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To most people, Lyme disease is a risk of life near wooded regions. But not long ago, there was little suspicion that a tick-borne disease could be causing rashes, arthritis, and neurologic conditions. And before the isolation and characterization of the causative spirochete, there was widespread doubt that such a disease complex was real.
Why discuss emerging organisms at a forum on Lyme disease? With such a history, the annual Lyme disease conference has become a platform to discuss other suspected and recognized emerging diseases. Over the course of this 2-day conference, investigators presented recent data on West Nile virus, the various forms of ehrlichiosis, a new strain of Borrelia burgdorferi in Missouri, human co-infection with Bartonella, and an unusual dinoflagellate that is responsible for major fish die-offs and human disease as well.
Detection of the virus was made possible by current DNA technology, which permits the simultaneous display of thousands of nucleic acid sequences through polymerase chain reaction (PCR) amplification techniques. These differential displays allow for recognition of conserved expression patterns, which can be isolated and subjected to further analysis, amplification, and segregation. From these data, a simple, single-stranded RNA flavivirus, distinct from the pathogen causing St. Louis encephalitis but similar to endemic West Nile virus, was identified. At the same time, over 400 cases of West Nile virus were diagnosed in Israel, with 29 fatalities. Both soft and hard-bodied ticks are known vectors for West Nile virus, and many of the bird species that tested positive for West Nile virus are natural hosts for these ticks in the United States. If current trends are predictive, it is likely that West Nile virus will become endemic to North America in the next several years.
Our experience with West Nile virus and its rapid spread throughout the eastern United States suggests that other viruses, as yet undetected and undefined, may also be involved in the pathogenesis of other idiopathic diseases. Regarding encephalitis alone, 50% to 70% of cases in the United States remain idiopathic. As the technology for cloning nucleic acids of pathogens from clinical specimens continues to advance, it is believed that more of these idiopathic entities will be identified.
Dr. Lipkin provided the example of Borna virus, which has been associated with hyperactivity, exaggerated startle responses, and dysfunction in cellular immunity in rat models in the acute setting, and with abnormal stereotypic motion behavior, dyskinesias, dystonia, and CNS lesions affecting dopamine regulation in chronic infection. Behavioral expression in adult rats is markedly different from that observed in infant rats exposed to Borna virus, and unlike chronic adult overexpression of dopamine, an upregulation of 5-hydroxytryptophan is found in the brains of infant rats, particularly in the hippocampus. Intriguing associations that have been ascribed to Borna virus include multiple sclerosis, amyotrophic lateral sclerosis, major depression disorder, bipolar disorder (where this organism has already been identified in select cases), schizophrenia, chronic fatigue syndrome, and panic disorder.
Infectious origins are suspected in other conditions, including pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and Sydenham's chorea. It is hoped that the new technologies currently being used in clinical research will eventually allow investigators to sequence microbial, nutritional, and environmental toxin patterns in order to determine what, if any, effects these and other undefined factors have on individuals at age-specific points in time.
In 1999, West Nile virus was first identified in North America as the cause of severe encephalitis in 62 patients, resulting in 7 fatalities.[4,5] Presenting symptoms included fever, muscle weakness, headaches, photophobia, and myalgias. Eventually, 2.6% of the population of Queens showed serologic evidence of West Nile virus exposure. At the same time, scores of exotic bird deaths were recorded at the Bronx Zoo, and thousands of bird deaths occurred in the surrounding area. An additional 21 cases were reported in the United States in 2000: 14 from New York, 6 from New Jersey, and 1 from Connecticut, with 2 deaths. While mosquitoes in 4 states tested positive for the presence of the virus in 1999, that number had risen to 12 states plus the District of Columbia in 2000. Bird studies have demonstrated that at least 15 bird species are currently affected, and the virus has been found in several mammals, including raccoons, bats, cats, rats, and horses.
Dr. Anderson concurs that the West Nile virus in North America is here to stay. Dr. Anderson also believes that there are viral triggers to a host of diseases, such as multiple sclerosis and autism, waiting to be defined.
Ehrlichia cause disease in both humans and domesticated animals, including dogs, horses, cattle, and deer, according to Dr. Louis Magnarelli, the Vice-Director of the Connecticut Agricultural Experiment Station. Symptoms of human ehrlichiosis include fever, headaches, myalgias, and lethargy. Outbreaks generally occur in the summer, and there is usually no rash. Marked thrombocytopenia and leukopenia are characteristic, and decreases in hemoglobin have also been reported. Most importantly, like its Lyme counterpart, ehrlichiosis is a curable disease when treated with the appropriate antibiotics. Ehrlichia chaffeensis and Ehrlichia phagocytophilia are considered to be human pathogens, although the latter affects horses and cattle as well. The Ixodes scapularis tick of Lyme disease fame serves as the chief vector, although E chaffeensis has been detected in Amblyomma americanum, the lone star tick.
Antibodies to a 44 kD antigen are most commonly seen in human granulocytic ehrlichiosis (HGE), and a recombinant ELISA antigen has been created for diagnostic testing. Both granulocytic and monocytic forms of ehrlichiosis exist, and these entities can be differentiated on Western Blot assay by the presence of the 44 kD band seen in HGE vs 29 kD and 28 kD bands observed in human monocytic ehrlichiosis (HME).
E phagocytophilia, the most prevalent Ehrlichia in Connecticut, is responsible for most HGE, of which there were 420 confirmed cases between 1995 and 2000 and an additional 839 suspected cases. With recent increases in the deer population, an accompanying rise in the tick population has followed, and E chaffeensis has been detected in 7.6% of ehrlichiosis cases in Connecticut and 11.5% of cases in Rhode Island. Because Lyme disease, ehrlichiosis, and babesiosis are all tick-borne diseases, Dr. Magnarelli recommended that any individual suspected of having any one of these diseases be tested for the full northeastern triad. He also attempted to dispel the myth that ehrlichiosis is a mild disease, particularly in those patients who may be infected with concurrent Lyme disease.
Babesiosis appears to have its own midwestern flavor. While Babesia divergens is responsible for the babesiosis seen in Europe, Babesia microti accounts for most cases on Nantucket Island and in the East as well as the upper Midwest. One case of babesiosis in Missouri was reported in which patient serum was strongly reactive by IFA for B divergens with only minimal reactivity to B microti. This "unique" bacteria was named Babesia MO1, although Dr. Masters suspects that B divergens and MO1 are really the same.
Lyme disease in the Midwest also differs from the northeastern version, and has been dubbed Masters' disease (among other names) by local wags. Patients are usually bitten by lone star ticks and often recall the particularly distinctive markings of that tick when describing it to their physicians.[10,11] The view under the microscope usually shows a lymphocytic infiltrate, compared to the plasmacytic infiltrate more characteristic of traditional Lyme disease. The incidence of EM lesions may be greater, and there may be more central clearing in EM lesions. Seropositivity, as defined by CDC guidelines, tends to be lower. Nevertheless, Dr. Masters indicated that "absence of proof IS NOT proof of absence," and so he treats his patients accordingly.
