All posts tagged borrelia

Post Treatment Lyme Disease Unmasked? Immune Hole in the Illness Identified

It’s one of the bigger puzzles in medicine and one that has obvious implications for chronic fatigue syndrome (ME/CFS): why some people given oral antibiotics recover from Lyme disease while others sometimes remain sick for decades. Given the infectious trigger often seen in ME/CFS, any post-viral or post-bacterial illness is of interest. For the most part, researchers don’t know why some people fail to recover fully from an infection; they’ve hardly touched the subject, but an answer in Lyme disease may be coming.

The Study

The study was not large, containing 32 patients and 18 healthy controls, but the results were exciting, providing for the first time a possible biological explanation for the puzzling problem of post-treatment Lyme disease syndrome (PTLDS).

targeted approach Lyme

The ability to target a specific part of the immune system was the key to this studies success.

It’s not taking away anything from the researchers that the study wasn’t particularly innovative. In fact, it did something rather obvious, something that’s been done and is being done in ME/CFS (by Lenny Jason). The study took people with early Lyme disease (n=32) and healthy controls (n=18) and then (after providing the standard antibiotic regimen) followed them over two years, measuring their immune status.

The difference between this successful Lyme disease study and the less successful ME/CFS studies that measured cytokines, gene expression, and autonomic functioning is that the Lyme researchers had a clear target. Mouse studies have shown that the Borrelia burgdorferi bacteria that cause Lyme disease hammer the B-cells, and that’s what the study focused on.

Results

We herein identify plasmablasts as a key B cell population that correlates with resolution of Bb infection and Lyme disease in humans. The authors

They found that B-cells called plasmablasts were elevated prior to antibiotic treatment in patients who returned to health.  Plasmablasts are activated B-cells which circulate for a time in the blood in response to an infection.  The higher level of plasmablasts in the recovered patients suggests that these patients simply mounted a stronger immune response to the infection. That was kind of a no-brainer, but the strength of the study was that they were able to specify what part of our amazingly complex immune system the problem was in.

They also determined that the patients who returned to health also exhibited significantly greater clonal expansion: their activated B-cells produced more clones designed to target and get rid of the bacteria. Again, in retrospect, not a surprising finding, but one that does open up a possible treatment option that hasn’t previously been available.

b-cell Lyme disease

A type of B-cell called a plasmablast turned out to be the key.

Along the way this group also produced a possible diagnostic test which may a) be able to identify Lyme disease infections very early on and b) have high rates of accuracy.  The current Lyme tests do neither; they’re only about 50% accurate during the early stages of infection when studies show treatments are most effective.

They also demonstrated that Lyme disease prompts the expansion of a type of memory B-cell (CD27−) associated with some infections and, more commonly, with autoimmune diseases (rheumatoid arthritis, lupus and multiple sclerosis).

Possible Therapy

Finally, the results point to an unexpected potential therapy – monoclonal antibody drugs. Monoclonal antibody drugs (the “mabs”, e.g. Rituximab) can be theoretically designed to trigger the immune system to target any cell in the body or to influence how the immune system works in other ways. In cancer, for instance, many monoclonal antibodies have been produced that target specific cancer cells. In autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and ulcerative colitis, monoclonal antibodies bind to and inhibit the pro-inflammatory cytokine TNF-a.

Over 75 monoclonal antibody drugs have been approved by the FDA.  Only one, interestingly, specifically has targeted an infection (HIV).  These drugs have, however, recently been effectively used in Ebola and syncytial virus infections.

The authors suggested that Borrelia burgdorferi (Bb)specific monoclonal antibodies could whack the bacteria hard enough to allow doxycycline to work in all patients, not just those with more robust B-cell responses.  In fact, recent developments in monoclonal antibody production suggest that an anti-Lyme drug could be used prophylactically to provide protection against the bug.  The limiting factor may be expense, but recent developments may bring the cost of these drugs down.

Prospecting in Chronic Fatigue Syndrome (ME/CFS)

This study indicates that prospective studies – studies which follow a population over time as some fall ill – can work really well if the study target is focused correctly.  Starting back with Dr. Lloyd’s Dubbo studies several have been done in ME/CFS. None have achieved the results that this Lyme study did, but they have been illuminating.

The Dubbo studies followed 253 people for 12 months after they were infected with one of three pathogens (EBV, Ross-River Virus, Coxiella burnetii). That 11% met the CDC criteria for ME/CFS after six months indicated that long standing illnesses after serious infections were surprisingly common.  Attempts to figure out why a significant number of people remained ill were largely ineffective though.

Some of the studies were quite small and are probably not conclusive but they suggested that neither increased herpes viral titers (herpes virus reactivation) nor changes in 35 cytokines nor gene expression nor psychological factors played a role.

