Chronic Lyme Disease: The Controversies and the Science

Paul M Lantos

Disclosures

Expert Rev Anti Infect Ther. 2011;9(7):787-797. 

In This Article

Post-lyme Disease Syndromes

The designation 'post-Lyme disease syndromes' has been proposed to describe patients who experience prolonged subjective symptoms following Lyme disease.[26] It is more properly thought of as a means of categorizing this patient cohort, rather than describing a clinical diagnosis. The case definition of post-Lyme disease syndromes differs from 'chronic Lyme disease' chiefly in its requirements that patients have: unequivocal documentation of appropriately-treated Lyme disease; and persistent subjective symptoms that cannot be explained by other medical illnesses (Box 3). The definition contains abundant exclusion criteria. In particular, this concept must be distinguished from treatment failure – for instance, persistence, relapse or development of objective signs of disease as occasionally happens in the treatment of Lyme disease.

The most common complaints among patients with post-Lyme disease syndromes are arthralgias, myalgias, headache, neck and backache, fatigue, irritability and cognitive dysfunction (particularly perceived difficulty with memory and concentration). While some patients have objective cognitive deficits, many who subjectively complain of cognitive dysfunction are found to be normal when formally tested.[3,7,61–65] The attribution of these symptoms to Lyme disease is complicated by their extraordinarily high background rate in the population at large, and in fact their frequency might be no greater than that expected by chance alone. Up to 20% of the general population experiences chronic fatigue.[66,67] In one survey using three different assessment instruments, 3.75–12.1% of the general population suffered severe pain and 36.4–45.1% moderate pain; in fact, only 42.5–59.1% of the general population was pain-free.[68] In a separate study 11.2% of respondents suffered chronic, widespread pain.[69] A quarter to a third of the general population describe chronic cognitive dysfunction.[68] These symptoms often coincide with anxiety or depression, which in turn affected 25% of subjects in this study.

The rarity of post-Lyme disease syndromes is exemplified by the great difficulty three investigative teams had in recruiting subjects for clinical trials investigating this condition.[2,4,5] Of 5846 patients screened over several years, only 222 (3.8%) could ultimately be randomized, a striking finding given that most of the 20,000 annual cases of Lyme disease occur in the region where these studies are conducted. The dominant reason for this is that very few of the screened patients had documentation of prior Lyme disease. This suggests that the attribution of chronic symptoms to Lyme disease is grossly out of proportion to its actual occurrence.

Interestingly, in most longitudinal studies of Lyme disease, the prevalence of chronic post-treatment symptoms is no higher than their prevalence in the population at large. From the many trials that distinguish treatment failures from syndromes with only subjective complaints, the following themes emerge: residual symptoms are common in the first weeks after therapy in persons who have no objective evidence of treatment failure; symptoms persisting many months or years are uncommon; and disabling symptoms lasting months or years are extremely rare. In ten prospective studies of erythema migrans and early disseminated Lyme disease, fewer than 10% of subjects described persistent symptoms such as myalgias and fatigue after 9 or more months (range 0–23%), and the prevalence of severe symptoms was 0–2.8%.[65,70–78] One recently published trial found that after 12 months, patients treated for erythema migrans were no more likely to have subjective symptoms than an uninfected control group.[70]

Objective clinical residua are well known to follow antibiotic therapy for confirmed Lyme disease. Facial nerve palsy and other objective neurologic defects may persist for months in patients treated for acute neurologic Lyme disease, exceeding 20% in some studies. Less than 1%, however, go on to have chronic fatigue, nonspecific pain or other symptom complexes compatible with the post-Lyme disease syndromes.[79–87] Approximately 10% of patients treated for Lyme arthritis go on to have a unique syndrome termed 'antibiotic-refractory Lyme arthritis', a persistent sterile synovitis that can last for months to years. This condition, based on factors including antibiotic refractoriness and strong association with HLA-DRB1*0401, appears to be a postinfectious autoimmune phenomenon.[88] Based on lack of evidence of viable B. burgdorferi and unresponsiveness to antibiotics, neither of these phenomena is thought to be an active infection.

Gradual convalescence is observed after many systemic infections. For example, following bacterial pneumonia nonspecific symptoms that impair quality of life can greatly exceed the duration of respiratory symptoms, sometimes by months.[89] It seems unlikely that post-Lyme symptoms are any more common than similar symptoms after other infections.

Biological Plausibility

No adequately controlled, hypothesis-driven study using a repeatable method has demonstrated that viable B. burgdorferi is found in patients with persistent post-Lyme symptoms any more frequently than in those with favorable outcomes. In three clinical trials, comprising more than 150 subjects with strictly-defined post-Lyme disease symptoms, no patient was found to have positive culture or PCR of cerebrospinal fluid.[2,4] However, these studies were unique in that they investigated evidence of persistent B. burgdorferi infection in a prospectively defined group of chronically ill subjects. Other sources of data include case reports and case-series, which however compelling are inherently incapable of testing a hypothesis. Advocates of chronic Lyme disease contend that our ability to detect the organism is hampered by current technology and an incomplete scientific understanding of B. burgdorferi, and that conventional diagnostic testing misses patients with chronic Lyme disease.[90,91] However, this begs the question of on what microbiologic basis we assume that chronic B. burgdorferi infection exists at all.

