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HHV6 and MS

Plague Time

Interferon is an anti-viral. Why does it work against MS?

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NEWS ARTICLE from THE MORNING JOURNAl, 11-25-00, By SARAH FENSKE, Morning Journal Writer

``Multiple sclerosis disease study covers all Lorain County now

ELYRIA -- A study of multiple sclerosis in Wellington has been expanded to include all of Lorain County, according to a state health official.

The study will seek to identify everyone in the county with the mysterious disease and then determine if that number is higher than expected.

State health officials first became interested in Wellington in 1999 after hearing reports of a higher-than-average multiple sclerosis rate.

A preliminary study by the county health department identified 25 potential cases in Wellington's 4,200 residents.

That rate, 595.2 cases per 100,000 persons, is almost five times the regional average of about 160 cases per 100,000.

Based on the study, the Agency for Toxic Substances and Disease Registry in Atlanta awarded the state $66,000 to study Wellington in greater depth.

Robert Indian, chief of community health assessment for the Ohio Department of Health, said yesterday that health officials have decided to include the entire county in the study ...

Indian said health officials would work with local neurologists to find multiple sclerosis patients. The study will include anyone who lived in Lorain County from Jan. 1, 1998 to Dec. 31, 2000 who is diagnosed with the disease.

The study will not neglect Wellington, Indian said.

''If Lorain County's rate is not high, there will be perhaps more significance to the numbers in Wellington,'' he said. ''We've already established the prevalence for Wellington. This will see if there is anything similar on the county level.

''In terms of risk factors, it may be more important to be a Lorain Countian than a Wellingtonian,'' he said. ''That's what we need to find out.''

The population in Lorain County, more than 250,000 people, will give the study more statistical relevance than a survey of the small village.

''In no way is this going to leave our work in Wellington behind,'' he said.

Dr. Sanjay Parikh, a neurologist based in Lorain, said he has treated a high numbers of patients, but not just from Wellington.

''I see patients from Vermilion, North Ridgeville, Avon Lake, Wellington and Elyria,'' he said. ''It's all over the county.'' ...

Multiple sclerosis has no known cause or cure. Scientists know that the body turns on itself, attacking the fatty sheath around nerve fibers, but they don't know why.

The result is an array of symptoms that can vary greatly from patient to patient, including loss of vision, numbness, fatigue and sometimes paralysis.

About 350,000 Americans suffer from the disease, with higher rates typically found in northern areas and among women.

... County Health Commissioner Ken Pearce could not be reached for comment.

sfenske@morningjournal.com

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ARTICLE from ViraCor Diagnostic Labs, By Dr. Donald Carrigan, Director of the Laboratory, and Dr. Konstance Knox, Director of Research,

ViraCor Diagnostic Labs

10437 Innovation Drive, Suite 32

Milwaukee, Wisconsin 53226

(800) 305-5198.

HHV-6 and Multiple Sclerosis

BACKGROUND

Multiple sclerosis (MS) is a chronic disease of the central nervous system, i.e. brain and spinal cord, that is caused by progressive loss of myelin, the main insulating material for the nerves that are responsible for the functioning of the Central Nervous System (CNS).

The reason for the destruction of the myelin in the CNS tissues of patients with MS is unknown. However, risk for developing MS is related to the major histocompatibility complex, and a virus infection of the CNS has long been suspected to be involved as a trigger of the disease process.

Over the past few years evidence has been obtained by our laboratory and other laboratories in the United States and Europe that suggests involvement of a specific member of the herpesvirus family, human herpesvirus six or HHV-6, in MS.

HHV-6 is a frequent cause of severe and often fatal CNS infections in immunologically normal people as well as in patients with various forms of immunodeficiency. In those cases in which it has been examined, the damage to the CNS tissues associated with active HHV-6 infections has been diffuse or focal demyelination, similar to that seen in MS.

