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Tick-borne Diseases: Laboratory Support of Diagnosis and Management
- Interpretive Guide
- Related Tests
|Laboratory Support of Diagnosis and Management|
|This information is provided for informational purposes only and is not intended as medical advice. A physician's test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient. The treating healthcare professional should refer to the manufacturer's approved labeling for prescribing, warnings, side effects and other important information relating to treatment options.|
Tick-borne diseases are caused by infections transmitted to humans via a tick vector such as the deer tick, dog tick, wood tick, or lone star tick. Causative agents include bacteria, viruses, parasites, and protozoa. The incidence varies by geographic location and causative agent (Table 1).1-4 Clinical manifestations also vary depending on the causative agent but frequently include fever, chills, sweating, headaches, myalgia, arthralgia, nausea, and vomiting; because of similar symptomology, tick-borne diseases have substantial clinical overlap (Table 2).5-8 Some patients develop a rash or lesion at the site of the bite. More severe disease may lead to hematologic, respiratory, cardiac, and neurologic complications, as well as kidney or liver failure and arthritis. Although tick-borne illnesses can be fatal, antimicrobial agents are usually effective for bacterial tick-borne diseases. Some ticks can harbor more than 1 infectious agent (eg, Borrelia burgdorferi and Babesia microti) that can be transmitted to humans, and coinfection may complicate the diagnosis and affect treatment selection.9
Preliminary differential diagnosis is primarily based on clinical presentation and a history of exposure in areas where vector ticks are endemic (Figure).10 In symptomatic patients, a rash or lesion may provide the first clue to the diagnosis; however, absence of a rash should not rule out a condition from the differential diagnosis. Identification of the tick can also be helpful, as some disease pathogens are carried by specific tick species. Because of rapid disease progression associated with some tick-borne infections (eg, tick-borne rickettsial diseases [TBRDs]), treatment should not be delayed pending the results of laboratory tests or the development of more serious symptoms.5
Lyme disease is by far the most common tick-borne disease in the United States (Table 1),1-4 where it is caused by B burgdorferi sensu stricto of the B burgdorferi sensu lato complex. It can also be caused by other species of the B burgdorferi sensu lato complex, including B garinii and B afzelii. Despite the stabilization within the last decade in the number of confirmed and probable Lyme disease cases, incidence has remained high since 2008, when about 35,000 cases were reported; more than 35,000 cases of Lyme disease were reported in 2016 and many more may go unrecognized. Borrelia burgdorferi is transmitted by Ixodes scapularis and I pacificus ticks. Because I scapularis may also harbor Babesia microti, Anaplasma phagocytophilum, deer tick virus, Borrelia miyamotoi, and Ehrlichia species Wisconsin, a single tick bite can lead to coinfection in humans.9,11
Lyme disease cases are heavily centered in New England and the Mid-Atlantic. However, they are also found in Wisconsin and Minnesota and, to a lesser extent, in other states in the Great Lakes region and in Pacific Coastal regions. Lyme disease is most common among children and middle-aged adults.11
The clinical presentation of Lyme disease can be either localized or disseminated. Characteristic of early localized disease is the presence of erythema migrans, a round or oval erythematous skin lesion; it usually develops 3 to 30 days (Table 3)9,11 after the tick bite and should be ≥5 cm in largest diameter for a firm Lyme disease diagnosis.9,11 Untreated, lesions can grow much larger. Some but not all such lesions present with a "bulls-eye" pattern of central clearing at the site of the tick bite. Erythema migrans occurs in approximately 70% to 80% of infected persons.
Additional smaller lesions may develop if Lyme disease is untreated, and these are often the first sign of early disseminated disease. Extracutaneous involvement in early disseminated disease can include the musculoskeletal, cardiac, or nervous system. Disseminated disease can also occur in the absence of a recognized skin lesion. In late-stage disease, Lyme carditis may overlap temporally with neurologic Lyme disease.
