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79Tick-Borne DiseasesTom E. Christian

C O R E P R I N C I P L E S

C H A P T E R C A S E S

LYME DISEASE

1 Lyme disease is a multisystem spirochetal disease transmitted by tick bite. Geography,tick species, and duration of attachment guide the decision to use antibioticprophylaxis.

Case 79-1 (Question 1)

2 Presence of erythema migrans skin rash is the only manifestation sufficiently specific toallow a clinical diagnosis without confirmatory tests.

Case 79-2 (Questions 1, 2)

3 The existence of post-Lyme disease syndromes, although controversial, has resulted incriteria for fulfilling a provisional diagnosis.


4 Prevention of tick-borne diseases is always preferable to acquisition. Personalprotective measures and other methodologies aid in prevention.


ENDEMIC RELAPSING FEVER

1 Tick-borne relapsing fever epidemiology varies with geography, tick, and spirochetespecies involved.


SOUTHERN TICK-ASSOCIATED RASH ILLNESS

1 Southern tick-associated rash illness (STARI) is a recently described tick-borne diseasewhose etiology and pathogenesis are still being defined.


HUMAN GRANULOCYTIC ANAPLASMOSIS

1 Because the clinical manifestations of human monocytic ehrlichiosis (HME) and humangranulocytic anaplasmosis (HGA) are so similar, the presence of a skin rash and otherfindings may lead to diagnosis.


BABESIOSIS

1 Babesiosis is an erythrocytophilic parasitic illness with symptoms that range fromasymptomatic disease to potential fatality, especially in immunocompromisedpatients.


COLORADO TICK FEVER

1 Colorado tick fever (CTF) is a virally mediated tick-borne disease that can be moresevere in children than adults.


TICK PARALYSIS

1 Tick paralysis occurs worldwide, affecting humans and livestock. It can be reversed bytick removal.


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T A B L E 7 9 - 1Tick-Borne Diseases

Disease Causative Agent Tick Vector Host Region

Lyme Borrelia burgdorferi Ixodes Wild rodents WorldwideRelapsing fever (endemic) Borrelia species Ornithodoros Wild rodents WorldwideSouthern tick-associated

rash illnessBorrelia lonestari? Amblyomma ? South-central to Northeast

United StatesTularemia Francisella tularensis Dermacentor Rabbits, ticks North America

AmblyommaRocky Mountain spotted

feverRickettsia rickettsii Dermacentor Wild rodents, ticks Western Hemisphere

Rhipicephalus ArizonaSpotted fever group Rickettsia parkeri,

othersAmblyomma Horses? United States

Various rickettsia Various species ? WorldwideBoutonneuse fever Rickettsia conorii Ixodes Wild rodents, dogs Africa, India, MediterraneanNorth Asian tick typhus Rickettsia sibirica Ixodes Wild rodents Mongolia, SiberiaQueensland tick typhus Rickettsia australis Ixodes Wild rodents, marsupials AustraliaQ fever Coxiella burnetii Dermacentor Sheep, goats, cattle, ticks,

catsWorldwide

AmblyommaBabesiosis Babesia species Ixodes Mice, voles Europe, North AmericaHuman monocytic

ehrlichiosisEhrlichia chaffeensis Amblyomma Deer, dogs United States, Mexico,

Europe, Africa, Middle EastDermacentor Deer

Human granulocyticanaplasmosis

Anaplasmaphagocytophilum

Ixodes pacificus Deer, elk, wild rodents United States, Europe

IxodesHuman ehrlichial ewingii Ehrlichia ewingii Amblyomma Dogs? United StatesColorado tick fever Coltivirus species Dermacentor Wild rodents, mammals North AmericaTick-borne encephalitis Flavivirus Ixodes Rodents Eurasia, Far EastTick paralysis Neurotoxin Dermacentor, others N/A Worldwide

N/A, not applicable.

OVERVIEW

Ticks belong to the class Arachnida, which includes scorpions,spiders, and mites. As a vector of human illness worldwide, ticksare second in importance only to mosquitoes.1 Ticks transmitmore infectious agents than any other arthropod. Disease canbe spread by ticks, either by transmission of microorganismsor by injection of tick toxin into a host. Bacterial, rickettsial,protozoal, and viral disease pathogens can be transmitted fromticks to humans (Table 79-1).

Tick GenusOnly two of the three families of ticks are of medical significanceto humans: the soft-bodied ticks, Argasidae, and the hard-bodiedticks, Ixodidae.2 Four of the 13 genera of Ixodidae transmit diseasein the United States: Dermacentor, Ixodes, Amblyomma, and Rhipi-cephalus. Among the five genera of Argasidae, only Ornithodorosare known to transmit pathogens to humans in the United States.Most hard ticks have a 2- to 3-year life cycle, comprising thelarval, nymphal, and adult stages.2 They require one blood mealduring each stage before they can mature into the next stage,and they usually remain attached to a host for hours or days. Incontrast, soft ticks may have multiple nymphal stages, and bothnymphal and adult forms can feast on blood multiple times, usu-ally for only 30 minutes. However, Argasidae can survive manyyears without blood sustenance and are long-lived.2 Humans arethe inadvertent hosts for the life cycle of almost all ticks andtick-borne diseases.

LYME DISEASE

Lyme disease, or more accurately Lyme borreliosis, is a multi-system spirochetal disease transmitted by a tick bite.3 Althoughthe responsible spirochete, Borrelia burgdorferi, was not identifieduntil 1982,4 late manifestations of a dermatitis produced by aBorrelia species were described in Europe more than a centuryago.

Spirochete Identificationand PathologyThree genomic subgroups of B. burgdorferi worldwide prob-ably account for the clinical variations observed in the dis-ease. The North American strains identified to date belongto the B. burgdorferi sensu stricto group. Although all threegroups have been found in Europe, most isolates are Borre-lia garinii or Borrelia afzelii. An example of a disease variationis the condition of acrodermatitis chronica atrophicans (Table79-2), a skin lesion associated predominantly with B. afzeliiinfection.3,4

Lyme disease is a multisystem condition, affecting the skin,joints, and cardiovascular and central and peripheral nervoussystems. The ailment is named for the villages of Lyme andOld Lyme, Connecticut, where arthritic complications of thisdisease were first recognized.5 In Europe and North Amer-ica, Lyme disease is the most commonly reported tick-bornedisease.3



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T A B L E 7 9 - 2Lyme Disease Clinical Manifestations

Early Localized InfectionErythema migrans skin rash

Early Disseminated Disease

Heart (<4% of untreated patients in United States)Myocarditis or pericarditisConduction defects, varying degrees of atrioventricular or

bundle-branch block, but permanent pacing not indicated

Nervous System (Neuroborreliosis)Cranial nerve (Bell’s) palsyMeningitis, lymphocyticRadiculoneuritis, myelitisSensory or motor peripheral neuropathy

SkinMultiple secondary erythema migrans lesions; lymphocytoma

(lymphadenosis benigna cutis) rare in the United States, but 1% inEurope

Late Disease

Musculoskeletal (less common in Europe)Persistent (<10% of untreated in United States) or intermittent

arthritis of >1 large joint, especially the knee

Skin (10% in Europe; rare in the United States)Acrodermatitis chronica atrophicans (unique to Lyme disease)

Late NeurologicPeripheral neuropathy, subacute encephalopathy (memory

impairment, sleep disturbance, dementia), and in Europe,progressive encephalomyelitis

Tick VectorSPIROCHETAL BEHAVIORThe tick acquires the B. burgdorferi spirochete from feeding onan infected host. The spirochete remains dormant in the tick’smidgut until the tick feeds again. The spirochete then passesthrough the salivary ducts of the tick and is injected throughthe skin of the new host with the tick bite. Few spirochetes aretransmitted from the tick to its host during the first 24 to 36 hoursof attachment. An infected nymphal tick, however, invariablytransfers spirochetes when attached to its host for more than72 hours.

TICK IDENTIFICATIONLarval and nymphal ticks are small, less than 3 mm, the size ofa freckle or poppy seed. Therefore, the tick often goes unno-ticed, and fewer than half of patients with Lyme disease recallhaving been bitten by a tick. The tick feeds on small, medium,or large mammals; lizards; or birds during its larval and nymphal(immature) stages.2 Larval ticks are not relevant vectors for Lymedisease, however, because they are rarely infected and become soonly after feeding on an infected host.3 Adult ticks parasitize onlymedium or large mammals.2 Humans are inadvertent hosts ofany stage of the tick. Although the tick can feed on many differ-ent animals, each tick species has preferred hosts. For example,the immature Ixodes scapularis prefers to be hosted by the white-footed mouse, whereas the mature tick prefers white-tailed deer.In the northeastern and Midwestern United States, I. scapularis(formerly dammini) is the primary vector, whereas I. pacificusis the primary vector in the western United States. In Europe,I. ricinus is the vector, and I. persulcatus is the primary vectorin Asia. The discovery of organisms such as B. burgdorferi fromI. ovatus in Japan and Haemaphysalis longicornis in China, both of

which parasitize domestic animals and humans, demonstrates agreater diversity of endemic vectors and cycles in Asia. There-fore, the geographic distribution of Lyme disease matches thegeographic range of the specific Ixodes species that harbor LymeBorrelia.

HOST IDENTIFICATIONThe host’s ability to harbor and transmit the spirochete tothe tick (i.e., reservoir competency) is an important considera-tion in understanding the epidemiology and prevalence of Lymedisease. The reservoir-competent white-footed mouse and thereservoir-incompetent (i.e., incapable of harboring and transmit-ting the spirochete) white-tailed deer are the preferred hosts forthe immature and adult forms of I. scapularis in the northeast-ern United States, respectively.2 Subadult I. pacificus organismspreferentially feed on the western fence lizard, which is reser-voir incompetent, and its blood is borrelicidal.3,6,7 Deer are notimportant hosts for mature I. pacificus. Similarly, in the south-ern United States, immature I. scapularis ticks feed primarily onlizards. The cotton mouse and cotton rat are the predominantreservoir hosts for the spirochete in the southern United States.In Europe, various reservoir-competent mice and vole species arereported hosts for I. ricinus as are more than 200 various speciesof birds, mammals, and lizards.2

How is Lyme borreliosis transmitted to humans in thewestern United States if the preferred hosts are not reservoircompetent? It is suggested that the dusky-footed wood rat andkangaroo rat, which can support B. burgdorferi, are the hosts ofthe spirochete for the few immature I. pacificus, which inciden-tally feed on the rats. Thus, an estimated 0% to 14% of I. pacificusorganisms are infected with spirochetes, contrasting with infec-tion rates for I. scapularis in the northeastern United States of20% to 40%.3 In Europe, I. ricinus infection rates vary from 4%to 40%. In addition, bird parasitism by ticks enables the ticks tobe carried long distances, even intercontinentally, during springand fall migrations. Birds can bring ticks into new areas and alsoserve as maintenance hosts.2

Thus, the complex interplay of spirochete, host, and vector ina particular area influences the risk of Lyme disease after a tickbite. Lyme disease is not transmitted directly between people.

Classification and Laboratory Testing ofLyme DiseaseThe clinical features of Lyme disease were historically dividedinto three stages: early localized (stage 1), early disseminated(stage 2), and chronic, persistent, or late disease (stage 3).It is debated whether or not “chronic” Lyme disease is trueentity.3 Currently, Lyme disease is classified as either “early” or“late” disease with the possible existence of post-Lyme diseasesyndromes.3 Although Lyme disease may be debilitating, it israrely fatal.8

The most specific marker of Lyme disease is a characteris-tic skin rash termed erythema migrans. This solitary skin lesionoccurs in 80% to 90% of patients with the disease.5 No otherphysical finding of Lyme disease is diagnostic, and no laboratorygold standard for diagnosis currently exists. Laboratory diagnosisof Lyme disease is problematic because sufficiently sensitive andspecific tests are lacking; deficiencies in laboratory standardiza-tion confound the issue.9 Positive blood antibody response sup-ports, but does not prove, a diagnosis of Lyme disease.3 Overuseof serologic testing and overreliance on the results has resultedin excessive and inaccurate diagnoses of Lyme disease.



