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Tick-borne Disease: Laboratory Support of Diagnosis Babesiosis, Ehrlichiosis, Lyme Disease, Q Fever, Rocky Mountain Spotted Fever, Tularemia

Interpretive Guide
Related Tests

Clinical Focus

Tick-borne Disease

Laboratory Support of Diagnosis and Management

Contents:

Clinical Background - Table 1 - Table 2 - Table 3 - Figure

Individuals Suitable for Testing

Test Availability - Table 4

Test Selection and Interpretation - Table 5 - Table 6 - Table 7

References

Clinical Background [return to contents]

Tick-borne diseases are caused by infections transmitted to humans via a tick vector such as the deer tick, dog tick, wood tick, and Lone Star tick. In the United States, transmission occurs primarily in the spring and summer months. Causative agents include bacteria (including rickettsia), viruses, and protozoa. The incidence varies by geographic location and causative agent (Table 1). Clinical manifestations also vary depending on the disorder, but frequently include fever, chills, sweating, headaches, myalgia, arthralgia, nausea, and vomiting. A rash or lesion at the site of the bite may or may not be present. More severe disease may result in hematologic, respiratory, cardiac, and neurologic complications as well as kidney or liver failure and arthritis. Although approximately 2% to 5% of the cases end in death, antimicrobial agents such as doxycycline and amoxicillin are usually effective.² Coinfection with more than 1 causative agent (eg, Borrelia burgdorferi and Babesia microti) may complicate the diagnosis and can affect antimicrobial selection.⁴

Table 1. Incidence of Tick-borne Diseases
Disorder	Causative Organism	Vector Tick	Reported Cases, US, 2006¹	US Geographic Distribution in Decreasing Incidence¹
Lyme disease	Borrelia burgdorferi	• Black-legged tick (Ixodes pacificus) • Deer tick (Ixodes scapularis)	19,931	• Mid-Atlantic (upstate NY, PA, NJ) • New England (CT, MA, NH) • South Atlantic (MD, VA, DE) • West North Central (MN)
Ehrlichiosis
Human granulocyte anaplasmosis (HGA)^a	Anaplasma phagocytophilum	• Black-legged tick (Ixodes pacificus) • Deer tick (Ixodes scapularis)	646	• Mid-Atlantic (upstate NY) • West North Central (MN)
Human monocyte (HME)	Ehrlichia chaffeensis	• Lone Star tick (Amblyomma americanum) • Dog tick (Dermacentor variabilis)	578	• Mid-Atlantic (upstate NY) • South Atlantic (NC) • West North Central (MO) • West South Central (OK)
Human E ewingii and other	E ewingii and unknown	• Lone Star tick (Amblyomma americanum) and unknown	231	• East North Central (WI) • South Atlantic (MD)
Colorado tick fever (CTF)	Coltivirus species	• Wood tick (Dermacentor andersoni)	200–300/yr²	• Western US
Q fever	Coxiella burnetii	• Wood tick (Dermacentor andersoni)	169	• Mountain (CO) • East North Central (IL) • Pacific (CA) • West North Central • South Atlantic
Tularemia	Francisella tularensis	• Lone Star tick (Amblyomma americanum) • Wood tick (Dermacentor andersoni) • Dog tick (Dermacentor variabilis)	95	• West North Central (MO) • Mountain (NM)
Tick-borne relapsing fever (TBRF)	Borrelia hermsii	• Ornithodoros species	35/yr³	• West, South, and Southwest US
Powassan encephalitis	Flavivirus species	• Ixodes cookei	1	• Wisconsin
Babesiosis	Babesia microti	• Black-legged tick (Ixodes pacificus) • Deer tick (Ixodes scapularis)	Unknown	• Northeastern coast, MN, WI
Tick paralysis	Tick neurotoxin	• Lone Star tick (Amblyomma americanum) • Dermacentor species	Unknown	• Western US; Rocky Mountains
^a Formerly known as human granulocytic ehrlichiosis (HGE).

Diagnosis is primarily based on a history of exposure to an area where ticks are endemic and on clinical presentation; in symptomatic patients, a rash or lesion may provide the first clue to the diagnosis (Figure). Characteristics and clinical features of each tick-borne disease, in order of incidence, follow.

