1429CHAPTER 186 Lyme Borreliosis

positive response detectable in acute-phase samples (usually only a

positive IgM response), whereas ~70–80% have a positive response

during convalescence (2–4 weeks later). After 4–8 weeks of infection

(by which time most patients with active Lyme disease have disseminated infection), the sensitivity and specificity of the IgG response to

the spirochete are both very high—in the range of 99%—as determined

by the two-test approach of ELISA and Western blot. At this point and

thereafter, a single test (that for IgG) is usually sufficient. In persons

with illness of >2 months’ duration, a positive IgM test result alone is

likely to be false-positive and therefore should not be used to support

the diagnosis.

According to current criteria adopted by the CDC, an IgM Western

blot is considered positive if two of the following three bands are present: 23, 39, and 41 kDa. However, the combination of two such bands

may still represent a false-positive result. Misuse or misinterpretation

of IgM blots has been a factor in the incorrect diagnosis of Lyme disease in patients with other illnesses. An IgG blot is considered positive

if 5 of the following 10 bands are present: 18, 23, 28, 30, 39, 41, 45,

58, 66, and 93 kDa. In European cases, no single set of criteria for the

interpretation of immunoblots results in high levels of sensitivity and

specificity in all countries.

A new methodology called the modified two-test approach, which is

now approved by the U.S. Food and Drug Administration, is a two-test

approach using two EIAs, thereby dispensing with the Western blot.

One such method employs a whole–B. burgdorferi sonicate ELISA

followed by a VlsE C6 peptide IgG ELISA. This approach, which gives

simply a positive or a negative result, increases sensitivity during the

first several weeks of infection without compromising specificity. For

more complex cases or in those with late infection, it is still valuable

to determine antibody specificities to multiple spirochetal proteins, as

is done with Western blots. More recently, line immunoblots or other

multiplexed antibody platforms have been developed as substitutes for

Western blots. These assays allow more objective interpretation, and

some platforms can provide quantitative data about antibody responses

to many spirochetal proteins. After successful antibiotic treatment,

antibody titers decline slowly, but responses (including that to the VlsE

C6 peptide) may persist for years. Moreover, not only the IgG but also

the IgM response may persist for years after therapy. Therefore, even a

positive IgM response cannot be interpreted as confirmation of recent

infection or reinfection unless the clinical picture is appropriate.

■ DIFFERENTIAL DIAGNOSIS

Classic EM is a slowly expanding erythema, often with partial central

clearing. If the lesion expands little, it may represent the red papule of

an uninfected tick bite. If the lesion expands rapidly, it may represent

cellulitis (e.g., streptococcal cellulitis) or an allergic reaction, perhaps

to tick saliva. Patients with secondary annular lesions may be thought

to have erythema multiforme, but neither the development of blistering

mucosal lesions nor the involvement of the palms or soles is a feature of

B. burgdorferi infection. In the eastern United States, an EM-like skin

lesion, sometimes with mild systemic symptoms, may be associated

with Amblyomma americanum tick bites. However, the cause of this

southern tick-associated rash illness (STARI) has not yet been identified. This tick may also transmit Ehrlichia chaffeensis, a rickettsial agent

(Chap. 187).

As stated above, I. scapularis ticks in the United States may transmit

not only B. burgdorferi but also B. microti, the red blood cell parasite

causing babesiosis (Chap. 225); A. phagocytophilum, the agent of

human granulocytotropic anaplasmosis (Chap. 187); B. miyamotoi, a

relapsing fever spirochete (Chap. 185); B. mayonii and Ehrlichia species Wisconsin, newly recognized species that occur in the upper midwestern United States; or (rarely) Powassan encephalitis virus (the deer

tick virus, which is closely related to European tick-borne encephalitis

virus), which may cause fatal infection (Chap. 209). Although babesiosis and anaplasmosis are most often asymptomatic, infection with any

of these agents may cause nonspecific systemic symptoms, particularly

in the young or the elderly, and co-infected patients may have more

severe or persistent symptoms than patients infected with a single

agent. Standard blood counts may yield clues regarding the presence

of co-infection with Anaplasma or Babesia. Anaplasmosis may cause

leukopenia or thrombocytopenia, and babesiosis may cause thrombocytopenia or (in severe cases) hemolytic anemia. IgM serologic

responses may confuse the diagnosis. For example, A. phagocytophilum

may elicit a positive IgM response to B. burgdorferi. The frequency of

co-infection in different studies has been variable. In one prospective

study, 4% of patients with EM had evidence of co-infection.

Facial palsy caused by B. burgdorferi, which occurs in the early disseminated phase of the infection (often in July, August, or September),

is usually recognized by its association with EM. However, in rare

cases, facial palsy without EM may be the presenting manifestation

of Lyme disease. In such cases, both the IgM and the IgG responses

to the spirochete are usually positive. The most common infectious

agents that cause facial palsy are herpes simplex virus type 1 (Bell’s

palsy; Chap. 192) and varicella-zoster virus (Ramsay Hunt syndrome;

Chap. 193).

