Skip to content

February 2015

Corticotropin releasing hormone, cortisol and mast cells

The term “HPA axis” refers collectively to the signals and feedback loops that regulate the activities of three glands: the hypothalamus, the pituitary gland, and the adrenal glands. The HPA axis is a critical component of the body’s stress response and also participates in digestion, immune modulation, emotions, sexuality and energy metabolism.

The hypothalamus is part of the brain. It performs several integral functions. It regulates metabolism, makes and releases neurohormones, and controls body temperature, hunger, thirst, circadian rhythm, sleep and energy level. It is also known to affect parenting and attachment behaviors. It effectively turns nervous system signals into endocrine signals by acting on the pituitary gland.

The pituitary gland is a small gland at the bottom of the pituitary. The anterior portion of the pituitary is part of the HPA axis. It makes and releases several hormones, including human growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone (ACTH), prolactin, luteinizing hormone and follicle stimulating hormone. All of these hormones are released when hormones released by the hypothalamus act on the pituitary.

The adrenal glands are located on top of the kidneys. They primarily synthesize and release corticosteroids like cortisol and catecholamines like epinephrine and norepinephrine in response to action by the pituitary.   It also produces androgens and aldosterone.

The hypothalamus synthesizes vasopressin and corticotropin releasing hormone (CRH).   Both of those hormones stimulate the release of ACTH by the pituitary gland. ACTH stimulates the adrenals to make glucocorticoids (mostly cortisol). The cortisol then tells the hypothalamus and pituitary to suppress CRH and ACTH production. This is called a negative feedback loop.

Cortisol acts on the adrenals to make epinephrine and norepinephrine. Epi and norepi then tell the pituitary to make more ACTH, which stimulates the production of cortisol.

When you take steroids regularly, it suppresses ACTH so that your body stops making its own steroids. This is why weaning steroids is very important. By weaning, your body should gradually start making its own cortisol to replace the deficit when you lower your steroid dose. However, this doesn’t always work. People who do not make enough cortisol on their own are called adrenally insufficient and are steroid dependent. People with this condition can suffer “Addisonian crises” if their steroid levels drop dangerously low. This is a medical emergency.

CRH is released by the hypothalamus in response to stress. This drives the production of cortisol to help manage stressful situations of either a physical or emotional nature. Mast cell attacks and anaphylaxis are examples of physically stressful situations that stimulate release of CRH.

CRH binds to CRHR-1 and CHRH-2 receptors on various cells, including mast cells. When it binds to mast cells, it stimulates the release of VEGF, but not histamine, tryptase or IL-8. This type of release is called selective release as it does not involve the release of preformed granules (degranulation.) Additionally, CRH is also released by mast cells. This can act on the mast cells or other cells with CRHR receptors, like those in the pituitary. The exact purpose of mast cells releasing CRH is not clear.



Theoharis C. Theoharides, et al. Mast cells and inflammation. Biochimica et Biophysica Acta 1822 (2012) 21–33.


Lyme disease: Chronic Lyme (part 7)

It is not clear why some Lyme patients are asymptomatic while others have debilitating symptoms, and why some develop EM and others don’t. Research foci on this topic include efficiency of host immune response; what amount of Borrelia introduced by a bite is always enough to provoke seroconversion compared to the amount necessary to provoke symptoms; host genetic factors; and combinations of these.

Borrelia is noteworthy for its numerous mechanisms for host immune evasion. It is able to change the proteins on its surface. An example of this is change from an OspA protein dominant surface to an OspC dominant one when blood swallowed by the tick reaches the midgut, where Borrelia lives prior to infecting humans. OspA promotes adhesion to the midgut. OspC allows Borrelia to establish infection in the new host. In the host, the surface protein OspC is downregulated while upregulating VlsE. This genes associated with VlsE undergo a complicated process called recombinational switching that means the sequence of this protein is highly variable.

Borrelia is also able to bind and deactivate complement proteins. It can also bind extracellular matrix proteins and use matrix metalloproteinases to enhance their ability to enter tissues. The body demonstrates a variety of immune mechanisms to response to Borrelia. IL-4, IL-10, IL-12p70, IFN-g and TNF-a are secreted by dendritic cells. IL-1b, IL-6, IL-8, IL-10, IL-12p70, TNF-a, RANTES, MCP-1, MIP-1a, MIP-1b and eotaxin are also elevated in whole blood during infection. Increased TNF-a secreting dendritic cells and T helper type 1 inflammatory responses may be associated with effective mitigation of Lyme disease. Borrelia has been shown to induce TNF-a secretion and degranulation in mast cells, but only low level degranulation and only at extremely high spirochete to mast cell ratio, such as would likely be impossible inside the body. (Talkington 1999) The immune response to Lyme disease has been thoroughly studied by many groups around the world and is well described for most stages of disease.

This characterized immune response has caused some to hypothesize that Lyme disease induces an autoimmune activity that continues after infection. Patients with antibiotic refractory Lyme arthritis, but not those who respond to antibiotics, more often carry the HLA type DRB1*0401. This is also associated with a more severe presentation of rheumatoid arthritis. It is thought that this activity perhaps persists after resolution of infection.

What is interesting about this is that eventually all cases of Lyme arthritis resolve, so does that mean that the autoimmune activity goes away? However, Behcet’s syndrome is known to spontaneously resolve over time, and rheumatic heart disease following Streptococcus infection also eventually wanes. Both of these fit the classic definitions of autoimmune disease.

