Chronic Lyme disease, post-Lyme disease syndrome and insights from the pathophysiology of sepsis

Chronic Lyme disease, now correctly termed post-Lyme disease syndrome (PLDS), has challenges and confuses practitioners and patients unfamiliar with the potential autoimmune sequelae of infection. Interestingly, a paper just published in the New England Journal of Medicine on the emerging understanding of the pathophysiology of sepsis offers insights into the mechanisms of post-Lyme disease syndrome 'aka' chronic Lyme disease:

"With the confirmation of germ theory by Semmelweis, Pasteur, and others, sepsis was recast as a systemic infection, often described as “blood poisoning,” and assumed to be the result of the host's invasion by pathogenic organisms that then spread in the bloodstream. However, with the advent of modern antibiotics, germ theory did not fully explain the pathogenesis of sepsis: many patients with sepsis died despite successful eradication of the inciting pathogen. Thus, researchers suggested that it was the host, not the germ, that drove the pathogenesis of sepsis...In 1992, an international consensus panel defined sepsis as a systemic inflammatory response to infection, noting that sepsis could arise in response to multiple infectious causes and that septicemia was neither a necessary condition nor a helpful term."

Before continuing with pertinent points presented in the NEJM paper, it's of interest to consider a brief review of the literature on chronic Lyme disease/PLDS.Regarding tests and treatment for Lyme disease, the authors of a paper published recently in American Family Physician note:

"The CDC and IDSA recommend serology as the preferred initial diagnostic test. Currently, the CDC recommends a two-tier protocol using an enzyme-linked immunosorbent assay initially, followed by the more specific Western blot to confirm the diagnosis when the assay samples are positive or equivocal. The accuracy of a two-tier protocol in an endemic area was recently demonstrated; however, the study may have overestimated the accuracy of this approach because of its case-control design...Polymerase chain reaction testing has the highest sensitivity for Lyme disease in synovial fluid samples from patients with untreated late Lyme arthritis. The IDSA recommends polymerase chain reaction testing as an option for selected patients with late Lyme arthritis or neurologic Lyme disease, but prefers testing for the presence of intrathecal antibody production with cerebrospinal fluid samples. The Lyme urine antigen test has a high false-positive rate and is generally not recommended."

Moreover...

"Physicians should understand reasons for false-positive and false-negative results with serology and the limitations inherent in this testing that often lead to an erroneous diagnosis and unnecessary antimicrobial treatment. Immunoglobulin M (IgM) and IgG produced in response to B. burgdorferi may persist for years following standard antimicrobial therapy; these persistently elevated levels are not an indication of ineffective treatment or chronic infection."

Regarding treatment...

"Some persons have advocated use of the term chronic Lyme disease to describe the persistence of nonspecific signs and symptoms in patients with or without clinical or laboratory evidence of Lyme disease. These advocates suggest that patients with the so-called post–Lyme disease syndrome (category 4) or antibiotic-refractory arthritis have a latent intracellular infection that may require months to years of antibiotic therapy for eradication. Critics of this position propose that the continued symptoms can be explained by an autoimmune response that is triggered by an association between Lyme disease and certain human leukocyte antigen haplotypes. Although controversy exists regarding post–Lyme disease syndrome and chronic Lyme disease treatment, four randomized clinical trials found no evidence that prolonged antibiotic therapy is of benefit. Therefore, the American Academy of Pediatrics, American Academy of Neurology, American College of Rheumatology, and IDSA do not recommend prolonged antibiotic therapy."

They review guidelines for tick removal and the use of doxycylcine:

"Removal of ticks within 24 hours of attachment can usually prevent acquisition of Lyme disease. Fine-tipped forceps are generally recommended for tick removal, with care taken to grasp the tick as close to the skin as possible without compressing the body. For engorged ticks or ticks that have been presumed to be attached for 36 hours or longer, antimicrobial prophylaxis with a single 200-mg dose of doxycycline is recommended for adults if it can be given within 72 hours of tick removal and there is at least a 20 percent rate of tick infection with B. burgdorferi in the area (e.g., any location within the top 12 endemic states). Children eight years or older also may be given a single dose of 4 mg per kg of doxycycline (maximal dose of 200 mg) for prophylaxis."