STUDIES BY ViraCor Diagnostic Labs

In studies performed by our laboratory (Abstract Number 1960; 39th Interscience Conference on Antimicrobial Agents and Chemotherapy and manuscript in press), we have documented that at least 59% (36/61) of patients with MS have active HHV-6 infections compared to 2% (2/89) of healthy control subjects and patients with other forms of neurologic disease. This difference is highly statistically significant (p less than 0.0001 by two-sided Fisher's Exact Test).

HHV-6 in MS CNS Tissues

More specifically, using an immunohistochemical staining procedure with brain tissues from patients with MS, we documented that active HHV-6 infections are not only present in the brains of most such patients, but that they are very closely involved in the actual damage being done to the brain tissue.

Only two other neurologic disease controls had cells actively infected with HHV-6 in their CNS tissues, and both of these were diagnosed as having HHV-6 encephalitis. The vast majority of the MS CNS tissues containing active demyelinative disease contained cells actively infected with HHV-6 compared to only a few of the tissues free of active demyelination (p less than 0.0001 by two-sided Fisher's Exact Test).

HHV-6 in MS LYMPHOID TISSUES AND BLOOD

Somewhat surprisingly, we also found that the active HHV-6 infections were present in the lymphoid tissues such as spleen and lymph nodes in most patients with MS but not in the lymphoid tissues of normal controls (p less than 0.015).

Consistent with this observation, we have also documented by means of a rapid HHV-6 culture assay that active HHV-6 infections are present in the blood of most patients with MS, but not in the blood of normal controls (p less than 0.0001). There was no significant difference between the incidence of active HHV-6 infection in the bloods of MS patient with chronic progressive and relapsing / remitting MS.

CRITICAL REVIEW of HHV-6/MS Scientific Literature

In order to evaluate the results of these studies and place them in the context of other published reports on the role of HHV-6 in the pathogenesis of MS, a MEDLINE search of the National Library of Medicine for two MESH headings [(1) Multiple Sclerosis and (2) Herpesvirus Six, Human] was performed. A total of 39 articles were identified by this search, and these were classified as follows:

(1) 15 review articles/commentaries,

(2) 2 case reports,

(3) 5 basic science reports and

(4) 17 diagnostic technique applications.

The articles describing diagnostic technique applications were retrieved and analyzed with respect to the methodologies used and the conclusions drawn. A manuscript describing these findings is currently in press, [10-17-00].

POLYMERASE CHAIN REACTION (PCR) OF CELLULAR SAMPLES

In studies using diagnostic technologies that could not distinguish between active and latent HHV-6 infections, i.e. PCR analysis of blood leukocytes, CSF containing cells or CNS tissue, essentially no differences were found between samples from patients with MS and control individuals.

Interpretation of these negative data with respect to the pathogenesis of MS is unclear and is made even more uncertain by the wide range of positive results seen with normal cells and tissues, e.g. normal leukocyte positivity rates of 5% to 95% and normal CNS tissue positivity rates of 15% to 85%.

CLASSICAL SEROLOGY

Studies in which classical serological methods were used, i.e. viral specific serum IgG titers and viral specific serum IgM detection, suggest a special role for HHV-6 in MS.

Six of eight studies showed either increased HHV-6 IgG titers or a higher rate of positive HHV-6 IgM in MS patients compared to controls. An additional study detected HHV-6 IgG in samples of CSF from patients with MS but not in controls, supporting the idea of a special role for the virus.

It should be noted that, while the serological methods used in these studies suggest a special role for HHV-6 in MS, results obtained for any one individual must be interpreted with caution since healthy individuals can have high titers of HHV-6 IgG and can occasionally be positive for HHV-6 IgM. Conversely, patients with MS who have an active HHV-6 viremia may have low titers of HHV-6 IgG and may be negative for HHV-6 IgM.

POLYMERASE CHAIN REACTION (PCR) of ACELLULAR SAMPLES (SERUM and CSF)

PCR analysis of serum samples yielded mixed results with some studies suggesting a special role for HHV-6 in MS and others failing to show such an association.

