Dr. Nevena Zubcevik’s suggestion during her recent appearance at grand rounds at Martha’s Vineyard Hospital (July 14, “Visiting physician sheds new light on Lyme disease”) that “recent research debunks several commonly held beliefs about the transmission … of tick-borne diseases” is erroneous. Specifically, she is wrong when she states that “the conception [sic] that the tick has to be attached for 48 hours to inject the bacteria is completely outdated.”
There has been no peer-reviewed, believable research accepted by the majority of experts who have spent many years studying ticks and their infections that negates the validity of the well-known grace period of 24 hours of attachment for the transmission of the agent of Lyme disease. In addition, she stated that the two-day course of doxycycline, often prescribed for people who find a tick embedded on their body, has little or no prophylactic value. We strongly disagree.
In a personal communication to one of the authors of this Op-Ed, she states that this is what is stated in a set of treatment guidelines authored by physicians affiliated with the International Lyme and Associated Diseases Society (ILADS). ILADS has no expertise whatever with tick biology or with tick-pathogen interactions, and their recommendations comprise opinions with no factual basis. The ILADS recommendation for 20 days of doxycycline for tick exposure regardless of duration of attachment is, in our opinion, unsupported by facts, and comprises overuse of antibiotics, which is not without risk.
The grace period is technically known as a period of “reactivation.” Pathogens transmitted by hard ticks almost universally (with the exception of viruses) require a period of reactivation and replication before they attain infectivity. The reason for this is best explained with reference to the deer tick–transmitted infections (Lyme disease, babesiosis, and human granulocytic anaplasmosis [HGA]). These are not inherited by the tick, and are acquired during one of the two bloodmeals that must take place before a larva (baby tick) develops into a reproductive adult tick.
The larva feeds on a mouse sometime during July and October. If fed, it will overwinter in the engorged state and start developing to the nymphal (teenager) stage in April. The nymph starts looking for a bloodmeal by the end of May. Thus, the pathogens acquired in September or earlier will spend eight to 10 months in the tick before they have another chance to infect a vertebrate host, such as mice or humans. If the pathogens were metabolically active, they would require energy resources — that of their host, the tick.
This would diminish the tick’s energy resources, and thus it would be less likely to survive to develop. We call this a negative fitness factor. Such negative fitness factors are a powerful target for natural selection, which likely has acted to favor those pathogens which require less energy during that overwintering period. Indeed, most hard tick–transmitted pathogens are metabolically dormant and noninfectious in the host-seeking nymphal tick. The pathogens “go to sleep” during the overwintering so that they don’t negatively impact their host. When the nymphal tick finds a warmblooded animal, its skin temperature is greater than that of the environment, and signals the pathogen: “Wake up.”
The pathogen reactivates, and starts to replicate with the new blood energy source that is coming in as the tick feeds. This is the physiology behind the 24-hour grace period. The pathogen must wake up, and must replicate, and it takes 24 or more hours to become numerous enough to get into the tick saliva to be transmitted into the skin. Very elegant, peer-reviewed molecular analyses demonstrate that there are complex Lyme bacteria gene-regulation events during the 24 hours, or even after the application of heat pulses to bacteria in test tubes or within ticks.
The outer surface proteins of the Lyme disease bacterium change. The babesia parasite develops infectious forms from a primordial cell mass. The bacteria that cause HGA, as well as those causing the related Rocky Mountain spotted fever (for which reactivation was first recognized back in the 1920s), change their density and cell surface. There is a large peer-reviewed scientific literature that establishes reactivation as a fact.
Science is not, however, black and white or yes or no — transmission is probabilistic, with the probability low (but not zero) that a tick attached 12 hours will transmit, increasing to very high probability as the duration of attachment increases, to near certainty if a tick completes its feeding. Are there cases of Lyme disease due to a tick attachment less than 24 hours? Probably, but relatively few, and likely explained by the fact that ticks may feed for a while, detach, reattach to a new host and continue feeding. About 1 in 500 deer tick nymphs collected from Martha’s Vineyard have evidence of a partial bloodmeal. Some of us have speculated that indoor-outdoor cats increase risk, because a tick will feed for awhile, detach by being groomed off by the cat or because the tick does not particularly like feeding on a cat, and because kitty is sleeping with its owner, the tick will resume feeding on the owner. After the tick has fed for who knows how many hours on the cat, it is likely that the grace period might no longer be 24 hours for that individual circumstance.
