Tuesday, July 29, 2014

The Lyme World On Its Head: Rapidly Emerging New Paradigms

The Lyme world is being turned upside down.

A recent study, as many are aware, performed PCR testing on stored sera of 52 patient samples from patients diagnosed with Lyme disease. Four were PCR positive. This underscores the problem with PCR. It has a low yield. If it were feasible to do 5-10 tests on every patient we would probably have a pretty good test. The finding are intriguing. Two of four, 50% were positive for Lyme as we know it, Borrelia burgdorderi. One was positive for B. Miyamotoi and one a "novel" species of Borrelia.  The paradigm is changing. "Lyme disease" more often than not may be caused by species other than the one over which there has been so much fuss:  B. burgdorferi.  This is just where the story begins. A recent survey of a nearby park (Montgomery County, Maryland)  was performed by Clongen (Dr. Kilani). His team collected 45 ticks. Two were dog tick and the rest were lone star ticks. Not one dear tick in the sampling. Why? Lone star ticks are known to be much more aggressive than deer ticks and appear to be taking over the ecological niche. Do these ticks cause Lyme disease? I think we can answer that question.  One quarter of the lone star ticks were infected with  B. lonestari. About 15% had anaplasmosis and one half showed infection with Babesia species. I do not think the Babesia species PCR is all inclusive, so it is possible that even a higher percentage of these more relevant ticks are laden with Babesia.

Fast forward to a patient I recently saw. This patient had a classic bull's eye rash on his foot in April. A doctor prescribed 3 weeks of doxycycline. When he complained of persisting symptoms another three weeks was prescribed. Symptoms continued. He was prescribed a course of Zithromax which provided little further relief. This patient has suffered with fatigue; night sweats; numbness and tingling; severe anxiety; memory problems and cognitive dysfunction; severe joint pain with swelling; palpitations, air hunger and shortness of breath, weight loss of 15 pounds and other symptoms. These symptoms persisted in the face of more than double the IDSA recommended course of therapy. Post treatment Lyme syndrome, right?  He had a Lyme Western blot through Labcorp: 41 IgG band only. He had PCR testing through Clongen: Positive for large numbers of Borrelia lonestari, not Lyme per se and negative for Babesia. 

Have we have a documented case of post-treatment B. lonstari showing persistence of the organism.  Maybe the first. The PCR test was not previously available. So the patient has STARI, Master's disease.

Wait a minute. Doesn't the IDSA/CDC crew say that STARI is no big deal? Oh yeah. They say the same about Lyme don't they.

Let's put this together. Lone star ticks are emerging as the dominant species of tiny hard body ticks which transmit tickborne disease and Lyme or its equivalent. They do not usually carry classic Lyme B. burdorferi, rather they carry a new germ about which we know very little; in half the cases of "old Lyme" transmitted by deer ticks, other species of Borrelia, rather than the expected B. Burdorferi may be the cause.  We have a paradigm which is being turned on its heels. Borrelia burdorferi as the causative agent of Lyme disease may soon be of historical importance.

Even with the conventional B. burdorferi, Lyme testing is known to be inaccurate (at least in Virginia). What now? We are bereft of any tests. I actually think there is some cross reactivity, so the appearance of CDC "nonspecific" bands may take on more importance in the short term. We are left with the idea that the diagnosis is a clinical one. This idea puts a real sour taste in the mouth of IDSAers who continue to promote an inaccurate, and now perhaps obsolete Lyme test as the basis for diagnosis as they discount the idea that the "subjective" (therefore untrustworthy)  history and physical exam can be used to make the diagnosis. When I went to medical school, a long time ago I know, we were taught that if you listened to the patient he would give you the diagnosis in the vast majority of cases.

How about Babesia? I have seen an epidemic on the rise. Babesia species. Which species? 

Back to the patient at hand. He was PCR negative for Babesia species and sero-negative for B. microti and B. duncani.  I did a blood smear and found a few, possible hemato-parasites. Test indeterminate.

The symptoms sounded classic for Babesia. And -- with anti-malaria therapy --  night sweats, air hunger and other symptoms have abated within only 2 weeks.

We don't have a dependable test for these largely unknown species of Babesia; but we have evidence that this tickborne disease may be playing a very major role in the exploding, frequently devastating (still invisible to many) epidemic.