Plasma cells from joint tissue of patients with antibiotic refractory Lyme arthritis show that antibiotics to Borrelia become continually robust, despite PCR negative results for Borrelia. (Ghosh 2005) Mouse studies have demonstrated that antigenic material can persist in joints after Lyme infection, despite repeated failure to culture and PCR negativity. (Bockenstedt 2012)

The fact that a number of patients go on to suffer post-Lyme disease treatment syndrome, as well as relapsing-remitting Lyme arthritis, has caused people to wonder whether or not Borrelia persists inside the body and causes a persistent infection. One important finding is that spirochetes have been isolated from ACA lesions more than ten years after infection (ACA is a skin manifestation of European Lyme disease, much like EM in the US.) Borrelia may also be able to hide inside host cells. In vitro, Borrelia has been able to remain viable in various types of cells for several weeks.

Imaging with electron microscopes has found that structures resembling spirochetes persist in synovium and ligaments.   Antibiotic refractory Lyme arthritis patients test positive for Borrelia DNA in their synovial fluid or tissue, sometimes for up to nine months after treatment (Lipowsky 2003). Such positivity is not associated with poor outcome, recurrence or longer duration of arthritis. Additionally, PCR is not able to distinguish between living and dead organisms. One study tried to identify mRNA transcripts in such PCR+ samples, which would indicate that these organisms were making proteins and viable. They were unable to detect mRNA transcripts. (mRNA is difficult to isolate as it is easily and quickly degraded, so I don’t assume that a researcher failing to isolate mRNA means the cell is not viable.) Wormser also published a paper regarding the presence of a few spirochetes in culture of synovial fluid from an untreated patient (Wormser 2012). These organisms could not be subcultured, which means they were not able to make new cells. They also could not move and seemed to be trapped in some sort of protein complex. Such findings have spurred forward the idea that the immune response to Lyme disease in some way attenuates the organisms and prevents them from being infectious, but leaves them structurally intact. There is precedent for this elsewhere in infectious disease (attenuated spores). Organisms incapable of producing new cells can still incite a host responsible, albeit in a much more limited fashion.

By contrast, three papers have reported that Borrelia has been grown in culture from synovium or tendon up to ten months after antibiotic treatment. (Frey 1998) I find this noteworthy as Borrelia is quite difficult to grow in culture and thus these successes indicate a vigorous and viable organismal state. Borrelia is known to exhibit multiple morphological states: spirochete, spheroplast and cystic/ roundbody forms. Round body forms are more common during lag phase growth, when the cells are maintaining and not increasing count. Round bodies (Brorson 2009) are formed during times of selective pressure (such as application of antibiotics), but can reversibly reform spirochetes. Each form has variable antibiotic susceptibility, and common first line Lyme treatments are not efficacious against roundbodies. However, there is not proof that roundbodies persist in humans during disease, especially as successful cultivation has involved spirochetes, and spirochete-like structures have been seen using imaging techniques, rather than roundbodies. More research is needed into this area. In my opinion, I think there is a chance that roundbody forms persist and become integrated into tissue. I am not convinced they later become spirochetes, but I don’t see why it’s not possible.

Patients with chronic Lyme sometimes tell me that their symptoms cycle as a result of Herxheimer reactions. I looked it up because I had only ever heard of Herxheimer reactions due to syphilis, but it is in fact seen in other infections. Herxheimer reactions are caused by the release of endotoxins from dying organisms when treating with antibiotics.

I want to summarize a few points here, mostly based on what I found on Lyme websites. Doctors who treat serology negative, chronic Lyme posit the following:

  • Borrelia persist in the body to cause long term symptoms.
  • When Lyme disease is treated with first line antibiotics, the Borrelia are driven to form round bodies, which are resistant to antibiotics.

However, many also posit:

  • Patients are persistently seronegative because of immune evasion by forming these roundbodies.
  • Patients cycle with flaring symptoms every four weeks because these round bodies make new viable cells every four weeks. This concept is based upon remarks of Dr. Burrascano:

“It has been observed that symptoms will flare in cycles every four weeks. It is thought that this reflects the organism’s cell cycle, with the growth phase occurring once per month (intermittent growth is common in Borrelia species). As antibiotics will only kill bacteria during their growth phase, therapy is designed to bracket at least one whole generation cycle. This is why the minimum treatment duration should be at least four weeks. If the antibiotics are working, over time these flares will lessen in severity and duration. The very occurrence of ongoing monthly cycles indicates that living organisms are still present and that antibiotics should be continued. With treatment, these monthly symptom flares are exaggerated and presumably represent recurrent Herxheimer-like reactions as Bb enters its vulnerable growth phase then are lysed.”

  • So following this logic, the Borrelia stay dormant for four weeks, then quickly change morphology and generate new cells. During this time, they are susceptible to antibiotics that target cell wall division, and are killed. Many Lyme patients are told this is the reason for their monthly flare and that they are experiencing Herxheimer reactions.

Okay, I have some things to say about this. The first is that I can’t find any evidence for this four week growth cycle. Borrelia is slow growing, but not that slow.

Second, Herxheimer reactions are associated with the release of toxins from the interior of the cell when it is lysed. I hear a lot about Lyme toxins and that you need to detox them out. Borrelia does not make any known toxins. None.

