Tickborne Diseases

Medical Experts

Contributor

Jackson

Brian R. Jackson, MD, MS

Adjunct Professor of Pathology and Biomedical Informatics, University of Utah

Medical Director, Business Development, ARUP Laboratories

Contributor

Slev

Patricia R. Slev, PhD, D(ABCC)

Professor of Pathology (Clinical), University of Utah

Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories

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 (also referred to as 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, when certain tickborne illnesses (eg, anaplasmosis, ehrlichiosis, Rocky Mountain spotted fever) are suspected based on clinical presentation, medical intervention should not be delayed pending test results.^,

Quick Answers for Clinicians

Where do tickborne diseases circulate in the United States?

In the United States, the general distribution of several human-biting ticks has expanded, as shown by the CDC’s tick surveillance maps. For example, the American dog tick, Dermacentor variabilis, now covers almost all of the eastern U.S.; the blacklegged tick, Ixodes scapularis, has expanded northward into northern New York and all of New England; the lone star tick, Amblyomma americanum, can be found in most of the eastern U.S. as well as large areas of the Midwest; and the Western blacklegged tick, Ixodes pacificus, has been discovered in new counties on the West Coast. Refer to the CDC Where Ticks Live page for additional details.

Which tests are available to diagnose tickborne disease?

Various testing methodologies are used to diagnose tickborne disease, including serology, nucleic acid amplification testing (NAAT) methods 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?

In individuals with a characteristic erythema migrans (EM) rash and plausible exposure to Lyme disease, a clinical diagnosis can be made without the need for testing, and treatment should begin immediately. However, laboratory testing is recommended for those with atypical manifestations or specific neurologic symptoms (eg, cranial neuropathy, meningitis, etc.).

When testing is pursued, the CDC recommends a two-tiered approach.^,The standard two-tiered approach historically includes a first-tier enzyme immunoassay (EIA) followed by an immunoblot assay, whereas the more recent modified two-tiered approach relies on two sequential EIAs.^, For details on results interpretation for these two strategies, refer to guidance from the Association of Public Health Laboratories.

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 specimen collection 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 R. rickettsii is closely related to other Rickettsia species, assays may cross-react with other rickettsial species such as R. akari and R. parkeri. Antibody reactivity to R. rickettsii antigen should be considered spotted fever group reactive. Biopsy of a skin lesion can establish an RMSF diagnosis, although the sensitivity of this test may decline after the initiation of antibiotic therapy. Nucleic acid amplification testing (NAAT) on whole blood can be used but is generally less sensitive in early disease.

Which laboratory tests can be used to diagnose alpha-gal syndrome?

Alpha-gal syndrome (AGS) may arise due to the development of immunoglobulin E (IgE) antibodies against galactose-alpha-1,3-galactose (alpha-gal) that is transmitted by the bite of a lone star tick. A serum IgE immunoassay can be used in conjunction with a detailed patient history and physical examination to diagnose AGS. Positive serum IgE results confirm the diagnosis of AGS, although a negative result does not rule out clinical allergy or even anaphylaxis. Intradermal skin tests can be used to investigate sensitization to beef, pork, and dairy, but serum IgE tests remain the preferred method to diagnose AGS.

What laboratory testing should be performed on a removed tick?

The Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) recommend that removed ticks undergo species identification by a qualified expert or laboratory to inform clinical decisions about antibiotic prophylaxis and patient counseling about early signs of tickborne diseases such as Lyme disease.

Removed ticks should not be tested for Borrelia burgdorferi. Studies show that the detection of B. burgdorferi in ticks is a poor predictor of Lyme disease development or asymptomatic seroconversion.

Even in areas that are highly endemic for Lyme disease, the probability of an individual developing Lyme disease after being bitten by an infected tick is low (<5%), so treatment decisions should not be based on the presence of B. burgdorferi in a removed tick.

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 an EM rash, 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 pending test results in individuals with clinical presentations suggestive of anaplasmosis, ehrlichiosis, or any spotted fever group rickettsiosis (eg, Rocky Mountain spotted fever [RMSF]), given that certain infections 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 the clinical presentation alone is not adequate. More detailed information about laboratory testing recommendations can be found in the Laboratory Testing section.