Dubbo studies

The Dubbo studies found that the severity of the initial infection played a role in who failed to recover from an initial infection.bo

The only finding that initially stood out was the severity of the initial infection. People with more severe symptoms initially were significantly more likely to come down with ME/CFS.  In 2008, however, the group found a possible genetic underpinning for the disease; it turned out that polymorphisms (unusual formations) in genes coding for two cytokines (IFN-y, IL-10) affected how ill a person got and how long they remained ill. The findings suggested that a genetic predisposition for an increased inflammatory response might be tipping some people over into prolonged illnesses.

In 2009 Vollmer-Conna, a member of the Dubbo group, working outside ME/CFS found more evidence that one’s immune status makes a difference. She found immune status prior to surgery significantly affected one’s immune functioning, distress levels and ability to recover after surgery.

Next Jason and Katz began a large study of adolescents that came down with infectious mononucleosis (IM). They found no evidence that reductions in peak work capacity, or activity levels, or problems with orthostatic intolerance,  or reductions in salivary cortisol or natural killer cell number and function played a role in an adolescents inability to recover from IM.  The study, however, did suggest that early damage to autonomic nervous system, to the ability to consume oxygen, as well as psychological factors and differences in cytokine networks  were present in those who failed to recover from IM.

Another Jason-Katz study which did not examine biological factors other than autonomic nervous system functioning found, as did the Dubbo study, that the severity of the initial infection – and the amount of bed rest it prompted – played the most significant role in who remained ill. Psychological factors such as “perceived stress, stressful life events, family stress, difficulty functioning and attending school, family stress, and psychiatric disorders” had no impact.

In 2013 Jason, Katz and others began an even larger study which tracked college students after coming down with infectious mononucleosis. They’ve collected blood samples from and have been following over 4,000 college students over the past couple of years. About 5%  contracted infectious mononucleosis, a common trigger for ME/CFS. Grants applications are being written to further assess autonomic functioning, as well as cytokine, metabolome and saliva biological risk factors..

If Jason et. al. have picked the right target, this fascinating study could tell us more about what goes wrong when someone gets ME/CFS. If it doesn’t then their samples –  banked in liquid nitrogen at -80 degrees C –  provide a potentially invaluable resource for the future.

By capturing the blood of people with ME/CFS before they got sick, as they were getting sick and then after the illness became established, Jason’s unique biobank could allow future researchers to quickly determine if the factor they believe plays a critical role in ME/CFS does – saving much time and money.

Small Non-profit Potentially Makes Big Difference

Showing that you don’t have to be large to potentially make a major difference, this potential Lyme breakthrough came not from the NIH or the CDC but from a small Lyme non-profit – The Bay Area Lyme Foundation  – that’s been in business for just over five years.  The study was the product of an 2014 award, The Bay Area Lyme Foundation Emerging Leader Award, that went to Lisa Blum, PhD, a former Stanford postdoc. That award specifically targets veteran researchers who have not previously worked in Lyme research.

The Simmaron Research Foundation is another non-profit that is seeking to scientifically redefine how a disease is understood and treated.  It is currently funding studies that are using proteomics and metabolomics to study cerebral spinal fluid in ME/CFS, that are assessing the effectiveness of underutilized treatments such as Ampligen, IVIG and Cidofovir, and that are seeking to understand why the rate of a lymphoma is increased in ME/CFS.

Is Chronic Lyme Disease – Not Lyme Disease At All?

Is Chronic Lyme Disease (CLD) actually Lyme disease? That’s one of the questions asked during the Simmaron Research Foundation’s Patient Day in September.

It was a full room in beautiful Incline Village sitting on the northern shore of Lake Tahoe in Nevada. Emily Taylor of SMCI came up from LA, Gunnar took time off from medical school. Maureen Hanson and Mady Hornig flew over from the East Coast; Dr. Konstance Knox from the Midwest. The locals included Anita Patton, Courtney Miller, Eric Johnson, and, of course, there was Dr. Peterson.

chronic lyme disease

Why some people remain ill after being treated for Lyme disease is a vexing question

Why some people who have been treated for Lyme disease remain ill is a knotty question, and it has pertinence for chronic fatigue syndrome (ME/CFS). Both in Lyme disease and chronic fatigue syndrome (ME/CFS) many people become and then remain ill after an infection.  Why that happens is a mystery.

Some people think that chronic Lyme disease is simply another subset of chronic fatigue syndrome; that the Borrelia burgdorfii infection which ticked off chronic Lyme disease is no different from the herpesvirus or enteroviral or  other infection that just happened to send ME/CFS patients’ systems into a tailspin. The idea is that it’s not the infection, it’s the fact that an infection occurred.  That’s what the Dubbo and other studies which have shown that ME/CFS can be triggered by a large of number of pathogens suggest.

