Tick-borne Infections in Children in North America

Abstract

Purpose of the Review:

Because both incidence and awareness of tick-borne infections is increasing, review of major infections and recent advances related to their diagnosis and management is important.

Recent Findings:

A new algorithm, termed modified two-tier testing, for testing for antibodies to Borrelia burgdorferi, the cause of Lyme disease, has been approved and may replace traditional two-tier testing. In addition, doxycycline is now acceptable to use for treatment of and/or prophylaxis for Lyme disease for up to 21 days in children of any age. Borrelia myamotoi, a bacteria in the relapsing fever type of Borrelia, is the first of this type of Borrelia that is transmitted by hard-bodied ticks such as Ixodes scapularis.

Summary:

Awareness of these infections and advances in their diagnosis and treatment is important to assure the best outcomes for affected patients. Table 1 contains a summary of infections discussed.

Bacterial infections

Lyme Disease

Lyme disease, caused by spirochetes in the Borrelia burgdorferi sensu lato complex, is the most common vector-borne disease in North America (1). Cases reported to the Centers for Disease Control (CDC) have increased over time, from approximately 10,000 cases in 1992 to nearly 43,000 cases in 2017 (2*). It occurs predominantly in New England and the mid-Atlantic regions, extending from Virginia north into Maine and west through Ohio, and in the upper Midwestern states, chiefly in Minnesota and Wisconsin and neighboring areas. There is a much lower incidence on the West Coast, with cases documented in northern California, Oregon, and Washington (3**). In North America, human infections are caused almost exclusively by B. burgdorferi sensu stricto (hereafter referred to as B. burgdorferi), with occasional B. mayonii infections occurring in the upper Midwest. In the US, the primary vector is Ixodes scapularis; I. pacificus is responsible for transmission in the western US (3**). The primary animal reservoirs are the white-footed mouse, chipmunks, and gray squirrels (4).

After transmission of the spirochete into the skin, the erythema migrans (EM) rash appears in 3–32 days (3**). It is the most common manifestation of Lyme disease and occurs in up to 95% of cases; however only approximately 25% of patients with EM recognized the tick bite that was responsible (2*). The classic “bulls eye” appearance with central clearing occurs in only about a third of patients. More commonly, the annular rash is uniformly erythematous and may continue to expand in size for several weeks if untreated (5**).

Early disseminated Lyme disease occurs within days to a few weeks after initial infection and is due to hematogenous dissemination of B. burgdorferi, leading to skin, cardiac, and neurological manifestations (2*). Patients can have multiple EMs, which are usually smaller than single EM lesions (3**). Neuroborreliosis occurs in up to 10% of patients and may affect both the peripheral and central nervous systems (6). The three most common syndromes are cranial neuropathy, lymphocytic meningitis and polyradiculopathy. Facial nerve palsy is the most common manifestation of neuroborreliosis, especially in children, among whom it occurs in up to 5% of patients (3**).

Patients with late Lyme disease typically present with inflammatory monoarticular or oligoarticular arthritis in large joints, most commonly the knee (1). It occurs in up to 7% of children with Lyme disease (3**). Children typically present with a subacute swollen joint, but the joint may mimic septic arthritis, with fever, pain, and inflammation (7).

Diagnostic tests for Lyme disease generally depend on detection of antibodies in serum, since sensitivity of cultures of blood, CSF, and joint fluid is poor. The EM rash usually occurs well before antibodies can be detected, so testing for antibodies is not recommended in those patients; treatment should be based on clinical history and the appearance of the rash (8). Sensitivity of serology is excellent for diagnosis of Lyme arthritis and for most manifestations of early disseminated disease except for multiple EM (1). Standard two-tier testing (STTT) for antibodies consists of an initial quantitative test, usually an enzyme immunoassay (EIA), followed by Western immunoblot (WB) tests if the initial results are either positive or equivocal (9**). Recently, a new algorithm, termed modified two-tier testing (MTTT), was approved because it can be completed faster, should be less expensive than STTT, and it avoids the subjectivity inherent in interpreting results of WB. It consists of two FDA-approved first-tier EIAs, run concurrently or sequentially (5**). Both EIAs must be positive for a result to be considered positive. MTTT is somewhat more sensitive than STTT for detecting early infections, but it is somewhat less specific (1). However, serologic test results cannot distinguish between active and past infection and have poor positive predictive values if done on patients with a low prior probability of Lyme disease (5**).

