Lyme Disease: IDSA, ILADS and my conclusions (Part 9)

As everyone knows, I have spent the last few months putting together posts on Lyme disease. It took me a lot longer to get through than any other topic I can think of. The reason for this is politics. Lyme, and especially chronic Lyme, and especially chronic Lyme in the absence of a known tick bite or EM rash, is very controversial. It makes it really difficult for patients to know what information can be trusted.

The Infectious Diseases Society of America is an organization that represents health care providers and scientists working in the ID field. My research has been presented at IDSA conferences. IDSA publishes position papers and makes recommendations about treatment standards for various infectious diseases.

The International Lyme and Associated Diseases Society (ILADS) was formed to advocate for the existence of chronic Lyme disease. I couldn’t find an exact date, but they were around by the early 2000’s. In particular, they believe that the IDSA guidelines for diagnosis and treatment for Lyme disease are incorrect. They publish, lobby, and host conferences to educate providers and patients on their views of Lyme disease and coinfections. They believe that the IDSA guidelines prevent access to care.

These views lead to the Connecticut Attorney General suing the IDSA under anti-trust law in 2006. I read through a lot of the literature generated by the IDSA antitrust investigation. The legal action was filed based upon the fact that the IDSA was considered a dominant organization that restricted “consumer choice” and excluded ILADS researchers from their decision making processes.

I’m not going to lie: the fact that a state sued the IDSA for making guidelines based on evidence really leaves a bad taste in my mouth. Because in reviewing the ILADS papers and data, they don’t rely on evidence. They rely on the holes in the presented evidence. (Which are real, in fairness. As I stated before, Lyme diagnostics are not good.)

Here’s an example of what I mean. Let’s say there is a sheet of red paper with a hole cut out of it.

IDSA is saying the sheet is red.

ILADS is saying the hole is blue. They’re not saying that they have proof that it’s not red, it’s blue. They’re saying that there’s a hole in the red paper, could it have been blue before they cut it out? And they say they can tell it was blue because they used a special test in special labs that basically say that if the paper has any color, the result is reported as blue. The options are blue or negative. And even if the lab says it’s not blue, the doctors assume it was blue anyway.

My first experience with ILADS was when I went to the 2011 IDSA conference in Boston. It was at the convention center in South Boston. As I walked along the length of the building to get to the main entrance, I saw a person in a tick costume standing in my path. Tick costumed person had signs with the name “ILADS” emblazoned on them. Tick costumed person was being corralled by security (I assume for blocking the general path of traffic, which they were). It was pretty unforgettable.

I noticed a theme pretty early on in my Lyme research – that ILADS researchers and IDSA researchers would often say the same thing, but with different turns of phrase that lent themselves to misinterpretation. Sneaky. I hate that. There were several papers that I just stopped reading because of the cattiness of the language. It is very obvious that these organizations resent each other, and some researchers make no attempt to hide that. Which is unfortunate, because I’m betting a lot of scientists stop reading because of it.

Anyway, here’s an example:

In August 2013, the CDC released a statement that approximately 300,000 Americans are diagnosed with Lyme disease each year.

But if you go on the ILADS website, that’s not what they say the CDC said. Here’s what they say:

“CDC Reports: Lyme disease infects 300,000 people a year.”

See what happened here? Because they’re similar, but not the same. A few years ago, the CDC began a large, three pronged study to better characterize the nature of Lyme disease in the US. Part of that was identifying how many people were told they have Lyme disease. Another part was figuring out how many of those patients met the diagnostic criteria for Lyme as laid out by the CDC. 300,000 people were told they had Lyme disease. 300,000 people did NOT meet the diagnostic criteria for Lyme as laid out by the CDC. This is really important.

Diagnoses are defined by diagnostic criteria. If you don’t meet the criteria, you’re not counted as being affected for statistical purposes. The CDC is NOT saying that there are 300,000 people annually who meet the diagnostic criteria for Lyme. They are not. Whether or not the CDC criteria is effective for identifying all the people who have Lyme disease is a different issue. (I don’t think it is, if you’re wondering.)

Let’s take another example:

Let’s say there is a disease called Orange Disease. When people swallow orange seeds, oranges grow out of their noses. You can only get this disease from eating orange seeds. It is known to affect 50 people a year.

Now let’s say a group of doctors say that if you eat lemon seeds, lemons will grow out of your nose. They see some patients with this problem. They give them a treatment similar to the one for Orange Disease. These doctors say this problem with lemon seeds is Orange Disease, even though you can only get Orange Disease from eating orange seeds and lemon seeds are not orange seeds. But these doctors say because both oranges and lemons are citrus and the treatments are similar, everyone with these issues has Orange Disease. The rest of the doctors will only diagnose you with Orange Disease if you ate orange seeds.

That is what is happening here.

I believe that something is making 300,000 people a year sick. I do. I think that for those who have been bitten by a tick, it is possible that infection can cause long term changes in your body that cause symptoms. I think that the controlled studies have not shown long term antibiotics to be effective in treating this. I also think too many people say long term antibiotics do help to just write it off. I think the antibiotics do something, in some people.

