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Home , Anaplasmosis, Babesia microti, Boutonneuse fever, Dermacentor, Gangrene, Lyme disease

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Tick-Borne 79 Tom E. Christian

CORE PRINCIPLES

CHAPTER CASES LYME

1 is a multisystem spirochetal disease transmitted by bite. Geography, Case 79-1 (Question 1) tick species, and duration of attachment guide the decision to use prophylaxis.

2 Presence of migrans skin is the only manifestation sufficiently specific to Case 79-2 (Questions 1, 2) allow a clinical diagnosis without confirmatory tests.

3 The existence of post-Lyme disease , although controversial, has resulted in Case 79-4 (Question 1) criteria for fulfilling a provisional diagnosis.

4 Prevention of tick-borne diseases is always preferable to acquisition. Personal Case 79-5 (Question 1) protective measures and other methodologies aid in prevention.

ENDEMIC RELAPSING

1 Tick-borne epidemiology varies with geography, tick, and spirochete Case 79-6 (Questions 1, 2) species involved.

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

1 Southern tick-associated rash illness (STARI) is a recently described tick-borne disease Case 79-7 (Question 1) whose etiology and are still being defined.

HUMAN GRANULOCYTIC

1 Because the clinical manifestations of human monocytic (HME) and human Case 79-8 (Question 1) granulocytic anaplasmosis (HGA) are so similar, the presence of a skin rash and other findings may lead to diagnosis.

BABESIOSIS

1 is an erythrocytophilic parasitic illness with symptoms that range from Case 79-9 (Questions 1, 2) disease to potential fatality, especially in immunocompromised patients.

COLORADO TICK FEVER

1 tick fever (CTF) is a virally mediated tick-borne disease that can be more Case 79-10 (Question 1) severe in children than adults.

TICK PARALYSIS

1 occurs worldwide, affecting humans and livestock. It can be reversed by Case 79-11 (Question 1) tick removal.

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2 TABLE 79-1 Tick-Borne Diseases

Disease Causative Agent Tick Region

Lyme burgdorferi Wild Worldwide Relapsing fever () Borrelia species Wild rodents Worldwide Southern tick-associated Borrelia lonestari? ? South-central to Northeast rash illness United States tularensis , North America Amblyomma Rocky Mountain spotted rickettsii Dermacentor Wild rodents, ticks Western Hemisphere fever Arizona group , Amblyomma Horses? United States others Various rickettsia Various species ? Worldwide Ixodes Wild rodents, dogs Africa, India, Mediterranean North Asian tick Ixodes Wild rodents , Siberia Ixodes Wild rodents, Australia Qfever Dermacentor Sheep, goats, , ticks, Worldwide cats Amblyomma

eto 14 Section Babesiosis species Ixodes Mice, voles Europe, North America Human monocytic Amblyomma , dogs United States, Mexico, ehrlichiosis Europe, Africa, Middle East Dermacentor Deer Human granulocytic Ixodes pacificus Deer, elk, wild rodents United States, Europe anaplasmosis phagocytophilum Ixodes netosDisease Infectious Human ehrlichial ewingii Amblyomma Dogs? United States Coltivirus species Dermacentor Wild rodents, mammals North America Tick-borne Ixodes Rodents , Far East Tick paralysis Neurotoxin Dermacentor, others N/A Worldwide

N/A, not applicable.

OVERVIEW LYME DISEASE

Ticks belong to the class Arachnida, which includes scorpions, Lyme disease, or more accurately Lyme borreliosis, is a multi- spiders, and . As a vector of human illness worldwide, ticks system spirochetal disease transmitted by a tick bite.3 Although are second in importance only to mosquitoes.1 Ticks transmit the responsible spirochete, , was not identified more infectious agents than any other . Disease can until 1982,4 late manifestations of a dermatitis produced by a be spread by ticks, either by of microorganisms Borrelia species were described in Europe more than a century or by of tick toxin into a host. Bacterial, rickettsial, ago. protozoal, and can be transmitted from ticks to humans (Table 79-1). Spirochete Identification Tick Genus and Only two of the three families of ticks are of medical significance Three genomic subgroups of B. burgdorferi worldwide prob- to humans: the soft-bodied ticks, , and the hard-bodied ably account for the clinical variations observed in the dis- ticks,.2 Fourofthe13generaofIxodidaetransmitdisease ease. The North American strains identified to date belong in the United States: Dermacentor, Ixodes, Amblyomma, and Rhipi- to the B. burgdorferi sensu stricto group. Although all three cephalus. Among the five genera of Argasidae, only Ornithodoros groups have been found in Europe, most isolates are Borre- are known to transmit pathogens to humans in the United States. lia garinii or . An example of a disease variation Most hard ticks have a 2- to 3-year life cycle, comprising the is the condition of acrodermatitis chronica atrophicans (Table larval, nymphal, and adult stages.2 They require one blood meal 79-2), a skin lesion associated predominantly with B. afzelii during each stage before they can mature into the next stage, .3,4 and they usually remain attached to a host for hours or days. In Lyme disease is a multisystem condition, affecting the skin, contrast, soft ticks may have multiple nymphal stages, and both joints, and cardiovascular and central and peripheral nervous nymphal and adult forms can feast on blood multiple times, usu- systems. The ailment is named for the villages of Lyme and ally for only 30 minutes. However, Argasidae can survive many Old Lyme, , where arthritic complications of this years without blood sustenance and are long-lived.2 Humans are disease were first recognized.5 In Europe and North Amer- the inadvertent hosts for the life cycle of almost all ticks and ica, Lyme disease is the most commonly reported tick-borne tick-borne diseases. disease.3 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

3 TABLE 79-2 which parasitize domestic and humans, demonstrates a Lyme Disease Clinical Manifestations greater diversity of endemic vectors and cycles in Asia. There- fore, the geographic distribution of Lyme disease matches the Early Localized Infection geographic range of the specific Ixodes species that harbor Lyme skin rash Borrelia. Early Disseminated Disease Heart (<4% of untreated patients in United States) HOST IDENTIFICATION Myocarditis or pericarditis Conduction defects, varying degrees of atrioventricular or The host’s ability to harbor and transmit the spirochete to bundle-branch block, but permanent pacing not indicated the tick (i.e., reservoir competency) is an important considera- Nervous System () tion in understanding the epidemiology and prevalence of Lyme Cranial nerve (Bell’s) palsy disease. The reservoir-competent white-footed mouse and the , lymphocytic reservoir-incompetent (i.e., incapable of harboring and transmit- Radiculoneuritis, ting the spirochete) white-tailed deer are the preferred hosts for Sensory or motor the immature and adult forms of I. scapularis in the northeast- 2 Skin ern United States, respectively. Subadult I. pacificus organisms Multiple secondary erythema migrans lesions; lymphocytoma preferentially feed on the western fence lizard, which is reser- , , (lymphadenosis benigna cutis) rare in the United States, but 1% in voir incompetent, and its blood is borrelicidal.3 6 7 Deer are not Europe important hosts for mature I. pacificus. Similarly, in the south- Late Disease ern United States, immature I. scapularis ticks feed primarily on lizards. The cotton mouse and cotton rat are the predominant Musculoskeletal (less common in Europe) Persistent (<10% of untreated in United States) or intermittent reservoir hosts for the spirochete in the southern United States. of >1 large joint, especially the knee In Europe, various reservoir-competent mice and vole species are reported hosts for I. as are more than 200 various species Skin (10% in Europe; rare in the United States) 2 Acrodermatitis chronica atrophicans (unique to Lyme disease) of birds, mammals, and lizards. How is Lyme borreliosis transmitted to humans in the Late Neurologic western United States if the preferred hosts are not reservoir Chapter 79 Peripheral neuropathy, subacute ( impairment, disturbance, ), and in Europe, competent? It is suggested that the dusky-footed wood rat and progressive kangaroo rat, which can support B. burgdorferi, are the hosts of the spirochete for the few immature I. pacificus, which inciden- tally feed on the rats. Thus, an estimated 0% to 14% of I. pacificus organisms are infected with spirochetes, contrasting with infec- Tick Vector tion rates for I. scapularis in the northeastern United States of 20% to 40%.3 In Europe, I. ricinus infection rates vary from 4% SPIROCHETAL BEHAVIOR to 40%. In addition, bird by ticks enables the ticks to Tick-Borne Diseases The tick acquires the B. burgdorferi spirochete from feeding on be carried long distances, even intercontinentally, during spring an infected host. The spirochete remains dormant in the tick’s and fall migrations. Birds can bring ticks into new areas and also midgut until the tick feeds again. The spirochete then passes serve as maintenance hosts.2 through the salivary ducts of the tick and is injected through Thus, the complex interplay of spirochete, host, and vector in the skin of the new host with the tick bite. Few spirochetes are a particular area influences the risk of Lyme disease after a tick transmitted from the tick to its host during the first 24 to 36 hours bite. Lyme disease is not transmitted directly between people. of attachment. An infected nymphal tick, however, invariably transfers spirochetes when attached to its host for more than 72 hours. Classification and Laboratory Testing of TICK IDENTIFICATION Lyme Disease Larval and nymphal ticks are small, less than 3 mm, the size of The clinical features of Lyme disease were historically divided a freckle or poppy seed. Therefore, the tick often goes unno- into three stages: early localized (stage 1), early disseminated ticed, and fewer than half of patients with Lyme disease recall (stage 2), and chronic, persistent, or late disease (stage 3). having been bitten by a tick. The tick feeds on small, medium, It is debated whether or not “chronic” Lyme disease is true or large mammals; lizards; or birds during its larval and nymphal entity.3 Currently, Lyme disease is classified as either “early” or (immature) stages.2 Larval ticks are not relevant vectors for Lyme “late” disease with the possible existence of post-Lyme disease disease, however, because they are rarely infected and become so syndromes.3 Although Lyme disease may be debilitating, it is only after feeding on an infected host.3 Adult ticks parasitize only rarely fatal.8 medium or large mammals.2 Humans are inadvertent hosts of The most specific marker of Lyme disease is a characteris- any stage of the tick. Although the tick can feed on many differ- tic skin rash termed erythema migrans. This solitary skin lesion ent animals, each tick species has preferred hosts. For example, occurs in 80% to 90% of patients with the disease.5 No other the immature prefers to be hosted by the white- physical finding of Lyme disease is diagnostic, and no laboratory footed mouse, whereas the mature tick prefers white-tailed deer. gold standard for diagnosis currently exists. Laboratory diagnosis In the northeastern and , I. scapularis of Lyme disease is problematic because sufficiently sensitive and (formerly dammini) is the primary vector, whereas I. pacificus specific tests are lacking; deficiencies in laboratory standardiza- is the primary vector in the western United States. In Europe, tion confound the issue.9 Positive blood response sup- I. ricinus is the vector, and I. persulcatus is the primary vector ports, but does not prove, a diagnosis of Lyme disease.3 Overuse in Asia. The discovery of organisms such as B. burgdorferi from of serologic testing and overreliance on the results has resulted I. ovatus in Japan and longicornis in China, both of in excessive and inaccurate diagnoses of Lyme disease. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