There have been some minor changes in recommendations for treatment of Lyme disease. Patients who live in an endemic area who find an Ixodes tick that was attached for >36 hours can be given a single dose of oral doxycycline within 72 hours to prevent Lyme disease (2*). Patients with EM should be treated with doxycycline, amoxicillin or cefuroxime (7). In patients unable to tolerate a first-line agent, azithromycin can be used. However, if there is reason to suspect coinfection with Anaplasma, doxycycline should be used (1). While doxycycline has traditionally been contraindicated in children ≤8-years-old, due to possible staining of permanent teeth, this was primarily based on experience with older tetracyclines. Doxycycline is now acceptable to use for ≤21 days in young children (7). In patients with Lyme neuroborreliosis, treatment should be with either ceftriaxone or doxycycline for 14–21 days (10). Long-term outcomes in children with Lyme neuroborreliosis are very favorable, with most patients making a complete recovery. Lyme carditis can be treated orally with doxycycline, amoxicillin, or cefuroxime. Hospitalized patients should be started on ceftriaxone until there is clinical improvement, at which time they can be transitioned to oral therapy for a total of 14–21 days (11). For patients with Lyme arthritis, the recommended treatment is for 28 days with the same oral agents recommended above (9**). There are some patients that report persistent symptoms after the first course of therapy, at which point they can either be retreated with an additional 28-days of oral therapy or with ceftriaxone for 14–28 days (7). Nonsteroidal antiinflammatory agents can be used for pain and may hasten clinical improvement (3**). There is no vaccine against B. burgdorferi currently available, although clinical trials of a vaccine are underway.

Some patients report having persistent or relapsing nonspecific symptoms (eg, arthralgia, myalgia, fatigue) after completing treatment for Lyme disease, which is referred to as post-treatment Lyme disease syndrome (PTLDS) if it lasts for ≥6 months and is associated with some degree of functional impairment, a subset of what is sometimes termed “chronic Lyme disease” (12, 13**). There is no accepted clinical definition as to what constitutes “chronic Lyme disease,” and the term is frequently applied to a highly heterogeneous group of patients, including many with no objective evidence of ever having had Lyme disease (7). Regardless of their underlying diagnoses, many patients diagnosed with “chronic Lyme disease” have significant disability from their symptoms (7). Children with Lyme disease are less likely to develop PTLDS (13**). Current evidence does not support prolonged antibiotic therapy for PTLDS, as it is unlikely to provide benefit and exposes these patients to significant risk (7).

Borrelia miyamotoi

Relatively recently, B. miyamotoi has been recognized as a cause of tick-borne relapsing fever (TBRF), the first such bacterium transmitted by hard-bodied ticks such as I. scapularis and I. pacificus. In 2016, the first case in a child was reported in a 5-year-old from Massachusetts (14). B. miyamotoi is genetically more closely related to the bacteria that cause tick-borne relapsing fever than to B. burgdorferi (15). It resides in the tick’s salivary glands and can be transmitted much more rapidly than B. burgdorferi, which resides in the tick midgut (16). Its primary reservoirs are rodents, such as squirrels, chipmunks and mice (17*).

The most common presentation is non-specific flu-like symptoms, including fever (may exceed 40°C), chills, fatigue, headaches, myalgias, arthralgias, and nausea (1,16). Relapsing fever is only seen in 10–40% of cases (15). The average interval between febrile episodes is nine days, but episodes occur less frequently and with fewer cycles than with relapsing fevers due to other Borrelia species (16,17*).