Patients infected with Bartonella first develop a papule, which eventually becomes vesicular and crusting. Regional lymphadenopathy is almost always present, and biopsy usually demonstrates a granuloma, from which the bacteria may be isolated. The incidence of neurologic involvement in a handful of patients -- including neuroretinitis, encephalopathy, radiculopathy, peripheral neuropathy, facial palsy, ataxia, myelopathy (with transverse myelitis), and positive brain biopsy for B henselae in one immunocompromised host -- led her to wonder whether co-infection with B burgdorferi and Bartonella were responsible.
To demonstrate the frequency of both B henselae and B burgdorferi in animals and ticks, Dr. Fein reviewed the medical literature. Studies in domestic cattle, cats, rodents, and deer have shown a bacteremia rate for B henselae ranging from 50% to 95%. Cats are positive for B henselae in 89% of cases, and even fleas test positive 34% of the time. In select cultures of mice, 75% have been positive for B burgdorferi, while 10% have been positive for B henselae. Ticks in The Netherlands have been shown to be positive for B henselae by PCR analysis in 70% of cases, while ticks in California (Ixodes pacificus) have just recently been shown by PCR analysis to carry B henselae in 19% of those tested.
One third of all New Jersey ticks tested have been positive for B henselae. When the backyards of these tick-bitten patients who presented with severe neurologic disease were tested, B henselae was found in the ticks. Most of these patients did not respond to conventional antibiotic treatment, and the case was made in the follow-up question period that patients resistant to treatment for Lyme disease may potentially be infected with Bartonella instead, or co-infected with B burgdorferi and B henselae. An intriguing question...but one that cannot be answered from the data currently available.
Dr. Burkholder started this work in the early 1990s in the North Carolina Albemarle-Pamlico estuary, the second largest estuary in the United States (after Chesapeake Bay), and the most important fishing hatchery in the United States. Beginning with several unexplained mass fish deaths in the 1980s, Pfiesteria was finally identified as the etiologic agent in 1991. The role that nutrient pollutants (farm and human sewage) played in the pathogenesis of these outbreaks was defined in 1992. Pfiesteria's capacity to emit toxins when stimulated by secretions from living fish was also elucidated.
The effects of Pfiesteria on human health were first reported in 1995. Ten individuals working in close proximity to Pfiesteria cultures in laboratory settings contracted symptoms after direct contact with culture water or after inhalation of aerosolized water from tank aeration systems. As described before, symptoms ranged from acute narcosis, eye irritation, respiratory distress, stomach cramps, and vomiting, to chronic skin ulcerations, cognitive impairment, and Alzheimer's-like short-term memory loss. Once contact with Pfiesteria was discontinued, these symptoms reversed over the course of several months, although peripheral nerve dysfunction and immunosuppression tended to linger for years. Anecdotal reports from individuals known to frequent these natural estuaries support these laboratory findings.[16,17]
The process of identifying the specific nature of Pfiesteria's toxic secretions has been slow. Dr. Burkholder states that the delays are largely due to political forces that have sought to deny the existence of a Pfiesteria epidemic. With pressure from the North Carolina tourist and seafood industries, several regional health agents worked to keep this information from public notice. According to Dr. Burkholder, the Centers for Disease Control and Prevention (CDC) launched its own investigative efforts that initially played into the hands of those who opposed public disclosure and directed funding to areas where no Pfiesteria outbreaks had ever been recorded. Eventually, the CDC's review panel received information that supported the findings of Burkholder and associates. Shortly thereafter, in October 2000, the review panel concluded that a health hazard existed. Unfortunately, the CDC specified that further funding would be restricted to the Pamlico estuary, where no Pfiesteria outbreak has occurred in several years. Nevertheless, the CDC's endorsement led to the allocation of $220 million in funding from the US Department of Agriculture (USDA) for elimination of nutrient pollution by North Carolina farmers.
As Dr. Burkholder sees it, economic forces first denied, then sought to bury data that could have a negative impact on the financial well-being of special interests, similar to the early experience with Lyme disease. Only when the scientific community uses its data to support individuals adversely affected by specific disease processes and strengthens its position with the help of public advocacy forums like the Sheridan Group can health policy change come to pass.
As anyone who studies Lyme disease knows all too well, the difficulty is often not how to treat the disease, but how to arrive at the diagnosis. Several speakers examined the current state of diagnostic testing, highlighting what is currently available, what may soon be available, and in 1 case, what might have been available.
Ideally, the identification of the Borrelia burgdorferi organism by culture or nucleic acid sequence recognition by polymerase chain reaction (PCR) would clinch the diagnosis, but these techniques are too insensitive. Consequently, the detection of antibodies against B burgdorferi became the standard basis for screening. The original tests utilized strains of B burgdorferi that were mostly devoid of immunodominant antigen expression, due to processing methods. Nonetheless, an IgM antibody to a 23 kDal antigen known as outer surface protein C (OspC), was found to be highly expressed in early disease, along with a 41 kDal protein. This early IgM antibody response gives way to IgG antibody expression, again for predictable antibodies.
A 2-tiered approach to Lyme disease testing was established by a panel convened by the Centers for Disease Control and Prevention (CDC) in conjunction with the Association of State and Territorial Public Health Laboratory Directors (ASTPHLD/CDC) meeting held in Dearborn, Michigan, in 1994. These criteria defined the levels at which antibody binding constituted a positive ELISA assay (first tier). Criteria for WB (second tier) interpretation were also established at this same meeting, based on work done by Dressler and Engstrom, which required the presence of 2 out of 3 bands detected by IgM antibodies or 5 out of 10 bands detected by IgG antibodies.
This 2-tiered approach can be problematic. There is a great degree of variability in ELISA sensitivity, based on which testing materials are used. In addition, the use of OspA vaccine renders ELISA interpretation useless, and the problem becomes greater as subsequent vaccine boosters are administered. While WB improves both sensitivity and specificity of results, the current blot interpretation criteria rely on B burgdorferi strains other than the B31 commonly used in reference labs. As indicated by Dr. Aguero-Rosenfeld, WB allows for discrimination between infection and administration of OspA vaccine, with an increase in the 31 kDal antibody[6,7]; however, additional boosters can add additional bands, making the WB indecipherable by the third vaccination. The cost of WB assays is generally high, and they are quite labor intensive. Blot reading is also a subjective process, dependent on the interpretive skills of individual technicians. In conclusion, WB assays can be highly sensitive and specific in diagnosing Lyme disease, but can be misused and abused, particularly in the wrong hands.
For these reasons, duPont has relied on its own interpretation of WB results. Any test with only 1 band is deemed nonreactive. Two to three bands that do not include those at 41 kDal, 60 kDal, or 69 kDal are unlikely to be positive. And finally, an antibody to the 41 kDal protein combined with another positive band in the 60- to 70-kDal molecular weight range, with 2 other expressed bands, is approximately 100% positive for Lyme disease. Of course, sensitivity and specificity are increased when WB analysis is reserved for individuals with high probability for having positive Lyme disease serology.
