Journal of Infection (2015) xx, 1e9
www.elsevierhealth.com/journals/jinf
Tick-borne diseases of the USA: Ten things clinicians should know Steven C. Buckingham* Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children’s Hospital, 50 N. Dunlap Street, Research Tower, Room 464R, Memphis, TN 38103 USA Accepted 21 April 2015 Available online - - -
KEYWORDS Tick-borne diseases; Rocky Mountain spotted fever; Ehrlichiosis; Lyme disease; Anaplasmosis; Tularemia; Babesiosis; Doxycycline; DEET
Summary This article highlights critical aspects of the epidemiology, diagnosis, and management of tick-borne infections in children. Principles that apply broadly across the continental United States are emphasized, rather than details of each disease. Tick-borne infections are often confused with other, more common childhood illnesses, in part because of their nonspecific initial clinical findings and because patients are usually unaware of their preceding tick exposures. This is a problem, because delays in starting appropriate antibiotic therapy increase the likelihood of adverse outcomes from these infections, especially Rocky Mountain spotted fever (RMSF). For patients in whom RMSF is a reasonable diagnostic consideration, therapy should be started presumptively, without awaiting the results of confirmatory diagnostic tests. For both adults and children, doxycycline is the drug of choice for RMSF and other American rickettsial infections. Concerns over the potential toxicity of doxycycline in young children are unfounded. Similarly groundless is the belief in “chronic Lyme disease” as an explanation for persistent nonspecific complaints after completing antibiotic therapy for Lyme disease. Prevention of tick-borne infections rests on avoidance of tick-bites and prompt removal of attached ticks. When used appropriately, insect repellents containing DEET are safe and effective for preventing tick exposures. ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Many species of ticks are endemic to the Unites States, and some of these serve as vectors for various bacteria, parasites, and viruses that are pathogenic to humans. Summary information regarding the principal established tick-borne infections of the USA are presented in Table 1,
while similar data for several emerging tick-borne infections are listed in Table 2. Detailed discussions of these infections are beyond the scope of this article. Instead, this review will emphasize key points that apply broadly to the epidemiology, diagnosis, treatment, and prevention of American tick-borne infections in children. The “ten things clinicians should know” that follow do not comprise a
* Tel.: þ1 901 287 6063. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jinf.2015.04.009 0163-4453/ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
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S.C. Buckingham Table 1
Established tick-borne infections of the USA.
Disease
Organism
Geographic distribution and vector
Prominent clinical findingsa
Rocky Mountain spotted fever (RMSF)
Rickettsia rickettsii
Fever, headache, petechial rash, hyponatremia, thrombocytopenia
Ehrlichiosisb
Ehrlichia chaffeensis
Eastern states: Dermacentor variabilis (dog tick) Mountain West: Dermacentor andersoni (wood tick) Southwestern deserts: Rhipicephalus sanguineus (brown dog tick) Southeastern and south-central states: Amblyomma americanum (Lone Star tick)
Anaplasmosisc
Anaplasma phagocytophilum
Lyme disease
Borrelia burgdorferi
Endemic relapsing fever Tularemia
Borrelia hermsii B. turicatae B. parkeri Francisella tularensis
Babesiosis
Babesia microti
Similar to RMSF, but rash is less common; leukopenia, thrombocytopenia, elevated transaminases Similar to HME, but rash is rarely present
Northeast and upper Midwest: Ixodes scapularis (blacklegged tick) Pacific coast: Ixodes pacificus Northeast and upper Midwest: I. scapularis First stage: fever, erythema Pacific coast: I. pacificus migrans (rash) Second stage: multiple skin lesions, conjunctivitis, arthralgias, myalgias, headache, cranial nerve palsies Third stage: arthritis; encephalopathy, dementia, peripheral neuropathy Western mountains and deserts: Fever, chills, relapsing course Ornithodoros species Eastern states: D. variabilis Mountain West: D. andersoni Southeastern and south-central states: A. americanum Northeast, Midwest, and West Coast: I. scapularis, other Ixodes species
Colorado tick fever Colorado tick fever Mountain West: D. andersoni virus (genus: Coltivirus)
Fever, cutaneous eschar, lymphadenopathy, pulseetemperature dissociation Fever, malaise, headache, hepatosplenomegaly, thrombocytopenia, hemolytic anemia Fever, headache, leukopenia, thrombocytopenia; biphasic course
a Not all patients with these diseases will have all of these findings, and some may present with additional features. Many cases present simply with fever and vague constitutional symptoms. b Also known as human monocytotropic ehrlichiosis (HME). c Also known as human granulocytotropic anaplasmosis (HGA); previously termed human granulocytic ehrlichiosis (HGE).
comprehensive overview of tick-borne infections. Rather, they are intended as a starting point for clinicians wishing to learn more about this topic.
Patients are exposed to ticks more frequently than you might think It may seem surprising, but most persons who experience a tick attachment are actually unaware of their exposure. This is because ticks, especially in their immature stages, are quite small (nymphs, for example, are only 1e2 mm in lengthdabout the size of the head of a pin), and because they frequently attach at hair-bearing body sites and other places where they tend to escape detection. Moreover, because their bites are generally painless, most tick
attachments pass unnoticed.1 It should also be noted that many patients with tick-borne infections lack supposed epidemiologic risk factors for these infections, such as having spent time in a wooded area. Tick-borne infections occur even in urban areas and among people who have never been on a camping trip.2 A multicenter study of 92 children with laboratory-diagnosed RMSF found that only 49% of patients reported a history of a known tick bite, while only 34% reported a history of exposure to a wooded area.3 Thus while the historical findings of tick bite or outdoor exposure may provide useful diagnostic clues, their absence never excludes the possibility of a tick-borne illness. Underscoring this point, data from seroprevalence studies indicate that more than 10% of children in the southeastern and south-central portions of the U.S. have significant antibody titers against Rickettsia rickettsii and
Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
Tick-borne diseases of the USA Table 2
3
Selected emerging tick-borne infections of the USA.
Disease
Organism
Geographic distribution and vector
Prominent clinical findingsa
Rickettsia parkeri infectionb
Rickettsia parkeri
Southeastern states: Amblyomma maculatum (Gulf Coast tick)
Rickettsia spp. 364D infectionb
Rickettsia spp. 364D
California: Dermacentor occidentalis (Pacific Coast tick)
Ehrlichia ewingii infection Southern tick-associated rash illness (STARI)
Ehrlichia ewingii
Southeastern and south-central states: Amblyomma americanum Southeastern and south-central states: A. americanum
Similar to RMSF, but with eschar at inoculation site; rash may be vesicular or pustular; gastrointestinal symptoms less prominent Fever, headache, myalgias, þ/ rash, cutaneous eschar Similar to anaplasmosis
Borrelia lonestari
Powassan encephalitis
Powassan virus (genus: Flavivirus)
Northeastern and north-central states: Ixodes species, D. andersoni
Heartland virus infection
Heartland virus (genus: Phlebovirus)
South-central states: A. americanum
Rash similar to erythema migrans, þ/ mild constitutional symptomsc Headache, seizures, altered sensorium, focal neurologic signs, meningismus Fever, headache, fatigue, nausea, myalgia, leukopenia, thrombocytopenia
a
Not all patients with these diseases will have all of these findings, and some may present with additional features. For these and other emerging infectious diseases, the full spectrum of clinical illness is still being elucidated. b Besides R. parkeri and Rickettsia species 364D, other rickettsial species that may cause spotted fever rickettsioses have been identified, but their roles as human pathogens are still under investigation. c Late manifestations of Lyme disease (e.g., arthritis, neuropathy) have not been described in patients with Southern tick-associated rash illness.