Later in the infection, oligoarticular Lyme arthritis most resembles

peripheral spondyloarthropathy in an adult or the pauciarticular form

of juvenile idiopathic arthritis in a child. Patients with Lyme arthritis

usually have the strongest IgG antibody responses seen in Lyme borreliosis, with reactivity to many spirochetal proteins.

The most common problem in diagnosis is to mistake Lyme

disease for chronic fatigue syndrome (Chap. 450) or fibromyalgia

(Chap. 373). This difficulty is compounded by the fact that a small

percentage of patients do in fact develop these chronic pain or fatigue

syndromes in association with or soon after Lyme disease. Moreover, a

counterculture has emerged that ascribes pain and fatigue syndromes

to chronic Lyme disease when there is little or no evidence of B. burgdorferi infection. In such cases, the term chronic Lyme disease, which is

equated with chronic B. burgdorferi infection, is a misnomer, and the

use of prolonged, dangerous, and expensive antibiotic treatment is not

warranted.

TREATMENT

Lyme Borreliosis

ANTIBIOTIC TREATMENT

As outlined in the algorithm in Fig. 186-2, the various manifestations of Lyme disease can usually be treated successfully with

orally administered antibiotics; the exceptions are severe objective

neurologic abnormalities and third-degree atrioventricular heart

block, which are generally treated with IV antibiotics, and arthritis that does not respond to oral therapy. For early Lyme disease,

doxycycline is effective and can be administered to men and nonpregnant women. An advantage of this regimen is that it is also

effective against A. phagocytophilum, B. miyamotoi, and B. mayonii,

which are transmitted by the same tick that transmits the Lyme

disease agent. Amoxicillin, cefuroxime axetil, and erythromycin

or its congeners are second-, third-, and fourth-choice alternatives, respectively, for the treatment of Lyme disease. In children,

amoxicillin is effective (not >2 g/d); in cases of penicillin allergy,

cefuroxime axetil or erythromycin may be used. In contrast to second- or third-generation cephalosporin antibiotics, first-generation

cephalosporins, such as cephalexin, are not effective. For patients

with infection localized to the skin, a 14-day course of therapy is

generally sufficient; in contrast, for patients with early disseminated

infection, a 21-day course is recommended. Approximately 15% of

patients experience a Jarisch-Herxheimer-like reaction during the

first 24 h of therapy. In multicenter studies, >90% of patients whose

early Lyme disease was treated with these regimens had satisfactory

outcomes. Although some patients reported symptoms after treatment, objective evidence of persistent infection or relapse was rare,

and re-treatment was usually unnecessary.

Oral administration of doxycycline or amoxicillin for 30

days is recommended for the initial treatment of Lyme arthritis

in patients who do not have concomitant neurologic involvement. Among patients with arthritis who do not respond to oral

1430 PART 5 Infectious Diseases

antibiotics, re-treatment with IV ceftriaxone for 28 days is appropriate. In patients with arthritis in whom joint inflammation persists

for months or even several years after both oral and IV antibiotics, treatment with nonsteroidal anti-inflammatory agents, therapy

with disease-modifying antirheumatic drugs, or synovectomy may

be successful.

In the United States, parenteral antibiotic therapy is usually

used for severe objective neurologic abnormalities. Patients with

such abnormalities are most commonly treated with IV ceftriaxone

for 14–28 days, but IV cefotaxime or IV penicillin G for the same

duration also may be effective. In Europe, similar results have been

obtained with oral doxycycline and IV antibiotics in the treatment

of acute neuroborreliosis. Although systematic trials have not been

conducted in the United States, oral doxycycline is now used by

some clinicians in this country for the treatment of patients with

less severe neurologic abnormalities, such as facial palsy alone or

uncomplicated Lyme meningitis. In patients with high-degree atrioventricular block or a PR interval of >0.3 s, IV therapy for at least

part of the course and cardiac monitoring are recommended, but

the insertion of a permanent pacemaker is not necessary.

It is unclear how and whether asymptomatic infection should

be treated, but patients with such infection are often given a course

of oral antibiotics. Because maternal–fetal transmission of B. burgdorferi seems to occur rarely (if at all), standard therapy for the

manifestations of the illness is recommended for pregnant women.

Long-term persistence of B. burgdorferi has not been documented

in any large series of patients after treatment with currently recommended regimens. Although an occasional patient requires a

second course of antibiotics, there is no indication for multiple,

repeated antibiotic courses in the treatment of Lyme disease.

CHRONIC LYME DISEASE

After appropriately treated Lyme disease, a small percentage of

patients continue to have subjective symptoms, primarily musculoskeletal pain, neurocognitive difficulties, or fatigue. This chronic

Lyme disease or post-Lyme syndrome is sometimes a disabling

condition that is similar to chronic fatigue syndrome or fibromyalgia. Five double-blind, placebo-controlled trials conducted in

the United States and Europe have failed to show benefit of further

antibiotic therapy in these patients. For example, in a large study,

one group of patients with post-Lyme syndrome received IV ceftriaxone for 30 days followed by oral doxycycline for 60 days, while

another group received IV and oral placebo preparations for the

same durations. No significant differences were found between

groups in the numbers of patients reporting that their symptoms

had improved, become worse, or stayed the same. Such patients are

best treated for the relief of symptoms rather than with prolonged

courses of antibiotics.