Figure. One approach to the differential diagnosis of tick-borne diseases

Lyme Disease

Lyme disease, caused by Borrelia burgdorferi, is by far the most common tick-borne disease (Table 1). Clinical presentation can either be localized or disseminated. Characteristic of early localized disease is the presence of erythema migrans, a round or oval erythematous skin lesion with a bull’s-eye pattern that develops at the site of the tick bite; it is usually present 7 to 14 days after the tick bite and should be ≥5 cm in largest diameter for a firm Lyme disease diagnosis.⁴ Disseminated disease that may affect the musculoskeletal, cardiac, or nervous system can follow erythema migrans within days or weeks and is considered early-stage disseminated disease. Lyme carditis may overlap temporally with neurologic Lyme disease (late-stage disseminated disease).

Tick-borne Rickettsial Diseases (TBRDs)

TBRDs include Rocky Mountain spotted fever (RMSF), human granulocytic anaplasmosis (HGA) (formerly known as human granulocytic ehrlichiosis), human monocytic ehrlichiosis (HME), and Ehrlichia ewingii infection.

RMSF has been reported from each of the 48 contiguous states, except Vermont and Maine. The causative organism, Rickettsia rickettsii, infects endothelial cells and causes a small-vessel vasculitis that usually results in a maculopapular or petechial rash. Vasculitis in organs such as the brain or lungs can lead to life-threatening complications.

Reported cases of E ewingii infection have primarily included immunocompromised patients from Missouri, Oklahoma, and Tennessee. ⁷ HME, caused by E chaffeensis, is mostly identified in South-central, Southeastern, and Mid-Atlantic states, whereas HGA cases due to infection with A phagocytophilum are usually found in the Northeastern and upper Midwestern states.

TBRDs commonly manifest with an acute onset of nonspecific symptoms that mimic benign viral infections, making diagnosis difficult (Table 2). The presence or absence of a rash can be a useful diagnostic aid. Because antibiotic treatment is most effective when given early, therapy for symptomatic patients with clinically suspected TBRDs should not be delayed pending confirmatory laboratory results.⁷ Once the presumptive diagnosis of TBRD is made based on endemic exposure and clinical signs and symptoms, doxycycline is generally the drug of choice for both children and adults.⁷

Table 2. Clinical Features of Tick-borne Rickettsial Diseases⁷
Disease	Incubation Period (Days)	Signs and Symptoms	Rash
Rocky Mountain spotted fever	2–14	Fever, headache, malaise, myalgia, nausea/vomiting	Maculopapular rash 2–4 days after fever onset in 50%–80% of adults and >90% of children; frequently on palms and soles
Human monocytic ehrlichiosis	5–14	Fever, severe headache, malaise, myalgia	Erythematous, maculopapular, or petechial rash in <30% of adults and ~60% of children
Human granulocytic anaplasmosis	5–21	Fever, headache, malaise, myalgia, vomiting	Rare
Ehrlichia ewingii infection	5–14	Fever, headache, myalgia, nausea/vomiting	Rare

Tick-borne Non-Rickettsial Diseases

Colorado Tick Fever
Colorado tick fever, which is caused by an arbovirus infection of erythrocytes, is found throughout the Rocky Mountain region of the United States. After a mean incubation time of 3 to 5 days, disease onset is abrupt; presenting symptoms include intense headache, severe myalgia, arthralgia, and a characteristic biphasic pattern of fever termed “saddleback” fever (Table 3). The fever lasts for 2 to 3 days, disappears, and then recurs for another 2 to 3 days. Rarely, severe complications such as central nervous system involvement and hemorrhage may occur, especially in children.

Table 3. Clinical Features of Tick-borne Non-Rickettsial Diseases^{6, 8-10}
Disease	Incubation Period (Days)	Signs and Symptoms
Colorado tick fever	3–10	Severe headache, severe myalgia, arthralgia, saddleback fever
Q fever	14–35	High-grade fever, pneumonia, hepatitis, myalgia, headache, fatigue
Tularemia	2–14	Fever, chills, headache, myalgia, arthralgia, papule/ulceration
Tick-borne relapsing fever	4– >18	Headache, myalgia, chills, nausea/vomiting, arthralgia
Babesiosis	7–42	Fever, fatigue, chills, sweating, headache

Q Fever
The highest incidence of Q fever is in the Midwest and California. Although C burnetii, the bacterium responsible for Q fever, may be transmitted by ticks, it is more likely transmitted by domestic ungulates (cattle, sheep, and goats) or pets (cats and dogs). Up to 60% of patients infected with this bacterium are asymptomatic, but Q fever can manifest as acute or chronic disease.¹¹ Acute presentation is characterized by fever (≥104 °F), sweating, myalgia, and arthralgia frequently accompanied by pneumonia and hepatitis (Table 3). The triad of fever, hepatitis, and atypical pneumonia should raise suspicion of acute Q fever.¹¹ Chronic Q fever, defined as infection lasting for >6 months,⁶ presents as endocarditis in up to 70% of cases; the second most common form is vascular infection. Patients with chronic Q fever typically have predisposing conditions such as heart valve lesions, immunodeficiencies, or vascular abnormalities. Acute Q fever should be treated promptly to avoid progression to chronic disease; doxycycline is the treatment of choice.¹¹ Combination therapy (doxycylcine plus hydroxychloroquine) is recommended for chronic disease.¹¹