The authors conclude:

"Doxycycline is often the preferred agent for oral treatment because of its activity against other tick-borne illnesses. Preventive measures include avoiding areas with high tick burdens, wearing protective clothing, using tick repellants (e.g., diethyltoluamide [DEET]), performing frequent body checks and bathing following outdoor activities, and instituting environmental landscape modifications (e.g., grass mowing, deer exclusion fencing) to reduce the tick burden. Although there is controversy regarding treatment of post–Lyme disease syndrome and chronic Lyme disease, there is no biologic or clinical trial evidence indicating that prolonged antibiotic therapy is of benefit."

The ineffectiveness of prolonged antimicrobial therapy for PLDS is echoed in a paper published in Expert Review of Anti-Infective Therapy:

"The diagnosis of chronic Lyme disease has been embroiled in controversy for many years. This is exacerbated by the lack of a clinical or microbiologic definition, and the commonality of chronic symptoms in the general population. An accumulating body of evidence suggests that Lyme disease is the appropriate diagnosis for only a minority of patients in whom it is suspected. In prospective studies of Lyme disease, very few patients go on to have a chronic syndrome dominated by subjective complaints. There is no systematic evidence that Borrelia burgdorferi, the etiology of Lyme disease, can be identified in patients with chronic symptoms following treated Lyme disease. Multiple prospective trials have revealed that prolonged courses of antibiotics neither prevent nor alleviate such post-Lyme syndromes. Extended courses of intravenous antibiotics have resulted in severe adverse events, which in light of their lack of efficacy, make them contraindicated."

The author of a paper published in Clinical Infectious Diseases expands on these points:

"Antibiotics such as doxycycline or amoxicillin are effective therapy for the majority of patients with early Lyme disease, with courses of 10–21 days. Parenteral drug therapy (most commonly ceftriaxone) is reserved for involvement of the CNS, for symptomatic cardiac involvement, or in late Lyme disease, such as in cases of oral antibiotic—refractory chronic Lyme arthritis...the contested stage is rather confusingly populated by cases that some persons label “chronic Lyme disease”. A small set of practitioners have advanced the notion that patients with chronic, subjective symptoms, such as fatigue, musculoskeletal aches, and neurocognitive symptoms, have ever-present infection with B. burgdorferi that requires treatment, with months to years of antibiotics often prescribed in combination or by parenteral administration. Although a small minority of patients with bona fide Lyme disease have persisting, subjective symptoms despite receipt of antibiotic treatment, realistic evidence that active infection accounts for this adverse outcome is lacking."

Regarding the term post-Lyme disease syndrome:

"Because use of the term “chronic Lyme disease” by some groups has blurred the exact role played by B. burgdorferi, an alternative description, “post—Lyme disease syndrome”, has been advocated to better separate patients who have resolution of objective symptoms of infection yet continue with these subjective complaints for many months or even years...The proposed definition of post–Lyme disease syndrome includes Lyme disease as defined by Centers for Disease Control and Prevention criteria; conclusion of an appropriate course of antibiotics, with resolution or stabilization of objective manifestation(s) of Lyme disease; presence of symptoms (such as fatigue, widespread musculoskeletal pain, cognitive problems, and substantial reduction in functional activities) <6 months after Lyme disease diagnosis, while excluding patients with documented coinfections, such as Babesia or Ehrlichia coinfection; presence of objective evidence of active Lyme disease; or presence of preexisting conditions, such as fibromyalgia or chronic fatigue syndrome, or an underlying condition that can simulate the symptom complex of Lyme disease (e.g., thyroid disease, psychiatric conditions, and anemia.)"

Unskilled diagnosis confounds the issue:

"...many patients who are told that they have Lyme disease may not have this diagnosis. For example, 788 patients presenting to a tertiary care center with the complaint of Lyme disease found that 57% did not have Lyme disease but, rather, a symptom complex better explained by fibromyalgia or chronic fatigue syndrome, whereas 20% were found to have prior Lyme disease without need for additional antibiotics. Some patients are told they have chronic Lyme disease based on unexplained symptoms without objective or valid laboratory evidence of infection. Moreover, other patients are advised improperly they have Lyme disease based on Lyme IgM western blot assays which should not be relied on for diagnosis of vague chronic symptoms because of high rates of false-positive results. Others are investigated using certain unvalidated assays, such as the Lyme urine antigen..."