Importantly, the two negative serum PCR studies failed to include positive serum controls, raising the question of whether their procedures could detect HHV-6 DNA in serum. Also, neither of these two studies controlled for inhibition of the PCR reaction by substances in the patient specimens.

Three of four studies using PCR analysis of acellular CSF samples demonstrated a clearly increased positivity of the MS patients compared to other neurologic disease (OND) controls.

While the negative acellular CSF study used a control for PCR inhibition, the control DNA used was 500 times higher than the lower limit of sensitivity of the PCR technique. Significant inhibition of the PCR reaction could have occurred that would not have been detected.

The three positive investigations using PCR analysis of acellular CSF samples deserve special comment. In the three studies, 14% (3/21), 11% (4/36) and 17% (2/12) of CSF samples from patients with MS were positive for HHV-6 DNA demonstrating active infection within their CNS tissues.

This reduced rate of positivity compared to that observed with immunohistochemical staining of CNS tissues probably reflects the relatively low level of active infection present in the CNS tissues of MS patients compared to that seen in the brains of immunocompromised patients with HHV-6 encephalitis.

It is well known that analysis of CSF samples by PCR in cases of herpes simplex encephalitis can give false negative results if the sample is obtained too early in the disease course when the infection is focal and limited in size.

IMMUNOHISTOCHEMICAL STAINING of MS CNS TISSUES

All three independent studies using immunohistochemical staining of CNS tissues from patients with MS and controls, demonstrated active HHV-6 infections only in the MS patients. Also striking is the fact that the percentage of MS patients who were positive in the three studies were quite similar, i.e. 50% (16/32), 73% (8/11) and 47% (7/15).

CONCLUSION

Thus, when appropriate diagnostic technologies are used, i.e. those that detect only active HHV-6 infections, a strong relationship between HHV-6 and the pathogenesis of MS is reproducibly observed.

In summary, this work from our laboratory, in combination with previous work by other investigators, demonstrates that a sizable proportion of patients with MS suffer from active, disseminated infections of HHV-6, including infection of their CNS. We believe that this infection is the fundamental cause of the disease which raises the possibility that MS may be amenable to effective treatment with pharmacologic agents capable of suppressing the replication of HHV-6.

Further information:

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In a bold new book, evolutionist Paul Ewald argues that viruses and bacteria play a huge, hidden role in heart disease, cancer and other modern plagues

By Geoffrey Cowley, NEWSWEEK, 11-27-00

`` Back in the 1880s, before tuberculosis had a known cause, experts attributed it to a combination of risk factors -- things like depression, bad ventilation, insufficient food and "family predisposition". One standard textbook noted expansively that "the idea of infection being a cause... still prevails in the South of Europe".

FAST-FORWARD TO the 1980s, and you hear similar accounts of peptic ulcers. The highly touted risk factors were stress, smoking, alcohol and, of course, "genetic predisposition." Never mind that an Australian researcher named Barry Marshall was successfully giving himself ulcers by swilling beakers of bacteria -- and curing them with antibiotics. The textbooks didn't even mention his work.

We now know that TB and ulcers are infectious conditions, caused by specific microbes and treatable with anti microbial drugs. Yet we're still laboring to explain most of our leading scourges -- cancer, heart disease, mental illness, Alzheimer's-- with long lists of risk factors.

In a compelling new book titled "Plague Time" (282 pages. Free Press $25), Amherst College biologist Paul Ewald argues that we're missing an obvious lesson here. Roughly translated: "It's the germs, stupid."

Though genes and lifestyle are no doubt important, Ewald says, the primary causes of today's "slow-burning plagues" are parasites --viruses, bacteria and other infectious microbes --whose long-term effects we have simply failed to recognize.

Ewald is not a virologist but a bold-minded evolutionist who, in past work, has created a whole new framework for thinking about infectious disease. To understand why microbes behave as they do, he considers their ecological incentives.

Cold viruses can't afford to be too virulent because they require mobile hosts. (A dying cold sufferer wouldn't get around enough to infect other people.)

