Economic impact of Lyme disease.

To assess the economic impact of Lyme disease (LD), the most common vectorborne inflammatory disease in the United States, cost data were collected in 5 counties of the Maryland Eastern Shore from 1997 to 2000. Patients were divided into 5 diagnosis groups, clinically defined early-stage LD, clinically defined late-stage LD, suspected LD, tick bite, and other related complaints. From 1997 to 2000, the mean per patient direct medical cost of early-stage LD decreased from $1,609 to $464 (p<0.05), and the mean per patient direct medical cost of late-stage LD decreased from $4,240 to $1,380 (p<0.05). The expected median of all costs (direct medical cost, indirect medical cost, nonmedical cost, and productivity loss), aggregated across all diagnosis groups of patients, was =$281 per patient. These findings will help assess the economics of current and future prevention and control efforts.

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Lyme disease (LD) is a multisystem, multistage, inflammatory tickborne disorder caused by the spirochete Borrelia burgdorferi. LD usually begins with an initial expanding skin lesion, erythema migrans (EM), which may be followed by musculoskeletal, neurologic, and cardiac manifestations in later stages of the disease (1-3). Enzyme-linked immunosorbent assay and Western blotting test are widely used to diagnose LD (4-6). LD is most responsive to antimicrobial drugs in the early stage, while further intensive therapy may be necessary in the late stage (7,8). A variety of prevention and control procedures can be implemented to prevent and reduce LD incidence, including, but not limited to, public education; personal protection measures such as wearing protective clothing (gloves, long clothes), checking one's body daily for ticks, avoiding tick-infested areas, and applying tick repellent (DEET, permethrin); host management; habitat modification; and chemical control (9,10). In 1998, the Food and Drug Administration approved a recombinant outer-surface protein A (rOspA) LD vaccine (LYMErix, SmithKline Beecham Biologicals, Rixensart, Belgium) for persons 15-70 years of age (11). However, in 2002, SmithKline withdrew the vaccine, citing low demand. Therefore, personal protection measures, early diagnosis, and early treatment are extremely important in preventing and controlling LD.

Since the first case reported in 1975 (12), LD has become the most common vectorborne inflammatory disease in the United States. Foci of LD are widely spread in the northeastern, mid-Atlantic, and north-central regions of the United States (13). Despite federal, state, and local efforts to prevent and control LD, total reported cases of LD increased almost 3-fold from 1991 to 2002 (Figure 1). In 2002, the Centers for Disease Control and Prevention (CDC) received reports of 23,763 LD cases, 95% of which were from Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin (14). In Maryland, the overall incidence of LD was more than twice as high as the overall incidence of LD in the United States (13.0 vs. 6.3 cases per 100,000 population) (13).

[FIGURE 1 OMITTED]

Assessing the economic impact of LD will help assess the economics of current and future prevention and control efforts. Although several studies of cost estimates of LD have been published (e.g., 15), information on the economic impact of LD is limited. Therefore, we conducted a 4-year study to estimate the economic impact of LD on the Maryland Eastern Shore.

Methods

Study Population and Data

This study was conducted in 5 counties (Caroline, Dorchester, Kent, Queen Anne, and Talbot) on the Maryland Eastern Shore, an area where LD is endemic (Table 1). The study population includes patients living in the 4 counties enrolled in Delmarva Health Plan (DHP, a managed healthcare organization) and non-DHP patients receiving health care from office-based physicians in Kent County from 1997 to 2000. Eligible patients were identified through records of encounters for ED, tick bites, insect bites, and serologic testing for LD antibodies. During 1997 and 1998, identified patients were contacted for informed consent. Patients who indicated that they did not wish to participate were excluded from our database. A cost and risk questionnaire (Appendix 1 available online at www.cdc.gov/ncidod/EID/vol12no04/05-0602_app1.htm) was sent to patients who gave informed consent. The response rate of the survey was [approximately equal to] 22%. Interviewers then reviewed patients' charts and consulted relevant sources (e.g., hospital, physician office, laboratory) to obtain the following information: patient demographics; insurance coverage; diagnosis; symptoms; dates of onset and diagnosis; dates of tick bite exposure; dates and costs of primary provider and consultant visits; dates and costs of hospitalizations and emergency department visits; dates, results, and costs of laboratory tests; and dates and costs of antimicrobial drug treatment. All abstracted information was kept confidential. After 1999, an anonymous abstraction of medical records was approved by the institutional review board (IRB) and implemented, allowing inclusion of more patients for all 4 study years, with the exclusion of the records of those who had previously declined participation. All protocols of this study were approved by IRBs from CDC, the state of Maryland, and the University of Maryland. Those patients identified as having received an LD vaccination were not included in this study.