How about resistance?  There is a lot of information about drug resistant versions of Malaria but none forthcoming about Babesia. Clinically we know this is a problem as we step up the ladder from Meporn to Malarone to Coartem and then to even Larium and Quinine with persisting symptoms.

In front of me is an abstract for J Parasitol 2014, Feb 28, Cao et al who state: "The resistance of Babesia parasites to current anti-babesiosis drugs is an issue of major concern." 

Thank you. Someone is taking notice.

None of this should be that surprising. We are dealing with a new and emerging disease. The tick vectors were barely known to exist before the 1970s. Borrelia are a very diverse genus as are Babesia of which more than 100 species are known to exist.

With incredulity I ask the rhetorical question: how can insurance companies, State Medical Boards, the CDC and the IDSA hold up guidelines written 8 years ago as the gold standard which defines the standard of care for the management of Lyme disease and other tickborne illnesses?

Thursday, May 15, 2014

Why do some patient develop chronic Lyme?



A new study may help us understand why some patients get better and other don’t.  This topical study: Serum Inflammatory Mediators as Markers of Human Lyme Disease Activity, was published in PLOS one-- the lead authors are from Johns Hopkins University. All published Lyme studies have had problems with patient selection. Patient groups are selected because they are supposed to have the same thing. IDSA criteria are generally used. The group in this study had early Lyme associated with EM rash.  As I have discussed previously, most patients with acute Lyme do not present with a rash; and more to the point, most patients with chronic Lyme are not diagnosed in a timely fashion. Nonetheless, this study conveys important information.  

This study demonstrates the exist of two distinct patient populations who have very different immunological responses to infection with Borrelia burgdorferi (Lyme) – one group has a robust response based on measurements of cytokines and markers of inflammation; the other group has a minimal immunological reaction using the same indicators. The two groups have very different clinical outcomes. 

I am pleased by a change in verbiage/terminology. In this study the authors use the words PTLDS, post-treatment Lyme disease syndrome, which replaces the old term PLDS, post-Lyme disease syndrome. This small change leaves the door open to the notion that Lyme organisms may persist after treatment. And here we are dealing with acute patients treated early in the course of the illness.
The study measures molecules which moderate immune responses.  The immune system is tasked with finding offending invaders, like germs, and eradicating them by a host of complex mechanisms and devices. (Seek out and destroy)  This study measures the messengers that help direct the traffic of the immune system – sending signals to an assortment of cells, telling them where to go and when.
The authors note the immune system alone is unable to eradicate Lyme infection and that late-stage arthritis develops in many patients. They describe a subset of patients who develop antibiotic refractory disease 12 months or more. The dogma that host immune responses is the major factor in such cases is discussed, but, from the mouse model -- another possibility is discussed.  “Delays in the generation of long-lived plasma cells (the cells that make antibodies) and a weak, largely IgM response (sound familiar) may be part of a Lyme (Borrelia burdorferi) strategy to avoid clearance.”(Yet another mechanism of survival).  The authors reflect that residual antigen or infection in some treated patient may explain the persistence of symptoms, in post-treatment Lyme disease, but state: “this is a very controversial area.” 

The scientists measures many molecules that traffic immune cells, with names like: CCL1 9, CXCL 19, CXCL 10, CRP, SAA, IL-1a, IL-18, IL33, IL6, TNF alpha, and others.
Two distinct responses were identified. On groups showed high levels of these markers of immune response while the other showed low levels of these markers.

One particular mediator of inflammation, IL-6 remained elevated in patients with late stage Lyme which the authors found surprising.  These patients with post-treatment, symptomatic Lyme disease showed immunological evidence of persistent inflammation – or infection. 

The group of patient with a high level of reaction (cytokines, chemokines) had lower WBC counts, increased liver function counts and higher levels of markers of inflammation such as CRP. This group produced Lyme antibodies, or seroconverted. This group showed clinical remission.  The group with low level reactions to the same molecules did not share these features: these patients had a tendency not to seroconvert. This group of patients was more likely to develop post treatment symptoms like chronic joint pain.  