Tularemia
Tularemia, found most often in Missouri, Arkansas, and Oklahoma, is characterized by an ulcerative lesion at the site of the tick bite and by lymphadenopathy. An erythematous, tender, or puritic papule typically appears within 2 to 5 days and subsequently enlarges to form an ulcer with a black base. Additional symptoms of F tularensis infection appear abruptly and include fever, chills, headache, and generalized myalgia and arthralgia (Table 3). Clinical consequences depend on the portal of entry and the extent of systemic involvement. Ulceroglandular and glandular forms account for 75% to 85% of cases; pneumonic tularemia, a pulmonary form that may be contracted by inhalation or hematogenous spread, accounts for about 18% of adult cases.¹² Less common forms include oropharyngeal and oculoglandular disease. Diagnosis is made presumptively based on a history of exposure to a tick-endemic region and clinical signs and symptoms. Gentamicin or another aminoglycoside is suggested for treatment.¹²

Tick-borne Relapsing Fever (TBRF)
TBRF is caused by Borrelia hermsii and occurs west of the Mississippi River, especially in forested mountainous areas of the far Western states. TBRF is characterized by recurrent acute episodes of spirochetemia and fever. Following a mean incubation period of 7 days, the onset of illness is sudden, with headache, myalgia, chills, nausea/vomiting, and arthralgias that may be severe (Table 3). Fever is typically ≥104 °F and may be accompanied by delirium. Leukocytosis and thrombocytopenia are common, and splenomegaly may be present.

Symptoms intensify without treatment, and thus, treatment should be administered when clinical suspicion is high.³ Treatment recommendations for adults and children under 8 years of age may be found in reference 3.

Babesiosis
Babesiosis is caused by a protozoan infection (Babesia microti) of erythrocytes and shares clinical features with malaria. Infection occurs mostly in New England, New York state, New Jersey, Minnesota, and Wisconsin. The disease may be asymptomatic, or symptoms may appear 1 to 6 weeks after the tick bite. Symptoms vary widely but may include a gradual onset of irregular fever, chills, sweating, myalgia, arthralgia, nausea/vomiting, and fatigue (Table 3). Mild hepatosplenomegaly and mild hemolytic anemia may develop.

Individuals Suitable for Testing [return to contents]

Symptomatic individuals with a history of exposure to a tick-endemic area

Test Availability [return to contents]

Laboratory tests that can help confirm the clinical diagnosis include tick identification, microscopic visualization of the causative organism in blood or other clinical specimens, various serologic techniques, culture, and polymerase chain reaction (PCR)-based assays (Table 4).