Having worked in infectious diseases for years, it is hard for me to feel like moving a condition from underwhelming diagnostic criteria to a diagnosis of exclusion is a good idea. Diagnoses of exclusion are just so fraught with danger. Because maybe some of these people who don’t remember a tick bite and have these major constitutional symptoms really do have Lyme disease, but maybe they don’t. I feel certain that part of why it took me so long to get diagnosed with mast cell disease was because I was receiving treatment that really confused the issue. And I worry that this is the case for a lot of people.

It is my finding that Lyme diagnostics are not good.

It is my finding that it is possible to have Lyme disease, both acute and long term, and test negative.

It is my finding that Lyme specialty labs use tests that are not FDA validated, that are not considered reliable by many people.

It is my finding that it is possible for viable Borrelia to persist in the body after treatment.

It is my finding that it is not clear if those Borrelia cause an ongoing infection, or if the previous infection causes a permanent immunologic change that manifests as symptoms.

It is my finding that coinfections are possible. The majority of these organisms are treated with the first line treatment for Lyme disease. However, some are not.

It is my finding that long term antibiotic treatment has not been shown scientifically to help with chronic Lyme symptoms.

It is my finding that long term antibiotic treatment could facilitate benefits in some through anti-inflammatory or immune modulating properties, rather than through treatment of ongoing infection.

It is my finding that long term antibiotic treatment can have serious, irrevocable consequences.

It is my finding that 300,000 people being diagnosed annually with Lyme disease is not the same as 300,000 people being infected annually with Lyme disease.

It is my finding that tweaking the language to change the meaning of a previous finding is rampant in Lyme scientific literature.

It is my finding that unless you run down every citation, there is no way to know the truth.

It is my finding that some of the 300,000 people diagnosed annually with Lyme disease probably do really have symptoms from either a current or previous Borrelia infection, even if they have negative tests. But I would venture that a lot of them don’t.

Lyme disease: Coinfections (part 8)

A lot of patients who are being treated for chronic Lyme are also being treated simultaneously for ongoing coinfections. There is a fairly long list of coinfections, most of which are known to be tickborne diseases. I focused on the ones that are thought to be the most common.

Ehrlichiosis, also known as human monocytic ehrlichiosis, is caused primarily by E. chaffeensis and E. ewingii. This organism infects monocytes and lives its life cycle inside them. This organism is transmitted primarily by the Lone Star tick, found mostly in the south east, south central and mid-west US. Well known in other animals, human infection was first described in 1986. Since then, more than 2300 cases have been reported to the CDC. Of cases reported from 2000-2007, 49% required hospitalization. 1.9% of cases were fatal.

Patients with ehrlichiosis often demonstrate low white counts, red counts and platelet counts fairly quickly. Liver function tests may be elevated. Up to 20% have significant neurocognitive effects, including meningitis type symptoms to 10%. Rash is less common in this condition than other tickborne diseases, affecting less than 30% of infected adults. Fever, severe headache, chills, malaise, muscle pain, nausea, vomiting, diarrhea and red eyes are common symptoms.

Ehrlichiosis is diagnosed by blood tests and in particular with a blood smear. However, like Lyme disease, testing can be negative in early infection. The most effective method for diagnosis is comparison of serum samples taken 2-3 weeks apart: a fourfold increase in IgM or IgG specific for this organism in the later sample compared to the earlier is considered diagnostic. A few of the papers I read on this topic commented that smear analysis alone only identifies microcolonies of Ehrlichia in the monocytes 20% of the time. I wasn’t able to find a primary reference for this statistic, and I would suspect it’s not that low, but I can’t find any evidence either way. I also saw the following phrase repeated in a few places: “Demonstrating the organism in tissue by immunohistochemistry or molecular studies in immunocompetent patients may be difficult, as few organisms are present.” I can’t find a primary reference for that either.

If ehrlichiosis is suspected, antibiotic treatment is recommended regardless of test results. Early treatment is key in avoiding severe complications, such as splenic rupture and death. It is treated with doxycycline orally or intravenously for 10-14 days. In children and adults, treatment with sulfonamide antibiotics are associated with increased morbidity.

Because the causative organisms live inside circulating white blood cells, it is possible it could be transmitted by blood transfusion or solid organ transplant. Multiple cases have been investigated, although no instances of ehrlichiosis spread by these methods have been confirmed.

There is also an infectious agent known as the Ehrlichia muria like Organism (EML). It is so called due to the similarity of disease as well as cross reactivity with Ehrlichia chaffeensis antibodies. This agent has been found to cause infections in Wisconsin and Minnesota. It is not yet clear what tick transmits this infection.


Anaplasmosis (formerly human granulocytic ehrlichiosis, now human granulocytic anaplasmosis) is caused by Anaplasmosis phagocytophilum. Very similar to the organism that causes ehrlichiosis, A. phagocytophilum was previously known as Ehrlichia phagocytophilum until it was reclassified. This organism infects neutrophils and lives its life cycle within them. This condition can be very difficult to distinguish from ehrlichiosis, especially during the acute phase. PCR testing can be used to distinguish based upon DNA sequences.

Anaplasmosis causes fever, severe headache, muscle pain, and chills. Presentation can be minor. Skin rash affects less than 10%. Low platelets and red counts, as well as elevated live function tests, are evident fairly early in infection. Like ehrlichiosis, it is treated with doxycycline and treatment should be started if suspected in spite of negative tests. Symptoms respond quickly to doxycycline, an dother antibiotics should be avoided as they are associated with poorer outcomes. Very ill patients may require longer treatment, but it is considered successful once the fever is resolved. Resistance of this organism to doxycycline has not been reported. I was not able to find evidence of relapse following post-treatment recovery.