Ehrlichia chaffeensis.4,5 These data suggest that many tickborne infections are never recognized as such and that such infections occur more frequently than once was thought.
Geography is important Understanding the epidemiology of tick-borne infections is key to making (or excluding) certain presumptive diagnoses. Specific tick-borne infections occur only in regions where their associated tick vectors are found (Tables 1 and 2). Thus, knowledge of where patients have beendthat is, their place of residence and travel historydshould enable clinicians to decide which tick-borne illnesses are likely, or even possible. For example, RMSF has been reported in virtually every area of the United States (Fig. 1), in part because at least 3 different tick vectors have been implicated in its transmission. Ehrlichiosis, on the other hand, is generally found only in the region from the Great Plains eastward (Fig. 2)dthat is, in the geographic range of the Lone Star tick, Amblyomma americanum. Both diseases, however, are especially prevalent in the southeastern, south-central, and mid-Atlantic portions of the United States, so clinicians in these regions should maintain a high index of suspicion for these diseases in febrile patients, particularly during the warmer months of the year. This situation contrast starkly with that of Lyme disease, which (like anaplasmosis and babesiosis) is highly prevalent in regions inhabited by Ixodes species ticksdthe Northeast, the upper Midwest, and to a lesser extent in mountain ranges along the Pacific coastdbut far less so in other parts of the country, including the Southeast (Fig. 3). The
absence of Ixodes ticks in certain portions of the United States makes testing for Lyme disease essentially obsolete, except among those who have recently traveled to an endemic area.6 In the southeastern and south-central USA, however, patients may present with skin lesions suggestive of erythema migrans not because they have Lyme disease, but because of a different, emerging disease: the aptly-named Southern tick-associated rash illness (STARI). While the true incidence and natural history of STARI are still being unraveled, no evidence suggests that it progresses if untreated to involve other organ systems, as happens with Lyme disease. Indeed, the need for antibiotic therapy for STARI remains unclear, though some experts have recommended treatment analogous to that prescribed for Lyme disease.7e9 The astute clinician who recognizes STARI in a patient who has not spent time in a Lymeendemic area can spare this patient not only the pain and expense of unnecessary testing for Lyme disease, but also the mental anguish that frequently accompanies that tentative diagnosis.
Tick-borne infections are seasonaldexcept when they’re not Across the United States, the vast majority of tick-borne infections are reported between April and October. This, of course, is not surprising; the warmer months are not only those when ticks are most active, but also those when people spend the most time outdoors, in potentially tickinfested habitats. For example, pediatric studies in the southeastern and south-central USA found that over 90% of
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S.C. Buckingham
Figure 1 Geographic distribution of spotted fever rickettsioses (mostly Rocky Mountain spotted fever) in the USA in 2012. Counties that reported 1e14 cases to CDC are shaded lightly, whereas those that reported >15 cases are shaded darkly. Note that while cases are widely dispersed geographically, they are especially concentrated in the south-central, southeastern, and mid-Atlantic regions of the United States. Reproduced from: CDC. Summary of Notifiable Diseases, 2012. Morb Mortal Wkly Rep 2014; 61(53): 89.
Figure 2 Geographic distribution of ehrlichiosis (i.e., E. chaffeensis infection) in the USA in 2012. Counties that reported 1e14 cases to CDC are shaded lightly, whereas those that reported >15 cases are shaded darkly. Note that cases are particularly concentrated in the south-central, southeastern, and mid-Atlantic regions, and that they are essentially absent in regions west of the central plains. Reproduced from: CDC. Summary of Notifiable Diseases, 2012. Morb Mortal Wkly Rep 2014; 61(53): 64. Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
Tick-borne diseases of the USA
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Figure 3 Geographic distribution of Lyme disease in the USA in 2012, based on cases reported to CDC. Counties with a disease incidence of 10.01e100 cases per 100,000 population are shaded lightly, whereas those with an incidence of >100.01 cases per 100,000 population are shaded darkly. Although cases are reported in many geographic regions, about 95% of cases are reported from states in the Northeast, mid-Atlantic, and upper Midwest. Reproduced from: CDC. Summary of Notifiable Diseases, 2012. Morb Mortal Wkly Rep 2014; 61(53): 80.
RMSF cases, and 88% of cases of ehrlichiosis, were diagnosed between the months of April and September; for both diseases, over 60% of cases presented in the peak months of May, June, and July.3,10 Nonetheless, it should be noted that ixodid ticks (including those of the genera Dermacentor, Amblyomma, and Ixodes, among others) have a two-year life cycle, and that although they generally become less active during the winter, they do not necessarily die.11 Hence, tick-borne infections can occur in all months of the year, and rare cases have been reported during winter months even in locations typified by cold winters. For instance, 3% of RMSF cases reported to CDC from 1997 to 2002 occurred between the months of December and February, from regions as far north as New England.12 Thus while tick-borne illnesses are distinctly unusual during periods of cold weather, clinicians should remember to include them in their differential diagnoses, even in the depth of winter.