Diagnosis can be made via either PCR assay or serology. The most specific test for B. miyamotoi is PCR that can target the GlpQ gene, either from whole blood or CSF (1,16). GlpQ is an antigen produced by B miyamotoi but not B. burgdorferi, and is the primary discriminatory marker (17*–19). Serologic testing is often negative during the first seven days of symptoms; however, paired with convalescent serum obtained at least 3 weeks after onset of symptoms, a 4-fold rise in specific antibodies indicates acute infection (1). Laboratory findings include leukopenia, thrombocytopenia and elevated hepatic transaminases (1,15,16). There are no randomized controlled trials that evaluate treatment regimens, but typical treatment is doxycycline for 14 days (1,16). Amoxicillin and ceftriaxone have also been used. Patients usually have symptomatic improvement within 24–72 hours and typically have a full recovery (20,21). The mortality rate is 4–10% in untreated patients (20). Deaths occur primarily in infants, older adults and patients who are immunosuppressed.

Rocky Mountain Spotted Fever

Rickettsia rickettsii is the causative agent of Rocky Mountain Spotted Fever (RMSF), so named because it was originally described in the Snake River Valley of Idaho (22). It is most prevalent in the south eastern, and south central states. In the US, R. rickettsii is transmitted primarily by Dermacentor variabilis, the American dog tick, in the eastern, central, and Pacific coastal states (23). D. andersoni, the Rocky Mountain wood tick, is responsible for transmission in the northern and western mountainous states (24). Recently, an additional vector has been identified in parts of Arizona and along the US-Mexico border: Rhipicephalus sanguineus, the brown dog tick (24). The highest incidence is in adults 60- to 69-years old; however the case-fatality rate is highest in children under 10-years-old (23).

Initial symptoms include sudden onset of fever, chills, malaise, headache, nausea, vomiting and myalgia (24). Children may also present with peripheral or periorbital edema (23). The characteristic rash appears 2–4 days after fever onset, and is more common in children <15-years-old, who are also more likely to develop the rash earlier in their illness (22). It usually begins as a faint maculopapular rash on the wrists and ankles, before spreading centripetally to the trunk (24). It can involve the palms and soles and become petechial as it progresses (23). In severe disease, patients can develop severe interstitial pneumonia, ARDS, acute renal failure, meningoencephalitis, coma, gangrene, multiorgan failure, and death (22). Laboratory abnormalities include thrombocytopenia, elevated hepatic transaminases, and hyponatremia, especially as the disease progresses (24). When CSF is evaluated, there can be lymphocytic pleocytosis (<100 cells/μl), with moderately elevated protein and normal glucose (22).

The gold standard for diagnosis is PCR assay or indirect immunofluorescence antibody (IFA) assay; however patients seldom have detectable antibodies within the first week of illness (22). IgM is non-specific, but IgG begins to increase around days 7–10 (24). Diagnosis requires at least a fourfold increase in antigen-specific IgG between acute and convalescent sera (22). Treatment is doxycycline, and should be started as soon as the diagnosis is suspected and continued until the patient has been afebrile for at least 3 days and is clinically improving (22).

Ehrlichiosis

There are three Ehrlichia species in the US responsible for the human infection: Ehrlichia chaffeensis, E. ewingii, and E. muris eauclairensis (1,23). They are all obligate intracellular gram-negative cocci and replicate within intracellular inclusion bodies, called morulae (25). The most common is E. chaffeensis, the causative agent of human monocytic ehrlichiosis (HME). It has been reported throughout the southeastern US, as well as north into the Midwestern and New England states (26). This coincides with the geographic range of its vector, Amblyomma americanum or the lone star tick (25). The white-tailed deer is the major animal reservoir (1).