Anaplasmosis can be transmitted to humans by at least three types of ticks and shares a vector for Lyme disease. One study found that about 10% of patients with serological evidence of anaplasmosis were also serologically positive for Lyme disease or babesiosis. It can theoretically be transmitted through blood transfusion or solid organ transplant.


Babesiosis in humans is primary caused by B. microti. There have been “isolated” cases of infection by other species in unlikely places, including B. divergens in the US and B. venatorum in Europe, among others. Babesiosis has long been known to affect other mammals, including cows and dogs. Unlike the other co-infecting organisms mentioned thusfar, Babesia spp. are not bacteria, but protozoan parasites. Babesia infection is not thought to be rare, and it is thought that up to half of children and a quarter of previously healthy adults have no symptoms when infected.

Symptomatic patients develop a syndrome similar to malaria patients. Symptoms usually start 1-4 weeks after tick bite, or 1-9 weeks after blood transfusion if contaminated. Symptoms are mostly generic: fever, chills, malaise, fatigue, chills, night sweats. However, it also causes low platelet count and hemolytic anemia. Like other infections, it is likely to be worst in those who with compromised immunity, including those who have no spleen.

Babesia infect red blood cells. It is primarily diagnosed by peripheral blood smears stained with Giemsa stain. PCR is also used. Unlike the other organisms mentioned here, doxycycline is not effective. There are two therapies: atovaquone and azithromycin OR clindamycin and quinine. In severe cases, patients may require exchange transfusion, in which their red cells are removed and replaced with healthy ones. Babesia can be life threatening or even fatal. It can cause heart attack, renal failure, and disseminated intravascular coagulation, among other things. Additionally, Babesia can be transmitted via transfusion, solid organ transplantation or in utero (through infection, not through inheritance – the baby does not inherit a “gene” for Babesia, but instead contracts the infection for the mother.)

So how often are B. burgdorferi, B. microti and A. phagocytophilum found in the same tick?

A 2014 paper found that B. burgdorferi and B. microti were found together 5.96%; A. phagocytophilum and B. burgdorferi together were 2.35%; and A. phagocytophilum and B. microti together were 0.53%. Triple infection was found in 0.52% ticks sampled.

Another 2014 paper found that in one location, 6.4% adult ticks were coinfected, and 5.2% nymphs were; in another location 4% of adults and 1% of nymphs were. In the location with the highest level of infection, 2.5% of adult ticks were infected with B. microti; 37.5%, B. burgdorferi; 7.5% with EML; 0.4% coinfected with A. phagocytophilum; 5% A. phagocytophilum and B. burgdorferi; 1% with A. phagocytophilum and EML; 0.4% with B. microti and B. burgdorferi; 3% with B. burgdorferi and EML; and 0.4% triple infected with B. burgdorferi, A. phagocytophilum and B. microti. Incident was less common in nymphs, except for solitary B. microti infection (3.3%), and B. microti and B. burgdorferi coinfection (2%).

So, sometimes, but not often. Also, the fact that they are found together does not mean they are always transmitted together. That needs to be studied.

It is my finding that yes, coinfection with Borrelia and another organism can cause symptomatic disease. But I find this to be true in a much narrower scope than the internet at large may lead you to believe.

Firstly, I want to clarify that the Lone Star tick is not known to carry Borrelia spp. and is not known to cause Lyme disease. It causes a similar illness through an unknown organism, but really, most tick borne diseases cause similar symptoms, at least at first. So if you are bitten by a Lone Star tick, there is no evidence that you can contract Borrelia this way.

Some people have said that they have both Lyme and ehrlichiosis. Because ehrlichiosis in the true sense is transmitted by the Lone Star tick, this is unlikely. It is possible in theory to be bitten by both ticks and to contract both separately. Some people mean they have contracted the EML agent and Borrelia from one bite. This may be possible, but we have no idea if it is. Additionally, the number of cases verified as being caused by the EML agent is extremely low. So even if this were possible, it is not yet widespread enough to be causative in the number of people who suspect they have both.

I cannot find reliably sourced information on a recurring/relapsing presentation of ehrlichiosis or anaplasmosis. By most accounts, they can cause grave illness if not treated promptly. So I find this idea of “dormancy” unlikely. I understand that the idea of living intracellularly lends for some people more plausibility to this idea of dormancy. While infected cells may live longer, they don’t live that much longer. We’re talking weeks/months, not years here. Also, please look further in the ways cells tell immune cells that they are infected. It is incredibly detailed and too much for me to get into.

I also cannot find reliably sourced information on recurring/relapsing presentation of babesiosis. I agree that it might take longer to find, and it will not be treated effectively with doxycycline. However, my gut feeling tells me that if any of the coinfecting organisms mentioned in this post were likely to cause a long term problem, it is probably going to Babesia spp. That does not mean that I think it can cause a remitting/relapsing type of infection. I just think it can take longer to find and effectively treat it.