Tick-borne infections are easily confused with other childhood illnesses Occasionally, certain combinations of clinical features can suggest a specific tick-associated diagnosis. Most often, however, children with tick-borne infections (including RMSF, ehrlichiosis, anaplasmosis, tularemia, and babesiosis) present with various nonspecific signs and symptoms such as fever, malaise, headache, nausea, vomiting, and myalgias. Thus, it is not surprising that most patients with tickborne infections are first suspected as having more common
childhood illnesses, such as gastroenteritis, streptococcal pharyngitis, or viral syndromes. An exception to this generalization is Lyme disease, which almost always presents with characteristic signs and symptoms such as erythema migrans, facial nerve palsy, or large-joint arthritis. Although patients with Lyme disease may also complain of various nonspecific symptoms (e.g., fatigue, arthralgia, or weakness), such complaints in the absence of characteristic findings should not prompt testing or treatment for that diagnosis.6 While it is useful to know the “typical” clinical findings associated with tick-borne diseases, it should be emphasized that not all patients present with these findings. This is especially problematic for RMSF, as the purportedly “classic triad” of fever, rash, and headache is present in fewer than 60% of patients with laboratory-confirmed disease.3,13,14 An alternative triaddfever, rash, and history of tick bitedhas demonstrated similarly poor sensitivity in published studies of RMSF.3,15,16 The poor sensitivity of these clinical triads can be partly explained by fact that patients with RMSF usually present with fever and vague constitutional symptoms; the rash may not appear until a few days into the disease course. Confounding matters, in some patients with RMSF the rash may be transient, difficult to appreciate (particularly in dark-skinned individuals), or absent altogether.17,18 And when the rash does appear, clinicians and caregivers may mistakenly attribute it to other explanations, such as a drug reaction, viral syndrome, scarlet fever, or Kawasaki disease.18 These observations also apply to ehrlichiosis, in which the rash is less frequently present, appears later in the disease course, is
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6 less frequently petechial and less likely to involve the palms and soles than in RMSF.10,19 Routine laboratory tests are usually of limited utility in differentiating tick-borne infections from more common childhood illnesses. Some laboratory findings are typically found with certain diseases; for example, children with ehrlichiosis frequently present with thrombocytopenia, leukopenia, and modest elevations of serum transaminases, and patients with babesiosis characteristically present with anemia, thrombocytopenia, and laboratory evidence of hemolysis (e.g., reticulocytosis, decreased haptoglobin, and elevated lactate dehydrogenase).10,19 Such results, however, are hardly unique to these diseases. Children with RMSF can present with a variety of laboratory abnormalities, including thrombocytopenia, leukopenia, leukocytosis, and hyponatremia, but neither the presence nor the absence of any combination of these has adequate sensitivity or specificity to establish or exclude the diagnosis.3
Therapy should not be delayed As a general rule, antimicrobial therapy for tick-borne infections should be started as soon as the diagnosis is seriously considered. This is particularly true for RMSF. Before the advent of effective antibiotic therapy, this disease was associated with a case fatality rate of nearly 30%.11 Although mortality rates are far lower today, deaths from RMSF still occur. One risk factor for mortality from RMSF, which has been consistently identified in studies published across several decades, is delayed initiation of appropriate antimicrobial therapy. Studies published in the 1970s and 1980s found that patients who died of RMSF started therapy with chloramphenicol or tetracycline an average of 2 days further into their disease course than did those who survived.16,18 During the 1990s, one study reported that the risk of mortality rose by 3.1-fold if appropriate therapy was delayed until the fifth day of illness or later, and another found a 3.5-fold increased risk if therapy was started after the fifth day of illness.13,20 Most recently, an analysis of RMSF cases from 1999 to 2007 found that patients who survived were hospitalized after a median of 3 days of illness, whereas those who died were hospitalized after a median of 6 days.21 Considering that hospitalization is a likely proxy for initiation of appropriate therapy, these data demonstrate that delays in starting antirickettsial therapy remain a significant risk factor for mortality from RMSF, even in our present century. Other tick-borne infections found in the USA are generally associated with lower rates of mortality and long-term morbidity than are seen with RMSF. Consequently, for these other diseases, it is less clear that delays in starting appropriate therapy are specifically linked to worse outcomes in children. In one study of adults with ehrlichiosis or anaplasmosis, those who had delayed initiation of doxycycline experienced significantly more complications during their hospitalizations compared with patients with no such delay.22 No such relationship has been documented among children with ehrlichiosis. Even so, there is no reason to withhold therapy from patients in whom any tick-borne bacterial illness is suspected.
S.C. Buckingham
Diagnoses are presumptivedand unfortunately, often delayed As a general rule, tick-borne infections should be diagnosed presumptivelydthat is, based on patients’ clinical findings and epidemiologic histories. This is understandably frustrating for many clinicians (not to mention patients and caregivers), who would often like a greater degree of diagnostic certainty before embarking on a course of antirickettsial therapy. Unfortunately, such certainty is chimerical. As discussed above, results of routine laboratory tests are usually of little utility in determining the likelihood of a tick-borne infection. Moreover, because serum antibodies are generally not detectable until at least 7e10 days into an illness course, serologic testing is expected to yield negative results early in the disease coursedwhich is precisely when these patients are expected to present to healthcare providers. Clinicians are thus forced to make a decision: either prescribe antirickettsial therapy presumptively, or withhold therapy and monitor the patient’s course clinically. No algorithm can substitute for the provider’s clinical judgment in this scenario. In any event, one thing is clear: clinicians should not withhold therapy while awaiting the results of specific diagnostic tests. The decision to test a patient for tickborne illnesses indicates a sufficiently high level of concern to initiate therapy empirically.1,23 Unfortunately, delays in the initiation of antirickettsial therapy among children with laboratory-confirmed RMSF or ehrlichiosis occur quite commonly. It should be noted that these delays are not explained by a lack of opportunities to start therapy. Children with RMSF or ehrlichiosis almost always present for care within the first few days of illness. In a case series of 92 children with laboratory-diagnosed RMSF, 75% of patients were taken to healthcare providers within 3 days of symptom onset. Still, only 4 patients were prescribed an antirickettsial antibiotic before hospital admission. Among the group, effective antibiotic therapy was not started until a median of 7 days of illness.3 Similar results were reported among a cohort of 32 children with laboratory-diagnosed ehrlichiosis.10 Children with tickborne illnesses experience delays in the initiation of antirickettsial therapy not because their caregivers fail to bring them in for care, but because their treating clinicians either fail to consider tick-borne illnesses in their initial assessments or purposely decide against starting specific antirickettsial therapy.18
Concerns over the toxicity of doxycycline in young children are unfounded Doxycycline is the drug of choice for tick-borne rickettsial illnesses, and this is true for both adults and children.1,23 Despite clear recommendations from the American Academy of Pediatrics (AAP), it appears that many pediatricians remain unaware of this recommendation.21 Years ago, chloramphenicol was recommended for treatment of RMSF in children aged less than 8 years because of the perceived potential of doxycycline to irreversibly stain permanent teeth. This practice has long been obsolete, for
Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
Tick-borne diseases of the USA several reasons. First, chloramphenicol is less effective than doxycycline for treatment of RMSF; patients treated with chloramphenicol alone are more likely to die than are those treated with a tetracycline-class antibiotic.24 Second, doxycycline provides effective therapy for ehrlichiosisdwhich cannot be reliably differentiated from RMSFdwhereas chloramphenicol does not.25 Third, chloramphenicol poses the risk of serious toxicities (including idiosyncratic aplastic anemia), and its erratic absorption and metabolism mandates close monitoring of serum levels.26 Indeed, these concerns have led clinicians to largely shun the use of chloramphenicol, to the point where it is no longer available as an oral formulation in USA.1,23 Finally, concerns over doxycycline’s rumored potential for dental staining are unfounded. To be sure, administration of repeated courses of tetracyclineddoxycycline’s older cousin, which is now seldom used in the U.S.dwas associated with unsightly discoloration of permanent teeth in young children. But such an effect has never been documented with doxycycline, presumably because it lacks tetracycline’s affinity for tooth enamel. Indeed, even with tetracycline, tooth discoloration was generally only noted after multiple courses of therapy.1,27 To date, published studies have not found evidence of dental staining among patients who received a single course of doxycycline.28e30 Even if doxycycline was associated with dental stainingdwhich it is notdthe risk of this cosmetic side effect would still have to be weighed against the potential morbidity posed by tick-borne rickettsial illnesses, including the risk of mortality from RMSF. Doxycycline is not the drug of choice for all patients with tick-borne infections. Most children with Lyme disease, for example, can be treated with amoxicillin. Babesiosis requires combination therapy with either clindamycin plus quinine or atovaquone plus azithromycin. For tularemia, gentamicin or streptomycin are considered drugs of choice, although doxycycline or ciprofloxacin are alternatives for patients with mild disease. When alternative drugs are available, doxycycline is best avoided. But in cases where RMSF or ehrlichiosis are reasonable diagnostic considerations, clinicians should not hesitate to prescribe doxycycline, even to very young children.