Case Definition

For the purpose of surveillance, a case of LD is defined as physician-diagnosed EM [greater than or equal to] 5 cm or at least 1 late rheumatologic, neurologic, or cardiac manifestation with laboratory evidence of B. burgdorferi infection (16). These criteria were developed as an epidemiologic case definition intended for surveillance purposes only. Although such a standard may aid comparison across clinical studies and facilitate development of research, exposure history and clinical features are critical. For example, treating patients with seasonal (summer) musculoskeletal flulike symptoms in areas where LD is endemic may be clinically appropriate (12). Because the data for this study were collected directly from healthcare organizations and physicians, we used a clinical definition of LD. This definition was based on physicians' determination in the medical record, according to patients' clinical findings, tick exposure, and other relevant details (e.g., laboratory results).

In our study, LD patients were identified by using a final diagnosis code in their medical records. LD patients were then divided into 5 diagnosis groups: clinically defined early-stage LD, clinically defined late-stage LD, suspected LD, tick bite, and other related complaints. Most clinically defined early-stage LD patients had EM; some also had musculoskeletal flulike symptoms such as malaise, fatigue, headache, fever, and chills (12). In this study, clinically defined late-stage LD patients included those with later manifestations (neurologic involvement, cardiac involvement, and arthritis) and patients with chronic LD. The diagnosis groups of suspected LD, tick bite, and other related complaints involved all patients without a clear final diagnosis of LD. Suspected LD referred to patients who had some symptoms that could be indicative of LD without further evidence and thus no definitive diagnosis of LD. Patients with tick bites without symptoms were placed in the tick bite group. The diagnosis group of other related complaints included all other diagnoses that were different from the above 4 diagnosis groups, such as unknown insect bites and screening among asymptomatic persons.

Study Design

We calculated the following total costs of LD: l) direct medical costs of LD diagnosis and treatment, 2) indirect medical costs, 3) nonmedical costs, and 4) productivity losses. Intangible costs (e.g., costs incurred because of pain and suffering) were not incorporated. Consumer price index (CPI) for medical care was used to adjust all medical payments into year 2000 dollars (17). For nonmedical costs and productivity losses, we adjusted costs by using the general CPI. We took a societal perspective, which incorporates all costs and all benefits no matter who pays costs or who receives benefits.

Charges were used to estimate the direct medical cost. To determine the direct medical costs associated with LD, we used charge data from both DHP and office-based healthcare providers in Kent County. Direct medical costs of LD included costs (charges) of physician visits, consultation, serology, procedure, therapy, hospitalization/emergency room (ER), and other related costs (Appendix 2 available online at www.cdc.gov/ncidod/EID/voll2no04/ 05-0602_app2.htm).

Indirect medical costs, nonmedical costs, and productivity losses were all acquired from a patient questionnaire used in 1997 and 1998. The questionnaire was sent to LD patients with informed consent forms. Collection of these data was restricted to those 2 years. In this study, indirect medical costs refer to extra prescription and nonprescription drug costs that patients paid out of pocket.

The patient's questionnaire also collected information on nonmedical payments made for home or health aides and miscellaneous services, such as travel (transportation) and babysitting. Each patient's transportation costs to a physician's office were estimated by using the US federal government reimbursement rate, multiplying the reported total travel miles per patient by $0.365/mile. Total travel mileage per patient was calculated by counting the number of physician visits and multiplying total visits by the distance of a round trip to the physician's office.

We used patient-reported time lost from work to estimate productivity losses due to LD on the basis of the human capital method and valued the time lost by using age- and sex-weighted productivity valuation tables (18). Because of the potential complexity of accurately answering the question, we did not ask patients to estimate the time they lost from household production. We did, however, ask patients if they paid anybody to do household tasks because their LD-related infirmities prevented them from doing those tasks. For patients <15 years of age, we assumed that their parents (usually the mother) had to take time off from their work to take care of them. Therefore, their mothers' values of lost days of work were included.