Others believe that the Borrelia infection is still there, deeply hidden, but grinding away in the chronically ill.

No one knows, but the idea that different pathogens are causing similar issues in ME/CFS and Lyme is belied by a study which found significantly different proteins in the cerebral spinal fluid of ME/CFS and Lyme disease.

Dr. Konstance Knox believes the two diseases may, in fact, be very different. In her Simmaron Patient Day presentation, she suggests a pathogen may be present in chronically ill Lyme disease patients but not the Borrelia bacteria; she believes that a tick-borne virus called the Powassan Deer Tick virus, which at its worst is fully as dangerous as Borrelia or more, may be doing its work.

 The Powassan Deer Tick Virus

The Powassan Tick-borne virus was first isolated from a person from Powassan, Canada in 1958.  (Powassan, like Lyme, Connecticut, is another small town that just happened to get stuck with the name of a disease.) The Powassan virus is a Flavivirus related to such nasties as Zika, Dengue, West Nile Virus, and tick-borne encephalitis virus (TBEV). All these viruses can cause brain swelling (encephalitis).

The scariest thing about the  Powassan virus is how quickly it can be transmitted. Because the Borrelia bacteria that causes Lyme is carried in the stomach of a tick, the tick has to feed for quite a while before the bacteria actually makes into humans. Because the Powassan virus, on the other hand, is carried in the saliva of the deer tick, it takes a mere 15 minutes or so for it to jump from a feeding tick into your bloodstream. A Powassan infected tick can jump on, feed for a bit – transmit the virus – and then jump off, without you ever knowing it.  Since ticks are so small and POWV transmission so rapid, few patients with Powassan encephalitis recall their tick bites.

Powassan virus symptoms - CDC

Most cases of Powassan virus infection are mild but at its worst a Powassan virus infection rivals Lyme disease in its severity

Most people infected with Powassan Virus (POWV) experience flu-like symptoms such as headache, sore throat, drowsiness and disorientation.  If the infection spreads to the brain, the virus can cause everything from lethargy, high fevers, vomiting, respiratory problems and difficulty speaking to paralysis, seizures, coma and even death.

Powassan-triggered encephalitis is accompanied by the infiltration of lymphocytes and monocytes into the brain and the widespread destruction of neurons in the motor areas of the brainstem (affecting movement), the cerebellum, basal ganglia (potentially affecting movement again) and the thalamus. MRI’s pick up only non-specific abnormalities and thus are not diagnostic but suggest that brainstem may be particularly effected.

Studies on Powassan infections are rare but some suggest that no less than fifty percent of Powassan survivors may be left with permanent neurological problems including partial paralysis, headaches, memory impairment and/or paralysis of the eye muscles.

A 2015 paper presenting eight verified cases of neuroinvasive Powassan virus infection in New England bore this out. Two of the patients died, four fairly quickly recovered and two exhibited from medium to long-term problems.  One 21 year old man who entered the hospital with vomiting, fever and confusion was given methylprednisolone and IVIG. He improved over time and left the hospital alert, oriented, and “speaking in short sentences”. He was unable to return to work for seven months.  Fifteen months later, a 52 year old man still had persistent headaches as well as problems with motor functioning and coordination.

Because surveillance of the Powassan virus has been poor, it’s difficult to estimate its true incidence in humans.  Luckily, far more ticks carry the Borrelia bacteria (20-50% of ticks in endemic areas) than carry the Powassan virus (1-10%). Unluckily, the Powassan virus appears to be spreading.

After Powassan virus caused the sudden death of a Massachusetts woman, a tick surveillance program found from 0-16% of ticks in a given area carried the virus. A Canadian survey suggested that 3% of residents of Ontario province in Canada had been exposed to the virus. These surveys suggest far more people have been exposed to the virus than suspected. Most undoubtedly experienced symptoms similar to those of a mild cold.  Others who were more seriously affected probably never got tested for Powassan.

Much of what we know about the Powassan virus comes from study of a closely related virus in the Europe and Asia called Tick-borne encephalitis virus which causes thousands of neurological illnesses every year.  Studies on the Powassan were almost non-existent until around 2011 when the research started picking up. Powassan virus is considered a “rare but severe neuroinvasive disease“.

Could Chronic Lyme Disease Caused by the Powassan Virus?

