Chapter 53: Tickborne Disease

General Considerations

Tickborne diseases are on the rise in the United States. Several factors contribute to this surge, including suburban development, climate change, a rise in human outdoor activities, and an increase in vector hosts such as White-Tailed deer. Lyme disease is the most widely known tickborne illness to the public, as well as the most common. During 2000–2010 there were 250,000 reported cases of Lyme disease in the United States, although there has not been an incremental increase in the number of cases reported each year. However, the incidence of reported cases of anaplasmosis, babesiosis, ehrlichiosis, and Rocky Mountain Spotted Fever have all increased over that period of time and are the next most common TBDs after Lyme. The tickborne illnesses mentioned above will be discussed in detail in this chapter. Numerous other diseases are associated with ticks as vectors, many of which are emerging. (For more information regarding these illnesses, visit the following CDC webpage: http://www.cdc.gov/ticks/).

One factor that is essential to the diagnosis and treatment of TBD is the geographic distribution of the particular disease (Figure 53-1). Lyme disease, Rocky Mountain Spotted Fever (RMSF), ehrlichiosis, human granulocytic anaplasmosis (HGA), and babesiosis are all associated with particular species of ticks. Table 53-1 lists the six tick species of significance for this chapter, including their distribution and primary hosts. However, the patient rarely presents with the actual tick attached, and therefore visual identification of species is typically unnecessary.

Pathogenesis

As is the case in any vector borne disease, ticks require hosts to survive and to transmit pathogens. Their lifecycle consists of egg, larval, nymph, and adult stages. Only ticks in the nymph and adult stages are able to attach to humans. These stages are most active during the summer months hence the seasonality of most TBDs. Humans are incidental, not primary, hosts. Primary hosts (mice, deer, dogs) serve as reservoirs for the diseases. Ticks attach to any host from outdoor contact with grasses, shrubs, and foliage, but vector-to-vector attachment can occur. Ticks feed on blood. In order to do so, they extend a mouthpiece into the host, secreting saliva with anesthetic properties. This saliva is where TBD pathogens are contained. In cases where saliva and blood contact is made, transmission can occur.

The pathogens themselves complicate the diagnosis of TBD. In the United States the causative organism of Lyme disease (Borrelia burgdorferi) is a spirochete, RSMF (Rickettsia rickettsii) is a gram-negative intracellular bacillus, ehrlichiosis (Ehrlichia chaffeensis/ewingii) and HGA (Anaplasma phagocytophilum) are intracellular gram-negative coccobacilli, and babesiosis (Babesia microti) is an intraerythrocyte protozoa. The atypical nature of these organisms makes for complicated pathophysiology in disease, but also complicates diagnosis and treatment.

Prevention

Primary prevention of tickborne disease is achieved through a reduction of bites. Wearing light-colored clothing to facilitate tick visualization, as well as decreasing exposed skin area, has been demonstrated to be effective. Skin examination and showering within 2 hours after spending extended periods outdoors is recommended in tick-endemic areas. If a tick is discovered, forceps (Figure 53-2) or a commercial tick removal device should be utilized to mechanically remove the arthropod. No chemical means of removal are recommended.

Environmental alterations such as cutting tall grass and reducing brush and leaf piles will reduce outdoor areas where people would likely be affected by ticks. These measures also prevent attracting native hosts such as deer and mice. An environmental pesticide can also be extremely useful in endemic areas for total tick population reduction. At the present there are no TBD vaccines available on the market for humans. A previously available Lyme disease vaccine has been off the market for many years. Those who were inoculated using this product should no longer consider themselves immunized against Lyme disease. Of the personal repellents, products with N,N-diethyl-3-metylbenzamide (DEET) are the most effective. DEET product concentration ranges from 5% to 100%. The American Academy of Pediatrics advises against using any concentration that is >30%, although the CDC specifically recommends concentrations >20% for tick bite prevention. Children aged >2 months can use DEET. Its efficacy in patients of all ages lasts between 1 to 5 hours depending on the concentration and extended periods outdoors merits reapplication to skin and clothing. The same rule applies for picaridin, which is effective for ≤3 hours and can been applied to the skin as well as clothing. No other repellents can be safely applied to the skin, but clothing immersed in permethrin solutions have been shown to be effective tick repellents.