“Chronic Lyme disease” is not a real thing The proliferation of misinformation about various medical conditions on the Internet is an unfortunate aspect of our current digital age, and this is particularly true in the case of Lyme disease. Particularly vexing are persistent references to “chronic Lyme disease,” a poorly-defined entity with no scientific basis for its existence as an actual disease process. To be sure, some patients, after completing therapy for Lyme disease, continue to experience persistent nonspecific symptoms, such as fatigue, musculoskeletal pain, and difficulty with concentration. However, there is no objective evidence to suggest that persistent Borrelia burgdorferi infection is responsible for these symptoms, which are also quite common in the general population. Although some clinicians prescribe prolonged courses of parenteral antibiotics for patients with persistent post-Lyme symptoms, it should be noted that
7 randomized controlled trials evaluating this practice have not shown any evidence of benefit. Thus, the Infectious Disease Society of America (IDSA) specifically recommends against the use of prolonged or repeated courses of antibiotic therapy (or other unconventional therapies) for patients with persistent post-Lyme symptoms.31 The prognosis of children with Lyme disease is good, particularly if treatment begins in the early phases of disease, and persistent nonspecific symptoms are no more common in children with Lyme disease than in control patients.32 Misperceptions about Lyme disease abound, but considerable evidence can be invoked to refute the assertions of so-called “Lyme-literate” physicians and others who claim that “chronic Lyme disease” is a real entity. To do justice to these arguments would require more space than is available here, so the interested reader is referred to the IDSA guideline and other pertinent reviews.31,33e35
Prevention relies on simple measures Vaccines to prevent tick-borne infections in the Americas are not available, and prophylactic antibiotic therapy after known tick exposures is generally not recommended. Thus, prevention of tick-associated infections rests on two essential principles: avoidance of tick bites and prompt removal of attached ticks. Avoiding ticks is easier said than done, given their ubiquity in the environment; but some measures can help to at least minimize the probability of exposure. Obviously, it makes sense to avoid regions known or likely to be tick-infested, including areas with dense growth of shrubs and small trees. When entering such areas, persons should wear light-colored clothing, with long-sleeved shirts buttoned at the cuffs, and long pants tucked into socks. They should also spray exposed skin and clothing with a DEET-containing insect repellent to reduce the risk of tick exposure. In addition, permethrin (an insecticide) can be sprayed on clothing (but not skin) before entry into wooded areas. Clothing pretreated with permethrin is also commercially available and is considered safe for use by adults and children.1,36 During warmer months, it is advisable to examine persons and pets who have spent time outdoors at least daily for attached ticks. Examiners should pay attention to hair-bearing regions where nymphs and larvae may hide (e.g., the head, neck, axilla, and scrotum). An attached tick should be removed by grasping with tweezers close to the skin and pulling gently with steady pressure. If tweezers are not available, the tick may be removed using fingers protected by gloves or tissue. The bite site should then be washed with soap and water. Alternative “folk remedy” methods of tick removal (including application of petroleum jelly, fingernail polish, isopropyl alcohol, or a hot, extinguished kitchen match to an attached tick) are specifically not recommended because they are ineffective and may actually increase the chances of pathogen transmission.1,36,37
When used properly, DEET is safe and effective Many insect repellents are commercially available, but those that contain N, N-diethyl-meta-toluamide (DEET), in
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8 concentrations of 10%e30%, are most effective for the prevention of tick and insect bites. DEET has undergone extensive safety testing, and billions of human applications, since it became commercially available in 1957. Extremely rare cases of serious neurotoxicity have been attributed to DEET, usually in cases where it was used inappropriately. Overall, however, it appears that DEET-containing products are remarkably safe when used properly.38 After reviewing safety data on DEET in detail, the U.S. Environmental Protection Agency recently concluded that “normal use of DEET does not present a health concern to the general U.S. population, including children.”39 The American Academy of Pediatrics has also endorsed the use of DEET, calling concerns over its toxicity “unfounded.”40 DEET-containing products should be used according to manufacturers’ directions, and care should be taken to avoid their ingestion. DEET is not recommended for infants younger than 2 months old.
Conflict of interest Dr. Buckingham has no conflicts of interest to disclose.
References 1. Chapman AS, Bakken JS, Folk SM, Paddock CD, Bloch KC, Krusell A, et al. Diagnosis and management of tick-borne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosisdUnited States. Morb Mortal Wkly Rep 2006;55(RR-4):1e28. 2. Salgo MP, Telzak EE, Currie B, Perlman DC, Litman N, Levi M, et al. A focus of Rocky Mountain spotted fever within New York City. N Engl J Med 1988;318(21):1345e8. 3. Buckingham SC, Marshall GS, Schutze GE, Woods CR, Jackson MA, Patterson LE, et al. Clinical and laboratory features of Rocky Mountain spotted fever in children. J Pediatr 2007;150(2):180e4. 4. Marshall GS, Stout GG, Jacobs RF, Schutze GE, Paxton H, Buckingham SC, et al. Antibodies reactive to Rickettsia rickettsii among children living in the southeast and south central regions of the United States. Arch Pediatr Adolesc Med 2003; 157(5):443e8. 5. Marshall GS, Jacobs RF, Schutze GE, Paxton H, Buckingham SC, DeVincenzo JP, et al. Ehrlichia chaffeensis seroprevalence among children in the southeast and south-central regions of the United States. Arch Pediatr Adolesc Med 2002;156(2): 166e70. 6. American Academy of Pediatrics. Lyme disease. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red Book: 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 474e9. 7. Campbell GL, Paul WS, Schriefer ME, Craven RB, Robbins KE, Dennis DT. Epidemiologic and diagnostic studies of patients with suspected early Lyme disease, Missouri, 1990e1993. J Infect Dis 1995;172(2):470e80. 8. James AM, Liveris D, Wormser GP, Schwartz I, Montecalvo MA, Johnson BJ. Borrelia lonestari infection after a bite by an Amblyomma americanum tick. J Infect Dis 2001;183(12):1810e4. 9. Masters EJ, Grigery CN, Masters RW. STARI, or Masters disease: Lone Star tick-vectored Lyme-like illness. Infect Dis Clin North Am 2008;22(2):361e76. 10. Schutze GE, Buckingham SC, Marshall GS, Woods CR, Jackson MA, Patterson LE, et al. Human monocytic ehrlichiosis in children. Pediatr Infect Dis J 2007;26(6):475e9.
