Tickborne Diseases

Tickborne diseases, including Lyme disease and Rocky Mountain spotted fever, are increasing in incidence and distribution in the United States. Tickborne diseases are transmitted to humans through the bite of an infected tick, and infections typically occur during the summer months when ticks are most active. Some of the more common tickborne diseases in the U.S. include Lyme disease and anaplasmosis.

Many tickborne illnesses have similar clinical presentations, including fever, headache, fatigue, and, in rare cases, paralysis (tick paralysis). Laboratory testing may aid in determining the treatment that can best minimize the risk of severe illness when tickborne disease is suspected. Laboratory testing for tickborne disease includes serology and nucleic acid amplification testing (NAAT). The appropriate testing strategy depends on the suspected infection and duration of symptoms. However, although laboratory testing can confirm diagnosis and inform treatment, medical intervention should not be delayed in patients with a suggestive clinical presentation. 

Quick Answers for Clinicians

Where do tickborne diseases circulate in the United States?

Ticks have expanded in range. The American dog tick, Dermacentor variabilis, covers almost all of the Eastern United States. The blacklegged tick, Ixodes scapularis, has expanded northward into northern New York and all of New England. Lone Star ticks, Amblyomma americanum, the major vector of human monocytic ehrlichiosis (HME), now cover most of the Eastern U.S. as well as large areas of the Mid-Central U.S.  Ixodes pacificus has been discovered in new counties on the West Coast and has been found to harbor the newly recognized human pathogen, Borrelia miyamotoi.  The general distribution of human-biting ticks in the contiguous U.S. can be found here. 

Which tests are available to diagnose tickborne disease?

Various testing methodologies are used to diagnose tickborne disease, including serology, nucleic acid amplification testing (NAAT) such as polymerase chain reaction (PCR), and blood smears. The most appropriate testing strategy depends on the suspected tickborne disease, the timing of testing relative to symptom onset, and the specimen available for testing. Diagnostic tests should be ordered and interpreted in the context of a compatible illness and epidemiologic setting to obtain optimal positive and negative predictive values. Without high pretest probability, test results can lead to confusion. For example, antibodies to tickborne pathogens can remain detectable for months to years after infection, but in the absence of a clinically compatible acute illness, antibodies are not indicative of an active infection that requires treatment.  

What is important to consider when Lyme disease is suspected?

If Lyme disease is suspected, treatment should not be delayed for laboratory test results. Additionally, in patients who exhibit a characteristic erythema migrans (EM) rash and have had exposure to an area in which Lyme disease is endemic, laboratory testing is not necessary for diagnosis. When performing testing, the CDC’s two-tier testing strategy should be used.  Conventional two-tiered Lyme disease testing strategies include a first-tier enzyme immunoassay (EIA) followed by an immunoblot assay. In 2019, the CDC introduced a modified two-tiered strategy that relies on two sequential or concurrent EIAs.   For second-tier immunoblot testing, only immunoglobulin G (IgG) testing is necessary for specimens taken ≥4 weeks after disease onset, due to higher antibody concentrations.

If neurologic manifestations (eg, cranial neuropathy, meningitis, cranial nerve deficits, or encephalitis) are present, cerebrospinal fluid (CSF) studies are necessary. 

Detailed information about laboratory testing for Lyme disease can be found in the Lyme Disease Testing Algorithm.

What is important to consider when Rocky Mountain spotted fever is suspected?

Rocky Mountain spotted fever (RMSF) is a serious disease caused by Rickettsia rickettsii and should be treated immediately if suspected, due to its high mortality rate in the absence of appropriate medical intervention. Treatment should not be delayed for laboratory test results. The testing strategy should be based on the timing of testing relative to symptom onset.  Serology is generally used for retrospective diagnosis and includes paired acute and convalescent specimens collected 2-4 weeks apart and compared to identify a fourfold titer increase in immunoglobulin G (IgG) concentration or seroconversion from IgM to IgG. Measurement of IgM alone is not recommended. Because Rickettsia rickettsii is closely related to other Rickettsia species, assays may cross-react with other rickettsial species such as Rickettsia akari and Rickettsia parkeri. Antibody reactivity to Rickettsia rickettsii antigen should be considered spotted fever group reactive. Biopsy of a skin lesion can establish an RMSF diagnosis, although sensitivity of this test may decline after initiation of antibiotic therapy. Nucleic acid amplification testing (NAAT) can be used but is generally insensitive in early disease. 

Where can I find the most up-to-date testing guidance for tickborne disease?

The CDC currently recognizes 18 tickborne pathogens in the United States. For a list of tickborne diseases in the U.S., click here. 