If initiated in the early stages of disease, treatment with appropriate antibiotics is usually effective.9 Prophylaxis after a tick bite is usually not indicated in areas where less than 20% of ticks are infected—and then in only selected patients.9
Tick-borne Rickettsial Diseases
Tick-borne rickettsial diseases (TBRD) include spotted fever rickettsiosis (SFR), human monocytic ehrlichiosis (HME) and other ehrlichioses, and anaplasmosis including human granulocytic anaplasmosis (HGA). TBRDs commonly manifest with an acute onset of nonspecific symptoms that mimic benign viral infections, making diagnosis difficult (Table 2).5-8 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.5,12
Spotted Fever Rickettsiosis
SFR includes Rocky Mountain spotted fever (RMSF) and well as Rickettsia parkeri and Rickettsia philipii (364D) rickettsiosis, which are difficult to distinguish with commonly available serologic tests. SFR has been reported from each of the 48 contiguous states and the District of Columbia, although 5 states accounted for about 63% of cases during 2008–2012 (Arkansas, Missouri, North Carolina, Oklahoma, and Tennessee).5 The peak season for infection coincides with tick activity level for the region, but infection has been reported throughout the year.5 The reported incidence has increased in recent decades to >11 cases per million population in 2014. This increase in incidence has been accompanied by a decrease in case fatality rate, to <0.5% in 2014.13 Although infection is most common in the 60- to 69-year-old age group, children younger than 10 years have the highest case-fatality rate.5
RMSF, the most severe of the rickettsial illnesses, is caused by Rickettsia rickettsii. This organism infects endothelial cells and causes small-vessel vasculitis that usually results in a maculopapular or petechial rash. Symptoms tend to appear 3 to 12 days after a bite. RMSF is also the most severe of the rickettsioses in the United States. Vasculitis in organs such as the brain or lungs can lead to life-threatening complications.
Of the other SFR infections, the first case of human R parkeri infection was documented in 2014; as of 2015, at least 40 cases have been identified.1 It is carried by the Gulf Coast tick (Amblyomma maculatum), and its geographic distribution extends from the Southern and Mid-Atlantic regions. Human infection with R philipii (364D) was first documented in 2010. Rickettsia philipii (364D) is transmitted by the Pacific Coast tick (Dermacentor occidentalis), which is present in California and Oregon. Of the few (<10) cases reported as of 2013, all were from California.1
Anaplasmosis, or human granulocytic anaplasmosis (HGA), is caused by infection with Anaplasma phagocytophilum. It is usually found in the Northeastern and upper Midwestern states. The incidence rate is 6.3 cases per million person-years in the United States, being highest in these geographical areas.5 Anaplasmosis has substantial overlap of features with early Lyme disease but tends to be a more severe illness.14 Infection is most common in adults 60 years and older; the case fatality rate (0.3%) is highest in adults 70 years and older, and those with compromised immune systems.15
The ticks that carry A phagocytophilum can also harbor B burgdorferi, B miyamotoi or B microti, and detection of coinfection is recommended as it may affect treatment choices.5
Ehrlichiosis can be caused by 3 bacteria in the United States: Ehrlichia chaffeensis (the cause of human monocytic ehrlichiosis), Ehrlichia ewingii, and the recently identified Ehrlichia muris-like agent that may share primary tick vectors with B burgdorferi in Lyme disease.5 Ehrlichia chaffeensis is the most common cause of ehrlichiosis. It is mostly identified in South-central, Southeastern, and Mid-Atlantic states. Although E ewingii infection had been thought to primarily affect immunocompromised patients from Missouri, Oklahoma, and Tennessee, a recent study found it to be more often found in immunocompetent individuals.16
The incidence of ehrlichiosis increased 4-fold from between the year 2000 to the 2008–2012 period; during the 2008–2012 period, 16 new cases per million persons were reported, or an incidence rate of 3.2 cases per million persons per year for E chaffeensis. The case fatality rate is highest for children younger than 5 years old (4%).16 Ehrlichia ewingii had a much lower incidence rate during the same time period and was not associated with fatality.16
Table 2. Clinical Features of Tick-borne Rickettsial Diseases5-8
Tick-borne Non-Rickettsial Diseases
Babesiosis is primarily caused by a protozoan parasite infection (Babesia microti). This organism infects erythrocytes, and the disease process shares clinical features with malaria. Babesiosis is now reportable in 18 states but is most common in New England, New York, New Jersey, Minnesota, and Wisconsin, which account for 97% of cases.9,17,18 Infection is primarily transmitted by ticks, although it can also be transmitted congenitally or through transfusion; 6 transfusion-associated cases were reported in 2014. The disease may be asymptomatic, or symptoms may appear 1 to 6 weeks after the tick bite (Table 3).9,17,18 Symptoms vary widely but may include a gradual onset of irregular fever, chills, sweating, myalgia, arthralgia, nausea/vomiting, and fatigue (Table 3).9,17,18 Mild hepatosplenomegaly and mild hemolytic anemia may develop.