WB analysis is particularly useful in the diagnosis of Lyme re-infection. Whereas antibody expression by ELISA often remains elevated after resolution of disease, the number and/or relative intensity of bands on WB decreases in the convalescent phase. Re-infection is accompanied by an increase in the number and intensity of WB bands, and also correlates with reappearance of EM.
One approach to improving the accuracy of diagnosis, particularly in atypical presentations, is to use a functional antibody assay, known as a borreliacidal antibody test (BAT). Borreliacidal antibodies attach to the pathologic spirochete, which in turn induces complement to form a membrane attack complex that, independent of phagocytosis, can kill the organism. A number of outer surface proteins can initiate this process, including OspA.
The findings of BAT are highly specific for Lyme disease when compared with results from a WB assay, especially among patients with early Lyme disease or patients with a single erythema migrans lesion. The improved specificity for BAT over WB derives from the use of 2 B burgdorferi sensu stricto strains in the borreliacidal assay: isolate 297 expresses OspA and OspB, and isolate 50772 expresses OspC.
According to Dr. Callister, BAT and WB assays were equivalent when used to confirm infection among patients with Lyme arthritis or Bell's palsy ( data to be published shortly). Because OspC expression is expressed in early Lyme disease, while OspA and OspB expression are more commonly seen in disseminated or arthritic Lyme disease, BAT was more sensitive in detecting early Lyme disease than WB. In this way, 11 patients (38%) who tested negative for Lyme disease on WB analysis were positive for disease on BAT. Unblinding revealed that most of these patients had atypical EM lesions in addition to other symptoms consistent with Lyme disease. BAT testing was negative for 14 patients (44%) who tested positive for WB. Again, unblinding these results revealed that these patients did not have clinical histories supportive of a Lyme disease diagnosis. Therefore, WB analysis would have misdiagnosed or failed to diagnose 25 (20%) of 124 patients with atypical symptoms in this study. Furthermore, Dr. Callister stated that BAT is inexpensive, not subject to interpretation of band color or intensity, and is not affected by previous vaccination with OspA (when the 50772 isolate is employed).
An alternative approach is to use an antigen common to all 3 species in an ELISA; this antigen should not cross-react with OspA. Dr. Philipp's group evaluated expression of antibodies to a synthetic peptide called C6, which corresponds to the invariable region (IR6) of the variable surface antigen (VIsE) of B burgdorferi. This peptide was shown to be antigenic in monkeys infected by B burgdorferi strains. IR6 was immunodominantly expressed in humans as well as in dogs. Over a 7-day period, 3 of 7 humans with Lyme disease produced antibodies that reacted with IR6 antigen, while 9 of 10 produced reactive antibodies between 5 and 10 weeks after symptom onset.
Sensitivity in acute-phase Lyme disease was 74%, while 85% and 90% sensitivity rates were recorded in chronic and convalescent phases. Specificity data were also quite impressive, derived from 77 serum samples taken from patients with chronic infections, autoimmune diseases, non-B burgdorferi infections, and neurologic diseases, as well as 99 serum controls from hospitalized patients in nonendemic areas for Lyme disease. Among the combined group of patients, only 2 false positives were identified out of 176 patients (99% specificity). Antibodies generated by vaccination with Bacterin and OspA did not cross-react with C6 in dogs or monkeys studied.
Monitoring of C6 reactivity in monkeys treated for 60 days with doxycycline demonstrated dramatic reductions in anti-C6 antibody responses. Similar reductions were observed in canines following treatment with ceftriaxone. In humans, posttreatment C6 levels correlated with resistance or sensitivity to treatment, depending on whether C6 titers decreased by greater than 4 or less than 4. According to Dr. Philipp, this promising technology is relatively inexpensive and reproducible between reference laboratories. Given its advantages, its efficacy in randomized clinical trials is eagerly anticipated.
Like syphilis at the turn of the previous century, Lyme disease can be considered the great impersonator. The myriad clinical presentations of this multisystem disease have been part of the diagnostic dilemma, especially for chronic Lyme disease. It is often difficult to determine whether specific symptoms are caused by Borrelia burgdorferi or are unrelated but occurring in a patient with serologic evidence of past infection.
A number of investigators at the 14th Lyme Disease Conference examined less common clinical presentations of Lyme disease, conditions for which B burgdorferi is not one of the usual suspects. These body systems include the gastrointestinal tract, the heart, and the skin (not counting the common dermatologic presentation of erythema migrans [EM]). And one speaker discussed the extremely rare syndrome of congenital Lyme disease.
Andrew G. Franks, Jr, MD, of New York University School of Medicine (NYU), believes there is a connection between the 2 diseases. For instance, it can be difficult to differentiate between EM and certain morphea lesions, especially if the EM lesion is not the typical bull's-eye with central clearing. The differential diagnosis for EM-like lesions is varied and can include spider bites, herpes simplex or zoster, cellulitis, fungus or tinea, granuloma annulare, drug eruption, erythema multiforme, and subacute lupus erythematosus. In many cases, it can be difficult to culture B burgdorferi from EM lesions.
Part of the disagreement between the US and other studies may be due to differences in B burgdorferi serotypes and strains that cause morphea, according to Dr. Franks. For instance, only the sensu stricto strain is found in the United States, but all 3 pathogenic strains are found in Europe. Two skin diseases -- acrodermatitis (similar in appearance to scleroderma) and lymphocytoma -- have been identified in Europe as linked to B burgdorferi; the former is associated with the B afzelii strain, and the latter with the B garinii strain.
Dr. Franks believes that serologic testing is unreliable in morphea. He said that in published US studies of B burgdorferi antibodies in morphea patients, the investigators did not check whether the subjects received antibiotics recently. Antibiotic treatment can alter the results of serologic testing. Polymerase chain reaction (PCR) testing for B burgdorferi DNA in morphea patients may also be inaccurate in the US. For instance, the PCR tests may have been too specific and missed strains or serotypes more likely to cause morphea-like skin disease. European studies have detected B burgdorferi DNA by PCR in patients with morphea. For instance, a PCR study by Fujiwara and colleagues tested for afzelii and garinii strains and found evidence of B burgdorferi in non-US cases. US PCR amplification has generally only tested for the sensu stricto strain.
Dr. Franks and colleagues at NYU have recently completed an unpublished study of the association of B burgdorferi, autoimmunity, and morphea. In this study, 82 patients (average age of 27 years; range, 2-61 years) with new-onset morphea were enrolled; 14 were male. The investigators tested for antibody to autoimmune disease and to B burgdorferi by IgG and IgM Western blot (WB), with all bands reported. They used their own criteria for diagnosis of underlying Lyme disease: more than 1 IgG band on WB was taken as a positive result for Lyme. None of the subjects had clinically defined Lyme disease during the trial. For autoimmune serology, any positive test was defined as positive.