4 They are usually less than 5 cm in diameter; they may have an TABLE 79-3 3 Treatment Recommendations for Lyme Disease urticarial appearance and usually disappear in 1 or 2 days. Prophylactic antibiotic preventive therapy with a single dose Erythema Migrans of 200 mg of oral (children 8 years or older at 4 mg/ Adults: Doxycycline (Vibramycin) 100 mg PO BID × 10 days kg to a maximum 200-mg dose) can be offered if the following Or criteria are met: (a) there are no contraindications to doxycycline × (Polymox) 500 mg PO TID 14–21 days use; (b) administration can start within 72 hours of tick removal; Or (c) the tick can be reliably identified as a nymphal or adult axetil (Ceftin) 500 mg PO BID × 14–21 days Children (<8 years): Amoxicillin 50 mg/kg/d PO in 3 divided doses I. scapularis tick with certainty of the duration of attachment (maximum, 500 mg/dose) × 14–21 days or cefuroxime 30 mg/kg/d of 36 hours or more based on the degree of engorgement or PO in 2 divided doses (maximum, 500 mg/dose) × 14–21 days time of exposure; and (d) the local rate of infection of ticks by Children (>8 years): May use doxycycline 4 mg/kg PO in 2 divided doses B. burgdorferi in the area of exposure is 20% or greater based on (maximum, 100 mg/dose) × 14–21 days current ecological evidence.3 Routine testing of ticks themselves for tick-borne is not recommended.3 Cardiac Disease: second- or third-degree , PR interval > Antibiotic prophylaxis after I. pacificus tick bites is generally 0.3 seconds 3 Adults: (Rocephin) 2 g IV Daily × 14–21 days not necessary. In summary, J.S. would not require prophylactic Or doxycyclinetreatmentorserologictestingforhistickbitebecause G (Pfizerpen) 3–4 million units IV every 4 hours × 14–21 days of the short duration of tick attachment and low prevalence of Or B. burgdorferi of I. pacificus ticks. For first- or second-degree heart block, PR interval <0.3 seconds: doxycycline or amoxicillin in doses as noted above × 14–21 days eto 14 Section BID, twice daily; IV,intravenous; PO, by mouth; TID, three times daily. ERYTHEMA MIGRANS

Signs, Symptoms, and Disease Course Treatment CASE 79-2 The clinical manifestations of Lyme disease should govern the netosDisease Infectious treatment strategy (Table 79-3).3 To affect a cure, it is not nec- QUESTION 1: K.T., a 34-year-old woman, presents with right essary to continue antibiotic treatment until all symptoms have knee pain and multiple, large, discrete skin that she resolved.3 has had for the past 10 days. Three months ago, in July, she visited friends in and spent much of her time engaged in outdoor activities. Two months ago, her CASE 79-1 husband noticed a circular area of intense redness, approx- QUESTION 1: J.S., age 38 years, visits his local physician imately 9 cm wide, in her left armpit. The rash grew con- with symptoms of low-grade fever and muscle aches 3 days siderably larger during the next 2 weeks and had a red after deer hunting in the state of Washington. After hunt- outer border. K.T. attributed the expansion of the rash to ing for approximately 6 hours, he noticed a small tick on his having scratched the mildly itchy area. The rash gradually thigh and immediately destroyed it. A small, itchy spot that disappeared. In late August, K.T. experienced , nau- he felt at the site of the tick bite is no longer symptomatic. sea, and for a week and thought it was “summer The temporal relationship of the tick bite with his symptoms flu.” In early September, she experienced right knee pain; of fever and prompts his physician to collect blood ibuprofen produced some relief. On examination, she was samples for Lyme disease antibody testing. Antibiotic ther- afebrile and had mild soft swelling of the right knee. apy also is initiated. Why is the blood test not likely to be Her (WBC) count was normal. sam- of value? Why is empiric antibiotic therapy not appropriate ples contained antibody titers to B. burgdorferi demon- for J.S.? strated by a sensitive ELISA ( ) fol- lowed by a for (IgM) and In general, the use of serologic testing or antimicrobial pro- IgG. A Venereal Disease Research Laboratory (VDRL) test phylaxis after a recognized tick bite is not recommended.3 The for and a pregnancy test were negative. antibody response to B. burgdorferi is not detectable for the first 4 K.T. is started on a 4-week course of oral doxycycline weeks after a tick bite. Therefore, the blood tests for to 100 mg twice daily. What characteristics of K.T.’s skin rash B. burgdorferi are unlikely to be positive, as J.S.’s tick bite occurred are consistent with the erythema migrans of Lyme disease? only 3 days ago. The risk of developing Lyme disease can be affected by the rate The erythema migrans of Lyme disease usually develops of transmission of the spirochete from infected ticks to humans, within 30 days (median, 7–14 days) of a usually asymptomatic tick the length of time before the tick is removed during its bite, the bite at the site of of the spirochete. The rash begins as degree of blood engorgement of the tick (“scutal index”), the an erythematous (red) macule or papule typically on the thigh, prevalence of spirochete infestation of ticks in an area (which back, shoulder, calf, groin, popliteal fossa, flank, , buttock, varies with the tick species), and the reservoir competency of or upper arm.5 In children, erythema migrans is often found on host animals in the region.3 the head at the hairline, neck, arms, or legs. It expands outwardly Although transmission rates of Lyme disease from an infected at 2 to 3 cm/day to a diameter of 5 to 70 cm (mean, 16 cm), occa- tick bite are estimated at approximately 10%, the risk is reduced sionally with some central clearing.5,10 Some cases of erythema dramatically if the tick is removed within 24 hours of attachment, migrans in the United States lack central clearing.3 The rash may as in J.S.’s case. The small, itchy spot experienced by J.S. probably be warm to the touch and is usually painless, but some patients represented a hypersensitivity reaction to the bite. These ery- have mild burning or itching. Up to 50% of patients with ery- thematous, noninfectious skin lesions develop within 48 hours thema migrans have multiple secondary lesions that most likely of tick detachment or may occur while the tick is still attached. represent blood-borne spread of the spirochete to other skin sites P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

rather than multiple tick bites.5 If untreated, erythema migrans can be administered orally; they are relatively inexpensive and 5 generally fades within several weeks; if treated, it usually resolves appear to have good in vitro activity.However, this in vitro activ- in several days. ity does not translate to in vivo efficacy. With the exception of Low-grade fever and other nonspecific symptoms, such as penicillin, none of the above agents have been found to be effec- , headache, myalgias, or , may accompany tive. In Europe, in particular, penicillin still is used with contin- erythema migrans. Some individuals may have no symptoms. ued success. A nondoxycycline regimen is preferred in pregnant Cough, rhinitis, sinusitis, and other respiratory symptoms do or breast-feeding women and in children younger than 8 years not usually occur in Lyme disease.5 Pitfalls in the diagnosis of of age.5 erythema migrans exist. Lesions are sometimes misdiagnosed.5 Compared with the third-generation cephalosporins, the oral K.T.’s skin rash was large (>9 cm), red, and had a red outer second-generation drug (Ceftin) has good border. It gradually faded over the course of a few weeks. in vitro activity and efficacy. However, it is more expensive These characteristics are consistent with a diagnosis of erythema than oral amoxicillin or doxycycline. Of the third-generation migrans. cephalosporins, ceftriaxone (Rocephin) has the most potent in vitro activity and a long half-life for once-daily dosing in an outpatient program. Ceftriaxone is expensive, however, and has Serologic Testing a higher of than other β-lactams, probably owing to extensive biliary excretion. CASE 79-2, QUESTION 2: What might have been the ratio- The (Biaxin) and nale for the laboratory tests that were undertaken in K.T., (Zithromax) are unpredictable in their in vitro activity.3 Similar and what would be reasonable interpretations of laboratory to erythromycin, they are less effective in the treatment of Lyme tests in patients with Lyme disease? disease. The combination of a with lysosomotropic agents, especially , anecdotally has been sug- An antibody titer measured by enzyme-linked immunosor- gested to be associated with increased symptom relief probably bent assay (ELISA) is considered positive for IgM when it is related to combined anti-inflammatory activity rather than direct greater than 1:100 and positive for IgG when it is greater than antimicrobial activity.3 Doxycycline is well absorbed orally and is 1:130. K.T.’s results (IgM of 1:60 and IgG of 1:400) support a diag- less expensive than parenteral ceftriaxone or . Doxy- nosis of Lyme disease because the IgM can naturally fall by this Chapter 79 cycline has a long serum half-life of 18 to 22 hours. In addition, time, yet IgG levels may remain elevated indefinitely.Guidelines doxycycline penetrates into the cerebrospinal fluid (CSF) at con- currently recommend a two-tier approach of ELISA and con- centrations of at least 10% of serum levels, even in the absence firmatory Western blotting.9 The sensitivity of such testing in , of meningeal inflammation. Although not as significant as with Lyme arthritis cases is 97% to 100%.9 11 However, routine use of , doxycycline can complex with divalent or trivalent testing for patients with early erythema migrans cannot cations in the gut, with an associated decrease in oral absorp- be recommended presently.5 Syphilis and other known biologic tion. On the other hand, administering doxycycline with food, causes (periodontal spirochetes) of false-positive serologic testing 3

to minimize , is recommended. Compared with other Tick-Borne Diseases should be excluded. Rheumatoid factor or antinuclear antibody , doxycycline has the least affinity for divalent cal- tests usually are negative in Lyme disease. These tests help dif- cium cations, and oral absorption is reduced by only 20% if given ferentiate or systemic erythematosus with milk. The major side effect of doxycycline is phototoxicity, from Lyme disease. The WBC count is normal or mildly elevated which is of concern because Lyme disease usually occurs during in Lyme disease. K.T. had a normal WBC. Pregnancy was ruled sunny times of the year. A less recognized side effect is the risk of out before initiating a tetracycline. Most interesting in K.T.is the doxycycline-induced esophageal ulceration. Patients should be presence of secondary erythema migrans lesions representing instructed to never take doxycycline or other tetracyclines near disseminated infection. bedtime and to take the while standing up with at The presence of erythema migrans as an early indicator of least 240 mL of clear fluid, especially with the capsule formula- Lyme disease gives physicians the best opportunity for early tion. Despite less in vitro activity compared with some β-lactam diagnosis and treatment. In the United States, the expression of , B. burgdorferi is sufficiently susceptible to doxycycline, erythema migrans is the only manifestation of Lyme disease that and clinical experience with doxycycline has been very favorable. is sufficiently distinctive to allow clinical diagnosis in the absence In conclusion, doxycycline was a suitable choice for K.T. of confirmatory laboratory information.3 Early treatment can prevent sequelae of disseminated disease. Chronic Lyme Arthritis LYME DISEASE TREATMENT CASE 79-2, QUESTION 4: K.T. continues to have knee inflammation for 4 months after receiving a second course Antibiotics of antibiotic treatment (ceftriaxone 2 g daily for 2 weeks) and is now considered to have chronic Lyme arthritis. Why CASE 79-2, QUESTION 3: Why was doxycycline should antibiotic therapy be repeated (or not repeated) for (Vibramycin) chosen to treat K.T.? K.T.’s arthritis?

