OVERVIEW: LYME DISEASE

About Author:
P. Bharath
Department of pharmacology
Teegala Ram Reddy College of Pharmacy
Hyderabad (AP), 500097.
pbharath760@gmail.com

Abstract:
Lyme disease (Lyme borreliosis) is an infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu strictois the main cause of Lyme disease in North America, whereas Borrelia afzelii and Borrelia garinii cause most European cases. The disease is named after the towns of Lyme and Old Lyme, Connecticut, US, where a number of cases were identified in 1975. Although it was known that Lyme disease was a tick-borne disease as far back as 1978, the cause of the disease remained a mystery until 1981, when B. burgdorferi was identified by Willy Burgdorfer.

Lyme disease is the most common tick-borne disease in the Northern Hemisphere. Borrelia is transmitted to humans by the bite of infected ticks belonging to a few species of the genus Ixodes ("hard ticks"). Early symptoms may include fever, headache, fatigue, depression, and a characteristic circular skin rash called erythema migrans (EM). Left untreated, later symptoms may involve the joints, heart, and central nervous system. In most cases, the infection and its symptoms are eliminated by antibiotics, especially if the illness is treated early. Delayed or inadequate treatment can lead to more serious symptoms, which can be disabling and difficult to treat.

REFERENCE ID: PHARMATUTOR-ART-2009

History
The evolutionary history of Borrelia burgdorferi genetics has been the subject of recent studies. One study has found that prior to the reforestation that accompanied post colonial farm abandonment in New England and the wholesale migration into the mid-west that occurred during the early 19th century, Lyme disease was present for thousands of years in America and had spread along with its tick hosts from the Northeast to the Midwest.

John Josselyn, who visited New England in 1638 and again from 1663–1670, wrote "there be infinite numbers of tikes hanging upon the bushes in summer time that will cleave to man's garments and creep into his breeches eating themselves in a short time into the very flesh of a man. I have seen the stockins of those that have gone through the woods covered with them."

This is also confirmed by the writings of Peter Kalm, a Swedish botanist who was sent to America by Linnaeus, and who found the forests of New York "abound" with ticks when he visited in 1749. When Kalm's journey was retraced 100 years later, the forests were gone and the Lyme bacterium had probably become isolated to a few pockets along the northeast coast, Wisconsin, and Minnesota.

Perhaps the first detailed description of what is now known as Lyme disease appeared in the writings of Reverend Dr John Walker after a visit to the Island of Jura (Deer Island) off the west coast of Scotland in 1764. He gives a good description both of the symptoms of Lyme disease (with "exquisite pain [in] the interior parts of the limbs") and of the tick vector itself, which he describes as a "worm" with a body which is "of a reddish colour and of a compressed shape with a row of feet on each side" that "penetrates the skin". Many people from this area of Great Britain immigrated to North America between 1717 and the end of the 18th century.

The examination of preserved museum specimens has found Borrelia DNA in an infected Ixodes ricinus tick from Germany that dates back to 1884, and from an infected mouse from Cape Cod that died in 1894. The 2010 autopsy of Ötzi the Iceman, a 5,300-year-old mummy, revealed the presence of the DNA sequence of Borrelia burgdorferi making him the earliest known human with Lyme disease.

The early European studies of what is now known as Lyme disease described its skin manifestations. The first study dates to 1883 in Breslau, Germany (now Wroc?aw, Poland), where physician Alfred Buchwald described a man who had suffered for 16 years with a degenerative skin disorder now known as acrodermatitis chronica atrophicans.

signs and symptoms
The Lyme disease has not yet spread throughout the body. The only area affected is where the infection has first come into contact with the skin. The classic sign of early local infection with Lyme disease is a circular, outwardly expanding rash called erythema chronicum migrans (also erythema migrans or EM), which occurs at the site of the tick bite three to thirty days after the tick bite. The rash is red, and may be warm, but is generally painless. Classically, the innermost portion remains dark red and becomes indurated (is thicker and firmer); the outer edge remains red; and the portion in between clears, giving the appearance of a bullseye. However, partial clearing is uncommon, and the bullseye pattern more often involves central redness.

The erythema migrans rash associated with early infection is found in approximately 80% of patients and can have a range of appearances including the classic target bull's-eye lesion and non target appearing lesions. The 20% without the erythema migrans and the non target lesions can often cause mis-identification of Lyme disease.

EM is thought to occur in about 80% of infected patients. Patients can also experience flu-like symptoms, such as headache, muscle soreness, fever, and malaise. Lyme disease can progress to later stages even in patients who do not develop a rash.