Treatment is not usually required for people without symptoms. For patients with clinical illness, treatment usually includes a combination of clindamycin and quinine, or atovaquone and azithromycin.9
Tularemia is caused by the bacterium, Francisella tularensis. Most commonly found in Missouri, Arkansas, and Oklahoma, transmission occurs through varying portals of entry including tick bites, skin contact with infected animals, and inhalation of contaminated aerosols or agricultural dusts. Infection via tick bites is characterized by an ulcerative lesion at the site of the tick bite and by lymphadenopathy. An erythematous, tender, or pruritic papule typically appears within 3 to 5 days and subsequently enlarges to form an ulcer with a black base. Additional symptoms of tularemia appear abruptly and include fever, chills, headache, and generalized myalgia and arthralgia (Table 3).19 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.19 Less common forms include oropharyngeal and oculoglandular disease. Presumptive diagnosis is based on a history of exposure to a tick-endemic region and clinical signs and symptoms. Treatments include streptomycin, gentamicin, and doxycycline.19 Ciprofloxacin is a non-FDA approved alternative when doxycycline is contraindicated.
Borrelia miyamotoi Disease (BMD)
First reported in the United States in 2013, BMD is caused by the transmission of Borrelia miyamotoi in infected I scapularis and I pacificus ticks.22 Recent surveillance suggests that the disease may be an emerging tick-borne infection in regions of the Northeast that include Massachusetts, Rhode Island, New Jersey, and New York.22 The clinical presentation of BMD is variable but shares a similar spectrum with other tick-borne diseases such as Lyme disease, anaplasmosis, and babesiosis.23 A constellation of nonspecific symptoms commonly includes fever, severe headache, myalgia, fatigue, and arthralgia; symptoms are characteristic of Lyme disease, babesiosis, and anaplasmosis which may be included in a differential diagnosis.23 A “toxic” appearance suggestive of sepsis is common on presentation and is often accompanied by elevated liver enzyme levels, neutropenia, and thrombocytopenia in patients hospitalized for suspected infection.22 A 2- to 4-week course of doxycycline is used to treat BMD infection.
Colorado Tick Fever (CTF)
CTF is caused by an arbovirus (Colorado tick fever virus) that infects erythrocytes. It is found throughout the Rocky Mountain region of the United States. Although CTF is not a nationally notifiable condition, an average of approximately 8 cases per year were reported to the CDC from 2002 through 2012. After a mean incubation time of 1 to 14 days, disease onset is abrupt; presenting symptoms include intense headache, severe myalgia, arthralgia, and a characteristic biphasic pattern of fever termed “saddleback” fever. The fever lasts for 2 to 3 days, disappears, and then may recur for another 2 to 3 days. In rare instances, severe complications such as central nervous system involvement and hemorrhage may occur, especially in children. Specific antiviral treatment is not available for Colorado tick fever.
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. Transmission typically occurs while sleeping in cabins or other rustic buildings that may house ticks in animal nests concealed in walls, attics, or crawl spaces. 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).10 Fever is typically ≥104°F and may be accompanied by delirium. Leukocytosis and thrombocytopenia are common, and splenomegaly may be present. Microscopy can be utilized to visualize the spirochetes in a blood smear, and thus, is useful in establishing the diagnosis.
Symptoms intensify without treatment, therefore, treatment should be administered when clinical suspicion is high. Tetracycline, or erythromycin if tetracycline is contraindicated, is recommended as the treatment of choice for TBRF.24
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). Panel components may be ordered individually.