This study has clearly identified a subset patient who are more likely to develop chronic Lyme disease even after IDSA recommended treatment for stage one disease. This study sheds light on why many patients are seronegative (do not make antibodies) or have weak IgM responses as we commonly see. This study lays the foundation for the development of a test which helps us predict which patients need more help early on -- those who are at higher risk for developing chronic disease.
On another note…

Another scientist’s face is displayed in a Johns Hopkins University magazine in an article which states he has beliefs contrary to the IDSA and that he believes in Lyme persiters which might respond to a drug for tuberculosis. The article say that while these ideas would not be controversial regarding tuberculosis they are very controversial when mentioned in the context of Lyme disease.  

Tuesday, May 13, 2014

Lyme from Lyme and Babesia too

People like to hear patient vignettes. Here's one that takes the cake. This is a new patient so I cannot say anything about treatment or outcome. We go back to where it all started.

A young woman from rural Massachusetts has always enjoyed spending a lot of time outdoors hiking and camping. She has had innumerable tick bites over a period of years. Her dog suffers with Lyme disease. A few years ago she went camping in Lyme Connecticut of all places. Lyme Connecticut. Over a period of years she developed a progressive illness. She developed a host of symptoms including:  migratory joint pains in her: elbows, wrists, hands fingers, knees, ankles and toes. A partial list of other symptoms includes: fatigue, poor endurance, rapid heart beats, anxiety, problems with focus and concentration, memory loss, unclear thinking, short-term memory loss, headaches, changes in vision and hearing, loss of coordination, numbness and tingling, trouble fully emptying her bladder, mood changes, anxiety, agitation and depression. She reported a history of night sweats and air hunger in the past only.

A few years ago she had a Lyme test which showed a positive ELISA and a negative Western Blot. This was considered a definite negative. She saw a variety of specialist from New England to New York who variably diagnosed her with fibromyalgia, depression or mixed connective tissue disease.  Lyme disease was not the answer according to the best medical minds from the best medical institutions.

A more recent Western Blot shows Lyme IgM antibody bands 23 and 41.  A C6 peptide test was 2.4. An IFA serological test for Babesia showed a positive reaction to WA1 (AKA) Babesia duncani with a titer of 1:256.

Pictures are worth a thousand words.  This is what her blood smear looks like.


Comments:

A positive ELISA is usually due to Lyme disease.  The other ELISA test usually not done, C6 peptide (which most doctors have never heard of) may provide the answer.   Patients rarely develop IgG Lyme Western Blot bands irrespective of how long they have had the disease --  despite repeated promulgations from the IDSA and the CDC.  Most US physicians have never heard of Babesia duncani.  Last week one of my patients (another patient)  showed a picture of a blood smear (taken by me)  to a  highly trained, university-based rheumatologist. He was captivated by the blood smear so he ordered a test for Babesia divergens.  This is a cow pathogen which has crossed over to humans and occurs in Europe only; it is virtually never seen on this side of the Atlantic. By keeping the parasite named WA1 -- even though the organism has had a proper name, B. duncani for more than a decade it feels like its existence is intentionally being kept from the general population of physicians. This name, which is never spoken, is never mentioned at continuing medical education lectures for general physicians.  

Academic medical experts are so dead-set against the Lyme diagnosis and perhaps B. duncani (since ILADS types always bring it up) -- that even with a history of innumerable tick bites and a history of camping in Lyme Connecticut of all places -- the diagnosis is readily discarded.  After all, there was no rash, Lyme is over-diagnosed and anyway chronic Lyme does not exist. To these experts It is clear the patient must suffer with a "real disease" like fibromyalgia. And so it goes.


Wednesday, May 7, 2014

Lyme disease as a New World disease



Has Lyme been around thousands of years?  Maybe. The spirochete responsible for Lyme, Borrelia burgdorferi was found in a hip bone fragment from the 5300 year old iceman discovered in the permafrost in the Swiss/ Austria Alps 2 decades ago.   Illness attributed to the spirochete before the 1970s appears to have been rare; sporadic cases of a relatively mild disease were reported in Europe dating back to the 1800s.  Lyme disease and its attendant spirochete were never know in the New World until quite recently, about 40 years ago.  The epidemic, for no apparent reason, suddenly appeared in Old Lyme Connecticut the 1970s. 

Cases of a new disease were reported to The Connecticut State Department of Health in 1975. The acting director of the Preventable Diseases Division in Connecticut discussed these cases with Dr. Steere and Dr Malwesta, rheumatology section Yale University of Medicine.

Why not the CDC?