PROPHYLAXIS AFTER A TICK BITE

The risk of infection with B. burgdorferi after a recognized tick

bite is so low that antibiotic prophylaxis is not routinely indicated.

However, if an attached, engorged I. scapularis nymph is found

or if follow-up is anticipated to be difficult, a single 200-mg dose

of doxycycline, which usually prevents Lyme disease when given

within 72 h after the tick bite, may be administered.

■ PROGNOSIS

The response to treatment is best early in the disease. Later treatment

of Lyme borreliosis is still effective, but the period of convalescence

may be longer. Eventually, most patients recover with minimal or no

residual deficits.

■ REINFECTION

Reinfection may occur after EM when patients are treated with antimicrobial agents. In such cases, the immune response is not adequate to

provide protection from subsequent infection. However, patients who

develop an expanded immune response to the spirochete over a period

of months (e.g., those with Lyme arthritis) have protective immunity

for a period of years and rarely, if ever, acquire the infection again.

■ PREVENTION

Protective measures for the prevention of Lyme disease may include

the avoidance of tick-infested areas, the use of repellents and acaricides, tick checks, and modification of landscapes in or near residential

areas. Although a vaccine for Lyme disease used to be available, the

manufacturer has discontinued its production. Another company is

planning testing of a similar vaccine in both the United States and

Europe. However, no vaccine is currently available commercially for

the prevention of this infection.

■ FURTHER READING

Arvikar SL, Steere AC: Diagnosis and treatment of Lyme arthritis.

Infect Dis Clin North Am 29:269, 2015.

Aucott JN: Posttreatment Lyme disease syndrome. Infect Dis Clin

North Am 29:309, 2015.

Branda JA, Steere AC: Laboratory diagnosis of Lyme borreliosis.

Clin Micro Rev 34:e00018, 2021.

Branda JA et al: Two-tiered antibody testing for Lyme disease with

use of 2 enzyme immunoassays, a whole-cell sonicate enzyme

immunoassay followed by a VlsE C6 peptide enzyme immunoassay.

Clin Infect Dis 53:541, 2011.

Klempner MS et al: Two controlled trials of antibiotic treatment in

patients with persistent symptoms and a history of Lyme disease. N

Engl J Med 345:85, 2001.

Lantos PM et al: Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology,

and the American College of Rheumatology (ACR): 2020 guidelines

for the prevention, diagnosis, and treatment of Lyme disease. Clin

Infect Dis 72:1, 2021.

Localized skin infection: 14 days

Early disseminated infection:

 21 days

Acrodermatitis: 30 days

Arthritis: 30−60 days**

Neurologic involvement:

 14–28 days

Cardiac involvement:

 28 days; complete course

 with oral therapy when

 patient is no longer in

 high-degree AV block

Skin

Erythema

 migrans

Acrodermatitis

Joint

Arthritis*

Heart

AV block

Nervous system

Facial

 palsy

 alone

Meningitis

Radiculoneuritis

Encephalopathy

Polyneuropathy

Oral therapy

First choice

 Age ≥9 years, not pregnant:

 doxycycline, 100 mg bid

 Age <9 years: amoxicillin,

 50 mg/kg per day

Second choice for adults:

 amoxicillin, 500 mg tid

Third choice for all ages:

 cefuroxime axetil, 500 mg bid

Fourth choice for all ages:

 erythromycin, 250 mg qid

Intravenous therapy

First choice:

 ceftriaxone, 2 g qd

Second choice:

 cefotaxime, 2 g q8h

Third choice:

 Na penicillin G, 5 million

 U q6h

Guidelines for duration of therapy

1˚,

2˚ 3˚

FIGURE 186-2 Algorithm for the treatment of the various early or late manifestations

of Lyme borreliosis. AV, atrioventricular. *For arthritis, oral therapy should be tried

first; if arthritis is unresponsive, IV therapy should be administered. **For Lyme

arthritis, IV ceftriaxone (2 g given once a day for 14–28 days) also is effective and is

necessary for patients who do not respond to oral therapy. However, compared with

oral treatment, this regimen is less convenient to administer, has more side effects,

and is more expensive.

1431CHAPTER 187 Rickettsial Diseases

Li X et al: Burden and viability of Borrelia burgdorferi in skin or joints

of patients with erythema migrans or Lyme arthritis. Arthritis Rheum

63:2238, 2011.

Lochhead RB et al: Robust interferon signature and suppressed tissue

repair gene expression in synovial tissue from patients with postinfectious, Borrelia burgdorferi-induced Lyme arthritis. Cell Microbiol

21:e12954, 2019.

Oschmann P et al: Stages and syndromes of neuroborreliosis. J Neurol

245:262, 1998.

Steere AC: Lyme disease. N Engl J Med 345:115, 2001.

Steere AC: Posttreatment Lyme disease syndromes: Distinct pathogenesis caused by maladaptive host responses. J Clin Invest 130:2148,

2020.