Analysis

We used the following formula to estimate the average per capita cost of LD, i.e., the mean cost (direct medical costs, indirect medical costs, nonmedical costs, and productivity losses) aggregated across all diagnosis groups of patients:

Expected mean cost of a LD outcome = [[summation].sub.direct medical costs. indirect medical costs, nonmedical costs, and productivity losses] (Mean cost of [outcome.sub.clinically defined early-stage LD, clinically defined late-stage LD, suspected LD, tick bite, and other related complaints] X Probability of [outcome.sub. clinically defined early-stage LD, clinically defined late-stage LD, suspected LD, tick bite, and other related complaints]).

Because the distribution of cost data is often not normal, we also calculated the medians of these costs and used both mean and median to estimate the most likely per capita cost of LD on the Maryland Eastern Shore. The median cost of an LD outcome was calculated by using the following formula:

Expected median cost of a LD outcome = [[summation].sub.direct medical costs, indirect medical costs, nonmedical costs, and productivity losses] (Median cost of [outcome.sub.clinically defined early-stage LD, clinically defined late-stage LD, suspected LD, tick bite and other related complaints] X [Probability of [outcome.sub.clinically defined early-stage LD, clinically defined late-stage LD, suspected LD, tick bite, and other related complaints])

Differences between annual mean direct medical costs were analyzed by using 1-way analysis of variance followed by a Bonferroni test. Differences were considered significant for p values <0.05. Additionally, we used a multivariate linear regression model to estimate the relative impact of a number of factors on the direct medical costs of LD. The ordinary linear regression (OLS) method was applied by using SAS 8.2 (SAS Institute, Cary, NC, USA) and Stata SE (StataCorp LP, College Station, TX, USA). The dependent variable was total direct medical cost per LD patient. We transformed total direct medical costs by using natural logarithms because the data were highly skewed. Independent

variables of the equation included cohort year, LD diagnosis groups, diagnostic and treatment procedures, and patient characteristics (e.g., sex, age). All independent variables, except age, were binomial (yes = 1, no = 0). Baseline costs (i.e., the intercept term in the regression equation) referred to those costs accrued by a woman who had tick bite only (without EM symptoms) diagnosed in 1997 during an office visit. Such a patient had no hospital or ER stay, no serologic tests, no consultation from other physicians, no antimicrobial drug therapy, and no other procedures outside a physician office and hospital/ER. Additional direct medical costs were added or subtracted to the baseline costs for each independent variable of interest if significant (Appendix 3, available online at http://www.cdc.gov/ncidod/EID/vol12no04/05-0602_app3.htm). We tested heteroscedasticity in Stata and corrected mild heteroscedasticity by using "robust" and "hc3" procedures. We also tested both linearity and multi-collinearity in SAS and Stata.

Results

From 1997 to 2000, we identified 3,415 LD-relevant patients in the 5 counties studied on Maryland Eastern Shore (Table 2). Among them, 10% had clinically defined early-stage LD while almost 5% of all patients had clinically defined late-stage LD. Of 284 patients who returned a completed patient questionnaire, 59 patients had clinically defined early-stage LD; 25 patients had clinically defined late-stage LD.

Table 3 provides cohort years, medians, means, and standard deviations of direct medical costs comparing the different diagnosis groups. During the study's time frame, the mean (range) direct medical cost of clinically defined early-stage LD decreased from $1,609 ($95-$11,286) in 1997 to $464 ($5-$5,338) in 2000 (p<0.05). The mean direct medical cost of clinically defined late-stage LD decreased from $4,240 ($275-$24,985) in 1997 to $1,380 ($45-$6,918) in 2000 (p<0.05).

From 1997 to 2000, the mean cost of therapy of all diagnosis groups decreased 75%, from $189 to $47, and the mean cost of hospitalization/ER decreased 61%, from $41 to $16 (Figure 2). During the same period, the mean cost of an office visit, consultation, and serologic tests also decreased 20%, 15%, and 4%, respectively. Additionally, the proportion of patients within the highest percentile (95th percentile for all 4 years) of therapy cost gradually decreased from 8% in 1997 to 7% in 1998, to 4% in 1999, and 3% in 2000 (data available upon request).