Tickborne Disease	Tick^a	Preferred Laboratory Testing^b
Lyme disease	Blacklegged tick (Ixodes scapularis) Western blacklegged tick (Ixodes pacificus)	2-tiered serologic testing; no testing if EM rash is present
Rocky Mountain spotted fever	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; treatment should not be delayed pending results
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; treatment should not be delayed pending results
Ehrlichiosis	Lone star tick (Amblyomma americanum) Blacklegged tick (Ixodes scapularis)	NAAT; treatment should not be delayed pending results
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 refer to the CDC Where Ticks Live page. ^bFor ARUP-specific testing, refer to the ARUP Laboratory Tests section. Sources: CDC, 2022; CDC, 2024

Laboratory Testing

Lyme Disease (Borrelia burgdorferi)

Lyme disease, caused by Borrelia burgdorferi, is the most common vectorborne disease in the U.S.

Testing for Lyme Disease

Lyme disease is usually identifiable by a characteristic EM skin rash. If an individual presents with this telltale rash following exposure to an area endemic for Lyme disease, laboratory testing is not required, and treatment should begin.^,^, However, some Lyme disease cases do not present with the typical “bull’s eye” rash.^, When clinical presentation is not confirmative, or when retroactive confirmation of a diagnosis is desired, laboratory testing for Lyme disease should be performed. Laboratory testing is also recommended in the presence of certain neurologic symptoms to assess for Lyme neuroborreliosis.

Serology

Serologic assays that detect antibodies against B. 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 B. burgdorferi are common serologic targets. When laboratory testing is performed, results should be considered alongside clinical findings and patient history to diagnose Lyme disease.

The standard two-tiered approach to Lyme disease testing historically includes a first-tier enzyme immunoassay (EIA), followed by a second-tier immunoblot assay when initial results are positive or equivocal. More recently, a modified two-tiered strategy that relies on a second-tier EIA has also been adopted.^, The use of assays that include both tiers of testing (as opposed to standalone assays) improves specificity. For additional information, refer to the Lyme Disease - Modified Two-Tiered Testing Algorithm.

Two-tiered serologic tests may include total or separate immunoglobulin M (IgM) and IgG antibody concentrations. When reported separately, IgM results should be disregarded for specimens collected more than 30 days after symptom onset. Additionally, false-positive results may occur in patients with other Borrelia diseases (eg, relapsing fever, B. miyamotoi disease), other bacterial or viral illnesses, and autoimmune diseases.

Nucleic Acid Amplification Testing

NAAT (eg, polymerase chain reaction [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), serum antibody testing that follows the two-tiered testing approach, rather than CSF testing, is recommended.^,

Rocky Mountain Spotted Fever (Rickettsia rickettsii)

RMSF, caused by Rickettsia rickettsii, is the most frequently fatal rickettsial illness in the U.S. Contrary to its name, RMSF is not limited to (or even most common in) the Rocky Mountain region; cases occur across the 48 contiguous states. Infection leads to systemic vasculitis that manifests externally as characteristic petechial skin lesions. Nonspecific signs and symptoms in the initial stages of RMSF make early diagnosis more challenging; thus, it is important to consider testing for RMSF in any individual with a compatible presentation and risk factors (eg, time spent in areas with ticks).

When RMSF is suspected based on clinical presentation and patient history, treatment should not be delayed pending test results.

Testing for Rocky Mountain Spotted Fever

Clinical diagnosis of RMSF is confirmed through serologic testing, molecular detection by PCR using a rash lesion biopsy (preferred over whole blood), or immunohistochemical staining of a skin biopsy. RMSF is often retrospectively diagnosed by serology; paired acute and convalescent specimens should be collected 2-4 weeks apart, the first within 2 weeks of symptom onset. Notably, it may take up to 10 days from symptom onset for antibody testing to yield positive results.