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T A B L E 7 9 - 3Treatment Recommendations for Lyme Disease

Erythema MigransAdults: Doxycycline (Vibramycin) 100 mg PO BID × 10 daysOrAmoxicillin (Polymox) 500 mg PO TID × 14–21 daysOrCefuroxime axetil (Ceftin) 500 mg PO BID × 14–21 daysChildren (<8 years): Amoxicillin 50 mg/kg/d PO in 3 divided doses

(maximum, 500 mg/dose) × 14–21 days or cefuroxime 30 mg/kg/dPO in 2 divided doses (maximum, 500 mg/dose) × 14–21 days

Children (>8 years): May use doxycycline 4 mg/kg PO in 2 divided doses(maximum, 100 mg/dose) × 14–21 days

Cardiac Disease: second- or third-degree heart block, PR interval>0.3 seconds

Adults: Ceftriaxone (Rocephin) 2 g IV Daily × 14–21 daysOrPenicillin G (Pfizerpen) 3–4 million units IV every 4 hours × 14–21 daysOrFor first- or second-degree heart block, PR interval <0.3 seconds:

doxycycline or amoxicillin in doses as noted above × 14–21 days

BID, twice daily; IV, intravenous; PO, by mouth; TID, three times daily.

TreatmentThe clinical manifestations of Lyme disease should govern thetreatment strategy (Table 79-3).3 To affect a cure, it is not nec-essary to continue antibiotic treatment until all symptoms haveresolved.3

CASE 79-1

QUESTION 1: J.S., age 38 years, visits his local physicianwith symptoms of low-grade fever and muscle aches 3 daysafter deer hunting in the state of Washington. After hunt-ing for approximately 6 hours, he noticed a small tick on histhigh and immediately destroyed it. A small, itchy spot thathe felt at the site of the tick bite is no longer symptomatic.The temporal relationship of the tick bite with his symptomsof fever and myalgias prompts his physician to collect bloodsamples for Lyme disease antibody testing. Antibiotic ther-apy also is initiated. Why is the blood test not likely to beof value? Why is empiric antibiotic therapy not appropriatefor J.S.?

In general, the use of serologic testing or antimicrobial pro-phylaxis after a recognized tick bite is not recommended.3 Theantibody response to B. burgdorferi is not detectable for the first 4weeks after a tick bite. Therefore, the blood tests for antibodies toB. burgdorferi are unlikely to be positive, as J.S.’s tick bite occurredonly 3 days ago.

The risk of developing Lyme disease can be affected by the rateof transmission of the spirochete from infected ticks to humans,the length of time before the tick is removed during its bite, thedegree of blood engorgement of the tick (“scutal index”), theprevalence of spirochete infestation of ticks in an area (whichvaries with the tick species), and the reservoir competency ofhost animals in the region.3

Although transmission rates of Lyme disease from an infectedtick bite are estimated at approximately 10%, the risk is reduceddramatically if the tick is removed within 24 hours of attachment,as in J.S.’s case. The small, itchy spot experienced by J.S. probablyrepresented a hypersensitivity reaction to the bite. These ery-thematous, noninfectious skin lesions develop within 48 hoursof tick detachment or may occur while the tick is still attached.

They are usually less than 5 cm in diameter; they may have anurticarial appearance and usually disappear in 1 or 2 days.3

Prophylactic antibiotic preventive therapy with a single doseof 200 mg of oral doxycycline (children 8 years or older at 4 mg/kg to a maximum 200-mg dose) can be offered if the followingcriteria are met: (a) there are no contraindications to doxycyclineuse; (b) administration can start within 72 hours of tick removal;(c) the tick can be reliably identified as a nymphal or adultI. scapularis tick with certainty of the duration of attachmentof 36 hours or more based on the degree of engorgement ortime of exposure; and (d) the local rate of infection of ticks byB. burgdorferi in the area of exposure is 20% or greater based oncurrent ecological evidence.3 Routine testing of ticks themselvesfor tick-borne infections is not recommended.3

Antibiotic prophylaxis after I. pacificus tick bites is generallynot necessary.3 In summary, J.S. would not require prophylacticdoxycycline treatment or serologic testing for his tick bite becauseof the short duration of tick attachment and low prevalence ofB. burgdorferi infestation of I. pacificus ticks.

ERYTHEMA MIGRANS

Signs, Symptoms, and Disease CourseCASE 79-2

QUESTION 1: K.T., a 34-year-old woman, presents with rightknee pain and multiple, large, discrete skin rashes that shehas had for the past 10 days. Three months ago, in July,she visited friends in Massachusetts and spent much of hertime engaged in outdoor activities. Two months ago, herhusband noticed a circular area of intense redness, approx-imately 9 cm wide, in her left armpit. The rash grew con-siderably larger during the next 2 weeks and had a redouter border. K.T. attributed the expansion of the rash tohaving scratched the mildly itchy area. The rash graduallydisappeared. In late August, K.T. experienced fatigue, nau-sea, and headache for a week and thought it was “summerflu.” In early September, she experienced right knee pain;ibuprofen produced some relief. On examination, she wasafebrile and had mild soft tissue swelling of the right knee.Her white blood cell (WBC) count was normal. Serum sam-ples contained antibody titers to B. burgdorferi demon-strated by a sensitive ELISA (enzyme immunoassay) fol-lowed by a Western blot for immunoglobulin M (IgM) andIgG. A Venereal Disease Research Laboratory (VDRL) testfor syphilis and a pregnancy test were negative.

K.T. is started on a 4-week course of oral doxycycline100 mg twice daily. What characteristics of K.T.’s skin rashare consistent with the erythema migrans of Lyme disease?

The erythema migrans of Lyme disease usually developswithin 30 days (median, 7–14 days) of a usually asymptomatic tickbite at the site of inoculation of the spirochete. The rash begins asan erythematous (red) macule or papule typically on the thigh,back, shoulder, calf, groin, popliteal fossa, flank, axilla, buttock,or upper arm.5 In children, erythema migrans is often found onthe head at the hairline, neck, arms, or legs. It expands outwardlyat 2 to 3 cm/day to a diameter of 5 to 70 cm (mean, 16 cm), occa-sionally with some central clearing.5,10 Some cases of erythemamigrans in the United States lack central clearing.3 The rash maybe warm to the touch and is usually painless, but some patientshave mild burning or itching. Up to 50% of patients with ery-thema migrans have multiple secondary lesions that most likelyrepresent blood-borne spread of the spirochete to other skin sites



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rather than multiple tick bites.5 If untreated, erythema migransgenerally fades within several weeks; if treated, it usually resolvesin several days.

Low-grade fever and other nonspecific symptoms, such asmalaise, headache, myalgias, or arthralgias, may accompanyerythema migrans. Some individuals may have no symptoms.Cough, rhinitis, sinusitis, and other respiratory symptoms donot usually occur in Lyme disease.5 Pitfalls in the diagnosis oferythema migrans exist. Lesions are sometimes misdiagnosed.5

K.T.’s skin rash was large (>9 cm), red, and had a red outerborder. It gradually faded over the course of a few weeks.These characteristics are consistent with a diagnosis of erythemamigrans.

Serologic Testing

CASE 79-2, QUESTION 2: What might have been the ratio-nale for the laboratory tests that were undertaken in K.T.,and what would be reasonable interpretations of laboratorytests in patients with Lyme disease?

An antibody titer measured by enzyme-linked immunosor-bent assay (ELISA) is considered positive for IgM when it isgreater than 1:100 and positive for IgG when it is greater than1:130. K.T.’s results (IgM of 1:60 and IgG of 1:400) support a diag-nosis of Lyme disease because the IgM can naturally fall by thistime, yet IgG levels may remain elevated indefinitely. Guidelinescurrently recommend a two-tier approach of ELISA and con-firmatory Western blotting.9 The sensitivity of such testing inLyme arthritis cases is 97% to 100%.9,11 However, routine use ofserology testing for patients with early erythema migrans cannotbe recommended presently.5 Syphilis and other known biologiccauses (periodontal spirochetes) of false-positive serologic testingshould be excluded. Rheumatoid factor or antinuclear antibodytests usually are negative in Lyme disease. These tests help dif-ferentiate rheumatoid arthritis or systemic lupus erythematosusfrom Lyme disease. The WBC count is normal or mildly elevatedin Lyme disease. K.T. had a normal WBC. Pregnancy was ruledout before initiating a tetracycline. Most interesting in K.T. is thepresence of secondary erythema migrans lesions representingdisseminated infection.

The presence of erythema migrans as an early indicator ofLyme disease gives physicians the best opportunity for earlydiagnosis and treatment. In the United States, the expression oferythema migrans is the only manifestation of Lyme disease thatis sufficiently distinctive to allow clinical diagnosis in the absenceof confirmatory laboratory information.3 Early treatment canprevent sequelae of disseminated disease.

LYME DISEASE TREATMENT

Antibiotics

CASE 79-2, QUESTION 3: Why was doxycycline(Vibramycin) chosen to treat K.T.?

Borrelia burgdorferi is susceptible to amoxicillin, tetracyclines,and some second- and third-generation cephalosporins. It isonly moderately sensitive to penicillin G (Pfizerpen) and isresistant to first-generation cephalosporins, rifampin (Rimac-tane), cotrimoxazole (Bactrim), aminoglycosides, chlorampheni-col (Chloromycetin), and the fluoroquinolones.3,5

Penicillin, tetracycline, and erythromycin historically were thedrugs of choice for the treatment of Lyme disease because they

can be administered orally; they are relatively inexpensive andappear to have good in vitro activity. However, this in vitro activ-ity does not translate to in vivo efficacy. With the exception ofpenicillin, none of the above agents have been found to be effec-tive. In Europe, in particular, penicillin still is used with contin-ued success. A nondoxycycline regimen is preferred in pregnantor breast-feeding women and in children younger than 8 yearsof age.5

Compared with the third-generation cephalosporins, the oralsecond-generation drug cefuroxime axetil (Ceftin) has goodin vitro activity and efficacy. However, it is more expensivethan oral amoxicillin or doxycycline. Of the third-generationcephalosporins, ceftriaxone (Rocephin) has the most potent invitro activity and a long half-life for once-daily dosing in anoutpatient program. Ceftriaxone is expensive, however, and hasa higher incidence of diarrhea than other β-lactams, probablyowing to extensive biliary excretion.

The macrolides clarithromycin (Biaxin) and azithromycin(Zithromax) are unpredictable in their in vitro activity.3 Similarto erythromycin, they are less effective in the treatment of Lymedisease. The combination of a macrolide with lysosomotropicagents, especially hydroxychloroquine, anecdotally has been sug-gested to be associated with increased symptom relief probablyrelated to combined anti-inflammatory activity rather than directantimicrobial activity.3 Doxycycline is well absorbed orally and isless expensive than parenteral ceftriaxone or cefotaxime. Doxy-cycline has a long serum half-life of 18 to 22 hours. In addition,doxycycline penetrates into the cerebrospinal fluid (CSF) at con-centrations of at least 10% of serum levels, even in the absenceof meningeal inflammation. Although not as significant as withtetracycline, doxycycline can complex with divalent or trivalentcations in the gut, with an associated decrease in oral absorp-tion. On the other hand, administering doxycycline with food,to minimize nausea, is recommended.3 Compared with othertetracyclines, doxycycline has the least affinity for divalent cal-cium cations, and oral absorption is reduced by only 20% if givenwith milk. The major side effect of doxycycline is phototoxicity,which is of concern because Lyme disease usually occurs duringsunny times of the year. A less recognized side effect is the risk ofdoxycycline-induced esophageal ulceration. Patients should beinstructed to never take doxycycline or other tetracyclines nearbedtime and to take the medication while standing up with atleast 240 mL of clear fluid, especially with the capsule formula-tion. Despite less in vitro activity compared with some β-lactamantibiotics, B. burgdorferi is sufficiently susceptible to doxycycline,and clinical experience with doxycycline has been very favorable.In conclusion, doxycycline was a suitable choice for K.T.