This is further confused by historical tendencies:

"...background problems in the population make interpretation of any subjective symptoms complex difficult, whether the symptoms are due to Lyme disease or to another disorder. In part, this is also why there have been long-standing directives not to perform Lyme diagnostic testing for subjects with only subjective complaints—because of the high potential for false-positive results...Finally, use of the “chronic Lyme disease” tag for some patients, especially when there has been a questionable diagnosis of B. burgdorferi infection, could be seen as a labeling of a functional syndrome that medical science cannot easily explain or solve [but can be in many cases]. Over the years, other attempted explanations for the etiology of chronic fatigue and other subjective complaints have included Epstein-Barr virus infection, chronic candidiasis, and even immunization. Use of a medical definition such as “chronic Lyme disease” for these problems can be self-perpetuating, as it can reinforce symptoms."

Furthermore, the persistence of Borrelia burgdorferi after appropriate antimicrobial therapy is biologically implausible:

"Studies designed to investigate prospectively whether B. burgdorferi can be recovered after antibiotic therapy have found evidence of the organism neither by skin biopsy culture in the area of prior erythema migrans nor by culture or PCR evidence with multiple samplings of plasma or CSF, in the largest study of patients with post–Lyme disease symptoms. Other studies said to show such persistent evidence of B. burgdorferi suffer from inability to replicate findings, inappropriate specimen testing, use of unvalidated tests, or inability to exclude reinfection or test contamination. Suggestions that B. burgdorferi can survive despite antibiotic therapy by adopting a cystic form has only been seen in certain in vitro conditions and is unproven in humans. Another hypothesis—that B. burgdorferi becomes latent during an intracellular phase of infection—remains without solid proof and stands in counterpoint to its known extracellular lifestyle."

To put this in a wider biomedical perspective:

"From a general perspective, no other spirochetal disorders appear to require long-term therapy for successful treatment, including tertiary syphilis or neurosyphilis. Both conditions respond to 2-week courses of parenteral penicillin therapy, with objective measures in cases of relapse. Description of antibiotic resistance in B. burgdorferi has not yet been documented in vitro or as evidence for treatment failure. For other infectious diseases that require long-term therapy—for example, tuberculosis or chronic Q fever—recommendations have evolved, because shorter-course therapy yields insufficient resolution and leads to objective relapse of infection. The rationale to use antibiotics in these scenarios is buttressed by supportive evidence, such as results of culture, serologic testing, or other quantitative measurements, in contradistinction to patients who experience posttreatment symptoms of Lyme disease."

As is well-known to clinicians expert in case management of autoimmunity...

"Postinfectious fatigue syndromes are not unique to Lyme disease, and at least with our current understanding, they are defined by the lack of evident active infection."

The author concludes:

"Protracted courses of antibiotics for post–Lyme disease syndrome do not result in the kind of efficacious benefit normally associated with the resolution of infection, and they may be injurious, with complications related to catheters, biliary disease, Clostridium difficile infection, and promotion of antibiotic resistance."

A paper published in the European Journal of Neurology reports specifically on European Federation of Neurological Societies guidelines for managing neuroborreliosis:

"The following three criteria should be fulfilled for definite LNB, and two of them for possible LNB: (i) neurological symptoms; (ii) cerebrospinal fluid (CSF) pleocytosis; (iii) Bb-specific antibodies produced intrathecally. PCR and CSF culture may be corroborative if symptom duration is <6 weeks, when Bb antibodies may be absent....There is also not enough evidence to recommend the following tests for diagnostic purposes: microscope-based assays, chemokine CXCL13, antigen detection, immune complexes, lymphocyte transformation test, cyst formation, lymphocyte markers. Adult patients with definite or possible acute LNB (symptom duration <6 months) should be offered a single 14-day course of antibiotic treatment. Oral doxycycline (200 mg daily) and intravenous (IV) ceftriaxone (2 g daily) are equally effective in patients with symptoms confined to the peripheral nervous system, including meningitis (level A). Patients with CNS manifestations should be treated with IV ceftriaxone (2 g daily) for 14 days and late LNB (symptom duration >6 months) for 3 weeks (good practice points). Children should be treated as adults, except that doxycycline is contraindicated under 8 years of age (nine in some countries). If symptoms persist for more than 6 months after standard treatment, the condition is often termed post-Lyme disease syndrome (PLDS). Antibiotic therapy has no impact on PLDS (level A)."