For treatment purposes, they classified the patients into 4 groups, depending on whether they were positive by WB and/or autoimmune serology. Generally, patients with positive WB received 6 weeks of doxycycline (or an alternative antibiotic), and those with negative WB were given 3 weeks of doxycycline, with an optional additional 3 weeks if improvement was seen during the first 3 weeks.
Of the 61 patients who completed the study, 34 had clinical improvement. The WB-positive, autoimmune serology-negative group was the most likely to respond to antibiotic therapy. The Lyme WB converted to negative in many treated patients.
Dr. Franks and colleagues believe that all patients with morphea are candidates for a therapeutic antibiotic trial, regardless of serologic test results. IgM and IgG WB may be helpful in the diagnosis, but current Lyme tests are unreliable in such patients. Because the risks are minimal with antibiotics, he believes it is worth trying this approach, especially since there is no effective treatment for morphea at the present time.
The NYU group will be conducting a second trial, making use of a recombinant, nested PCR B burgdorferi assay. They are looking for patients to enroll in this and future studies. If you have any new, untreated morphea patients in your practice, call 917-816-2714 to receive a consent form and instructions for obtaining a 4-mm punch biopsy for PCR.
Typical complaints of Lyme disease patients with cardiac involvement are chest pain, mild to moderate exertional dyspnea, and palpitations. (However, these symptoms also may be due to neuropsychiatric problems and musculoskeletal infection, so testing is important.) To evaluate such patients, cardiac testing should include thallium stress electrocardiography (ECG) and coronary angiography.
What does cardiac infection look like, and where are the organisms localized? Stanek and colleagues found thickening of the walls of small endomysial vessels and infiltration by mononuclear cells. In murine studies, Pachner and colleagues found 3 predominant locations for B burgdorferi in the heart. In mice infected for less than a month, spirochetes could be found mostly around blood vessels. By contrast, for longer infection periods, B burgdorferi could also be seen in cardiac myocytes, often surrounded by clear areas. B burgdorferi were also commonly found among collagen fibers.
Based on her series of cases and a review of the literature, Dr. Keszler drew the following conclusions. Thallium imaging typically reveals diffuse and patchy uptake of isotope in the myocardium, probably indicating involvement of the small vessels of the heart. Patients generally experience decreased exertional tolerance, as exhibited by a rapid increase in heart rate, but there is no ECG evidence of ischemia to account for the decreased tolerance. A variety of arrhythmias are seen, both ventricular and supraventricular, and are more common than heart block. At this time, it is not known whether treatment of Lyme disease will alter the thallium imaging. However, one study has found that cardiac abnormalities do not persist in patients treated for Lyme disease.
Evaluation of patients suspected of having Lyme disease includes the ever-important history, physical examination, CBC, liver function tests, and endoscopic examination. The Lyme WB is generally not helpful, but PCR testing of biopsy specimens for B burgdorferi OspA can be useful. Silver staining of biopsy specimens can reveal spirochetes. For those who test positive by PCR, RNA polymerase testing of the biopsy sample can indicate whether the spirochetes are actively multiplying.
The differential diagnosis includes the majority of gastrointestinal diseases, such as pancreatitis, stool infections, peptic ulcer, Crohn's disease, and inflammatory bowel disease. Skin tags are an indication that the patient has Crohn's rather than a complication of Lyme disease. Crohn's patients have a malabsorption syndrome and are therefore generally underweight. By contrast, those with GI Lyme disease often also have fatigue or arthritis, and the inactivity may make them overweight.
Treatment involves antibiotics, but regular follow-up is important to detect recurrences and lack of response. Dr. Fried has seen B burgdorferi persist in the GI tract despite multiple rounds of antibiotics over many years.
How rare are these conditions? According to published figures, 16,000-17,000 cases of Lyme disease are reported each year in the United States. Roughly 8000 cases are in women, and approximately 1200-3400 cases are in women of childbearing age (20-49 years old). Dr. Gardner did some back-of-the envelope estimates to get a sense of how many cases of gestational Lyme disease may be occurring. If you assume that one quarter of the women in the child-bearing age group are pregnant (a gross overestimate, by Dr. Gardner's admission), and that 10% are either untreated or inadequately treated, and that one fifth transmit the organism to the fetus or newborn, this calculates to approximately 40 cases of congenital Lyme disease a year in the United States. It would be unusual for any large city to have more than 1 or 2 cases a year, and it would be extremely rare for any physician to see more than a few cases in a lifetime.
Dr. Gardner has conducted an extensive literature review (through 1998) that turned up 263 cases. She found that 25% resulted in adverse outcomes: 8% resulted in fetal death and 2% in neonatal death. Fifteen percent of the babies were liveborn but were ill or had an abnormality. The effect of antibiotic therapy was dramatic in these patients: with antibiotics, 85% of neonates were normal, while 15% had an adverse outcome. In striking contrast, without antibiotics, only 33% were normal, while 67% had an adverse outcome. The conclusion: Proper, prompt diagnosis and antibiotic therapy are vital for healthy neonates born with congenital Lyme disease.
However, it can be quite difficult to recognize such a rare disease. The differential diagnosis is extensive and includes sepsis/meningoencephalitis (bacterial or viral), other congenital infectious diseases (eg, syphilis, leptospirosis, relapsing fever, toxoplasmosis), congenital heart or bone disease, inherited or infectious immunodeficiency, sudden infant death syndrome, and more. A history suggestive of Lyme disease in the mother or positive serologic or other tests for B burgdorferi can suggest the diagnosis. Dr. Gardner has provided a list of clues to the various presentations of congenital Lyme disease (Table). One interesting radiologic clue is "celery stalking" -- lucent metaphyseal bands -- on the long bones of the neonate. These are occasionally seen in infants with gestational syphilis or viral infections. In 2 neonates Dr. Gardner has treated, the bands disappeared shortly after treatment.
|Stage||Mild Early||Severe Early||Late|
|Onset||Usually first 2 weeks of life||Usually first week of life||Usually > 2 wks and < 2 yrs of age|
|Maternal gestational Lyme borreliosis||Usually first or second trimester||Usually first or second trimester||Usually second or third trimester|
|Signs and symptoms|
|Prematurity?||< 4 weeks||< 5 weeks||--|
The prognosis for gestational Lyme disease is good if diagnosed and treated adequately. The prognosis for neonates with early congenital Lyme disease depends on prompt diagnosis, especially in severe early cases. Similarly, the prognosis in late congenital Lyme depends not only on prompt diagnosis and treatment, but also on the extent of irreversible damage present at the time of diagnosis. Long-term follow-up is important for detecting possible recurrence of disease.