Lyme disease is the only TBD for which antibiotic prophylaxis is recommended. If a patient presents with the history of tick attachment for >36 hours, antibiotic prophylaxis may be given within 72 hours after the removal. Doxycycline is the only antibiotic indicated for this: 200 mg by mouth (PO) once or ≤200 mg per 8 mg/kg for children aged >8 years. Prophylaxis with doxycycline is recommended only in the Lyme-endemic areas, which include locations with a tick infection rate of >20%. These areas are the Northeast from Maryland to Maine, Minnesota and Wisconsin, but not the West Coast when prevalence rates are low.

General Considerations

A. Symptoms & Signs

Overall, 94% of Lyme cases are reported from Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Jersey, New Hampshire, New York, Pennsylvania, Virginia, and Wisconsin. Although Lyme disease is the most common vectorborne disease in the United States, the diagnosis is complicated by two potential stages of illness with variable presentations involving dermatologic, musculoskeletal, neurologic, and cardiac findings.

The localized stage of Lyme disease is most likely to present in the summer months 3–30 days after a tick bite. The hallmark of localized Lyme disease is erythema migrans (EM) (Figure 5-3). EM is typically at the site of prior tick attachment, often presenting for 7 days after the initial bite. It is characterized by an erythematous, ring or target macular lesion, typically measuring ≥5 cm. Rashes at the site of tick bites in the first 48 hours after a bite are typically local reactions and not indicative of TBD. EM is diagnostic of Lyme disease, and its presence is the only instance in which confirmatory testing is not necessary. This Lyme rash can present alternatively as a nontargetoid bluish lesion, as a rash with central crusting and no clearing, or as multiple red lesions with dusky centers known collectively as disseminated erythema migrans, which is indicative of disease spread. 70-80% of patients with Lyme disease present with EM, which typically resolves within 3–4 weeks without treatment. Along with EM, the most common presenting symptoms of Lyme are fever, headache, myalagias, malaise, and fatigue, which are mostly consistent with a flulike illness but lack upper respiratory or gastrointestinal symptoms (Table 53-2).

The disseminated stage of Lyme disease typically occurs weeks after the initial infection. This can be manifested as disseminated EM as well as the persistence of flulike symptoms. Disseminated Lyme should be suspected in patients presenting in late summer/fall with aseptic meningitis, cranial nerve palsies (particularly Bell palsy), atrioventricular block, myocarditis/pericarditis, migratory joint pain, and large joint monoarthritis or oligoathritis. Late- stage Lyme can manifest with one or more of these symptoms, and in endemic areas it is important to include TBD in the differential for any of these symptoms so that proper laboratory workup can be performed (Table 53-2).

B. Laboratory Findings

Laboratory evaluation in localized Lyme is often nonspecific. An elevated erythrocyte sedimentation rate, elevated liver enzymes, and hematuria or proteinuria can be seen. If a patient is suspected to have aseptic meningitis presenting with fever and headache, the cerebrospinal fluid (CSF) can demonstrate elevated lymphocytes/lymphocytic predominance, mild increase in protein, and normal glucose. The CDC has two accepted diagnosis methodologies for Lyme disease: EM and the presence of at least one sequela of late-stage disease and confirmatory testing. Serologic antibody testing is the laboratory diagnosis of choice. However, antibody testing is not helpful for early disease, as IgM does not develop until 2–4 weeks after initial disease and IgG typically takes longer than 4 weeks to develop. When ELISA testing is ordered, positive or indeterminate tests are typically followed by Western blot confirmation as false positives are common. Lyme disease–specific antibodies from CSF may be helpful in diagnosing cases of meningitis (Table 53-2).