This perspective is supported by the authors of a paper published in the International Journal of Medical Microbiology:

"The diagnostic criteria of active neuroborreliosis include inflammatory changes of the cerebrospinal fluid (CSF) and an elevated specific Borrelia CSF-to-serum antibody index, indicating intrathecal Borrelia antibody production...The measurement of serum and CSF antibodies is not suitable for follow-up, because they frequently persist. Post-Lyme disease (PLD) syndrome is characterized by persistent complaints and symptoms after previous treatment for Lyme borreliosis, e.g., musculoskeletal or radicular pain, dysaesthesia, and neurocognitive symptoms that are often associated with fatigue...Recent controlled studies do not support the use of additional antibiotics in these patients, but recommend primarily symptomatic strategies."

The authors of a paper published in Current Opinion in Rheumatology weigh in with similar observations pertaining to Lyme disease and arthritis, and bring up the extremely important element of autoimmunity:

"In the United States, intermittent or chronic mono- or oligoarthritis, particularly affecting the knee, is the most common manifestation of late Lyme disease (LD)...Virtually all untreated patients with LA have high levels of serum immunoglobulin G antibodies, and sometimes low levels of immunoglobulin M antibodies, to Borrelia burgdorferi (Bb) by ELISA and Western blot. These responses may persist for many years after antibiotic treatment, and therefore, serologic results do not accurately distinguish between active or past infection. Most patients with LA respond well to standard courses of antibiotic treatment, but a small percentage have persistent knee synovitis, in some cases possibly related to the triggering of intrasynovial autoimmunity. Other patients develop a syndrome of diffuse arthralgia, myalgia, fatigue, and subjective cognitive difficulty during or soon after LD, which persists despite antibiotic treatment. Patients with this post-treatment, post-LD syndrome were recently studied in a placebo-controlled double-blind antibiotic trial. There was no evidence of Borrelial infection in these patients by culture or detection of Bb DNA in blood or spinal fluid. Furthermore, there was no difference in responsiveness of these patients to a 3-month course of antibiotic compared with placebo treatment. Thus, LA caused by active Bb infection, post-treatment LA with persistent knee synovitis and post-LD syndrome are distinct and distinguishable clinical entities."

The authors of an article in Acta Neurological Scandinvavica also agree that prolonged antibiotic therapy is not indicated in the treatment of supposed chronic Lyme disease:

"Strict guidelines should be applied in diagnostics of chronic Lyme, and several differential diagnoses, including neurological disease, rheumatologic disease, post-Lyme disease syndrome, chronic fatigue syndrome, and psychiatric disease, should be considered in the diagnostic workup...Combination antimicrobial therapy or antibiotic courses longer than 4 weeks are not recommended. Patients who attribute their symptoms to chronic Lyme on doubtful basis should be offered a thorough and systematic diagnostic approach, and an open and respectful dialogue."

The foregoing observations correspond with a study also published in the European Journal of Neurology in which the authors thoroughly examined 29 patients who attributed their complaints to chronic Lyme disease:

"We found no evidence of ongoing Borrelia burgdorferi (Bb) infection in any of the 29 included patients using current diagnostic guidelines and an extended array of tests. Eight (28%) had other well-defined illnesses. Twenty-one (72%) had symptoms of unknown cause, of those six met the suggested criteria for post-Lyme disease syndrome. Fourteen (48%) had presence of anti-Bb antibodies...Other well-defined illnesses or sequelae from earlier Lyme disease were probable as main explanatory factor in some cases. The patients were not more depressed, anxious, or hypochondriacal than the normal population, but they had poorer health-related quality of life, more fatigue, and negative expectations about their illness."

Autoimmunity comes up again in a study published in the European Journal of Clinical Microbiology & Infectious Diseases:

"The symptoms of Lyme borreliosis are similar to those of a variety of autoimmune musculoskeletal diseases. Persistence of complaints is frequently interpreted as unsuccessful antibiotic treatment of Borrelia-associated infections. However, such refractory cases are rare, and re-evaluation of differential diagnoses helps to avoid the substantial risk of long-term antibiotic therapy."

