Tick Bites and Lyme Disease in an Endemic Setting: Title and subTitle BreakProblematic Use of Serologic Testing and Prophylactic Antibiotic Therapy FREE

SINCE ITS DESIGNATION as a nationally reportable disease in January 1991, Lyme disease (LD) has been by far the most commonly reported vector-borne infectious disease in the United States.¹ It is understandably a cause for much concern among physicians and patients in endemic areas. In the absence of erythema migrans, the diagnosis of LD is based on clinical criteria assisted by serologic testing in patients with characteristic clinical manifestations.

The appropriate management of patients bitten by ticks in endemic areas has proved problematic. Although most of the literature dealing with management of tick bites does not recommend antibiotic prophylaxis,^{2 - 5} even in highly endemic areas, a large proportion of practicing physicians prescribe antibiotics for tick bites.^{6 - 8} Further, the use of serologic testing in the management of LD has proved a source of confusion and controversy^{9 - 11} and has rarely been discussed in the context of tick bites. Retrospective studies of the clinical context in which serologic testing for LD has been performed have called into question physicians' use of these tests.^{12 - 13}

The Eastern Shore of Maryland is an area endemic for LD, having the highest incidence in the state.¹⁴ In 1995, the incidence rate of reported LD in Kent County was 86 cases per 100000 population and varied in the 4 adjacent counties from 14 to 64 cases per 100000 population.¹⁵ We assessed patterns of use of serologic tests and antibiotic therapy for tick bites and LD by physicians in this rural, endemic setting.

Patients prospectively identified with clinical diagnoses of tick bites, LD, or suspected LD seen by primary care practitioners in Kent County, Maryland, and within the Delmarva Health Plan (DHP) in the adjacent 4-county area on the Eastern Shore of Maryland from January through November 1995 were included in the study. Patients seeking medical advice following tick bites, but without symptoms of LD, were designated as having tick bite. Cases for which the physician recorded a diagnosis of LD in the medical record were designated as having LD. The data used to make the diagnoses were not evaluated. Patients with LD noted in the medical record as a possible diagnosis, but not considered by the physician as a definite diagnosis, were designated as having suspected LD.

Arrangements were made with the offices of primary care practitioners to keep a roster of all patients seen with LD, suspected LD, or tick bites. The communicable disease surveillance nurses of the Kent County Health Department visited offices in Kent County weekly to abstract data from the medical records of patients appearing on the rosters. A nurse made visits to the practices in the DHP periodically in response to calls from the physicians' offices and/or receipt of computer lists from the DHP of encounters for LD and insect bites, or of lists of those undergoing serologic tests for LD, abstracting data from the medical records of patients identified through these mechanisms.

The following information was extracted from the patient charts: diagnosis, date of onset, dates and types of visits to the physician, dates of diagnostic tests and their results, dates of procedures and their results, dates of hospitalizations, and therapy prescribed. Charges for physician and/or hospital visits, serologic tests, procedures, and antibiotic therapy were ascertained. For patients within DHP, all enzyme immunoassays (EIAs) were performed in the same laboratory using the Lyme Stat Test Kit (Whittaker Bioproducts, Walkersville, Md). Serologic test specimens for patients in Kent County who were not members of DHP, in addition to being sent to the above laboratory, were sent to several commercial laboratories, each of which used a different kit. Western blot confirmation tests for LD were performed in several commercial laboratories.

Since no patient identifiers were to be retained following the collection of preexisting medical record information, this study received an exemption from informed consent by the institutional review boards of the University of Maryland at Baltimore and the Maryland Department of Health and Mental Hygiene. Data were recorded and analysis was performed using Epi Info, version 6.¹⁶

Of a total of 270 medical records reviewed, 232 patients with diagnoses of tick bite, LD, and suspected LD were identified: 142 (61.2%) with tick bite, 40 (17.2%) with LD, and 50 (21.6%) with suspected LD. There was a similar number of males and females (50.4% female). The mean age was 38.7 years, with a range of 1 to 91 years. There was no significant difference among the 3 categories for sex or age (data not shown). Sixty-seven percent of the patients were seen by family practitioners, 18% by internists, 12% by pediatricians, and 3% by gynecologists. Patients were seen by 11 physicians in Kent County and 38 physicians through the DHP in the adjacent 4 counties.