Parasites that can survive outside their hosts don't have to be so considerate -- especially if they can travel from host to host via mosquitoes or drinking water. A dying malaria sufferer is, if anything, preferable to a healthy one from the parasite's perspective. All the person has to do to spread infection is lie still and get bit.

In "Plague Time" he takes a similar approach. By his reasoning, our genes shouldn't cause much heart disease, Genes that impede our survival tend to die out over time, as their owners fail to reproduce.

By contrast, the parasites with the best tricks for exploiting us are the most likely to stay in the game. THERE IS NO QUESTION THAT VIRUSES AND BACTERIA CAN TAKE UP LONG-TERM RESIDENCE IN OUR BODIES. Some hide deep within our cells to avoid detection by the immune system, while others disguise themselves to resemble our own tissues.

We know the consequences can be serious. Suppose the immune system catches sight of a streptococcal bug that normally evades detection by masking itself as a heart cell. As the body attacks the invader, it may demolish the organ as well.

The question is whether these chronic infections are as pervasive as Ewald suspects. Some experts would scoff at the notion, but the recent findings are impressive. "Until the 1980s," he writes, "it was generally not appreciated that women who were suffering and dying from cervical cancer were the victims of a venereal disease epidemic".

Today it's undeniable. Epidemiologists have puzzled for more than a century over the link between sexual promiscuity and cervical cancer. But over the past 15 years, studies have revealed that human papillomaviruses, America's most common sexually transmitted pathogens, are present in some 93 percent of cervical tumors. Scientists have even identified the proteins that HPVs use to release the brakes on normal cell division.

TIP OF THE ICEBERG

Cervical cancer may be the tip of an iceberg. Less definitive studies have linked childhood strep infection to obsessive-compulsive disorder and Tourette's syndrome.

Traces of a virus that causes mammary cancer in mice have been recovered from human breast tumors.

Researchers in Japan and Germany have linked borna virus --a brain infection seen in horses, sheep and cats-- to schizophrenia and bipolar disorder in people.

A growing body of evidence suggests that Chlamydia pneumoniae, a common respiratory bug, may play a key role in coronary artery disease, the leading cause of death throughout the Western world. Since 1988, researchers have consistently found the bacterium in clogged vessels but not in healthy ones. They've caused arterial lesions in rabbits by infecting them with the germ. They have even found hints that antibiotics can slow the progression of heart disease in infected patients.

As these connections are borne out, they could change medicine as profoundly during the 21st century as germ theory did in the 20th. The question is whether they'll get the attention they deserve.

As Ewald observes, "Those who control access to funding and the channels of scientific communication tend to be believers in the established views."

When Edward Jenner hit upon the notion of a smallpox vaccine in 1797, the Royal Society of London scolded him for risking his reputation on something "so much at variance with established knowledge, and withal so incredible."

When the Hungarian physician Ignaz Semmelweis figured out that physicians' unwashed hands were causing fatal infections among new mothers at the University of Vienna in the 1850s, he lost his own position there.

Though Barry Marshall first reported his findings on the infectious cause of ulcers in 1983, his peers ignored the discovery until 1990, when the National Enquirer got hold of the story and told the world. Let's hope the scientific community is less slow to notice this book. ''

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NEWS ARTICLE from REUTERS HEALTH, 12-4-00

[Interferon is an anti-viral. Why does it work against MS?]

"WESTPORT, CT, Interferon-beta-1a treatment can significantly slow declines in memory and information processing ability in patients with relapsing multiple sclerosis (MS), according to a report by the Multiple Sclerosis Collaborative Research Group.

"This is the first study of any treatment showing we can decrease the chances of the patients becoming cognitively impaired," Dr. Dennis N. Bourdette, of the Oregon Health Sciences University, in Portland, told Reuters Health.