[FIGURE 2 OMITTED]

A patient with clinically defined early-stage LD paid an average of $164 in 1997 and $307 in 1998 (in 2000 dollars) for extra prescription and nonprescription drugs (Table 4). Those with clinically defined late-stage LD paid, for similar items, an average of $579 in 1997 and $389 in 1998. The mean nonmedical cost for clinically defined early-stage LD was $109 in 1997 and $23 in 1998. For patients with clinically defined late-stage LD, mean nonmedical costs were $60 in 1997 and $6,703 in 1998. During the survey period, the mean productivity loss of clinically defined early-stage LD was $411 in 1997 and $88 in 1998, and the mean productivity loss of clinically defined late-stage LD was $7,762 in 1997 and $9,108 in 1998. For all 3 types of costs shown in Table 4, a large difference was seen between mean and median values, with the latter often less than half of the mean value, indicating that a small number of LD patients account for a large portion of total costs.

Using multivariate linear regression analysis, we found that patients with clinically defined early- and late-stage LD had direct medical costs that were [approximately equal to] 50% and 100%, respectively, higher (p<0.001) relative to patients who only had tick bite, if the impact from other factors was not considered (Table 5). Moreover, patients who were hospitalized or made ER visits, who underwent serologic testing, who needed therapy, who were referred for consultation, and who had other procedures had substantially (p<0.001) higher direct medical cost than those who did not (Table 5). No cost difference was seen between men and women. After controlling for other factors, direct medical costs per LD patient in 2000 were lower than those in 1997 (Table 5).

In year 2000 dollars, the expected mean total cost attributable to LD was $1,965 per patient, and the expected median total cost attributable to LD was estimated at $281 per patient (Figure 3). For LD patients at the clinically defined early stage, the median total cost was [approximately equal to] $397 (mean $1,310), whereas for patients at the clinically defined late stage, the median cost rose to $923 (mean $16,199). Suspected LD cases, tick bite cases, and other LD-related complaints had median costs of $238 (mean $461), $108 (mean $316), and $256 (mean $714), respectively.

[FIGURE 3 OMITTED]

Discussion

Previous studies of the economic impact of LD were often based on numerous assumptions and experts' suggestions (e.g., Maes et al. [15]). Only a few studies provided cost estimates of LD based on data collected from the field (e.g., Fix et al. [19], Strickland et al. [20]). Even in those studies, however, cost estimates only related to direct medical charges or certain diagnosis or treatment procedures. By combining data from medical records with results from a patient survey, this study more comprehensively documents the economic impact of LD from a societal perspective.

To approximate the annual economic impact of LD nationwide, we extrapolated our results to the total number of LD cases reported nationwide. In this study, the annual total direct medical cost of LD cases on Maryland Eastern Shore was $1,455,081; 490 cases were in the clinically defined early or late stage of LD. Total indirect medical costs, nonmedical costs, and productivity losses were $436,949; 84 cases were clinically defined early- or late-stage LD. Therefore, in general, an LD patient (clinically defined early or late stage) costs $2,970 in direct medical costs plus $5,202 in indirect medical costs, nonmedical costs, and productivity losses. In 2002, 23,763 LD cases were reported to CDC. Hence, the estimated nationwide annual economic impact of LD and relevant complaints was [approximately equal to] $203 million (in 2002 dollars). However, since LD cases reported on the basis of the surveillance case definition are believed to be underreported (13,21), this nationwide estimate is likely to be low.

We found that the average cost per LD case decreased over the study period. In LD-endemic areas, personal protection measures are frequently emphasized and insecticides are widely used (22). Persons in LD-endemic areas likely visit physicians more frequently whenever they have an exposure or an insect bite, and physicians attending patients from an LD-endemic area likely order serologic testing for possible LD patients and provide prompt treatment. However, our current evidence was limited in that we were only able to find a decrease in per capita cost within diagnosis groups (e.g., clinically defined early- and late-stage LD), but we could not find a shift in the number of cases from late to early stage. Therefore, we don't know what caused the decrease in average cost per LD case.