HME initially presents as a nonspecific flu-like illness, with fever, chills, headache, malaise, myalgia and nausea. Gastrointestinal (GI) symptoms are more common in children (1). Rash, involving the extremities and trunk, as well as the palms and soles, is also more common in children (up to 60%) (25). It presents around day 5 of illness, varying from petechial to maculopapular to diffuse erythema (23). Severe disease can present with systemic, multiorgan involvement (1). Children usually are asymptomatic or have mild infections; however those under 10-years-old have the highest case-fatality rate (23).

PCR assays or IFA assay for antibody-specific IgG and IgM are the most commonly used confirmatory tests; IFA assay is considered positive if there is a 4-fold increase in titers between acute and convalescent sera or a single IgG titer ≥ 1:256 (23,25). There can be high rates of cross-reactivity with Anaplasma phagocytophilum, so in areas where there is overlap of these pathogens, serologic testing for both should be performed (23). Common laboratory findings include leukopenia with lymphopenia, thrombocytopenia, hyponatremia, and elevated serum hepatic transaminases (1). Treatment with doxycycline should be initiated as soon as HME is suspected, regardless of the patient’s age (23), and should be continued for at least 3 days after defervescence and until there is evidence of clinical improvement (25).

Anaplasmosis

Human granulocytic anaplasmosis (HGA) is caused by the obligate intracellular gram-negative bacterium, Anaplasma phagocytophilum (27). A. phagocytophilum is found in the eastern and midwestern US and Canada, where it is transmitted by I. scapularis, as well as in the western US and Canada, where it is transmitted by I. pacificus (27). The primary animal reservoirs are the white-footed mouse and the Eastern chipmunk (27). The majority of infections due to HGA is detected in late spring and early summer (28).

Infection in children is rare, although this may be due to underdiagnosis since many are asymptomatic or mild, self-limited illnesses. The most common symptoms are nonspecific, including fever, malaise, myalgia, headache and anorexia (27). Some patients also report GI symptoms, which are more common in children, especially abdominal pain (29). In most cases, HGA is a self-limited illness. Severe or life-threatening disease is rare. Common laboratory findings include leukopenia, thrombocytopenia, and elevated hepatic transaminases (30). Neutrophilia, lymphopenia, anemia, and detection of morulae are all associated with more severe disease (23,31). However, children are less likely to have these laboratory abnormalities (32).

Diagnosis is confirmed with PCR, which has a sensitivity of 74% and specificity of 100% (33). Antibody seroconversion can also be used, with a fourfold increase between acute and convalescent titers; however this has a much lower sensitivity (32%), due to high rate of antibody cross-reactivity (27). Empiric treatment should begin prior to confirmation of the diagnosis (27). Doxycycline is the treatment of choice, regardless of age (25). In patients with doxycycline allergy, rifampin is the second line option (25). However, given the possibility of co-infection with B. burgdorferi, it is important to remember that rifampin will not treat this bacteria, and therefore a second agent should be added (27).

Tularemia

Tularemia is caused by Francisella tularensis, a small, fastidious, non-spore-forming, aerobic gram-negative coccobacillus. It is one of the most infectious microorganisms; as few as 10 organisms can cause infection in humans. It is classified as a Category A biowarfare agent (34,35). There are two subspecies responsible for human disease: F. tularensis subsp. tularensis (type A) and F. tularensis subsp. holarctica (type B). Type A is the more virulent, found almost exclusively in North America (36). Its primary animal reservoir is the cottontail rabbit (37). Most cases are reported in the southern and central states (34,35). The annual incidence is highest in children 5- to 9-years-old and in men aged 65–69 years (35). Transmission can occur through numerous mechanisms and the method impacts disease presentation (36). Dermacentor ticks are the only kind that transmit tularemia to humans, which results in glandular and ulceroglandular disease (34,38). This presents as tender regional lymphadenopathy, and in ulceroglandular tularemia, a soft, painless ulcer develops at the site of the arthropod bite and evolves into a scar; this is absent in glandular tularemia (34,39,40).