They evaluated 86 patients with previous suspected or diagnosed Lyme disease, all but 12 of whom had already received or were undergoing antibiotic treatment:

"Nine percent had ongoing or recent Lyme borreliosis. Twenty-nine percent showed clinical symptoms and radiographic changes compatible with degenerative disorders of the cervical and/or lumbar spine...Seventeen percent had arthropathies related to psoriasis or rheumatoid arthritis. Twelve percent were positive for the HLA B27 antigen [ankylosing spondylitis]. Other diseases were less frequent. Six patients (7%) could not be diagnosed conclusively, and four of these patients had negative Borrelia immunoassay results. In conclusion, Borrelia-associated diseases were rare in this study. Differential diagnoses helped to initiate a successful disease-specific therapeutic strategy."

Some have advanced the notion that 'chronic Lyme disease' might be perpetuated by a deficiency of natural killer cells. A study just published in Clinical and Vaccine Immunology appears to put that assertion to rest:

"It has been reported that patients diagnosed with chronic Lyme disease have a decreased number of natural killer cells, as defined by the CD57 marker, and that the changes in the number of CD57+ cells can be monitored as evidence of response to therapy. CD57 was initially used as a marker for NK cells, but it is not expressed by all NK cells and is also expressed by T-cell subpopulations...Currently, the most common approach for identifying NK cells utilizes a combination of CD56 and CD16 surface markers used together with CD3 to exclude T cells expressing NK markers (NK T cells). The CD57 test is offered in some clinical laboratories and is being used by some health practitioners to evaluate and follow patients diagnosed with chronic Lyme disease. To further evaluate the utility of NK cell numbers in evaluating and/or monitoring this patient group, we performed immunophenotyping in 9 patients with PLDS, 12 individuals who recovered from Lyme disease, and 9 healthy volunteers."

To subtype lymphocyte types the used anti-human monoclonal antibodies against CD3, CD4, CD8, CD20, CD16, CD56, and CD57 markers and found no differences between their PLDS subjects and healthy controls:

"There was no significant difference between the three groups regarding the number of CD3− CD57+ or CD16+ or CD56+ CD3− cells. There was also no difference between the groups regarding the numbers of CD3− CD8+ CD57+, CD3− CD56+ CD57+, and CD3− CD56− CD57+ cells. Very few cells were CD3− CD56− CD57+, and the Spearman rank-order correlation coefficient between CD3− CD57+ and CD3− CD56+ CD57+ cells was 0.98. We conclude that the numbers of NK cells do not differ between patients with PLDS, individuals who have recovered from Lyme disease, and healthy volunteers and that the number of CD57+ non-T (CD3−) cells is not helpful in evaluation or management of these patients."

Regarding the use of PCR (polymerase chain reaction for amplification of Borrelia DNA), a study published in the Annals of Medicine offers evidence that examining for the presence of the pathogen's DNA can help to discriminate between past and present infection. The authors followed 14 out of 136 patients who had persistent Borrelia DNA following their antimicrobial therapy. 13 had a clinical relapse, and nine of these responded to which cleared the PCR. They concluded:

"By using PCR, it is possible to avoid unnecessary retreatment of patients with 'post-Lyme syndrome' and those with 'serological scars' remaining detectable for months or years after infection."

Autoimmunity triggered by infection is an immense topic that has been addressed by earlier posts with likely plenty more to come. But we can appreciate a smattering of the evidence in a study on anti-neural antibodies in patients with symptoms persisting after Lyme treatment published in Brain, Behavior, and Immunity:

"Considering the lack of evidence for the presence of live spirochetes in PLS [post-Lyme syndrome] patients who have received recommended antibiotics, persistent infection is currently not thought to account for the symptoms of PLS by most investigators...Mechanisms other than active infection, including the possibility of involvement of adaptive or innate immune system abnormalities, have been suggested...The aim of this study was to characterize the level and specificity of antibody reactivity to neural antigens in PLS patients...Here, we show evidence of heightened anti-neural antibody levels in PLS, indicating the presence of objective immunologic abnormalities in affected patients that may be relevant to the pathogenic mechanism of the disease."

They examined 83 individuals with a history of Lyme borreliosis and persistent symptoms, along 15 patients with systemic lupus erythematosus (SLE) and 20 healthy individuals for IgG anti-borrelia antibody and anti-neural antibody levels:

"Approximately half of the examined PLS patients had heightened levels of antibodies to neural proteins, compared with 18.5% of post-Lyme healthy subjects and 15% of normal healthy controls. In fact, the heightened antibody response level in PLS was statistically similar to that in SLE, a multisystem autoimmune disease. Immunohistochemical analysis with representative PLS patient sera demonstrated binding of the antibodies to pyramidal neurons in the cerebral cortex and neurons of the DRG, highlighting their relevance in the context of central and peripheral nervous system disease."