Table 4. Tests Available for Diagnosis and Management of Tick-borne Diseases
Test Code	Assay	Method	Clinical Use
All Tick-borne Diseases
3946X	Tick (and other Arthopods) Identification	Microscopy	Identify tick to determine risk of tick-borne disease; assist with differential diagnosis
Test Code	Assay	Method	Clinical Use
Lyme Disease
34194	Borrelia burgdorferi Antibody Index for CNS Infection Includes B burgdorferi IgG and IgM, total IgG and IgM, and albumin (all in CSF and serum) as well as B burgdorferi antibody index and albumin ratio.	ELISA; nephelometry	Diagnose neurologic Lyme disease
29477X	Lyme Disease Antibody (IgG), Western Blot	Western blot	Diagnose Lyme disease in patients with equivocal or positive serology
8593	Lyme Disease Antibodies (IgG, IgM), Western Blot	Western blot
6646	Lyme Disease Antibody, Total, EIA with Reflex to Western Blot (IgG, IgM)^a	EIA	Diagnose Lyme disease
10672X	Lyme Disease C6 Antibodies, Total, EIA with Reflex to IgG and IgM, Western Blot^a	ELISA	Diagnose Lyme disease especially in those exposed to European Borrelia species and those vaccinated with OspA vaccine (ie, LYMErix™′)
34287	Lyme Disease (Borrelia burgdorferi) DNA, QL, Real-Time PCR, Blood^b,c	PCR	Diagnose Lyme disease
30297	Lyme Disease (Borrelia burgdorferi) DNA, QL, Real-Time PCR, CSF or Synovial Fluid^b,c	PCR	Diagnose neurologic Lyme disease or Lyme arthritis
15510	Lyme Disease (Borrelia spp) DNA, Qualitative, Real-Time PCR, Tick^c^,^d	PCR	Detect B burgdorferi in tick to assess risk of Lyme disease
15868	Lyme Disease (Borrelia spp) DNA, Qualitative, Real-Time PCR, Urine^c^,^d	PCR	Diagnose Lyme disease
10710	Tick ID with Reflex to Lyme Disease DNA, Real-Time PCR, Tick^a,b,c	Microscopy; reflex to PCR	Identify tick and B burgdorferi to assess risk of tick-borne disease and assist with differential diagnosis
Test Code	Assay	Method	Clinical Use
Rocky Mountain Spotted Fever
70191	Rickettsia rickettsii DNA, Real-Time PCR^b,c	PCR	Diagnose RMSF
6419	Rickettsia (RMSF) Antibodies (IgG, IgM) with Reflex to Titers^a	IFA	Diagnose RMSF
37507	Rickettsia Antibody Panel with Reflex to Titers^a Includes IgG and IgM to causative organisms of RMSF and typhus fever.	IFA	Differential diagnosis of rickettsial disease
37478X	Rickettsial Disease Panel^a Includes IgG and IgM to causative organisms of RMSF, typhus fever, and Q-fever (phase I and II).	IFA	Differential diagnosis of rickettsial disease
Test Code	Assay	Method	Clinical Use
Ehrlichiosis
34464X	Anaplasma phagocytophilum Antibodies (IgG, IgM)^d	IFA	Diagnose HGA
17320	Anaplasma phagocytophilum DNA, Qualitative, Real-Time PCR^b,c	PCR	Diagnose HGA
10611X	Anaplasma phagocytophilum and Ehrlichia chaffeensis Antibody Panel^d Includes IgG and IgM for both organisms.	IFA	Differential diagnosis of ehrlichiosis
34271X	Ehrlichia chaffeensis Antibodies (IgG, IgM)^d	IFA	Diagnose HME
11353	Ehrlichia chaffeensis DNA, Real-Time PCR^b,c	PCR	Diagnose HME
70194	Ehrlichia ewingii DNA, Real-Time PCR^b,c	PCR	Diagnose E ewingii infection
Test Code	Assay	Method	Clinical Use
Colorado Tick Fever
34986X	Colorado Tick Fever Antibody, IFA^d Includes IgG and IgM.	IFA	Diagnose Colorado tick fever
Test Code	Assay	Method	Clinical Use
Q Fever
37071X	Q Fever (Coxiella burnetii) Antibodies (IgG, IgM) with Reflex to Titers^a Includes antibodies for phase I and II disease.	IFA	Diagnose Q fever; distinguish acute from chronic disease; monitor therapy; detect relapse
37478X	Rickettsial Disease Panel^a Includes IgG and IgM to causative organisms of RMSF, typhus fever, and Q fever (phase I and II).	IFA	Differential diagnosis of rickettsial disease
Test Code	Assay	Method	Clinical Use
Tularemia
35176X	Francisella tularensis Antibody, DA	Direct Agglutination	Diagnose tularemia
Test Code	Assay	Method	Clinical Use
Tick-borne Relapsing Fever
34690X	Borrelia hermsii Antibody Panel, IFA^d Includes IgG and IgM.	IFA	Diagnose TBRF
Test Code	Assay	Method	Clinical Use
Babesiosis
34300	Babesia microti Antibodies (IgG, IgM)^d	IFA	Diagnose babesiosis
37314X	Babesia microti DNA, Real-Time PCR^b,c	PCR	Diagnose babesiosis
37509X	Malaria/Babesia Examination by Giemsa Stain	Microscopy	Diagnose babesiosis
EIA, ELISA, enzyme immunoassays; PCR, polymerase chain reaction; IFA, immunofluorescence assay; HGA, human granulocyte anaplasmosis, formerly known as human granulocytic ehrlichiosis (HGE); HME, human monocyte ehrlichiosis; TBRF, tick-borne relapsing fever. ^a Reflex tests are performed at an additional charge and are associated with an additional CPT code(s). ^b This test was developed and its performance characteristics have been determined by Focus Diagnostics. Performance characteristics refer to the analytical performance of the test. ^c Polymerase chain reaction (PCR) is performed pursuant to a license agreement with Roche Molecular Systems, Inc. ^d This test was developed and its performance characteristics have been determined by Focus Diagnostics. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.