Chronic Lyme Arthritis

CASE 79-2, QUESTION 4: K.T. continues to have kneeinflammation for 4 months after receiving a second courseof antibiotic treatment (ceftriaxone 2 g daily for 2 weeks)and is now considered to have chronic Lyme arthritis. Whyshould antibiotic therapy be repeated (or not repeated) forK.T.’s arthritis?

Acute Lyme arthritis occurs from the accumulation ofneutrophils, cytokines, immune complexes, complement, andmononuclear cells induced by the spirochete.12 Appropriateantimicrobial treatment of acute Lyme arthritis is usuallysuccessful.3 A minority subset of patients may have persistentLyme arthritis.12 It is very unlikely that this is attributable to thecontinued presence of B. burgdorferi in the joint, but rather to thepatient’s continued inflammatory response or autoimmunity.12



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Polymerase chain reaction (PCR) testing of synovial fluid canbe considered, and if negative, symptomatic therapies maybe offered rather than repeated antibiotic courses. Such patientsoften respond well to synovectomy, suggesting that the presenceof synovitis may not be the result of persistence of the infec-tion. Nonsteroidal anti-inflammatory agents, disease-modifyingantirheumatic agents, intra-articular corticosteroid injections, orsynovectomy may be offered.3,12 However, it should be notedthat before the antibiotic treatment era for Lyme disease, eventhe most prolonged cases of persistent Lyme arthritis eventu-ally improved without treatment, although sometimes lastingfor months to years.12

NeuroborreliosisCASE 79-3

QUESTION 1: E.C., a 54-year-old man, presents with symp-toms of late Lyme encephalopathy, including mild memoryand cognitive deficits. Serum two-tier IgG seropositivity wasconfirmed. Should E.C. be treated with antibiotics? If so, forhow long should he be treated?

Although very rare, late neurologic complications of Lymedisease may present as encephalopathy, peripheral neuropathy,or encephalomyelitis.3 Lyme encephalomyelitis is more commonin Europe than in the United States.3 Although the acute neu-rologic manifestations of Lyme disease can remit spontaneously,late neuroborreliosis is antibiotic responsive.13 An oral antibiotictreatment regimen may suffice in many cases, but parenteral reg-imens for 2 to 4 weeks are appropriate for severe cases.13 A par-enteral treatment regimen beyond 4 weeks provides minimal,if any, benefit.13,14 Other candidates for intensive intravenous(IV) regimens of antibiotic therapy include patients with third-degree atrioventricular (AV) block or acute Lyme meningitis orradiculopathy.3 In conclusion, E.C. could be treated with a par-enteral third-generation cephalosporin such as ceftriaxone 2 g IVdaily for 2 to 4 weeks.

Post-Lyme Disease SyndromesCASE 79-4

QUESTION 1: A friend from an area not endemic for Lymedisease calls you to say that she has been recently diag-nosed with “chronic Lyme disease.” She was never found tohave early or late Lyme disease. She’d like more informationabout it. How should you respond?

Chronic Lyme disease is a confusing term.15 Most authori-ties agree that there may be “post-Lyme disease syndrome,” butits definition is evolving and not yet well accepted.3 Objectiveevidence of a prior B. burgdorferi infection must be establishedbefore invoking the possibility of chronic Lyme disease. Criteriafor diagnosing a post-Lyme disease syndrome include fatigue,widespread musculoskeletal pain, cognitive difficulties, or sub-jective symptoms of such severity that a substantial reductionin quality of life has occurred. The subjective symptoms mustinclude an onset within 6 months of the initial Lyme diseasediagnosis and persistence for at least 6 months after comple-tion of antimicrobial therapy. If adherence to a recommendedLyme treatment regimen is confirmed, the existence of symp-tomatic, chronic infection by B. burgdorferi is difficult to confirm.After appropriately targeted antibiotic therapy for early Lymedisease, treatment failure is exceedingly rare.5,16 The organ-ism has not been shown to develop antibiotic resistance.3 Forthese patients with chronic subjective symptoms for more than

6 months, repeated or prolonged antibiotic therapy is not usefulor recommended.3,15

What is apparent is that the term “chronic Lyme disease”has been used for patients with vague, undiagnosed complaintswho have never had the disease. In fact, most patients regardedas having chronic Lyme disease, when rigorously evaluated atuniversity-based medical centers, have had no evidence of currentor prior B. burgdorferi infection.3

The friend should be encouraged to seek additional diagnosticworkup for other diseases. Even in patients who have had verifiedLyme disease, the aches and pains of daily living they experienceappear to be more related to their posttreatment symptoms thanto Lyme disease itself.3

For an audio podcast on the legal challengesto Infectious Diseases Society of Americalyme disease guidelines, go tohttp://thepoint.lww.com/AT10e.

Lyme Disease PreventionCASE 79-5

QUESTION 1: A family living in a Lyme disease endemicarea is concerned regarding their risk for contracting thedisease. How would you advise them?

Most vector-borne diseases optimally are prevented throughvector control. This has proved difficult for tick-borne diseasesbecause of a lack of efficacy or environmental concerns with theuse of pesticides. Evaluated methods include habitat destructionby fire, chemical spraying agents such as acaricides to achievetick eradication, culling or removal of host deer, or protection ofmice from tick infestation.5,17

The first step in prevention of Lyme disease is personal pro-tection and tick avoidance.17 Tick repellents may be appliedto the skin or clothing. N,N-diethyl-m-toluamide (DEET) skinrepellents (Repel Sportsmen) combined with a permethrin (Per-manone) clothing repellent offer the best overall protection.3

DEET has been tested against Ixodid ticks for repellence andis more effective than dibutyl phthalate, dimethyl phthalate,pyrethrum, and two combination products. Citronella-basedproducts, eucalyptus oil, and garlic are inferior to DEET forpreventing tick bites.

DEET is generally safe17; however, excessive DEET applica-tion has been associated with seizures in children.3,17 These arerare events, however, and if the products are used according totheir labeling, the adverse reaction risk is low, even for childrenolder than 2 months of age.3 Prolonged or excessive applicationis not recommended. It may be prudent to use the lowest effec-tive concentration of DEET-containing repellents, such as thosecontaining 20% to 30%. To minimize DEET toxicity, the productshould be applied sparingly, inhalation or introduction into theeyes should be avoided, repellent-treated skin should be washedwhen coming inside, use on children’s hands (that are likely tohave contact with the eyes or mouth) should be avoided, and itshould be applied only to intact skin or clothing.

An insect repellent alternative to DEET is picaridin (CutterAdvanced), also known as icaridin.18 An advantage of picaridinis that it is safe to use on plastics whereas DEET may damagecertain synthetics including eyeglass frames.17 Although picaridinis equally efficacious compared with DEET in tick bite preventionduring the first hour after application, it is inferior to DEET forthis purpose after 2 or more hours.17



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Physical barriers to ticks, such as wearing protectivegarments—long pants, and long-sleeved shirts—tucking shirtsinto pants and pants into boots, and wearing closed-toed shoes,prevent infection. Ticks are easier to spot on light-coloredclothing.17 Checking the body for ticks regularly is recom-mended; any that are found should be promptly removed. Avoid-ing tick habitats is the best protection against tick-borne diseases.Effective postexposure antibiotic prophylaxis can be adminis-tered in Lyme disease endemic areas after a tick bite.5,17

Human vaccine for Lyme disease has been withdrawn fromthe market. Citing low demand, the U.S. manufacturer discontin-ued production in 2002. However, creative vaccines such as anti-tick or antitick salivary protein vaccines are being investigated.17

ENDEMIC RELAPSING FEVER (TBRF)

Relapsing fever exists in two forms: epidemic and endemic. Thebacterial spirochete Borrelia recurrentis, the agent responsible forepidemic relapsing fever, is transmitted between humans bythe human body louse.19 Epidemic relapsing fever prevailed incrowded conditions in various countries. The last US outbreakwas in 1871.19 Mortality rates of up to 40% have been reportedin some epidemics. Endemic relapsing fever, which is caused bya variety of Borrelia species, occurs worldwide and is spread byticks.19

Spirochete IdentificationIn Europe, the identified responsible spirochete is Borrelia his-panica. In Africa, they are Borrelia duttonii and Borrelia crocidurae;in North America, the species are Borrelia hermsii, Borrelia turi-catae, and Borrelia parkeri.19 Other Borrelia species may produceLymelike diseases or relapsing fevers worldwide. The terms tick-borne relapsing fever (TBRF) and endemic or sporadic relapsing feverare considered interchangeable. In contrast to epidemic relapsingfever, death from TBRF is rare, and most patients recover. How-ever, mortality from TBRF has occurred during pregnancy.19

As the name implies, this disease is characterized by intermit-tent bouts of recurring fever and other nonspecific symptoms.19

The Borrelia have the genetic ability to alter their outer sur-face proteins. This capacity allows the spirochete to elude hostdefenses and is the presumed explanation for the recurrent natureof relapsing fever.19

Tick VectorTICK IDENTIFICATIONThe predominant tick vector for relapsing fever is of the genusOrnithodoros, a soft-bodied tick. These ticks feed on wild rodentsor domestic animals and, incidentally, on humans. In NorthAmerica, three tick species carry the agents of endemic relapsingfever with apparent strict specificity. In fact, the names of theresponsible Borrelia species have been adopted from the threetick species that transmit them: Ornithodoros hermsii, Ornithodorosparkeri, and Ornithodoros turicata.19 Although the ticks themselvesmay serve as reservoir hosts, the Borrelia usually circulate amongwild rodents, ticks, and possibly birds.20 Similar to Lyme disease,greater worldwide variations of endemic cycles and vectors forTBRF may exist than in North America.

TICK GEOGRAPHYIn North America, relapsing fever is an uncommon disease largelyconfined to the geographic distribution of the tick species thatharbor the Borrelia. These ticks are usually found in the remotenatural settings of the mountains and semiarid plains of the far

west and Mexico. In the United States, most cases of relapsingfever are caused by B. hermsii. TBRF can develop when peoplevisit tick- or rodent-infested cabins or summer homes. O. hermsiiand O. parkeri inhabit forested mountain areas, usually at highaltitudes. The health significance of O. parkeri and its spirocheteis uncertain because only one human case has been reported.19

O. turicata transmits its Borrelia in the semiarid plains, fromKansas to central Mexico, creating outbreaks in people visitingcaves, especially limestone ones in central Texas.19

SPIROCHETAL BEHAVIORTicks acquire spirochetes from blood feeding on small wildrodents. If high levels of Borrelia are present in the animal’s blood,large numbers of spirochetes will be ingested by the tick andreside in the tick’s midgut. During the next few days, the spiro-chetes invade the midgut wall, traverse the hemolymph system,and within a few weeks infect the salivary glands as well as othertick tissues and organs. Females may develop infected ovariesand transmit Borrelia to offspring in some Ornithodoros species,but this is rare in O. hermsii.19 Having reached the tick’s sali-vary glands, the spirochetes are poised to invade the tick’s nexthost.

TICK BEHAVIORIn contrast to the hard-bodied ticks, these ticks feed rapidly, oftendetaching after 30 to 90 minutes.19,20 They feed at night whilepeople are sleeping, and their bite is usually painless. Therefore,most people are unaware that they have been bitten.19

Disease CharacterizationThe hallmark of endemic relapsing fever is an abrupt onset ofhigh fever (often >39◦C) after an incubation period of 4 to18 days.19 The patient may experience shaking chills, severeheadache, abdominal pain, myalgias, arthralgias, nausea, vom-iting, and malaise. A few cases of acute respiratory distress syn-drome have recently been recognized.19 The fever usually breaksin 3 days (range, 12 hours to 17 days) in untreated patients.19

After a variable afebrile period of 3 to 36 days (usually 7 days),cyclical periods of fever and constitutional symptoms reappear.Each febrile attack progressively diminishes in severity. Three tofive relapses typically occur in untreated patients.