Steere AC et al: Prospective study of serologic tests for Lyme disease.

Clin Infect Dis 47:188, 2008.

Steere AC et al: Lyme borreliosis. Nat Rev Dis Primers 2:16090, 2016.

Section 10 Diseases Caused by Rickettsiae,

Mycoplasmas, and Chlamydiae

187

Rickettsiae are a heterogeneous group of small, obligately intracellular, gram-negative coccobacilli and short bacilli, most of which are

transmitted by a tick, mite, flea, or louse vector. Except in the case of

louse-borne typhus, humans are incidental hosts. Among rickettsiae,

Coxiella burnetii, Rickettsia prowazekii, and Rickettsia typhi have the

well-documented ability to survive for an extended period outside the

reservoir or vector and to be extremely infectious: inhalation of a single

Coxiella microorganism can cause pneumonia. High-level infectivity

and severe illness after inhalation make R. prowazekii, R. rickettsii,

R. typhi, R. conorii, and C. burnetii bioterrorism threats (Chap. S3).

Clinical infections with rickettsiae can be classified according to (1)

the taxonomy and diverse microbial characteristics of the agents, which

belong to seven genera (Rickettsia, Orientia, Ehrlichia, Anaplasma, Neorickettsia, “Candidatus Neoehrlichia,” and Coxiella); (2) epidemiology; or

(3) clinical manifestations. The clinical manifestations of all the acute

presentations are similar during the first 5 days: fever, headache, and

myalgias with or without nausea, vomiting, and cough. As the course

progresses, clinical manifestations—including a macular, maculopapular, or vesicular rash; eschar; pneumonitis; and meningoencephalitis—

vary from one disease to another. Given the many etiologic agents with

varied mechanisms of transmission, geographic distributions, and associated disease manifestations, the consideration of rickettsial diseases as

a single entity poses complex challenges (Table 187-1).

Establishing the etiologic diagnosis of rickettsioses is very difficult during the acute stage of illness, and definitive diagnosis usually

requires the examination of serum samples during the acute and convalescent phases of illness. Heightened clinical suspicion is based on

epidemiologic data, history of exposure to vectors or reservoir animals,

travel to endemic locations, clinical manifestations (sometimes including rash or eschar), and characteristic laboratory findings (including

thrombocytopenia, normal or low white blood cell [WBC] counts,

elevated hepatic enzyme levels, and hyponatremia). Such suspicion

should prompt empirical treatment. Doxycycline is the empirical drug

of choice for most of these infections. Only one agent, C. burnetii,

has been documented to cause chronic illness. One other species,

Rickettsial Diseases

David H. Walker, J. Stephen

Dumler, Lucas S. Blanton,

Chantal P. Bleeker-Rovers

R. prowazekii, causes recrudescent illness (Brill-Zinsser disease) when

latent infection is reactivated years after resolution of the acute illness.

Rickettsial infections dominated by fever may resolve without further clinical evolution. However, after nonspecific early manifestations,

the illnesses can also evolve along one or more of several principal

clinical lines: (1) development of a macular or maculopapular rash;

(2) development of an eschar at the site of tick or mite feeding, which

can occur during the incubation period; (3) development of a vesicular

rash (often in rickettsialpox, R. parkeri infection and African tick-bite

fever); (4) development of pneumonitis with chest radiographic opacities and/or rales (Q fever and severe cases of Rocky Mountain spotted

fever [RMSF], Mediterranean spotted fever [MSF], louse-borne typhus,

human monocytotropic ehrlichiosis [HME], human granulocytotropic

anaplasmosis [HGA], scrub typhus, and murine typhus); (5) development of meningoencephalitis (louse-borne typhus and severe cases of

RMSF, scrub typhus, HME, murine typhus, MSF, and [rarely] Q fever);

and (6) progressive hypotension and multiorgan failure as seen with

sepsis or toxic shock syndromes (RMSF, MSF, louse-borne typhus,

murine typhus, scrub typhus, HME, HGA, and neoehrlichiosis).

Epidemiologic clues to the transmission of a particular pathogen

include (1) environmental exposure to ticks, fleas, or mites during the

season of activity of the vector species for the disease in the appropriate

geographic region (spotted fever and typhus rickettsioses, scrub typhus,

ehrlichiosis, anaplasmosis); (2) travel to or residence in an endemic geographic region during the incubation period (Table 187-1); (3) exposure

to parturient ruminants, cats, and dogs (Q fever); (4) exposure to flying

squirrels (R. prowazekii infection); and (5) history of previous louseborne typhus (recrudescent typhus).

Clinical laboratory findings such as thrombocytopenia (particularly

in spotted fever and typhus rickettsioses, ehrlichiosis, anaplasmosis,

and scrub typhus), normal or low WBC counts, mild to moderate

serum elevations of hepatic aminotransferases, and hyponatremia suggest some common pathophysiologic mechanisms.

Application of these clinical, epidemiologic, and laboratory principles requires consideration of a rickettsial diagnosis and knowledge of

the individual diseases.