Third, I have heard that these roundbodies contain lots of “babies” and release them during these four week cycles and that is what causes the Herx type reaction rather than toxins. I agree roundbodies are real. But they represent one cell. Electron microscopy has shown a flagellum inside the cell, so I think this might read as confusing. One spirochete turns into one roundbody, which can turn back into one spirochete. It is not a reproductive reservoir that then releases lots of spirochetes at once. In theory, a large reintroduction of spirochetes could happen when all the roundbodies turn back into spirochetes, but that’s not the same thing. And regardless, we are likely talking about a small number of organisms, here. Because if there were so many of them, they would be detected readily on biopsy.

Up next: Co-infections.



Wormser GP, Nadelman RB, Schwartz I. The amber theory of Lyme arthritis: initial description and clinical implications. Clin Rheumatol 2012;31:989-94.

Lipowsky C, Altwegg M, Michel BA, Bruhlmann P. Detection of Borrelia burgdorferi by species-specific and broad-range PCR of synovial fluid and synovial tissue of Lyme arthritis patients before and after antibiotic treatment. Clin Exp Rheumatol 2003; 21:271.

Andrea T. Borchers, Carl L. Keen, Arthur C. Huntley, M. Eric Gershwin. Lyme disease: A rigorous review of diagnostic criteria and treatment. Journal of Autoimmunity 57 (2015) 82-115.

Ghosh S, Steere AC, Stollar BD, Huber BT. In situ diversification of the antibody repertoire in chronic Lyme arthritis synovium. J Immunol 2005;174:2860-9.

Bockenstedt LK, Gonzalez DG, Haberman AM, Belperron AA. Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy. J Clin Invest 2012;122:2652e60.

Frey M, Jaulhac B, Piemont Y, Marcellin L, Boohs PM, Vautravers P, et al. Detection of Borrelia burgdorferi DNA in muscle of patients with chronic myalgia related to Lyme disease. Am J Med 1998;104:591-4.

Talkington, Jeffrey, Nickell, Steven P. Borrelia burgdorferi Spirochetes Induce Mast Cell Activation and Cytokine Release. Infect Immun. 1999 Mar; 67(3): 1107–1115.

Stricker RB, et al. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis. 2007; Jul 15; 45(2):149-57.

Emir Hodzic, Sunlian Feng, Kevin Holden, Kimberly J. Freet, and Stephen W. Barthold. Persistence of Borrelia burgdorferi following Antibiotic Treatment in Mice. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2008, p. 1728–1736.

Lynn Margulis, Andrew Maniotis, James MacAllister. Spirochete round bodies Syphilis, Lyme disease & AIDS: Resurgence of “the great imitator”? SYMBIOSIS(2009) 47, 51–58

Brorson O, Brorson SH. An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine. Int Microbiol. 2002 Mar; 5(1): 25-31.

Brorson O, Margulis L, et al. Destruction of spirochete Borrelia burgdorferi round-body propagules (RBs) by the antibiotic Tigecycline. Proc Natl Acad Sci U S A. 2009 Nov 3; 106(44): 18656–18661.

Feng, Jie, et al. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library. Emerging Microbes & Infections (2014) 3.

Barthold, Stephen W., et al. Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2010, p. 643–651.


Lyme Disease: Chronic Lyme (part 6)

Sometimes labs get slick with calling something validated because people assume it means FDA validated. It does not. A lab can do an internal study to determine the sensitivity and specificity of a test, write up a report and call it internally validated without ever needing to involve outside parties. Internally validated tests can have value, but it is difficult to ascertain without getting into the very gory details of the data, a lot of which is unpublished. Likewise, labs can develop their own “in house laboratory criteria” for FDA validated tests.

Some doctors send their samples to “Lyme specialty” laboratories based upon the belief that the ELISAs and Western blots performed there will be more sensitive. The 2014 paper mentioned in the previous post (Fallon 2014) looked at how likely four labs were to correctly perform Lyme diagnostics. They used one university reference lab, one commercial lab, and two Lyme specialty labs. Importantly, this study also included the in-house validated tests (NOT FDA validated tests) performed at the specialty lab, which included an ELISA for a different Lyme target (C6), used alone or in combination with the standard ELISAs or western blots using different criteria than the CDC recommended tests.

Specialty Lab A defined an IgM western blot as positive if at least two of the following bands were present: 23, 39, 41, 83/93 (these numbers refer to the size of the targets), and defined an IgG western blot as positive if at least 3 of the following bands were present: 20, 23, 31, 34, 35, 39, 83/93. Specialty Lab B defined an IgM western blot as positive if at least two of the following bands were present: 23-25, 31, 34, 39, 41, 83/93 (these numbers refer to the size of the targets), and defined an IgG western blot as positive if at least 2 of the following bands were present: 23-25, 31, 34, 39, 41, 83/93.

Here’s how the results shook out:

Standard IgM/IgG ELISA: University reference lab: 62.2% positive; commercial and specialty lab: 67.6% positive. The commercial and specialty labs both ran samples in pairs. Pairs in which one is positive and the other is not are called discordant. The commercial lab had 12 discordant pairs, specialty lab A had 14 discordant pairs, and specialty lab B had 8 discordant pairs.

C6 ELISA: Specialty lab A, 67.6% positive; specialty lab B, 62.6% positive, not run in pairs.