Routine laboratory testing is of little value. Moderate anemiaand an increased erythrocyte sedimentation rate (ESR) are com-mon. Leukocyte counts may be normal, yet moderate to severethrombocytopenia is commonly observed but is considered non-specific. The diagnosis of relapsing fever is made by direct obser-vation of the spirochete on a peripheral blood smear while thepatient is febrile.19 Observation of the smear is enhanced withWright’s or Giemsa staining. Few diagnostic laboratories performantibody serology tests; however, these tests lack specificity.19

Skin biopsy of a rash to identify the spirochete is unreliable.Direct culture of the spirochete from the blood into a specialculture medium is the most specific diagnostic tool, but this is aslow technique confined to research laboratories.

TREATMENTDoxycycline postexposure prophylaxis against a specific species,Borrelia persica, of TBRF has been shown to be successful in anIsraeli study.21 Whether this approach can be translated to othersettings for other Borrelia species is unknown.

These borrelia have not demonstrated antibiotic resistance.Successful treatment regimens usually include a 7- to 10-daycourse of antibiotics.19 Tetracyclines are preferred, and doxycy-cline, 100 mg orally two times a day, is usually used. Erythromycin



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is also effective at a dose of 500 mg orally four times a day. Hos-pitalization and administration of IV antibiotics may be requiredin severely ill patients.

CASE 79-6

QUESTION 1: O.T. is a 52-year-old man who visits his fam-ily practitioner with a sudden onset of high fever, severeheadache, malaise, nausea, vomiting, and myalgias. Hereturned a week ago, at the end of July, from a stay ina rustic cabin on the north rim of the Grand Canyon. Theclinician orders a manual complete blood count (CBC) andchemistry panel and asks the laboratory to observe a bloodsmear with Giemsa stain. What clues suggest a diagnosis ofendemic relapsing fever?

The disease occurs more often in men, and the nonspecificconstitutional symptoms exhibited by O.T. are consistent withthis disease. The history is more revealing: the patient visiteda location and setting where prior outbreaks of relapsing feverhave been documented.19 In addition, cases of endemic relapsingfever peak in the summer months when ticks are warmer andmore active.

CASE 79-6, QUESTION 2: After confirming the presence ofBorrelia in the blood smear, the physician prescribes a 10-day course of tetracycline. Two hours after the first dose,O.T.’s wife calls the physician’s office with concerns that thedisease is worsening. O.T. experiences an increased temper-ature, faintness, and chills, and has a rapid pulse and respi-ration rate. What do these symptoms represent? Is this anadverse drug reaction?

Up to 54% of patients with relapsing fever experience a reac-tion, a Jarisch-Herxheimer reaction, to the first dose of antibiotic(see Chapter 69, Sexually Transmitted Diseases).19 It may occurin louse-borne relapsing fever, TBRF, and in other spirochetaldiseases, such as syphilis or Lyme disease.3 The dramatic reac-tion consists of a rise in temperature, chills, myalgias, tachycar-dia, hypotension, increased respiratory rate, and vasodilation.19

Treatment of the reaction consists of supportive care. Severe reac-tions may require hospitalization for vital signs monitoring andmanagement of hypovolemia. Although this is a reaction to theadministration of an antibiotic drug, it is not an allergic response,and the antibiotic should be continued.

SOUTHERN TICK-ASSOCIATED RASH ILLNESS (STARI)OR MASTERS DISEASE

CASE 79-7

QUESTION 1: M.G., a 46-year-old man living in southernMissouri, recently experienced a rash resembling erythemamigrans after a lone star tick bite. Because this tick is not avector for Lyme disease, what could be the cause?

Amblyomma americanum (the lone star tick) is found through-out the southeast and south-central United States and alongthe Atlantic coast as far north as Maine, and its territory isexpanding.22 Therefore one may question the appropriatenessof terming this illness STARI.22 The lone star tick aggressivelybites humans in the southern states, as opposed to I. scapularisticks.5,22 Spirochetes detected by microscopy and culture havebeen found in 1% to 5% of lone star ticks and are named Borrelialonestari.2,5,22 B. lonestari and B. burgdorferi, however, were ruledout as the cause of erythema migrans–like skin lesions knownas STARI in one Missouri investigation.5,22 Attempts to culture

the agent of this Lymelike illness, although exhaustive, have beenunsuccessful.22 It appears that B. lonestari is not the likely cause ofSTARI. There are differences in the appearance and content of therashes of STARI and the erythema migrans of Lyme disease. Forexample Lyme erythema migrans rashes show an abundance ofplasma cells contrasted with a predominantly lymphocytic infil-trate seen in STARI.22 Limited data support treating STARI withregimens similar to those used for Lyme disease.22 For example,doxycycline may be given for 10 to 30 days, with longer dura-tions reserved for evidence of dissemination beyond the rash,such as fever, severe headache, lymphadenopathy, or multiplerashes.22

OTHER BACTERIAL DISEASES:TULAREMIA

TularemiaETIOLOGY AND EPIDEMIOLOGYIn 1911, George W. McCoy and Charles W. Chapin from the USPublic Health Service investigated a plaguelike disease in wildground squirrels harvested in Tulare County, California, and dis-covered the infectious etiology of tularemia.23 The bacteriumis a small, pleomorphic, catalase-positive, nonmotile, aerobic,nonencapsulated, gram-negative coccobacillus now named Fran-cisella tularensis in honor of Edward Francis for his fieldwork andcontributions to tularemia research. He proposed the terminol-ogy tularemia because the disease is associated with bacteremia.23

Five tularemia subspecies (tularensis, holarctica, mediasiatica, novi-cida, and philomiragia) are recognized.23 Type A tularemia, themost virulent form to humans, is caused by F. tularensis, whichwas formerly thought to exist only in North America yet has beenidentified in a single report from Slovakia in 1998.23 It is fatal in upto 2% of cases.23 The important reservoir hosts for F. tularensis arewild rabbits, ticks, and tabanid flies.23 Type B tularemia from F.holarctica exists throughout the Northern Hemisphere, and reser-voir hosts include hares, semiaquatic rodents, ticks, mosquitoes,and tabanid flies.23 Type B tularemia is associated with aquaticenvironments such as streams, rivers, ponds, and flooded areas,where the live organism is shed into the aquatic environmentby the reservoir hosts.23 F. holarctica infection is milder and haslower mortality rates.23 Before 1950, most human cases of thedisease developed from direct contact with infected animals, usu-ally hares or rabbits, and tularemia cases that occurred in the fallor winter were usually associated with hunting season exposure.Tick bite transmission, however, now accounts for more thanhalf of tularemia cases west of the Mississippi River in the UnitedStates. In summer months, tick or fly bites appear to be the mainmode of transmission of tularemia to humans. Other modes oftransmission include ingestion of, or contact with, infected meat,water, or soil; inhalation of aerosolized bacteria; or bites frominfected animals, mosquitoes, or deerflies.23,24 Direct person-to-person spread of the disease is rare.

Although tularemia is found worldwide, it occurs primar-ily in the Northern Hemisphere.23 In the United States, casesin Arkansas, Missouri, Oklahoma, Kansas, and South Dakotaaccount for 56% of the total.23 The North American tick vec-tors are Dermacentor variabilis (dog tick), Amblyomma americanum(lone star tick), and Dermacentorandersoni (wood tick). Tick-bornetularemia occurs most often in the spring and summer, match-ing the likelihood of exposure. Reported cases of tularemia inthe United States have steadily declined since 1950 from a casereport high of 2,291 in 1939 to current levels of fewer than 200per year since 1967.



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CLINICAL PRESENTATIONThe clinical manifestations of tularemia are related to the modeof transmission, patient characteristics, and bacterial subspeciescausing infection.23 Classically, six types of tularemia presenta-tion have been identified: ulceroglandular, glandular, typhoidal,oculoglandular, oropharyngeal, and pneumonic. The last threeforms were presumably not tick-borne, reflecting alternativeavenues of transmission. Today the clinical manifestations fallinto two main groups: ulceroglandular and typhoidal.23

Ulceroglandular is the most common form of tularemia,accounting for approximately 75% of cases.23 Sixty percent ofulceroglandular cases are characterized by an ulcer that formsat the site of entry, usually on the lower extremities, perineum,buttocks, or trunk from arthropods that tend to bite the lowerextremities or on the upper extremities from mammalian bites.23

The lesion starts as a firm, erythematous papule that ulceratesand heals over the course of several weeks. It is accompanied byregional, painful lymphadenopathy, usually inguinal or femoral.Typhoidal tularemia, occurring in approximately 25% of cases, ischaracterized by fever, chills, headache, debilitation, abdominalpain, and prostration. Fever and chills are common with all formsof tularemia.23

After exposure to the bacteria and an incubation period of4 to 5 days, patients become ill with a sudden onset of fever, chills,headache, cough, arthralgias, myalgias, fatigue, and malaise. Theseverity of symptoms is quite variable, ranging from a mild,limited disease (probably type B tularemia) to rare cases of septicshock (probably type A tularemia). A hallmark manifestationis a high fever without an accompanying increase in pulse, orpulse–temperature disparity.23 Common complications are mildhepatitis, secondary pneumonia, and pharyngitis. With antibiotictreatment of uncomplicated tularemia, mortality rates are only1% to 3%. Increased morbidity and mortality are seen in themore rare typhoidal forms.23 The most lethal form of tularemia isfrom pulmonary infection.23 In the health care setting, standardprecautions are all that is required when caring for tularemia-infected patients because they are not a source for secondaryinfection. However, any suspected outbreaks should be reportedand investigated.23

DIAGNOSISLaboratory diagnosis of tularemia is limited to the demonstra-tion of an antibody response to the bacteria. Routine laboratorytesting is of little help in establishing the diagnosis. Because anantibody response to the illness requires 10 to 14 days for detec-tion, treatment is usually empiric. The diagnosis is based on clin-ical suspicion from the epidemiologic history and the presenceof compatible findings. The customary serologic test demon-strates F. tularensis antibody agglutination. Although a single tubeagglutination test with a titer of 1:160 or more (or 1:128 or moreusing a microagglutination study) in a suspected case is highlysuggestive of a tularemia diagnosis, a fourfold or greater rise intiters between the acute and convalescent stages 2 weeks apartis diagnostic.23 After a bout of tularemia, detectable antibodiesmay persist for many years.23

TREATMENTIn adults, streptomycin 7.5 to 10 mg/kg intramuscularly (IM) orIV 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 for7 to 14 days.

Streptomycin was historically the drug of choice for tularemia,but it is often unavailable commercially. Some clinicians believethat gentamicin is the best alternative aminoglycoside for thetreatment of nonmeningitic tularemia. Its advantages comparedwith streptomycin include lower minimal inhibitory concentra-

tions (MIC), less vestibular toxicity, and wider commercial avail-ability. Although considered comparable in efficacy to strepto-mycin, gentamicin has been associated with increased treatmentfailure and relapse. Tobramycin (Nebcin) is inferior to gentamicinor streptomycin and should not be used.

Initial cure rates and response to tetracycline are equivalent tothose for gentamicin, but therapy with tetracycline has resultedin a significantly greater risk of relapse. Although unproven,these results suggest bactericidal agents are required for suc-cessful tularemia treatment. Despite this concern, doxycycline isincluded as an alternative tularemia biodefense agent.23

Reported cure rates for chloramphenicol therapy of tularemiaare significantly lower than those for streptomycin. Similar totetracycline, chloramphenicol is bacteriostatic.23 Chlorampheni-col does penetrate into the CSF, with or without inflamedmeninges, better than aminoglycosides or tetracyclines. There-fore, when tularemic meningitis is suspected, chloramphenicolplus streptomycin should be considered. Cephalosporins, such asceftriaxone (Rocephin) and ceftazidime (Fortaz), demonstrate invitro efficacy against F. tularensis, but unacceptable treatment fail-ure has been observed with ceftriaxone. In general,β-lactams andmacrolides cannot be recommended for tularemia treatment.Of the fluoroquinolones studied, ciprofloxacin (Cipro) has theoptimal minimal bactericidal concentration (MBC) in in vitrodata. Promising results with ciprofloxacin treatment have beendocumented. Because pneumonia is a common complication oftularemia, concern exists about the potential for overwhelmingstreptococcal meningitis or sepsis during ciprofloxacin therapy.