However, it is important to realize that a fair amount of people test positive for Babesia who have no symptoms of any kind. There are clear demarcations for what populations are most likely to have severe infections and it is people over 50, people who have HIV, people who are being treated with sulfonamides, and people who are immunocompromised, including those who are asplenic.

Diagnostics for Lyme have been well studied. Diagnostics for these organisms have been less well studied and are less well controlled. However, after early infection, I feel like smears are going to telling. Furthermore, all of these organisms can cause major blood count deficits, which is hard to miss. I think the likelihood of being symptomatic with one of these infections for years without ending up in the hospital or at least ending up on an effective antibiotic empirically (Babesia not withstanding) is pretty low.

Something else I haven’t gotten around to is the fact that you can get reinfected Lyme disease by another tick bite after having (and resolving) Lyme disease previously. I’m not sure if this is true for the other organisms due to the much lower rate of infection and the fact that it has not been well researched.

In literature, a unifying characteristic of the bacterial coinfections is that once the fever is gone, treatment is successful. Antibiotic treatment is recommended until a short time after the fever has broken. Given that I can’t find support for “persistent” infection of these coinfectors, I likewise cannot understand why long term antibiotics are helpful, beyond the inherent anti-inflammatory and immune modulating behaviors of antibiotics. (Which I’m not ignoring – I think if you have continuous health issues years after being bitten by a tick, and antibiotics help – that’s an important clue – but does not necessarily mean it helps because it treats an ongoing infection.)

I addressed before the fact that controlled trials of long term antibiotics have not shown gains in the group receiving antibiotics above the placebo group. About 1/3 of the patients in the largest study improved on placebo. But as a scientist, this idea that every person who feels better with antibiotics is experiencing a placebo effect is… unsatisfying. I don’t know how to explain it. It just seems unlikely to me. Which means I think the antibiotics are doing something. But I’m not convinced that what they are doing is treating long term infections. Especially not of these coinfecting organisms.

Furthermore, antibiotics and antimalarials are not benign. I think some people are really playing with fire here. Especially those people who get IV antibiotics long term and who have indwelling lines for that purpose. Like everything else, this is a risk/reward situation, and I’m not judging anyone who is choosing the risk because these drugs make them feel better. I just feel like there is somewhere in this mess an explanation that may allow them to use more benign medications. And I want that.

Tomorrow I’m going to give you the view on IDSA/ILADS from where I’m sitting and then I’ll be calling it a day on Lyme disease and coinfections. Once tomorrow’s post goes up, feel free to ask questions and discuss. Please be civil. I am sensitive to the fact that a significant number of patients are being treated for chronic Lyme and I have tried to be thorough and fair in my assessment of the situation. If you feel that I have gotten something factually wrong, please provide a peer reviewed literature source. If I have read it, it has already factored into my interpretation. If I haven’t, I will read it, and make amendments if I feel appropriate. I make mistakes and have no problem with people fact checking me. Just please remember that I have really tried to get to the best of my ability to get to the bottom of this.



Hersh, Michelle H., et al. Co-infection of blacklegged ticks with Babesia microti and Borrelia burgdorferi is higher than expected and acquired from small mammal hosts. PLOS One 2014.

Stromdahl et al. Comparison of phenology and pathogen prevalence, including infection with the Ehrlichia muris-like (EML) agent, of Ixodes scapularis removed from soldiers in the midwestern and the northeastern United States over a 15 year period (1997-2012). Parasites & Vectors 2014 7:553.

Pritt BS, Sloan LM, Johnson DK, Munderloh UG, Paskewitz SM, McElroy KM, McFadden JD, Binnicker MJ, Neitzel DF, Liu G, Nicholson WL, Nelson CM, Franson JJ, Martin SA, Cunningham SA, Steward CR, Bogumill K, Bjorgaad ME, Davis JP, McQuiston JH, Warshauer DM, Wilhelm MP, Patel R, Trivedi VA, Eremeeva ME: Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. New Engl J Med 2011, 365:422-429.

Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman RB: The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006, 43:1089-1134.

Steiner FE, Pinger RR, Vann CN, Grindle N, Civitello D, Clay K, Fuqua C: Infection and co-infection rates of Anaplasma phagocytophilum variants, Babesia spp., Borrelia burgdorferi, and the rickettsial endosymbiont in Ixodes scapularis (Acari : Ixodidae) from sites in Indiana, Maine, Pennsylvania, and Wisconsin. J Med Entomol 2008, 45:289-297.

Nonaka E, Ebel GD, Wearing HJ: Persistence of pathogens with short infectious periods in seasonal tick populations: the relative importance of three transmission routes. PLoS ONE 2010, 5:e11745.

Dahlgren F, Mandel E, Krebs J, Massung R, McQuiston J (2011) Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000–2007. Am J Trop Med Hyg 85: 124–131 doi:10.4269/ajtmh.2011.10-0613.

Ostfeld RS (2010) Lyme disease: the ecology of a complex system. New York, NY, USA: Oxford University Press. 232 p.

Krause PJ, McKay K, Thompson CA, Sikand VK, Lentz R, et al. (2002) Disease-specific diagnosis of coinfecting tickborne zoonoses: Babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 34: 1184–1191 doi:10.1086/339813.