The authors conclude:

"In light of the results from the aforementioned clinical trials of antibiotic treatment and the lack of convincing evidence for active infection in PLS, other hypotheses, including a role for involvement of the immune system, have been suggested. If present, immune abnormalities—possibly triggered by the original infection—may offer clues about the disease. Considering the neurologic and psychiatric nature of post-Lyme symptoms, we sought to assess the presence of nervous system-specific antibodies in patients and control subjects...As such, this study points to the presence of a differential immune response in PLS in comparison to healthy individuals...At this juncture, it is logical to assume that further study of immune system response in PLS is likely to yield more clues about the etiopathogenesis of the disease and provide insights that may pave the way for developing safe and effective treatments."

Post-Lyme autoimmunity can also be expressed through antiphospholipid antibodies (aPL) as evidenced in a study published in the journal Lupus:

"Antiphospholipid antibody (aPL) positive patients and patients with purported chronic Lyme disease (‘CLD’) share many clinical features. After identifying significant aPL in sera of several index patients with ‘CLD’, we performed aPL tests on all patients referred in whom ‘CLD’ was suspected, diagnosed or treated."

The authors examined their study cohort of subjects with suspected, diagnosed or treated ‘chronic Lyme disease’ and reportedly ‘positive’ Lyme assays for antiphospholipid antibodies including anticardiolipin antibodies (aCL), anti-beta-2-glycoprotein-1 antibodies (anti-β2GP1) and lupus anticoagulant (LAC). The autoimmune phenomena were clearly apparent:

"One hundred and six patients were evaluated, of whom 82% had neurologic symptoms and 51% rheumatologic symptoms. Eighty-eight of 106 (83%) patients had positive Lyme serologies (enzyme-linked immunosorbent assay [ELISA] 62/106, 58.4%; western blot [WB] 64/106, 60%), while 18/106 (16.9%) were negative or equivocal. aPL was found in all ‘CLD’ categories. aCL and/or anti-β2GP1 were positive in 85/106 (80%), with aCL present in 69/106 (65%) and anti-β2GP1 present in 69/106 (65%). For all assays, IgM isotypes predominated: WB 55/64 (85%), aCL 63/69 (91%), anti-β2GP1 52/69 (75%), aCL and/or anti-β2GP1 74/85 (87%). Anti-β2GP1 assays occurred in higher titer than aCL: 36/69 (52%) versus 63/69 (91%), p<0.001. Seventeen patients had aPL-related events. Only 12/106 (11.3%) had true post-Lyme syndromes (PLS), category IV, or late Lyme disease (LLD). Most patients had been treated for Lyme: 82/106 (79%)."

They conclude:

"aPL occurs frequently in patients with ‘CLD’. IgM anti-β2GP1, IgM aCL and IgM WB were frequently found. Documented PLS or LLD was uncommon."

Gender bias is another feature that PLDS has in common with autoimmune disease. Findings posted here earlier (see report on Sjögren's disease) have indicated that estrogen dominance (elevated estrogen/progesterone ratio) can contribute to immune loss of tissue tolerance. The authors of a study published in the Journal of Women's Health set out to...

"......determine if the population of patients with chronic Lyme disease differs from the populations of patients with either Lyme disease or post-Lyme disease syndrome by examining the gender of patients with these diagnoses."

They examined data for 43,282 patients reported to the CDC with Lyme disease which included 184 designated PLDS and 490 labeled 'chronic Lyme disease' and found a strong gender bias:

"Patients with chronic Lyme disease were significantly more likely to be female than were patients diagnosed with either Lyme disease (odds ratio [OR] 2.42) or with post-Lyme disease syndrome (OR 2.32)."

That's more than double in both cases. Moreover...

"These findings suggest that patients who are labeled as having chronic Lyme disease comprise a different population from patients who are symptomatic because of either current or past infection with B. burgdorferi. The findings are consistent with those of prior investigations in which patients with putative Lyme disease were reevaluated at academic Lyme disease referral centers. Those studies were the first to suggest that large numbers of patients were being inappropriately treated with often prolonged courses of antibiotic therapy for a presumptive infection with B. burgdorferi that they did not actually have."