This summer, Dr. Gardner will be starting the North American Gestational and Congenital Lyme Disease Watch to evaluate the relationship of various factors (clinical and laboratory characteristics, antibiotic regimens) to outcomes for gestational Lyme disease, and to evaluate short- and long-term outcomes (infants, stillborns, miscarriages) of pregnancies complicated by Lyme disease and develop clinical and laboratory case definitions of these outcomes. Interested people (physicians and affected women) can enroll on the Internet once the sites are launched in July 2001:
Maraspin V, Cimperman J, Lotric-Furlan S, et al. Treatment of erythema migrans in pregnancy. Clin Infect Dis. 1996;22:788-793. Abstract available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids= 8722932&dopt=Abstract
First, one must evaluate patients with persistent Lyme encephalopathy by asking the following questions:
For investigators in this field, there have been numerous and differing definitions of Lyme encephalopathy. One of the earlier attempts at defining the problem was made by Logigian and colleagues in 1990. This group listed the chronic neurologic abnormalities of Lyme encephalopathy as memory loss, depression, sleep disturbance, irritability, and difficulty finding words. However, there is much overlap between these symptoms and those of depression unrelated to Lyme disease.
Some further possibilities for defining the condition include self reporting of cognitive deficits, self reporting plus laboratory signs of CNS involvement, objective evidence of deficits on cognitive testing, or objective deficits plus laboratory signs of central nervous system (CNS) involvement. Signs of CNS involvement have included elevated cerebrospinal fluid (CSF) protein or pleocytosis, abnormal brain scans or tests (single photon emission computed tomography [SPECT], magnetic resonance imaging [MRI], or electroencephalogram [EEG]), intrathecal antibody production, or a positive polymerase chain reaction (PCR) for Borrelia burgdorferi DNA or a positive culture. However, objective tests often do not agree with patients' perceptions. This is especially true for memory in depression.
A further complication is how one defines and measures these deficits. One approach is to compare to age-matched norms. A second approach is to compare to actual or estimated premorbid or general ability levels. Comparison to age-matched norms provides simple, clear criteria for measurement and comparison, a cut-off score. But if the deficit being compared is correlated with a general ability (such as memory and general intelligence), then people with higher intelligence but with memory impairment may not be detected by this method. For example, if a subject has a general intelligence IQ of 130 and a memory score of 100, his full-scale IQ is 2 standard deviations above the age-norm, while his memory score is exactly at the age-norm. Compared to age-norms, this subject would not have memory impairment. Compared to his full-scale IQ, his memory score would be 2 standard deviations below expected -- which clearly would suggest impairment. One method identifies this subject as normal, the next identifies him as impaired.
In contrast to the age-norm method, comparison to general levels of ability can allow for a more customized approach to assessing cognitive impairment, thus enhancing sensitivity. However, general abilities can be decreased by illness, regardless of a specific effect on that ability. In addition, this approach assumes that the domain of interest is strongly correlated with general ability.
The ideal screening tool for Lyme encephalopathy should have maximal sensitivity and specificity. Premorbid ability should be taken into account, by using norms adjusted for age, sex, and education level, or with balanced premorbid assessment of ability. It is still not clear whether a single- or multiple-domain definition of neurocognitive impairment should be used.
There are many screening tools for assessing premorbid ability, including verbal IQ, verbal comprehension index, vocabulary subtest score, reading subtest score (WRAT-R [Wide range achievement test-Revised]), demographic composite (Barona demographic equation), and national adult reading test (NART). Of course, different investigators have used different methods of assessing premorbid ability, thus further complicating comparisons between studies.
One of the few studies that actively evaluated patients with Lyme encephalopathy was conducted by Logigian and coworkers in 1997. This study reveals some of these diagnostic problems discussed above. In this study, the investigators screened patients for Lyme encephalopathy and then evaluated the change in SPECT scan perfusion after treatment. Starting with clearly defined criteria for "definite Lyme encephalopathy" -- subjective complaints of cognitive deficits, along with either a past or present CSF abnormality (intrathecal antibodies or PCR positivity) or objective cognitive deficits (as measured by 2 standard deviations below normal on verbal or visual memory tests, or 1 SD below normal on both tests) -- they examined whether brain perfusion improved after treatment. While the brain imaging results were of interest in that all of the patients with definite Lyme encephalopathy showed improved perfusion after treatment, this study also demonstrated that the definition of Lyme encephalopathy, if restricted to cognitive testing, would have been too restrictive using their criteria. In other words, 5 of the 13 patients with "definite Lyme encephalopathy" did not have cognitive impairment using their criteria for impairment. Yet, these very same patients had abnormal SPECT scans that improved after treatment. Their cognitive criteria, which used age-norms for comparison, failed to identify 38% of patients with CNS abnormalities.
Dr. Fallon described an ongoing study of Lyme encephalopathy he is conducting at the NY State Psychiatric Institute. Because previous studies disagree about which is more accurate, single- or multiple-domain evaluation, they will collect data in 6 domains: motor skills, psychomotor skills, attention, memory, working memory, and verbal fluency. Data are preliminary, but so far the most sensitive method for the detection of impairment appears to be one that incorporates testing from multiple cognitive domains. Memory and working memory seem to be the most affected neurocognitive areas. Even so, about one quarter of the control subjects appeared to have neurocognitive deficits, compared to two thirds of the patients with complaints of memory impairment secondary to Lyme disease. Dr. Fallon suggested that the best method for detecting memory impairment in particular might be one that makes use of ethnicity- and education-adjusted norms. The Psychological Corporation is expected to publish such norms within the next year.
Substance abuse (often not reported by the patient, must interview family/friends)
Over-reading of cognitive tests
Medications/toxins (drugs associated with cognitive impairment are listed in Table 2)
HIV and other infections
Menopausal mood changes
Metabolic/endocrine disorders (eg, thyroid disease)
Other CNS diseases
Hysterical dementia is often overdiagnosed in patients with Lyme encephalopathy, but it is rare for this to occur alone as a conversion symptom. The label of "hysterical" is often applied when phenomena are outside the clinician's experience. For instance, females and male homosexuals more often receive this label. Based on studies over the past 50 years, many patients who are initially given the diagnosis of hysterical dementia go on to develop an organic CNS disorder.
Dr. Fallon is conducting a randomized, placebo-controlled study of brain imaging and treatment of persistent Lyme encephalopathy (Columbia University - National Institute of Neurological Disorders and Stroke [NINDS]). Treatment will involve IV ceftriaxone for 10 weeks, with a 14-week antibiotic-free follow-up period. At the end of the 24-week study, patients who had been randomized to receive placebo will be given 6 weeks of IV ceftriaxone. Evaluations will be conducted at baseline and 12 and 24 weeks. PET and MRI imaging as well as neuropsychiatric tests are being used to evaluate response to treatment. Patients will be recruited for this study over the course of the next 3 years.
The clinical syndromes studied included cranial (facial) neuropathy, radiculoneuritis, meningitis, and arthritis. The major symptoms (ie, seen in more than two thirds of patients) in adults with acute disease included fatigue, headache, sleep problems, stiff neck, and myalgia. Those with chronic disease had a different constellation of major symptoms, such as concentration difficulties, fatigue, arthralgias, myalgias, mood disturbance, memory loss, sleep problems, word-finding difficulties, knee pain, confusion, and stiff neck. Children with disseminated Lyme disease experienced major symptoms of headache and fatigue. By symptom score, the major initial defining syndrome for the acute adult group was meningitis, followed by multifocal EM, cranial nerve palsy, radiculoneuritis, and single EM; for the chronic adult group, single EM was the most common presenting symptom, followed by arthritis, cranial nerve palsy, and multifocal EM; and for children with disseminated disease, extraneural symptoms.