Borrelia burgdorferi is susceptible to amoxicillin, tetracyclines, Acute Lyme arthritis occurs from the accumulation of and some second- and third-generation cephalosporins. It is , cytokines, immune complexes, complement, and only moderately sensitive to penicillin G (Pfizerpen) and is mononuclear cells induced by the spirochete.12 Appropriate resistant to first-generation cephalosporins, rifampin (Rimac- antimicrobial treatment of acute Lyme arthritis is usually tane), cotrimoxazole (Bactrim), aminoglycosides, chlorampheni- successful.3 A minority subset of patients may have persistent col (Chloromycetin), and the fluoroquinolones.3,5 Lyme arthritis.12 It is very unlikely that this is attributable to the Penicillin,tetracycline,anderythromycinhistoricallywerethe continued presence of B. burgdorferi in the joint, but rather to the drugs of choice for the treatment of Lyme disease because they patient’s continued inflammatory response or .12 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

6 Polymerase chain reaction (PCR) testing of synovial fluid can 6 months, repeated or prolonged antibiotic therapy is not useful be considered, and if negative, symptomatic therapies may or recommended.3,15 be offered rather than repeated antibiotic courses. Such patients What is apparent is that the term “” often respond well to synovectomy,suggesting that the presence has been used for patients with vague, undiagnosed complaints of may not be the result of persistence of the infec- who have never had the disease. In fact, most patients regarded tion. Nonsteroidal anti-inflammatory agents, disease-modifying as having chronic Lyme disease, when rigorously evaluated at antirheumatic agents, intra-articular injections, or university-basedmedicalcenters,havehadnoevidenceofcurrent synovectomy may be offered.3,12 However, it should be noted or prior B. burgdorferi infection.3 that before the antibiotic treatment era for Lyme disease, even The friend should be encouraged to seek additional diagnostic the most prolonged cases of persistent Lyme arthritis eventu- workup for other diseases. Even in patients who have had verified ally improved without treatment, although sometimes lasting Lyme disease, the aches and pains of daily living they experience for months to years.12 appear to be more related to their posttreatment symptoms than to Lyme disease itself.3 Neuroborreliosis CASE 79-3 For an audio podcast on the legal challenges to Infectious Diseases Society of America QUESTION 1: E.C., a 54-year-old man, presents with symp- lyme disease guidelines, go to toms of late Lyme encephalopathy, including mild memory http://thepoint.lww.com/AT10e. and cognitive deficits. Serum two-tier IgG seropositivity was confirmed. Should E.C. be treated with antibiotics? If so, for how long should he be treated? eto 14 Section

Although very rare, late neurologic complications of Lyme Lyme Disease Prevention disease may present as encephalopathy, peripheral neuropathy, CASE 79-5 orencephalomyelitis.3 Lymeencephalomyelitisismorecommon QUESTION 1: A family living in a Lyme disease endemic in Europe than in the United States.3 Although the acute neu- area is concerned regarding their risk for contracting the

netosDisease Infectious rologic manifestations of Lyme disease can remit spontaneously, disease. How would you advise them? late neuroborreliosis is antibiotic responsive.13 An oral antibiotic treatment regimen may suffice in many cases, but parenteral reg- Most vector-borne diseases optimally are prevented through imens for 2 to 4 weeks are appropriate for severe cases.13 A par- vector control. This has proved difficult for tick-borne diseases enteral treatment regimen beyond 4 weeks provides minimal, , because of a lack of efficacy or environmental concerns with the if any, benefit.13 14 Other candidates for intensive intravenous use of . Evaluated methods include habitat destruction (IV) regimens of antibiotic therapy include patients with third- by fire, chemical spraying agents such as to achieve degree atrioventricular (AV) block or acute Lyme meningitis or 3 tick eradication, or removal of host deer, or protection of . In conclusion, E.C. could be treated with a par- , mice from .5 17 enteral third-generation cephalosporin such as ceftriaxone 2 g IV The first step in prevention of Lyme disease is personal pro- daily for 2 to 4 weeks. tection and tick avoidance.17 Tick repellents may be applied to the skin or clothing. N,N-diethyl-m-toluamide (DEET) skin Post-Lyme Disease Syndromes repellents (Repel Sportsmen) combined with a (Per- manone) clothing repellent offer the best overall protection.3 CASE 79-4 DEET has been tested against Ixodid ticks for repellence and QUESTION 1: A friend from an area not endemic for Lyme is more effective than dibutyl phthalate, dimethyl phthalate, disease calls you to say that she has been recently diag- pyrethrum, and two combination products. Citronella-based nosed with “chronic Lyme disease.” She was never found to products, eucalyptus oil, and garlic are inferior to DEET for have early or late Lyme disease. She’d like more information preventing tick bites. about it. How should you respond? DEET is generally safe17; however, excessive DEET applica- tion has been associated with seizures in children.3,17 These are Chronic Lyme disease is a confusing term.15 Most authori- rare events, however, and if the products are used according to ties agree that there may be “post-Lyme disease ,” but their labeling, the adverse reaction risk is low, even for children its definition is evolving and not yet well accepted.3 Objective older than 2 months of age.3 Prolonged or excessive application evidence of a prior B. burgdorferi infection must be established is not recommended. It may be prudent to use the lowest effec- before invoking the possibility of chronic Lyme disease. Criteria tive concentration of DEET-containing repellents, such as those for diagnosing a post-Lyme disease syndrome include fatigue, containing 20% to 30%. To minimize DEET toxicity,the product widespread musculoskeletal pain, cognitive difficulties, or sub- should be applied sparingly, inhalation or introduction into the jective symptoms of such severity that a substantial reduction eyes should be avoided, repellent-treated skin should be washed in quality of life has occurred. The subjective symptoms must when coming inside, use on children’s hands (that are likely to include an onset within 6 months of the initial Lyme disease have contact with the eyes or mouth) should be avoided, and it diagnosis and persistence for at least 6 months after comple- should be applied only to intact skin or clothing. tion of antimicrobial therapy. If adherence to a recommended An repellent alternative to DEET is picaridin (Cutter Lyme treatment regimen is confirmed, the existence of symp- Advanced), also known as icaridin.18 An advantage of picaridin tomatic, chronic infection by B. burgdorferi is difficult to confirm. is that it is safe to use on plastics whereas DEET may damage After appropriately targeted antibiotic therapy for early Lyme certainsyntheticsincludingeyeglassframes.17 Althoughpicaridin disease, treatment failure is exceedingly rare.5,16 The organ- isequallyefficaciouscomparedwithDEETintickbiteprevention ism has not been shown to develop antibiotic resistance.3 For during the first hour after application, it is inferior to DEET for these patients with chronic subjective symptoms for more than this purpose after 2 or more hours.17 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

Physical barriers to ticks, such as wearing protective west and Mexico. In the United States, most cases of relapsing 7 garments—long pants, and long-sleeved shirts—tucking shirts fever are caused by B. hermsii. TBRF can develop when people into pants and pants into boots, and wearing closed-toed shoes, visit tick- or -infested cabins or summer homes. O. hermsii prevent infection. Ticks are easier to spot on light-colored and O. parkeri inhabit forested mountain areas, usually at high clothing.17 Checking the body for ticks regularly is recom- altitudes. The health significance of O. parkeri and its spirochete mended; any that are found should be promptly removed. Avoid- is uncertain because only one human case has been reported.19 ing tick habitats is the best protection against tick-borne diseases. O. turicata transmits its Borrelia in the semiarid plains, from Effective postexposure antibiotic prophylaxis can be adminis- Kansas to central Mexico, creating outbreaks in people visiting tered in Lyme disease endemic areas after a tick bite.5,17 caves, especially limestone ones in central .19 Human for Lyme disease has been withdrawn from the market. Citing low demand, the U.S. manufacturer discontin- SPIROCHETAL BEHAVIOR ued production in 2002. However, creative such as anti- Ticks acquire spirochetes from blood feeding on small wild 17 tick or antitick salivary protein vaccines are being investigated. rodents. If high levels of Borrelia are present in the ’s blood, large numbers of spirochetes will be ingested by the tick and reside in the tick’s midgut. During the next few days, the spiro- ENDEMIC RELAPSING FEVER (TBRF) chetes invade the midgut wall, traverse the hemolymph system, and within a few weeks infect the salivary glands as well as other Relapsing fever exists in two forms: epidemic and endemic. The tick tissues and organs. Females may develop infected ovaries bacterial spirochete , the agent responsible for and transmit Borrelia to offspring in some Ornithodoros species, epidemic relapsing fever, is transmitted between humans by but this is rare in O. hermsii.19 Having reached the tick’s sali- 19 the human body . Epidemic relapsing fever prevailed in vary glands, the spirochetes are poised to invade the tick’s next crowded conditions in various countries. The last US outbreak host. was in 1871.19 Mortality rates of up to 40% have been reported in some epidemics. Endemic relapsing fever, which is caused by TICK BEHAVIOR a variety of Borrelia species, occurs worldwide and is spread by 19 In contrast to the hard-bodied ticks, these ticks feed rapidly,often ticks. 19,20 detaching after 30 to 90 minutes. They feed at night while Chapter 79 people are sleeping, and their bite is usually painless. Therefore, Spirochete Identification most people are unaware that they have been bitten.19 In Europe, the identified responsible spirochete is Borrelia his- panica. In Africa, they are Borrelia duttonii and Borrelia crocidurae; Disease Characterization in North America, the species are , Borrelia turi- catae, and .19 Other Borrelia species may produce The hallmark of endemic relapsing fever is an abrupt onset of high fever (often >39◦C) after an of 4 to

Lymelike diseases or relapsing worldwide. The terms tick- Tick-Borne Diseases 19 borne relapsing fever (TBRF) and endemic or sporadic relapsing fever 18 days. The patient may experience shaking chills, severe are considered interchangeable. In contrast to epidemic relapsing headache, , myalgias, arthralgias, nausea, vom- fever, from TBRF is rare, and most patients recover. How- iting, and malaise. A few cases of acute respiratory distress syn- 19 ever, mortality from TBRF has occurred during pregnancy.19 drome have recently been recognized. The fever usually breaks 19 As the name implies, this disease is characterized by intermit- in 3 days (range, 12 hours to 17 days) in untreated patients. tent bouts of recurring fever and other nonspecific symptoms.19 After a variable afebrile period of 3 to 36 days (usually 7 days), The Borrelia have the genetic ability to alter their outer sur- cyclical periods of fever and constitutional symptoms reappear. face proteins. This capacity allows the spirochete to elude host Each febrile attack progressively diminishes in severity. Three to defensesandisthepresumedexplanationfortherecurrentnature five relapses typically occur in untreated patients. of relapsing fever.19 Routine laboratory testing is of little value. Moderate and an increased erythrocyte sedimentation rate (ESR) are com- mon. Leukocyte counts may be normal, yet moderate to severe Tick Vector is commonly observed but is considered non- TICK IDENTIFICATION specific. The diagnosis of relapsing fever is made by direct obser- The predominant tick vector for relapsing fever is of the genus vation of the spirochete on a peripheral blood smear while the 19 Ornithodoros, a soft-bodied tick. These ticks feed on wild rodents patient is febrile. Observation of the smear is enhanced with or domestic animals and, incidentally, on humans. In North Wright’sorGiemsastaining.Fewdiagnosticlaboratoriesperform 19 America, three tick species carry the agents of endemic relapsing antibody serology tests; however, these tests lack specificity. fever with apparent strict specificity. In fact, the names of the Skin of a rash to identify the spirochete is unreliable. responsible Borrelia species have been adopted from the three Direct culture of the spirochete from the blood into a special tick species that transmit them: Ornithodoroshermsii,Ornithodoros culture medium is the most specific diagnostic tool, but this is a parkeri,andOrnithodorosturicata.19 Althoughtheticksthemselves slow technique confined to research laboratories. may serve as reservoir hosts, the Borrelia usually circulate among wild rodents, ticks, and possibly birds.20 Similar to Lyme disease, TREATMENT greater worldwide variations of endemic cycles and vectors for Doxycycline postexposure prophylaxis against a specific species, TBRF may exist than in North America. Borrelia persica, of TBRF has been shown to be successful in an Israeli study.21 Whether this approach can be translated to other TICK GEOGRAPHY settings for other Borrelia species is unknown. InNorthAmerica,relapsingfeverisanuncommondiseaselargely These borrelia have not demonstrated antibiotic resistance. confined to the geographic distribution of the tick species that Successful treatment regimens usually include a 7- to 10-day harbor the Borrelia. These ticks are usually found in the remote course of antibiotics.19 Tetracyclines are preferred, and doxycy- natural settings of the mountains and semiarid plains of the far cline,100mgorallytwotimesaday,isusuallyused.Erythromycin P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