The inconsistency between in vitro susceptibility and clinicalsuccess for tularemia is not well explained; however, it may berelated to the fact that F. tularensis is predominantly an intracellu-lar organism. However, aminoglycosides, tetracyclines, rifampin,and fluoroquinolones demonstrate the most potent in vitro activ-ity, and these drugs are the most useful agents in the treatmentof tularemia.

In many of the reported studies of antimicrobial therapy fortularemia, short courses of treatment were used. To preventtularemia from worsening or relapsing, longer regimens (10–14days) should be used, especially in more severe cases. Jarisch-Herxheimer reactions can occur with antibiotic treatment oftularemia. Antibiotic prophylaxis for people exposed to thosewith tularemia is not recommended, but prophylactic antibioticsmight be used for suspected bioterrorism attacks of tularemia.Acute febrile illness with pneumonia and other signs of infectionoccur 3 to 5 days after exposure to airborne tularemia organ-isms from an intentionally set weapon. No tularemia vaccinesare available in the United States. A partially protective one wasdeveloped in the former Soviet Union but was only used for at-risk personnel such as for certain laboratory workers.23 Personalprotective measures, as discussed for Lyme disease, should beused when spending time outdoors in endemic areas.23

THE RICKETTSIA: ROCKY MOUNTAINSPOTTED FEVER, RICKETTSIAPARKERI INFECTION, EHRLICHIOSIS,AND ANAPLASMOSIS

Rocky Mountain Spotted Fever (RMSF)Rocky Mountain spotted fever is the most prevalent and virulentrickettsial disease in the United States. As early as 1872, RMSFinfected white settlers of the Northwest and it may have beenprevalent in Native Americans of the region before that time. Itwas first described in residents of the Bitterroot, Snake, and Boise



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river valleys of Montana and Idaho in the late 1800s. HowardRicketts discovered the causative agent, Rickettsia rickettsii, in1908.25 The rickettsia is a small (0.3 × 1 μm), pleomorphic,weakly gram-negative, obligate intracellular coccobacillus thatcan survive only briefly outside of a host.25

EPIDEMIOLOGYRMSF is found throughout North America including the UnitedStates, Canada, and Mexico, and in parts of Central and SouthAmerica.25 It has not been documented outside of the WesternHemisphere. The term “Rocky Mountain spotted fever” is actu-ally a misnomer because the disease has shifted eastward fromthe Rocky Mountain states, and the greatest incidence of RMSFnow occurs in North and South Carolina, Virginia, Oklahoma,Arkansas, and Tennessee.25,26 Most RMSF infections arise fromtick exposure in rural or suburban locations, although rare out-breaks in urban environments have occurred.

The prevalence of RMSF is highest in children 5 to 9 years ofage.27 Another peak prevalence is seen in men older than 60 yearsof age. Risk factors include male sex, residence in wooded areas,and exposure to tick-infected dogs. RMSF, like other tick-bornediseases, is highly seasonal, with greatest incidence in late springand early summer.25

TICK VECTORS AND HOSTSIn the east, south, and west coasts of the United States, the tickvector for RMSF has been identified as the dog tick, Dermacentorvariabilis.2 In the Rocky Mountain states, the wood tick, D. ander-soni, is the vector.25 In Mexico, the tick vectors are Rhipicephalussanguineus and Amblyomma cajennense, with the latter also beingresponsible in Central and South America.25 The brown dog tick,R. sanguineus, has been identified as a new tick vector for RMSFin a defined area of Arizona.25,26,28

Dermacentor ticks feed on humans only during their adultstage.25 Larval Dermacentor ticks may be infected while feedingon small mammals that have sufficient rickettsemia for transmis-sion, such as chipmunks, ground squirrels, cotton rats, snowshoehares, and meadow voles. Dogs are not considered reservoirsfor R. rickettsii but are susceptible to RMSF and may introduceinfected ticks into households.25,26 Adult ticks transmit the rick-ettsia transovarially to their progeny with high efficiency andestablish newly infected tick lines. If the rickettsia burden is largein the adult tick, however, it may cause tick death, thereby reduc-ing infected tick lines. Therefore, there must be nontick reser-voirs, as mentioned previously, to develop newly infected tickgenerational lines; otherwise, RMSF would slowly disappear.In summary, ticks are both vectors and hosts for R. rickettsii.25

Humans are dead-end accidental hosts of R. rickettsii.25

DISEASE COURSE, SYMPTOMS, AND FATALITIESRickettsia rickettsii is usually transmitted to humans from aninfected tick bite.25 The organism can also gain access to humansthrough broken skin if an infected tick is being crushed withbare fingers, and such crushing may generate infectious aerosolsthat might be inhaled. Conjunctival contact with infected ticktissues or feces provides another route for rickettsial entry. Con-taminated blood transfusions and needle stick injuries have alsotransmitted R. rickettsii.25

After introduction of the organisms into the body, the rick-ettsia spread hematogenously with a predilection for the vascularendothelium, especially in capillaries and medium-sized bloodvessels.25 During an incubation period of 2 to 14 days, inducedphagocytosis allows rickettsial entry into endothelial cells, wherethey replicate by binary fission in the cytoplasm and nuclei ofinfected cells. This induces a generalized vasculitis leading toactivation of clotting factors, capillary leakage, and microinfarc-

tions in various organs.25 Exotoxins are not secreted by rickettsia;however, they do induce oxidative and peroxidative damage tohost cell membranes, resulting in necrosis.25 In severe infections,hypotension and intravascular coagulation may coexist and cul-minate in cell, tissue, or organ destruction.

Dehydration is an early sign of RMSF, followed byincreased vascular permeability, edema, decreased plasma vol-ume, hypoproteinemia, reduced serum oncotic pressure, andprerenal azotemia. RMSF is a multisystem disease, but a partic-ular organ may be the major focus of the disease. If the brainor lungs are severely infected, death can ensue. An increasedseverity of illness is associated with edema, particularly in chil-dren, and hypoalbuminemia. Hypotension is present in 17% ofpatients and hyponatremia in 56%. Extensive infection of the pul-monary microvascular endothelium can cause noncardiogenicpulmonary edema.

A common finding in RMSF is myalgia (72%–83%) or muscu-lar tenderness, which are manifestations of skeletal muscle necro-sis. Striking creatinine kinase elevations have been described.Thrombocytopenia resulting from consumption of platelets dur-ing intravascular coagulation processes occurs in 35% to 52% ofpatients. True disseminated intravascular coagulation with atten-dant hypofibrinogenemia is exceptional, however, even in severeor fatal cases.25 Blood loss or hemolysis in some may cause ane-mia, which is seen in 30% of patients and reflects blood vesseldamage. Fatalities usually occur 8 to 15 days after illness onsetif no treatment is given or is delayed. Long-term sequelae fromsevere forms of RMSF can include partial paralysis of the lowerextremities, gangrene of extremities requiring amputation, deaf-ness or hearing loss, incontinence, and movement or speech dis-orders, but these occur in a minority of patients who receiveprompt antibiotic therapy.25

“Fulminant” RMSF is best defined as a disease with a rapidlyfatal course with death occurring in approximately 5 days. Thisform of disease is characterized by an early onset of neurologicsigns and late or absent skin rash; it is highly associated withglucose-6-phosphate dehydrogenase deficiency, advanced age,male sex, and possibly heavy alcohol use.25,26 In the preantibioticera, RMSF mortality rates were as high as 30%, but they havefallen to 5% in antibiotic-treated cases today.25,26

The classically defined triad of RMSF symptoms at initial pre-sentation is fever, rash, and headache, but this is found in only upto 5% of cases during the first 3 days of illness and up to approxi-mately 60% of cases 2 weeks after exposure.25,27 The RMSF skinrash typically begins 2 to 4 days after fever onset as pink, 1- to5-mm blanchable macules that later become papules.26 It beginson the ankles, wrists, and forearms and soon thereafter involvesthe palms or soles. It then spreads to the arms, thighs, and trunkand typically evolves into a petechial exanthem. The utility ofthese findings in the differential diagnosis is limited because rashmay be absent, transient, or late; it may never become petechial;or it may have an unusual distribution.

DIAGNOSISAs for most tick-borne diseases, confirmatory serologic analy-sis is not particularly useful in early diagnosis of disease, andantirickettsial treatment should begin immediately to preventmorbidity and mortality.25,26 R. rickettsii is difficult to culture.Immunohistologic demonstration of R. rickettsii in biopsy speci-mens of rash lesions is the only approach that can yield diagnosticresults in a timely manner, but this approach is applicable only tothose presenting with a skin rash, and these tests are not readilyavailable.25

The best serologic test for RMSF is the indirect immunoflu-orescence assay (IFA) test, but antibodies typically appear onlyafter 10 to 14 days.25 More striking laboratory abnormalities of



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RMSF disease include a normal leukocyte count with a shiftto the left, hyponatremia, thrombocytopenia, elevated serumtransaminases or creatinine kinase, and CSF pleocytosis. Thesefindings are observed late in the disease course, however, and arenot helpful in early disease recognition.

Clinical findings and history are essential to early diagno-sis and successful treatment. Therapy must precede laboratoryconfirmation of RMSF.25 In a febrile, tick-exposed person witha rash, RMSF should be considered. RMSF should be stronglyconsidered in febrile children, adolescents, or men older than60 years of age, especially if they reside in or have traveled tothe southern Atlantic or south-central United States from Maythrough September. A delay in treatment for RMSF beyond5 days of symptom onset increases the mortality rates from 5%to 22%.

TREATMENTR. rickettsii is very susceptible to chloramphenicol, tetracycline,and doxycycline. The recommended treatment is doxycycline 100mg orally or IV two times a day for at least 5 to 7 days, including atleast 3 days after the temperature has normalized.25 Contraindi-cations to doxycycline use include history of severe hypersensitiv-ity reactions to tetracyclines, and it is relatively contraindicatedin pregnancy.25 Chloramphenicol is reserved for use in the firstor second trimesters of pregnancy. However, owing to the riskof gray baby syndrome from chloramphenicol if used during at-term or near-term pregnancy, doxycycline can be substituted.25

The erythromycins, penicillins, sulfonamides, aminoglycosides,and cephalosporins are not effective for RMSF. Although fluo-roquinolones have shown in vitro activity in other spotted feverrickettsial diseases, their use in human RMSF disease cannot berecommended at this time.

A crucial component in the management of RMSF is appro-priate supportive care.25 Those with severe disease should behospitalized and managed with hemodynamic, renal, pul-monary, and fluid support as needed.25

In 1994, the American Academy of Pediatrics (AAP) Commit-tee on Infectious Diseases revised the RMSF treatment optionsfor young children after weighing chloramphenicol’s potentialtoxicity and the dental staining concerns for tetracyclines. TheAAP now acknowledges tetracyclines as acceptable RMSF treat-ment in children of any age. Doxycycline is the tetracycline agentof choice in pediatric RMSF because it is dosed less frequentlythan other tetracyclines, improving compliance, and does notbind calcium as strongly as other tetracyclines. The dosage is4.4 mg/kg orally divided into two doses on day 1 followed by2.2 mg/kg/day orally each day for 7 to 10 days or 2 to 3 days afterthe fever abates and clinical improvement occurs.

PREVENTIONIn addition to the same guidelines for prevention of Lyme disease,keeping pets free of ticks can reduce exposure. Ticks must not becrushed in a way that might introduce rickettsia into cutaneouslesions, mucous membranes, or the conjunctiva. No RMSF vac-cine is available.25 Antirickettsial antibiotic prophylaxis after atick bite is not warranted as only a tiny proportion (<1%) ofticks in an endemic area are infected with R. rickettsii.25

Rickettsia Parkeri and Other SpottedFever Group (SFG) RickettsiaIn the past 20 years new pathogenic spotted fever group(SFG) rickettsia have been discovered worldwide causing novelrickettsioses.25,29 Fifteen of the 20 SFG rickettsia found world-wide can be pathogenic to humans.30 In the United States, SFG

rickettsial pathogens other than R. rickettsii have recently beenrecognized, including Rickettsia felis (flea-borne spotted fever),Rickettsia akari (rickettsialpox), Rickettsia parkeri, and a new one inCalifornia called Rickettsia 364D.30 At least three cases of R. park-eri human infection transmitted by tick bite have been reported.31

R. parkeri infection is associated with fever, malaise, and escharformation (rarely seen in RMSF), especially at the site of the GulfCoast tick, Amblyomma maculatum, bite.31 R. parkeri infection ismilder than RMSF and can be diagnosed by PCR testing of aneschar or papular lesion.31 Doxycycline treatment has resultedin prompt (<1 or 2 days) resolution of symptoms.31 It is likelythat some prior cases of presumed RMSF may actually have beencaused by SFG rickettsia.