Two 100mg doses (or one 200mg dose) of doxycycline have been demonstrated to effectively reduce the risk of acquiring Lyme disease when taken within 24 hours of a recognized tick bite. In fact, the peer-reviewed New England Journal of Medicine paper (Nadelman et al. 2001, volume 345, July 12, 2001) that provides the evidence for this practice also provides empirical evidence for the grace period.
Partially fed nymphal ticks transmitted to 10 percent of 81 patients in the placebo group, but unfed ticks (attached but less than 24 hours, determined by measuring the length and width of the ticks) did not transmit at all to 59 patients. Only one of 78 receiving a single 200mg dose of doxycycline after the bite of a partially fed tick developed acute Lyme disease (as defined by erythema migrans). These results clearly demonstrate that the risk of developing Lyme disease is greatly diminished by taking a single 200mg tablet of doxycycline. The equivalent is two tablets of 100mg within a single day.
Although similar prospective clinical trials have not been done for other deer tick–transmitted infections that are treated with doxycycline (human granulocytic anaplasmosis, Borrelia miyamotoi disease), it is very likely that the same 200mg prophylactic dose would work well. (Sadly, babesiosis or deer tick virus would remain unaffected.) In fact, this prophylaxis might also work to reduce the risk of acquiring Rocky Mountain spotted fever or tularemia after a dog tick bite; or monocytic ehrlichiosis and rickettsiosis after Lone Star tick bite. The efficacy is probably due to the fact that relatively few organisms are delivered during the tick bite, and that doxycycline in the blood and lymph binds to the bacteria as they disseminate from the site of the bite through the bloodstream or lymphatic vessels. Ticks do not deliver pathogens into a blood vessel like a hypodermic syringe; they are delivered into the skin, and must make their way to the bloodstream, which takes many hours. There is published evidence that if a Lyme-infected tick feeds on a mouse ear, and the ear skin where the tick fed is removed as many as 24 hours later, the mouse fails to become infected. Of course, there is no need for the drastic action of cutting out a piece of flesh for a human tick bite.
Other comments by Dr. Zubcevik are arguable. Although there may be some diversity in Lyme disease bacteria nationwide, the diversity is very limited here on Martha’s Vineyard. The Telford laboratory has no evidence that there is any species of borrelia in ticks or mice here other than B. burgdorferi, B. miyamotoi, or B. andersoni (a rabbit-infecting species). She also fails to understand that Lyme disease, at least the acute early stage, is a clinical diagnosis, and is not dependent on testing. The statement “with current testing, 69 out of 100 patients who have Lyme disease may go untreated” is not widely accepted, and in fact largely reflects a misuse of testing or misinterpretation of the results.
There is no point in testing a blood sample for antibodies (ELISA and Western blot, the standard two-tiered test) when someone presents with erythema migrans or with a febrile illness suspected to be acute Lyme disease without rash, because the body has not yet made antibodies that are detectable. There are, however, some tests (such as polymerase chain reaction testing or culture of blood) that may directly detect the bacteria in blood of acutely (a clinical term for recent or new) ill patients, but they are not widely used.
Finally, her statement that “the bull’s-eye rash only happens 20 percent of the time” should be carefully interpreted. It is correct (the textbook bull’s-eye rash is not necessarily common), but should not be interpreted as there not being a rash at all. There is an expanding rash of some sort in 60 percent to 70 percent of acute Lyme disease patients.
We do applaud Dr. Zubcevik commenting on the use of doxycycline in children. There has been an unfounded reluctance of physicians to prescribe this drug to pediatric patients due to the alleged staining of teeth. There is little basis to this reluctance, and CDC has published guidelines that recommend doxycycline as the drug of choice for treating suspected or actual Rocky Mountain spotted fever in any child. Physicians should consider the 200mg doxycycline prophylaxis for children bitten by ticks.
We strongly recommend that all patients who have been bitten by a tick be evaluated by a healthcare professional for possible one- or two-dose doxycycline prophylaxis. There is, of course, no need to worry about a tick that is found crawling on the body and is not attached; nor is there much to worry about if the tick is lightly attached and one can say with certainty that it has not been attached for more than a couple of hours. We remind readers that the tick you find may not be the important one; having one bite means you should check very carefully for another one. And having been bitten is hard evidence that you need to do a better job of protecting yourself from additional bites.
Visit the Martha’s Vineyard Tick Borne Disease Initiative website (mvboh.org/abouttbi.html) for ways to reduce your risk of Lyme disease and other tick-borne infections.
Sam Telford, Sc.D.
Professor of Infectious Disease and Global Health, Tufts University
Michael Jacobs, M.D., Jim Butterick, M.D., Michael Loberg, Ph.D.
Vineyard Medical Center and Vineyard Center for Clinical Research