S.C. Buckingham 11. Harrell GT. Rocky Mountain spotted fever. Medicine 1949;28: 333e70. 12. Chapman AS, Murphy SM, Demma LJ, Holman RC, Curns AT, McQuiston JH, et al. Rocky Mountain spotted fever in the United States, 1997e2002. Vector Borne Zoonotic Dis 2006; 6(2):170e8. 13. Dalton MJ, Clarke MJ, Holman RC, Krebs JW, Fishbein DB, Olson JG, et al. National surveillance for Rocky Mountain spotted fever, 1981e1992: epidemiologic summary and evaluation of risk factors for fatal outcome. Am J Trop Med Hyg 1995; 52(5):405e13. 14. Treadwell TA, Holman RC, Clarke MJ, Krebs JW, Paddock CD, Childs JE. Rocky Mountain spotted fever in the United States, 1993e1996. Am J Trop Med Hyg 2000;63(1e2):21e6. 15. Bradford WD, Hawkins HK. Rocky Mountain spotted fever in childhood. Am J Dis Child 1977;131(11):1228e32. 16. Helmick CG, Bernard KW, D’Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis 1984;150(4):480e8. 17. Woods CR. Rocky Mountain spotted fever in children. Pediatr Clin North Am 2013;60(2):455e70. 18. Hattwick MAW, Retailliau H, O’Brien RJ, Slutzker M, Fontaine RE, Hanson B. Fatal Rocky Mountain spotted fever. JAMA 1978;240(14):1499e503. 19. Buckingham SC. Tick-borne diseases in children: epidemiology, clinical manifestations and optimal treatment strategies. Paediatr Drugs 2005;7(3):163e76. 20. Kirkland KB, Wilkinson WE, Sexton DJ. Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis 1995;20(5):1118e21. 21. Dahlgren FS, Holman RC, Paddock CD, Callinan LS, McQuiston JH. Fatal Rocky Mountain spotted fever in the United States, 1999-2007. Am J Trop Med Hyg 2012;86(4): 713e9. 22. Hamburg BJ, Storch GA, Micek ST, Kollef MH. The importance of early treatment with doxycycline in human ehrlichiosis. Medicine 2008;87(2):53e60. 23. American Academy of Pediatrics. Rocky Mountain spotted fever. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red Book: 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 623e5. 24. Holman RC, Paddock CD, Curns AT, Krebs JW, McQuiston JH, Childs JE. Analysis of risk factors for fatal Rocky Mountain spotted fever: evidence for superiority of tetracyclines for therapy. J Infect Dis 2001;184(11):1437e44. 25. American Academy of Pediatrics. Ehrlichia and Anaplasma infections. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red Book: 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 312e5. 26. Abramson JS, Givner LB. Should tetracycline be contraindicated for therapy of presumed Rocky Mountain spotted fever in children less than 9 years of age? Pediatrics 1990;86(1): 123e4. 27. Smith M, Unkel JH, Fenton SJ, DeVincenzo JP. The use of tetracyclines in pediatric patients. J Pediatr Pharmacol Ther 2001;6:66e71. 28. Forti G, Benincori C. Doxycycline and the teeth. Lancet 1969; 1(7598):782e3. 29. Lochary ME, Lockhart PB, Williams WT. Doxycycline and staining of permanent teeth. Pediatr Infect Dis J 1998;17(5): 429e31. 30. Volovitz B, Shkap R, Amir J, Calderon S, Varsano I, Nussinovitch M. Absence of tooth staining with doxycycline treatment in young children. Clin Pediatr 2007;46(2):121e6. 31. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment, and
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32.
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prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43(9): 1089e134. Skogman BH, Croner S, Nordwall M, Eknefelt M, Ernerudh J, Forsberg P. Lyme neuroborreliosis in children: a prospective study of clinical features, prognosis, and outcome. Pediatr Infect Dis J 2008;27(12):1089e94. Lantos PM, Charini WA, Medoff G, Moro MH, Mushatt DM, Parsonnet J, et al. Final report of the Lyme disease review panel of the Infectious Diseases Society of America. Clin Infect Dis 2010;51(1):1e5. Feder HM, Johnson BJ, O’Connell S, Shapiro ED, Steere AC, Wormser GP. A critical appraisal of “chronic Lyme disease”. N Engl J Med 2007;357(14):1422e30. Halperin JJ, Baker P, Wormser GP. Common misconceptions about Lyme disease. Am J Med 2013;126(3):264.e1e7.
9 36. American Academy of Pediatrics. Prevention of tick-borne infections. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red Book: 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 207e9. 37. Needham GR. Evaluation of five popular methods for tick removal. Pediatrics 1985;75(6):997e1002. 38. Fradin MS, Day JF. Comparative efficacy of insect repellents against mosquito bites. N Engl J Med 2002;347(1):13e8. 39. Environmental Protection Agency web site. DEET. 2014 review. http://www.epa.gov/pesticides/factsheets/chemicals/deet. htm?srcZQHA099. [accessed 11.10.14]. 40. American Academy of Pediatrics. Prevention of mosquitoborne infections. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red Book: 2012 report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 209e11.
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Tick-borne diseases of the USA: Ten things clinicians should know Steven C. Buckingham* Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children’s Hospital, 50 N. Dunlap Street, Research Tower, Room 464R, Memphis, TN 38103 USA Accepted 21 April 2015 Available online - - -
KEYWORDS Tick-borne diseases; Rocky Mountain spotted fever; Ehrlichiosis; Lyme disease; Anaplasmosis; Tularemia; Babesiosis; Doxycycline; DEET
Summary This article highlights critical aspects of the epidemiology, diagnosis, and management of tick-borne infections in children. Principles that apply broadly across the continental United States are emphasized, rather than details of each disease. Tick-borne infections are often confused with other, more common childhood illnesses, in part because of their nonspecific initial clinical findings and because patients are usually unaware of their preceding tick exposures. This is a problem, because delays in starting appropriate antibiotic therapy increase the likelihood of adverse outcomes from these infections, especially Rocky Mountain spotted fever (RMSF). For patients in whom RMSF is a reasonable diagnostic consideration, therapy should be started presumptively, without awaiting the results of confirmatory diagnostic tests. For both adults and children, doxycycline is the drug of choice for RMSF and other American rickettsial infections. Concerns over the potential toxicity of doxycycline in young children are unfounded. Similarly groundless is the belief in “chronic Lyme disease” as an explanation for persistent nonspecific complaints after completing antibiotic therapy for Lyme disease. Prevention of tick-borne infections rests on avoidance of tick-bites and prompt removal of attached ticks. When used appropriately, insect repellents containing DEET are safe and effective for preventing tick exposures. ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Many species of ticks are endemic to the Unites States, and some of these serve as vectors for various bacteria, parasites, and viruses that are pathogenic to humans. Summary information regarding the principal established tick-borne infections of the USA are presented in Table 1,
while similar data for several emerging tick-borne infections are listed in Table 2. Detailed discussions of these infections are beyond the scope of this article. Instead, this review will emphasize key points that apply broadly to the epidemiology, diagnosis, treatment, and prevention of American tick-borne infections in children. The “ten things clinicians should know” that follow do not comprise a
* Tel.: þ1 901 287 6063. E-mail address: [email protected] http://dx.doi.org/10.1016/j.jinf.2015.04.009 0163-4453/ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
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S.C. Buckingham Table 1
Established tick-borne infections of the USA.
Disease
Organism
Geographic distribution and vector
Prominent clinical findingsa
Rocky Mountain spotted fever (RMSF)
Rickettsia rickettsii
Fever, headache, petechial rash, hyponatremia, thrombocytopenia
Ehrlichiosisb
Ehrlichia chaffeensis
Eastern states: Dermacentor variabilis (dog tick) Mountain West: Dermacentor andersoni (wood tick) Southwestern deserts: Rhipicephalus sanguineus (brown dog tick) Southeastern and south-central states: Amblyomma americanum (Lone Star tick)
Anaplasmosisc
Anaplasma phagocytophilum
Lyme disease
Borrelia burgdorferi
Endemic relapsing fever Tularemia
Borrelia hermsii B. turicatae B. parkeri Francisella tularensis
Babesiosis
Babesia microti
Similar to RMSF, but rash is less common; leukopenia, thrombocytopenia, elevated transaminases Similar to HME, but rash is rarely present
Northeast and upper Midwest: Ixodes scapularis (blacklegged tick) Pacific coast: Ixodes pacificus Northeast and upper Midwest: I. scapularis First stage: fever, erythema Pacific coast: I. pacificus migrans (rash) Second stage: multiple skin lesions, conjunctivitis, arthralgias, myalgias, headache, cranial nerve palsies Third stage: arthritis; encephalopathy, dementia, peripheral neuropathy Western mountains and deserts: Fever, chills, relapsing course Ornithodoros species Eastern states: D. variabilis Mountain West: D. andersoni Southeastern and south-central states: A. americanum Northeast, Midwest, and West Coast: I. scapularis, other Ixodes species
Colorado tick fever Colorado tick fever Mountain West: D. andersoni virus (genus: Coltivirus)
Fever, cutaneous eschar, lymphadenopathy, pulseetemperature dissociation Fever, malaise, headache, hepatosplenomegaly, thrombocytopenia, hemolytic anemia Fever, headache, leukopenia, thrombocytopenia; biphasic course
a Not all patients with these diseases will have all of these findings, and some may present with additional features. Many cases present simply with fever and vague constitutional symptoms. b Also known as human monocytotropic ehrlichiosis (HME). c Also known as human granulocytotropic anaplasmosis (HGA); previously termed human granulocytic ehrlichiosis (HGE).
comprehensive overview of tick-borne infections. Rather, they are intended as a starting point for clinicians wishing to learn more about this topic.