The authors conclude:

"Patients with chronic Lyme disease differ with regard to gender from those with either B. burgdorferi infection or post-Lyme disease syndrome. This finding suggests that illnesses with a female preponderance, such as fibromyalgia, chronic fatigue syndrome, or depression, may be misdiagnosed as chronic Lyme disease."

What about guidelines for treating a clinically verified Lyme infection? For how many days should doxycycline be taken? A study recently published in Clinical Infectious Diseases suggests that 10 days may be as effective as 15 days. The authors' subjects were patients presenting with erythema migrans (the classic bulls-eye rash).

"In a noninferiority trial, the efficacies of 10 days and 15 days of oral doxycycline therapy were evaluated in adult European patients with erythema migrans. The prevalence of nonspecific symptoms was compared between patients with erythema migrans and 81 control subjects without a history of Lyme borreliosis. The efficacy of treatment, determined on the basis of clinical observations and microbiologic tests, was assessed at 14 days and at 2, 6, and 12 months. Nonspecific symptoms in patients and controls were compared at 6 months after enrollment."

Th outcomes for 10 days of doxycycline were as good as 15 days:

"A total of 117 patients (52%) were treated with doxycycline for 15 days, and 108 (48%) received doxycycline for 10 days. Twelve months after enrollment, 85 of 91 patients (93.4%) in the 15-day group and 79 of 86 (91.9%) in the 10-day group had complete response. At 6 months, the frequency of nonspecific symptoms in the patients was similar to that among controls."

The authors state:

"Antibiotics are used to suppress the microorganisms causing bacterial infectious diseases. However, resolution of clinical symptoms sometimes lags behind bacterial eradication and is not hastened by extending antibiotic treatment. Thus, the persistence of symptoms after treatment should not automatically justify prolongation of antibiotic therapy...In comparison with lengthy treatment, short courses of antibiotics are safer, cheaper, and more convenient and have fewer detrimental ecologic effects. The challenge is to achieve a favorable treatment result with the shortest possible course of antibiotics."

Maintaining the viability of antibiotic therapy in the face of widespread resistance is critically important and its effectiveness must be safeguarded by appropriate use.

"In conclusion, doxycycline treatment for European patients with solitary erythema migrans is highly effective. The efficacy of a 10-day regimen of doxycycline was not inferior to that of the 15-day regimen. Six months after treatment, the frequency of nonspecific symptoms among patients did not exceed that in a control group."

Before returning to the NEJM paper introduced at the beginning of this post, comments published in Transactions of the American Clinical and Climatological Association are worth noting:

"In stark contrast and contrary to evidence in hand, over the last 20 years, a number of healthcare providers (mostly private practitioners), patients, and patient advocacy groups have embraced the concept of chronic Lyme disease as an explanation for long-standing fatigue, musculoskeletal pains, and neurocognitive dysfunction. These individuals attribute such symptoms to persistent B. burgdorferi infection that they believe can only be effectively treated with antimicrobials, often taken in combination for months or years. Why this approach has gained traction and remained forceful within certain sectors of the medical community and the lay public rests on a number of elements that are far from the traditional venues that use grounded scientific evidence and sound clinical judgment."

Furthermore...

"Over-diagnosis of Lyme disease can harm an individual patient in ways that include diagnostic delay and the repercussions of not receiving timely, appropriate care. Further, treatment of non-existent Lyme disease with long-term antibiotics has caused death, Clostridium difficile colitis, and adverse drug reactions, and it may drive the emergence of antibiotic-resistant organisms."

Clinicians experienced in the functional case management of autoimmunity triggered by infection may be very familiar with all of the above. But with this as a background, the NEJM paper referenced at the beginning of this post offers some fresh insights into underlying mechanisms:

"...it has become apparent that infection triggers a much more complex, variable, and prolonged host response, in which both proinflammatory and antiinflammatory mechanisms can contribute to clearance of infection and tissue recovery on the one hand and organ injury and secondary infections on the other. The specific response in any patient depends on the causative pathogen (load and virulence) and the host (genetic characteristics and coexisting illnesses), with differential responses at local, regional, and systemic levels."