IgM Western blot using CDC criteria: university reference lab: 21.6% positive; commercial lab: 16.2% positive, 8 discordant pairs; specialty lab A: 2.7% positive, 7 discordant pairs; specialty lab B: 43.2% positive, 10 discordant pairs.

IgM Western blot using inhouse lab criteria: specialty lab A: 2.7% positive, 7 discordant pairs; specialty lab B: 62.2% positive, 15 discordant pairs.

IgG Western blot using CDC criteria: university reference lab: 56.8% positive; commercial lab: 43.2% positive, 5 discordant pairs; specialty lab A: 43.2% positive, 5 discordant pairs; specialty lab B: 48.6% positive, 3 discordant pairs.

IgG Western blot using inhouse lab criteria: specialty lab A: 37.8% positive, 7 discordant pairs; specialty lab B: 70.3% positive, 7 discordant pairs.

Two tier: standard IgM/IgG ELISA and IgG western blot (CDC criteria): university reference lab: 48.6% positive; commercial lab: 40.5% positive, 3 discordant pairs; specialty lab A: 37.8% positive, 6 discordant pairs; specialty lab B: 43.2% positive, 6 discordant pairs.

Two tier: C6 ELISA and IgG western blot (CDC criteria): specialty lab A: 40.5% positive, not run in pairs; specialty lab B: 45.9% positive, not run in pairs.

Two tier: Standard ELISA and C6 ELISA: specialty lab A: 59.5% positive, not run in pairs; specialty lab B: 48.6% positive, not run in pairs.

When running a standardized test (the CDC recommended ELISA and western blots), Lyme specialty labs find the same amount of positives as the commercial lab using the ELISA; find much fewer or much more positives using the IgM blot; and find the same amount of positives, or very close to the same, as the commercial lab for the IgG blot. When running the two recommended two tier test, they find almost the same amount of positives as the commercial lab.

When running the C6 ELISA, they find similar results to when they run the IgM/IgG ELISA. When they run their own criteria IgM blots, one lab got the same results as CDC criteria, and one found almost 20% more positives. When running their own criteria IgG blots, one lab found fewer positives than the CDC criteria and the other found almost 22% more positives. (Both of these large increases were found at the lab which had the least stringent criteria.)

Both labs found had a small increase in the number of positives found when running the two tier test with C6 ELISA and their own western blots. When they used only ELISAs (C6 and standard), one lab saw almost a 20% increase, while the other saw less than 3% increase in positives. I am not surprised by increases when using two ELISA tests together – the specific reason for using a western blot as the second step is that ELISAs frequently report false positives.

The results found on standardized tests are heavily dependent on the lab. However, the Lyme specialty labs do not always find more positives. When you look at the CDC two tier test, the University reference lab found the most positives, with the commercial lab and Lyme specialty labs finding positives in the same range. The two tier test using the C6 ELISA and in house western blots found positives slightly higher than the CDC two tier test when run by Lyme specialty labs. By contrast, their two tier, two ELISA test (C6 and standard) offers huge gains at one lab but not the other.

The take home from this study is this: When running standardized tests, the results are very specific to the lab, but when diagnostic two tier testing is performed in accordance with CDC guidelines, Lyme specialty labs have similar results as commercial labs. Lyme specialty labs actually find fewer positives with the CDC two tier test than the universe reference lab, which had the highest degree of accuracy in this study.

ELISA and western blots are used together to correct for ELISA finding false positives. When using in house tests and criteria, the Lyme specialty labs had a very modest increase (less than 3%) in positives. When using two ELISA test, one lab showed an increase in positivity of less than 3%, while the other lab showed almost a 20% increase. Please note that because ELISAs find false positives, using two ELISAs means you will find more false positives. The increases sometimes seen when using the blot tests alone are not because the Lyme specialty labs run the tests more accurately. They are because the labs have their own in house criteria which drop the bar significantly.

Also, discordancy is the death knell of diagnostics. And while commercial labs have a fair amount of discordancy (about 8% using the two tier test), both Lyme labs tested here have double that discordancy when running the diagnostic two tier test.



Brian A. Fallon, Martina Pavlicova, Samantha W. Coffino, and Carl Brenner. A Comparison of Lyme Disease Serologic Test Results From 4 Laboratories in Patients With Persistent Symptoms After Antibiotic Treatment Comparison of Serologic Test Results. Clinical Infectious Diseases 2014: 59 (15 December) , 1705-1710.

Andrea T. Borchers, Carl L. Keen, Arthur C. Huntley, M. Eric Gershwin. Lyme disease: A rigorous review of diagnostic criteria and treatment. Journal of Autoimmunity 57 (2015) 82-115.


I am rare

A year ago this week, I started writing regular posts about mast cell disease and chronic illness. In honor of Rare Disease Day, the last day of February, I decided to put up short posts on Facebook daily for the remaining days of February. I could not have predicted that this would eventually give way to a website that is visited thousands of times a month by people all over the world.

I wanted to write a post about having a rare disease and what it meant to be a rare patient, but I have actually been too busy dealing with my rare disease to do it. This week, it occurred to me that I actually have multiple rare diseases. Today, I learned that four of my diagnoses are classified as rare diseases in the US. I have four individual rare diseases. This is not uncommon for mast cell patients.