Ehrlichiosis and AnaplasmosisSPECIES IDENTIFICATIONThree tick-borne rickettsial human diseases have emerged inrecent years: human monocytic ehrlichiosis (HME), causedalmost exclusively by Ehrlichia chaffeensis, human granulocyticanaplasmosis (HGA), caused by Anaplasma phagocytophilum, andhuman granulocytic Ehrlichia ewingii infection (HEE).3,26,32,33

The agents of HME, HGA, and HEE parasitize white bloodcells.

In 1987, the first reported case of human ehrlichial infection inthe United States was found in a soldier at Fort Chaffee, Arkansas.It was initially misinterpreted as being the same agent that infectsdogs, Ehrlichia canis. Subsequent studies revealed that it wasa unique species, E. chaffeensis. Cases of HME have now beenreported in many states, Europe, and Africa. Retrospective anal-ysis has revealed that 10% to 20% of unconfirmed, presumptivediagnoses of RMSF were actually HME. The number of HMEcases is greater than RMSF in several states today.

Anaplasmosis was first described in 1994. Since HGA’s discov-ery, more cases have been reported than for HME.26 During 2001to 2002, HGA rates were especially high in Rhode Island, Wis-consin, Minnesota, Connecticut, New York, and Maryland.26 Todate the highest incidence of HGA in the United States is reportedin the upper Midwest and northeastern states.32

TICK VECTORS AND DISEASE HOSTSThe primary tick vector of HME is A. americanum, the lonestar tick, and its geographic distribution matches that of mostcases of HME, occurring in the south central and southeasternUnited States. E. chaffeensis also has been recovered in D. variabilis,I. pacificus, and A. cajennense ticks. Cases of HME that havebeen diagnosed in the northeastern United States are prob-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,coyotes, squirrels, rabbits, and goats have shown natural infec-tion with E. chaffeensis.26,33 HME begins with the introduction ofE. chaffeensis into the skin of a host from the bite of an infectedtick. The bacteria spread throughout the body hematoge-nously. They become established within the cells of monocyticmacrophages in the spleen, lymph nodes, liver, bone marrow,lung, and kidney. Characteristic, microscopically visible intra-cellular inclusion bodies called morulae (for their mulberrylikeappearance) develop. Each morula is actually a membrane-boundrickettsial colony that grows and divides within the mono-cyte’s cytoplasm. Necrosis in heavily infected cells occurs, andit is believed that cell rupture and the subsequent release ofrickettsia allows infection of more monocytes, repeating thecycle.

Tick vectors that harbor the agent of HGA include I. scapularisand I. pacificus, which are also Lyme disease transmitters.32 One



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study in an endemic area found an I. scapularis HGA, Lyme coin-fection rate in ticks of 16%.34 In Europe, I. ricinus is the vector.The main reservoir for A. phagocytophilum is the white-footedmouse. Other hosts include white-tailed deer, elk, and otherwild rodents.26,32 In northeastern China domesticated sheep aswell as wild rodents carry A. phagocytophilum, and it has infectedhumans, ticks, and rodents in China, Korea, Japan, and otherAsian countries.35 Humans are incidental dead-end hosts forthis organism, and infection is of short duration and does notpersist.32 Alternative routes for human acquisition of HGA ratherthan by tick bite are documented.32 After binding to neutrophilsand becoming internalized, A. phagocytophilum alters neutrophilfunction.32 However, only systemic inflammatory processes maybe triggered, and macrophage activation with excessive cytokineproduction may cause associated tissue injury if present.32,36

Tick removal from the body is less likely to be effective fordisease prevention than it is in Lyme disease because of the rapidtransmission of A. phagocytophilum during the nymphal tick bite.Tick exposure is defined by geography and season. Simply beingin an area where ticks can be found, particularly during springand summer, constitutes exposure.

CLINICAL AND LABORATORY FINDINGSHuman ehrlichiosis and anaplasmosis usually present as non-specific, febrile, flulike illnesses resembling RMSF. The symp-toms begin 5 to 21 days after tick exposure.3,32 Patients maybe entirely asymptomatic, but there have been occasional fatali-ties reported, particularly in immunocompromised patients withHGA.3,32 HME and HGA share similar clinical features. Both dis-play fever as the major symptom in nearly 100% of cases. Theother common symptoms of malaise, myalgia, and headachesare found in most cases of HGA but somewhat less in HME.3,32

Other less common symptoms found in both diseases includediaphoresis, nausea, vomiting, cough, diarrhea, abdominal pain,arthralgia, pharyngitis, rash, and confusion.32 HEE infectionoccurs almost exclusively in immunocompromised patients, yetno fatalities have been documented.26,37

As with many other tick-borne diseases, serologic find-ings of antibody response to ehrlichiosis or anaplasmosis assist

only by retrospectively confirming the diagnosis. Currently, afourfold change between acute and convalescent indirect IFAserology is the gold standard test for both HGA and HME.Blood detection by PCR or culture is also useful for HGAdiagnosis.32 The following signs often are noted, however: hyper-transaminemia, leukopenia (often with a shift to the left), andthrombocytopenia.32 These findings may increase the suspicionfor HME or HGA infection. However, leukopenia and thrombo-cytopenia usually normalize after 2 weeks in HGA even if foundon initial presentation.32 A peripheral blood smear showing neu-trophilic morulae is diagnostic for probable HGA, but negativeresults do not rule out the diagnosis.32 In HME, peripheral bloodsmears are rarely diagnostic. HME morulae are more likely tobe identified in macrophages with biopsy or postmortem speci-mens of the liver, spleen, or bone marrow anecdotally. A periph-eral blood smear examination for morulae should probably beundertaken because this method is a quick and easy way formaking a provisional diagnosis. Confirmatory testing by serol-ogy or PCR or direct culture is still required to establish thediagnosis.3,26,32

The nonspecific manifestations of HME and HGA are con-sidered indistinguishable. Although considered an uncommonfinding, skin rash is consistent with either disease. In HME, skinrashes are seen in almost 60% of children but in less than 30% ofadults.26 In HGA, skin rashes occur in 10% or less of patients andmay actually reflect coinfection with Lyme disease. Therefore,if a skin rash is present, HME is much more likely than HGA(Table 79-4).

Human monocytic ehrlichiosis and HGA can be differenti-ated by serologic evaluation or PCR. Treatment should never bedelayed pending the results of testing because the mortality rateis 2% to 3% for HME and 0.5% to 1% for HGA.26,32 Delays indiagnosis and treatment are related to a substantial proportionof death from the diseases.

TREATMENT AND PREVENTIONDoxycycline (Vibramycin) 100 mg orally twice daily for 10 to 14days is the drug of choice for both HME and HGA.26 For HGA,doxycycline for only 7 to 10 days is usually sufficient, but a full

T A B L E 7 9 - 4Tick-Borne Disease Findings

a

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, humanmonocytic ehrlichiosis; LD, Lyme disease; LFTs, liver function tests; RF; relapsing fever; RMSF, Rocky Mountain spotted fever; WBCs, white blood cell counts.



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14-day course should be used if Lyme coinfection is present.3,32

In children 8 years of age or younger, doxycycline is given ata 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

For those older than 8 years of age but weighing less than 45kg, the above dosing scheme should be used, and adult dosesof 100 mg every 12 hours are used for children weighing morethan 45 kg.3,32 (See RMSF section for a discussion of the pediatricuse of doxycycline.) If tetracyclines are absolutely contraindi-cated, rifampin 300 mg orally twice daily for 7 to 10 days is analternative in mild HGA disease.3,32 Pediatric rifampin dosingfor HGA is 10 mg/kg (to a maximum 300-mg dose) twice dailyfor 5 to 7 days.3,32 Chloramphenicol (Chloromycetin) is ineffec-tive in vitro and should not be used.3 Fluoroquinolones maynot be curative for HGA and should not be used.3,32 Ineffectiveantibiotics for ehrlichiosis or anaplasmosis include gentamicin(Garamycin), ceftriaxone (Rocephin), cotrimoxazole (Bactrim),erythromycin (E-Mycin), metronidazole (Flagyl), clindamycin(Cleocin), sulfonamides, and penicillin. Asymptomatic, seropos-itive patients with antibodies to A. phagocytophilum should not betreated.3

Prevention of HME or HGA disease is preferable to treat-ment. Tick avoidance and detection strategies, as outlined forLyme disease, are recommended. No evidence supports the rou-tine administration of prophylactic antibiotics for HME or HGAprevention in patients with known tick bites. Vaccines may bedeveloped but are not currently available.32

CASE 79-8

QUESTION 1: G.K., a 78-year-old man living in northwestWisconsin, presents with an influenzalike illness in late May.He has a 2-day history of fever, shaking chills, headache,myalgias, nausea, and anorexia. On examination, his tem-perature is 39.4◦C, but other physical findings are unre-markable. No skin rashes are found. During questioning,he stated he had multiple tick bites 1 week ago while hewas fur trapping. The physician suspects anaplasmosis andprescribes doxycycline 100 mg PO twice daily for 10 days.Blood is drawn for serology, CBC with differential, chem-istry profile, and a Wright’s stain microscopic examination.Immediately available abnormal results include neutrophilicmorulae on microscopy, a WBC count of 2,500/μL, a plateletcount of 80 × 103/μL, C-reactive protein of 136 mg/L (nor-mal, 4–8 mg/L), aspartate aminotransferase (AST) of 150IU/L, and lactate dehydrogenase of 700 IU/L. Serology isstill pending. Two days later, G.K.’s fever abated, and hewas feeling better. How does this case fulfill a diagnosis ofHGA?

G.K.’s history is significant for HGA. He was in the rightplace, the upper Midwestern United States, and was outdoorsduring the right season; most patients are diagnosed with HGA inMay through August.32 The usual incubation period from tickbite to illness onset ranges from 5 to 21 days.9,32

His symptoms are also important. Nearly 100% of patientswith HGA have a fever of greater than 37.6◦C. Other symp-toms in G.K. consistent with HGA are rigors (shaking chills),headache, myalgias, nausea, and anorexia.32 Matching labo-ratory findings include neutrophilic morulae. The observedleukopenia and thrombocytopenia strongly support the diag-nosis. Evidence of mild to moderate hepatic injury, as seen bythe elevated liver enzyme results, is helpful in HGA diagnosis.Finally, the good response to doxycycline, with fever resolution in2 days, is customary.32 Fever persisting for more than 2 daysafter doxycycline treatment suggests that the diagnosis of HGAis incorrect.3,32

THE PROTOZOA: BABESIOSIS

BabesiosisHISTORYInvestigating the deaths of 30,000 to 50,000 head of Romanian cat-tle with febrile hemoglobinuria in 1888, Victor Babes describedan intraerythrocytic organism that was thought to be bacterial,and it was named Haematococcus bovis.38 While investigating ahemolytic cattle fever in Texas in 1893, Smith and Kilborne estab-lished that the causative organism was a protozoan, Babesia bigem-ina, and introduced the concept of an arthropod-borne transmis-sion of the disease.38 The first human case of babesiosis wasdefinitively identified in a 33-year-old Croatian cattle farmer in1957.38 His febrile hemoglobinuria and intraerythrocytic organ-isms were attributed to the bovine pathogen Babesia divergens. Hehad undergone a previous splenectomy and died of renal failure.38

Postmortem inquiry revealed that his cattle were infected with abovine babesial species. Possible tick vectors identified were I. rici-nus and Dermacentor silvarum. To date, rare, often fatal, humancases of babesiosis in Europe have been caused by B. divergensand Babesia microti.3,38 Sporadic cases of babesiosis have beenreported in Asia, South America, and Africa.3,38 European casespresent with a fulminant, febrile illness 1 to 3 weeks after a tickbite. In 84% of these cases, the patients have been asplenic. Comaand death have occurred in greater than 50% of cases. Customaryfindings there are hemoglobinuria, hemolysis, jaundice, chills,sweats, myalgia, pulmonary edema, and renal insufficiency.