TICK-, MITE-, LOUSE-, AND FLEA-BORNE

RICKETTSIOSES

These diseases, caused by organisms of the genera Rickettsia and Orientia in the family Rickettsiaceae, result from endothelial cell infection

and increased vascular permeability. Pathogenic rickettsial species are

very closely related, have small genomes (as a result of reductive evolution, which eliminated many genes for biosynthesis of intracellularly

available molecules), and are traditionally separated into typhus and

spotted fever groups on the basis of lipopolysaccharide antigens. Some

diseases and their agents (e.g., R. africae, R. parkeri, and R. sibirica)

are too similar to require separate descriptions. Indeed, the similarities

among MSF (R. conorii [all strains] and R. massiliae), North Asian tick

typhus (R. sibirica), Japanese spotted fever (R. japonica), and Flinders

Island spotted fever (R. honei) far outweigh their minor variations.

The Rickettsiaceae that cause life-threatening infections are, in order

of decreasing case–fatality rate, R. rickettsii (RMSF); R. prowazekii

(louse-borne typhus); Orientia tsutsugamushi (scrub typhus); R. conorii

(MSF); R. typhi (murine typhus); and, in rare cases, other spotted

fever–group (SFG) organisms. Some agents (e.g., R. parkeri, R. africae,

Rickettsia 364D, R. akari, R. slovaca, R. honei, R. felis, R. massiliae,

R. helvetica, R. heilongjiangensis, R. aeschlimannii, and R. monacensis)

have never been documented to cause a fatal illness. The most prevalent SFG rickettsia in the United States, R. amblyommatis, has been

circumstantially associated with asymptomatic seroconversion in most

persons and with self-limited illness in others.

■ ROCKY MOUNTAIN SPOTTED FEVER

Epidemiology RMSF occurs in 47 states (with the highest prevalence in the south-central and southeastern states) as well as in

Canada, Mexico, and Central and South America. The infection is

transmitted by Dermacentor variabilis, the American dog tick, in the

1432 PART 5 Infectious Diseases

TABLE 187-1 Features of Selected Rickettsial Infections

DISEASE ORGANISM TRANSMISSION

GEOGRAPHIC

RANGE

INCUBATION

PERIOD, DAYS

DURATION,

DAYS RASH, % ESCHAR, % LYMPHADENOPATHYa

Rocky Mountain

spotted fever

Rickettsia

rickettsii

Tick bite: Dermacentor

andersoni, D. variabilis

United States 2–14 10–20 90 <1 +

Amblyomma cajennense

sensu lato, A. aureolatum

Central/South

America

Rhipicephalus

sanguineus

Mexico, Brazil,

United States

Mediterranean

spotted fever

R. conorii Tick bite: R. sanguineus,

R. pumilio

Southern

Europe, Africa,

Middle East,

central Asia

5–7 7–14 97 50 +

African tick-bite

fever

R. africae Tick bite: A. hebraeum,

A. variegatum

Sub-Saharan

Africa,

West Indies

4–10 4–19 50 90 +++

Maculatum

disease

R. parkeri Tick bite: A. maculatum,

A. triste, A. tigrinum,

A. ovale

United States,

South America

2–10 6–16 88 94 ++

Pacific Coast tick

fever

Rickettsia 364D Tick bite: D. occidentalis United States 3–9 5–14 14 100 +++

Rickettsialpox R. akari Mite bite: Liponyssoides

sanguineus

United States,

Ukraine, Turkey,

Mexico, Croatia

10–17 3–11 100 90 +++

Tick-borne

lymphadenopathy

R. slovaca Tick bite: D. marginatus,

D. reticularis

Europe 7–9 17–180 5 100 ++++

Flea-borne

spotted fever

R. felis Flea (mechanism

undetermined):

Ctenocephalides felis

Worldwide 8–16 8–16 80 15 —

Epidemic typhus R. prowazekii Louse feces: Pediculus

humanus humanus,

fleas and lice of

flying squirrels, or

recrudescence

Worldwide 7–14 10–18 80 None —

Murine typhus R. typhi Flea feces: Xenopsylla

cheopis, C. felis, others

Worldwide 8–16 9–18 80 None —

Human

monocytotropic

ehrlichiosis

Ehrlichia

chaffeensis

Tick bite: A. americanum,

D. variabilis

United States 1–21 3–21 26 None ++

Ewingii

ehrlichiosis

E. ewingii Tick bite: A. americanum United States 1–21 4–21 0 None

Unnamed

ehrlichiosis

E. muris ssp.

eauclairensis

Tick bite: Ixodes

scapularis

United States Unknown 3–14 12 None

Human

granulocytotropic

anaplasmosis

Anaplasma

phagocytophilum

Tick bite: I. scapularis,

I. ricinus, I. pacificus,

I. persulcatus,

Haemaphysalis concinna

United States,

Europe, Asia

4–8 3–14 Rare None —

Unnamed disease A. capra I. persulcatus Northeastern

China, France

Unknown 11–21 17 9 +

Neoehrlichiosis “Candidatus

Neoehrlichia

mikurensis”