In the US, any disease that affects less than 200,000 at one time is considered rare. These diseases can be infectious diseases, cancers, genetic disorders, autoimmune diseases, and so on. Rare diseases are defined differently by different countries and organizations. Likewise, a disease can be rare in one region and common in another.

There are over 7000 known rare diseases. Worldwide, they affect 300,000,000 people. In the US, they affect 25,000,000. If all rare diseases live together in one country, it would be the third most populous country in the world.

Almost 10% of the American population has at least one rare disease. 2/3 of Americans living with rare disease are children. Currently, only 350 rare diseases have an FDA approved treatment. This means that most of the medications we use are not designed for us and we don’t know how they will affect us.

Almost half of primary care physicians in the US say they feel uncomfortable with taking on a rare disease patient. It can take us up to six years to receive a correct diagnosis. Some people are never diagnosed.

80% of rare disease patients have one of 350 rare diseases, with the rest being significantly more rare. Mastocytosis is not one of those 350 diseases.


My name is Lisa Klimas. I am 31 years old and I live with four rare diseases.

Mast cell disease causes severe allergic reactions to things I am not actually allergic to.

Ehlers Danlos Syndrome causes hernias, joint instability, and poor wound healing.

Postural Orthostatic Tachycardia Syndrome causes dysregulation of blood pressure and heart rate.

Mixed connective tissue disease causes autoimmune activity against various tissues in my body.

All of these conditions are chronic, incurable, and painful.  Together they can cause life threatening complications.

February 28th is Rare Disease Day. For many people, it is just another day. But for me, it is a celebration.

It is a reminder that there are other people like me all over the world.

Alone, we are rare, but together we are many.  We are strong.  We are an army.

My name is Lisa Klimas and I am rare.


I am rare




*All figures from the National Organization for Rare Disorders (NORD).

Lyme Disease: Chronic Lyme (part 5)

The number of patients diagnosed with negative serology Lyme seems to be ever growing. These patients largely have nonspecific symptoms and no obvious explanation for them. They may or may not remember a previous tick bite. Patients in these groups repeatedly test negative for Lyme in various validated tests. This population account for a much higher number of Lyme diagnoses than PTLDS.

Negative serology Lyme patients are diagnosed by medical professionals who believe that they have active, ongoing Borrelia infections despite negative tests. They believe that while taking continuous antibiotics, Borrelia is driven to form hardy structures that can survive adverse conditions (sort of like how molds can form spores that survive for thousands of years.) When the antibiotics are discontinued, patients once again become symptomatic. They believe this is because the Borrelia convert back to infectious forms.

Furthermore, negative tests are ignored for these patients on the basis that Lyme diagnostics are not good. And they’re not.

There is a lot going on here. So let’s look at the data.

I discussed testing at great length in one of the other posts. They function well in a certain time period for a certain group of people. Importantly, those people likely constitute the majority (but not all) of true Borrelia cases in the US. The data on this is currently being generated in a very large, three prong study by the CDC.

When most people get an infection, they generate IgM and IgG antibodies that last for some time. IgM concentrations decrease after about a year (this varies a lot depending on what the infecting organism is, so I’m being general here), but IgG concentrations often persist for years, sometimes even decades. This is why people who got the chicken pox as a kid are unlikely to get it when their kid gets it thirty years later. Your body has really fascinating mechanisms for remembering pathogens for a long time.

But exactly how long do those IgG antibodies last? It’s hard to say. And it’s especially hard to say for this population because they repeatedly test negative, sometimes immediately after onset of symptoms. So I thought the best way to figure this out would be look at how long people with serology positive Lyme disease (positive for IgM or IgG) test positive.

Importantly, the papers that look at this specific issue were mostly written before the CDC recommendation for 2-tier testing (ELISA and blot.) It is really important when you are comparing data sets on a particular topic that they use the same criteria. So while I did read them, I did not feel they were an accurate representation of what I was looking for.

A 2006 paper (Glatz 2006) looked at the IgG and IgM antibodies to Borrelia burgdorferi in 113 patients who had had the EM rash. They analyzed samples taken before treatment began (using standard, short term antibiotic treatment) and samples taken at least one year after treatment concluded. 12% of patients were positive for IgM before and after treatment; 11% were positive for IgG before and after treatment. 56% were negative for IgG before and after treatment; 42% were negative for IgM before and after treatment. 43% were positive for IgM before treatment and later became negative; 30% were positive for IgG before treatment and later became negative.

This study used ELISA testing, which is not likely to miss a positive antibody response. Before therapy, IgG and IgM tests are negative in about half of patients with the EM rash due to the time lapse in the way your body makes antibodies. Also, sometimes all the Borrelia spirochetes stay in the skin at the site of the rash, and your body is less likely to make antibodies to things that don’t actually go inside your body. So the initial negative is not as surprising as the fact that many patients never seroconvert (or that the tests never detect this seroconversion.) Importantly, this study did NOT find that persistent positivity correlated with poor outcome. However, it did find that patients who were persistently positive were more likely to have larger EM rashes or that those rashes lasted longer.

A 2014 paper (Fallon 2014) looked at the accuracy of Lyme tests (the CDC recommended tests and others done by Lyme labs) by using patient samples from two previous studies. All of these patients had tested positive, some by ELISA and some by IgG western blot. The first group of 37 was recruited from 1999-2005; the second of 11 was recruited from 2005-2007. In the Lyme patients, 62.2-67.6% was positive by ELISA; 2.7-43.2% were positive by IgM western blot; 43.2-56.8% were positive by IgG western blot; and 37.8-48.6% were positive by the two tier CDC recommended testing. (More on this tomorrow.)