Test Selection and Interpretation [return to contents]

Presence or absence of clinical symptoms, including the type of rash or lesion when present, guides the initial differential diagnosis of patients exposed to a tick-endemic area (Figure). This, in turn, guides appropriate test selection, presumably leading to confirmation of the suspected disorder.

Lyme Disease
Test Selection for Early Lyme Disease
Diagnosis of Lyme disease (B burgdorferi infection) is best made on the basis of a history of exposure to the vector tick or tick habitat and clinical findings. Clinical findings, as well as laboratory testing, vary with the stage of the disease (Table 5). Diagnosis of early-stage, localized Lyme disease can be made on the basis of erythema migrans alone without laboratory testing.⁴ When there is diagnostic uncertainty, positive IgG and/or IgM serology results on acute- and convalescent-phase (ie, 2 to 4 weeks after the acute phase) samples can support the diagnosis (Table 5).

Table 5. Lyme Disease: Clinical Features¹³ and Recommended Laboratory Testing⁴
Stage of Disease	Clinical Features	Laboratory Testing
Early-stage (localized)	Erythema migrans, fever, myalgia, headache, nausea, fatigue	<2 weeks after the tick bite: testing not recommended 2–4 weeks after the tick bite: acute and convalescent 2-tier^a IgG, IgM serology (if diagnosis uncertain)
Early-stage disseminated (cardiac involvement)	Atrioventricular heart block sometimes with myopericarditis; migratory pain in joints, bone, and muscle; secondary annular lesions; malaise; fatigue	2–4 weeks after the tick bite: acute and/or convalescent 2-tier^a IgG, IgM serology >4 weeks after the tick bite: acute and/or convalescent 2-tier^a IgG serology
Late-stage disseminated (neurologic and/or arthritic involvement)	Encephalopathy; polyneuropathy; lymphocytic meningitis; prolonged, chronic arthritis; lymphocytoma; fatigue	Acute and/or convalescent 2-tier^a IgG serology in serum; consider serology and/or detection of B burgdorferi DNA in CSF or synovial fluid
^a Two-tier testing is a follow-up of a positive or equivocal EIA with a Western blot test as recommended by the Centers for Disease Control and Prevention and the Association of State and Territorial Public Health Laboratory Directors.¹⁴

Test Selection for Disseminated Lyme Disease
In the absence of erythema migrans, Lyme disease cannot be diagnosed on the basis of disseminated disease manifestations alone, because these symptoms are nonspecific.⁴ Diagnosis requires demonstration of seropositive test results.⁴ EIA testing for IgG is recommended >4 weeks after the tick bite, whereas combined IgG and IgM testing is performed for patients 2 to 4 weeks after the tick bite (Table 5).⁴ Western blot testing is recommended as a confirmatory test for all specimens positive or equivocal by EIA.¹⁴

Immunoassays used to detect Lyme disease antibodies utilize whole spirochete preparations or synthetic C6 peptide antigen. The C6 peptide antigen is a 26-amino acid sequence derived from the VlsE membrane protein of Borrelia. The C6 antibody test is used to detect infection from both American and European Borrelia species and to reduce false positives that may be caused by antibodies cross-reacting with similar organisms or by Lyme disease vaccination.¹⁵

Methods that detect B burgdorferi DNA may be used to support the diagnosis of disseminated Lyme disease. For neurologic Lyme disease, DNA detection in cerebrospinal fluid (CSF) has a sensitivity of 38% (≥93% specificity).¹⁶ Alternatively, intrathecal antibody production using a CSF to serum antibody ratio may be used (sensitivity, 75%; specificity, 97%).¹⁷ Positive DNA findings in synovial fluid supports the diagnosis of Lyme arthritis (sensitivity, 78%; specificity,100%).¹⁶ However, because spirochetemia is typically transient or absent, detection of B burgdorferi DNA in whole-blood specimens has low clinical sensitivity (14%) rendering negative results non-informative.¹⁶

Test Interpretation
IgM antibodies may be present within a few weeks of disease onset, whereas IgG antibodies are produced later. A positive IgM result as determined by 2-tier testing, in conjunction with a negative IgG result, is presumptive evidence of early infection unless obtained on a specimen collected more than 1 month following onset. In the latter scenario, a positive IgM finding is more likely to represent a false-positive unless IgG is also positive. A positive IgG result by 2-tier testing is required to confirm the diagnosis of disseminated disease.⁴

