Eye on ID

Where has Lyme disease gone?

Lyme disease is here and doing well. It now is the most commonly reported vector-borne illness in the United States, with about 20,000 to almost 30,000 confirmed cases reported annually. In fact, the number may be considerably higher; the CDC estimates that the actual number of Lyme disease cases diagnosed annually may be as high as 300,000. Cases have been reported in every state in the last 10 years, with the exception of Hawaii. However, this disease is heavily concentrated in certain regions, with 96% of cases reported in 13 northeastern and north-central states [CDC. Lyme Disease Data. www.cdc.gov/lyme/stats/index.html (2014)], which correspond with the known geographic distribution of the Lyme disease vector Ixodes scapularis, the blacklegged or deer tick. Additional underreporting likely occurs in some highly endemic areas, like beach communities with transient summer residents, because diseases are reported by county of residence, rather than where the disease actually was acquired.

Because of complications of delayed arthritis, peripheral neuropathy, cardiac manifestations and/or encephalomyelitis in untreated patients, Lyme disease is a larger problem than just the acute infection. Approximately 10% to 20% of patients treated for Lyme disease with the usually recommended 2- to 4-week course of antibiotics will have lingering symptoms of fatigue, joint and muscle aches, persistent pain, impaired cognitive function, or unexplained numbness. This condition in some patients can last for more than 6 months. According to the CDC, although this entity is often called “chronic Lyme disease,” the condition is properly known as “post-treatment Lyme disease syndrome,” or PTLDS [CDC. Post-Treatment Lyme Disease Syndrome. www.cdc.gov/lyme/postLDS/ (2014)]; its cause is unknown.

The two major questions with Lyme disease currently are: 1) Why isn’t there a vaccine for humans as there are for dogs and horses and 2) Why are there two distinctly different guidelines for prevention and treatment of Lyme disease, one as proposed by the International Lyme and Associated Diseases Society (ILADS) and the other by the Infectious Diseases Society of America (IDSA). Both questions have complex answers.

In the US, there are four veterinary vaccines, but no vaccine currently is available to prevent Lyme disease in humans. LYMErix (GlaxoSmithKline), a recombinant Lyme disease vaccine containing an outer surface protein (OspA) from Borrelia burgdorferi, was first licensed in 1998. Its mechanism of action was unusual: OspA antigen in the vaccine stimulated circulating anti-OspA antibodies that would be ingested by the tick during a blood meal and kill B. burgdorferi within the tick’s gut as it fed on the human host, before the bacteria were able to enter the body. The vaccine was about 80% effective in protecting against the infection, but three doses were required during a 12-month period, so that people were not fully protected in the first year of vaccination. Further, the duration of protection was unknown so additional booster injections may have been necessary, and the vaccine was not approved for use in children aged younger than 15 years.

The vaccine manufacturer discontinued production in 2002 as a result of insufficient consumer demand, as well as public concern about adverse effects (arthritis) and class action lawsuits. The concerns about OspA vaccine side effects involved a theoretically possible inflammatory arthritis due to antibodies against B. burgdorferi antigens that could cross-react with autoantigens (ie, molecular mimicry) in people with HLA-DR4 haplotype. This experience certainly put a crimp in plans for the development of any Lyme disease vaccine in the future.

Despite these historical complications, there is a place for a properly marketed vaccine aimed at people who live or vacation in the states with high incidence rates. A vaccine based on a component of B. burgdorferi other than OspA that did not require multiple injections would be desirable. A new, potentially safer second-generation vaccine for humans that excludes the cross-reactive epitope is being studied. Whether it would be commercially successful is an open question.

Donald Kaye

Donald Kaye

The other question about approaches to prevention or management of Lyme disease and PTLDS, or “chronic Lyme disease,” is more complicated. It is understandable that people who have chronic symptoms look for ways to try to alleviate these symptoms, and advocacy groups exist for virtually every disease or symptom complex. The Lyme disease advocacy groups and the physicians affiliated with these groups recommend longer courses of antibiotic therapy for virtually every aspect of Lyme disease, including the entity of PTLDS, or “chronic Lyme disease,” which probably constitutes many different entities. The guidelines of the ILADS recommend:

The assumptions of the ILADS supporting its recommendations are related mainly to reinterpretation and reanalysis of existing papers used by the IDSA as evidence in developing its guidelines, often questioning the quality of some randomized clinical trials as compared with the IDSA and emphasizing the clinical judgment of the treating physician. The general theme of the ILADS recommendations is that Lyme disease is often chronic, causing fatigue, aches and pains, and neurocognitive difficulties related to persistence of live B. burgdorferi in the body. To give credit for transparency, each of its recommendations is followed by “(Recommendation, very low-quality evidence).” The recommendations are mainly driven by the ILADS’ perception of risk/benefit, where the perceived risk is treatment failure or “chronic Lyme disease,” and the perceived benefit is the possibility of preventing or treating these complications.

After reviewing both sets of guidelines and the reasoning behind them, it seems to us that the major difference is how much credence is put on the published randomized clinical trials that suggest no advantage in prolonged therapy, and the evaluation of perceived risk/benefit and cost/benefit of prolonged therapy. To us, the recommendations of the IDSA make most sense until or unless studies demonstrate a clear-cut advantage of prolonged therapy.

For more information:

Matthew E. Levison, MD, is a ProMED-mail bacterial disease moderator, professor of public health, Drexel University of Public Health, and adjunct professor of medicine and former chief of the division of infectious diseases, Drexel University College of Medicine.
Donald Kaye, MD, is a professor of medicine at Drexel University College of Medicine, associate editor of ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member. 

Disclosure: Kaye and Levison report no relevant financial disclosures.