At that time the CDC had something of a storied history.  The CDC was founded in 1946 but initially was a small organization with a small staff of engineers and etymologists studying malaria in war torn areas.  Epidemiology was added in 1949. Disease surveillance became the cornerstone of the CDC’s mission. With the Korean War the focus changed to bio-warfare. The Public Health Service merged with the CDC in the late 1950s and the CDC took over the Tuskegge study which observed the effects of untreated syphilis on black males. The CDC underplays this on their website, defensively mentioning the words television and the media.  The CDC touts its successes:  polio, immunizations, small pox, Legionnaires disease, toxic shock syndrome and HIV/AIDS.  Lyme is not mentioned. 

In the mid-1970s, instead of involving the Federal Government, an acting director in public health sought the advice of Dr. Steer, a rheumatology fellow, a doctor still in training.
In the initial report 39 children and 12 adults in Old Lyme and East Haddam were reported to have what was described as mild arthritis. Cases mostly occurred in rural and wooded areas. Half the patients had only joint pain while others also complained of fever, headaches, weakness and a rash. An unusual skin lesion was reported in one quarter of the cases. The cause was unknown and thought to be a virus. 

Where did it come from?

Historically, many diseases have jumped from one continent to the next; imported by humans. Syphilis was imported the Americas along with Christopher Columbus and other conquistadors from Europe in the late 15th century with devastating consequences. The even more devastating plague of smallpox, another “gift” from the “old word” to the New World was yet to follow. 

We do not know the origins of Lyme although there is much speculation.

Local state departments and the CDC continue to deny the existence of Lyme disease in various locations.  I am now seeing a cohort of Lyme patients from central Florida. I have patients who have contracted Lyme disease in such heretofore unlikely of places such as New Mexico. 

We have a pretty good idea of how Lyme is spread from one community to the next. Migratory patterns of a wide variety of birds. This mode of transmission has been very efficient. 

Comment:  Why did the CDC suddenly increase its estimate of the number of new cases of Lyme disease annually from 30,000 to 300,000? The CDC always knew that the number 30,000, the number of reported cases was a fraction of the true number of cases  The majority of cases they count are not reported, cases associated with a rash, treated by primary care physicians. Over 2 million Lyme disease test ordered annually and this is probably and an under-estimation. How many new cases of Lyme are missed, the diagnosis tragically overlooked because the signs and symptoms of the disease were not recognized by treating physicians - or "providers."


Seventy five percent of new cases are associated with a rash according to the CDC? The CDC case definition emphasizes the presence of EM rash causing a bias in this manufactured number.  The earliest data presented here show that only 25% of patients with acute Lyme recalled a rash. This suggests that no more than 25% of patients with acute Lyme disease present with a rash – not 75%.
Unfortunately, as I hear over and over again for my patients, poorly informed physicians tell patients they cannot have Lyme disease since they never had a rash.

I sense that the CDC suffers with an identity crisis. What is its mission? Surveillance. Epidemiology. Disease prevention. Aiding doctors in the management of acute and threatening epidemics. Medical research.  Coordinating research with NIH. Working with other strategic partners. The CDC has a lot on its plate and seems to be understaffed.  What is the basis for its alliance with the Infectious Disease Society of America? Are the IDSA guidelines evidence-based? Are they peer-reviewed? The IDSA guidelines are opinion driven, steeped in politics and certainly not peer-reviewed by any outside organization.

The NIH is still busy doing research on this 40 year old, new and emerging and most controversial disease -- how can the CDC pen guidelines written in stone? How can these guidelines be used to deprive physicians of medical licenses and deprive patients of access to care? 

Sweeping generalizations have been made of the basis of limited studies with tiny numbers of patients through of the eyes of a few biased, academically linked researchers with an axe to grind. 

We do not know the true incidence of the disease. We do not know how many cases are chronic. We know even less about other tickborne coinfections. Very few physicians have ever heard of Babesia duncani, yet it appears to infect as many as one in three patients with Lyme disease -- not to mention new and emerging species of Bartonella many of which are yet named. The 40-year-olds of today are the first generation of America who suffer with more fatigue, joint pain, disability and impaired quality of life than their parents.  What truly is the scope of this hidden epidemic, swept under the rug?

And then finally one must ask the questions: who is running the mental hospital? The inmates?  Where does this leave all the patients who are yet unable to find answers and frequently greeted with hostility from the very health care providers who should be providing them sympathy and support?



