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EML is unknown and the clinical presentation is undifferentiated from other Ehrlichia

species.

Anaplasmosis is a bacterial disease, caused by Anaplasma phagocytophilum,

which was first recognized as a disease in humans in 1994.

4 Though previously

known as human granulocytic ehrlichiosis (HGE), a taxonomic change in 2001

identified that this organism belongs to the genus Anaplasma and resulted in the name

change to human granulocytic anaplasmosis (HGA). To date, the highest incidence of

HGA in the United States is reported in the upper Midwest and northeastern states

with transmission by the black-legged tick (Ixodes scapularis). Along the West

Coast, it is transmitted by the western black-legged tick (I. pacificus).

CLINICAL AND LABORATORY FINDINGS

Human ehrlichiosis and anaplasmosis usually present as nonspecific, febrile, flu-like

illnesses resembling RMSF. The symptoms caused by infection generally develop 1

to 2 weeks following the bite of an infected tick and are variable. Patients who are

immunocompromised (e.g., receiving corticosteroids, cancer chemotherapy, longterm immunosuppressive therapy following organ transplant), or who have HIV

infection or splenectomy may experience more severe disease and greater risk of

mortality.

The following signs often are noted: hypertransaminemia, leukopenia (often with a

shift to the left), and thrombocytopenia. A skin rash is an uncommon feature of

ehrlichiosis and is rarely seen with anaplasmosis. However, up to 60% of children

can experience a rash caused by Ehrlichia chaffeensis. The diagnosis of ehrlichiosis

and anaplasmosis must be made based on clinical findings, as treatment should never

be delayed pending the results of confirmatory laboratory testing or be withheld on

the basis of an initial negative laboratory result. In patients presenting with known

tick exposure, fever, thrombocytopenia, and increased liver function test, a

peripheral smear should be performed. A peripheral blood smear showing

neutrophilic morulae supports a provisional diagnosis, though this characteristic

finding is not present in most cases. Confirmatory testing by serology or PCR or

direct culture is still required to establish a diagnosis.

31 As with many other tickborne diseases, serologic findings of antibody response to ehrlichiosis or

anaplasmosis assist only by retrospectively confirming the diagnosis.

TREATMENT AND PREVENTION

CASE 82-8

QUESTION 1: G.C., a 68-year-old man living in northwest Wisconsin, presents with an influenza-like illness in

late May. He has a two-day history of fever, shaking chills, headache, myalgias, nausea, and anorexia. On

examination, his temperature is 39.4°C, but other physical findings are unremarkable. No skin rashes are found.

G.C. states that he had multiple tick bites 1 week ago while he was fur trapping. The physician suspects

anaplasmosis. Blood is drawn for serology, CBC with differential, chemistry profile, and a Wright stain

microscopic examination. Immediately available abnormal results include neutrophilic morulae on microscopy, a

WBC count of 2,500/μL, a platelet count of 80 × 10

3

/μL, C-reactive protein of 136 mg/L (normal, 4–8 mg/L),

aspartate aminotransferase (AST) of 150 IU/L, and lactate dehydrogenase of 700 IU/L. Serology is still

pending. What antibiotic treatment should be initiated?

G.C.’s history is significant for HGA. He was in the right place, the upper

Midwestern US, and was outdoors during the right season; most patients are

diagnosed with HGA in May through August, and his history fall within the usual 1-

to 2-week incubation period from tick bite to onset of illness.

His symptoms are also important. Nearly 100% of patients with HGA have a fever

of greater than 37.6°C. Other symptoms in G.C. consistent with HGA are rigors

(shaking chills), headache, myalgias, nausea, and anorexia. Matching laboratory

findings include neutrophilic morulae. The laboratory findings of leukopenia and

thrombocytopenia strongly support the diagnosis of anaplasmosis. Evidence of mildto-moderate hepatic injury, as seen by the elevated liver enzyme results, is helpful in

HGA diagnosis.

Doxycycline is the first-line treatment for G.C. and should be used for both adults

and children of all ages whenever anaplasmosis or ehrlichiosis is suspected.

4,5

In

patients such as G.C. who are treated within the first 5 days of the disease, a good

response to doxycycline occurs with fever resolution generally in 2 days.

32 Fever

persisting for more than 2 days after doxycycline treatment suggests that the diagnosis

is incorrect.

THE PROTOZOA: BABESIOSIS

Babesia, Ticks, and Hosts

There are more than 100 species of Babesia having a worldwide geographic range.

4

However, only relatively few species have caused documented cases of human

infection, including B. microti, B. divergens, B. duncani, and currently an unnamed

agent designated MO1.

4,32 The most common cause of human babesiosis is B. microti,

which is transmitted by Ixodes scapularis ticks, primarily in the endemic regions in

the Northeast and upper Midwest of the United States; however, sporadic cases of

babesiosis have occurred in other regions, including the West Coast. In addition to

the Ixodes ticks, Babesia species are also transmitted by Dermacentor,

Haemaphysalis, and Rhipicephalus ticks. Because B. microti is typically transmitted

by the nymphal stage of I. scapularis tick (about the size of a poppy seed), infected

patients may not recall a tick bite.