Lyme disease is here and doing well. It now is the most commonly reported vector-borne illness in the United States, with about 20,000 to almost 30,000 confirmed cases reported annually. In fact, the number may be considerably higher; the CDC estimates that the actual number of Lyme disease cases diagnosed annually may be as high as 300,000. Cases have been reported in every state in the last 10 years, with the exception of Hawaii. However, this disease is heavily concentrated in certain regions, with 96% of cases reported in 13 northeastern and north-central states [CDC. Lyme Disease Data. www.cdc.gov/lyme/stats/index.html (2014)], which correspond with the known geographic distribution of the Lyme disease vector Ixodes scapularis, the blacklegged or deer tick. Additional underreporting likely occurs in some highly endemic areas, like beach communities with transient summer residents, because diseases are reported by county of residence, rather than where the disease actually was acquired.

Because of complications of delayed arthritis, peripheral neuropathy, cardiac manifestations and/or encephalomyelitis in untreated patients, Lyme disease is a larger problem than just the acute infection. Approximately 10% to 20% of patients treated for Lyme disease with the usually recommended 2- to 4-week course of antibiotics will have lingering symptoms of fatigue, joint and muscle aches, persistent pain, impaired cognitive function, or unexplained numbness. This condition in some patients can last for more than 6 months. According to the CDC, although this entity is often called “chronic Lyme disease,” the condition is properly known as “post-treatment Lyme disease syndrome,” or PTLDS [CDC. Post-Treatment Lyme Disease Syndrome. www.cdc.gov/lyme/postLDS/ (2014)]; its cause is unknown.

The two major questions with Lyme disease currently are: 1) Why isn’t there a vaccine for humans as there are for dogs and horses and 2) Why are there two distinctly different guidelines for prevention and treatment of Lyme disease, one as proposed by the International Lyme and Associated Diseases Society (ILADS) and the other by the Infectious Diseases Society of America (IDSA). Both questions have complex answers.

In the US, there are four veterinary vaccines, but no vaccine currently is available to prevent Lyme disease in humans. LYMErix (GlaxoSmithKline), a recombinant Lyme disease vaccine containing an outer surface protein (OspA) from Borrelia burgdorferi, was first licensed in 1998. Its mechanism of action was unusual: OspA antigen in the vaccine stimulated circulating anti-OspA antibodies that would be ingested by the tick during a blood meal and kill B. burgdorferi within the tick’s gut as it fed on the human host, before the bacteria were able to enter the body. The vaccine was about 80% effective in protecting against the infection, but three doses were required during a 12-month period, so that people were not fully protected in the first year of vaccination. Further, the duration of protection was unknown so additional booster injections may have been necessary, and the vaccine was not approved for use in children aged younger than 15 years.

The vaccine manufacturer discontinued production in 2002 as a result of insufficient consumer demand, as well as public concern about adverse effects (arthritis) and class action lawsuits. The concerns about OspA vaccine side effects involved a theoretically possible inflammatory arthritis due to antibodies against B. burgdorferi antigens that could cross-react with autoantigens (ie, molecular mimicry) in people with HLA-DR4 haplotype. This experience certainly put a crimp in plans for the development of any Lyme disease vaccine in the future.

Despite these historical complications, there is a place for a properly marketed vaccine aimed at people who live or vacation in the states with high incidence rates. A vaccine based on a component of B. burgdorferi other than OspA that did not require multiple injections would be desirable. A new, potentially safer second-generation vaccine for humans that excludes the cross-reactive epitope is being studied. Whether it would be commercially successful is an open question.

Donald Kaye

Donald Kaye

The other question about approaches to prevention or management of Lyme disease and PTLDS, or “chronic Lyme disease,” is more complicated. It is understandable that people who have chronic symptoms look for ways to try to alleviate these symptoms, and advocacy groups exist for virtually every disease or symptom complex. The Lyme disease advocacy groups and the physicians affiliated with these groups recommend longer courses of antibiotic therapy for virtually every aspect of Lyme disease, including the entity of PTLDS, or “chronic Lyme disease,” which probably constitutes many different entities. The guidelines of the ILADS recommend:

The assumptions of the ILADS supporting its recommendations are related mainly to reinterpretation and reanalysis of existing papers used by the IDSA as evidence in developing its guidelines, often questioning the quality of some randomized clinical trials as compared with the IDSA and emphasizing the clinical judgment of the treating physician. The general theme of the ILADS recommendations is that Lyme disease is often chronic, causing fatigue, aches and pains, and neurocognitive difficulties related to persistence of live B. burgdorferi in the body. To give credit for transparency, each of its recommendations is followed by “(Recommendation, very low-quality evidence).” The recommendations are mainly driven by the ILADS’ perception of risk/benefit, where the perceived risk is treatment failure or “chronic Lyme disease,” and the perceived benefit is the possibility of preventing or treating these complications.

After reviewing both sets of guidelines and the reasoning behind them, it seems to us that the major difference is how much credence is put on the published randomized clinical trials that suggest no advantage in prolonged therapy, and the evaluation of perceived risk/benefit and cost/benefit of prolonged therapy. To us, the recommendations of the IDSA make most sense until or unless studies demonstrate a clear-cut advantage of prolonged therapy.

For more information:

Matthew E. Levison, MD, is a ProMED-mail bacterial disease moderator, professor of public health, Drexel University of Public Health, and adjunct professor of medicine and former chief of the division of infectious diseases, Drexel University College of Medicine.
Donald Kaye, MD, is a professor of medicine at Drexel University College of Medicine, associate editor of ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member. 

Disclosure: Kaye and Levison report no relevant financial disclosures.