"The untreated natural history of MS is that 10 to 15 years after onset, over 50% of patients are unemployed because of the MS," Dr. Bourdette pointed out. "The biggest single factor in becoming unemployed is cognitive impairment...By instituting treatment early and decreasing the risk of developing cognitive impairment, we'll keep more patients employed longer. "

A total of 166 patients who had symptoms for at least 1 year and at least 2 documented exacerbations were treated with placebo or interferon-beta-1a (Avonex) 30 mcg intramuscularly once weekly for 2 years. Dr. Bourdette and associates report their results in the Annals of Neurology for December.

"It's interesting," Dr. Bourdette commented, "that the treatment effect on delaying cognitive impairment was more robust than the effects on physical impairment."

After 2 years, results on the information processing and memory component of the comprehensive neuropsychological battery were significantly better in the treatment group than in the placebo group ..."

Ann Neurol 2000;48:885-892.

NEWS ARTICLE from REUTERS, 5-8-01

More Evidence Links Viral Infection With Risk of MS

WESTPORT, CT (Reuters Health) May 08 -, 2001 Late infection with common viruses is associated with an increased risk of multiple sclerosis, according to findings from a case-control study nested within the Nurses' Health Study II.

Dr. Miguel A. Hernan, of the Harvard School of PubliDr. Miguel A. Hernan, of the Harvard School of Public Health in Boston, and associates identified 301 women with MS and matched them with 1416 healthy controls. The subjects completed questionnaires regarding such issues as lifetime history of various viral diseases and exposure to pets.

The odds ratio of a subject with a history of infectious mononucleosis developing MS was 2.1, the researchers report in the May issue of Epidemiology. For mumps or measles after age 15, the odds ratios were 2.3 and 2.8, respectively.

"Whether these viruses cause the elevated risk or are only surrogates for the actual etiologic exposure cannot be determined from our findings," Dr. Hernan's group cautions.

The investigators observed no association of MS with other common viral diseases, exposure to canine distemper virus, cat ownership, birth order or number of siblings. The risk of MS was moderately increased among dog owners, "but the 95% confidence interval was wide."

Epidemiology 2001;12:301-306.

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DISCOVER Vol. 21 No. 11 (11-00), BOOK REVIEW by Annie Murphy Paul

Plague Time: How Stealth Infections Cause Cancer, Heart Disease, and Other Deadly Ailments

By Paul W. Ewald, The Free Press, $25.

Reviewed by Annie Murphy Paul

`` "Humans have never escaped plagues of infectious disease," declares Amherst College biologist Paul Ewald. Despite antibiotics, exterminators, and indoor plumbing, our era is no exception: AIDS, West Nile encephalitis, tuberculosis, and other illnesses regularly threaten.

They may be just the tip of the infection iceberg, however. With an argument certain to stir controversy, Ewald asserts that germs are the culprits for almost every serious ailment plaguing humans today, including cancer, heart disease, diabetes, Alzheimer's, schizophrenia, and arthritis.

We may believe that our bodies are failing because of faulty genes or risky lifestyles or "just falling apart from the wear and tear of life," Ewald says, but really they're suffering the ravages wrought by slow-acting viruses, bacteria, and other pathogens.

A cautious and conventional medical establishment has always been slow to recognize the role of infection, Ewald says, citing the histories of syphilis and, most recently, peptic ulcers.

Moreover, scientists have been laggard in appreciating microbes' ability to evolve and evade our attempts to eradicate them. It's the protean nature of the human immunodeficiency virus, for example, that has made a cure for AIDS so elusive.

To redress these failings, Ewald urges researchers to relax the standards of proof when it comes to identifying a causative agent, accepting "a compelling body of evidence" in place of a definitive demonstration, and granting greater weight to anecdotal evidence.

As for combating pathogens, he advocates finding new ways to piggyback on the powers of the human immune system.

He also proposes some broad policy measures. Strict standards of hygiene, relaxed after the introduction of antibiotics, should be reinstated at hospitals.

Employees who are sick should be urged to stay at home.

In developing countries, where diseases like cholera and malaria still thrive, the emphasis should be on ensuring clean water supplies, adequate waste disposal, and mosquito-proof housing, instead of sophisticated medicine ... ''

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