Our concern with PLDS and any chronic post-infectious immune dysregulation is a persistent, dysfunctional proinflammatory response due to loss of tolerance, similar to what occurs in severe sepsis:

"In general, proinflammatory reactions (directed at eliminating invading pathogens) are thought to be responsible for collateral tissue damage in severe sepsis...Pathogens activate immune cells through an interaction with pattern-recognition receptors, of which four main classes — toll-like receptors, C-type lectin receptors, retinoic acid inducible gene 1–like receptors, and nucleotide-binding oligomerization domain–like receptors — have been identified, with the last group partially acting in protein complexes called inflammasomes. These receptors recognize structures that are conserved among microbial species, so-called pathogen-associated molecular patterns, resulting in the up-regulation of inflammatory gene transcription and initiation of innate immunity. The same receptors also sense endogenous molecules released from injured cells, so-called damage-associated molecular patterns, or alarmins, such as high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and histones."

Interestingly, this also yields insight into the mechanisms that produce inflammation in osteoarthritis (see earlier posts on the complement-mediated autoimmune component of osteoarthritis/DJD):

"Alarmins are also released during sterile injury such as trauma, giving rise to the concept that the pathogenesis of multiple organ failure in sepsis is not fundamentally different from that in noninfectious critical illness."

Clinical note: The principles of managing autoimmunity, triggered by infection or not, entail discernment of the multiple underlying mechanisms contributing to loss of immune tolerance of self-tissue. This requires resolving the key questions in each case, determining the strategy of objective tests to answer those questions, and organizing the findings into a rational treatment plan. The authors touch on several facets including neuroendocrine regulation and the HPA axis that engage vagal activity and adrenocortical function to inhibit proinflammatory cytokine production; the expansion or regulatory T cells and myeloid suppressor cells; inhibition of proinflammatory gene transcription; antiinflammatory cytokines, soluble cytokine receptors and negative regulation of TLR signaling—these and numerous others must be borne in mind by the clinician managing either sepsis or autoimmunity triggered by Lyme or other infections. Future posts will address relevant topics as new science emerges.

Update: Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease

In a report just released by the CDC (Centers for Disease Control and Prevention( in  Mortality and Morbidity Weekly Report:

The term “chronic Lyme disease” is used by some health care providers as a diagnosis for various constitutional, musculoskeletal, and neuropsychiatric symptoms. Patients with a diagnosis of chronic Lyme disease have been provided a wide range of medications as treatment, including long courses of intravenous (IV) antibiotics. Studies have not shown that such treatments lead to substantial long-term improvement for patients, and they can be harmful. This report describes cases of septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess resulting from treatments for chronic Lyme disease. Patients, clinicians, and public health practitioners should be aware that treatments for chronic Lyme disease can carry serious risks."

Treatments may be rendered that have no evidence of effectiveness.

"Patients given a diagnosis of chronic Lyme disease have been prescribed various treatments for which there is often no evidence of effectiveness, including extended courses of antibiotics (lasting months to years), IV infusions of hydrogen peroxide, immunoglobulin therapy, hyperbaric oxygen therapy, electromagnetic frequency treatments, garlic supplements, colloidal silver, and stem cell transplants. At least five randomized, placebo-controlled studies have shown that prolonged courses of IV antibiotics in particular do not substantially improve long-term outcome for patients with a diagnosis of chronic Lyme disease and can result in serious harm, including death."

Great care should be taken when there is no objective evidence to validate a diagnosis of infection. Importantly, an inappropriate diagnosis diverts the patient from the benefit of a thorough investigation of complex chronic disorders, often involving autoimmune phenomena.

"A diagnosis of chronic Lyme disease might be based solely on clinical judgment and without laboratory evidence of B. burgdorferi infection, objective signs of infection, or a history of possible tick exposure in an area with endemic Lyme disease . There is a belief among persons who support the diagnosis and treatment of chronic Lyme disease that B. burgdorferi can cause disabling symptoms even when standard testing is negative, despite evidence that the recommended two-tiered serologic testing is actually more sensitive the longer B. burgdorferi infection has been present. Some practitioners use tests or testing criteria that have not been validated for the diagnosis of Lyme disease. A significant concern is that after the diagnosis of chronic Lyme disease is made, the actual cause of a patient’s symptoms might remain undiagnosed and untreated."