8 is also effective at a dose of 500 mg orally four times a day. Hos- the agent of this Lymelike illness, although exhaustive, have been pitalization and administration of IV antibiotics may be required unsuccessful.22 It appears that B. lonestari is not the likely of in severely ill patients. STARI.Therearedifferencesintheappearanceandcontentofthe rashes of STARI and the erythema migrans of Lyme disease. For CASE 79-6 example Lyme erythema migrans rashes show an abundance of plasma cells contrasted with a predominantly lymphocytic infil- QUESTION 1: O.T. is a 52-year-old man who visits his fam- trate seen in STARI.22 Limited data support treating STARI with ily practitioner with a sudden onset of high fever, severe regimens similar to those used for Lyme disease.22 For example, headache, malaise, nausea, vomiting, and myalgias. He doxycycline may be given for 10 to 30 days, with longer dura- returned a week ago, at the end of July, from a stay in tions reserved for evidence of dissemination beyond the rash, a rustic cabin on the north rim of the Grand Canyon. The such as fever, severe headache, , or multiple clinician orders a manual complete blood count (CBC) and rashes.22 chemistry panel and asks the laboratory to observe a blood smear with Giemsa stain. What clues suggest a diagnosis of endemic relapsing fever? OTHER BACTERIAL DISEASES: The disease occurs more often in men, and the nonspecific TULAREMIA constitutional symptoms exhibited by O.T. are consistent with this disease. The history is more revealing: the patient visited a location and setting where prior outbreaks of relapsing fever Tularemia 19 have been documented. In addition, cases of endemic relapsing ETIOLOGY AND EPIDEMIOLOGY

eto 14 Section fever peak in the summer months when ticks are warmer and In 1911, George W.McCoy and Charles W.Chapin from the US more active. Public Health Service investigated a plaguelike disease in wild ground squirrels harvested in Tulare County,California, and dis- CASE 79-6, QUESTION 2: After confirming the presence of covered the infectious etiology of tularemia.23 The bacterium Borrelia in the blood smear, the physician prescribes a 10- is a small, pleomorphic, catalase-positive, nonmotile, aerobic, day course of tetracycline. Two hours after the first dose, nonencapsulated, gram-negative coccobacillus now named Fran- netosDisease Infectious O.T.’s wife calls the physician’s office with concerns that the cisella tularensis in honor of Edward Francis for his fieldwork and disease is worsening. O.T. experiences an increased temper- contributions to tularemia research. He proposed the terminol- ature, faintness, and chills, and has a rapid pulse and respi- ogy tularemia because the disease is associated with bacteremia.23 ration rate. What do these symptoms represent? Is this an Five tularemia subspecies (tularensis, holarctica, mediasiatica, novi- adverse drug reaction? cida, and philomiragia) are recognized.23 Type A tularemia, the most virulent form to humans, is caused by F. tularensis, which Up to 54% of patients with relapsing fever experience a reac- was formerly thought to exist only in North America yet has been tion, a Jarisch-Herxheimer reaction, to the first dose of antibiotic identified in a single report from Slovakia in 1998.23 It is fatal in up (see Chapter 69, Sexually Transmitted Diseases).19 It may occur to 2% of cases.23 The important reservoir hosts for F.tularensis are in louse-borne relapsing fever, TBRF, and in other spirochetal wild rabbits, ticks, and tabanid flies.23 Type B tularemia from F. diseases, such as syphilis or Lyme disease.3 The dramatic reac- holarctica exists throughout the , and reser- tion consists of a rise in temperature, chills, myalgias, tachycar- voir hosts include hares, semiaquatic rodents, ticks, mosquitoes, dia, , increased respiratory rate, and vasodilation.19 and tabanid flies.23 Type B tularemia is associated with aquatic Treatment of the reaction consists of supportive care. Severe reac- environments such as streams, rivers, ponds, and flooded areas, tions may require hospitalization for vital signs monitoring and where the live organism is shed into the aquatic environment management of hypovolemia. Although this is a reaction to the by the reservoir hosts.23 F. holarctica infection is milder and has administration of an antibiotic drug, it is not an allergic response, lower mortality rates.23 Before 1950, most human cases of the and the antibiotic should be continued. disease developed from direct contact with infected animals, usu- ally hares or rabbits, and tularemia cases that occurred in the fall SOUTHERN TICK-ASSOCIATED RASH ILLNESS (STARI) or winter were usually associated with hunting season exposure. OR MASTERS DISEASE Tick bite transmission, however, now accounts for more than half of tularemia cases west of the Mississippi River in the United CASE 79-7 States. In summer months, tick or fly bites appear to be the main QUESTION 1: M.G., a 46-year-old man living in southern mode of transmission of tularemia to humans. Other modes of Missouri, recently experienced a rash resembling erythema transmission include ingestion of, or contact with, infected meat, migrans after a lone star tick bite. Because this tick is not a water, or soil; inhalation of aerosolized ; or bites from , vector for Lyme disease, what could be the cause? infected animals, mosquitoes, or deerflies.23 24 Direct person-to- person spread of the disease is rare. (the lone star tick) is found through- Although tularemia is found worldwide, it occurs primar- out the southeast and south-central United States and along ily in the Northern Hemisphere.23 In the United States, cases the Atlantic coast as far north as Maine, and its territory is in , Missouri, Oklahoma, Kansas, and South Dakota expanding.22 Therefore one may question the appropriateness account for 56% of the total.23 The North American tick vec- of terming this illness STARI.22 The lone star tick aggressively tors are (dog tick), Amblyomma americanum bites humans in the southern states, as opposed to I. scapularis (lonestartick),andDermacentorandersoni(woodtick).Tick-borne ticks.5,22 Spirochetes detected by microscopy and culture have tularemia occurs most often in the spring and summer, match- been found in 1% to 5% of lone star ticks and are named Borrelia ing the likelihood of exposure. Reported cases of tularemia in lonestari.2,5,22 B. lonestari and B. burgdorferi, however, were ruled the United States have steadily declined since 1950 from a case out as the cause of erythema migrans–like skin lesions known report high of 2,291 in 1939 to current levels of fewer than 200 as STARI in one Missouri investigation.5,22 Attempts to culture per year since 1967. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

CLINICAL PRESENTATION tions (MIC), less vestibular toxicity, and wider commercial avail- 9 The clinical manifestations of tularemia are related to the mode ability. Although considered comparable in efficacy to strepto- of transmission, patient characteristics, and bacterial subspecies mycin, has been associated with increased treatment causing infection.23 Classically, six types of tularemia presenta- failureandrelapse.Tobramycin(Nebcin)isinferiortogentamicin tion have been identified: ulceroglandular, glandular, typhoidal, or and should not be used. oculoglandular, oropharyngeal, and pneumonic. The last three Initial cure rates and response to tetracycline are equivalent to forms were presumably not tick-borne, reflecting alternative those for gentamicin, but therapy with tetracycline has resulted avenues of transmission. Today the clinical manifestations fall in a significantly greater risk of relapse. Although unproven, into two main groups: ulceroglandular and typhoidal.23 these results suggest bactericidal agents are required for suc- Ulceroglandular is the most common form of tularemia, cessful tularemia treatment. Despite this concern, doxycycline is accounting for approximately 75% of cases.23 Sixty percent of included as an alternative tularemia agent.23 ulceroglandular cases are characterized by an that forms Reported cure rates for therapy of tularemia at the site of entry, usually on the lower extremities, perineum, are significantly lower than those for streptomycin. Similar to buttocks, or trunk from that tend to bite the lower tetracycline, chloramphenicol is bacteriostatic.23 Chlorampheni- extremities or on the upper extremities from mammalian bites.23 col does penetrate into the CSF, with or without inflamed The lesion starts as a firm, erythematous papule that ulcerates meninges, better than aminoglycosides or tetracyclines. There- and heals over the course of several weeks. It is accompanied by fore, when tularemic meningitis is suspected, chloramphenicol regional, painful lymphadenopathy, usually inguinal or femoral. plus streptomycin should be considered. Cephalosporins, such as Typhoidal tularemia, occurring in approximately 25% of cases, is ceftriaxone (Rocephin) and ceftazidime (Fortaz), demonstrate in characterized by fever, chills, headache, debilitation, abdominal vitro efficacy against F.tularensis, but unacceptable treatment fail- pain, and prostration. Fever and chills are common with all forms urehasbeenobservedwithceftriaxone.Ingeneral,β-lactamsand of tularemia.23 macrolides cannot be recommended for tularemia treatment. After exposure to the bacteria and an incubation period of Of the fluoroquinolones studied, ciprofloxacin (Cipro) has the 4 to 5 days, patients become ill with a sudden onset of fever, chills, optimal minimal bactericidal concentration (MBC) in in vitro headache, cough, arthralgias, myalgias, fatigue, and malaise. The data. Promising results with ciprofloxacin treatment have been severity of symptoms is quite variable, ranging from a mild, documented. Because is a common of limited disease (probably type B tularemia) to rare cases of septic tularemia, concern exists about the potential for overwhelming Chapter 79 shock (probably type A tularemia). A hallmark manifestation streptococcal meningitis or during ciprofloxacin therapy. is a high fever without an accompanying increase in pulse, or The inconsistency between in vitro susceptibility and clinical pulse–temperature disparity.23 Common complications are mild success for tularemia is not well explained; however, it may be hepatitis,secondarypneumonia,andpharyngitis.Withantibiotic related to the fact that F.tularensis is predominantly an intracellu- treatment of uncomplicated tularemia, mortality rates are only lar organism. However, aminoglycosides, tetracyclines, rifampin, 1% to 3%. Increased morbidity and mortality are seen in the andfluoroquinolonesdemonstratethemostpotentinvitroactiv- 23

more rare typhoidal forms. The most lethal form of tularemia is ity, and these drugs are the most useful agents in the treatment Tick-Borne Diseases from pulmonary infection.23 In the health care setting, standard of tularemia. precautions are all that is required when caring for tularemia- In many of the reported studies of antimicrobial therapy for infected patients because they are not a source for secondary tularemia, short courses of treatment were used. To prevent infection. However, any suspected outbreaks should be reported tularemia from worsening or relapsing, longer regimens (10–14 and investigated.23 days) should be used, especially in more severe cases. Jarisch- Herxheimer reactions can occur with antibiotic treatment of DIAGNOSIS tularemia. Antibiotic prophylaxis for people exposed to those Laboratory diagnosis of tularemia is limited to the demonstra- with tularemia is not recommended, but prophylactic antibiotics tion of an antibody response to the bacteria. Routine laboratory might be used for suspected attacks of tularemia. testing is of little help in establishing the diagnosis. Because an Acute febrile illness with pneumonia and other signs of infection antibody response to the illness requires 10 to 14 days for detec- occur 3 to 5 days after exposure to airborne tularemia organ- tion, treatment is usually empiric. The diagnosis is based on clin- isms from an intentionally set weapon. No tularemia vaccines ical suspicion from the epidemiologic history and the presence are available in the United States. A partially protective one was of compatible findings. The customary serologic test demon- developed in the former but was only used for at- strates F.tularensis antibody agglutination. Although a single tube risk personnel such as for certain laboratory workers.23 Personal agglutination test with a titer of 1:160 or more (or 1:128 or more protective measures, as discussed for Lyme disease, should be using a microagglutination study) in a suspected case is highly used when spending time outdoors in endemic areas.23 suggestive of a tularemia diagnosis, a fourfold or greater rise in titers between the acute and convalescent stages 2 weeks apart is diagnostic.23 After a bout of tularemia, detectable antibodies 23 THE RICKETTSIA: ROCKY MOUNTAIN may persist for many years. SPOTTED FEVER, RICKETTSIA TREATMENT PARKERI INFECTION, EHRLICHIOSIS, In adults, streptomycin 7.5 to 10 mg/kg intramuscularly (IM) or AND ANAPLASMOSIS IV every 12 hours for 7 to 14 days is the treatment of choice. Pediatric dosing is 20 to 40 mg/kg IM divided twice daily for 7to14days. Rocky Mountain Spotted Fever (RMSF) Streptomycinwashistoricallythedrugofchoicefortularemia, Rocky Mountain spotted fever is the most prevalent and virulent but it is often unavailable commercially. Some clinicians believe rickettsial disease in the United States. As early as 1872, RMSF that gentamicin is the best alternative aminoglycoside for the infected white settlers of the Northwest and it may have been treatment of nonmeningitic tularemia. Its advantages compared prevalent in Native Americans of the region before that time. It with streptomycin include lower minimal inhibitory concentra- was first described in residents of the Bitterroot, Snake, and Boise P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