Tick bite: I. ricinus,

I. persulcatus,

Haemaphysalis concinna

Europe, China ≥8 11–75 10 None

Scrub typhus Orientia

tsutsugamushi

Mite bite:

Leptotrombidium

deliense, others

Asia, Australia,

Pacific and

Indian Ocean

islands

9–18 6–21 50 35 +++

Q fever Coxiella burnetii Inhalation of aerosols

of infected parturition

material (goats, sheep,

cattle, cats, others),

ingestion of infected milk

or milk products

Worldwide

except New

Zealand,

Antarctica

3–30 5–57 <1 None —

a

++++, severe; +++, marked; ++, moderate; +, present in a small proportion of cases; —, not a noted feature.

eastern two-thirds of the United States and California; by D. andersoni, the Rocky Mountain wood tick, in the western United States; by

Rhipicephalus sanguineus, the brown dog tick, in Mexico, Arizona, and

probably Brazil; and by Amblyomma sculptum, A. mixtum, A. patinoi,

A. cajennense, A. tonelliae, and A. aureolatum in Central and/or South

America. Maintained partially by transovarian transmission from one

generation of ticks to the next, R. rickettsii can be acquired by uninfected ticks through the ingestion of a blood meal from rickettsemic

small mammals or by co-feeding adjacent to an infected tick.

Humans become infected during tick season (in the Northern

Hemisphere, from April to September), although some cases occur in

winter. The mortality rate was 20–25% in the preantibiotic era and has

1433CHAPTER 187 Rickettsial Diseases

FIGURE 187-1 A. Petechial lesions of Rocky Mountain spotted fever on the lower

legs and soles of a young, previously healthy patient. B. Close-up of lesions from the

same patient. (Photos courtesy of Dr. Lindsey Baden; with permission.)

A

B

been reported at ~3–5% in the postantibiotic era, principally because

of delayed diagnosis and treatment. Recent reporting of a relatively low

mortality rate (0.4%) for spotted fever rickettsiosis is likely an artifact

related to the abundance of less pathogenic SFG rickettsial species and

to a relatively low proportion of diagnostically confirmed cases. Indeed,

the reported case–fatality rates in confirmed cases in the United States

and in parts of Arizona, where R. rickettsii is the sole infecting SFG

species, are 9% and 10%, respectively. The case–fatality rate is highest among children (<10 years of age) and in the later decades of life

(>70 years). For unknown reasons, the case–fatality rate of RMSF in

Mexico and Brazil approaches 50%.

Pathogenesis R. rickettsii organisms are inoculated into the dermis

along with secretions of the tick’s salivary glands after ≥6 h of feeding.

The rickettsiae spread lymphohematogenously throughout the body

and infect numerous foci of contiguous endothelial cells. The dose-dependent incubation period is ~1 week (range, 2–14 days). Occlusive

thrombosis and ischemic necrosis are not the fundamental pathologic

bases for tissue and organ injury. Instead, increased vascular permeability, with resulting edema, hypovolemia, and ischemia, is responsible.

Consumption of platelets results in thrombocytopenia in 32–52% of

patients, but disseminated intravascular coagulation (DIC) with hypofibrinogenemia is rare. Activation of platelets, generation of thrombin,

and activation of the fibrinolytic system all appear to be homeostatic

physiologic responses to endothelial injury by nonocclusive hemostatic

plugs.

Clinical Manifestations Early in the illness, when medical attention usually is first sought, RMSF is difficult to distinguish from many

self-limiting viral illnesses. Fever, headache, malaise, myalgia, nausea,

vomiting, and anorexia are the most common symptoms during the

first 3 days. The patient becomes progressively more ill as vascular

infection and injury advance. In one large series, only one-third of

patients were diagnosed with presumptive RMSF early in the clinical

course and treated appropriately as outpatients. In the tertiary-care setting, RMSF is all too often recognized only when late severe manifestations, developing at the end of the first week or during the second week

of illness in patients without appropriate treatment, prompt return to a

physician or hospital and admission to an intensive care unit.

The progressive nature of the infection is clearly manifested in the

skin. Rash is evident in only 14% of patients on the first day of illness

and in only 49% during the first 3 days. Macules (1–5 mm) appear first

on the wrists and ankles and then on the remainder of the extremities

and the trunk. Later, more severe vascular damage results in frank

hemorrhage at the center of the maculopapule, producing a petechia

that does not disappear upon compression (Fig. 187-1). This sequence

of events is sometimes delayed or aborted by effective treatment. However, the rash is a variable manifestation, appearing on day 6 or later

in 20% of cases and not appearing at all in 9–16% of cases. Petechiae

occur in 41–59% of cases, appearing on or after day 6 in 74% of cases

that manifest a rash. Involvement of the palms and soles, often considered diagnostically important, usually develops relatively late in

the course (after day 5 in 43% of cases) and does not develop at all in

18–64% of cases.

Hypovolemia leads to prerenal azotemia and (in 17% of cases)

hypotension. Infection of the pulmonary microcirculation leads to

noncardiogenic pulmonary edema; 12% of patients have acute respiratory distress syndrome, and 8% require mechanical ventilation. Cardiac involvement manifests as dysrhythmia in 7–16% of cases.