Robert B. Nadelman, M.D., Klára Hanincová, Ph.D., Priyanka Mukherjee, B.S., Dionysios Liveris, Ph.D.,

John Nowakowski, M.D., Donna McKenna, A.N.P., Dustin Brisson, Ph.D., Denise Cooper, B.S., Susan Bittker, M.S., Gul Madison, M.D., Diane Holmgren, R.N., Ira Schwartz, Ph.D., and Gary P. Wormser, M.D. Differentiation of Reinfection from Relapse in Recurrent Lyme Disease. N Engl J Med 2012. 367; 20.


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.


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).

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.

Lyme Disease: Chronic Lyme (part 3)

The next three posts will be on the phenomenon of Chronic Lyme disease with specific attention to those patients who test negative in validated laboratory tests. Please wait until these Chronic Lyme posts are complete to engage in discussion with me about this. There is a lot of information to present and this makes it easier for me to present it in a way that is understandable for people who are not familiar with Lyme disease. Thanks!


“Chronic Lyme disease” is a term applied to multiple patient populations of different characteristics. It is sometimes used to refer to “Post treatment Lyme disease syndrome,” a condition affecting up to 1/3 of Lyme diagnosed patients that causes persistent symptoms for some time following the completion of antibiotics. It sometimes refers to untreated, disseminated, late-stage Lyme diseases, particularly those with Lyme arthritis or neuroborreliosis. It sometimes refers to a patient group with various ongoing symptoms who demonstrate no objective evidence of previous or current Lyme infection.

Right now, I am going to address PTLDS and what I call “negative serology Lyme,” which I am defining as follows:

PTLDS: patients with well documented laboratory evidence of Lyme disease who continue to have persistent symptoms for many months after antibiotic therapy is discontinued.

“Negative serology Lyme”: patients who demonstrate no laboratory evidence of current or previous Lyme infection, but who have ongoing, serious symptoms attributable to Lyme disease. Importantly, doctors who diagnose this condition believe that these people are continuously infected with Borrelia. They do not believe that symptoms are from a previous infection, but from an active one.

I want to be clear about the fact that my naming this group “negative serology Lyme” rather than “chronic Lyme” does NOT mean that I don’t believe that they have Lyme derived health problems. I am going to review the available data with you guys and give you my thoughts on what causes each distinct pathology. I am simply differentiating between them since both are called chronic Lyme in literature and it can be really confusing.

Both of these patient groups report a variety of symptoms, including fatigue, night sweats, sore throat, swollen glands, stiff neck, joint and muscle pain, palpitations, abdominal pain, nausea, diarrhea, sleep disturbance, poor concentration, irritability, depression, back pain, headache and dizziness. Some report a severe level of disability.

One paper (Klempner 2001) reported on two trials done by the same group, one on 78 PTLDS patients and one on 51 negative serology patients. These trials were double blind, randomized, placebo controlled trials, the gold standard. All patients in both groups were required to have a history of acute Lyme contracted in the US, with at least one of the following: history of at least one bull’s eye rash; early neurologic or cardiac symptoms attributed to Lyme disease, radiculoneuropathy or Lyme arthritis. Documented previous treatment of Lyme with recommended antibiotic regimen by a knowledgable doctor was also required. All patients in both groups had at least one of the following: widespread musculoskeletal pain, cognitive impairment, radicular pain, paresthesias or dysesthesias. Profound fatigue was a noted symptom in some, but not all, patients. These symptoms started within six months of contracting Lyme disease and persisted for some time between 6 months and 12 years. Patients in the PTLDS group were blot positive for Borrelia IgG.

Enrollees could not have previously received IV antibiotic therapy for 60 days or more for current symptoms, have active inflammatory synovitis, had a coincident diagnosis that could explain some or all symptoms, or could not discontinue medications that could affect treatment response, like pain medications or steroids. They were also excluded if they had a positive PCR test for B. burgdorferi in plasma or cerebrospinal fluid. (Remember this – I’m coming back to it later.)

In each group, half received antibiotics, while half received placebo. The antibiotic treatment selected was 30 days of IV ceftriaxone, 2 gm/day, followed by 60 days of oral doxycycline, 100 mg twice daily. The placebo group received an IV dextrose solution the same color as the IV ceftriaxone, and placebo capsules identical looking to the doxycycline.

The objective of the study was to determine if the patients’ health related quality of life improved, which was determined by a self reported survey called the SF-36. This survey assesses physical functioning, vitality, bodily pain, general health perceptions, social functioning, emotional limitations on typical daily activities, social functioning, and mental health. Additional questionnaires measured pain, cognition, and how well patients could execute basic daily activities.

55% of patients in the antibiotic group had improved health status, as well as 42% of the placebo group. 14% in the antibiotic group had worsened health status, as well as 19% in the placebo group. There was no statistically significant difference between the two groups. Statistically, the antibiotic group and the placebo group had similar outcomes. During the six month period encompassing the treatment and three months after, 36% in the placebo group reported an improved health status, 39% had worsened health status and 25% had no significant change. So without any treatment, 36% improved. Two major adverse events occurred, both in the antibiotic group: one had a life threatening pulmonary embolism, and the other had fever, anemia and GI bleeding.