Friday, April 25, 2014

The Lyme literate patient (and Babesia)

Babesia ring forms
A 52 year old male from central Pennsylvania presented with a mysterious, multi-system and progressive illness which began 10 years ago. It began with flu-like symptoms, burning eyes, abdominal pain and persistent elevation of white blood cell count. He later developed severe muscle and joint pain, especially involving the lumbar spine. Eight years ago, based on recommendations from Hopkins, he had extensive spinal surgery including an anterior fusion of his lumbar spine. Afterwards the pain intensified and become unbearable.He has been unable to sleep in a bed, only a recliner ever since.  Of interest, a local orthopedist in his community told him should not have the surgery. When he discussed the divergence of opinion with has family doctor he was told, "Who are you going to believe? Hopkins of course." Apparently God ("The John") is not always right. He is now a regular patron of a pain management clinic which readily doles out copious amounts of opiods --  which are ineffective, for this intractable pain.

He now suffers with severe, abdominal pain, unremitting daily headaches and diffuse spinal pain which has spread to his cervical spine. He has hand pain and swelling, numbness and tingling and burning sensations in his hands. He complains of "charlie horses" in his legs, twitching muscles, disrupted sleep, cognitive decline with memory loss, progressive weakness, frequent urination with a recent diagnosis of prostatitis given, loose stools, an lack of energy and of course profound fatigue. The review of systems was significantly positive for shortness of breath and night sweats.

Prior to our meeting he had been treated by another doctor for 18 months with IV Rocephin. The only treatment has been Rocephin.  The physician gradually tapered the dose and frequency of the IV medicine. The doctor told him he (the doctor) understood Lyme disease because a family member had suffered with the illness. The patient was never treated with other antibiotics and never treated for co-infections.The Rocephin had provided a modicum of relief. When this was abruptly stopped (because he had enough treatment) --  he knew the plug had been pulled and he found himself circling around the drain. He was referred by one of my patients.

Blood work for coinfections previously was limited.

New testing showed a Babesia duncani or WA1 titer of 512.  His Lyme WB testing from Stony Brook yielded interesting results. The IgM was called negative with bands: 18, 25, 28, 31, 66, 72 and 93.  The IgG was reported as indeterminate with band 41 and 58 present only. His blood smear is shown above.

My elaborate discussions of West Blots can be found elsewhere.

This patient relayed (incorrect) information given to him by his doctor --  I hear the same mantra every day:  " My doctor(s) told that one  type of antibody shows new infection (IgM I think_) and other shows old infection - I forget which is which." "The doctors said I most have been bittern again and have a new infection."  Newsflash: Lyme does not play by those rules. See my last Blog.

There is difference between a doctor being Lyme aware and a doctor knowing how to treat Lyme disease.  The Lyme was not treated adequately with the appropriate "cocktails" and  Babesia, in this case -- florid, dangerous infection - easily diagnosable,  was entirely missed. Few doctors are able to set up a CLIA approved labs and do Giemsa smears, but a simple antibody test through Labcorp was positive.

When patients ask me if I am a Lyme Literate Medical Doctor my answer is: "Are you a Lyme literate patient? this is what is important."  Unfortunately there is no official certification for a specialty which is not officially acknowledged to exist.  The term LLMD has no real meaning. Anyone can use it.  Patients have to be their own advocates and know as much about the disease as possible.  Learning about the disease is daunting under the best of circumstances and impossible for most patients  suffering with"Lyme brains." Nonetheless, keep plugging away.  Hopefully a friend, family member or spouse can be helpful. 

Wednesday, April 9, 2014

The IgM question, is it chronic Lyme? Revisited.



I have been blogging since 2008. To date the most popular page views is “The IgM question, is it chronic Lyme.” I last wrote about this in 2009.

Many patients I see have been told by their physicians that the IgM results on a Western Blot test  indicate only recent infection; and many of these patients have been told that their positive Lyme test was a false positive when the expected IgG bands did not appear.

This is not surprising. This conclusion corresponds with statements made by the IDSA and CDC.  These groups (CDC/IDSA) admit recommended test lack sensitivity in early Lyme disease but claim their two-tier test is 99% accurate in late disease, at which time the requisite 5/10 IgG antibody bands will reliably appear. 