10 river valleys of Montana and Idaho in the late 1800s. Howard tions in various organs.25 are not secreted by rickettsia; Ricketts discovered the causative agent, , in however, they do induce oxidative and peroxidative damage to 1908.25 The rickettsia is a small (0.3 × 1 μm), pleomorphic, host cell membranes, resulting in .25 In severe infections, weakly gram-negative, obligate intracellular coccobacillus that hypotension and intravascular coagulation may coexist and cul- can survive only briefly outside of a host.25 minate in cell, tissue, or organ destruction. Dehydration is an early sign of RMSF, followed by EPIDEMIOLOGY increased vascular permeability, edema, decreased plasma vol- RMSF is found throughout North America including the United ume, hypoproteinemia, reduced serum oncotic pressure, and States, Canada, and Mexico, and in parts of Central and South prerenal azotemia. RMSF is a multisystem disease, but a partic- America.25 It has not been documented outside of the Western ular organ may be the major focus of the disease. If the brain Hemisphere. The term “Rocky Mountain spotted fever” is actu- or are severely infected, death can ensue. An increased ally a misnomer because the disease has shifted eastward from severity of illness is associated with edema, particularly in chil- the Rocky Mountain states, and the greatest incidence of RMSF dren, and hypoalbuminemia. Hypotension is present in 17% of now occurs in North and South Carolina, Virginia, Oklahoma, patients and hyponatremia in 56%. Extensive infection of the pul- Arkansas, and Tennessee.25,26 Most RMSF infections arise from monary microvascular endothelium can cause noncardiogenic tick exposure in rural or suburban locations, although rare out- pulmonary edema. breaks in urban environments have occurred. A common finding in RMSF is (72%–83%) or muscu- The prevalence of RMSF is highest in children 5 to 9 years of lar tenderness, which are manifestations of skeletal muscle necro- age.27 Another peak prevalence is seen in men older than 60 years sis. Striking creatinine kinase elevations have been described. of age. Risk factors include male sex, residence in wooded areas, Thrombocytopenia resulting from consumption of platelets dur- and exposure to tick-infected dogs. RMSF, like other tick-borne ing intravascular coagulation processes occurs in 35% to 52% of

eto 14 Section diseases, is highly seasonal, with greatest incidence in late spring patients. True disseminated intravascular coagulation with atten- and early summer.25 dant hypofibrinogenemia is exceptional, however, even in severe or fatal cases.25 Blood loss or in some may cause ane- TICK VECTORS AND HOSTS mia, which is seen in 30% of patients and reflects blood vessel In the east, south, and west coasts of the United States, the tick damage. Fatalities usually occur 8 to 15 days after illness onset vector for RMSF has been identified as the dog tick, Dermacentor if no treatment is given or is delayed. Long-term sequelae from netosDisease Infectious variabilis.2 In the Rocky Mountain states, the wood tick, D. ander- severe forms of RMSF can include partial paralysis of the lower soni, is the vector.25 In Mexico, the tick vectors are Rhipicephalus extremities, of extremities requiring , deaf- sanguineus and , with the latter also being ness or hearing loss, incontinence, and movement or speech dis- responsible in Central and South America.25 The brown dog tick, orders, but these occur in a minority of patients who receive R. sanguineus, has been identified as a new tick vector for RMSF prompt antibiotic therapy.25 in a defined area of Arizona.25,26,28 “Fulminant” RMSF is best defined as a disease with a rapidly Dermacentor ticks feed on humans only during their adult fatal course with death occurring in approximately 5 days. This stage.25 Larval Dermacentor ticks may be infected while feeding form of disease is characterized by an early onset of neurologic on small mammals that have sufficient rickettsemia for transmis- signs and late or absent skin rash; it is highly associated with sion, such as chipmunks, ground squirrels, cotton rats, snowshoe glucose-6-phosphate dehydrogenase deficiency, advanced age, hares, and meadow voles. Dogs are not considered reservoirs male sex, and possibly heavy alcohol use.25,26 In the preantibiotic for R. rickettsii but are susceptible to RMSF and may introduce era, RMSF mortality rates were as high as 30%, but they have infected ticks into households.25,26 Adult ticks transmit the rick- fallen to 5% in antibiotic-treated cases today.25,26 ettsia transovarially to their progeny with high efficiency and The classically defined triad of RMSF symptoms at initial pre- establish newly infected tick lines. If the rickettsia burden is large sentation is fever, rash, and headache, but this is found in only up in the adult tick, however, it may cause tick death, thereby reduc- to 5% of cases during the first 3 days of illness and up to approxi- ing infected tick lines. Therefore, there must be nontick reser- mately 60% of cases 2 weeks after exposure.25,27 The RMSF skin voirs, as mentioned previously, to develop newly infected tick rash typically begins 2 to 4 days after fever onset as pink, 1- to generational lines; otherwise, RMSF would slowly disappear. 5-mm blanchable macules that later become papules.26 It begins In summary, ticks are both vectors and hosts for R. rickettsii.25 on the ankles, wrists, and forearms and soon thereafter involves Humans are dead-end accidental hosts of R. rickettsii.25 the palms or soles. It then spreads to the arms, thighs, and trunk and typically evolves into a petechial . The utility of DISEASE COURSE, SYMPTOMS, AND FATALITIES these findings in the is limited because rash Rickettsia rickettsii is usually transmitted to humans from an may be absent, transient, or late; it may never become petechial; infected tick bite.25 The organism can also gain access to humans or it may have an unusual distribution. through broken skin if an infected tick is being crushed with bare fingers, and such crushing may generate infectious aerosols DIAGNOSIS that might be inhaled. Conjunctival contact with infected tick As for most tick-borne diseases, confirmatory serologic analy- tissues or feces provides another route for rickettsial entry. Con- sis is not particularly useful in early diagnosis of disease, and taminated blood transfusions and needle stick injuries have also antirickettsial treatment should begin immediately to prevent transmitted R. rickettsii.25 morbidity and mortality.25,26 R. rickettsii is difficult to culture. After introduction of the organisms into the body, the rick- Immunohistologic demonstration of R. rickettsii in biopsy speci- ettsia spread hematogenously with a predilection for the vascular mens of rash lesions is the only approach that can yield diagnostic endothelium, especially in capillaries and medium-sized blood results in a timely manner, but this approach is applicable only to vessels.25 During an incubation period of 2 to 14 days, induced those presenting with a skin rash, and these tests are not readily phagocytosis allows rickettsial entry into endothelial cells, where available.25 they replicate by binary fission in the cytoplasm and nuclei of The best serologic test for RMSF is the indirect immunoflu- infected cells. This induces a generalized leading to orescence assay (IFA) test, but antibodies typically appear only activation of clotting factors, capillary leakage, and microinfarc- after 10 to 14 days.25 More striking laboratory abnormalities of P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

RMSF disease include a normal leukocyte count with a shift rickettsial pathogens other than R. rickettsii have recently been 11 to the left, hyponatremia, thrombocytopenia, elevated serum recognized, including (flea-borne spotted fever), transaminases or creatinine kinase, and CSF pleocytosis. These Rickettsiaakari(),Rickettsiaparkeri,andanewonein findings are observed late in the disease course, however, and are California called Rickettsia 364D.30 At least three cases of R. park- not helpful in early disease recognition. eri human infection transmitted by tick bite have been reported.31 Clinical findings and history are essential to early diagno- R. parkeri infection is associated with fever, malaise, and sis and successful treatment. Therapy must precede laboratory formation (rarely seen in RMSF), especially at the site of the Gulf confirmation of RMSF.25 In a febrile, tick-exposed person with Coast tick, Amblyomma maculatum, bite.31 R. parkeri infection is a rash, RMSF should be considered. RMSF should be strongly milder than RMSF and can be diagnosed by PCR testing of an considered in febrile children, adolescents, or men older than eschar or papular lesion.31 Doxycycline treatment has resulted 60 years of age, especially if they reside in or have traveled to in prompt (<1 or 2 days) resolution of symptoms.31 It is likely the southern Atlantic or south-central United States from May that some prior cases of presumed RMSF may actually have been through September. A delay in treatment for RMSF beyond caused by SFG rickettsia. 5 days of symptom onset increases the mortality rates from 5% to 22%. Ehrlichiosis and Anaplasmosis TREATMENT SPECIES IDENTIFICATION R. rickettsii is very susceptible to chloramphenicol, tetracycline, Three tick-borne rickettsial human diseases have emerged in and doxycycline. The recommended treatment is doxycycline 100 recent years: human monocytic ehrlichiosis (HME), caused mg orally or IV two times a day for at least 5 to 7 days, including at almost exclusively by Ehrlichia chaffeensis, human granulocytic least 3 days after the temperature has normalized.25 Contraindi- anaplasmosis (HGA), caused by Anaplasma phagocytophilum, and 3,26,32,33 cations to doxycycline use include history of severe hypersensitiv- human granulocytic Ehrlichia ewingii infection (HEE). ity reactions to tetracyclines, and it is relatively contraindicated The agents of HME, HGA, and HEE parasitize white blood in pregnancy.25 Chloramphenicol is reserved for use in the first cells. or second trimesters of pregnancy. However, owing to the risk In 1987, the first reported case of human ehrlichial infection in the United States was found in a soldier at Fort Chaffee, Arkansas.

of gray baby syndrome from chloramphenicol if used during at- Chapter 79 term or near-term pregnancy, doxycycline can be substituted.25 It was initially misinterpreted as being the same agent that infects The erythromycins, , sulfonamides, aminoglycosides, dogs, Ehrlichia canis. Subsequent studies revealed that it was and cephalosporins are not effective for RMSF. Although fluo- a unique species, E. chaffeensis. Cases of HME have now been roquinolones have shown in vitro activity in other spotted fever reported in many states, Europe, and Africa. Retrospective anal- rickettsial diseases, their use in human RMSF disease cannot be ysis has revealed that 10% to 20% of unconfirmed, presumptive recommended at this time. diagnoses of RMSF were actually HME. The number of HME A crucial component in the management of RMSF is appro- cases is greater than RMSF in several states today. 25 priate supportive care. Those with severe disease should be Anaplasmosis was first described in 1994. Since HGA’s discov- Tick-Borne Diseases 26 hospitalized and managed with hemodynamic, renal, pul- ery,more cases have been reported than for HME. During 2001 monary, and fluid support as needed.25 to 2002, HGA rates were especially high in Rhode Island, Wis- 26 In 1994, the American Academy of Pediatrics (AAP) Commit- consin, , Connecticut, New York, and Maryland. To tee on Infectious Diseases revised the RMSF treatment options date the highest incidence of HGA in the United States is reported 32 for young children after weighing chloramphenicol’s potential in the upper Midwest and northeastern states. toxicity and the dental staining concerns for tetracyclines. The AAP now acknowledges tetracyclines as acceptable RMSF treat- TICK VECTORS AND DISEASE HOSTS ment in children of any age. Doxycycline is the tetracycline agent The primary tick vector of HME is A. americanum, the lone of choice in pediatric RMSF because it is dosed less frequently star tick, and its geographic distribution matches that of most than other tetracyclines, improving compliance, and does not cases of HME, occurring in the south central and southeastern bind calcium as strongly as other tetracyclines. The dosage is United States. E.chaffeensis also has been recovered in D.variabilis, 4.4 mg/kg orally divided into two doses on day 1 followed by I. pacificus, and A. cajennense ticks. Cases of HME that have 2.2 mg/kg/day orally each day for 7 to 10 days or 2 to 3 days after been diagnosed in the northeastern United States are prob- the fever abates and clinical improvement occurs. ably propagated by A. americanum. HME cases in Europe, Africa, and some US states suggest other vectors. An impor- tant reservoir for E. chaffeensis is white-tailed deer.26,33 Dogs, PREVENTION , squirrels, rabbits, and goats have shown natural infec- In addition to the same guidelines for prevention of Lyme disease, , tion with E. chaffeensis.26 33 HME begins with the introduction of keeping pets free of ticks can reduce exposure. Ticks must not be E. chaffeensis into the skin of a host from the bite of an infected crushed in a way that might introduce rickettsia into cutaneous tick. The bacteria spread throughout the body hematoge- lesions, mucous membranes, or the conjunctiva. No RMSF vac- nously. They become established within the cells of monocytic cine is available.25 Antirickettsial antibiotic prophylaxis after a in the , lymph nodes, , bone marrow, tick bite is not warranted as only a tiny proportion (<1%) of lung, and kidney. Characteristic, microscopically visible intra- ticks in an endemic area are infected with R. rickettsii.25 cellular inclusion bodies called morulae (for their mulberrylike appearance)develop.Eachmorulaisactuallyamembrane-bound Rickettsia Parkeri and Other Spotted rickettsial colony that grows and divides within the mono- cyte’s cytoplasm. Necrosis in heavily infected cells occurs, and Fever Group (SFG) Rickettsia it is believed that cell rupture and the subsequent release of In the past 20 years new pathogenic spotted fever group rickettsia allows infection of more monocytes, repeating the (SFG) rickettsia have been discovered worldwide causing novel cycle. rickettsioses.25,29 Fifteen of the 20 SFG rickettsia found world- Tick vectors that harbor the agent of HGA include I. scapularis wide can be pathogenic to humans.30 In the United States, SFG and I. pacificus, which are also Lyme disease transmitters.32 One P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