The first human babesiosis case in a person with an intactspleen was reported in 1969 in a patient from Nantucket Island,Massachusetts. Since then, “Nantucket fever” has been found tobe caused by the babesial rodent agent B. microti. In contrast tomost European cases and those reported in California, humanbabesiosis in endemic areas of the Great Lakes regions and thenortheastern United States commonly occurs in normosplenicpatients.3 The presenting complaints are usually nonspecific andconsist of malaise, fatigue, low-grade fever or shaking chills,headache, generalized musculoskeletal complaints, emotionallability, nausea, emesis, and weight loss. Fatal cases have beenfound in distinct areas of Wisconsin, Missouri, Rhode Island, andCalifornia. Severe, nonfatal cases have occurred in Minnesota,Washington State, and California. Additional cases have beenreported in New York, Connecticut, Maryland, Virginia, andGeorgia, as well as in Mexico. Members of Babesia are calledpiroplasms because of their pear-shaped appearance of dividingparasites within erythrocytes. These are the only cells infectedby babesia as they are obligate parasites of red blood cells.38 A dif-ferent type of Babesia piroplasm recently emerged in the westernUnited States. It was initially isolated in a resident in WashingtonState and is now called Babesia duncani.3,38 B. divergens–like organ-isms, originally termed MO-1, have caused human infection inMissouri, Washington State, and Kentucky.3,38

BABESIA, TICKS, AND HOSTSThere are more than 100 species of Babesia having a worldwidegeographic range.38 To date, only four species are known humanpathogens: B. divergens, B. microti, B. duncani, and B. divergens–likeorganisms.38 The most common cause of human babesiosis isB. microti.38 The babesia are transmitted by Ixodes, Dermacentor,Haemaphysalis, and Rhipicephalus ticks. B. microti is transmittedin the northeastern United States by I. scapularis, the deer tick ofLyme disease and HGA, and in the United Kingdom by Ixodestrianguliceps. In Europe, bovine babesiosis is transmitted by I.ricinus. In the western United States, I. pacificus is the probablevector. High infection rates of B. microti in field mice (Microtus



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pennsylvanicus) and white-footed mice (Peromyces leucopus) havebeen found on Nantucket Island in Massachusetts during inves-tigations of transmission cycles. Other reservoirs for B. microtiare chipmunks, meadow voles, shrews, and rats. In the south-eastern United States, nymphal stage I. scapularis ticks feed onlizards, which are poor reservoirs for B. microti, possibly explain-ing why babesiosis is rarely reported here. Babesia species alsoare transmitted from the larval to nymphal stage of the tick (thatis, transstadial transmission occurs).

SYMPTOMS AND DIAGNOSIS

CASE 79-9

QUESTION 1: H.W., age 64 years, spent July on Martha’sVineyard. A week later, he felt fatigued and lost hisappetite. He presents to his local physician in the mid-dle of August with complaints of fever, headache, drench-ing sweats, aches and pains, and occasional dark-coloredurine. He does not recall a tick bite. On physical exam-ination, he has splenomegaly and hepatomegaly. Lab-oratory tests show a severe normochromic, normocyticanemia, decreased hemoglobin, hemoglobinuria, throm-bocytopenia, and increased liver enzymes. His tempera-ture is 40◦C. Examination of a Giemsa-stained thin bloodsmear reveals the presence of unpigmented ring-shapedintraerythrocytic parasites in more than 10% of his ery-throcytes. The physician institutes an atovaquone plusazithromycin regimen. What was the clue to the diagnosis ofbabesiosis?

The diagnosis of babesiosis was confirmed by the direct obser-vation of the protozoan inside the red blood cells. Although theGiemsa-stain test is a commonly used tool, it is subject to false-negative results because the rate of parasitemia is typically low.Usually, multiple blood smears need to be examined because lessthan 1% of erythrocytes may be infected early in the course of thedisease when most people seek medical help.3,38 Because bloodsmear inspection is often not successful in diagnosing babesiosisor may only detect a few parasites, additional supportive labora-tory results are advocated, such as serology using IFA for IgM andIgG antibabesial antibodies or PCR detection of babesial DNA inthe blood.3

Most patients with B. microti babesiosis are asymptomatic.This form of babesiosis can be viewed as a distinct, occult,asymptomatic disease with few known sequelae.38 A number oftransfusion-acquired infections have been documented, reflect-ing the existence of an asymptomatic form of babesiosis in blooddonors.

A second form of babesiosis has been termed a “mild-to-moderate viral-like illness.”38 It has a gradual onset of fatigueand malaise and later fever accompanied by one or more ofthese symptoms: chills, sweats, headache, arthralgias or myal-gias, anorexia, or cough.38 Rash is rare. It can last weeks tomonths, sometimes with a prolonged recovery time of up toa year or more.38

A third form of babesiosis is a potentially life-threateninghemolytic one that occurs in people predisposed to severe infec-tion because of advanced age, immune suppression as a resultof HIV disease or immunosuppressants, malignancy, or priorsplenectomy.38 Although babesial infection is as prevalent in chil-dren as it is in adults, it is more severe in adults older than 50 yearsof age. Complications seen in severe babesiosis include acuterespiratory failure, disseminated intravascular coagulation, con-gestive heart failure, coma, and renal failure, with a 5% to 9%mortality rate.3,38

In the northeastern United States, infections commonly occurin patients with spleens, as in H.W. Clinically apparent cases aremost common in 50- to 60-year-old patients, many of whomdo not recall a tick bite. Most symptoms of babesiosis arecaused by hemolysis or the systemic inflammatory responses toparasitemia.38 The usual incubation period is 1 to 6 weeks after atick bite based on limited data.38 Nonspecific, virallike symptomsthat are gradual in onset appear first, as in H.W.’s case, followedseveral days later by the other symptoms H.W. displayed. A hall-mark of the disease is hemolytic anemia of varying severity. Ahigh index of suspicion for babesiosis should be maintained inany patient with an unexplained febrile illness who lives in or hastraveled to a region where the infection is endemic during Junethrough August, as in H.W.’s case, particularly if there is a historyof tick bite.

TREATMENT

CASE 79-9, QUESTION 2: Why were atovaquone andazithromycin chosen to treat H.W.? What other drugs havebeen used?

The discovery of an original human babesiosis treatment reg-imen combining clindamycin (Cleocin) and quinine was a for-tuitous one. An 8-week-old infant with presumed transfusion-acquired malaria was initially treated with chloroquine. Becauseof a lack of response, treatment was switched to quinine plusclindamycin, and the patient’s fever decreased. A correct diag-nosis of babesiosis was subsequently confirmed. Although thistreatment combination is still used, frequent side effects (e.g.,tinnitus, vertigo, and diarrhea) occur, often resulting in dosereduction or discontinuation.3,38 Treatment failures with thisregimen have occurred in splenectomized patients, patientswith HIV infection, or those receiving concurrent corticos-teroids.3

For mild-to-moderate babesiosis, atovaquone plus azi-thromycin is the regimen of choice, as H.W. received. Thisregimen has also achieved cures in pediatric cases, although acontrolled trial study has not been performed.38 On the otherhand, persistent relapsing babesiosis and emergence of resis-tance have occurred in immunocompromised patients receiv-ing this regimen.39,40 It has been suggested that the usual 7- to10-day course treatment regimen may not be adequate inthese patients.40 Combination therapy of azithromycin with ato-vaquone is better tolerated than clindamycin–quinine combina-tions. The dosing is atovaquone 750 mg orally every 12 hoursand azithromycin 500 mg to 1,000 mg orally on day 1 and250 mg to 1,000 mg on subsequent days for 7 to 10 days.38

Increased azithromycin doses of 600 mg to 1,000 mg/day maybe used in immunocompromised patients.3 Children shouldreceive atovaquone 20 mg/kg (maximum, 750 mg dose) every12 hours and azithromycin 10 mg/kg (maximum, 500-mg dose)on day 1 and 5 mg/kg (maximum, 250-mg dose) orally thereafterfor 7 to 10 days.3,38

For severe babesial illness the intravenous clindamycin plusoral quinine should be given.38 Dosing recommendations foradults are clindamycin 300 mg to 600 mg IV every 6 hours plusquinine 650 mg orally every 6 to 8 hours for 7 to 10 days; childrenshould receive clindamycin 7 to 10 mg/kg (maximum, 600-mgdose) IV every 6 to 8 hours plus quinine 8 mg/kg (maximum, 650mg dose) orally every 8 hours for 7 to 10 days.3,38

Antimicrobials should be used in all patients with symp-tomatic, active babesiosis once the diagnosis is confirmed by PCRor blood smear, owing to the risk of disease complications.38

Antibody-seropositive, symptomatic patients without identifi-able parasites on blood smear or PCR positivity should not be



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treated. Similarly, asymptomatic patients should not be treatedregardless of serologic results, blood smear examinations, orPCR findings. A course of treatment should be considered inasymptomatic patients, however, if these tests are positive andrepeat testing demonstrates persistent parasitemia for more than3 months.3,38

Partial or complete red blood cell transfusions may be life-saving in severe babesiosis for patients having high-grade para-sitemia (10% or more infected erythrocytes), significant hemol-ysis, or pulmonary, renal, or hepatic compromise.3 Rapidlyincreasing parasitemia leading to massive intravascular hemoly-sis and renal failure mandates immediate treatment for this formof the disease.

Babesiosis prevention is the same as for other tick-borne dis-eases. Asplenic patients should avoid areas where babesiosis isendemic. To date no supportive data for the use of prophylac-tic antibiotics to prevent babesial infection after a tick bite areavailable.38 Although developed for use in cattle, babesial vac-cines are not available for humans.

THE VIRUSES: COLORADO TICKFEVER AND TICK-BORNEENCEPHALITIS

Colorado Tick FeverDISEASE HISTORY“Mountain fever” has been described since the first immigrantsarrived in the Rocky Mountains. It was later renamed Coloradotick fever (CTF), and the Colorado tick fever virus (CTFV) wasidentified as the cause.

VIRUS IDENTIFICATIONCTF is caused by a double-stranded RNA Coltivirus. It is anintraerythrocytic virus. At least 22 strains of CTFV are known,but antigenic variation among human strains is low.41 The virusis an arbovirus because it replicates inside ticks. The primarynidus of infection is thought to be CTFV invasion of hematopoi-etic progenitor erythroblasts, and it remains sheltered in matureerythrocytes.41,42

TICKS AND HOST RESERVOIRSCTF is a viral illness transmitted by the bite of an infected tick.42

Although at least eight tick species have been found to be infectedwith the virus, adult D. andersoni ticks are the primary tick vec-tor that transmits CTF to humans.41,42 D. andersoni feeds onnumerous mammals, but ground squirrels, porcupines, and chip-munks are the primary reservoirs for CTFV as well as the ticksthemselves.41,42 Transstadial transmission of CTF virus withinthe tick ensures it is infected for life.42

PREVALENCECTF is contracted in forested mountain areas at higher elevationsof the western Black Hills and Rocky Mountain regions of theUnited States and Canada, especially on the south-facing brushslopes and dry rocky surfaces of mountains east of the Conti-nental Divide.41,42 Neutralizing CTFV antibodies are found inup to 15% of perennial campers.43 Although CTF can developfrom March to October, May through July are peak incidencemonths.42,43

SYMPTOMS

CASE 79-10

QUESTION 1: T.M., a previously healthy 28-year-old nativeof Atlanta, Georgia, returns from a 1-week late-spring camp-ing trip in the eastern Colorado Rocky Mountains. Fourdays later, he experiences fever, chills, headache, myalgias,photophobia, retro-orbital pain, conjunctivitis, and lethargy.He recalls no tick bites and has no skin rashes. SuspectingRMSF, his physician prescribes doxycycline. T.M.’s symptomsand fever initially resolve, but 2 days later his symptomsreturn. Physical examination at this time reveals a tempera-ture of 39◦C. Routine laboratory tests are normal, althoughleukopenia is observed with a WBC count of 2,400/μL. Whydo T.M.’s symptoms suggest a diagnosis of CTF?