The samples in these papers were from the time period surrounding treatment, which in some cases was ten years earlier. Antibodies are very sensitive. They are easily influenced and can deteriorate if not stored or handled correctly.

A 2001 paper looked at the current serum antibody response to 79 patients who had previously been serology positive for IgM or IgG 10-20 years earlier. None of these patients had any ongoing symptoms or signs of active Lyme disease. This study used the CDC recommended two-tier process. Among patients who had only had early disease, 10% were still IgM positive and 25% were still IgG positive. Patients who had had Lyme arthritis, 15% were still IgM positive and 62% were still IgG positive.

I do feel that you can test negative to Lyme and still have it. As you can see, it is possible for people to be diagnosed with Lyme disease while being persistently negative. It is also possible to be positive before treatment and have this decline to negativity later. And you can be positive and stay positive for decades. Patients who have longer active infection are more likely to be persistently positive.

So what does this mean in light of my previous comments on testing? The fact of the matter is that tests are forced to show a burden of proof in large scale trials before being validated by the FDA. They must be used in the manner described in order to be valid. The fact that you can test negative and have Lyme disease does not mean that western blots that show a few bands but not enough to be called positive are showing an active infection. Negative controls often show a few bands on western blots. It means better tests are needed.

But what about Lyme specialty labs? That’s getting its own post.



Akin E, McHugh GL, Flavell RA, Fikrig E, Steere AC. The immunoglobulin (IgG) antibody response to OspA and OspB correlates with severe and prolonged arthritis and the IgG response to P35 correlates with mild and brief arthritis. Infect Immun 1999;67:173-181.

Phillips SE, Mattman LH, Hulinska D, Moayad H. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Infection 1998;26:364-367

Marques AR, Stock F, Gill V. Evaluation of a new culture medium for Borrelia burgdorferi. J Clin Microbiol 2000;38:4239-4241

Tilton RC, Barden D, Sand M. Culture of Borrelia burgdorferi. J Clin Microbiol 2001;39:2747-2747

Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms: a PCR study of 97 cases. Infection 1996;24:347-353

Stricker RB, Johnson L. Persistent infection in chronic Lyme disease: does form matter? Research Journal of Infectious Diseases 2013.

Brian A. Fallon, Martina Pavlicova, Samantha W. Coffino, and Carl Brenner. A Comparison of Lyme Disease Serologic Test Results From 4 Laboratories in Patients With Persistent Symptoms After Antibiotic Treatment Comparison of Serologic Test Results. Clinical Infectious Diseases 2014: 59 (15 December) , 1705-1710.

Andrea T. Borchers, Carl L. Keen, Arthur C. Huntley, M. Eric Gershwin. Lyme disease: A rigorous review of diagnostic criteria and treatment. Journal of Autoimmunity 57 (2015) 82-115.

Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008; 70:992-1003.

Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003; 60:1923-30.

Marques AR, Stock F, Gill V. Evaluation of a new culture medium for Borrelia burgdorferi. J Clin Microbiol 2000; 38:4239-41.

Tilton RC, Barden D, Sand M. Culture of Borrelia burgdorferi. J Clin Microbiol 2001; 39:2747.

Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms: a PCR study of 97 cases. Infection 1996; 24:347-53.

Aguero-Rosenfeld, M. E., et al. Evolution of the Serologic Response to Borrelia burgdorferi in Treated Patients with Culture-Confirmed Erythema Migrans. Journal of Clinical Microbiology, Jan. 1996, p. 1–9.

Aguero-Rosenfeld, M. E., et al. Serodiagnosis in Early Lyme Disease. Journal of Clinical Microbiology, Dec. 1993, p. 3090-3095.

Glatz, Martin, et al. Clinical relevance of different IgG and IgM serum antibody responses to Borrelia burgdorferi after antibiotic therapy for erythema migrans. Arch Dermatol. 2006; 142(7):862-868.


Kalish, Robert A., et al. Persistence of Immunoglobulin M or Immunoglobulin G Antibody Responses to Borrelia burgdorferi 10-20 years after Active Lyme Disease. Clin Infect Dis. (2001) 33 (6): 780-785.


Aberer, E., et al. Course of antibody response in Lyme borreliosis patients before and after therapy. ISRN Immunology Volume 2012 (2012).

Go big or go home

In December of 2012, my surgeon told me I probably needed a colostomy. I wasn’t really ready to hear that. It didn’t seem like it should be so complicated. I just wanted to be able to go to the bathroom. But my lower GI tract was fundamentally broken. There would be no easy fix.

When I had my surgery in 2013, my rectum was not removed. I think they were worried I would have buyer’s remorse and want to go back to bowel prepping myself twice a week. I remember thinking that leaving the rectum in was a bad idea, but there wasn’t any obvious reason to remove it, and it wasn’t clear if it was a problem by itself or because I couldn’t go to the bathroom. So it stayed. And became a problem.

It was always very clear to me that if I got an ostomy, I would have it forever. I had seen several people about this, gotten several opinions. I did not think I could heal enough to ever not have the ostomy. A fair amount of ostomates get their ostomy reversed only to need a second one placed within a couple of years due to major issues. If I always assumed that if I got the ostomy, that that would be it. I would live with it forever.