The interpretation of Western blot antibody assays is based on the number of positive bands: 2 of 3 bands (23, 39, 41kDa) for IgM positivity and 5 of 10 bands (18, 23, 28, 30, 39, 41, 45, 58, 66, or 93 kDa) for IgG positivity. The Western blot is to be used only following initial EIA testing, and positive results confirm B burgdorferi infection.⁴

False-positive antibody test results may be due to vaccination, infectious mononucleosis, systemic lupus erythematosus, or other diseases caused by spirochetes such as syphilis, yaws, pinta, leptospirosis, and relapsing fever. The Lyme disease C6 antibody test does not typically yield false-positive results in the above conditions.¹⁵ Additionally, positive antibody test results, including those from the C6 EIA, may be due to active or past B burgdorferi infection.

Negative serology results may indicate lack of infection or lack of seroconversion, which may occur if samples are collected too early after disease onset or when early antibiotic therapy blunts the antibody response. Untreated patients who continue to be symptomatic but are seronegative for 6 to 8 weeks are unlikely to have Lyme disease, and another diagnosis should be considered.⁴

Expression of paired CSF and serum B burgdorferi antibody results as an antibody index can be used as an aid in the diagnosis of neuroborreliosis. An index >1.2 is deemed positive for intrathecal antibody production if accompanied by a control antibody index <1.0 and an albumin ratio <0.0078. Elevation of either the control antibody index, the albumin ratio, or both may indicate leakage of antibody across the blood-brain barrier and a falsely elevated B burgdorferi antibody index.

In a seropositive patient, positive DNA results support the diagnosis of Lyme disease.⁴ However, in a seronegative patient, positive results should be interpreted with caution.⁴

Testing for Tick-borne Rickettsial Diseases (TBRDs)
Ehrlichioses and anaplasmosis are characterized by infection of leukocytes, in which the causative agents multiply in cytoplasmic membrane-bound vacuoles called morulae. E ewingii and A phagocytophilum infect granulocytes, whereas E chaffeensis infects monocytes. Thus, visualization of morulae on a routine blood smear may provide the first clue for diagnosis and help differentiate HME from HGA and E ewingii infection. Positive results may be seen in up to 60% of patients with HGA and to a lesser extent in patients with HME.⁷

In patients with RMSF, increased band neutrophil counts are generally observed on a complete blood count (CBC), and since they are less commonly seen with viral infection, aid in the differential diagnosis. Symptomatic patients have an increased likelihood of HGA when platelets, WBC’s, or both are reduced; the relative risk was 5.2 when the WBC count was <2.5 x 10⁹ cells/L and 10.3 when the platelet count was <100 x 10⁹ cells/L.¹⁸ Laboratory test results associated with the various TBRDs are listed in Table 6.

Table 6. Laboratory Confirmation of Tick-borne Rickettsial Diseases⁷
Disease	Common Laboratory Abnormalities	Confirmatory Laboratory Tests	Laboratory Criteria for Confirmation of Diagnosis
Rocky Mountain spotted fever	• WBC count N • Platelet count ↓ • Sodium slight ↓ • Transaminases slight ↑	Acute and convalescent serology or	4-fold increase in antibody titer
		R rickettsii DNA	Detected

Human monocytic ehrlichiosis	• WBC count ↓ in ≤53% • Platelet count ↓ in ≤94% • Transaminases ↑ (2–8 times ULN)	Acute and convalescent serology or	4-fold increase in antibody titer
		E chaffeensis DNA or	Detected
		Identification of morulae in WBCs and serology	Morulae detected and positive antibody titer
Human granulocytic anaplasmosis	• WBC count ↓ in ≤53% • Platelet count ↓ in ≤94% • Transaminases ↑ (2–8 times ULN)	Acute and convalescent serology or	4-fold increase in antibody titer
		A phagocytophilum DNA or	Detected
		Identification of morulae in WBCs and serology	Morulae detected and positive antibody titer
Ehrlichia ewingii infection	• WBC count ↓ • Platelet count ↓ • Transaminases ↑	E ewingii DNA	Detected
N, normal; ↑, increased; ↓, decreased; ULN, upper limit of normal.

Laboratory confirmation validates the accuracy of the presumptive diagnosis and is important from an epidemiology and public health perspective. Confirmatory laboratory testing for TBRDs includes serology and highly specific nucleic acid detection (Table 6). Immunofluorescence assays (IFA) are considered the gold standard for TBRD serology testing.⁷ A 4-fold rise in titer of IgG or IgM in paired acute and convalescent samples collected 2 to 3 weeks apart is essential to confirm acute infection. Most patients have positive IgG or IgM antibody by the second week of illness. For RMSF, IgG and IgM increase concurrently; IgM wanes after 3 to 4 months, whereas IgG persists for 7 to 8 months.