Patients are exposed to ticks more frequently than you might think It may seem surprising, but most persons who experience a tick attachment are actually unaware of their exposure. This is because ticks, especially in their immature stages, are quite small (nymphs, for example, are only 1e2 mm in lengthdabout the size of the head of a pin), and because they frequently attach at hair-bearing body sites and other places where they tend to escape detection. Moreover, because their bites are generally painless, most tick
attachments pass unnoticed.1 It should also be noted that many patients with tick-borne infections lack supposed epidemiologic risk factors for these infections, such as having spent time in a wooded area. Tick-borne infections occur even in urban areas and among people who have never been on a camping trip.2 A multicenter study of 92 children with laboratory-diagnosed RMSF found that only 49% of patients reported a history of a known tick bite, while only 34% reported a history of exposure to a wooded area.3 Thus while the historical findings of tick bite or outdoor exposure may provide useful diagnostic clues, their absence never excludes the possibility of a tick-borne illness. Underscoring this point, data from seroprevalence studies indicate that more than 10% of children in the southeastern and south-central portions of the U.S. have significant antibody titers against Rickettsia rickettsii and
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Tick-borne diseases of the USA Table 2
3
Selected emerging tick-borne infections of the USA.
Disease
Organism
Geographic distribution and vector
Prominent clinical findingsa
Rickettsia parkeri infectionb
Rickettsia parkeri
Southeastern states: Amblyomma maculatum (Gulf Coast tick)
Rickettsia spp. 364D infectionb
Rickettsia spp. 364D
California: Dermacentor occidentalis (Pacific Coast tick)
Ehrlichia ewingii infection Southern tick-associated rash illness (STARI)
Ehrlichia ewingii
Southeastern and south-central states: Amblyomma americanum Southeastern and south-central states: A. americanum
Similar to RMSF, but with eschar at inoculation site; rash may be vesicular or pustular; gastrointestinal symptoms less prominent Fever, headache, myalgias, þ/ rash, cutaneous eschar Similar to anaplasmosis
Borrelia lonestari
Powassan encephalitis
Powassan virus (genus: Flavivirus)
Northeastern and north-central states: Ixodes species, D. andersoni
Heartland virus infection
Heartland virus (genus: Phlebovirus)
South-central states: A. americanum
Rash similar to erythema migrans, þ/ mild constitutional symptomsc Headache, seizures, altered sensorium, focal neurologic signs, meningismus Fever, headache, fatigue, nausea, myalgia, leukopenia, thrombocytopenia
a
Not all patients with these diseases will have all of these findings, and some may present with additional features. For these and other emerging infectious diseases, the full spectrum of clinical illness is still being elucidated. b Besides R. parkeri and Rickettsia species 364D, other rickettsial species that may cause spotted fever rickettsioses have been identified, but their roles as human pathogens are still under investigation. c Late manifestations of Lyme disease (e.g., arthritis, neuropathy) have not been described in patients with Southern tick-associated rash illness.
Ehrlichia chaffeensis.4,5 These data suggest that many tickborne infections are never recognized as such and that such infections occur more frequently than once was thought.
Geography is important Understanding the epidemiology of tick-borne infections is key to making (or excluding) certain presumptive diagnoses. Specific tick-borne infections occur only in regions where their associated tick vectors are found (Tables 1 and 2). Thus, knowledge of where patients have beendthat is, their place of residence and travel historydshould enable clinicians to decide which tick-borne illnesses are likely, or even possible. For example, RMSF has been reported in virtually every area of the United States (Fig. 1), in part because at least 3 different tick vectors have been implicated in its transmission. Ehrlichiosis, on the other hand, is generally found only in the region from the Great Plains eastward (Fig. 2)dthat is, in the geographic range of the Lone Star tick, Amblyomma americanum. Both diseases, however, are especially prevalent in the southeastern, south-central, and mid-Atlantic portions of the United States, so clinicians in these regions should maintain a high index of suspicion for these diseases in febrile patients, particularly during the warmer months of the year. This situation contrast starkly with that of Lyme disease, which (like anaplasmosis and babesiosis) is highly prevalent in regions inhabited by Ixodes species ticksdthe Northeast, the upper Midwest, and to a lesser extent in mountain ranges along the Pacific coastdbut far less so in other parts of the country, including the Southeast (Fig. 3). The
absence of Ixodes ticks in certain portions of the United States makes testing for Lyme disease essentially obsolete, except among those who have recently traveled to an endemic area.6 In the southeastern and south-central USA, however, patients may present with skin lesions suggestive of erythema migrans not because they have Lyme disease, but because of a different, emerging disease: the aptly-named Southern tick-associated rash illness (STARI). While the true incidence and natural history of STARI are still being unraveled, no evidence suggests that it progresses if untreated to involve other organ systems, as happens with Lyme disease. Indeed, the need for antibiotic therapy for STARI remains unclear, though some experts have recommended treatment analogous to that prescribed for Lyme disease.7e9 The astute clinician who recognizes STARI in a patient who has not spent time in a Lymeendemic area can spare this patient not only the pain and expense of unnecessary testing for Lyme disease, but also the mental anguish that frequently accompanies that tentative diagnosis.
Tick-borne infections are seasonaldexcept when they’re not Across the United States, the vast majority of tick-borne infections are reported between April and October. This, of course, is not surprising; the warmer months are not only those when ticks are most active, but also those when people spend the most time outdoors, in potentially tickinfested habitats. For example, pediatric studies in the southeastern and south-central USA found that over 90% of
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S.C. Buckingham
Figure 1 Geographic distribution of spotted fever rickettsioses (mostly Rocky Mountain spotted fever) in the USA in 2012. Counties that reported 1e14 cases to CDC are shaded lightly, whereas those that reported >15 cases are shaded darkly. Note that while cases are widely dispersed geographically, they are especially concentrated in the south-central, southeastern, and mid-Atlantic regions of the United States. Reproduced from: CDC. Summary of Notifiable Diseases, 2012. Morb Mortal Wkly Rep 2014; 61(53): 89.