Another study (Krupp 2003) with 55 PTLDS patients with severe fatigue received either ceftriaxone or placebo for 28 days. 22% of patients receiving ceftriaxone saw an improvement in fatigue, compared to 9% placebo group, in a self reported survey. There was no significant difference in cognitive improvement or reported health status when surveyed. However, patients in the ceftriaxone group were much more able to correctly identify their treatment protocol than placebo patients, meaning the study may have been compromised and that the improvements in fatigue may have been due to the placebo effect.

A variety of other studies have been done on both PTLDS and negative serology patient groups. Some of them report improvement with long term antibiotic treatment of negative serology patients. However, as these studies were uncontrolled, the findings cannot be considered reliable. Additionally, criteria for acceptance to these studies were very broad, and unvalidated tests have been used to interpret findings. As a researcher, these particular aspects are very troubling.

(Continued in the next post)



Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85-92

Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60:1923-1930

Donta ST. Macrolide therapy of chronic Lyme disease. Med Sci Monit 2003;9:I-136.

Stricker RB, et al. Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. Int J Gen Med. 2011; 4:639-46.

Fallon BA, Tager F, Fein L, et al. Repeated antibiotic treatment in chronic Lyme disease. J Spirochetal Tickborne Dis 1999;5:94-102.

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.

Lyme Disease: CDC Recommended Diagnostics (part 2)

Diagnosis of Lyme disease is a complicated affair. Part of the complication is the way our immune system responds to Lyme disease, and part of it is the current tests available to test for infection.

An antigen is anything that generates an immune response inside your body. Borrelia spp., the causative agents of Lyme disease, are antigens. They enter your body, your immune system recognizes it as a threat, and generates a specific IgM in response to Borrelia. This IgM is present in your serum about a week after infection, and persists in good quantities until about 12 weeks after infection, with concentration of specific IgM peaking around 4-6 weeks.

About 4 weeks after infection, your body generates Borrelia spp. IgG. This change from making IgM to IgG is called seroconversion. This IgG persists in good quantities for about 9-10 months after infection. While both IgM and IgG titers decrease over time, they can persist in serum for years after infection is resolved.

The standard Lyme diagnostics look for IgM and IgG. To be honest, I was pretty surprised at the abundance of different Lyme diagnostics, including others that look at that antigen and PCR based tests. There are multiple types of tests, and for each type of test, there are multiple companies that make them. It is a bit of a hot mess. So let’s look at the CDC recommended testing first, and then I’ll get to the others.

The CDC recommends a two step process for diagnosing Lyme. The first step is an ELISA and the second is a Western blot.

The Lyme ELISA (enzyme linked immunoassay) tests look for IgM and/or IgG, the antibodies made in response to the infection. These tests are sensitive, meaning that almost everyone with Lyme will test positive IF TESTED FOUR WEEKS AFTER SYMPTOMS PRESENT. (Note: I saw the phrase “almost everyone with Lyme will test positive” in relation to ELISA testing for Lyme several times. This test is most likely to correctly identify positives after patients have seroconverted.) However, these tests are not that specific, so they will provide 5-7% false positives. So with this test, if you have Lyme, you are likely to get a positive result, but if you don’t have it, you might still get a positive result. If the ELISA test is positive, then blot testing is done to confirm the result. If the ELISA test is negative, then the blot is not run, and the patient is told they do not have Lyme disease.

Western blots look for proteins specific to the organism in question. Western blots for Lyme testing are usually called immunoblots. These tests look for the specific IgG and IgM. Like the ELISA, the blot for IgG is more accurate, but requires the patient to have seroconverted. Blots for IgM are more likely to give false positives, so people who don’t have Lyme disease may have a positive test. The CDC guidelines recommend only running IgM blots in the first four weeks of illness due to the higher risk of false positive.

A Western blot works by showing “bands” to demonstrate that particular antigens were found. The bands are visible to the person reading the result. In order for an IgM blot to be considered positive, two of three possible bands must be positive. In order for an IgG blot to be considered positive, five of ten possible bands must be positive.


Let’s review.

You have had symptoms for two weeks. Your IgM ELISA is positive. Your IgG ELISA is negative (because your body hasn’t made IgG yet for Borrelia spp.) Your IgM blot shows 3/3 bands. Your IgG blot is negative. You are diagnosed with Lyme disease.

You have had symptoms for two weeks. Your IgM ELISA is positive. Your IgG ELISA is negative (because your body hasn’t made IgG yet for Borrelia spp.) Your IgM blot shows 1/3 bands. Your IgG blot is negative. You are not diagnosed with Lyme disease.

You have had symptoms for two weeks. Your IgM ELISA is negative. Your IgG ELISA is negative (because your body hasn’t made IgG yet for Borrelia spp.) No blots are run. You are not diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is positive. Your IgG ELISA is positive. Your IgM blot shows 2/3 bands. Your IgG blot shows 5/10 bands. You are diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is negative. Your IgG ELISA is positive. Your IgM blot is negative. Your IgG blot shows 5/10 bands. You are diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is negative. Your IgG ELISA is positive. Your IgM blot is positive. Your IgG blot shows 4/10 bands. You are not diagnosed with Lyme disease.

You have had symptoms for six weeks. Your IgM ELISA is positive. Your IgG ELISA is negative. Your IgM blot shows 3/3 bands. Your IgG blot shows 4/10 bands. You are not diagnosed with Lyme disease.