Detection of DNA in whole blood is especially useful for confirming HGA, HME, and E. ewingii infection because these organisms infect circulating leukocytes. For RMSF, detection of R rickettsii in blood is more likely in advanced disease or fulminant infection. Whereas positive results confirm TBRD, negative results do not exclude the diagnosis.

Testing for Tick-borne Non-Rickettsial Diseases
Colorado Tick Fever
Leukopenia is characteristically seen in a CBC, and thrombocytopenia may be present. Acute and convalescent serology should be considered for patients with clinically suspected Colorado tick fever (Table 7). A 4-fold rise of IgG or IgM titer in paired acute and convalescent samples confirms the diagnosis; the detection of IgM indicates acute infection.

Table 7. Laboratory Confirmation of Tick-borne Non-Rickettsial Diseases^{6, 8-11}
Disease	Common Laboratory Abnormalities	Confirmatory Laboratory Tests	Laboratory Criteria for Confirmation of Diagnosis
Colorado tick fever	• WBC count ↓ • ↓ Platelet count ±	Acute and convalescent serology	4-fold increase in antibody titer; positive IgM antibody titer
Q fever	• Transaminases ↑ (2–10 times ULN) • ↓ Platelet count ±	Acute and convalescent serology	4-fold increase in IgG antibody titer and/or positive IgM antibody titer against phase II antigens
Tularemia	• ↑ Transaminases ±	Acute and convalescent serology	4-fold increase in antibody titer
Tick-borne relapsing fever	• Platelet count ↓	Acute and convalescent serology	4-fold increase in antibody titer
Babesiosis	• Hematocrit ↓ • Reticulocyte count ↑ • Platelet count ↓ • ↑ Transaminases ±	Serology or	Antibody titer ≥1024
		B microti DNA or	Detected
		Identification of parasites in RBC’s confirmed by DNA testing or serology	Parasites detected and positive DNA or antibody titer
ULN, upper limit of normal; ↑, increased; ↓, decreased; ±, may be present.

Q Fever
C burnetii infection exhibits 2 antigenic phases (I and II) that are valuable in diagnosing and staging Q fever. Acute disease is characterized by elevated phase II antibodies, whereas chronic disease is reflected by phase I antibodies. Thus, a ratio of phase II to phase I antibody titers >1 suggests acute Q fever, while a ratio <1 suggests chronic Q fever. Active Q fever infections are diagnosed on the basis of a 4-fold increase in serum IgG titers between acute and convalescent samples and/or elevated IgM antibodies directed against phase II antigens (Table 7). Phase II antibodies may be detected within 2 weeks of infection; if not present at 4 weeks, another diagnosis should be considered.¹¹

Phase I IgG testing at 3 and 6 months is suggested for patients who have yet to be treated.¹¹ If the phase I IgG titer is elevated, treatment should be considered if supported by echocardiography or PCR testing (not currently available).¹¹ Thereafter, IgG titers should be tested at 3-month intervals to monitor therapy¹¹; a reduction in titer is suggestive of therapeutic response. Once therapy has been discontinued (or if therapy was not initiated), a 4-fold increase in IgG titer at 3 and 6 months indicates relapse.¹¹ Persistently elevated phase I IgG titers suggest the presence of endocarditis and chronic disease.¹¹

Tularemia
F tularensis serology testing can confirm a diagnosis of tularemia (Table 7). An antibody titer ≥1:20 is suggestive of acute or past infection and a 4-fold increase in titer between acute and convalescent sera collected 2 to 3 weeks apart is considered diagnostic. Antibody begins to appear 2 to 3 weeks post-onset and peaks at about 5 weeks. However, up to 30% of patients infected for 3 weeks have negative serology results.¹² Because Brucella antibodies cross-react with this test, positive specimens should also be tested for Brucella antibody.

Tick-borne Relapsing Fever (TBRF)
Diagnosis of TBRF is made by the detection of spirochetes in the patient’s blood during periods of high fever (sensitivity ≥70%).³ Diagnosis is confirmed by serology testing. The presence of B hermsii IgM titers ≥1:16 are associated with acute infection, while IgG titers ≥1:64 reflect later stages of disease. Single IgG titers ≥1:64 are considered presumptive evidence of infection and a 4-fold increase in titer between acute and convalescent sera provides evidence of recent or current infection (Table 7). Because other Borrelia and Treponema species cross-react in the IFA test, positive specimens should be tested for antibodies to these organisms.