These investigators concluded that the children with disseminated disease are less symptomatic than adults, but they have more inflammatory CSF changes. Among the adult patients, those with chronic disease were more symptomatic than those with acute disease. They had more cognitive, mood, and joint disturbances; more severe symptoms; and more current depression, anxiety, and adjustment problems. However, it was the acute disease patients who were more likely to show objective cognitive deficits.
The overall goal of cognitive remediation is to improve the life of the patient, by first addressing the neurocognitive deficits, using preserved capabilities as a base to develop compensatory strategies, ameliorating cognitive impairments, improving functional capabilities, and hopefully, enhancing life satisfaction.
Dr. Shea favors the compensatory model for improving deficits, rather than the restorative model. Whereas the restorative approach attempts to recreate tasks directly with a repetitive, saturation approach, the compensatory model uses an indirect approach of finding strategies or alternatives to "get around the roadblocks" and improve function. He also favors the process-specific approach, rather than a shotgun (trying to cover many deficits) or a functional approach. One of the benefits of the process-specific approach is that it can be customized for each client.
A structured approach to cognitive remediation is the 3-step PIE model used at NYU: Preparation, Implementation, and Evaluation. The preparation/orientation step involves getting to know the patient's problems. One of the most time-consuming tasks is getting hold of the medical records for review, since some of these patients have seen numerous physicians and therapists. Dr. Shea also suggests interviewing the referring physician, as well as adjunct physicians and therapists. Interviewing family and other supportive people can also provide valuable information. The patient undergoes evaluation during this step, including neuropsychological assessment and measurement of specific cognitive deficits. The patient also provides a self-analysis of his or her problems during the clinical interview.
In the implementation step, the patient and therapist prepare long-term (6-month) and short-term (1- to 3-month) goals, and formalize this in a patient contract. The therapist selects the first cognitive remediation task, which is sometimes a task the patient is already good at, to build a positive attitude about the process. With each task, the therapist administers a baseline test, training, and a posttest.
During the evaluation and analysis step, the therapist evaluates domain-specific results, as well as generalization of the learned tasks to other deficits and the ecological validity of the learning. The therapist prepares a progress report each month, and a cognitive progress index is prepared quarterly. This is a time-consuming process, but necessary for insurance reimbursement. In fact, one can expect difficulties with health insurance companies, even when following guidelines. The therapist and patient revise short-term goals quarterly, and long-term goals semiannually.
A number of cognitive domains are addressed in patients with Lyme disease, including attention/concentration, memory, spatial/perceptual ability, efficient processing (both accuracy and speed), fluency, higher-level reasoning, and executive functioning.
The therapist monitors 4 cognitive markers to gauge the patient's state of mind about the process. One of the most important markers is the patient's awareness of the deficit. Not surprisingly, greater awareness can at first lead to depression and anxiety, as the patient realizes the impact these deficits have on his or her daily functioning and life in the long term. Other markers include an openness and willingness to face the deficit, acquiring the skills or the ability to compensate for the deficit, and acceptance. This can be especially hard on the patient, such as accepting that one can no longer handle one's previous career.
Dr. Shea has conducted a small study of 9 patients who underwent cognitive remediation. All met CDC diagnostic criteria for Lyme disease. He measured attention, concentration, processing efficiency (speed and accuracy), and depression, and asked the patients for self-ratings of physical, cognitive, emotional, and behavioral functioning. A number of training programs were used to address deficits in these areas, as well as intravenous antibiotic therapy. The results are listed in Table 3. Overall, in this small study, patients improved significantly with cognitive remediation.
|Baseline||8 Weeks of Intervention||3 Months After Intervention|
|Attention||2 below 1 SD||7 avg, 2 mild||9 avg|
|Concentration||2 below 1 SD||5 avg, 2 mild, 2 mod||9 avg|
|Processing Efficiency||9 below 1 SD|
|5 avg, 3 mild, 1 mod||6 avg, 3 mild|
|2 avg, 3 mild, 4 mod||4 avg, 3 mild, 2 mod|
|Zung Depression Index||2 normal, 2 mild, 3 mod, 2 sev||2 normal, 5 mild, 2 mod||4 normal, 3 mild, 2 mod|
|Self-rating of Functioning||2 or more impaired categories||improved in most categories
-- no improvement in emotion in 4 subjects or in behavior in 3 subjects
|improved in all categories
-- no improvement for 2 subjects in emotion
SD = standard deviation; avg = average; mod = moderate deficit; sev = severe deficit
Dr. Pietrucha highlighted the following recommendations:
Fallon BA, Schwartzberg M, Bransfield R, et al. Late-stage neuropsychiatric Lyme borreliosis. Differential diagnosis and treatment. Psychosomatics. 1995;36:295-300.
Fallon J, Bujak DI, Guardino S, Weinstein A. The Fibromyalgia Impact Questionnaire: a useful tool in evaluating patients with post-Lyme disease syndrome. Arthritis Care Res. 1999;12:42-47. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids= 10513489&dopt=Abstract
Pietrucha DM, Sensakovic JW. Treating Lyme disease: different approaches. N J Med. 1996;93(7):51-4.
It should be noted that this possible association is quite controversial. Some investigators do not believe that vaccine-related disease reactivation is supported by the data.[2,3] And there is currently a class-action lawsuit against SmithKline Beecham (now Glaxo SmithKline), maker of the Lyme disease vaccine, claiming that this product leads to autoimmune arthritis in approximately one third of vaccine recipients genetically predisposed to the disease.
Nevertheless, some intriguing information can be gleaned from Dr. Donta's case studies. The Western blot (WB) results in his patients show an IgM response to OspA, but in addition, there are both IgM and IgG responses to other B burgdorferi antigens, suggesting previous infection. Although the cause of reactivation is not known, autoimmunity, an underlying infection that was not adequately treated, or an interaction between the two could be responsible for this condition. Dr. Donta drew a parallel between these cases and the development of zoster in those with recent exposure to a case of varicella.
Additional case reports on vaccine use and disease reactivation were provided by Paul T. Fawcett, PhD, of the A. I. duPont Hospital for Children, Wilmington, Delaware, during an unscheduled presentation. While conducting a small-scale serologic survey of 20 employees of the hospital who received the Lyme disease vaccine, he came across 2 patients who subsequently developed arthritis. They developed arthritis within 24 hours of the second dose of the vaccine. Neither had a previous history of B burgdorferi infection. Dr. Fawcett also presented 2 case reports of children who developed arthritis after receiving the vaccine; the data suggested that one child became infected during the vaccine trial.