Serologic testing was performed on two thirds of the patients with tick bite (Table 1). Three patients (3.2%) had initially positive or equivocal EIA results. For the 93 patients with initial negative or equivocal serologic test results, repeat specimens were sent for 24 (Table 2), with one of these patients demonstrating seroconversion (nonsimultaneous testing of acute and convalescent sera). Repeat EIA testing was performed, on average, 42 days (range, 10-94 days) after initial testing. None of the patients with tick bite had Western blot testing.

Seventy-eight patients (54.9%) seen for tick bites received prophylactic antibiotic therapy (Table 1). A third of patients with tick bite both underwent serologic testing and received antibiotic therapy, with therapy initiated prior to or simultaneous with submission of serologic specimens for 88% of the patients who were both tested and treated (Table 3).

The majority of treated patients received either doxycycline (44.9%) or amoxicillin (35.9%), with another 11.5% receiving oral cephalosporins, mostly cefadroxil. The remaining 6 patients received azithromycin or ciprofloxacin (2 each) or clarithromycin or amoxicillin with clavulanate (1 each). The mean (SD) duration of therapy was 12.7 (3.9) days.

There were no cases of clinical LD among the patients who presented with tick bites.

Serologic testing for LD was used more frequently in DHP than in Kent County (94% vs 50%, respectively; P<.001), and antibiotics were prescribed less often (40% vs 64%, respectively; corrected χ²P=.01). These differences were attributable primarily to 4 physicians in Kent County who used serologic testing less frequently and treated more often, although there was no characteristic pattern between their use of serologic testing and antibiotic treatment.

Enzyme immunoassay testing was performed for approximately 90% of patients with LD and suspected LD (Table 4 and Table 5). The results were positive for 86% of the LD patients and 9% of the suspected LD patients.

Antibiotic therapy was prescribed for 95% of LD patients and 38% of suspected LD patients (Table 4 and Table 5). As was the case for patients with tick bite, this therapy was prescribed before or simultaneous with obtaining specimens for serologic testing in most patients receiving antibiotics (Table 3). The 2 LD patients who did not receive antibiotic therapy had serum specimens sent within a few days of presentation, with negative results for both. All 8 patients who did not have serologic testing performed received antibiotic therapy (Table 4 and Table 5). Most patients with LD or suspected LD received doxycycline (53% for both groups) or amoxicillin (29% and 37%, respectively) as initial therapy. Five LD patients (13%) received intravenous ceftriaxone at some time during their treatment. The manifestations of patients receiving ceftriaxone included arthritis, facial palsy, and other neurologic symptoms. None of the suspected LD patients received ceftriaxone.

Six patients (16.2%) had Western blot testing (5 with LD and 1 with suspected LD) performed. All had unequivocally positive EIA results, and all but 1 (LD diagnosis) had positive Western blot results.

Convalescent samples were not submitted for most patients with LD and suspected LD who had initial negative or equivocal EIA results (Table 2). Two of the LD patients with negative acute test results demonstrated seroconversion on convalescent testing. The 2 patients with a diagnosis of LD who did not receive antibiotic therapy were among those with a single, negative serologic test. Two thirds of the 37 suspected LD patients with negative or equivocal, single serologic test results were not treated with antibiotics (Table 2).