Besides respiratory failure, central nervous system (CNS) involvement is the other important determinant of the outcome of RMSF.

Encephalitis, presenting as confusion or lethargy, is apparent in

26–28% of cases. Progressively severe encephalitis manifests as stupor

or delirium in 21–26% of cases, ataxia in 18%, coma in 10%, and seizures in 8%. Numerous focal neurologic deficits have been reported.

Meningoencephalitis results in cerebrospinal fluid (CSF) pleocytosis

in 34–38% of cases; usually there are 10–100 cells/μL and a mononuclear predominance, but occasionally there are >100 cells/μL and

a polymorphonuclear predominance. The CSF protein concentration

is increased in 30–35% of cases, but the CSF glucose concentration is

usually normal.

Acute kidney injury, often reversible with rehydration, is caused by

acute tubular necrosis in severe cases with shock. Hepatic injury with

increased serum aminotransferase concentrations (38% of cases) is due

to multifocal death of individual hepatocytes without hepatic failure.

Jaundice is recognized in 9% of cases and an elevated serum bilirubin

concentration in 18–30%.

Life-threatening bleeding is rare. Anemia develops in 30% of cases

and is severe enough to require transfusions in 11%. Blood is detected

in the stool or vomitus of 10% of patients, and death has followed massive upper-gastrointestinal hemorrhage.

Other characteristic clinical laboratory findings include increased

plasma levels of proteins of the acute-phase response (C-reactive

protein, fibrinogen, ferritin, and others), hypoalbuminemia, and

hyponatremia (in 56% of cases) due to the appropriate secretion of

antidiuretic hormone in response to the hypovolemic state. Myositis

occurs occasionally, with marked elevations in serum creatine kinase

levels and multifocal rhabdomyonecrosis. Ocular involvement includes

conjunctivitis in 30% of cases and retinal vein engorgement, flame

hemorrhages, arterial occlusion, and papilledema with normal CSF

pressure in some instances.

Severe RMSF can present as sepsis or septic shock. In untreated fatal

cases, death occurs 8–15 days after onset. A rare presentation, fulminant RMSF, is fatal within 5 days after onset. This fulminant presentation is seen most often in male black patients with glucose-6-phosphate

dehydrogenase (G6PD) deficiency and may be related to an undefined

effect of hemolysis on the rickettsial infection. Although survivors

1434 PART 5 Infectious Diseases

of RMSF usually return to their previous state of health, permanent

sequelae, including neurologic deficits and gangrene necessitating

amputation of extremities, may follow severe illness.

Diagnosis The diagnosis of RMSF during the acute stage is more

difficult than is generally appreciated. The most important epidemiologic factor is a history of exposure to a potentially tick-infested environment within the 14 days preceding disease onset during a season

of possible tick activity. However, only 60% of patients actually recall

being bitten by a tick during the incubation period.

The differential diagnosis for early clinical manifestations of RMSF

(fever, headache, and myalgia without a rash) includes influenza,

enteroviral infection, infectious mononucleosis, viral hepatitis, leptospirosis, typhoid fever, gram-negative or gram-positive bacterial

sepsis, HME, HGA, murine typhus, sylvatic flying-squirrel typhus,

and rickettsialpox. Enterocolitis may be suggested by nausea, vomiting, and abdominal pain; prominence of abdominal tenderness has

resulted in exploratory laparotomy. CNS involvement can masquerade

as bacterial or viral meningoencephalitis. Cough, pulmonary signs, and

chest radiographic opacities can lead to a diagnostic consideration of

bronchitis or pneumonia.

At presentation during the first 3 days of illness, only 3% of patients

exhibit the classic triad of fever, rash, and history of tick exposure.

When a rash appears, a diagnosis of RMSF should be considered.

However, many illnesses considered in the differential diagnosis also

can be associated with a rash, including rubeola, rubella, meningococcemia, disseminated gonococcal infection, secondary syphilis, toxic

shock syndrome, drug hypersensitivity, immune thrombocytopenic

purpura, thrombotic thrombocytopenic purpura, Kawasaki syndrome,

and immune complex vasculitis. Conversely, any person in an endemic

area with a provisional diagnosis of one of the above illnesses could

have RMSF. Thus, if a viral infection is suspected during RMSF season

in an endemic area, it should always be kept in mind that RMSF can

mimic viral infection early in the course; if the illness worsens over the

next couple of days after initial presentation, the patient should return

for reevaluation.

The most common serologic test for confirmation of the diagnosis

is the indirect immunofluorescence assay. Not until 7–10 days after

onset is a reactive titer of ≥64 first detectable. The sensitivity and specificity of the indirect immunofluorescence IgG assay are 89–100% and

99–100%, respectively. Detection of IgM is no more sensitive in early

illness and is subject to nonspecific cross-reactivity. It is important to

understand that serologic tests for RMSF are usually negative at the

time of presentation for medical care and that treatment should not be

delayed while a positive serologic result is awaited.