Dr. Konstance Knox,       Coppe Lab

Simmaron Scientific Board member and collaborator, Konnie Knox has been leading a recent surge in research publications on the Powassan virus. Her recent survey of the Ixoides scapularis ticks known to carry Lyme disease and Powassan virus in Wisconsin found that 5% carried the Powassan virus. Rather ominously half of the ticks carrying Lyme disease also carried the Powassan virus.

With Lyme disease fairly common in Wisconsin (@ 187 cases/100,000)  Knox’s finding strongly suggested that Powassan infections were being under-reported in Wisconsin.  (If Knox’s findings are validated, then Powassan virus infections probably occur on the order of at 90 cases per 100,000 in Wisconsin, or as much as 5400 cases per year.)

Next, Knox tested 95 patients seen at a clinic for possible Lyme disease over four months in 2015 in northern Wisconsin.  Lyme disease,  POWV, West Nile virus (WNV), Tick-borne encephalitis virus, V, yellow fever virus, dengue viruses 1–4, and Japanese encephalitis virus were tested for.

Powassan virus Lyme disease

Could chronic Lyme disease actually be a Powassan virus infection?

Serologic evidence of POWV infection was present in 10% of the patients and confirmed in 3% of them by other testing.  Almost half of the patients with an acute Borrelia infection were infected with the Powassan virus. When the patients with a validated Powassan infection were tested, 87% were also found to be infected with Lyme disease. None, fortunately, had signs of a neuroinvasive disease.

The fact that 10% of Lyme patients come down with Chronic Lyme Disease and, Knox’s findings suggest that about 10% of patients with Lyme disease may also be infected with the Powassan Virus, is of course, more than intriguing.

Could chronic Lyme disease or ME/CFS patients be suffering from a unusual, untreated infection? Knox’s present research into ME/CFS patients could help answer that question. Knox will be testing several hundred ME/CFS patients for evidence of Lyme Disease, Powassan virus, and other tick and insect-borne diseases.

Lyme Disease Or ?

  • Konstance Knox who owns a diagnostic laboratory, noted that Lyme testing has improved and that good Lyme testing is not impossible. (She liked the CDC protocol which calls for a two-step testing process.)  She’s confident in the results from her lab which uses machine testing rather than subjective human testing to assess the test results.

She noted that one of the biggest problems with Lyme diagnosis is getting tested too early. Because it takes about four weeks for the Lyme immune factors to show up in the blood, the tests aren’t accurate until you’ve been infected for about a month.

The Lyme diagnosis question, of course, is a big one.  Get it wrong, as the story of one ME/CFS patient in the audience indicated, and you could be in for years of expensive treatments which leave you worse off.  After a diagnosis based on neurological and non-specific symptoms, a CD 57 test, and a negative Western blot test from Igenex, this patient had been on and off antibiotics for about five years. Talking to her later she said she’d improved tremendously on antibiotics at times, but the treatment ultimately failed and left her worse off than ever. (She suspected that the anti-inflammatory effects of the antibiotics had temporarily helped.)

She would be in the chronic Lyme disease category except for the fact that she never have had Lyme disease in the first place. In fact, her symptoms didn’t really fit. She’d marveled at other “Lyme patients” who were able to exercise. Despite the fact that she’d visited a clinic that treated complex, chronic diseases, she didn’t know that her main symptom – post-exertional malaise – was the defining characteristic of ME/CFS until she visited an ME/CFS clinic last year.

Knox suggested that a lot of putative “Lyme” patients may not be Lyme patients at all. She’s found, for instance, a very low incidence of Lyme disease in Dr. Peterson’s patients, many of whom probably hail from the Western United States. She did, however, find evidence of a tick borne virus in about 11% of a 200 patient sample.

Conclusion

People who still suffer from the symptoms of Lyme disease after being appropriately treated for it are a medical mystery.  Some doctors believe the Lyme bacteria is still present. Others believe that the Lyme infection may have triggered an ME/CFS-like condition. Simmaron Research Foundation Board member and collaborator, Dr. Konstance Knox, believes some people with chronic Lyme disease may be suffering from an unidentified Powassan virus infection transmitted by the same tick.

Powassan virus is a poorly studied virus that can be quickly transmitted by ticks. While most people probably pass off the virus quickly, a neuroinvasive infection can cause serious symptoms including paralysis, stroke, coma and even death.

Dr. Konstance Knox’s studies suggest that Powassan virus is often present in ticks harboring the Borrelia bacteria that causes Lyme disease, and that about 10% of Lyme disease patients have been exposed to the virus. That’s an intriguing finding given that about 10% of Lyme patients come down with chronic Lyme disease.

Dr. Knox is currently studying the incidence of the Lyme disease bacteria, Powassan virus and other insect vectors in Dr. Peterson’s chronic fatigue syndrome (ME/CFS) patients. Stay tuned…