This study has certain limitations. First, we used clinical case definition (physician determination) instead of surveillance case definition of LD because of limited data. Thus, we may have overestimated the number of LD cases. As a result of case definition, our estimation of cost not only included the cost of LD (clinically defined early- and late-stage LD) but also the costs of LD-relevant complaints (suspected LD, tick bite, and other related complaints). Second, medical charges used in our study may not reflect the true cost. Third, our results are likely to underestimate the costs per case because some of the costs were not included. Costs that were omitted included any costs incurred by a patient beyond the study period. Likewise, Steer et al. reported that [approximately equal to] 7% of LD cases remained asymptomatic within the 20-month study (23). These asymptomatic patients may have costs beyond the study. Public health surveillance and administration costs and intangible costs (e.g., costs incurred because of pain and suffering) were also not incorporated in the study. Fourth, because of the large variance between mean and median costs, using mean cost to estimate national impact could be an overestimation. Finally, this study is also limited in that we only had information for indirect medical costs, nonmedical costs, and productivity losses from [approximately equal to] 8% of total patients in the study. Therefore, the results from survey data were extrapolated to represent the whole study population. This method may have biased our results.

LD is the most common vectorborne zoonotic inflammatory disease in the United States. The long-term sequelae of LD are debilitating to patients and costly to society. The emergence of LD and previous experience predict the feasibility of public health interventions for LD control and prevention (24). More research on the social behavior of LD patients and economic evaluation of LD prevention interventions is needed.

Acknowledgments

We thank David T. Dennis and G. Thomas Strickland for their help and support.

This project was supported by CDC.

Dr Zhang is a health services researcher and health economist with CDC. His research interests include economic evaluation of disease prevention, public health intervention, medical technology, and strategic development of public health planning and emergency preparedness.

References

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(2.) Bujak DI, Weinstein A, Dornbush RL. Clinical and neurocognitive features of the post Lyme syndrome. J Rheumatol. 1996;23:1392-7.

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(4.) Johnson B J, Robbins KE, Bailey RE, Cao BL, Sviat SL, Craven RB, et al. Serodiagnosis of Lyme disease: accuracy of a two-step approach using a flagella-based ELISA and immunoblotting. J Infect Dis. 1996;174:346-53.

(5.) Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis. 1993;167:392-400.

(6.) Tugwell P, Dennis DT, Weinstein A, Wells G, Shea B, Nichol G, et al. Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med. 1997;127:1109-23.

(7.) Steere AC, Levin RE, Molloy P J, Kalish RA, Abraham JH III, Liu NY, et al. Treatment of Lyme arthritis. Arthritis Rheum. 1994;37:878-88.

(8.) Wormser GP, Nadelman RB, Dattwyler RJ, Dennis DT, Shapiro ED, Steere AC, et al. Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis. 2000;31(Suppl 1):S1-14.

(9.) Benenson AS. Control of communicable diseases manual. 16th ed. Washington: American Public Health Association; 1995.

(10.) Hayes EB, Maupin GO, Mount GA, Piesman J. Assessing the prevention effectiveness of local Lyme disease control. J Public Health Manag Pract. 1999;5:84-92.

(11.) Centers for Disease Control and Prevention. Recommendations for the use of Lyme disease vaccine: recommendations of the Advisory Committee on immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 1999;48(RR-7):1-17, 21-5.

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(13.) Centers for Disease Control and Prevention. Lyme disease--United States, 2000. MMWR Morb Mortal Wkly Rep. 2002;51;29-31.

(14.) Centers for Disease Control and Prevention. Notice to readers: final 2002 reports of notifiable diseases. MMWR Morb Mortal Wkly Rep. 2003;52:741-50.

(15.) Maes E, Lecomte P, Ray N. A cost-of-illness study of Lyme disease in the United States. Clin Ther. 1998;20:993-1008.

(16.) Centers for Disease Control and Prevention. Case definitions for infectious conditions under public health surveillance. MMWR Morb Mortal Wkly Rep. 1997;46(RR-10):20-1.

(17.) US Department of Labor. Consumer price index. [cited 2004 June 16]. Available from http://www.bls.gov/cpi/home.htm

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(19.) Fix AD, Strickland GT, Grant J. Tick bites and Lyme disease in an endemic setting: problematic use of serologic testing and prophylactic antibiotic therapy. JAMA. 1998;279:206-10.

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(22.) Barbour AG, Fish D. The biological and social phenomenon of Lyme disease. Science. 1993;260:1610-6.

(23.) Steer AC, Sikand VK, Schoen RT, Nowakowski J. Asymptomatic infection with Borrelia burgdorferi. Clin Infect Dis. 2003;37:528-32.

