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Diagnosing and Treating Lyme Disease

Imagine you went out in the woods and you came back with an attached tick. You quickly remove it, but begin feeling unwell in the next few days. What do you do? Is it Lyme disease? And, if so, how do you treat it? This blog will focus on how Lyme disease is most commonly diagnosed and treated, as well as how Borrelia burgdorferi copes with these treatments.

Diagnosing Lyme disease can be tricky. Most of the diagnostic tests that are currently used for Lyme disease are not perfect, which is why there are several cases of both false negatives and false positives every year (Borchers et al. 2015). Doctors generally approach suspected Lyme disease cases in the following way. First, a patient history is taken in order to establish a patient’s probable exposure to infected Ixodes ticks. The doctor should consider whether the areas visited are endemic areas for Lyme disease and if it occurred at an appropriate time of year (nymph season or adult season for ticks). Next, the doctor will assess the physical symptoms of the patient. Unless the patient is exhibiting erythema migrans (a circular skin rash commonly called a “bull’s eye,” see picture), a doctor cannot diagnose a patient with Lyme disease using only physical symptoms and patient history (CDC 2011). Most symptoms of Lyme disease are very general and could be due to other pathogens (Borchers et al. 2015). The erythema migrans, however, is specific to Lyme disease and doctors often decide not to use serological tests if the patient has both the distinct rash and exposure to infected ticks.

If the doctor feels a serological test is needed, he/she will usually begin with a sensitive enzyme immunoassay (EIA), such as the enzyme-linked immunosorbent assay (ELISA) (Borchers et al. 2015). Some doctors prefer to use an indirect immunofluorescence assay instead of an EIA, although this is rare. If results from these initial tests are positive or indeterminate, the blood serum will undergo immunoblotting, such as a western blot. An immunoblot is considered positive if it meets the CDC’s recommended number and types of IgM and IgG bands (CDC 1995). It should be noted that serological confirmation can be hampered if the patient is tested before antibodies against the Borrelia species are generated. For example, IgM antibodies are usually not detectable for the first 1-2 weeks while IgG antibodies may not emerge until 4-6 weeks after the initial infection (Craft et al. 1984; Aguero-Rosenfeld et al. 1993; Berglund et al. 1995; Engstrom et al. 1995; Aguero-Rosenfeld et al. 1996; Glatz et al. 2008; Steere et al. 2008). Another laboratory test that is sometimes used by doctors is to culture the bacteria (Borchers et al. 2015). This procedure is not common, however, since culture is expensive and requires special media and laboratory expertise. Additionally, results from culture are not available for 2-6 weeks, making it less useful for clinical decision making.

So what happens if you do test positive for Lyme disease? Lyme disease is routinely treated with antibiotics. The main antibiotics used include β-lactams (especially cephalosporins), tetracyclines (ex. Doxycycline), and macrolides (though not as effective as the other two kinds) (Borchers et al. 2015). The antibiotic prescribed depends on certain patient characteristics, such as age, antibiotic allergies, and pregnancy. There is currently a big debate on how long the treatment should last. This is due to the large variety present in both patient immunocompetence and Borrelia strain pathology (Preac Mursic et al. 1996). Several randomized controlled trials and retrospective studies found that there is no benefit in extending the duration of Doxycycline treatment from 10 days to 15 or 20 days (Wormser et al. 2003; Kowalski et al. 2010; Stupica et al. 2012). Similarly, Oksi et al (2007) found that patients who received both a 3-week course of I.V. ceftriaxone and 100 days of amoxicillin did not have a significantly improved outcome when compared to patients who only received the 3-week course of I.V. ceftriaxone. Borchers et al (2015) point out, however, that some patients may benefit from a longer and/or more aggressive therapy. Doctors have to therefore carefully assess the risk-benefit ratio for each individual patient.

Dosages depend on the antibiotic prescribed and the patient’s age and symptoms. For example, adult patients with classic early Lyme symptoms (erythema migrans rash, flu-like symptoms) are prescribed 2 x 100 mg of doxycycline (for 10-21 days), while children with similar symptomology receive 2 x 2 mg/kg of doxycycline (also for 10-21 days) (Wormser et al. 2006; Mygland et al. 2010; BIA 2011). Given the same set of symptoms, the dosage for amoxicillin would be 3 x 500 mg (14-21 days) for adults and 50 mg/kg in 3 divided doses for children. If the adult patient is exhibiting signs of Lyme neuroborreliosis, however, their doxycycline dosage would be increased to 2 x 200 mg (for 10-28 days).

As mentioned in earlier blogs, Borrelia burgdorferi is an expert at hiding itself in the body which allows it to evade the body’s immune system. Examples include B. burgdorferi residing in areas that are less accessible to the host’s immune system (eyes, joints, central nervous system; Janeway and Travers, 1996), hiding within cells (endothelial cells, macrophages, synovial cells, Kupffer cells, fibroblasts; Ma et al. 1991; Klempner et al. 1993; Montgomery et al. 1993; Girschick et al. 1996; Sambri et al. 1996), or encysting itself (Murgia et al. 2002). This evasion, however, also applies to antibiotics. Smith et al (2014) argue that antibiotic treatment is only effective in the early stages of Lyme disease before the bacteria has a chance to hide itself. Once the bacteria is well-established, as with chronic Lyme disease, common antibiotic treatments lose some or all of their effectiveness (Smith et al. 2014). Sharma et al. 2015 found that B. burgdorferi does not necessarily become resistant to antibiotics but instead forms drug-tolerant persister cells. Persister cells are dormant variants of regular cells that can tolerate the presence of antibiotics. This is another potential reason for why so many people progress to the later stages of Lyme disease, which are characterized by symptoms such as arthritis, meningitis, encephalopathy, and carditis (Reznick et al. 1986; Fallon and Nields, 1994; Puius and Kalish, 2008).

So why don’t we just spray a bunch of insecticides to reduce the tick populations? Won’t this help reduce the incidence of Lyme disease? Targeted spraying of acaricides seems to help lower the tick concentration in residential areas (Curran et al. 1993; Allain and Patrican, 1995; Schulze et al. 2001). Examples of acaricides currently used include permethrin, deltamithrin, carbaryl, and chlorpyrifos. Schulze et al (2005) found that a single application of granular deltamethrin reduced the tick population by 100% for up to 12 weeks. However, the chance of ticks developing resistance to acaricides increases with overuse of insecticides. Rhipicephalus (Boophilus) microplus ticks, more commonly known as cattle ticks, in the United States are showing resistance against both organophospates and permethrin (Kunz and Kemp, 1994; Miller et al. 2007). The Boophilus tick is in the same family as Ixodes scapularis (Family Ixodidae), suggesting that this resistance may also develop in the main vector of Lyme disease in North America. A main difference between these two tick species, however, is that Boophilus is a single-host tick while I. scapularis is a multi-host tick (three hosts to be exact). These multi-host ticks typically do not develop resistance to insecticides as quickly as ticks who depend on just one host (Kunz and Kemp, 1994). It should be noted, however, that multi-host ticks have already developed resistance to earlier acaricides, including OP-carbamate, toxaphene, and lindane acaricides (Kunz and Kemp, 1994). Therefore, resistance against the newer acaricides will probably develop over time.

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