Studies meant to support the etiologic role of B. burgdorferi in chronic symptom complexes have, at times, relied on investigational testing methods. This has included the use of novel culture media, detection of B. burgdorferi DNA in urine specimens and enumeration of CD57-positive lymphocytes.[92–95] Subsequent investigations, however, have discredited the reliability of these initial reports and cast doubt more generally on their utility as diagnostic tests.[96–99] Other arguments, meant to illustrate the plausibility that B. burgdorferi can persist following antibiotic therapy, have noted the detection of the organism by xenodiagnosis, culture or PCR.[100–104] However, these reports are at best circumstantial, in that they have only been performed in patients with early Lyme disease, Lyme arthritis and in laboratory animals – never in patients with a putative diagnosis of chronic Lyme disease. Furthermore, the complete eradication of microorganisms is, only in rare cases, a measure of treatment success; rather, clinical end points are what usually guide anti-infective therapy. Morphologic variants of B. burgdorferi, variably known as 'cyst forms', 'spheroplasts' or 'cell wall-deficient forms' have not been isolated from patients with post-Lyme disease.[105–109] Despite their frequent mention as the underlying cause of chronic Lyme disease, their actual role remains purely hypothetical. As these forms have been most often observed in antibiotic-treated specimens or in ex vivo conditions, it is possible that they represent sick or stressed microorganisms. Their virulence has not been established.

Risk Factors for Post-lyme Disease Syndromes

As there is a lack of evidence that post-Lyme disease patients remain infected with B. burgdorferi, it is perhaps not surprising that the duration of initial antibiotic therapy does not influence the persistence of subjective symptoms. A prospective trial of therapy for 180 patients with early Lyme disease found that after 30 months, neuropsychologic deficits were equally common among patients treated for 10 versus 20 days.[77] In a retrospective study of 607 patients treated for early Lyme disease, 99 ± 0.2% of patients were well after 2 years of follow-up, regardless of whether they had received less than 10, 11–14 or greater than 14 days of therapy.[110] In a randomized, open-label trial of therapy for late Lyme disease, patients treated for 14 days were no more likely to have severe symptoms than those treated for 28 days – despite the fact that objective treatment failures were significantly more likely in the 14-day arm.[111] Lengthy courses of antibiotics, meant to prevent the development of persistent symptoms, are no more effective than conventional courses. Following 3 weeks of parenteral ceftriaxione, an additional 100 days of oral amoxicillin was no better than placebo at improving cognitive and somatic outcomes.[112]

Since the earliest treatment trials of Lyme disease, the factor that has most consistently predicted persistence of symptoms is their severity before initiation of therapy.[113–115] Severe headache, arthritis, arthralgias and fatigue at presentation predicted persistent symptoms in a retrospectively examined cohort of 215 patients.[116] In a prospective treatment trial for early Lyme disease, persistent symptoms at several late follow-up visits (6 months through 5 years) were more common in patients who had more symptoms, higher symptom scores and multiple (versus solitary) erythema migrans lesions.[75] Patients with a longer duration of symptoms may also be at higher risk of persistent symptoms: a review of 38 subjects who had been previously treated for Lyme disease found that persistent somatic and neuropsychological sequelae were strongly associated with prolonged illness prior to treatment.[7]

Extended Antibiotics for the Treatment of Post-lyme Disease Syndromes

To date, three research groups have prospectively examined the utility of prolonged antibiotics in treating post-Lyme disease syndromes.[2–5] All trials had strict entrance criteria, requiring that enrollees have firm documentation of prior Lyme disease and receipt of appropriate antibiotic therapy, followed within 6 months by persistent symptoms. The first study, published in 2001 by Klempner et al., reported two parallel trials in which their cohort of 129 study patients was divided into seropositive (n = 78) and seronegative (n = 51) arms.[4] Patients randomized to treatment groups received 30 days of intravenous (iv.) ceftriaxone followed by 60 days of oral doxycycline. Patients randomized to the placebo arm received a placebo iv. infusion for 30 days, followed by an oral placebo for 60 days. The primary outcome of interest was health-related quality of life as assessed by standardized instruments (the Medical Outcomes Study 36-item Short-Form General Health Survey [SF-36] and the Fibromyalgia Impact Questionnaire). These instruments were administered at baseline, then 30, 90 and 180 days. There was no significant difference in any outcome measure between placebo and treatment groups in either the seropositive or seronegative arm. In a separate publication, the same team of investigators reported the performance of this study cohort on a detailed battery of neuropsychological tests, which included measurements of cognitive function, somatic symptoms and mood.[3] Although all patients complained of cognitive dysfunction at baseline (and the primary complaint in more than 70%), objective measures of cognitive function, such as memory and attention, were normal compared with age-referenced normative data. Depression, anxiety and somatic complaints improved in all groups between baseline and day 180, but there was no difference between the treatment and placebo groups.

