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Lyme Disease - 5/22/2013

posted May 22, 2013, 10:46 AM by Rohit Das   [ updated Jun 5, 2013, 9:52 AM by Purnema Madahar ]

Ticks, ticks, ticks…and the bugs they carry. We recently had a case of a young man, who had recently visited upstate New York, with a history of a recent rash and nonspecific systemic symptoms who subsequently developed pericarditis. The thought was that he had Lyme Disease related cardiac manifestations, and though that probably was incorrect for various reasons I’ll get into a bit later, it did get me reading about the most common vector-borne disease in the U.S…

·         What’s the history behind Lyme Disease?

·         How exactly is transmitted? How common is it…and when and where does it occur?

·         What are the main clinical manifestations?

·         How is it diagnosed?

·         How is it treated and what’s the prognosis?

What causes Lyme Disease, and how is it transmitted? How common is it?

·         The story behind the origins of Lyme Disease is fascinating, and worth bantering about for a bit. It first began in 1975 with a little old lady, Polly Murray, who resided in the little old town of Lyme, Connecticut. She reported to the state health department that two of her children were diagnosed with juvenile RA, but also knew of other children who had similar symptoms during a similar time frame. This was then brought to the attention of a renown rheumatology guru – Allen Steere (then at Yale, now at Harvard – his review article on Lyme is attached) – who found around 50 similar cases and explored things further…

·         Several of the patients Steere talked too reported a skin rash preceding their rheumatologic symptoms. He then linked this rash to work done by a Swedish dermatologist, Arvid Afzelius, who first described “erythema migrans” in 1909 and speculated causation by bites from the Ixodes tick. Further work in Europe reported that the rash responded to penicillin, suggesting that the etiology of the rash was bacterial in nature. FINALLY, in the early 1980s, Willy Burgdorfer (insect expert) identified the transmitted pathogen as a spirochete, subsequently named in his honor – Borrelia burgdorferi.

That’s the story in a very brief nutshell – if you’re really interested, there’s a book all about it titled “Bull’s-Eye.” Clever.

How exactly is transmitted? How common is it…and when and where does it occur?

·         The central player here is the blood-sucking Ixodes tick, and specifically in the Northeast, the vector species is Ixodes scapularis. Ticks generally have three stages of life – larvae, nymph and adult – and require a yummy blood meal at each stage to survive and reproduce. Ixodes has two main hosts during their life cycle - rodents (for larvae and nymph) and white-tailed deer (for adult ticks). Rodents (particularly chipmunks and mice) are natural reservoirs for Borrelia, and so ticks and their blood meals leads to an extremely efficient horizontal cycle of transmission. Though white-tailed deer are very important for the tick’s life cycle, they have nothing to do with, at least directly, Borrelia and its life cycle.

·         So…what does this have to do with Lyme Disease? Well, when humans are around, ticks enjoy their blood too. Nymph bites, in particular, are most closely associated with incident Lyme Disease. Since nymphs quest for blood peaks during May to July, that’s also the epidemiologic timeframe for cases of Lyme Disease.

·         As mentioned, Lyme Disease is the most common vector borne disease in the U.S., and since CDC surveillance begun in 1982, the number of reported cases has increased dramatically. Currently, nearly 20,000 cases are reported every year. The area in which Lyme Disease occurs – Northeast (Maine to Virgina), Minnestota and Michigan - correlates well with the presence of a white-tailed deer population, highlighting their importance for those nasty ticks’ life cycle.

·         It’s not completely clear why Lyme Disease has become an issue in the latter part of the 20th century. Though it’s likely that the disease has been around for a while, it’s thought that alteration in local ecology significantly impacted the incidence of disease. European colonization led to deforestation for agricultural purposes, and for that purpose, deer were hunted nearly to extinction in certain areas. The reversion of that ecology to now more forested areas has allowed deer and mice to proliferate, thus giving an opportunity for Ixodes to set up shop.

What are the main clinical manifestations?

This gets complicated, and definitely best to think of things occurring in stages…

·         Early Localized Infection – the characteristic erythema migrans (EM) rash occurs 3 to 30 days after the initial tick bite in 70-80% of patients. Typically, EM progresses and expands slowly (~1 cm/day), which is a VERY important factor when considering the main differential – allergic reaction to tick saliva – which expands much more rapidly. Usually the lesions expand with bright-red borders and partial central clearing, and are most often located in the thigh, groin and axilla. It is usually very warm to touch, and patients may experience pruritis, but typically not pain.

o   Additionally, within days to weeks of the onset of the initial EM lesion, patients may develop secondary annular skin lesions that are usually smaller than the initial EM lesion and not associated with previous tick bites. The lesions appear and fade, and their borders may merge to give a more confluent presentation. Also, around 20% of patients will report nonspecific systemic symptoms – anorexia, headache, myalgias, arthralgias, fever, etc…

·         Early Disseminated Infection – several weeks to months after the initial EM lesion, patients may develop manifestations of disseminated disease. The most common organ systems involved in untreated patients are neurologic (15%), cardiac (5%) and ocular (more rare).

o   Neurologic Lyme Disease – the classic, but rare, triad is fluctuating symptoms of meningitis along with cranial neuropathy (particularly facial nerve palsy) and motor and/or sensory radiculoneuropathy. Importantly, any one of these three can occur as the sole manifestation. More rare complications include cerebellar ataxia, myelitis and encephalitis. In patients with meningitis, CSF usually has a lymphocytic pleocytosis of up to 100 cells/mm3, with elevated protein levels and normal glucose levels.