Because R. rickettsii is closely related to other Rickettsia species, assays may cross-react with other rickettsial species. Antibody reactivity to R. 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 generally has reduced sensitivity in early disease and in individuals receiving therapy.

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

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

Testing for Tickborne Relapsing Fever

Laboratory testing for TBRF and hard tick relapsing fever (B. miyamotoi infection) includes molecular detection by NAAT (eg, PCR) and serology. When TBRF is suspected, dark field microscopy or a stained peripheral blood smear can also be used to detect spirochetes in blood collected during the symptomatic stage of illness, although these diagnostic methods have poor sensitivity and require considerable experience.

NAAT is most useful when performed early (ie, before treatment commences) using a specimen collected during a symptomatic episode. If serology is performed, an acute specimen and a convalescent specimen collected 21 days or more after symptom onset should be tested. NAAT and serologic tests may cross-react with other Borrelia species, including B. burgdorferi; tick exposure history can be helpful to distinguish between possible causative agents.^,

Babesiosis (Babesia microti)

Babesiosis is an uncommon, 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 B. 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, PCR assays, and serology.^,

Testing for Babesiosis

The CDC’s case definition for babesiosis requires confirmation of infection by blood smear or NAAT. NAAT is often the preferred first-line test to diagnose babesiosis because several blood smears may be required. Additionally, blood smears may not differentiate between Babesia and Plasmodium species.^, Although serology may be used to support a diagnosis of babesiosis and identify a causative agent, it is not useful to distinguish between a current or previous infection.^,

Anaplasmosis (Anaplasma phagocytophilum) and Ehrlichiosis (Ehrlichia chaffeensis)

Anaplasmosis (also known as human granulocytic anaplasmosis) is, in most cases, a mild illness, although it can vary in progression and severity depending on factors such as age, immune status, and the presence of comorbidities. Clinical presentation is usually marked by nonspecific symptoms (eg, fever, chills, and headache), and life-threatening illness is less common than in other tickborne rickettsial diseases.

Ehrlichia chaffeensis, the cause of human monocytic ehrlichiosis (HME), is associated with severe, life-threatening disease, whereas E. ewingii and E. muris eauclairensis (EML) are not known to cause fatal illness.^,

When anaplasmosis or ehrlichiosis is suspected, treatment should not be delayed pending results.

Testing for Anaplasmosis and Ehrlichiosis

Laboratory testing is required to confirm A. phagocytophilum and E. chaffeensis infections. The CDC’s case definition for confirmed infection includes NAAT, paired species-specific IgG serology by indirect fluorescent antibody (IFA) testing, immunohistochemistry (IHC), and culture. NAAT is the primary mode of testing during acute infection and is preferred over IHC or culture. NAAT sensitivity may be reduced in those receiving antibiotic treatment.^,^, If serology is performed, paired serum specimens (the first collected within 7 days of symptoms and the second collected 2-4 weeks later) should be tested.^,

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 the initial presentation usually includes nonspecific symptoms such as chills, fever, headache, and generalized aches. Clinicians may also consider testing for other similar disorders, including R. rickettsii (RMSF) and R. typhi (typhus fever).

Testing for Tularemia

Serology and culture can help confirm a diagnosis of tularemia. Although isolation of F. tularensis via culture provides a definitive diagnosis, this method is time consuming and extended incubation is required.^,

When performed, serology should be interpreted in the context of compatible exposure and clinical presentation. Seroconversion from negative to positive IgM and/or IgG in paired sera is diagnostic. The first specimen should be collected within a week of initial illness, and the second should be collected 2-3 weeks later.^, Antibodies are not detectable until 2-3 weeks after symptom onset.

Because IgM and IgG may remain detectable for several years after infection, serology is not useful to monitor therapy response. False-positive EIA results are possible due to cross-reactivity with Brucella or Yersinia or as a result of low IgM and IgG levels. Confirmation by direct agglutination (DA) is recommended. Notably, DA does not distinguish between IgM and IgG antibodies.

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 frequently encountered diseases. Clinical consideration should be used to determine if laboratory testing for these diseases is indicated.