In the usual course of events when our bodies are exposed to pathological infectious agents oour immune system first makes IgM antibodies; but after a period of days or weeks the relatively ineffective IgM antibodies are supplanted by the more effective IgG antibodies. But as I frequently explain to my patients: Lyme does not play by these rules.

There is much that controversial about this disease and some of the controversies are legitimate. The IDSA/CDC statements about antibody responses associated with Lyme disease are completely false and should be expunged from the controversy. The immunological responses seen in Lyme disease, in all stages of the disease show a predominant IgM antibody response and a poor IgG response in the majority of cases. Of course there are exceptions to this rule.  In general, overall production of antibodies of either class in response to infection may be quite poor.

Why this occurs I do not know. The immune system is incredibly complex and scientist are learning more about it every day. There is an interplay between invading germs and immune responses. These relationships are different with every single pathogenic germ. With Lyme disease, it has been widely reported that infection causes down-regulation of cytokines and inactivation of complement fixation as a mechanism for survival. 

Both IgM and IgG antibodies are made by the same B lymphocytes and plasma cells. These cells which manufacture antibodies receive signals from specialized proteins and cytokines which leads to change in DNA transcription and the manufacture of the new class of antibodies. This is referred to as class switching. Defects in this switching mechanism have been described in both genetic and acquired diseases. It is not difficult to imagine that infection with Lyme somehow influences this switching mechanism so that IgM antibodies are favored. If this is correct it may underlie a novel mechanism of immunosuppression. Of course many practitioners see Lyme disease, chronic infection with Borrelia burgdorferi species and strains, as an immune suppressed state in the host or patient.

I am looking at a patient laboratory report from Stony Brook University Medical Ctr., Lyme Disease laboratory, Western blot results are: IgM bands, 18, 23, 25, 31, 41, 64 and 93. The IgG Western Blot strips to appear identical to the control. No bands are identified.

If I was of the IDSA ilk I might conclude this test shows serological evidence of acute Lyme infection only. I would have a hard time explaining the 31 band. The 31 band represents a reaction with outer surface protein A (OspA). This particular antigen is expressed in the gut of the Ixodes tick, disappears in the salivary glands before the spirochetes are injected into the host and does not reappear in the host for at least six months. If I was of the IDSA persuasion I would have to call the 31 band a false positive. Otherwise the results would make no sense. There are two problems with this resolution. First, this reaction is highly specific -- this protein is found only on the surface of Borrelia burgdorferi thus false positives would be unexpected; and --  second, these results are from one of the country’s top Lyme disease laboratories whose credentials are unimpeachable. But luckily I am not of the IDSA persuasion. Because I know that only IgM antibodies or a predominance of IgM antibodies are frequently seen in patients with chronic Lyme disease.

This patient has been sick with Lyme disease since 1988 at which time she presented with Bell’s palsy and acute meningitis. These lab results are from two weeks ago. She has been treated for chronic Lyme disease by several physicians for more than two decades with a variety of intravenous and oral antibiotics. She has many unresolved chronic symptoms but is able to function reasonably well. She becomes disabled with severe relapses whenever antibiotics have been discontinued. The use of long-term antibody therapy allows for some reasonable quality of life. Without access to antibiotics her quality of life would be zilch.

The answer to the question: can IgM antibodies alone are seen in chronic Lyme is clearly yes.
It is frequently argued by the IDSA that Lyme disease must act in a particular way or test in a particular way because there are no precedents in nature to backup contentions to the contrary. This thesis is specious. 

According to the CDC, tuberculosis is one of the deadliest diseases and infects one third of the world’s population. An awful lot of research is been done over many years looking for antibody test to help physicians diagnose this infection. To date, none has been found.  90% of patients infected with tuberculosis produce antibodies. The specific antibodies produced vary from patient to patient in ways that are impossible to predict. After decades of research there is no antibody test for tuberculosis with a sensitivity greater than 20%.

Tuberculosis which is usually localized to the lungs, requires treatment with several antimicrobials for numerous months and relapses may occur.

According to the CDC, patients with Q fever causing cardiac involvement need treatment with two antibiotics for at least six months.

According to the CDC advanced cases of brucellosis may require treatment for six months with dual antibiotic therapy.

Many infectious diseases are entirely unique and without precedents in nature.

Lyme disease is different from other infectious diseases in numerous ways. One of those ways is that infection tends to be associated with production of IgM antibodies and not IgG antibodies. An investigation into this anomaly should be fertile ground for future research.