours later she suffered severe pain, a high fever, swollen joints and respiratory problems. Until her fever broke, Fluck lost the use of her legs. "At the time," she says, "the damage was already done or started. I didn't know at that point what the whole disease process was."

As did so many other victims, Fluck went from doctor to doctor until one finally told her that the symptoms might indicate a reaction to the hepatitis B vaccine. But vaccine manufacturers repeatedly told her that they never had seen problems like this. As months passed, Fluck needed a walker, and by September 1998 she required full leg braces and elbow crutches to get around. Now she receives weekly intravenous gamma-globulin treatments for severe demyelination (a progressive condition in which the sheath surrounding and protecting human nerves deteriorates).

Since Fluck's brief appearance on the 20/20 episode, she says, "Every day I hear people with stories that are just like mine and doctors telling them it can't be the vaccine. Essentially, we're write-offs. Just the casualties of war [on disease]."

This month Fluck testified before an Indiana State Senate hearing considering whether to set a July 1999 mandate for all children to receive the vaccine before they enter kindergarten. As a result of the hearings, the committee tabled the bill and voted unanimously to recommend that the vaccine be administered only at the parents' request.

For now, the federal health bureaucracy devotes its resources primarily to expanding and enforcing its mass vaccination policies rather than to evaluating adverse reports. Samuel Katz of the Vaccine Initiative of the Infectious Disease Society of America called Insight from the Atlanta airport en route from the February 1999 ACIP conference where his colleague, Chen, of the CDC's National Immunization Program, presented an update on hepatitis B recommendations. Katz said the committee "reaffirmed the value of the vaccine" and of "moving ahead with the program to vaccinate children, teenagers and adults at risk."

But the French and Canadian governments already are funding research on hepatitis B adverse-event reports, says Dunbar. "There are many of us who are not going to go away." And Congress should take notice.

HHS Flagrant Disregard of 'Acceptable' Heavy Metals Exposures