There has been evidence in animals linking the Lyme disease vaccine and chronic symptoms. In one study, hamsters given OspA developed arthritis after challenge with various strains of B burgdorferi.
Both Dr. Donta and Dr. Fawcett suggest that patients with apparent reactivation from the vaccine be treated as if they have chronic Lyme disease, with a tetracycline, a macrolide, or hydroxychloroquine. Further observation and investigation are definitely needed. Dr. Donta suggests that the Food and Drug Administration show greater caution in recommending who receives the vaccine. For instance, it might be prudent for those who have had Lyme disease to avoid getting vaccinated with the current vaccine. He believes that those at high risk for Lyme disease, such as landscapers and outdoor workers, should still get vaccinated.
There are additional vaccine candidates in development, and it is not known whether they will have any effect on disease reactivation.
But why be concerned? Guidelines are not ironclad rules for treatment. Physicians generally individualize treatment, using their clinical judgement when a presentation varies from the typical, or when the patient doesn't respond to first-line treatment. Individualization is the basis of medical care.
If only that were still true. In the United States, most medical care is paid for by insurance companies -- managed care organizations, preferred provider organizations, and other healthcare companies. Insurance companies use guidelines from respected medical groups to determine whether treatments should be "covered" and which should not. Therefore, if a set of guidelines suggests that there is no evidence to support certain types of treatment, it can be difficult or impossible for the patient and physician to receive reimbursement from the insurance company.
At the 14th Lyme Disease Meeting, Daniel J. Cameron, MD, of Westchester, New York, presented a critique of the guidelines as well as other issues in the diagnosis and treatment of Lyme disease. His major areas of concern were the lack of acceptance of subjective symptoms of encephalopathy in the diagnosis of recurrent Lyme disease (only encephalopathy confirmed by objective tests is included in the guidelines), resistance to using long-term antibiotic treatment for both acute and recurrent Lyme disease in the United States, and exclusion of patients from clinical trials who do not meet the current diagnostic criteria for Lyme disease (the 2-tier approach to diagnosis, based on a positive ELISA test and a positive IgG Western blot [WB]).
Dr. Cameron expressed 5 additional concerns about the guidelines and the committee that drafted them:
Patricia Coyle, MD, SUNY at Stony Brook School of Medicine, was a member of the expert committee that drafted the IDSA guidelines. She also noted that guidelines are used negatively by insurance companies to deny treatment.
There is a parallel between these guidelines and the original diagnostic criteria for AIDS. Early on, a number of opportunistic infections (OIs) were not included as indicative of AIDS. Patients developing only these OIs were therefore not diagnosed with AIDS, and had greater difficulty receiving reimbursement from insurance companies and other benefits afforded to people with AIDS. This was eventually remedied when the Centers for Disease Control and Prevention (CDC) revised the diagnostic criteria to include other common OIs.
Dr. Cameron also believes that long-term treatment of Lyme disease should be explored in greater detail. The guidelines state:
"Randomized controlled studies of treatment of patients who remain unwell after standard courses of antibiotic therapy for Lyme disease are in progress. To date, there are no convincing published data that repeated or prolonged courses of either oral or IV antimicrobial therapy are effective for such patients. The consensus of the Infectious Diseases Society of America (IDSA) expert-panel members is that there is insufficient evidence to regard 'chronic Lyme disease' as a separate diagnostic entity."
The guidelines recommend 14-21 days of therapy for erythema migrans and 14-28 days for other forms of Lyme disease. However, small studies, especially from Europe, suggest that longer-term treatment may be more effective. For instance, Oksi and colleagues had a 90% success rate with 100-day treatment.
In addition, a few studies suggest that recurrence is common, and that longer treatment initially may reduce the recurrence rate. For example, Shadick and colleagues conducted a population-based, retrospective study of 38 patients and found that 13 (34%) had long-term sequelae from Lyme disease: 6 with arthritis or recurrent arthralgias, 4 with neurocognitive impairment, and 3 with neuropathy or myeloneuropathy. Similarly, Asch and coworkers conducted a retrospective evaluation of 215 patients a mean of 3.2 years after initial evaluation. They found that 19 (9%) required retreatment for synovitis or worsening objective neurologic features, and they thought that 114 (53%) should be observed for post Lyme sequelae (persistent symptoms of arthralgia, arthritis, cardiac or neurologic involvement with or without fatigue).
Dr. Cameron believes that longer treatment may improve outcomes. Three randomized, double-blind, placebo-controlled clinical trials -- 2 that are ongoing -- specifically examine this issue: those conducted by Klempner and colleagues, Fallon and colleagues, and Cameron. Dr. Klempner's trial involved 4 weeks of IV ceftriaxone + 2 months of oral doxycycline. According to Dr. Cameron, this trial was closed before completion because no benefit was seen. Dr. Fallon's trial uses 10 weeks of IV ceftriaxone, and Dr. Cameron's trial uses 12 weeks of oral amoxicillin.
Dr. Cameron also believes that the guidelines for treatment of fibromyalgia need to be revised. Treatment currently consists of an antidepressant and an exercise routine. However, in a study by Dinerman and Steere, only 6 of 15 patients showed some improvement using this regimen, and illness was resolved in only 1 of those patients after 2.5 years of treatment.
It ought to be safe to take a walk in the woods. Can we return to such environments, without endangering ourselves? Two speakers at the 14th Lyme disease meeting focused on strategies for prevention of Lyme disease.
Dr. Edward Bosler from the State University of New York at Stony Brook School of Medicine, discussed passive and active host-targeted abatement programs to remove potentially infective ticks from mice and other small mammals on which the ticks like to feed. Previous attempts to eradicate tick nymphs have been unsuccessful. A passive system designed to kill ticks by treating mice with pesticide-impregnated cotton balls resulted in no reduction in Borrelia burgdorferi infection rates (although Dr. Bosler noted that the treated mice appeared to be healthier and happier with their tick burdens removed!).
A Rube Goldbergesque contraption was devised to address the role played by larger mammals in maintaining both tick and spirochete life cycles. This device, activated by a trip pedal, sprayed raccoons, opossums, squirrels, chipmunks, and rats with pyrethrin and other pesticides. Although a dramatic reduction in tick infestations was demonstrated, approval to use this tool has not been granted by the Centers for Disease Control and Prevention (CDC). Instead, bait houses in which pesticide bait was consumed were approved. These devices proved to be most unsuccessful, due to the effects of human and raccoon vandalism and prolonged inclement weather. In spite of its unconventional design, Dr. Bosler is currently pleading for the CDC to reconsider and approve the mechanical sprayer.
A community-based strategy, focused on ways in which the public can prevent Lyme disease, was presented by Dr. Kirby Stafford III, Director of the Connecticut Agricultural Experiment Station in New Haven. Campaigns have been moderately successful in getting individuals to use topical repellants, wear protective clothing, and check for ticks after going outside. Vaccination drives have been less successful. Residential tick control through landscape management -- involving leaf clearance and use of wood chips -- has proven to be effective, particularly when combined with pesticide use.