In a separate trial, Krupp and colleagues evaluated 28 days of parenteral ceftriaxone (n = 28) versus iv. placebo (n = 24) in a cohort of patients with persistent fatigue following treated Lyme disease.[5] The primary outcome measure was score on the Fatigue Severity Scale (FSS-11). Additional outcomes were visual analogue scales (VAS) of fatigue and pain, the SF-36 and the Center for Epidemiologic Studies Depression Scale, and a comprehensive battery of cognitive function. Outcomes were measured at baseline and at 6 months. Baseline fatigue was severe. At follow-up, there was a statistically significant but partial improvement on the FSS-11 in the ceftriaxone arm compared with placebo, with 18/26 (69%) versus 5/22 (23%) showing improvement from baseline. The fatigue VAS, although not statistically significant, corroborated a benefit for the treatment arm (p = 0.08). No measure of mood or cognitive function differed at 6 month follow-up. It was noted that a much higher proportion of patients on ceftriaxone correctly guessed their treatment assignment. Whether this was a failure of masking or rather a placebo effect (i.e., the majority in both groups believed they were on active therapy), and whether this would have affected the outcome of a subjective measure like fatigue, is difficult to discern. The commonality and nonspecificity of fatigue, and the observation that antibiotics may improve chronic fatigue in noninfectious or other postinfectious illnesses, raise doubts as to whether it was the elimination of B. burgdorferi that resulted in this outcome.[117–119]

The efficacy of more prolonged parenteral therapy was investigated by Fallon et al..[2] In this cohort, 23 patients were randomized to receive iv. ceftriaxone and 14 patients to receive iv. placebo for 10 weeks, followed by 14 weeks of observation off of therapy. Six domains of cognitive function were tested and compiled to produce a composite 'cognitive index' score. The primary outcome of interest was cognitive index compared with baseline and between groups at week 24. An interim evaluation at week 12 demonstrated significant improvement over baseline in the ceftriaxone group (p < 0.01), whereas this was not the case for the placebo group. A between-group comparison approached statistical significance (p = 0.053) at week 12 also. At week 24, however, these differences had disappeared: both groups had significantly and equally improved over their within-group baseline, and there was no difference between groups (p = 0.76). Three ceftriaxone and two placebo patients (13.5% of the randomized subjects) withdrew from the trial due to adverse events related to either the iv. catheter or the drug, leaving only 20 drug and 12 placebo patients available for statistical analysis. An additional four ceftriaxone patients remained in the study despite adverse events that truncated their therapy. The patients who dropped out were not analyzed by intention to treat, which, given the small sample size in this trial, might have affected the published statistics.

Adverse events, in fact, abounded in these studies, particularly catheter-associated venous thromboembolism, catheter-associated septicemia, allergic reactions and ceftriaxone-induced gallbladder toxicity. In the Klempner et al. trial, one patient on ceftriaxone suffered a pulmonary embolism and one experienced a syndrome of fever, anemia and gastrointestinal bleeding that was thought to be an allergic phenomenon.[3,4] In the Krupp et al. trial, three patients on iv. placebo developed line sepsis, and one patient on ceftriaxone had an anaphylactic reaction.[5] In the Fallon et al. trial, six patients on ceftriaxone had adverse events: two venous thromboembolic events, three allergic reactions and one case of ceftriaxone-induced cholecystitis (treated with cholecystectomy), in addition to a placebo patient who developed line sepsis.[2]

Other studies reiterate the frequency of adverse events in persons with prolonged exposure to intravenous catheters and antibiotics. In an observational study by Stricker et al., there were 19 potentially life-threatening adverse events among 200 patients on long term iv. antibiotics for the treatment of chronic Lyme disease.[120] These included four cases of venous thrombosis, six cases of suspected line sepsis, seven patients with allergic reactions and two patients who developed ceftriaxone-induced gallbladder disease (both cases managed with cholecystectomy). The mean duration of antibiotic therapy in this cohort was 118 days, and the adverse events reported occurred after a mean of 81 days from initiation of therapy. This rate of severe adverse events – nearly 10% of subjects – is exceeded only by the Fallon et al. trial (24%).[2] The duration of exposure to central venous access devices and iv. drug therapy in these two studies differentiate them from the Klempner et al. and Krupp et al. studies, and this almost certainly explains the high rate of adverse events. While no deaths occurred in these studies, there have indeed been documented fatalities and near-fatalities due to prolonged iv. antibiotic therapy for putative Lyme disease.[121–123]

While controlled data demonstrate that prolonged antibiotics are unlikely to be helpful, the critical judgment is whether they are worth the risk. The prospective clinical trials, which were designed to address questions of efficacy, speak much more clearly to the risk of toxicity. Without a doubt there is a significant risk to patients who are on months of iv. antibiotics. Given the risks, it is impossible to argue that prolonged iv. antibiotics are ethically justified for patients with post-Lyme disease syndromes. These same risks naturally apply to other situations in medicine in which prolonged antibiotic therapy is required. The risk/benefit calculus is quite different, though, for infections such as osteomyelitis or endocarditis when the therapy is demonstrably limb-saving or life saving.

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