Which testing algorithms are related to this topic?

Indications for Testing

In general, tickborne disease may be suggested by a combination of clinical presentation and supportive travel history, activity, or geographic area of residence. Some tickborne diseases present with telltale symptoms; for example, individuals with Lyme disease typically have a characteristic erythema migrans (EM) rash. In patients with characteristic symptoms such as EM, laboratory testing is often not required but can be used to confirm a diagnosis. If typical signs and symptoms are not present, laboratory testing can confirm a diagnosis of tickborne disease. 

Treatment should not be delayed if tickborne disease is suspected, given that some tickborne diseases can be rapidly fatal if not promptly treated. 

The table below describes the ticks that cause particular tickborne diseases, along with the general laboratory testing methodologies that are recommended for diagnosis when clinical presentation alone is not adequate. More detailed information about laboratory testing recommendations can be found in the Laboratory Testing section.

Tickborne Disease Ticka Preferred Laboratory Testingb
Lyme diseasec

Blacklegged tick (Ixodes scapularis)

Western blacklegged tick (Ixodes pacificus)

No testing if EM is present; otherwise, CDC’s two-step serology testing is recommended
Rocky Mountain spotted feverc

American dog tick (Dermacentor variabilis)

Brown dog tick (Rhipicephalus sanguineus)

Rocky Mountain wood tick (Dermacentor andersoni)

Serology using paired acute and convalescent specimens, skin biopsy
Tickborne relapsing fever

Blacklegged tick (Ixodes scapularis)

Western blacklegged tick (Ixodes pacificus)

Soft ticks (Ornithodoros spp)

NAAT
Babesiosis Blacklegged tick (Ixodes scapularis) NAAT
Anaplasmosis

Western blacklegged tick (Ixodes pacificus)

Blacklegged tick (Ixodes scapularis)

NAAT
Ehrlichiosis

Lone Star tick (Amblyomma americanum)

Blacklegged tick (Ixodes scapularis)

NAAT
Tularemia

American dog tick (Dermacentor variabilis)

Rocky Mountain wood tick (Dermacentor andersoni)

Lone Star tick (Amblyomma americanum)

Serology using paired acute and convalescent specimens

aFor more information about these ticks, including their geographic distribution, please visit the CDC's Tick Resources website. 

bFor ARUP-specific testing, see the ARUP Laboratory Tests section.

cTreatment should not be delayed for laboratory test results.

Sources: CDC, 2018 ; CDC, 2020 

Laboratory Testing

Lyme Disease (Borrelia burgdorferi)

Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in the U.S. 

Laboratory Testing

Lyme disease is usually identifiable by a characteristic EM skin rash. If an individual presents with this telltale rash and accompanying clinical symptoms, laboratory testing is not required, and treatment should begin.   In cases with clear clinical presentation, laboratory testing may be useful to retroactively confirm diagnosis. Many lesions do not present with the typical “bull’s eye” rash, and homogenously erythematous lesions are common.   When clinical presentation is not confirmative, laboratory testing may be necessary for definitive diagnosis.  However, treatment should not be delayed for laboratory test results if Lyme disease is suspected.  

Serology

Serologic assays that detect antibodies against Borrelia burgdorferi are currently the only type of laboratory test approved by the U.S. Food and Drug Administration (FDA) and recommended by the CDC for the diagnosis of Lyme disease.  Antibodies against VSLE C10 peptides of Borrelia burgdorferi are common serologic targets. Laboratory results should be considered along with clinical findings for the diagnosis of Lyme disease. Conventional two-tiered Lyme disease testing strategies include a first-tier enzyme immunoassay (EIA) followed by a more specific immunoblot assay. In 2019, the CDC introduced a modified two-tiered strategy that relies on two sequential or concurrent EIAs.   See the Lyme Disease Testing Algorithm for detailed information about the CDC’s two-step testing process.

Second-tier immunoblot assays performed in the first 4 weeks after disease onset should include both immunoglobulin G (IgG) and IgM immunoblot assays. Only IgG immunoblot is necessary for specimens taken ≥4 weeks after symptom onset, due to higher antibody concentrations. IgM immunoblot testing is not recommended in the chronic stage and does not aid in the diagnosis of neuroborreliosis or chronic Lyme disease.  

False-positive results may be seen in patients with other Borrelia diseases (eg, relapsing fever, Borrelia miyamotoi disease), other bacterial or viral illnesses, and autoimmune diseases. Patients previously vaccinated for Lyme disease may also have positive results. 