Babesiosis
Laboratory abnormalities may include hemolytic anemia with an elevated reticulocyte count, thrombocytopenia, proteinuria, and elevated levels of liver enzymes, blood urea nitrogen, and creatinine. Because clinical symptoms are nonspecific, diagnosis requires identification of babesial parasites in blood by microscopy, DNA detection, or positive serology (Table 7).⁴

Because of the resemblance to malarial parasites, microscopic identification of intraerythrocytic parasites using Giemsa-stained thin or thick blood smears may require confirmation by additional laboratory testing. Specific B microti antibodies are usually present by the time the patient exhibits parasitemia and invariably within 4 weeks of onset, unless the patient is immunocompromised. Although most patients with acute illness have titers ≥1024, testing of acute and convalescent sera is recommended to confirm the diagnosis. Elevated titers can persist for months following resolution of symptoms. The IFA serology method is known to cross-react with other Babesia species (at lower titers) as well as with other blood and tissue parasites and various tick-borne organisms. Detection of Babesia DNA in blood can also confirm the diagnosis and is slightly more sensitive than serology or microscopic detection of parasites.⁴

Laboratory test results, combined with clinical symptoms, are used to make treatment decisions.⁴ Treatment is recommended in symptomatic patients when babesial parasites have been identified or DNA results are positive.⁴ Treatment is not recommended in symptomatic patients whose blood is negative for babesial parasites or DNA, even if serology testing is positive. Also, treatment is not recommended for asymptomatic individuals, regardless of laboratory test results. Asymptomatic individuals with positive babesial smears and/or DNA results should have these tests repeated, and treatment should be considered if repeat testing is positive >3 months later.

References [return to contents]

McNabb SJ, Jajosky RA, Hall-Baker PA, et al. Summary of Notifiable Diseases–United States, 2006. MMWR Morb Mortal Wkly Rep. March 21, 2008;55:1-94.
Bratton RL, Corey GR. Tick-borne disease. Am Fam Physician. 2005;71:2323-2330.
Dennis DT, Hayes EB. Relapsing fever. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, eds. Harrison’s Principles of Internal Medicine, 16th ed. New York, NY: McGraw-Hill; 2005:991-995.
Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43:1089-1134.
Tsai TF. Coltiviruses (Colorado tick fever). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. New York, NY:Churchill Livingstone; 2000:1694-1696.
Choi E. Tularemia and Q fever. Med Clin North Am. 2002;86:393-416.
Chapman AS, Bakken JS, Folk SM, et al. Diagnosis and management of tick-borne rickettsial diseases: Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis—United States. MMWR Recomm Rep. March 31, 2006;55:1-27.
Klasco R. Colorado tick fever. Med Clin North Am. 2002;86:435-440.
Dworkin MS, Schwan TG, Anderson DE. Tick-borne relapsing fever in North America. Med Clin North Am. 2002;86:417-433.
Krause PJ. Babesiosis. Med Clin North Am. 2002;86:361-373.
Hartzell JD, Wood-Morris RN, Martinez LJ, et al. Q fever: Epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2008;83:574-579.
Jacobs RF. Tularemia. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison’s Principles of Internal Medicine, 16th ed. New York, NY: McGraw-Hill; 2005:917-921.
Depietropaolo DL, Powers JH, Gill JM. Diagnosis of Lyme disease. Am Fam Physician. 2005;72:297-304.
Centers for Disease Control and Prevention. Recommendations for test performance and interpretation from the Second National Conference on Serological Diagnosis of Lyme Disease. MMWR.1995;44:590-591.
Mogilyansky E, Loa CC, Adelson ME, et al. Comparison of Western immunoblotting and C6 Lyme antibody test for laboratory detection of Lyme disease. Clin Diagn Lab Immunol. 2004;11:924-929.
Aguero-Rosenfeld ME, Wang G, Schwartz I, et al. Diagnosis of Lyme borreliosis. Clin Microbiol Rev. July 2005;18:484-509.
Blanc F, Jualhac B, Fleury M, et al. Relevance of the antibody index to diagnose Lyme neuroborreliosis among seropositive patients. Neurology. 2007;69:953-958.
Bakken JS, Aguero-Rosenfeld ME, Tilden RL, et al. Serial measurements of hematologic counts during the active phase of human granulocytic ehrlichiosis. Clin Infect Dis. 2001;32:862-870.

Polymerase chain reaction (PCR) is performed pursuant to a license agreement with Roche Molecular Systems, Inc.

Content reviewed 12/2011

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* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.