The total direct charges for diagnosing and managing tick bites and LD for our 232 subjects was $47595 (Table 6). The charge for physician visits represented 35.5%, while the charges for serologic testing for LD, antibiotic therapy, procedures, and other medical expenses were 33.0%, 24.6%, and 6.9%, respectively. The average direct charge per patient was $205, being the least for patients with tick bite ($109) and the most for patients with LD ($569). Tick bites accounted for the largest (43.0%) proportion of charges for serologic testing for LD, 43.1% of the charges for physician visits, and 32.6% of total charges. Because of the high cost of intravenous ceftriaxone given to 5 patients with LD, LD accounted for 84.1% of charges for antibiotics and 47.8% of the direct charges for the 3 categories of patients.

It is not surprising that more patients were seen for tick bites than for diagnosed or suspected LD. A previous survey of physicians in the state showed that almost 4 times as many visits to physicians resulted from tick bites as from diagnosed and suspected LD.⁷ In a different geographic region, Falco and Fish,¹⁷ identifying patients through the submission of ticks for analysis, found that two thirds of subjects had consulted their physicians about the bite. Ley et al,¹² retrospectively identifying patients who had serologic tests for LD performed in California, reported that one fifth of patients had serologic specimens submitted because of tick bites. In our study, through prospective identification of office visits, patients with tick bites constituted not only the majority of patients seen by physicians, but also the majority of patients for whom LD serologic testing was performed.

The 3.2% prevalence of Borrelia burgdorferi antibodies in acute specimens in our subjects with tick bites probably represents the background seropositivity rate and is consistent with seroprevalence rates in other endemic areas.¹⁰ The extent of use of serologic testing for these patients with tick bites is curious. Recommendations regarding the use of serologic testing for tick bites have not been made, and we are unaware of any prospective study of the use of serologic testing for patients with tick bites. Serologic testing is unlikely to contribute to the management of patients presenting with tick bites. Antibodies are often not detectable until several weeks after infection, early therapy can abort antibody response, and patients who have been infected with B burgdorferi may remain seropositive for years despite having been treated appropriately and despite being free of disease.^{18 - 21} Serologic testing is of theoretical use when assessing for asymptomatic seroconversion among those initially seronegative with attached, engorged ticks, but convalescent testing was performed for only one quarter of our seronegative patients with tick bite. The use of serologic tests makes little if any contribution to the management of patients with tick bites and is not a small issue in light of the associated costs.

Slightly over half the patients with tick bite received prophylactic antibiotic therapy, results similar to those reported by Falco and Fish,¹⁷ and up to twice as frequently as reported in physician surveys.^{6 - 8} Prophylactic therapy for tick bites is controversial. Clinical trials have not found a significant advantage to treatment, but, given the low rate of infection among the untreated patients (1.1%-3.4%), the sample sizes may have been too small to demonstrate significant differences,^{2 - 5} and the only patients in those studies with clear evidence of subsequent disease, unequivocal seroconversion, or both were those not treated. Nonetheless, it appears that approximately 100 patients with tick bites in areas endemic for LD would require treatment to prevent LD in 1 or 2 patients, and most of these could be easily identified for early treatment of LD. In light of the lack of convincing evidence of the benefit of prophylactic therapy, it is generally suggested that patients with tick bite exposures should be managed expectantly,^{2 - 4} especially as early LD can be easily and effectively treated.^{22 - 24} Further, it has been suggested that, as with Rocky Mountain spotted fever, prophylactic therapy may simply delay onset and obscure diagnosis.²⁵ The Centers for Disease Control and Prevention (CDC) do not recommend the routine use of prophylactic antibiotic therapy for tick bites, but rather advise primary preventive measures backed by secondary prevention through patient and physician education for prompt recognition of signs and symptoms of LD.²⁶

Prophylactic therapy may be judicious in certain circumstances,^{27 - 29} ie, in the case of an attached, engorged tick in an endemic area, and late manifestations of LD have been reported among patients who did not recall acute symptoms of LD.^{30 - 31} It must be stressed, however, that if antibiotic prophylaxis is to be given, it should be restricted to medications of proven efficacy for LD.³²

Our study suggests that physicians managing patients with tick bites in communities with endemic disease are either unaware of recommendations against routine prophylactic antibiotic therapy, disagree with them, or find them infeasible in practice. Many patients on the Maryland Eastern Shore are intensely concerned about LD and strongly desire chemoprophylaxis as well as serologic testing for tick bites. Their physicians may simply be responding to these patients' concerns, as indicated in our communications with these physicians (unpublished data).