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Xinzhi Zhang, * Martin I. Meltzer, * Cesar A. Pena, ([dagger]) (1) Annette B. Hopkins, ([dagger]) Lane Wroth, ([double dagger]) and Alan D. Fix ([dagger])

* Centers for Disease Control and Prevention, Atlanta, Georgia, USA; ([dagger]) University of Maryland, Baltimore, Maryland, USA; and ([double dagger]) Care First-Easton Branch (previously Delmarva Health Plan), Easton, Maryland, USA

(1) Current affiliation: Maryland Department of Health and Mental Hygiene, Baltimore, Maryland, USA

Address for correspondence: Xinzhi Zhang, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop D59, Atlanta, GA 30333, USA; fax: [phone]; email: [e-mail]

Table 1. Reported cases * of Lyme disease (LD) in Maryland Eastern
Shore, 1997-2000 ([dagger])

County        1997    1998    1999    2000    Total

Caroline       18      17      26      21       82
Dorchester      3       4       3       4       14
Kent           24      47      20      34      125
Queen Anne     32      31      40      35      138
Talbot         13      22      33      37      105

Total          90     121     122     131      464

* Reported cases defined according to the national surveillance
definition. For the purpose of surveillance, a case of LD is defined
as physician-diagnosed erythema migrans [greater than or equal to] 5 cm
or [greater than or equal to] 1 late rheumatologic, neurologic, or
cardiac manifestation with laboratory evidence of Borrelia burgdorferi
infection.

([dagger]) Source: Maryland Department of Health and Mental Hygiene.
Available from http://www.edcp.org/vet_med/lyme_disease.html

Table 2. Distribution of Lyme disease (LD) cases * in Maryland
Eastern Shore, 1997-2000

                     No. LD cases (%)
                   from medical record          No. LD cases (%)
Diagnosis group    abstraction ([double          from follow-up
([dagger])               dagger])          patient survey ([section])

Early stage               334 (10)                  59 (21)
Late stage                156 (5)                   25 (9)
Suspected LD              718 (21)                  54 (19)
Tick bite                 539 (16)                  62 (22)
Other                   1,668 (49)                  84 (30)

Total                   3,415 (100)                284 (100)

* LD cases in the study are clinically defined LD cases, which may not
fit surveillance definition because the data were collected directly
from healthcare organizations and physicians.

([dagger]) Patients were divided into 5 diagnosis groups: clinically
defined early-stage LD, clinically defined late-stage LD, suspected LD,
tick bite, and other related complaints.

([double dagger]) Number of patients (1997-2000) who were identified
through records of encounters for LD, tick bites, insect bites, and
serologic testing.

([section]) Number of patients (1997-1998) who answered a questionnaire
recording indirect medical costs, nonmedical costs, and productivity
losses.

Table 3. Summary of direct medical cost * ([dagger]) per Lyme disease
(LD) patient in Marvland Eastern Shore, 1997-2000

                                                Cost per case
                                                    (US$))
Diagnosis                             No.
group ([double dagger])    Cohort    cases    Median    Mean

Early-stage LD              1997        77       565    1,609
                            1998        63       337      869
                            1999       122       282      455
                            2000        72       288      464
Late-stage LD               1997        28     3,673    4,240
                            1998        24       654    1,472
                            1999        59       588    1,286
                            2000        45       589    1,380
Suspected LD                1997       153       169      326
                            1998        79       174      255
                            1999       242       198      321
                            2000       244       238      361
Tick bite                   1997       143        92      140
                            1998        55        93      227
                            1999       202        87      120
                            2000       139        70      121
Other                       1997       490       196      319
                            1998       154       273      479
                            1999       573       215      321
                            2000       451       256      381

                                        Cost per case (US$))
Diagnosis
group ([double dagger])    Cohort    Minimum    Maximum     SD

Early-stage LD              1997       95        11,286    2,010
                            1998       78         9,720    1,542
                            1999       42         3,574      630
                            2000        5         5,338      738
Late-stage LD               1997      275        24,985    5,132
                            1998      125         6,417    1,839
                            1999       74         5,402    1,334
                            2000       45         6,918    1,652
Suspected LD                1997       45         9,564      948
                            1998       48         2,285      281
                            1999       51         3,869      445
                            2000       42         7,816      601
Tick bite                   1997       33           836      129
                            1998       34         3,432      502
                            1999       17           527       98
                            2000       16         1,181      141
Other                       1997        8         6,236      495
                            1998       34         3,721      561
                            1999       36         5,091      435
                            2000       17         4,157      452