Symptoms of CTF usually start 3 to 5 days after a tick bite,although more than half of patients do not remember beingbitten.41,42 The most common initial symptoms are fever of rapidonset, headache, chills without true rigors, and myalgias.42 Arash, which may be petechial, maculopapular, or macular, canoccur in 5% to 15% of patients.42 A biphasic (“saddle-back”) ortriphasic pattern of fever and other symptoms lasting 5 to 10 dayshas been observed.41,42 CTFV infection is usually self-limiting,and sequelae are rare, although fatigue and malaise may last formonths.42 One- to three-week periods of convalescence are usual.Children, however, experience complications more frequentlythan adults. The two reported cases of mortality from CTF, sec-ondary to generalized hemorrhage and shock, occurred in chil-dren. No deaths have been reported in adults.42 Severe forms ofCTF may involve central nervous system (CNS) infection (asep-tic meningitis, meningoencephalitis, or encephalitis), which hasbeen reported in 5% to 10% of children, usually within a week ofillness onset.42 Less commonly reported complications includehemorrhagic fever, myocarditis or pericarditis, hepatitis, pneu-monitis, and a rheumatic fever–like illness.41,42 A prolonged con-valescence does not imply persistent viremia, although viremiacan last for 3 to 4 months because of the intraerythrocytic loca-tion of the virus avoiding immune clearance.41

LABORATORY FINDINGSModerate to significant leukopenia is the most important find-ing in CTF. Leukocyte counts are usually normal on the firstday, but decrease to 2,000 to 4,000/μL by the fifth or sixth dayof illness with a lymphocytic predominance.42 In one third ofconfirmed CTF cases, however, the leukocyte counts remainedaround 4,500/μL. Counts return to normal within a week of feverabatement in most cases. Thrombocytopenia may occur.41,42

Although the CSF may show a lymphocytic pleocytosis, this doesnot distinguish CTF from other causes of meningoencephalitis.42

DIAGNOSIS AND TREATMENTCTF diagnosis can be made serologically, either with IFA stainingof erythrocytes, complement fixation, or ELISA.41,42 The mostsensitive isolation system is intracerebral injection of infectedblood into suckling mice.41,42 A reverse transcriptase PCR of spec-imens can be diagnostic within the first 5 days of illness, whereasserological tests are more relevant for diagnosis 2 weeks aftersymptom onset.42 Treatment is limited to supportive care.41,42

Aspirin use as an antipyretic should be avoided as it can exacerbatethe thrombocytopenic hemorrhagic complications of CTF.42 Inanimal models, ribavirin improved CTF survival, but no datasupport its use in humans currently.42 Long-term immunity isgenerally conferred by CTFV infection.41 Experimental CTFvaccines are no longer made.41 The best protection for CTFis tick prevention strategies.42



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TICK-BORNE ENCEPHALITIS (TBE)Tick-borne encephalitis is divided into three subtypes, CentralEuropean (western subtype), Siberian, and Far Eastern (Russianspring-summer or eastern subtype), and is endemic to centraland eastern Europe, Russia, and the Far East, with some overlapin geography.44

The etiologic agents are spherical, lipid-enveloped RNAviruses in the genus Flavivirus.44 The western subtype is trans-mitted to humans by I. ricinus, and the Siberian and Far Easternsubtypes are transmitted by I. persulcatus, although I. ovatus is thevector in Japan.44 A minority of TBE cases have followed the con-sumption of infected unpasteurized milk or cheese directly with-out a tick vector.44 The main virus reservoirs are small rodents.44

Ticks are vectors, and humans are accidental hosts of the virus.Ticks can become infected for life by the virus at larval, nymphal,or adult stages, can acquire it during mating, and can maintain thevirus transovarially and transstadially.44 TBE viruses are trans-mitted from the saliva of an infected tick very rapidly, withinminutes of the bite, so early removal of the tick may not preventsubsequent encephalitis.

As the disease name implies, the ultimate outcome of theinfectious process is manifested as CNS involvement, with symp-toms of aseptic meningitis, meningoencephalitis, and menin-goencephalomyelitis. TBE begins as a febrile headache with pro-gression to CNS manifestations. Treatment is supportive. Fourpreventive human TBE vaccines are available in Europe, two foradults and two for children.44 For eastern TBE subtype preven-tion, two vaccines are available in Russia.17 Prompt vaccinationfor postexposure tick bite prophylaxis is not effective unless usedas a booster for someone previously immunized in the prior2 years.44

THE TOXINS: TICK PARALYSIS

Tick ParalysisCASE 79-11

QUESTION 1: A.M., a 3-year-old girl residing in Spokane,Washington, complains of weakness in both legs. The nextday, she begins experiencing flaccid paralysis in both legsand the lower trunk, although she is alert and oriented. Hermother discovers a tick attached to A.M.’s scalp under herhair and removes it. A.M. is back to full health in 2 days.What happened?

Tick paralysis (tick toxicosis) occurs worldwide in humansand many animals and was first described by the explorer Hov-ell in Australia in 1824.45 Although 60 tick species worldwidecan produce tick paralysis in animals and humans, it is predomi-nantly caused in humans by D. andersoni and D. variabilis in NorthAmerica.45 In Australia, Ixodes holocyclus is the culprit.45

Most human cases occur during the spring and summer inAustralia and North America. In the United States, it is mostcommon in the Pacific Northwest and adjacent areas of south-western Canada and in the Rocky Mountain states.45 In children,girls are more commonly affected; however, in adults, more menare affected.45 Of epidemiological significance, a young girl’s longhair provides camouflage for feeding ticks.45

The cause of tick paralysis is the secretion of a neurotoxinpresent in the large salivary glands of female ticks. They mustusually be attached to a host for 4 to 5 days before symp-toms develop.45 The toxin affects motor neurons, decreasesacetylcholine release, and may have a mechanistic similarity tobotulinum toxin.45 Paresthesias and symmetric weakness in the

lower extremities with motor difficulties progress to an ascend-ing flaccid paralysis in several hours or days. Cerebral senso-rium is usually spared, pain is absent, and the blood and CSF arenormal.45 If the tick is not removed, the toxicosis can progressto respiratory paralysis and death.45 Initially reported mortalityrates of 10% have fallen dramatically with our modern inten-sive care units and available respiratory care.45 A WashingtonState case series of 33 patients conducted over the course of50 years revealed a mortality rate of 6%, with the last two patients’deaths occurring in the 1940s.45 Children are likely more vulner-able to tick paralysis than adults because the dose of neurotoxinpresent per kilogram of body weight is higher.45 Diagnosis shouldinclude a complete body examination of the skin for the presenceof an engorged tick.45

In North America, tick removal commonly results in com-plete recovery within hours to days. In Australia, the disease ismore acute, and paralysis may continue to progress for 2 daysafter tick removal. Recovery from the disease in Australia maytake several weeks. Treatment is supportive. Antitoxin derivedfrom dogs is the treatment of choice for animals, but it also hasbeen used occasionally in humans in Australia with severe tickparalysis.45 Local experts must determine its use on a case-by-case basis because of the risk of serum sickness or acute allergicreactions.45

MIXED INFECTIONS

Because the tick vectors and mammalian hosts are the same forbabesiosis, anaplasmosis, and Lyme disease in the northeasternUnited States, all three diseases, theoretically, could be transmit-ted to a human from one tick bite. Human coinfection by theagents of Lyme disease, babesiosis, or anaplasmosis can occur,especially in endemic areas.5 Coinfection may alter the natu-ral course for each disease or increase clinical manifestations,especially flulike symptoms, in concurrent Lyme disease withbabesiosis or HGA. Because the same tick vector in Europe andRussia can carry Lyme disease and TBE, dual infection may resultin more severe disease.44

Dual infection may affect the choice of initial antibiotic ther-apy. For example, although amoxicillin is sometimes used to treatearly Lyme disease, it is not effective for HGA. Doxycycline, how-ever, is useful in both of these diseases. Thus, some cases of Lymedisease that were believed to be treatment failures may actuallyhave been confounded by coinfection. Patients with concurrentLyme disease and babesiosis have more symptoms and a longerduration of illness compared with patients with single infections.When moderate to severe Lyme disease is diagnosed, the pos-sibility of concomitant babesial or anaplasmal infection shouldbe considered in regions where both diseases are endemic. Neu-tropenia and thrombocytopenia are associated with anaplasmo-sis, anemia and thrombocytopenia are associated with babesiosis,and neither is routinely found in Lyme disease.5 For patientswith Lyme disease who experience a prolonged flulike illnessthat fails to respond to appropriate antiborrelial therapy in anendemic area, clinicians should consider testing for babesiosisand anaplasmosis.5

SUMMARY

Most of the research into tick-borne human disease demonstratesa close historical relationship of endemic tick-deer-rodent cyclesfor various microorganisms. Given the recent explosion of deerpopulations in the United States and Europe, the increase in tick-borne human diseases may reflect the reduction of natural deer



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predators, the continued expansion of human populations fromurban to rural environments, or both.2 Therefore, it is likelythat we will continue to encounter increasing cases of tick-bornehuman disease of known or unknown cause.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found athttp://thePoint.lww.com/AT10e. Below are the key referencesand website for this chapter, with the corresponding refer-ence number in this chapter found in parentheses after thereference.

Key ReferencesAguero-Rosenfeld ME. Lyme disease: laboratory issues. Infect DisClin North Am. 2008;22(2):301, vii. (9)

Bakken JS, Dumler S. Human granulocytic anaplasmosis. InfectDis Clin North Am. 2008;22(3):433, viii. (32)

Chapman AS et al; Tickborne Rickettsial Diseases WorkingGroup; CDC. Diagnosis and management of tickborne rick-ettsial diseases: Rocky Mountain spotted fever, ehrlichioses, andanaplasmosis—United States: a practical guide for physicians andother health-care and public health officials. MMWR Recomm Rep.2006;55(RR-4):1. (26)

Clark RP, Hu LT. Prevention of Lyme disease and other tick-borne infections. Infect Dis Clin North Am. 2008;22(3):381, vii.(17)

Dandache P, Nadelman RB. Erythema migrans. Infect Dis ClinNorth Am. 2008;22(2):235, vi. (5)

Dworkin MS et al. Tick-borne relapsing fever. Infect Dis Clin NorthAm. 2008;22(3):449, viii. (19)

Edlow JA, McGillicuddy DC. Tick paralysis. Infect Dis Clin NorthAm. 2008;22(3):397, vii. (45)

Kaiser R. Tick-borne encephalitis. Infect Dis Clin North Am.2008;22(3):561, x. (44)

Marques A. Chronic Lyme disease: a review. Infect Dis Clin NorthAm. 2008;22(2):341, vii. (15)

Masters EJ et al. STARI, or Masters disease: Lone Star tick-vectored Lyme-like illness. Infect Dis Clin North Am. 2008;22(2):361, viii. (22)

Nigrovic LE, Wingerter SL. Tularemia. Infect Dis Clin North Am.2008;22(3):489, ix. (23)

Puius YA, Kalish RA. Lyme arthritis: pathogenesis, clinical pre-sentation, and management. Infect Dis Clin North Am. 2008;22(2):289, vi. (12)

Romero JR, Simonsen KA. Powassan encephalitis and Coloradotick fever. Infect Dis Clin North Am. 2008;22(3):545, x. (42)

Vannier E et al. Human babesiosis. Infect Dis Clin North Am.2008;22(3):469, viii. (38)

Wormser GP et al. The clinical assessment, treatment, and pre-vention of Lyme disease, human granulocytic anaplasmosis, andbabesiosis: clinical practice guidelines by the Infectious DiseasesSociety of America [published correction appears in Clin InfectDis. 2007;45(7):941]. Clin Infect Dis. 2006;43(3):1089. (3)

Key WebsiteCenters for Disease Control and Prevention. Tickborne diseasesof the U.S. http://www.cdc.gov/ticks/diseases/

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