Almost all of the patients with the clinical diagnosis of LD received antibiotic therapy, regardless of whether serologic testing was performed. The significant difference in seropositivity between those diagnosed as having LD and those with suspected LD (P<.001) could simply reflect that those with a clear clinical diagnosis of LD were more likely to have positive serologic findings, but it is also consistent with physicians having used the results of serologic testing to categorize the patients. Because 80% of patients with suspected LD and LD who received antibiotic therapy were prescribed antibiotics before or simultaneous with drawing specimens for serologic testing, serologic testing contributed to the treatment of only a few of these patients. Performance of serologic testing for LD may have complicated the management of the 2 patients designated as LD who had negative serologic test results and were not treated, one of whom had a "bull's-eye rash."

The failure to obtain convalescent serologic testing for most of the suspected LD patients with negative initial studies is of particular interest, especially since two thirds of this group did not receive antibiotic therapy. If some of these untreated patients with suspected LD actually had LD, they would be at risk for the development of late manifestations.²²

The CDC and other sources have recently recommended that, in the absence of erythema migrans, a 2-tiered approach be used in serologic testing for LD, with initial positive or equivocal EIA results confirmed by Western blot.^{33 - 35} Only 6 of the 41 patients in our study with positive or equivocal EIA results had confirmatory Western blot. Our data support the conclusion that many patients in endemic areas suspected of having LD are being treated on the basis of clinical impression and not laboratory testing, consistent with a recent physician survey.⁸ For patients without the characteristic clinical manifestations of LD, especially in areas of low prevalence in which EIA has much lower positive predictive value, confirmatory Western blot must be used to assist in making therapeutic decisions. The use of Western blot confirmation is of particular importance when considering expensive and potentially harmful antibiotic therapy.³⁶ Due to the expense of ceftriaxone, LD patients accounted for the overwhelming majority of the charges for antibiotic therapy, and antibiotic therapy accounted for a large proportion of total direct charges for those with LD. None of the 5 LD patients who received ceftriaxone had erythema migrans, and only 1 underwent Western blot testing.

We believe that we captured almost all the 1995 patient encounters in the Kent County sample and the majority of those in the DHP sample but were unable to estimate completeness of ascertainment. If incomplete capture introduced bias, it would most likely be in relative underreporting of cases of tick bite and, to a lesser extent, of suspected LD. Tick bite encounters most likely to be missed would be those for which the tick bite was a secondary issue for the visit. For DHP patients, ascertainment would be disproportionately high for those tick bite cases for whom serologic testing was ordered, having used a computer-generated list of serologic testing. This may bias the estimate of the proportion of patients with tick bite for whom serologic testing is ordered, but could only underestimate the costs engendered by tick bites.

The clustering of patients with several physicians, primarily in Kent County, influences the estimates for the use of serologic testing and antibiotic therapy for tick bites among the 11 Kent County physicians, but their elimination would not substantially alter the conclusions of the study.

In summary, we found that tick bites account for a substantial portion of the burden of LD-related costs and patient-physician encounters. Most patients with tick bites are undergoing costly serologic testing of no benefit, and the majority are receiving prophylactic antibiotic therapy, an intervention of unproven benefit. Results of serologic testing had minimal impact on the treatment of our patients diagnosed as having LD. Increased educational efforts among physicians regarding appropriate use of serologic testing seems warranted, as well as anticipatory counseling of patients in endemic areas regarding management of tick bites. In light of the extensive use of prophylactic antibiotic therapy for tick bites, it is imperative that definitive evaluation of the effectiveness of such therapy be performed.