12 study in an endemic area found an I. scapularis HGA, Lyme coin- only by retrospectively confirming the diagnosis. Currently, a fection rate in ticks of 16%.34 In Europe, I. ricinus is the vector. fourfold change between acute and convalescent indirect IFA The main reservoir for A. phagocytophilum is the white-footed serology is the gold standard test for both HGA and HME. mouse. Other hosts include white-tailed deer, elk, and other Blood detection by PCR or culture is also useful for HGA wild rodents.26,32 In northeastern China domesticated sheep as diagnosis.32 The following signs often are noted, however: hyper- well as wild rodents carry A. phagocytophilum, and it has infected transaminemia, (often with a shift to the left), and humans, ticks, and rodents in China, Korea, Japan, and other thrombocytopenia.32 These findings may increase the suspicion Asian countries.35 Humans are incidental dead-end hosts for for HME or HGA infection. However, leukopenia and thrombo- this organism, and infection is of short duration and does not cytopenia usually normalize after 2 weeks in HGA even if found persist.32 Alternative routes for human acquisition of HGA rather on initial presentation.32 A peripheral blood smear showing neu- than by tick bite are documented.32 After binding to neutrophils trophilic morulae is diagnostic for probable HGA, but negative and becoming internalized, A. phagocytophilum alters results do not rule out the diagnosis.32 In HME, peripheral blood function.32 However, only systemic inflammatory processes may smears are rarely diagnostic. HME morulae are more likely to be triggered, and activation with excessive cytokine be identified in macrophages with biopsy or postmortem speci- production may cause associated tissue injury if present.32,36 mens of the liver, spleen, or bone marrow anecdotally. A periph- Tick removal from the body is less likely to be effective for eral blood smear examination for morulae should probably be disease prevention than it is in Lyme disease because of the rapid undertaken because this method is a quick and easy way for transmission of A. phagocytophilum during the nymphal tick bite. making a provisional diagnosis. Confirmatory testing by serol- Tick exposure is defined by geography and season. Simply being ogy or PCR or direct culture is still required to establish the in an area where ticks can be found, particularly during spring diagnosis.3,26,32 and summer, constitutes exposure. The nonspecific manifestations of HME and HGA are con-

eto 14 Section sidered indistinguishable. Although considered an uncommon finding, skin rash is consistent with either disease. In HME, skin CLINICAL AND LABORATORY FINDINGS rashes are seen in almost 60% of children but in less than 30% of Human ehrlichiosis and anaplasmosis usually present as non- adults.26 In HGA, skin rashes occur in 10% or less of patients and specific, febrile, flulike illnesses resembling RMSF. The symp- 3,32 may actually reflect with Lyme disease. Therefore, toms begin 5 to 21 days after tick exposure. Patients may if a skin rash is present, HME is much more likely than HGA

netosDisease Infectious be entirely asymptomatic, but there have been occasional fatali- (Table 79-4). ties reported, particularly in immunocompromised patients with 3,32 Human monocytic ehrlichiosis and HGA can be differenti- HGA. HME and HGA share similar clinical features. Both dis- ated by serologic evaluation or PCR. Treatment should never be play fever as the major symptom in nearly 100% of cases. The delayed pending the results of testing because the other common symptoms of malaise, myalgia, and 26,32 3,32 is 2% to 3% for HME and 0.5% to 1% for HGA. Delays in are found in most cases of HGA but somewhat less in HME. diagnosis and treatment are related to a substantial proportion Other less common symptoms found in both diseases include of death from the diseases. diaphoresis, nausea, vomiting, cough, diarrhea, abdominal pain, , pharyngitis, rash, and .32 HEE infection occurs almost exclusively in immunocompromised patients, yet TREATMENT AND PREVENTION no fatalities have been documented.26,37 Doxycycline (Vibramycin) 100 mg orally twice daily for 10 to 14 As with many other tick-borne diseases, serologic find- days is the drug of choice for both HME and HGA.26 For HGA, ings of antibody response to ehrlichiosis or anaplasmosis assist doxycycline for only 7 to 10 days is usually sufficient, but a full

TABLE 79-4 Tick-Borne Disease Findingsa

LD RF Tularemia HME HGA RMSF Babesiosis CTF

Rash +++ + + ++ + +++ – +/– Fever ++ ++++ + – +++ ++++ ++++ ++++ ++ + Rigors – +++ + – +++ +++ ++++ +++ ++ – Headache ++ ++++ + – +++ +++ ++++ ++++ + + Myalgia ++ + + – +++ +++ ++++ ++++ ++ +++ Anemia – ++ – ++ ++ +++ +++ + Nausea/vomiting + +++ – ++ ++ +++ + + Cough ++++ +++– + – Confused ++– +++++– + Malaise ++++ ++ + – +++ ++++ ++++ ++++ ++ – Arthralgias +++ ++ + ++ + – + – LFTs + ++ ++ ++++ ++++ ++ + + Increased WBCs +++/– – – +/– – – Decreased WBCs – – – ++ +++ +/– – +++ ESR – ++ ––––++ Decreased platelet count – +++ – +++ ++++ ++ ++ +

aCaution: Routine laboratory testing is of little value in diagnosing or differentiating tick-borne diseases. +, ≤25% association; –, not usually associated; CTF, Colorado tick fever; ESR, erythrocyte sedimentation rate; HGA, human granulocytic anaplasmosis; HME, human monocytic ehrlichiosis; LD, Lyme disease; LFTs, liver function tests; RF; relapsing fever; RMSF, Rocky Mountain spotted fever; WBCs, white blood cell counts. P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

, 14-day course should be used if Lyme coinfection is present.3 32 THE PROTOZOA: BABESIOSIS 13 In children 8 years of age or younger, doxycycline is given at a dosage of 4.4 mg/kg/day PO (or IV if unable to take orally), divided into two daily doses of 100 mg maximum each dose.3,32 Babesiosis For those older than 8 years of age but weighing less than 45 HISTORY kg, the above dosing scheme should be used, and adult doses Investigatingthedeathsof30,000to50,000headofRomaniancat- of 100 mg every 12 hours are used for children weighing more tle with febrile hemoglobinuria in 1888, Victor Babes described 3,32 than 45 kg. (See RMSF section for a discussion of the pediatric an intraerythrocytic organism that was thought to be bacterial, use of doxycycline.) If tetracyclines are absolutely contraindi- and it was named Haematococcus bovis.38 While investigating a cated, rifampin 300 mg orally twice daily for 7 to 10 days is an hemolytic cattle fever in Texas in 1893, Smith and Kilborne estab- 3,32 alternative in mild HGA disease. Pediatric rifampin dosing lishedthatthecausativeorganismwasaprotozoan,Babesiabigem- for HGA is 10 mg/kg (to a maximum 300-mg dose) twice daily ina, and introduced the concept of an arthropod-borne transmis- 3,32 for 5 to 7 days. Chloramphenicol (Chloromycetin) is ineffec- sion of the disease.38 The first human case of babesiosis was 3 tive in vitro and should not be used. Fluoroquinolones may definitively identified in a 33-year-old Croatian cattle farmer in 3,32 not be curative for HGA and should not be used. Ineffective 1957.38 His febrile hemoglobinuria and intraerythrocytic organ- antibiotics for ehrlichiosis or anaplasmosis include gentamicin isms were attributed to the bovine Babesia divergens.He (Garamycin), ceftriaxone (Rocephin), cotrimoxazole (Bactrim), hadundergoneaprevioussplenectomyanddiedofrenalfailure.38 erythromycin (E-Mycin), metronidazole (Flagyl), clindamycin Postmortem inquiry revealed that his cattle were infected with a (Cleocin), sulfonamides, and penicillin. Asymptomatic, seropos- bovinebabesialspecies.PossibletickvectorsidentifiedwereI.rici- itive patients with antibodies to A. phagocytophilum should not be nus and Dermacentor silvarum. To date, rare, often fatal, human 3 treated. cases of babesiosis in Europe have been caused by B. divergens Prevention of HME or HGA disease is preferable to treat- and .3,38 Sporadic cases of babesiosis have been ment. Tick avoidance and detection strategies, as outlined for reported in Asia, South America, and Africa.3,38 European cases Lyme disease, are recommended. No evidence supports the rou- present with a fulminant, febrile illness 1 to 3 weeks after a tick tine administration of prophylactic antibiotics for HME or HGA bite. In 84% of these cases, the patients have been asplenic. Coma prevention in patients with known tick bites. Vaccines may be