                                       Significance ([section])
Diagnosis
group ([double dagger])    Cohort    1997    1998    1999    2000

Early-stage LD              1997      NA
                            1998      S       NA
                            1999      S       NS      NA
                            2000      S       NS      NS      NA
Late-stage LD               1997      NA
                            1998      S       NA
                            1999      S       NS      NA
                            2000      S       NS      NS      NA
Suspected LD                1997      NA
                            1998      NS      NA
                            1999      NS      NS      NA
                            2000      NS      NS      NS      NA
Tick bite                   1997      NA
                            1998      S       NA
                            1999      NS      S       NA
                            2000      NS      S       NS      NA
Other                       1997      NA
                            1998      S       NA
                            1999      NS      S       NA
                            2000      NS      NS      NS      NA

* Direct medical costs were collected from medical record abstraction
(1997-2000). Direct medical costs of LD included costs of physician
visits, consultation, serologic testing, procedure, therapy,
hospitalization/ER, and other relevant costs.

([dagger]) All costs were converted to 2000 equivalent.

([double dagger]) Patients were divided into 5 diagnosis groups:
clinically defined early-stage LD, clinically defined late-stage LD,
suspected LD, tick bite, and other related complaints.

([section]) Differences between annual mean direct medical costs were
analyzed by using 1-way analysis of variance followed by Bonferroni
test; p<0.05; SD, standard deviation, NA, not available;
S, significant, NS, not significant.

Table 4. Indirect medical cost, nonmedical cost, and productivity
loss * ([dagger]) per Lyme disease (LD) patient in Maryland Eastern
Shore, 1997-1998

                                              Indirect medical cost
                                                (US$) ([section])
Diagnosis
group ([double dagger])    Cohort    No.    Median    Mean     SD **

Early-stage                 1997     20       20        164       428
LD                          1998     39       8         307     1,773
Late-stage LD               1997      6       35        579     1,295
                            1998     19       11        389     1,448
Suspected LD                1997     22       5          25        49
                            1998     32       0          12        22
Tick bite                   1997     31       0          37       105
                            1998     31       0          11        40
Other                       1997     33       0          31       102
                            1998     51       0          11        21

                                       Nonmedical cost (US$)
                                          ([paragraph])
Diagnosis
group ([double dagger])    Cohort    Median    Mean       SD

Early-stage                 1997       27        109       219
LD                          1998        8         23        71
Late-stage LD               1997       22         60        85
                            1998       37      6,703    22,405
Suspected LD                1997        8         24        37
                            1998        4         12        17
Tick bite                   1997        9        155       731
                            1998        8         17        50
Other                       1997       11        143       696
                            1998        4         23        95

                                     Productivity loss (US$) (#)
Diagnosis
group ([double dagger])    Cohort    Median    Mean       SD

Early-stage                 1997       28        411     1,095
LD                          1998       49         88        85
Late-stage LD               1997      273      7,762    17,458
                            1998       46      9,108    28,284
Suspected LD                1997       26         83       164
                            1998       44        109       197
Tick bite                   1997        7         73       151
                            1998       19         66        79
Other                       1997       28        233       605
                            1998       19        300     1,539

* Indirect medical costs, nonmedical costs, and productivity losses
were acquired from patient questionnaire (1997-1998).

([dagger]) All costs were converted to 2000 equivalent.

([double dagger]) Patients were divided into 5 diagnosis groups:
clinically defined early-stage LD, clinically defined late-stage LD,
suspected LD, tick bite, and other related complaints.

([section]) Indirect medical costs refer to prescription and
nonprescription drug costs patients paid out of pocket.

([paragraph]) Nonmedical costs are payments made for home/health
aides and miscellaneous services, such as transportation and
babysitting.

(#) Productivity losses refer to losses in earning due to illness.