In most cases, presumptive diagnosis of tick-borne illnesses is based on clinical grounds. Treatment should not be delayed pending confirmatory laboratory results except in the prophylaxis of Lyme disease in persons bitten by I scapularis or I pacificus ticks where empiric treatment is not recommended. The clinical symptoms and type of rash or lesion, if present, guide the initial differential diagnosis among patients exposed to a tick-endemic area (Figure).10 This, in turn, guides appropriate test selection, presumably leading to confirmation of the suspected disorder. The sections below outline characteristic test results for each of the tick-borne diseases discussed.
The information in the text, tables, and the figure is provided for informational purposes only and is not intended as medical advice. A physician's test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
Early Lyme Disease
Diagnosis of Lyme disease (B burgdorferi infection) generally relies on clinical findings and a history of exposure to the vector tick or tick habitat. Clinical findings, as well as laboratory testing, vary with the stage of the disease (Table 5).9,25,26 Diagnosis of early-stage, localized Lyme disease can sometimes be made on the basis of erythema migrans alone without laboratory testing.9 When there is diagnostic uncertainty, positive IgG and/or IgM serology results from acute- and convalescent-phase (ie, 2 to 4 weeks after the acute phase) samples can support the diagnosis (Table 5).9,25,26
Extracutaneous/Disseminated Lyme Disease
In the absence of erythema migrans, Lyme disease cannot be diagnosed on the basis of extracutaneous disease manifestations alone, because these symptoms are nonspecific.4 Diagnosis requires demonstration of seropositive test results; in cases where diagnosis of Lyme disease is not clear, support or confirmatory testing by PCR may be considered.4 Combined IgG and IgM testing by ELISA (or IFA) is recommended for patients 2 to 4 weeks after the tick bite (Table 5).9,25,26 Western blot (ie, immunoblot) testing is recommended as a confirmatory test for all specimens positive or equivocal by EIA.4
IgM antibodies may be present within a few weeks of disease onset, whereas large increases in IgG titers are produced months 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 result unless IgG is also positive. A positive IgG result by 2-tier testing is required to confirm the diagnosis of disseminated disease.4
Immunoassays used to detect Lyme disease antibodies utilize whole spirochete preparations or purified antigens, such as VlsE. The VlsE protein contains a C6 epitope that binds IgG and IgM antibodies produced in response to B burgdorferi infection. The VlsE antibody (IgG+IgM) test is specific to the C6 epitope and used to detect infection from both American and European Borrelia species while reducing false-positives that may be caused by antibody cross-reaction with similar organisms.27
The interpretation of Western blot assays is based on the number of positive bands: 2 of 3 bands (23, 39, 41 kDa) 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; positive results confirm B burgdorferi infection.
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, and relapsing fever. Positive IgG antibody test results do not differentiate between recent and 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. PCR-based assays can be useful in the workup of B burgdorferi infection if seroconversion has not yet occurred; these assays, however, are limited by low clinical sensitivity (18%).28 Untreated patients who continue to be symptomatic but are seronegative for 6 to 8 weeks are unlikely to have Lyme disease, and a differential diagnosis should be considered.9
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. The resulting antibody index, or AI, helps differentiate whether antibody present in CSF is due to intrathecal antibody as opposed to passive transfer across the blood-brain barrier (sensitivity, 75%; specificity, 97%).28,29 In the absence of elevated control antibody index or albumin ratio, an elevated B burgdorferi antibody index indicates intrathecal production of Borrelia antibody production and strongly suggests neuroborreliosis. However, a negative result does not rule out CNS involvement.
DNA detection in CSF has a sensitivity of 38% (≥93% specificity) for neurologic Lyme disease.
Methods that detect B burgdorferi DNA may also be used to support the diagnosis of rheumatologic manifestations of Lyme disease. Positive DNA findings in synovial fluid support the diagnosis of Lyme arthritis (sensitivity, 78%; specificity,100%).28 However, because spirochetemia is typically transient or absent, detection of B burgdorferi DNAin whole-blood specimens has low clinical sensitivity (14%), rendering negative results non-informative. For evaluation on rheumatologic manifestations, positive DNA results via PCR in a seropositive patient support the diagnosis of Lyme disease.9 However, in a seronegative patient, positive results should be interpreted with caution.9
Tick-borne Rickettsial Disease
Diagnosis of TBRDs is primarily clinical. However, laboratory testing can play important roles in distinguishing among these closely related diseases and in confirming infection.