I got some news on Tuesday that I wasn’t expecting. My mast cell specialist told me that he felt there was a second surgical option for me. This other option would be more complicated up front and less of a sure thing. But if it worked, I would no longer have an ostomy.

I was stunned. I am stunned. We had mulled this option over for my 2013 surgery and decided it wasn’t a good idea. But now, he thinks, it’s worth discussing. I fired off an email to my surgeon and sat down to stew about it. I’ve been stewing ever since.

I feel like this should be good news but I’m not sure that it is. It’s complicated. It would require removing a lot more tissue. It would be more invasive, with a harder recovery. I think it is less likely to work. I think it will work for a while and then I’ll need more surgery and a second ostomy in a few years. It’s not the safe decision, for sure. It could be a huge failure. In several ways.

I don’t really know how I should feel about this, or how I want to feel about this. I prefer not to think about the possibility of not having an ostomy. I had to write it off to survive. I couldn’t focus on an idea that would probably never be real. So I didn’t.

I’m super casual now about my ostomy. I make jokes about poop and colostomy bags and farting in meetings. I don’t care if people see the bag or the lump under my clothes. I incorporated this reality into my identity two years ago and I never looked back.

I don’t regret getting the ostomy, but this is making me realize that I might be happier if I didn’t have it. It’s a lot of work. It’s a lot of work anyway, but it is especially a lot when you have both an ostomy and a central line. I am sterilizing things constantly. And the ostomy works better than my rectum did before, but I wouldn’t say it works well. It works okay. Maybe less well than what they could whip up surgically. Maybe.

I don’t know how I got here, to this place in my life where it’s no big deal to talk about constipation or my rectum on the internet. It was less of a transition and more like diving into the ocean: sudden, jarring, but not bad.  And this is hard for me to say, but I think I am a better person for doing it and I feel like reversing the ostomy would change me. I think when you live with a bag adhered to your body that it makes you less self conscious and less concerned about things you can’t control. I really don’t care about how people perceive me because of it and it factors very little into my self image. And I think that’s a good thing.

And what if they reverse it and it works for a while and then they have to reverse the reversal and I’m in the same position as I am now? Can I live with that? Can I live with the disappointment of regaining normalcy in this one very crucial way only to lose it, again?

When I was young, I had this very clear idea of how my life would go.  It did not include getting sick or having an ostomy. It did not include these things being so mundane that I can discuss them anywhere, with anyone, without getting upset. But they are. This is my reality and I don’t know that I can take having to get okay with this reality a second time.  I don’t know that I can take even the fear of it.

And the very hardest part: that I don’t want to be responsible for my own suffering.  I don’t want to be the one who decides not to take the chance at reversing the ostomy when doctors are telling me it could work.

I’ve always been the kind of girl who goes big or goes home. But it’s getting harder to take risks. And I don’t know whether or not it’s time to just go home.


Screaming at the sun

I woke this morning to several more inches of snow. I watched it fall as I hovered in the doorway, the dog chasing it around the yard. My city has seen over three feet of accumulation in under a week with more on the way. It makes life more difficult, but it wasn’t difficult yet first thing this morning. It covered everything, pushed away the peripheral realities of life. Not a problem yet, just me and this sparkling, crystalline oblivion.

I am grieving right now. The isolation that accompanies snow storms is a good fit these days. I drink entire pots of coffee and fresh juices and type furiously while listening to the Beatles. There is no one to ask about this pain. It is just as well, because I haven’t felt like talking about it.

I funnel this frenetic energy into work, into writing posts, into cutting up fruits and vegetables to juice. I don’t want to sleep because I feel like I should be doing something. I can’t sit still because I am so uncomfortable in this body and if I stop moving, it feels like this sorrow will be upon me.

I grieve all big decisions, whether or not I realize it at the time. This swell of emotion has been building for some time, all the small upsets snowballing around this weighty core. I realized last week that I can no longer feel the difference along the scale of emotional pain. There are no little things right now. Every pain hurts exactly the same.

I will have the surgery and recuperate. I will feel better when I am healed. I will be taken care of. I will be fine. I will do all the things I have to. Everything will get done. I will be fine. I will be fine.

I don’t get upset when I see a blizzard is coming. The sheer enormity makes it pointless. It’s like screaming at the sun. There’s no point.

It’s the same with this pain. I know there’s no point in trying to change it. But sometimes I scream at the sun anyway.

Lyme Disease: Chronic Lyme (part 4)

I want to talk about this idea of persistent Borrelia infection for a bit. This post deals with patients who previously had documented Lyme disease, either clinically or serologically (some did not have blood tests, but had the EM rash.) There is some history to this research focus that I want to share.

One often cited report (Bayer 1996) found B. burgdorferi DNA in the urine of 72/97 patients with previously documented bull’s eye rash who had received multiple courses of antibiotics, while finding it in none of the controls. This finding was very exciting for the chronic Lyme community. However, closer investigation revealed some problems. PCR looks for a certain sequence of DNA and makes many copies of it so that it can be detected. The sequence of DNA this study used was for OspA, a protein that has been considered diagnostically useless for decades. (The reason for this is because other proteins of similar size often crossreact. Some blots use OspA as a marker and it is often the source of positive bands in an otherwise negative test.) Anyway, a lot of microorganisms have similar genes and DNA sequences, especially those that help with infection and increase survival. In order to know for certain that the PCR amplified the OspA sequence from B. burgdorferi instead of a similar organism, it has to be sequenced. But they didn’t do that in this study. One study did find that OspA antibodies were found in patients with severe Lyme arthritis (Akin 1999 – not that Akin.)