Diagnosis is made with serologic testing. Initial serum antibody titer ≥1:128 by microagglutination (MA) or ≥ 1:160 by tube agglutination (TA) constitutes a presumptive diagnosis (36,40). If initial testing is non-diagnostic, a repeat titer should be obtained in 4 weeks, and the diagnosis is confirmed with a ≥ 4-fold increase in titers (40,41). In children, gentamicin is the drug of choice (34,39–41). Treatment is usually for 10 days, but can be shortened to 5–7 days in mild disease. Ciprofloxacin is an alternative to treat mild disease (41). Despite antibiotic treatment, suppuration of lymph nodes can still occur, and is the most common complication in tularemia, which occurs in up to 30% of patients (36,41).

Parasitic infections

Babesiosis

Babesiosis is caused by intra-erythrocytic protozoa of the genus Babesia, part of the same phylum as Plasmodium, Toxoplasma, and Cryptosporidium (42,43). In North America, most human cases can be attributed to Babesia microti, and much less commonly, to B. duncani (44) and B. divergens (45,46). Since it was first reported in North America in 1969 (47), the incidence has increased substantially, as has the geographic range of its primary vector, I. scapularis (48,49). More than 2,000 cases are reported annually to the CDC; however this is felt to be a gross underestimate (50), due to the high prevalence of asymptomatic infection (~50% of children and ~25% of adults) and because most symptoms are nonspecific (42,48). Almost all cases occur in the Northeast and Upper Midwest (42). The primary vertebrate host for B. microti are white-footed mice (42,51). While it is transmitted primarily by ticks, it can also be transmitted via blood transfusion (52–54), organ transplantation (53) and perinatally (55–57). In fact, Babesia is the most common transfusion-transmitted parasitic infection in the US (58). In 2019, the FDA issued recommendations to screen all blood donations for Babesia in endemic states (58–60). The incubation period is 1–4 weeks following a tick bite, but can be up to 24 weeks following a contaminated blood transfusion (42,51,61).

Like malaria, symptomatic babesiosis is characterized by fever and hemolytic anemia. Clinical manifestations include fever, chills, fatigue, malaise, headache, myalgia, arthralgia, anorexia, and nausea (42,51,62). Severe and even fatal disease is more common in neonates, elderly patients, and in those with asplenia or impaired immune function (42,62,63).

Definitive diagnosis is made either by identification of intraerythrocytic parasites on a peripheral blood smear or by positive B. microti PCR assay result (64,65). A single positive antibody result cannot be used to establish a diagnosis because Babesia antibodies can persist for years following clearance of infection, with or without treatment (64). Recommended treatment is with a combination of atovaquone and azithromycin for 7 to 10 days (42,64,66). In patients with severe disease, treatment can be given intravenously until symptoms abate and transition can be made to oral therapy. Clindamycin plus quinine sulfate is an alternative choice (42,64,66). Delay in diagnosis and in treatment is associated with severe disease (42,51,61).

Viral infections

Powassan Virus

Powassan virus (POWV) is an emerging public health threat. It is the only tick-borne flavivirus that infects humans in North America, and is found mostly in Canada and in the northeastern and upper midwestern United States (67,68). Since its detection in 1958, approximately 270 cases have been reported in the US and Canada (68) and yearly case numbers are rising (69). POWV consists of two genetically distinct lineages. Lineage I is primarily transmitted by Ixodes cookei, which feeds on groundhogs and skunks (70). Lineage II is primarily maintained by I. scapularis and small mammals, such as shrews (71). I. scapularis more frequently feeds on humans, so lineage II is responsible for most cases of human disease (70). Infection within POWV can occur within 15 minutes after the tick attaches (72).

The clinical presentation remains to be fully described, as the proportion of unrecognized infections is unknown, but may be large. Symptoms range from mild to severe, with a prodrome of malaise, headache, sore throat, nausea, and disorientation (1). Severe manifestations include encephalitis or meningoencephalitis, which occur in 95% of recognized patients (73). Up to half of reported cases have long-term neurological damage, and the mortality rate among reported cases is approximately 10% (74).