Figure 2 Geographic distribution of ehrlichiosis (i.e., E. chaffeensis infection) in the USA in 2012. Counties that reported 1e14 cases to CDC are shaded lightly, whereas those that reported >15 cases are shaded darkly. Note that cases are particularly concentrated in the south-central, southeastern, and mid-Atlantic regions, and that they are essentially absent in regions west of the central plains. Reproduced from: CDC. Summary of Notifiable Diseases, 2012. Morb Mortal Wkly Rep 2014; 61(53): 64. Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
Tick-borne diseases of the USA
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Figure 3 Geographic distribution of Lyme disease in the USA in 2012, based on cases reported to CDC. Counties with a disease incidence of 10.01e100 cases per 100,000 population are shaded lightly, whereas those with an incidence of >100.01 cases per 100,000 population are shaded darkly. Although cases are reported in many geographic regions, about 95% of cases are reported from states in the Northeast, mid-Atlantic, and upper Midwest. Reproduced from: CDC. Summary of Notifiable Diseases, 2012. Morb Mortal Wkly Rep 2014; 61(53): 80.
RMSF cases, and 88% of cases of ehrlichiosis, were diagnosed between the months of April and September; for both diseases, over 60% of cases presented in the peak months of May, June, and July.3,10 Nonetheless, it should be noted that ixodid ticks (including those of the genera Dermacentor, Amblyomma, and Ixodes, among others) have a two-year life cycle, and that although they generally become less active during the winter, they do not necessarily die.11 Hence, tick-borne infections can occur in all months of the year, and rare cases have been reported during winter months even in locations typified by cold winters. For instance, 3% of RMSF cases reported to CDC from 1997 to 2002 occurred between the months of December and February, from regions as far north as New England.12 Thus while tick-borne illnesses are distinctly unusual during periods of cold weather, clinicians should remember to include them in their differential diagnoses, even in the depth of winter.
Tick-borne infections are easily confused with other childhood illnesses Occasionally, certain combinations of clinical features can suggest a specific tick-associated diagnosis. Most often, however, children with tick-borne infections (including RMSF, ehrlichiosis, anaplasmosis, tularemia, and babesiosis) present with various nonspecific signs and symptoms such as fever, malaise, headache, nausea, vomiting, and myalgias. Thus, it is not surprising that most patients with tickborne infections are first suspected as having more common
childhood illnesses, such as gastroenteritis, streptococcal pharyngitis, or viral syndromes. An exception to this generalization is Lyme disease, which almost always presents with characteristic signs and symptoms such as erythema migrans, facial nerve palsy, or large-joint arthritis. Although patients with Lyme disease may also complain of various nonspecific symptoms (e.g., fatigue, arthralgia, or weakness), such complaints in the absence of characteristic findings should not prompt testing or treatment for that diagnosis.6 While it is useful to know the “typical” clinical findings associated with tick-borne diseases, it should be emphasized that not all patients present with these findings. This is especially problematic for RMSF, as the purportedly “classic triad” of fever, rash, and headache is present in fewer than 60% of patients with laboratory-confirmed disease.3,13,14 An alternative triaddfever, rash, and history of tick bitedhas demonstrated similarly poor sensitivity in published studies of RMSF.3,15,16 The poor sensitivity of these clinical triads can be partly explained by fact that patients with RMSF usually present with fever and vague constitutional symptoms; the rash may not appear until a few days into the disease course. Confounding matters, in some patients with RMSF the rash may be transient, difficult to appreciate (particularly in dark-skinned individuals), or absent altogether.17,18 And when the rash does appear, clinicians and caregivers may mistakenly attribute it to other explanations, such as a drug reaction, viral syndrome, scarlet fever, or Kawasaki disease.18 These observations also apply to ehrlichiosis, in which the rash is less frequently present, appears later in the disease course, is
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6 less frequently petechial and less likely to involve the palms and soles than in RMSF.10,19 Routine laboratory tests are usually of limited utility in differentiating tick-borne infections from more common childhood illnesses. Some laboratory findings are typically found with certain diseases; for example, children with ehrlichiosis frequently present with thrombocytopenia, leukopenia, and modest elevations of serum transaminases, and patients with babesiosis characteristically present with anemia, thrombocytopenia, and laboratory evidence of hemolysis (e.g., reticulocytosis, decreased haptoglobin, and elevated lactate dehydrogenase).10,19 Such results, however, are hardly unique to these diseases. Children with RMSF can present with a variety of laboratory abnormalities, including thrombocytopenia, leukopenia, leukocytosis, and hyponatremia, but neither the presence nor the absence of any combination of these has adequate sensitivity or specificity to establish or exclude the diagnosis.3
Therapy should not be delayed As a general rule, antimicrobial therapy for tick-borne infections should be started as soon as the diagnosis is seriously considered. This is particularly true for RMSF. Before the advent of effective antibiotic therapy, this disease was associated with a case fatality rate of nearly 30%.11 Although mortality rates are far lower today, deaths from RMSF still occur. One risk factor for mortality from RMSF, which has been consistently identified in studies published across several decades, is delayed initiation of appropriate antimicrobial therapy. Studies published in the 1970s and 1980s found that patients who died of RMSF started therapy with chloramphenicol or tetracycline an average of 2 days further into their disease course than did those who survived.16,18 During the 1990s, one study reported that the risk of mortality rose by 3.1-fold if appropriate therapy was delayed until the fifth day of illness or later, and another found a 3.5-fold increased risk if therapy was started after the fifth day of illness.13,20 Most recently, an analysis of RMSF cases from 1999 to 2007 found that patients who survived were hospitalized after a median of 3 days of illness, whereas those who died were hospitalized after a median of 6 days.21 Considering that hospitalization is a likely proxy for initiation of appropriate therapy, these data demonstrate that delays in starting antirickettsial therapy remain a significant risk factor for mortality from RMSF, even in our present century. Other tick-borne infections found in the USA are generally associated with lower rates of mortality and long-term morbidity than are seen with RMSF. Consequently, for these other diseases, it is less clear that delays in starting appropriate therapy are specifically linked to worse outcomes in children. In one study of adults with ehrlichiosis or anaplasmosis, those who had delayed initiation of doxycycline experienced significantly more complications during their hospitalizations compared with patients with no such delay.22 No such relationship has been documented among children with ehrlichiosis. Even so, there is no reason to withhold therapy from patients in whom any tick-borne bacterial illness is suspected.