Another study found that Borrelia DNA was only found in 8% of urine samples from patients with Bull’s eye rashes who had not received treatment. This study was a lot less fast and loose with the PCR specifications.

A really important point here is that detection of DNA is not necessarily an indicator of active infection. There are several notable instances in which organisms or DNA persist in the human body following infection without causing symptoms or immune response. A good example of this is the chicken pox virus. Varicella persists in nerve cells for life following resolution of infection. Sometimes, this reactivates as shingles, but most people never have any further infection. In some of these patients with inactive Varicella infection, DNA can be detected in fluids.

I also find that people really want to compare the behavior and lifecycle of Borrelia to Treponema, the agent that causes syphilis. They do this because they are shaped the same and feel logically they should behave the same. Don’t make that mistake. Just because they look alike doesn’t mean they are alike. Please consider that MRSA is found as round cells in groups (cocci in clusters), as is Micrococcus luteus, one of the world’s most common lab contaminants, which is completely harmless.

In 1998, Phillips reported that his group had identified a way to reliably grow Borrelia in culture. B. burgdorferi does not grow well in culture; in fact, it is thought that less than 1% of microorganisms can be grown in pure culture. He further stated that he had cultured B. burgdorferi from 43/47 chronic Lyme patients.

I have some weird first hand history that I’m going to disclaim here: a couple of groups tried to replicate this finding while I was in college and it was something I followed. I did some lab work in college on difficult to cultivate organisms so I was interested to see what they had done. The lynch pin of the whole cultivation was the media, or the substances prepared for the organism to grow in. The recipe for this media specifically included Detroit tap water, and for obvious reasons, tap water can be highly variable in conditions that matter for growth, like concentration of metals, etc. One of the groups that tried to replicate this experiment actually found that the media made with the recipe provided killed B. burgdorferi (Marques 2002). Another group was also unable to replicate the data (Tilton 2001).

One of the things people get hung up on regarding chronic infection is the fact that you can continue to have symptoms for a long time after treatment. Another thing I see a lot is that patients with neuroborreliosis often test negative for active infection, but have ongoing symptoms. They feel this wouldn’t happen if there was no active infection. But there is huge precedent for this happening. Some organisms are known to induce a change in immune behavior that can later cause symptoms or even organ damage despite years of being infection free. The most well characterized instance of this follows infection by Streptococcus, which can cause rheumatic fever and other complications. We will take a look at how the immune system responds to Borrelia in another post.

Something that really irritates me is when an article groups dissimilar things together so that people will think they are alike and will say, look at this table of 30 animal models for persistent infection in Lyme disease. I’m looking at one right now that includes references from 1990-2012 and lists rodent, dog, monkey and horse models of persistent infection. And then at the bottom, you see that only some of them mean persistent treatment AFTER infection. Some of these were done in vitro (meaning using animal cells, not a live animal) and some were done in vivo. This data is all over the map. It uses culture, histology, PCR and xenodiagnosis in various combinations. Persistence does not equal infection and clinical symptoms, even in these models.

It’s frustrating because as a scientist, I can actually buy into the idea of persistent infection. I just can find very, very little solid data to support it. Most of the papers on this topic in the last fifteen years are published by one of a handful of papers and are published by a single author. When one person repeatedly publishes alone on the same topic, it is a big red flag. It literally means there is no one “on the ground” vetting what has been written. When you publish a paper, it is submitted for peer review, but it is very difficult for this process to detect any slight of hand with the data. That is why you work in groups and make sure the process is reproducible. When four scientists put their names on a paper, there is more of a perception that the data is real, because at least four people who understand the consequences are saying it’s true. When one person publishes alone for years, it is really suspect. Especially when that person was previously caught falsifying data for a project funded by a federal grant in the 90’s.

So I guess the bottom line is that I would not be surprised if at some point, data came out that a small percentage of people needed longer antibiotic treatment to eradicate active symptomatic infection. But I haven’t seen anything that convinces me yet. The data places me more into the camp that Borrelia infection causes a long term immunologic dysfunction that induces symptoms in previously infected patients.

I know you’re wondering if I’m going to talk about Lyme cysts. I am. In the next post.




Akin E, McHugh GL, Flavell RA, Fikrig E, Steere AC. The immunoglobulin (IgG) antibody response to OspA and OspB correlates with severe and prolonged arthritis and the IgG response to P35 correlates with mild and brief arthritis. Infect Immun 1999;67:173-181.

Phillips SE, Mattman LH, Hulinska D, Moayad H. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Infection 1998;26:364-367.

Marques AR, Stock F, Gill V. Evaluation of a new culture medium for Borrelia burgdorferi. J Clin Microbiol 2000;38:4239-4241.

Tilton RC, Barden D, Sand M. Culture of Borrelia burgdorferi. J Clin Microbiol 2001;39:2747-2747.

Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms: a PCR study of 97 cases. Infection 1996;24:347-353.

Stricker RB, Johnson L. Persistent infection in chronic Lyme disease: does form matter? Research Journal of Infectious Diseases 2013.