Both the CDC and the United States Department of Agriculture are also supporting community-based tick eradication programs. One such program, utilizing the fipronil bait box, was originally tested in Colorado and showed a 100% rodent tick eradication rate, with effects lasting for 7 weeks. Further testing with fipronil is ongoing throughout Connecticut. Another program, started in 1997 throughout 5 northeastern states, is known as "Target Lyme Disease." A 4-post device topically treats white-tailed deer in an effort to reduce tick infestation. To date, more than 90% of local deer have been exposed to the device. In Connecticut alone, tick populations have declined by more than 70% in the treatment areas, and the average number of ticks per deer has decreased from 34 to 3.5.
Wang IN, Dykhuizen DE, Qiu W, et al. Genetic diversity of ospC in a local population of Borrelia burgdorferi sensu stricto. Genetics. 1999;151:15-30. Available at: http://www.genetics.org/cgi/content/full/151/1/15?view= full&pmid=9872945
Ijdo JW, Wu C, Magnarelli LA, Stafford KC 3rd, et al. Detection of Ehrlichia chaffeensis DNA in Amblyomma americanum ticks in Connecticut and Rhode Island. J Clin Microbiol. 2000 Dec;38(12):4655-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids= 11101616&dopt=Abstract
Stafford KC 3rd, Massung RF, Magnarelli LA, et al. Infection with agents of human granulocytic ehrlichiosis, Lyme disease, and babesiosis in wild white-footed mice (Peromyscus leucopus) in Connecticut. J Clin Microbiol. 1999 Sep;37(9):2887-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve &db=PubMed&list_uids= 10449470&dopt=Abstract
A similar study by Giambartolomei and coworkers showed that Borrelia can stimulate interleukin-10 (IL-10) production, a downregulator of the immune system. In this series of experiments, heat-killed B burgdorferi caused peripheral blood mononuclear cells of humans and rhesus monkeys to produce this cytokine. Another study, by Keane-Myers and Nickell, found that B burgdorferi could suppress T-cell responses in mice, specifically T-helper cells.
Even the tick itself may play a role in immunosuppression. Urioste and colleagues showed that the saliva of Ixodes dammini ticks contains an uncharacterized substance that can suppress the immune response, specifically suppressing lymphocyte proliferation and other markers of immune system activity.
Looking at the issue of immune suppression from the other side -- that is, by boosting the immune response with the use of cytokines -- Zeidner and colleagues showed that tumor necrosis factor alpha (TNF-alpha), IL-2, and interferon-gamma could suppress B burgdorferi infection in mice.
By contrast, it appears that infection with B burgdorferi can also overstimulate the immune system, and this may explain many of the symptoms of both acute and chronic Lyme disease. For instance, Lim and colleagues showed that CD4+ T cells play a role in the arthritis seen in the hamster model of Lyme disease.
Richard T. Marconi, PhD,[9,10] of the Medical College of Virginia at Virginia Commonwealth University, Richmond, has examined potential candidate proteins for antigenic variation in Lyme disease. The most likely candidate, based on his research, is outer surface protein E (OspE). The genes for these surface-exposed lipoproteins have 2 hypervariable domains (the variation is due to insertions and deletions in the gene) as well as repeat regions (which can lead to recombination with other genes, and thus new antigens). OspE variation has been shown to occur in vivo, at least in mice. A number of variants have been shown to be antigenically distinct and to arise at different times during infection.
By contrast, the OspF genes are stable; that is, they do not show the variability seen with OspE genes. However, different members of the OspF family are expressed at different times during infection, suggesting that this surface protein may also play a role in antigenic variation.
Other investigators have suggested that VlsE may be involved in immune evasion as well, since VlsE genes exhibit both variation and mutation during infection. However, Dr. Marconi's work suggests that the resulting VlsE are not antigenically distinct. In other words, even though the VlsE genes mutate during infection, the changes in the second or third generation VlsE proteins are not sufficient to evade the antibodies produced against the first generation of VlsE surface protein. Therefore, he believes it is unlikely VlsE plays a prominent role in immune evasion.
It appears that B burgdorferi may have its own approach to fighting back. John T. Skare, PhD, of Texas A&M University Health Science Center, College Station, examined one such battle tactic Borrelia use against humans: resisting oxidative stress. (Oxidative stress is the use of hydrogen peroxide, superoxide, and other active oxygen radicals to kill invading organisms.)
Dr. Skare's group has examined a gene called BB0647 to see what role it may play in resisting oxidative stress. Originally, this gene was thought to resemble a ferric uptake regulator, or Fur. Oddly enough, though, Borrelia don't require iron. This puzzling finding prompted Dr. Skare to search databases for genes that more closely resemble BB0647. He found that the most homologous gene is one that produces a peroxide regulatory protein, PerR. This protein controls the expression of catalases and peroxidases, enzymes that play a major role in defending cells against oxidative stress. To confirm these findings, Dr. Skare showed that B burgdorferi containing an active form of the BB0647 gene was indeed able to resist hydrogen peroxide, around 3000 times better than a strain containing a mutated form of the gene.
Dr. Scott Samuels, PhD, of the University of Montana, Missoula, presented some highly technical research on how the Lyme disease spirochete manages this transformation. The process appears to be mediated by supercoiling of DNA. (For a description and pictures of DNA supercoiling, see the handy Web site from the Mount Sinai School of Medicine.) Supercoiled DNA can be visualized as a coiled phone cord; the more you twist it, the more tightly wrapped it becomes. Untwisting the DNA opens up the loops and coils.
It turns out that the degree of supercoiling is determined by the temperature: at the lower temperature of ticks, B burgdorferi DNA is more supercoiled, and the OspC gene is expressed at only a low level. By contrast, at the higher temperatures seen in mammals, DNA is less supercoiled, and the OspC gene is expressed at higher levels. The next step for Dr. Samuels' team is to determine what is affecting expression of the other 2 surface protein genes.
Brian A. Fallon, MD, MPH, MEd
Director, Lyme Disease Program, NYS Psychiatric Institute. Dr. Fallon is Associate Professor of Clinical Psychiatry, Columbia University, New York City.
Disclosure: Brian A. Fallon, MD, receives clinical grant funding from National Institutes of Health.
Harry Goldhagen, MS
Managing Editor Medscape Infectious Diseases
Disclosure: Harry Goldhagen, MS, has no financial interest to disclose.
Robert S. Mocharnuk, MD
Clinical Instructor of Hematology, University of Southern California Keck School of Medicine, Los Angeles, California
Disclosure: Robert S. Mocharnuk, MD, has no financial interest to disclose.
Julie Rawlings, MPH
Director, Sections of Reporting and Surveillance and Vector-Borne Disease, Infectious Disease Epidemiology and Surveillance (IDEAS) Division, Texas Department of Health, Austin, Texas.
Disclosure: Julie Rawlings, MPH, has no financial interest to disclose.
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