and death have occurred in greater than 50% of cases. Customary Chapter 79 32 developed but are not currently available. findings there are hemoglobinuria, hemolysis, , chills, CASE 79-8 sweats, myalgia, pulmonary edema, and renal insufficiency. The first human babesiosis case in a person with an intact QUESTION 1: G.K., a 78-year-old man living in northwest spleen was reported in 1969 in a patient from Nantucket Island, , presents with an influenzalike illness in late May. Massachusetts. Since then, “Nantucket fever” has been found to He has a 2-day history of fever, shaking chills, headache, be caused by the babesial rodent agent B. microti. In contrast to myalgias, nausea, and . On examination, his tem- most European cases and those reported in California, human perature is 39.4◦C, but other physical findings are unre- babesiosis in endemic areas of the Great Lakes regions and the Tick-Borne Diseases markable. No skin rashes are found. During questioning, northeastern United States commonly occurs in normosplenic he stated he had multiple tick bites 1 week ago while he patients.3 The presenting complaints are usually nonspecific and was fur trapping. The physician suspects anaplasmosis and consist of malaise, fatigue, low-grade fever or shaking chills, prescribes doxycycline 100 mg PO twice daily for 10 days. headache, generalized musculoskeletal complaints, emotional Blood is drawn for serology, CBC with differential, chem- lability, nausea, emesis, and weight loss. Fatal cases have been istry profile, and a Wright’s stain microscopic examination. found in distinct areas of Wisconsin, Missouri, Rhode Island, and Immediately available abnormal results include neutrophilic California. Severe, nonfatal cases have occurred in Minnesota, morulae on microscopy, a WBC count of 2,500/μL, a platelet Washington State, and California. Additional cases have been count of 80 × 103/μL, C-reactive protein of 136 mg/L (nor- reported in New York, Connecticut, Maryland, Virginia, and mal, 4–8 mg/L), aspartate aminotransferase (AST) of 150 , as well as in Mexico. Members of Babesia are called IU/L, and lactate dehydrogenase of 700 IU/L. Serology is piroplasms because of their pear-shaped appearance of dividing still pending. Two days later, G.K.’s fever abated, and he parasites within erythrocytes. These are the only cells infected was feeling better. How does this case fulfill a diagnosis of by babesia as they are obligate parasites of red blood cells.38 A dif- HGA? ferent type of Babesia piroplasm recently emerged in the western United States. It was initially isolated in a resident in Washington G.K.’s history is significant for HGA. He was in the right State and is now called Babesiaduncani.3,38 B.divergens–like organ- place, the upper Midwestern United States, and was outdoors isms, originally termed MO-1, have caused human infection in during the right season; most patients are diagnosed with HGA in Missouri, Washington State, and Kentucky.3,38 May through August.32 The usual incubation period from tick bite to illness onset ranges from 5 to 21 days.9,32 His symptoms are also important. Nearly 100% of patients BABESIA, TICKS, AND HOSTS with HGA have a fever of greater than 37.6◦C. Other symp- There are more than 100 species of Babesia having a worldwide toms in G.K. consistent with HGA are rigors (shaking chills), geographic range.38 Todate, only four species are known human headache, myalgias, nausea, and anorexia.32 Matching labo- pathogens: B. divergens, B. microti, B. duncani, and B. divergens–like ratory findings include neutrophilic morulae. The observed organisms.38 The most common cause of human babesiosis is leukopenia and thrombocytopenia strongly support the diag- B. microti.38 The babesia are transmitted by Ixodes, Dermacentor, nosis. Evidence of mild to moderate hepatic injury, as seen by Haemaphysalis, and Rhipicephalus ticks. B. microti is transmitted the elevated liver enzyme results, is helpful in HGA diagnosis. in the northeastern United States by I. scapularis, the deer tick of Finally,the good response to doxycycline, with fever resolution in Lyme disease and HGA, and in the United Kingdom by Ixodes 2 days, is customary.32 Fever persisting for more than 2 days trianguliceps. In Europe, bovine babesiosis is transmitted by I. after doxycycline treatment suggests that the diagnosis of HGA ricinus. In the western United States, I. pacificus is the probable is incorrect.3,32 vector. High infection rates of B. microti in field mice (Microtus P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

14 pennsylvanicus) and white-footed mice (Peromyces leucopus) have In the northeastern United States, infections commonly occur been found on Nantucket Island in Massachusetts during inves- in patients with , as in H.W.Clinically apparent cases are tigations of transmission cycles. Other reservoirs for B. microti most common in 50- to 60-year-old patients, many of whom are chipmunks, meadow voles, shrews, and rats. In the south- do not recall a tick bite. Most symptoms of babesiosis are eastern United States, nymphal stage I. scapularis ticks feed on caused by hemolysis or the systemic inflammatory responses to lizards, which are poor reservoirs for B. microti, possibly explain- parasitemia.38 The usual incubation period is 1 to 6 weeks after a ing why babesiosis is rarely reported here. Babesia species also tick bite based on limited data.38 Nonspecific, virallike symptoms are transmitted from the larval to nymphal stage of the tick (that that are gradual in onset appear first, as in H.W.’s case, followed is, transstadial transmission occurs). several days later by the other symptoms H.W.displayed. A hall- mark of the disease is hemolytic anemia of varying severity. A high index of suspicion for babesiosis should be maintained in SYMPTOMS AND DIAGNOSIS any patient with an unexplained febrile illness who lives in or has traveled to a region where the infection is endemic during June CASE 79-9 through August, as in H.W.’s case, particularly if there is a history QUESTION 1: H.W., age 64 years, spent July on Martha’s of tick bite. Vineyard. A week later, he felt fatigued and lost his appetite. He presents to his local physician in the mid- TREATMENT dle of August with complaints of fever, headache, drench- ing sweats, aches and pains, and occasional dark-colored CASE 79-9, QUESTION 2: Why were atovaquone and urine. He does not recall a tick bite. On physical exam- azithromycin chosen to treat H.W.? What other drugs have ination, he has splenomegaly and hepatomegaly. Lab- been used?

eto 14 Section oratory tests show a severe normochromic, normocytic anemia, decreased hemoglobin, hemoglobinuria, throm- The discovery of an original human babesiosis treatment reg- bocytopenia, and increased liver . His tempera- imen combining clindamycin (Cleocin) and quinine was a for- tureis40◦C. Examination of a Giemsa-stained thin blood tuitous one. An 8-week-old infant with presumed transfusion- smear reveals the presence of unpigmented ring-shaped acquired was initially treated with chloroquine. Because intraerythrocytic parasites in more than 10% of his ery- of a lack of response, treatment was switched to quinine plus netosDisease Infectious throcytes. The physician institutes an atovaquone plus clindamycin, and the patient’s fever decreased. A correct diag- azithromycin regimen. What was the clue to the diagnosis of nosis of babesiosis was subsequently confirmed. Although this babesiosis? treatment combination is still used, frequent side effects (e.g., tinnitus, , and diarrhea) occur, often resulting in dose The diagnosis of babesiosis was confirmed by the direct obser- reduction or discontinuation.3,38 Treatment failures with this vation of the protozoan inside the red blood cells. Although the regimen have occurred in splenectomized patients, patients Giemsa-stain test is a commonly used tool, it is subject to false- with HIV infection, or those receiving concurrent corticos- negative results because the rate of parasitemia is typically low. teroids.3 Usually,multiple blood smears need to be examined because less For mild-to-moderate babesiosis, atovaquone plus azi- than 1% of erythrocytes may be infected early in the course of the thromycin is the regimen of choice, as H.W. received. This disease when most people seek medical help.3,38 Because blood regimen has also achieved cures in pediatric cases, although a smear inspection is often not successful in diagnosing babesiosis controlled trial study has not been performed.38 On the other or may only detect a few parasites, additional supportive labora- hand, persistent relapsing babesiosis and emergence of resis- tory results are advocated, such as serology using IFA for IgM and tance have occurred in immunocompromised patients receiv- IgG antibabesial antibodies or PCR detection of babesial DNA in ing this regimen.39,40 It has been suggested that the usual 7- to the blood.3 10-day course treatment regimen may not be adequate in Most patients with B. microti babesiosis are asymptomatic. these patients.40 Combination therapy of azithromycin with ato- This form of babesiosis can be viewed as a distinct, occult, vaquone is better tolerated than clindamycin–quinine combina- asymptomatic disease with few known sequelae.38 A number of tions. The dosing is atovaquone 750 mg orally every 12 hours transfusion-acquired infections have been documented, reflect- and azithromycin 500 mg to 1,000 mg orally on day 1 and ing the existence of an asymptomatic form of babesiosis in blood 250 mg to 1,000 mg on subsequent days for 7 to 10 days.38 donors. Increased azithromycin doses of 600 mg to 1,000 mg/day may A second form of babesiosis has been termed a “mild-to- be used in immunocompromised patients.3 Children should moderate viral-like illness.”38 It has a gradual onset of fatigue receive atovaquone 20 mg/kg (maximum, 750 mg dose) every and malaise and later fever accompanied by one or more of 12 hours and azithromycin 10 mg/kg (maximum, 500-mg dose) these symptoms: chills, sweats, headache, arthralgias or myal- on day 1 and 5 mg/kg(maximum, 250-mg dose) orally thereafter gias, anorexia, or cough.38 Rash is rare. It can last weeks to for7to10days.3,38 months, sometimes with a prolonged recovery time of up to For severe babesial illness the intravenous clindamycin plus a year or more.38 oral quinine should be given.38 Dosing recommendations for A third form of babesiosis is a potentially life-threatening adults are clindamycin 300 mg to 600 mg IV every 6 hours plus hemolytic one that occurs in people predisposed to severe infec- quinine 650 mg orally every 6 to 8 hours for 7 to 10 days; children tion because of advanced age, immune suppression as a result should receive clindamycin 7 to 10 mg/kg (maximum, 600-mg of HIV disease or immunosuppressants, malignancy, or prior dose) IV every 6 to 8 hours plus quinine 8 mg/kg(maximum, 650 splenectomy.38 Although babesial infection is as prevalent in chil- mg dose) orally every 8 hours for 7 to 10 days.3,38 dren as it is in adults, it is more severe in adults older than 50 years Antimicrobials should be used in all patients with symp- of age. Complications seen in severe babesiosis include acute tomatic, active babesiosis once the diagnosis is confirmed by PCR respiratory failure, disseminated intravascular coagulation, con- or blood smear, owing to the risk of disease complications.38 gestive heart failure, coma, and renal failure, with a 5% to 9% Antibody-seropositive, symptomatic patients without identifi- mortality rate.3,38 able parasites on blood smear or PCR positivity should not be P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

treated. Similarly, asymptomatic patients should not be treated SYMPTOMS 15 regardless of serologic results, blood smear examinations, or CASE 79-10 PCR findings. A course of treatment should be considered in asymptomatic patients, however, if these tests are positive and QUESTION 1: T.M., a previously healthy 28-year-old native repeat testing demonstrates persistent parasitemia for more than of Atlanta, Georgia, returns from a 1-week late-spring camp- 3 months.3,38 ing trip in the eastern Colorado Rocky Mountains. Four Partial or complete transfusions may be life- days later, he experiences fever, chills, headache, myalgias, saving in severe babesiosis for patients having high-grade para- , retro-orbital pain, conjunctivitis, and lethargy. sitemia (10% or more infected erythrocytes), significant hemol- He recalls no tick bites and has no skin rashes. Suspecting ysis, or pulmonary, renal, or hepatic compromise.3 Rapidly RMSF,his physician prescribes doxycycline. T.M.’s symptoms increasing parasitemia leading to massive intravascular hemoly- and fever initially resolve, but 2 days later his symptoms sis and renal failure mandates immediate treatment for this form return. Physical examination at this time reveals a tempera- ◦ of the disease. ture of 39 C. Routine laboratory tests are normal, although Babesiosis prevention is the same as for other tick-borne dis- leukopenia is observed with a WBC count of 2,400/μL. Why eases. Asplenic patients should avoid areas where babesiosis is do T.M.’s symptoms suggest a diagnosis of CTF? endemic. To date no supportive data for the use of prophylac- tic antibiotics to prevent babesial infection after a tick bite are Symptoms of CTF usually start 3 to 5 days after a tick bite, 38 although more than half of patients do not remember being available. Although developed for use in cattle, babesial vac- , cines are not available for humans. bitten.41 42 The most common initial symptoms are fever of rapid onset, headache, chills without true rigors, and myalgias.42 A rash, which may be petechial, maculopapular, or macular, can occur in 5% to 15% of patients.42 A biphasic (“saddle-back”) or THE VIRUSES: COLORADO TICK triphasic pattern of fever and other symptoms lasting 5 to 10 days has been observed.41,42 CTFV infection is usually self-limiting, FEVER AND TICK-BORNE and sequelae are rare, although fatigue and malaise may last for ENCEPHALITIS months.42 One-tothree-weekperiodsofconvalescenceareusual. Children, however, experience complications more frequently Chapter 79 Colorado Tick Fever than adults. The two reported cases of mortality from CTF, sec- ondary to generalized hemorrhage and shock, occurred in chil- DISEASE HISTORY dren. No have been reported in adults.42 Severe forms of “Mountain fever” has been described since the first immigrants CTF may involve (CNS) infection (asep- arrived in the Rocky Mountains. It was later renamed Colorado tic meningitis, , or encephalitis), which has tick fever (CTF), and the Colorado tick fever virus (CTFV) was been reported in 5% to 10% of children, usually within a week of identified as the cause. illness onset.42 Less commonly reported complications include hemorrhagic fever, myocarditis or pericarditis, hepatitis, pneu- Tick-Borne Diseases monitis, and a –like illness.41,42 A prolonged con- VIRUS IDENTIFICATION valescence does not imply persistent viremia, although viremia CTF is caused by a double-stranded RNA Coltivirus.Itisan can last for 3 to 4 months because of the intraerythrocytic loca- intraerythrocytic virus. At least 22 strains of CTFV are known, tion of the virus avoiding immune clearance.41 but among human strains is low.41 The virus is an arbovirus because it replicates inside ticks. The primary LABORATORY FINDINGS nidus of infection is thought to be CTFV invasion of hematopoi- Moderate to significant leukopenia is the most important find- etic progenitor erythroblasts, and it remains sheltered in mature ing in CTF. Leukocyte counts are usually normal on the first 41,42 erythrocytes. day, but decrease to 2,000 to 4,000/μL by the fifth or sixth day of illness with a lymphocytic predominance.42 In one third of confirmed CTF cases, however, the leukocyte counts remained TICKS AND HOST RESERVOIRS around 4,500/μL. Counts return to normal within a week of fever CTF is a viral illness transmitted by the bite of an infected tick.42 abatement in most cases. Thrombocytopenia may occur.41,42 Although at least eight tick species have been found to be infected Although the CSF may show a , this does with the virus, adult D. andersoni ticks are the primary tick vec- not distinguish CTF from other causes of meningoencephalitis.42 tor that transmits CTF to humans.41,42 D. andersoni feeds on numerous mammals, but ground squirrels, porcupines, and chip- DIAGNOSIS AND TREATMENT munks are the primary reservoirs for CTFV as well as the ticks , CTF diagnosis can be made serologically,either with IFA staining themselves.41 42 Transstadial transmission of CTF virus within of erythrocytes, complement fixation, or ELISA.41,42 The most the tick ensures it is infected for life.42 sensitive isolation system is intracerebral injection of infected bloodintosucklingmice.41,42 AreversetranscriptasePCRofspec- imens can be diagnostic within the first 5 days of illness, whereas PREVALENCE serological tests are more relevant for diagnosis 2 weeks after CTF is contracted in forested mountain areas at higher elevations symptom onset.42 Treatment is limited to supportive care.41,42 of the western Black Hills and Rocky Mountain regions of the Aspirinuseasanantipyreticshouldbeavoidedasitcanexacerbate United States and Canada, especially on the south-facing brush the thrombocytopenic hemorrhagic complications of CTF.42 In slopes and dry rocky surfaces of mountains east of the Conti- animal models, ribavirin improved CTF survival, but no data nental Divide.41,42 Neutralizing CTFV antibodies are found in support its use in humans currently.42 Long-term immunity is up to 15% of perennial campers.43 Although CTF can develop generally conferred by CTFV infection.41 Experimental CTF from March to October, May through July are peak incidence vaccines are no longer made.41 The best protection for CTF months.42,43 is tick prevention strategies.42 P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