The only diagnostic test that has proven useful during the acute

illness is immunohistologic examination of a cutaneous biopsy sample from a rash lesion for R. rickettsii. Examination of a 3-mm punch

biopsy from such a lesion is 70% sensitive and 100% specific, and polymerase chain reaction (PCR) on a rash biopsy would likely yield even

higher sensitivity. PCR amplification for detection of R. rickettsii DNA

in peripheral blood is not adequately sensitive. Although rickettsiae

are present in large quantities in heavily infected foci of endothelial

cells, there are relatively low quantities in the circulation. Cultivation

of rickettsiae in cell culture is feasible but is seldom undertaken because

of technical difficulty and biohazard concerns. The recent dramatic

increase in the reported incidence of RMSF correlates with the use of

single-titer SFG cross-reactive enzyme immunoassay serology. Few

cases are specifically determined to be caused by R. rickettsii. Currently,

many febrile persons who do not have RMSF present with crossreactive antibodies, possibly because of previous exposure to the highly

prevalent SFG rickettsia R. amblyommatis.

TREATMENT

Rocky Mountain Spotted Fever

The drug of choice for the treatment of both children and adults

with RMSF is doxycycline. Because of the severity of RMSF, immediate empirical administration of doxycycline should be strongly

considered for any patient with a consistent clinical presentation in

the appropriate epidemiologic setting. Doxycycline is administered

orally (or, with coma or vomiting, intravenously) at 100 mg twice

daily. For children with suspected RMSF, up to five courses of doxycycline may be administered with minimal risk of dental staining.

In patients with allergy to doxycycline, desensitization should be

considered. Once considered an alternative during pregnancy, chloramphenicol is not readily available in the United States. Although

available in much of the world, it is less effective than doxycycline.

Fortunately, there is little evidence to support the occurrence of

tetracycline-associated adverse events in mothers (hepatotoxicity)

and fetuses (staining of deciduous teeth and teratogenicity) who

receive doxycycline. The antirickettsial drug should be administered until the patient is afebrile and improving clinically—usually

3–5 days after defervescence. β-Lactam antibiotics, erythromycin,

and aminoglycosides have no role in the treatment of RMSF, and

sulfa-containing drugs are associated with more adverse outcomes

than no treatment at all. There is little clinical experience with

fluoroquinolones, clarithromycin, and azithromycin, which are not

recommended. The most seriously ill patients are managed in

intensive care units, with careful administration of fluids to achieve

optimal tissue perfusion without precipitating noncardiogenic pulmonary edema. In some severely ill patients, hypoxemia requires

intubation and mechanical ventilation; oliguric or anuric acute

renal failure requires renal replacement therapy; seizures necessitate

the use of antiseizure medication; anemia or severe hemorrhage

necessitates transfusions of packed red blood cells; or bleeding with

severe thrombocytopenia requires platelet transfusions.

Prevention Avoidance of tick bites is the only available preventive

approach. Use of protective clothing and tick repellents, inspection of

the body once or twice a day, and removal of ticks before they inoculate

rickettsiae reduce the risk of infection. Prophylactic doxycycline treatment of tick bites has no proven role in preventing RMSF.

■ MEDITERRANEAN SPOTTED FEVER

(BOUTONNEUSE FEVER), AFRICAN TICK-BITE

FEVER, AND OTHER TICK-BORNE SPOTTED FEVERS

Epidemiology and Clinical Manifestations R. conorii is prevalent in southern Europe, Africa, and southwestern and south-central

Asia. The disease is characterized by high fever, rash, and—in most

geographic locales—an inoculation eschar (tâche noire) that appears

before the onset of fever at the site of the tick bite. A severe form of the

disease (mortality rate, 50%) occurs in patients with diabetes, alcoholism, or heart failure.

African tick-bite fever, caused by R. africae, occurs in rural areas of

sub-Saharan Africa and in the Caribbean islands and is transmitted by

Amblyomma hebraeum and A. variegatum ticks. The average incubation period is 4–10 days. The mild illness consists of headache, fever,

eschar, and regional lymphadenopathy. Amblyomma ticks, a high portion of which are infected with R. africae, often feed in groups, with the

consequent development of multiple eschars. Rash may be vesicular,

sparse, or absent altogether. Because of tourism in sub-Saharan Africa,

African tick-bite fever is the rickettsiosis most frequently imported

into Europe and North America. Maculatum disease, a similar disease caused by the closely related species R. parkeri, is transmitted by

A. maculatum and found in a low percentage of A. americanum ticks

in the United States. It is also transmitted by A. triste in South America

and Arizona as well as A. tigrinum and A. ovale in South America.

R. japonica causes Japanese spotted fever, which also occurs in Korea

and China. Similar diseases in northern Asia are caused by R. sibirica

and R. heilongjiangensis. Queensland tick typhus due to R. australis is

transmitted by Ixodes holocyclus ticks. Flinders Island spotted fever,

found on the island for which it is named as well as in Tasmania,

mainland Australia, and Asia, is caused by R. honei. In Europe, patients

infected with R. slovaca after a wintertime Dermacentor tick bite usually manifest an afebrile illness with an eschar (usually on the scalp)

and painful regional lymphadenopathy.