So let’s talk about this two step process. It has been studied, a lot. The two step process was implemented in the mid-90’s due to the lack of specificity, meaning that people were being treated for Lyme disease who didn’t have it. When the two step process is run and interpreted by skilled operators, according to recommendations, it has 99% specificity. This means a 1% chance of calling someone negative when they really have Lyme disease.

But this doesn’t seem to translate well to clinical practice. A key weakness of these diagnostics in practice is their inability to correctly diagnose people who are newly infected. One study found that the sensitivity and specificity for the two tier test was 100% and 99% for people who no longer had the bull’s eye rash, which happens during the acute phase. But it only had 29% sensitivity for patients in the acute phase with the rash. (Steere 2008) Another study looking particularly at clinical practice found that 50/182 patients had a false positive IgM blot. 78% of them received unnecessary antibiotics. (Seriburi 2012)

I understand why these tests work fine in some studies and not in others. As far as ELISAs giving false positives, that’s no surprise to anyone who has run them before. They’re “sticky.” They crossreact with a lot of things. The reagents are optimized to minimize this, but it is a persistent problem with this type of test. Instead of getting an exact match for your target (Borrelia spp.), you get a “close enough.” You get a positive result if you get a close enough match, and things that match close enough include antibodies for anaplasmosis, leptospirosis, syphilis, Epstein Barr virus, and lupus, among others.

Western blots are also problematic. They are time consuming and complicated. There are a lot of steps and there is a lot of repetition. Reading the results can be confusing. You are comparing the intensity of a band to a control. So let’s say the darker it is, the more positive it is. Just seeing a band does not make it positive. It has to also be as dark as the control for the same band. And things like darkness are subjective.

A sticking point for a lot of people seems to be the fact that they have some bands on their Western blots but not enough to meet the positive criteria. A lot of people feel that if they are positive for some bands that this should be sufficient for a diagnosis. I understand why this is confusing. It’s confusing because it seems like if these blots test for proteins specific to Lyme disease that having any of them should be indicative of infection. But that’s not true.

Remember how I said ELISA tests are sticky, that you can get a good enough match that’s not specific? There’s some of that happening in Western blotting, too. And remember how I said that the procedure is difficult, that the results are subjective? Those facts mean that you can get a few bands through operator error. That’s why it is so important that ALL the required bands show up.

Diagnostic development involves employing a lot of measures to ensure you compensate for errors borne out of biologic crossreaction (like sticky antibodies) and procedural inadequacies. The result is very specific criteria for what is considered positive and what is not. The FDA requires this.

Another thing to keep in mind for later is that diagnostics that are FDA validated are designed for very particular uses. That means that if you have an FDA validated test for Lyme IgG in serum and you use that test to test whole blood or cerebrospinal fluid or synovial fluid, and you get a positive result, it is meaningless. It is not positive. It is nothing. If you have an FDA validated test that tells you to use 100 ul of serum and 100 ul of something else per tube, and you use 150 ul of serum and 150 ul of something else per tube, and you get a positive result, it is meaningless. This also generates a lot of confusion because people feel like if you are looking for the same thing (Lyme IgG), it shouldn’t matter where you find it. But it does.

It matters because sample matrices (like serum or whole blood or whatever) have their own specific “backgrounds.” This means that they contain different proteins and have different fluid dynamics and they could cause additional crossreaction or they could cause less crossreaction. The chemistry involved in diagnostics is very fine. Tests that have a large tolerance for changes like this are called “robust.” The Lyme diagnostics discussed here are not robust.



Steere AC, McHugh G, Damle N, Sikand VK. Prospective study of serologic tests for Lyme disease. Clin Infect Dis. 2008;47(2):188–195. doi: 10.1086/589242.

Wormser GP, Carbonaro C, Miller S, Nowakowski J, Nadelman RB, Sivak S, Aguero-Rosenfeld ME. A limitation of 2-stage serological testing for Lyme disease: enzyme immunoassay and immunoblot assay are not independent tests. Clin Infect Dis. 2000;30(3):545–548. doi: 10.1086/313688

Klempner, M. S., C. H. Schmid, L. Hu, A. C. Steere, G. Johnson, B. McCloud, R. Noring, and A. Weinstein. 2001. Intralaboratory reliability of serologic and urine testing for Lyme disease. Am. J. Med. 110:217-219

Reed, Kurt D. Laboratory Testing for Lyme Disease: Possibilities and Practicalities. J Clin Microbiol. Feb 2002; 40(2): 319–324.

Ang, C. W., et al. Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur J Clin Microbiol Infect Dis. Aug 2011; 30(8): 1027–1032.

Woods, Charles R. False-Positive Results for Immunoglobulin M Serologic Results: Explanations and Examples. J Ped Infect Dis (2013).

Seriburi, N. Ndukwe, Z. Chang, M. E. Cox and G. P. Wormser . High frequency of false positive IgM immunoblots for Borrelia burgdorferi in Clinical Practice. Clin Microbiol Infect 2012; 18: 1236–1240

Branda, John A, et al. 2-Tiered Antibody Testing for Early and Late Lyme Disease Using Only an Immunoglobulin G Blot with the Addition of a VlsE Band as the Second-Tier Test. Clin Infect Dis. (2010) 50 (1): 20-26.