Preliminary diagnosis is made based on the patient’s clinical signs and symptoms, geographic location and risk of tick exposure. Confirmatory diagnosis requires testing for POWV-specific antibodies in the serum or CSF, first with an IgM capture ELISA, followed by confirmatory neutralizing antibody testing performed by a local health department or the CDC (74). Lumbar puncture generally demonstrates CSF pleocytosis, mild protein elevation and normal glucose (75,76). There are no specific therapies available, so treatment consists of supportive care (74).

Conclusion:

The incidence of tick-borne infections in the US is rising, new pathogens continue to be recognized. It is important for practitioners to understand the clinical presentations, geographical distributions, and treatment of these infections. Reduction of risk of exposure, swift removal of ticks, and early treatment can be beneficial. Further research is needed regarding vaccines for these pathogens, as primary prevention is crucial in protecting children.

Table 1:

Summary

Disease	Pathogen	Vector	Clinical Manifestations	Diagnosis	Treatment
Lyme Disease	Borrelia burgdorferi sensu stricto (most common), B. mayonii	Ixodes scapularis, I. pacificus	Early localized: erythema migrans (EM); Early disseminated: multiple EM, carditis, facial nerve palsy, lymphocytic meningitis; Late disseminated: arthritis	For early localized: appearance of rash; Standard two-tier test: enzyme immunoassay (EIA), followed by Western immunoblot (WB) test; Modified two-tier test: two EIAs	Doxycycline Amoxicillin Cefuroxime Ceftriaxone
Tick-borne Relapsing Fever (hard ticks)	Borrelia miyamotoi	I. scapularis, I. pacificus	Flu-like illness, relapsing fevers (10–40%)	PCR assay or serology	Doxycycline Amoxicillin Ceftriaxone
Rocky Mountain Spotted Fever	Rickettsia rickettsii	Dermacentor variabilis, D. andersoni, Rhipicephalus sanguineus	Flu-like illness, fever, peripheral or periorbital edema, rash	PCR assay or serology	Doxycycline
Human Monocytic Ehrlichiosis	Ehrlichia chaffeensis (most common), E. ewingii, E. muris eauclairensi	Amblyomma americanum	Flu-like illness, fever, headache, GI symptoms, rash (up to 60%), thrombocytopenia, lymphopenia	PCR assay or serology	Doxycycline Rifampin (if allergy to doxy)
Human Granulocytic Anaplasmosis	Anaplasma phagocytophilum	I. scapularis, I. pacificus	Flu-like illness, fever, headache, GI symptoms, thrombocytopenia, neutropenia	PCR assay	Doxycycline Rifampin (if allergy to doxy)
Tularemia	F. tularensis subsp. Tularensis (type A), F. tularensis subsp. Holarctica (type B)	Dermacentor ticks	Glandular: tender regional lymphadenopathy; Ulceroglandular: like glandular, with the addition of a soft, painless ulcer that develops at the site of the tick bite and evolves into a scar	Serology	Gentamicin Ciprofloxacin
Babesiosis	Babesia microti (most common), B. duncani, B. divergens	I. scapularis, I. pacificus	Fever, hemolytic anemia	Peripheral blood smear; PCR assay	Atovaquone plus azithromycin Clindamycin plus quinine sulfate
Powassan	Powassan Virus	I. cookei (lineage I), I. scapularis (lineage II)	Encephalitis, meningoencephalitis	Serology	Supportive care

Key points:

• Tick-borne infections in children are becoming more frequent, due to geographic expansion of tick vectors, as well as to emergence of new pathogens.

• Symptoms of these infections are often non-specific, with considerable overlap, which makes it crucial for these diseases to be understood by practitioners in endemic areas, as prompt diagnosis and treatment is important.

• Doxycycline (for up to 21 days) is now acceptable treatment for children of all age groups.