Nucleic Acid Amplification Testing

NAAT, such as polymerase chain reaction (PCR), is not used to diagnose Lyme disease. PCR testing is generally not recommended for blood and cerebrospinal fluid (CSF) specimens due to its low sensitivity (eg, a negative result does not exclude neurologic or Lyme arthritis).  False-positive results are common.

Cerebrospinal Fluid Studies

When assessing patients for neuroborreliosis in the presence of neurologic manifestations (eg, cranial neuropathy, meningitis, cranial nerve deficits, or encephalitis), CSF studies are recommended.   The detection of Borrelia antibodies in CSF is indicative of neuroborreliosis.

In Lyme meningitis, CSF studies typically show lymphocytic pleocytosis, slightly elevated protein, and normal glucose.  Testing for intrathecal IgM or IgG antibodies may be helpful in certain situations, such as when a compromised blood-brain barrier is suspected. 

Rocky Mountain Spotted Fever (Rickettsia rickettsii)

Rocky Mountain spotted fever (RMSF), caused by Rickettsia rickettsii, is the most frequently fatal rickettsial illness in the U.S.  RMSF leads to systemic vasculitis that manifests externally as characteristic petechial skin lesions.  The classic triad of fever, rash, and reported tick bite is often seen in only a minority of patients at initial presentation; therefore, laboratory confirmation should not be relied on to make a treatment decision.   Treatment for RMSF should not be delayed for definitive diagnosis. RMSF is most commonly diagnosed by serology.

Laboratory Testing

Clinical diagnosis is confirmed through serologic testing or staining of skin biopsy. RMSF is typically retrospectively diagnosed by serology and requires paired acute and convalescent specimens taken 2-4 weeks apart.  Because Rickettsia rickettsii is closely related to other Rickettsia species, assays may cross-react with other rickettsial species.  Antibody reactivity to Rickettsia rickettsii antigen should be considered spotted fever group reactive. Biopsy of a skin lesion can establish the diagnosis of RMSF, although the sensitivity of this test may decline after initiation of antibiotic therapy. NAAT can be used but is generally insensitive in early disease and in patients receiving therapy. 

Relapsing Fever (Borrelia hermsii, Borrelia turicatae, Borrelia parkeri, Borrelia miyamotoi)

Borrelia hermsii, Borrelia turicatae, and Borrelia parkeri cause tickborne relapsing fever (TBRF). TBRF can cause a cycle of symptoms marked by 3 days of fever, 7 days without fever, followed by another 3 days of fever. Without treatment, the pattern can repeat several times.   Borrelia miyamotoi disease, also referred to as hard tick relapsing fever, is closely linked to the bacteria that causes TBRF.

Laboratory Testing

The CDC recommends diagnosis by dark field microscopy or peripheral blood smears during the active (symptomatic) stage of TBRF illness.   However, it should be noted that this traditional method of diagnosis has poor sensitivity and requires considerable experience. Blood smear is not used to diagnose Borrelia miyamotoi disease. The preferred method of diagnosis is NAAT.  NAAT is most useful within 7 days of symptom onset and may aid in diagnosis during the active (symptomatic) stage of illness in both TBRF and Borrelia miyamotoi disease.  PCR testing is unable to differentiate the causative species (Borrelia hermsii, Borrelia parkeri, Borrelia turicatae, or Borrelia miyamotoi).

Babesiosis (Babesia microti)

Babesiosis is a rare, sometimes severe disease caused by the bite of a tick infected with Babesia microti. In the U.S., the blacklegged tick, commonly known as the deer tick (Ixodes scapularis), is responsible for transmitting Babesia microti. The clinical features of babesiosis are similar to those of malaria, and clinical presentation ranges in severity from asymptomatic to rapidly fatal.  Laboratory testing for babesiosis includes Giemsa-stained blood films, serology, and PCR assays.

Laboratory Testing

The CDC’s case definition for babesiosis  requires confirmation of infection by blood smear or NAAT. NAAT is often the preferred first-line test for diagnosing babesiosis because several blood smears may be required. Additionally, blood smears may not differentiate between Babesia and Plasmodium species.  

Anaplasmosis (Anaplasma phagocytophilum) and Ehrlichiosis (Ehrlichia chaffeensis)

Anaplasmosis (also known as human granulocytic anaplasmosis) is, in most cases, a mild, self-limited illness that resolves within about a month, even without antibiotic therapy.   Clinical presentation is usually marked by nonspecific symptoms (eg, fever, chills, and headache) and is typically mild.

Ehrlichia chaffeensis, the cause of human monocytic ehrlichiosis (HME), is associated with severe, life-threatening disease. Ehrlichiosis caused by Ehrlichia ewingii and Ehrlichia muris eauclairensis (EML) has not been associated with death.  