S.C. Buckingham
Diagnoses are presumptivedand unfortunately, often delayed As a general rule, tick-borne infections should be diagnosed presumptivelydthat is, based on patients’ clinical findings and epidemiologic histories. This is understandably frustrating for many clinicians (not to mention patients and caregivers), who would often like a greater degree of diagnostic certainty before embarking on a course of antirickettsial therapy. Unfortunately, such certainty is chimerical. As discussed above, results of routine laboratory tests are usually of little utility in determining the likelihood of a tick-borne infection. Moreover, because serum antibodies are generally not detectable until at least 7e10 days into an illness course, serologic testing is expected to yield negative results early in the disease coursedwhich is precisely when these patients are expected to present to healthcare providers. Clinicians are thus forced to make a decision: either prescribe antirickettsial therapy presumptively, or withhold therapy and monitor the patient’s course clinically. No algorithm can substitute for the provider’s clinical judgment in this scenario. In any event, one thing is clear: clinicians should not withhold therapy while awaiting the results of specific diagnostic tests. The decision to test a patient for tickborne illnesses indicates a sufficiently high level of concern to initiate therapy empirically.1,23 Unfortunately, delays in the initiation of antirickettsial therapy among children with laboratory-confirmed RMSF or ehrlichiosis occur quite commonly. It should be noted that these delays are not explained by a lack of opportunities to start therapy. Children with RMSF or ehrlichiosis almost always present for care within the first few days of illness. In a case series of 92 children with laboratory-diagnosed RMSF, 75% of patients were taken to healthcare providers within 3 days of symptom onset. Still, only 4 patients were prescribed an antirickettsial antibiotic before hospital admission. Among the group, effective antibiotic therapy was not started until a median of 7 days of illness.3 Similar results were reported among a cohort of 32 children with laboratory-diagnosed ehrlichiosis.10 Children with tickborne illnesses experience delays in the initiation of antirickettsial therapy not because their caregivers fail to bring them in for care, but because their treating clinicians either fail to consider tick-borne illnesses in their initial assessments or purposely decide against starting specific antirickettsial therapy.18
Concerns over the toxicity of doxycycline in young children are unfounded Doxycycline is the drug of choice for tick-borne rickettsial illnesses, and this is true for both adults and children.1,23 Despite clear recommendations from the American Academy of Pediatrics (AAP), it appears that many pediatricians remain unaware of this recommendation.21 Years ago, chloramphenicol was recommended for treatment of RMSF in children aged less than 8 years because of the perceived potential of doxycycline to irreversibly stain permanent teeth. This practice has long been obsolete, for
Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
Tick-borne diseases of the USA several reasons. First, chloramphenicol is less effective than doxycycline for treatment of RMSF; patients treated with chloramphenicol alone are more likely to die than are those treated with a tetracycline-class antibiotic.24 Second, doxycycline provides effective therapy for ehrlichiosisdwhich cannot be reliably differentiated from RMSFdwhereas chloramphenicol does not.25 Third, chloramphenicol poses the risk of serious toxicities (including idiosyncratic aplastic anemia), and its erratic absorption and metabolism mandates close monitoring of serum levels.26 Indeed, these concerns have led clinicians to largely shun the use of chloramphenicol, to the point where it is no longer available as an oral formulation in USA.1,23 Finally, concerns over doxycycline’s rumored potential for dental staining are unfounded. To be sure, administration of repeated courses of tetracyclineddoxycycline’s older cousin, which is now seldom used in the U.S.dwas associated with unsightly discoloration of permanent teeth in young children. But such an effect has never been documented with doxycycline, presumably because it lacks tetracycline’s affinity for tooth enamel. Indeed, even with tetracycline, tooth discoloration was generally only noted after multiple courses of therapy.1,27 To date, published studies have not found evidence of dental staining among patients who received a single course of doxycycline.28e30 Even if doxycycline was associated with dental stainingdwhich it is notdthe risk of this cosmetic side effect would still have to be weighed against the potential morbidity posed by tick-borne rickettsial illnesses, including the risk of mortality from RMSF. Doxycycline is not the drug of choice for all patients with tick-borne infections. Most children with Lyme disease, for example, can be treated with amoxicillin. Babesiosis requires combination therapy with either clindamycin plus quinine or atovaquone plus azithromycin. For tularemia, gentamicin or streptomycin are considered drugs of choice, although doxycycline or ciprofloxacin are alternatives for patients with mild disease. When alternative drugs are available, doxycycline is best avoided. But in cases where RMSF or ehrlichiosis are reasonable diagnostic considerations, clinicians should not hesitate to prescribe doxycycline, even to very young children.
“Chronic Lyme disease” is not a real thing The proliferation of misinformation about various medical conditions on the Internet is an unfortunate aspect of our current digital age, and this is particularly true in the case of Lyme disease. Particularly vexing are persistent references to “chronic Lyme disease,” a poorly-defined entity with no scientific basis for its existence as an actual disease process. To be sure, some patients, after completing therapy for Lyme disease, continue to experience persistent nonspecific symptoms, such as fatigue, musculoskeletal pain, and difficulty with concentration. However, there is no objective evidence to suggest that persistent Borrelia burgdorferi infection is responsible for these symptoms, which are also quite common in the general population. Although some clinicians prescribe prolonged courses of parenteral antibiotics for patients with persistent post-Lyme symptoms, it should be noted that
7 randomized controlled trials evaluating this practice have not shown any evidence of benefit. Thus, the Infectious Disease Society of America (IDSA) specifically recommends against the use of prolonged or repeated courses of antibiotic therapy (or other unconventional therapies) for patients with persistent post-Lyme symptoms.31 The prognosis of children with Lyme disease is good, particularly if treatment begins in the early phases of disease, and persistent nonspecific symptoms are no more common in children with Lyme disease than in control patients.32 Misperceptions about Lyme disease abound, but considerable evidence can be invoked to refute the assertions of so-called “Lyme-literate” physicians and others who claim that “chronic Lyme disease” is a real entity. To do justice to these arguments would require more space than is available here, so the interested reader is referred to the IDSA guideline and other pertinent reviews.31,33e35
Prevention relies on simple measures Vaccines to prevent tick-borne infections in the Americas are not available, and prophylactic antibiotic therapy after known tick exposures is generally not recommended. Thus, prevention of tick-associated infections rests on two essential principles: avoidance of tick bites and prompt removal of attached ticks. Avoiding ticks is easier said than done, given their ubiquity in the environment; but some measures can help to at least minimize the probability of exposure. Obviously, it makes sense to avoid regions known or likely to be tick-infested, including areas with dense growth of shrubs and small trees. When entering such areas, persons should wear light-colored clothing, with long-sleeved shirts buttoned at the cuffs, and long pants tucked into socks. They should also spray exposed skin and clothing with a DEET-containing insect repellent to reduce the risk of tick exposure. In addition, permethrin (an insecticide) can be sprayed on clothing (but not skin) before entry into wooded areas. Clothing pretreated with permethrin is also commercially available and is considered safe for use by adults and children.1,36 During warmer months, it is advisable to examine persons and pets who have spent time outdoors at least daily for attached ticks. Examiners should pay attention to hair-bearing regions where nymphs and larvae may hide (e.g., the head, neck, axilla, and scrotum). An attached tick should be removed by grasping with tweezers close to the skin and pulling gently with steady pressure. If tweezers are not available, the tick may be removed using fingers protected by gloves or tissue. The bite site should then be washed with soap and water. Alternative “folk remedy” methods of tick removal (including application of petroleum jelly, fingernail polish, isopropyl alcohol, or a hot, extinguished kitchen match to an attached tick) are specifically not recommended because they are ineffective and may actually increase the chances of pathogen transmission.1,36,37
When used properly, DEET is safe and effective Many insect repellents are commercially available, but those that contain N, N-diethyl-meta-toluamide (DEET), in
Please cite this article in press as: Buckingham SC, Tick-borne diseases of the USA: Ten things clinicians should know, J Infect (2015), http://dx.doi.org/10.1016/j.jinf.2015.04.009
8 concentrations of 10%e30%, are most effective for the prevention of tick and insect bites. DEET has undergone extensive safety testing, and billions of human applications, since it became commercially available in 1957. Extremely rare cases of serious neurotoxicity have been attributed to DEET, usually in cases where it was used inappropriately. Overall, however, it appears that DEET-containing products are remarkably safe when used properly.38 After reviewing safety data on DEET in detail, the U.S. Environmental Protection Agency recently concluded that “normal use of DEET does not present a health concern to the general U.S. population, including children.”39 The American Academy of Pediatrics has also endorsed the use of DEET, calling concerns over its toxicity “unfounded.”40 DEET-containing products should be used according to manufacturers’ directions, and care should be taken to avoid their ingestion. DEET is not recommended for infants younger than 2 months old.
Conflict of interest Dr. Buckingham has no conflicts of interest to disclose.
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