Lyme disease: Disease staging and typical treatment recommendations (Part 1)

Vectorborne diseases are infectious diseases transmitted to people via blood sucking arthropods, like mosquitos, flies and ticks. Lyme disease, caused by spirochete bacteria of the genus Borrelia, is the most common such disease in North America. In the US, more than 20,000 cases have been reported annually in the years since 2002. 94% of cases occur in New England, the Mid-Atlantic, and the upper Midwest. (CDC, 2010) Every year, 1-3% of people living in endemic regions of the US become infected. Cumulatively, you can see infection rates of as high as 15%. (Tugwell 1997)

Most people with Lyme are diagnosed in early disease. A hallmark erythema migrans (EM) rash, commonly called the Bull’s eye rash, is found at the site of the tick bite in the majority of Lyme patients. Accompanying symptoms include fever and headache. However, up to 16% of patients never develop a rash. In the absence of this rash, many people think they had a virus and do not seek treatment. (Steere 2003)

Lyme disease has three distinct phases:

  1. Early localized infection. This is the initial presentation of viral type symptoms, like headache, soreness, fever, tiredness, and often the Bull’s eye rash. At this point, the infection is in the skin where the tick bite occurred. (Auwaerter 2004)
  2. Early disseminated infection. This is when the bacteria enter the bloodstream and spread. The EM rash may occur in places other than the site of the bite. In Europe, patients may develop borrelial lymphocytomas, which are darkly colored bumps. This symptom is specific to the European species of Borrelia. Neurologic problems affect 10-15% of patients in this stage. It can cause meningitis, facial palsy, memory loss, shooting pains, psychiatric changes and sleep disturbances. Some patients may also experience cardiac problems such as atrioventricular block (AV block.) (Stanek 2012)
  3. Late disseminated infection. Untreated or undertreated patients can progress to this stage after several months. About 5% of untreated patients develop chronc neurologic problems, including polyneuropathy and Lyme encephalopathy. (Seltzer 2000) Encephalomyelitis can cause cognitive impairment, weakness in the legs, difficulty walking and balance disturbances, among other things. Psychosis, panic attacks and anxiety can all occur. Lyme arthritis can occur, usually in the knees, but sometimes elsewhere. (Puius 2008)

Early localized or early disseminated infection (without neurologic or cardiac symptoms) is treated with short courses of antibiotics: doxycycline 100mg twice daily; or amoxicillin 500mg three times a day; or cefuroxime axetil 500mg twice daily, for 14 days. In the presence of neurologic symptoms of early disseminated disease, the recommended treatment is ceftriaxone 2gm daily IV for 14 days; or cefotaxine 2gm IV every 8 hours, or penicillin G 18-24 million units per day, in divided doses every 4 hours, for 14 days; or oral doxycycline 200-400 mg daily in 2 divided doses for 10-28 days. These recommendations are for adults. Patients with cardiac issues secondary to Lyme should be treated with either oral or IV antibiotics for 14 days while hospitalized. Ceftriaxone is usually used for this purpose. (Wormser 2006)

In late disseminated infection, Lyme arthritis can be treated successfully with doxycycline, amoxicillin or cefuroxime axetil as detailed above. Adults with arthritis and evidence of neurologic disease should receive IV ceftriaxone for 2-4 weeks. If joint swelling recurs, retreatment for 4 weeks of oral antibiotics or 2 weeks of IV antibiotics is recommended. Late neurologic disease can be treated with IV ceftriaxone for 2-4 weeks. Existing inflammation may take some time to wane and response to treatment may be slow. (Wormser 2006)

About 10-20% of patients treated for Lyme disease with 2-4 weeks of antibiotics continue to have fatigue and joint/muscle pain for some time after treatment is completed. These ongoing symptoms can last upwards of six months and indeed can last for years. This is termed Post-Treatment Lyme Disease Syndrome (PTLDS) and the exact reason for this is unknown. Many people also refer to this as “chronic Lyme disease.” (Aucott 2012) We are going to go through the competing theories on “chronic Lyme” and the evidence presented for both sides in the upcoming posts.



John N Aucott, Ari Seifter and Alison W Rebman.  Probable late lyme disease: a variant manifestation or untreated Borellia burgdorferi infection.  BMC Infectious Diseases 2012, 12:173.

Wormser, Gary P. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis. (2006) 43 (9): 1089-1134.

Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED (February 2000). “Long-term outcomes of persons with Lyme disease”. JAMA 283 (5): 609–16.

Puius YA, Kalish RA (June 2008). “Lyme arthritis: pathogenesis, clinical presentation, and management”. Infect. Dis. Clin. North Am. 22 (2): 289–300, vi–vii.

Auwaerter PG, Aucott J, Dumler JS (January 2004). “Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment”. Expert Rev Mol Med 6 (2): 1–22.

Stanek G, Wormser GP, Gray J, Strle F (February 2012). “Lyme borreliosis”. Lancet 379 (9814): 461–73.

Tugwell P, Dennis DT, Weinstein A, Wells G, Shea B, Nichol G, Hayward R, Lightfoot R, Baker P, Steere AC: Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997, 127(12):1109-1123.

Steere AC, Dhar A, Hernandez J, Fischer PA, Sikand VK, Schoen RT, Nowakowski J, McHugh G, Persing DH: Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease. Am J Med 2003, 114(1):58-62.

Centers for Disease Control. Lyme disease data, 2010.