16 TICK-BORNE ENCEPHALITIS (TBE) lower extremities with motor difficulties progress to an ascend- Tick-borne encephalitis is divided into three subtypes, Central ing flaccid paralysis in several hours or days. Cerebral senso- European (western subtype), Siberian, and Far Eastern (Russian rium is usually spared, pain is absent, and the blood and CSF are spring-summer or eastern subtype), and is endemic to central normal.45 If the tick is not removed, the toxicosis can progress and eastern Europe, Russia, and the Far East, with some overlap to respiratory paralysis and death.45 Initially reported mortality in geography.44 rates of 10% have fallen dramatically with our modern inten- The etiologic agents are spherical, lipid-enveloped RNA sive care units and available respiratory care.45 A Washington viruses in the genus Flavivirus.44 The western subtype is trans- State case series of 33 patients conducted over the course of mitted to humans by I. ricinus, and the Siberian and Far Eastern 50yearsrevealedamortalityrateof6%,withthelasttwopatients’ subtypes are transmitted by I. persulcatus, although I. ovatus is the deaths occurring in the 1940s.45 Children are likely more vulner- vector in Japan.44 A minority of TBE cases have followed the con- able to tick paralysis than adults because the dose of neurotoxin sumption of infected unpasteurized milk or cheese directly with- presentperkilogramof bodyweightishigher.45 Diagnosisshould out a tick vector.44 The main virus reservoirs are small rodents.44 include a complete body examination of the skin for the presence Ticks are vectors, and humans are accidental hosts of the virus. of an engorged tick.45 Ticks can become infected for life by the virus at larval, nymphal, In North America, tick removal commonly results in com- or adult stages, can acquire it during mating, and can maintain the plete recovery within hours to days. In Australia, the disease is virus transovarially and transstadially.44 TBE viruses are trans- more acute, and paralysis may continue to progress for 2 days mitted from the saliva of an infected tick very rapidly, within after tick removal. Recovery from the disease in Australia may minutes of the bite, so early removal of the tick may not prevent take several weeks. Treatment is supportive. Antitoxin derived subsequent encephalitis. from dogs is the treatment of choice for animals, but it also has As the disease name implies, the ultimate outcome of the been used occasionally in humans in Australia with severe tick eto 14 Section infectious process is manifested as CNS involvement, with symp- paralysis.45 Local experts must determine its use on a case-by- toms of , meningoencephalitis, and menin- case basis because of the risk of serum sickness or acute allergic goencephalomyelitis. TBE begins as a febrile headache with pro- reactions.45 gression to CNS manifestations. Treatment is supportive. Four preventive human TBE vaccines are available in Europe, two for adults and two for children.44 For eastern TBE subtype preven- MIXED INFECTIONS netosDisease Infectious tion, two vaccines are available in Russia.17 Prompt for postexposure tick bite prophylaxis is not effective unless used Because the tick vectors and mammalian hosts are the same for as a booster for someone previously immunized in the prior babesiosis, anaplasmosis, and Lyme disease in the northeastern 2 years.44 United States, all three diseases, theoretically, could be transmit- ted to a human from one tick bite. Human coinfection by the agents of Lyme disease, babesiosis, or anaplasmosis can occur, especially in endemic areas.5 Coinfection may alter the natu- THE TOXINS: TICK PARALYSIS ral course for each disease or increase clinical manifestations, especially flulike symptoms, in concurrent Lyme disease with Tick Paralysis babesiosis or HGA. Because the same tick vector in Europe and Russia can carry Lyme disease and TBE, dual infection may result CASE 79-11 in more severe disease.44 QUESTION 1: A.M., a 3-year-old girl residing in Spokane, Dual infection may affect the choice of initial antibiotic ther- Washington, complains of weakness in both legs. The next apy.For example, although amoxicillin is sometimes used to treat day, she begins experiencing flaccid paralysis in both legs early Lyme disease, it is not effective for HGA. Doxycycline, how- and the lower trunk, although she is alert and oriented. Her ever, is useful in both of these diseases. Thus, some cases of Lyme mother discovers a tick attached to A.M.’s scalp under her disease that were believed to be treatment failures may actually hair and removes it. A.M. is back to full health in 2 days. have been confounded by coinfection. Patients with concurrent What happened? Lyme disease and babesiosis have more symptoms and a longer duration of illness compared with patients with single infections. Tick paralysis (tick toxicosis) occurs worldwide in humans When moderate to severe Lyme disease is diagnosed, the pos- and many animals and was first described by the explorer Hov- sibility of concomitant babesial or anaplasmal infection should ell in Australia in 1824.45 Although 60 tick species worldwide be considered in regions where both diseases are endemic. Neu- can produce tick paralysis in animals and humans, it is predomi- tropenia and thrombocytopenia are associated with anaplasmo- nantly caused in humans by D. andersoni and D. variabilis in North sis,anemiaandthrombocytopeniaareassociatedwithbabesiosis, America.45 In Australia, is the culprit.45 and neither is routinely found in Lyme disease.5 For patients Most human cases occur during the spring and summer in with Lyme disease who experience a prolonged flulike illness Australia and North America. In the United States, it is most that fails to respond to appropriate antiborrelial therapy in an common in the Pacific Northwest and adjacent areas of south- endemic area, clinicians should consider testing for babesiosis western Canada and in the Rocky Mountain states.45 In children, and anaplasmosis.5 girls are more commonly affected; however, in adults, more men areaffected.45 Ofepidemiologicalsignificance,ayounggirl’slong hair provides camouflage for feeding ticks.45 SUMMARY The cause of tick paralysis is the secretion of a neurotoxin present in the large salivary glands of female ticks. They must Mostoftheresearchintotick-bornehumandiseasedemonstrates usually be attached to a host for 4 to 5 days before symp- a close historical relationship of endemic tick-deer-rodent cycles toms develop.45 The toxin affects motor neurons, decreases for various microorganisms. Given the recent explosion of deer acetylcholine release, and may have a mechanistic similarity to populations in the United States and Europe, the increase in tick- botulinum toxin.45 and symmetric weakness in the borne human diseases may reflect the reduction of natural deer P1: Trim: 8.375in × 10.875in Top: 0.373in Gutter: 0.664in LWBK915-79 LWW-KodaKimble-educational June 21, 2011 21:25

predators, the continued expansion of human populations from Dworkin MS et al. Tick-borne relapsing fever. InfectDisClinNorth 17 urban to rural environments, or both.2 Therefore, it is likely Am. 2008;22(3):449, viii. (19) that we will continue to encounter increasing cases of tick-borne Edlow JA, McGillicuddy DC. Tick paralysis. Infect Dis Clin North human disease of known or unknown cause. Am. 2008;22(3):397, vii. (45) Kaiser R. Tick-borne encephalitis. Infect Dis Clin North Am. KEY REFERENCES AND WEBSITES 2008;22(3):561, x. (44) Marques A. Chronic Lyme disease: a review. Infect Dis Clin North A full list of references for this chapter can be found at Am. 2008;22(2):341, vii. (15) http://thePoint.lww.com/AT10e. Below are the key references Masters EJ et al. STARI, or Masters disease: Lone Star tick- and website for this chapter, with the corresponding refer- vectored Lyme-like illness. Infect Dis Clin North Am. 2008;22(2): ence number in this chapter found in parentheses after the 361, viii. (22) reference. Nigrovic LE, Wingerter SL. Tularemia. Infect Dis Clin North Am. 2008;22(3):489, ix. (23) Key References Puius YA, Kalish RA. Lyme arthritis: pathogenesis, clinical pre- Aguero-Rosenfeld ME. Lyme disease: laboratory issues. Infect Dis sentation, and management. Infect Dis Clin North Am. 2008; Clin North Am. 2008;22(2):301, vii. (9) 22(2):289, vi. (12) Bakken JS, Dumler S. Human granulocytic anaplasmosis. Infect Romero JR, Simonsen KA. and Colorado Dis Clin North Am. 2008;22(3):433, viii. (32) tick fever. Infect Dis Clin North Am. 2008;22(3):545, x. (42) Chapman AS et al; Tickborne Rickettsial Diseases Working Vannier E et al. Human babesiosis. Infect Dis Clin North Am. Group; CDC. Diagnosis and management of tickborne rick- 2008;22(3):469, viii. (38) ettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and Wormser GP et al. The clinical assessment, treatment, and pre- anaplasmosis—United States: a practical guide for physicians and vention of Lyme disease, human granulocytic anaplasmosis, and other health-care and public health officials. MMWR Recomm Rep. babesiosis: clinical practice guidelines by the Infectious Diseases Chapter 79 2006;55(RR-4):1. (26) Society of America [published correction appears in Clin Infect Clark RP, Hu LT. Prevention of Lyme disease and other tick- Dis. 2007;45(7):941]. Clin Infect Dis. 2006;43(3):1089. (3) borne infections. Infect Dis Clin North Am. 2008;22(3):381, vii. (17) Key Website Dandache P, Nadelman RB. Erythema migrans. Infect Dis Clin Centers for Disease Control and Prevention. Tickborne diseases North Am. 2008;22(2):235, vi. (5) of the U.S. http://www.cdc.gov/ticks/diseases/ Tick-Borne Diseases