** SD, standard deviation.

Table 5. Impact on direct medical cost * due to cohort year, Lyme
disease (LD) diagnosis groups, diagnostic and treatment procedures,
and patient characteristics in Maryland Eastern Shore (regression
results, n = 3,415)

                                               Direct medical cost
                                                      (US$)

Baseline cost ([double dagger])                       60.88
Additional direct medical cost ([section])
  Clinically early stage                              34.93
  Clinically late stage                               67.05
  Suspected LD                                         3.16
  Other LD-relevant complaint                          8.33
  Serologic test ([paragraph])                        38.27
  Procedure (#)                                       26.13
  Hospitalization/emergency room (ER) **             114.96
Consultation ([dagger][dagger])                       84.68
  Therapy ([double dagger][double dagger])            36.66
  Miscellaneous ([subsection])                        46.96
  Erythema migrans ([paragraph][paragraph])           -9.56
  Male                                                -0.68
  Each year of age (##)                                0.11
  Year 1998                                           -5.05
  Year 1999                                          -12.74
  Year 2000                                           -9.09

                                               5th CI ([dagger]) (US$)

Baseline cost ([double dagger])                        55.94
Additional direct medical cost ([section])
  Clinically early stage                               22.59
  Clinically late stage                                45.57
  Suspected LD                                         -0.68
  Other LD-relevant complaint                           4.28
  Serologic test ([paragraph])                         28.20
  Procedure (#)                                        17.68
  Hospitalization/emergency room (ER) **               89.85
Consultation ([dagger][dagger])                        68.09
  Therapy ([double dagger][double dagger])             29.15
  Miscellaneous ([subsection])                         38.21
  Erythema migrans ([paragraph][paragraph])           -13.02
  Male                                                 -2.72
  Each year of age (##)                                 0.05
  Year 1998                                            -9.28
  Year 1999                                           -15.11
  Year 2000                                           -12.09

                                               95th CI
                                                (US$)        p

Baseline cost ([double dagger])                  66.26    <0.0001
Additional direct medical cost ([section])
  Clinically early stage                         50.65    <0.0001
  Clinically late stage                          94.97    <0.0001
  Suspected LD                                    7.96     0.171
  Other LD-relevant complaint                    13.29    <0.0001
  Serologic test ([paragraph])                   50.59    <0.0001
  Procedure (#)                                  36.58    <0.0001
  Hospitalization/emergency room (ER) **        145.83    <0.0001
Consultation ([dagger][dagger])                 104.56    <0.0001
  Therapy ([double dagger][double dagger])       45.56    <0.0001
  Miscellaneous ([subsection])                   57.27    <0.0001
  Erythema migrans ([paragraph][paragraph])      -4.90    <0.0001
  Male                                            1.84     0.571
  Each year of age (##)                           0.19    <0.0001
  Year 1998                                       0.54     0.0003
  Year 1999                                      -9.50     0.0371
  Year 2000                                      -5.08    <0.0001

* Direct medical costs of LD included costs of physician visits,
consultation, serologic testing, procedure, therapy,
hospitalization/ER, and other relevant costs. Patients were divided
into 5 diagnosis groups: clinically defined early-stage LD, clinically
defined late-stage LD, suspected LD, tick bite, and other related
complaints. All costs were converted to 2000 equivalent.

([dagger]) CI, confidence interval.

([double dagger]) Baseline costs refer to those costs accrued by a
female patient who had tick bite only (with no erythema migrans
symptoms), diagnosed in 1997 during an office visit. She had no
hospital or ER stay, no serologic tests, no consultation, no therapy,
and no other procedures ([R.sup.2] = 0.67).

([section]) Additional direct medical costs are added or subtracted to
the baseline costs for each variable of interest if significant (see
online Appendix 3 for details).

([paragraph]) Serologic test (yes = 1, no = 0) refers to patients who
had serologic test (e.g., enzyme-linked immunosorbent assay or Western
blotting test).

(#) Procedure (yes = 1, no = 0) refers to patients who had other
procedures that were not performed in hospital/ER, consultation, or
physician office.

** Hospitalization/ER (yes = 1, no = 0) refers to patients who had
hospital or ER stay.

([dagger][dagger]) Consultation (yes = 1, no = 0) refers to patients
who received consultation from other physicians.

([section][section]) Therapy (yes = 1, no = 0) refers to patients who
had therapy charges including antimicrobial agents and additional costs
associated (e.g., registered nurse home visits).

([subsection]) Miscellaneous (yes = 1, no = 0) refers to patients who
had other appropriate charges such as charges for additional laboratory
tests.

([paragraph][paragraph]) Refers to patients with erythema migrans
(yes = 1, no = 0).

(##) Age is a continuous variable and refers to each additional year of
age of the patient.