o   Cardiac Lyme Disease – the most common manifestation is variable degrees of atrioventricular block, though some patients have evidence of more diffuse cardiac involvement – myocarditis and rarely dilated cardiomyopathy.  Usually, the duration of cardiac manifestations is brief (3 days to 6 weeks), and pacemaker placement is rarely ever needed for AV-block, even if severe.

o   Late Infection – months to a few years after onset of EM, within the context of a strong immune response to Borrelia, 60% of patients develop symptoms of late infection, which is characterized by an inflammatory arthritis that mimics reactive arthritis in adults. People experience intermittent attacks of large-joint arthritis, usually involving one or two joints and particularly the knee. Though the frequency of attacks decreases as time goes on, the duration of each attack may prolong. Most patients, even if untreated, will have complete resolution after several years. On the other end of the spectrum, there is a proportion of patients who have “antibiotic-refractory Lyme arthritis,” which is linked to HLA-DRB1. Apparently, the epitope to which HLA-DRB1 binds (a Borrelia protein called OspA) leads to very high levels of proinflammatory cytokines, thus implicating inflammation as the cause for symptoms in refractory cases. Rarely, patients can have chronic neurologic abnormalities, including radicular neuropathies and even subtle cognitive disturbances.

·         Post-Lyme Syndrome – this is a very vaguely understood syndrome that occurs despite resolution of objective manifestations of infection. It closely resembles other poorly defined, similar syndromes – chronic fatigue syndrome and fibromyalgia. Such patients have no objective evidence of joint inflammation, have normal neurologic evaluation and also have a higher incidence of co-morbid psychiatric illness. A large randomized trial pretty definitively showed that antibiotics have no role in the treatment of this disorder, and management remains reassurance and support.

·         Co-Infection – important caveat worth mentioning. Ixodes also carries around Babesia microti and Anaplasma phagocytophilum, so patients with Lyme Disease are thus at risk for co-infection with those organisms, and their consequent diseases (which I won’t go into). Rates of co-infection vary, and range between 2-40% depending on what you read. Importantly, neither of those two organisms causes chronic manifestations past the initial acute illness, which, as described above, Lyme Disease is notorious for.

How is it diagnosed?

·         Not easily. Culture is the gold standard, but Lyme is best cultured from EM lesions, and less often from other body sites (plasma, CSF, joint fluid, etc.). In later disease, PCR is a much more accurate test, but is also much more expensive and not widely available. So…where to turn? Serology, of course.

·         The CDC has guidelines for the diagnosis of Lyme Disease based on serology, and requires a two-tiered testing algorithm involving screening with ELISA, and confirmation with Western Blot.

o   IgM – only 30% of patients with EM are IgM positive, but by 2-4 weeks, up to 80% will show reactivity. Titers wane over time and with treatment, and after two months, any positive IgM is considered a false-positive, and only IgG testing is recommended. Importantly, there are specific Western blot bands that need to be present for a positive test – 23, 39 and 41kDa; two out of three need to be positive.

o   IgG – these appear in basically all patients with active infection 4-8 weeks into the illness, and remain positive for late Lyme Disease. For IgG, five out of the following ten specific bands need to be positive – 18, 23, 28, 30, 39, 41, 45, 58, 66 and 93kDa.

So the bottom line – diagnosis is a bit difficult, but mainly requires putting symptoms into the right epidemiology and clinical context, in conjunction with positive serology. The presented patient had a relatively rare manifestation of cardiac Lyme Disease (isolated pericarditis), had a positive IgM but with a 25 and 41kDa band (1/3), and a negative IgG – probably not Lyme, but went home with a PICC for Ceftriaxone…whatevs.

How is it treated and what’s the prognosis?

·         Except for the rare subset of patients who get refractory arthritis and so-called Post-Lyme syndrome, prognosis is excellent. Treatment of choice is oral Doxycycline (or Amoxicillin in children < 8 years old and pregnant patients) for 14-21 days (though recent studies seem to show that 10 days is good enough). Acute neurologic Lyme and severe cardiac Lyme should be treated with IV Ceftriaxone for a similar course. And, finally, Lyme arthritis can also be treated effectively with Doxycycline, though usually for an extended course (30 days)…

·         How to prevent Lyme Disease is also a good question…SmithKline Beecham actually created a vaccine in 1998 (called LYMErix) that was approved and licensed. It was actually pretty good, with 78% efficacy in adults. Due to costs, public lawsuits due to supposed adverse effects (not backed up by subsequent studies) and negative media coverage, it was withdrawn from the market in 2002. New vaccines are being studied…otherwise, stay away from ticks, and if you see one, don’t let it chill beyond 24 hours – removal before that makes Borrelia transmission very unlikely. Also, if a nymph tick is found, a single 200mg dose of Doxycyline is pretty effective in preventing Lyme Disease If given within 72 hours of the bite.

Gotta love zoonotic disease. I’ve attached a good review article as well as an interesting piece on diagnostic testing for Lyme Disease.

Oh, and alas, given the holidays coming and such, this will be my last post ever…it’s been fun while its lasted, and hope this thing doesn’t turn into dust in the wind. Thanks to all who enjoyed this blog along with me! Good luck, and keep reading!

Lyme Disease
Steere, NEJM 2001, Volume 345 (2): 115-125

Tugwell et. al., Ann Int Med 1997, Volume 127: 1109-1123