C. Other Considerations

Imaging studies may be useful in ruling out other etiologies when considering Lyme disease. The differential diagnosis should include other tickborne diseases, especially HGA, babesiosis, and Southern Tick-Associated Rash Illness (STARI). STARI is an emerging tick-borne disease with unknown etiology, but very similar presentation to early Lyme. At present the CDC recommends using the same antibiotics to treat STARI that are used to treat Lyme (Table 53-3). Non-tick related differentials for EM include local tick bite reaction, cellulitis, erythema multiforme, nummular eczema, granuloma annulare, contact dermatitis, and alternative arthropod bites. For late stage Lyme the differential includes juvenile idiopathic arthritis, rheumatoid arthritis, septic arthritis, gout, pseudogout, viral meningitis, multiple sclerosis, other etiologies of Bell palsy, and lymphoma.

Treatment

The treatment of Lyme disease is complicated by the local and disseminated stages. Treatment options for those presenting with erythema migrans are doxycycline, cefuroxime, and amoxicillin for a ≥14-day course. There is some evidence supporting doxycycline use for only 10 days. Intravenous dosing with cetriaxone, cefotaxime, and penicillin G is indicated in patients with central nervous system (CNS) and cardiac manifestations. Arthritis manifestations without CNS manifestations can be treated with the aforementioned oral medications for 28 days (Table 53-3).

Prognosis

Prognosis for Lyme is good, especially with early treatment. Even if disease progresses to disseminated stage, disability is uncommon. Treatment at any stage portends a high likelihood of symptom resolution, but lasting symptoms typically consist of arthralgias and/or sensory deficits (CN VII). Chronic Lyme disease is a separate entity with symptoms typically consisting of musculoskeletal pain and fatigue. Chronic or posttreatment Lyme continues to be an area of controversy. Studies are ongoing as to potential etiologies, but continued antibiotic treatment after resolution of active disease is not indicated.

General Considerations

A. Symptoms & Signs

Rocky Mountain Spotted Fever cases have been reported in most US states. It is a medical misnomer as 60% of cases occur in North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri. RMSF is considered to be the most severe tickborne illness in the United States as it causes a systemic, small vessel vasculitis and has a mortality rate of ≥25% without treatment. The classic presentation of RMSF is fever, rash, and headache 2–14 days after a tick bite. However, myalgias, nausea, and changes in mental status are common on acute presentation. The hallmark rash of RMSF is maculopapular and occurs in ≤90% of patients, typically 2–5 days after the fever presents. The rash classically first appears as discrete, blanchable lesions on the wrists, ankles, and forearms that spreads to the trunk, palms, and soles (Figure 53-4). However, diagnosis should not be based on the appearance of a rash, as this can delay treatment (Table 53-2).

Because of the vasculitic nature of the disease, petechiae can occur after 6 days of symptoms. Development of petechiae often occurs in untreated disease and is a poor prognostic sign. Another poor prognostic sign is CNS involvement with meningismus and altered mental status. Clinical diagnosis is imperative to initiating proper treatment, which significantly reduces morbidity.

B. Laboratory Findings

Early disease is associated with thrombocytopenia (most common), a mild elevation in liver enzymes, anemia, and hyponatremia. Again, RMSF is a clinical diagnosis as antibodies are detectable only 7–10 days after illness onset. In the event of a positive IgG antibody test, repeat testing 2–4 weeks following the initial testing is recommended. If the follow-up IgG testing demonstrates a fourfold titer increase, RMSF is confirmed. For those patients presenting with CNS symptoms, cerebrospinal fluid analysis is typically unremarkable (Table 53-2).

C. Other Considerations

Twenty percent of RSMF cases are in children, making the diagnosis even more difficult given initial symptom overlap with other viral illnesses as well as other TBDs. It is important to bear in mind that 90% of cases are reported between April and September. In those patients who are acutely ill, it is important to obtain infectious disease consultation early in the course of the evaluation and treatment.

Treatment

The key treatment decision when RMSF is considered in the differential is to select doxycycline as the antibiotic of choice. Clinical suspicion merits treatment. Doxycycline is first-line therapy for patients of all ages, including children. There is no evidence to show permanent teeth discoloration with limited dosing, and unfortunately the use of other antibiotics has been shown to increase mortality (Table 53-3).

Prognosis

In patients who receive early antibiotics, the mortality rate with RMSF is approximately 2–3%. A delay in antibiotic treatment to >5 days increases that rate to >20%. Although most patients who are treated with antibiotics recover without long-term complications, some patients have persistent neurologic symptoms such as gait abnormalities, speech difficulty, dysphagia, and/or encephalopathy. These symptoms may resolve over time, but reinforce the critical nature of early treatment with doxycycline.

