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.

 

References:

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).