Diagnosis
Lyme disease is diagnosed clinically based on symptoms, objective physical findings (such as erythema migrans, facial palsy or arthritis) or a history of possible exposure to infected ticks, as well as serological blood tests. The EM rash is not always a bullseye, i.e., it can be red all the way across. When making a diagnosis of Lyme disease, health care providers should consider other diseases that may cause similar illness. Not all patients infected with Lyme disease will develop the characteristic bullseye rash, and many may not recall a tick bite.

Because of the difficulty in culturing Borrelia bacteria in the laboratory, diagnosis of Lyme disease is typically based on the clinical exam findings and a history of exposure to endemic Lyme areas. The EM rash, which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when serologic blood tests are negative. Serological testing can be used to support a clinically suspected case, but is not diagnostic by itself.

Diagnosis of late-stage Lyme disease is often complicated by a multifaceted appearance and nonspecific symptoms, prompting one reviewer to call Lyme the new "great imitator." Lyme disease may be misdiagnosed as multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, lupus, Crohn's disease, HIV or other autoimmune and neurodegenerative diseases.

* Enzyme-linked immunosorbent assay (ELISA) test. The test used most often to detect Lyme disease, ELISA detects antibodies to B. burgdorferi. But because it can sometimes provide false-positive results, it's not used as the sole basis for diagnosis. This test may not be positive during the early stage of Lyme disease, but the rash is distinctive enough to make the diagnosis without further testing in people who live in areas infested with ticks that transmit Lyme disease.

* Western blot test. If the ELISA test is positive, another test — the Western blot — is usually done to confirm the diagnosis. In this two-step approach, the Western blot detects antibodies to several proteins of B. burgdorferi.

* Polymerase chain reaction (PCR). This test helps detect bacterial DNA in fluid drawn from an infected joint. It's not as effective at detecting infection of blood or urine. It's used for people who may have chronic Lyme arthritis. It may also be used to detect persistent infection in the cerebrospinal fluid of people who have nervous system symptoms.

Prevention
Protective clothing includes a hat, long-sleeved shirts and long trousers tucked into socks or boots. Light-colored clothing makes the tick more easily visible before it attaches itself. People should use special care in handling and allowing outdoor pets inside homes because they can bring ticks into the house.

Permethrin sprayed on clothing kills ticks on contact, and is sold for this purpose. Insect repellents with Picaridin, IR3535, DEET or Oil of Lemon Eucalyptus repel ticks as well.

A community can reduce the incidence of Lyme disease by reducing the numbers of primary hosts on which the deer tick depends, such as rodents, other small mammals, and deer. Reduction of the deer population may, over time, help break the reproductive cycle of the deer ticks and their ability to flourish in suburban and rural areas.

An unusual, organic approach to control of ticks and prevention of Lyme disease involves the use of domesticated guinea fowl. Guinea fowl are voracious consumers of insects and arachnids, and have a particular fondness for ticks. Localized use of domesticated guinea fowl may reduce dependence on chemical pest-control methods.

Vaccines
New vaccines are being researched using outer surface protein C (OspC) and glycolipoprotein as methods of immunization. Vaccines have been formulated and approved for prevention of Lyme disease in dogs. There are currently three Lyme disease vaccines available. The first is LymeVax, formulated by Fort Dodge Laboratories. This vaccine contains intact dead spirochetes which expose the host to the organism. The second vaccine is Galaxy Lyme, or Intervet-Schering-Plough's vaccine. This formula targets proteins OspC and OspA. The OspC antibodies kill any of the bacteria that has not been killed by the OspA antibodies. The third vaccine, Canine Recombinant Lyme, formulated by Merial, generates antibodies against the OspA protein so that a tick feeding on a vaccinated dog draws in blood full of anti-OspA antibodies, which kill the spirochetes in the tick's gut before they are transmitted to the dog.

Treatment:

oral antibiotics options
The choice of antibiotic therapy is guided by weighing the greater activity of intravenous antibiotics in the central nervous system against the lower cost and easy administration of oral antibiotics for B. burgdorferi.

First-line drug therapies for Lyme disease may include (in alphabetical order): oral amoxicillin, azithromycin, cefuroxime, clarithromycin, doxycycline, and tetracycline. These antibiotics have similar favorable results in comparative trials of early Lyme disease.

Intravenous Antibiotic Options
It is common practice to consider intravenous antibiotics upon failure of oral medications in patients with persistent, recurrent, or refractory Lyme disease, and as the first line of therapy for certain conditions, (i.e., encephalitis, meningitis, optic neuritis, joint effusions, and heart block).

Ideally, the intravenous antibiotic should be selected on the basis of in vitro sensitivity testing or clinical experience. Intravenous antibiotics are also justified by concern for penetration into the central nervous system.