General Considerations

A. Symptoms & Signs

Ehrlichiosis and HGA have similar clinical manifestations, but are associated with two different species of ticks. HGA, commonly known as anaplasmosis, is associated with the Ixodes species and is also the tick that carries Lyme disease. Therefore coinfection is possible as HGA is found in the same primary range of the Great Lakes and northeastern United States. Ehrlichiosis is reported most frequently in the southeastern United States. Both diseases present with fever, headache, malaise, and myalgias 1–2 weeks after tick bite. These nonspecific symptoms make the diagnosis difficult, and occasionally nausea, vomiting, and a maculopapular rash (particularly in children) complicate the diagnostic picture, due to a clinical presentation similarity to RSMF or Lyme.

Laboratory Findings

Nonspecific findings for both HGA and ehrlichiosis include mild anemia, thrombocytopenia, leucopenia, and liver enzyme elevation. During the early phase of illness morulae, or HGA/Ehrlichial inclusion bodies, may be visualized in leukocytes and are highly indicative of acute infection. However, the absence of morulae on peripheral smears does not exclude either diagnosis.Similar to RMSF, antibody testing is the gold standard for confirmation of disease. Initial IgG antibody titers positive for HGA or ehrlichiosis occur 7–10 days after symptoms start. Confirmation of disease is made by repeating IgG testing in 2–4 weeks and noting a fourfold increase in titers. Unlike RMSF, early polymerase chain reaction (PCR) testing is available, but most sensitive in the first week of illness, particularly before the administration of antibiotics.

Treatment

Despite the complexity in diagnosis plus overlapping range and symptoms with other TBDs, ehrlichiosis, HGA, Lyme, and RMSF can all be treated with doxycycline (Table 53-3). The rule of thumb should be if a serious TBD is considered in the differential, use doxycycline for treatment. It can easily be discontinued or treatment refined if an alternative diagnosis is made. However, as with RMSF, doxycycline is the only antibiotic that is highly effective against HGA and ehrlichiosis. As in the case with all TBDs and pregnancy, consider an infectious disease consultation.

Prognosis

Mortality rates with HGA and ehrlichiosis are between 1% and 3% of those with known infections. Although 35–50% of patients will require hospitalization, a majority of those will recover completely with no long-term affects. The elderly and immunocompromised patients are at higher risk.

General Considerations

A. Symptoms & Signs

Unlike the TBDs described above, babesiosis is a protozoan-induced infection. It is reported in the northeastern United States and Great Lakes region, but sporadic cases have been noted across the country, and its incubation period ranges from 1 week to >2 months. The geographic variability and delayed presentation also confirm that babesiosis can be contracted via blood transfusion, which is unique among TBDs. There are approximately 10 such case reports a year.

Babesiosis can be asymptomatic, with only 60% of children and 80% of adults presenting with signs of infection. Typical symptoms include fever, chills, malaise, arthralgias, anorexia, nausea, and dark urine. The physical exam may demonstrate hepatosplenomegaly and jaundice secondary to hemolysis. Patients with hemolysis can have fulminant disease.

B. Laboratory Findings

Anemia secondary to this hemolysis is often noted in babesiosis, as is elevated blood urea nitrogen (BUN) and serum creatinine. Acutely, elevated liver enzymes and thromobocytopenia may also be noted. Microscopic identification of Babesia in the erythrocytes by peripheral blood smear is diagnostic, but the sensitivity is low. PCR analysis positive for Babesia is confirmatory, and IgG testing can be supportive, but does not distinguish between acute and past infection.

Treatment

Similar to malaria, babesiosis requires the use of antiprotozoals. Two combination therapies are recommended: atovaquone plus azithromycin or quinine plus clindamycin. The latter combination is recommended in cases of serious infection. Treatment duration of 7–10 days is usually adequate.

Prognosis

Symptoms of fatigue may persist weeks to months after successful treatment, but complete resolution is common without persisting disability. Recurrence of infection, particularly in the elderly, immunocompromised and asplenic requires extended treatment.