Laboratory Testing

Laboratory testing is required to confirm infection. The CDC’s case definition for confirmed anaplasmosis and ehrlichiosis requires serologic evidence of disease, NAAT, immunohistochemistry (IHC), or culture.  NAAT is the primary mode of testing for anaplasmosis and ehrlichiosis during acute infection and is preferred over IHC or culture.  NAAT sensitivity may be reduced if patient is on antibiotics.   

Tularemia (Francisella tularensis)

Francisella tularensis causes potentially severe zoonotic disease in humans. It is sometimes referred to as rabbit fever or deer-fly fever. Tularemia is a rare disease that is often difficult to diagnose because initial presentation often includes nonspecific symptoms such as chills, fever, headache, and generalized aches.  Clinicians may also consider testing for other similar disorders, including Rickettsia rickettsii (Rocky Mountain spotted fever) and Rickettsia typhi (typhus fever).

Laboratory Testing

Serology and culture can help confirm a diagnosis of tularemia. Seroconversion from negative to positive IgM or IgG in paired sera collected at appropriate time points can be diagnostic. Antibodies are not detectable until 2-3 weeks after symptom onset. IgM and IgG may remain detectable for several years after infection; therefore, serology should not be used to monitor therapy response, relapse, or reinfection. False-positive EIA results are possible when IgM and IgG levels are low. Confirmation by direct agglutination (DA) is recommended. However, DA does not distinguish between IgM and IgG. False-positive results may also occur due to cross-reaction in patients who have been infected with Brucella or Yersinia. Tularemia is a rare disease and should be interpreted in the context of compatible clinical symptoms and possible exposure.

Additional Tickborne Diseases

Tickborne diseases such as Southern tick-associated rash illness (STARI), deer tick virus (Powassan virus), heartland virus, and Bourbon virus are uncommon but may present similarly to more commonly encountered diseases. Clinical consideration should be used to determine if laboratory testing for these diseases is indicated.

ARUP Laboratory Tests

Panel Testing for Multiple Tickborne Diseases

Preferred panel for diagnosing possible tickborne disease (ie, anaplasmosis, ehrlichiosis, or babesiosis) during the acute phase of the disease

Lyme Disease

Preferred reflex test to detect Lyme disease in individuals with clinical symptoms for ≤4 weeks or tick exposure within previous 4 weeks

Positive/equivocal screen confirmed by immunoblot

Preferred reflex test to detect Lyme disease in individuals with >4 weeks of clinical symptoms or exposure to tick

Positive/equivocal screen confirmed by immunoblot

Preferred CSF reflex panel for workup of suspected neuroborreliosis

Includes reflex to immunoblot

Rocky Mountain Spotted Fever

Preferred test for acute or convalescent phase of disease

Acute and convalescent titers often necessary

Tickborne Relapsing Fever

Use to diagnose relapsing fever caused by various Borrelia species during the symptomatic phase of infection

Babesiosis

First-line test for diagnosing acute babesiosis

Detects nucleic acid from B. microti and detects but does not differentiate between B. duncani, B. divergens, strain MO-1, and strain EU-1

Blood smears are also appropriate for diagnosing and monitoring babesiosis disease; refer to Parasites Smear (Giemsa Stain), Blood (0049025)

If also investigating anaplasmosis or ehrlichiosis, consider Tick-Borne Disease Panel by PCR, Blood (2008670)

Anaplasmosis and Ehrlichiosis

Preferred panel to diagnose possible tickborne disease (ie, anaplasmosis or ehrlichiosis) during the acute phase of the disease

If also investigating babesiosis, consider Tickborne Disease Panel by PCR, Blood (2008670)

Francisella tularensis

Preferred test for detecting antibodies during acute or convalescent phase

Medical Experts

Contributor

Slev

Patricia R. Slev, PhD, D(ABCC)
Associate Professor of Pathology (Clinical), Codirector, Clinical Chemistry Fellowship program, University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory; Medical Director, Serologic Hepatitis and Retrovirus and Immunology Core Laboratory; Medical Director, Microbial Immunology, ARUP Laboratories

References

  1. CDC - Lyme

    U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Lyme disease. [Last reviewed: Mar 2021; Accessed: Apr 2021]

  2. CDC - Babesiosis

    U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Babesiosis. [Last reviewed: Oct 2017; Accessed: Apr 2021]

  3. CDC - Tularemia

    U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Tularemia. [Last reviewed: Dec 2018; Accessed: Apr 2021]