Until recently, ceftriaxone, cefotaxime, and penicillin were the only intravenous antibiotics routinely studied for use in Lyme disease. Intravenous imipenem, azithromycin, and doxycycline have an adequate antispirochetal spectrum of activity and may represent suitable alternative therapies. However, the latter two drugs are often considered for intravenous use only if they are not tolerated orally.

Intramuscular Antibiotic Options
Intramuscular benzathine penicillin (1.2 to 2.4 million units per week) is sometimes effective in patients who do not respond to oral and intravenous antibiotics. If intramuscular benzathine penicillin is used, long-term therapy may be necessary due to the low serum concentration of this form of penicillin. Benzathine penicillin has mainly been used in patients who have had multiple relapses while receiving oral or intravenous antibiotic therapy or who are intolerant of oral or intravenous antibiotics.

Combination Antibiotic Treatment
Combination therapy with two or more antibiotics is now increasingly used for refractory Lyme disease and has also been given as initial therapy for some chronic presentations.

This approach is already used for another tick-borne illness, babesiosis. Oral amoxicillin, cefuroxime, or (more recently) cefdinir combined with a macrolide (azithromycin or clarithromycin)are examples of combination regimens that have proven successful in clinical practice, although controlled clinical trials are lacking in persistent, recurrent, and refractory Lyme disease.

Combination therapy in patients with Lyme disease raises the risk of adverse events. This risk must be weighed against the improved response to combination therapy in Lyme disease patients failing single agents.

Sequential Treatment
Clinicians increasingly use the sequence of an intravenous antibiotic followed by an oral or intramuscular antibiotic. In two recent case series that employed combination therapy and sequential therapy, most patients were successfully treated. A logical and attractive sequence would be to use intravenous therapy first (e.g., intravenous ceftriaxone), at least until disease progression is arrested and then follow with oral therapy for persistent and recurrent Lyme disease.

Dosage
Increasingly, clinicians recommend that certain drugs used for Lyme disease be given at higher daily doses: for example, 3,000–6,000 mg of amoxicillin, 300–400 mg doxycycline, and 500–600 mg of azithromycin. Some clinicians prescribe antibiotics using blood levels to guide higher doses. Close monitoring of complete blood counts and chemistries are also required with this approach.

With higher doses, there may be an increase in adverse events in general and gastrointestinal problems in particular. Acidophilus has reportedly reduced the incidence of Clostridium difficile colitis and non-C. difficile antibiotic-related diarrhea.

Serious adverse effects of antibiotics, however, were less common than previous estimates. In a recent clinical trial of chronic Lyme disease, the overall serious adverse event rate was 3% after three months of antibiotics, including 1 month of intravenous antibiotics. Clinicians who have experience with higher dose antibiotic therapy must balance the benefit of higher drug levels achieved with this therapy against the modest risk of gastrointestinal and other side effects.

Duration of Therapy
Because of the disappointing long-term outcome with shorter courses of antibiotics, the practice of stopping antibiotics to allow for a delayed recovery is no longer recommended for patients with persistent, recurrent, and refractory Lyme disease. Reports show failure rates of 30–62% within 3 years of short-course treatment using antibiotics thought to be effective for Lyme disease. Conversely for neurologic complications of Lyme disease, doubling the length of intravenous ceftriaxone treatment from 2 to 4 weeks improved the success rate from 66 to 80%.

The management of chronic Lyme disease must be individualized, since patients will vary according to severity of presentation and response to previous treatment.

Concurrent risk factors (i.e., coinfections, previous treatment failures, frequent relapses, neurologic involvement, or previous use of corticosteroids) or evidence of unusually severe Lyme disease should lead to the initiation of prolonged and/or intravenous antibiotic treatment. Physicians should always assess the patient’s response to treatment before deciding on appropriate duration of therapy (i.e., weeks versus months).

Treatment Failure
When patients fail to respond or their conditions deteriorate after initiation of empiric therapy, a number of possibilities should be considered other than Jarisch-Herxheimer reaction. These include adverse events that limit treatment, allergic history to medication, inappropriate or inadequate dosing regimen, compliance problems, incorrect medication, immune sequelae, and sequestering of the organism (e.g., in the central nervous system). An alternative diagnosis or coinfection should also be considered.

Conclusion
Lyme can be controlled if appropriate policies are followed, effective clinical and public health management is ensured, and there are committed and co-ordinated efforts from within and outside the health sector. However, in the context of a large epidemic of lyme incidence will inevitably increase. By 2001, more than 30% of global Lyme cases were reported to have received effective diagnosis, treatment and monitoring. Rapid expansion of effective Lyme control services is urgently required, both to avert the continued high burden of morbidity and mortality from Lyme.

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