Anaplasmosis and ehrlichiosis infections are characterized by infection of leukocytes, in which the causative agents multiply in cytoplasmic membrane-bound vacuoles called morulae.30 Anaplasma phagocytophilum and E ewingii 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.5
Routine laboratory tests are also useful in assessing patients suspected of having tick-borne illness, and can provide supportive evidence of specific illnesses; test results associated with the TBRDs are listed in Table 6.5 For example, patients with HGA often present with slightly decreased platelet and WBC counts and elevated liver enzymes. Although such abnormalities are suggestive of HGA, these markers tend to stabilize over time. Therefore, normal levels do not rule out HGA, especially in patients who have had symptoms for more than 1 week.31 Patients with early RMSF often have normal or slightly altered laboratory values. Band neutrophil counts may be increased; because such band increases are uncommon in viral infections, they can be helpful in differential diagnosis. Markers of tissue injury may arise later during the disease course.
Laboratory confirmation validates the accuracy of the presumptive clinical diagnosis and is important from an epidemiology and public health perspective. Confirmatory laboratory testing for TBRDs includes serology and nucleic acid testing (Table 6).5 IFAs are considered the gold standard for TBRD serology testing.5 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. For RMSF, IgG and IgM increase concurrently; IgM wanes after 3 to 4 months, whereas IgG persists for 7 to 8 months.
Note: although most patients have positive IgG or IgM antibody by the second week of illness, many people will be seronegative at the time of the first test (especially if done within the first week or so of illness). Therefore, negative results on serologic tests should not lead to discontinuation of therapy.
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.
Table 6. Laboratory Confirmation of Tick-borne Rickettsial Diseases5
Tick-borne Non-Rickettsial Diseases
The current case definition for babesiosis requires the presence of clinical evidence (fever, anemia, or thrombocytopenia) and/or at least 1 subjective symptom (chills, sweats, headache, myalgia, or arthralgia). Laboratory confirmation of infection may include microscopic identification or nucleic acid amplification detection of Babesia species DNA (Table 7).9,17,18,21,32 Serologic studies may provide supportive laboratory evidence (Table 7).9,17,18,21,32 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.
Additional laboratory abnormalities may include hemolytic anemia with an elevated reticulocyte count, thrombocytopenia, proteinuria, and elevated levels of liver enzymes, blood urea nitrogen, and creatinine.
Laboratory test results, combined with clinical symptoms, are used to make treatment decisions.9 Treatment is recommended in symptomatic patients when babesial parasites have been identified in peripheral blood smears or when DNA results are positive.9 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.
Various methods are available to assist in the diagnosis of tularemia. Positive results for F tularensis using direct agglutination assay provides presumptive evidence. Culture of F tularensis from appropriate sites provides definitive evidence of tularemia, but requires biosafety level 3 precautions. Francisella tularensis serology testing is the primary laboratory approach to confirm a diagnosis of tularemia (Table 7).19 A 4-fold increase in antibody titer between acute and convalescent sera (collected at least 4 weeks after onset) is considered diagnostic.19
Borrelia miyamotoi Disease (BMD)
PCR amplification of B miyamotoi DNA is part of an acute molecular panel of tests used to confirm a presumptive diagnosis of BMD based on clinical presentation. CSF, synovial fluid, whole blood or urine are acceptable specimen types for analysis. Detection of B miyamotoi DNA in suspected tick specimens is supportive for the diagnosis of infection. Guidelines also suggest serologic testing to confirm the diagnosis of BMD.34 Positive results on serology by ELISA or IgM and IgG immunoblot, however, may indicate coinfection by Borrelia species such as B hermsii and/or B burgdorferi. Negative results do not necessarily rule out infection and may be due to testing prior to seroconversion during the acute phase of infection.35
Colorado Tick Fever (CTF)
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).20 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.
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%).10 The 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).33 Because other Borrelia and Treponema species cross-react in the IFA test, positive specimens should be tested for antibodies to these organisms.
Content reviewed 08/2018
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