SYMPTOMS AND DIAGNOSIS

CASE 82-9

QUESTION 1: H.W., age 68 years, lives in Martha’s Vineyard in Massachusetts. During the month of July he

enjoyed a day of boating, fishing and hiking at a nearby lake. About a week later, he felt fatigued and lost his

appetite. He presents to his local PCP in the middle of August with complaints of fever, headache, drenching

sweats, aches and pains, and occasional dark-colored urine. He does not recall a tick bite. On physical

examination, he has splenomegaly and hepatomegaly. Laboratory tests show a severe normochromic,

normocytic anemia, decreased hemoglobin, hemoglobinuria, thrombocytopenia, and increased liver enzymes. His

temperature is 40°C. Examination of a Giemsa-stained thin blood smear reveals the presence of unpigmented

ring-shaped intraerythrocytic parasites in more than 5% of his erythrocytes. The PCP institutes an atovaquone

plus azithromycin regimen. What was the clue to the diagnosis of babesiosis?

The diagnosis of babesiosis was confirmed by the direct observation of the

protozoan inside the red blood cells. Although the Giemsa-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 less than

1% of erythrocytes may be infected early in the course of the disease when most

people seek medical help.

3,32 Because blood smear inspection is often not successful

in diagnosing babesiosis or may only detect a few parasites, additional supportive

laboratory results are advocated, such as serology using IFA for IgM and IgG

antibabesial antibodies or PCR detection of babesial DNA in the blood.

3

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p. 1727

The clinical findings in patients with babesiosis are similar to those of malaria,

ranging in severity from asymptomatic to severe complications and death.

11 Most

patients with B. microti babesiosis are asymptomatic, though some people may

develop nonspecific flu-like symptoms, such as fever, chills, sweats, headache,

myalgias, and nausea. This form of babesiosis can be viewed as a distinct, occult,

asymptomatic disease with few known sequelae.

32 A number of transfusion-acquired

infections have been documented, reflecting the existence of an asymptomatic form of

babesiosis in blood donors.

A second form of babesiosis has been termed a “mild-to-moderate viral-like

illness.”

33

It has a gradual onset of fatigue and malaise and later fever accompanied

by one or more of these symptoms: chills, sweats, headache, arthralgias or myalgias,

anorexia, or cough.

30 Rash is rare. It can last weeks to months, sometimes with a

prolonged recovery time of up to a year or more.

33

A third form of babesiosis is a potentially life-threatening hemolytic one that

occurs in people predisposed to severe infection because of advanced age, immune

suppression as a result of HIV disease or immunosuppressants, malignancy, or prior

splenectomy.

32 Although babesial infection is as prevalent in children as it is in

adults, it is more severe in adults older than 50 years of age. Complications seen in

severe babesiosis include acute respiratory failure, disseminated intravascular

coagulation, congestive heart failure, coma, and renal failure, with a 5% to 9%

mortality rate.

3,32

In the northeastern US, infections commonly occur in patients with spleens, as in

H.W. Clinically apparent cases are most common in 50- to 60-year-old patients,

many of whom do not recall a tick bite. Most symptoms of babesiosis are caused by

hemolysis or the systemic inflammatory responses to parasitemia.

30 The usual

incubation period is 1 to 6 weeks after a tick bite based on limited data.

34

Nonspecific, viral-like symptoms that are gradual in onset appear first, as in H.W.’s

case, followed several days later by the other symptoms H.W. displayed. A hallmark

of the disease is hemolytic anemia of varying severity. A high index of suspicion for

babesiosis should be maintained in any patient with an unexplained febrile illness

who lives in or has traveled to a region where the infection is endemic during June

through August, as in H.W.’s case, particularly if there is a history of tick bite.

TREATMENT

CASE 82-9, QUESTION 2: Is atovaquone and azithromycin an appropriate treatment regimen for H.W.?

What other drugs have been used?

The discovery of an original human babesiosis treatment regimen combining

clindamycin and quinine was a fortuitous one. In 1982, an 8-week-old infant with

presumed transfusion-acquired malaria was initially treated with chloroquine.

Because of a lack of response, treatment was switched to quinine plus clindamycin,

and the patient’s fever decreased. A correct diagnosis of babesiosis was

subsequently confirmed. Although this treatment combination is still used, frequent

side effects (e.g., tinnitus, vertigo, and diarrhea) occur, often resulting in dose

reduction or discontinuation.

3,32 Treatment failures with this regimen have occurred in

splenectomized patients, patients with HIV infection, or those receiving concurrent

corticosteroids.

3

For mild-to-moderate babesiosis, atovaquone plus azithromycin is the regimen of

choice, as H.W. received. This regimen has also achieved cures in pediatric cases,

although a controlled trial study has not been performed.

32 On the other hand,

persistent relapsing babesiosis and emergence of resistance have occurred in

immunocompromised patients receiving this regimen.

33,35

It has been suggested that

the usual 7- to 10-day course treatment regimen may not be adequate in these

patients.

35 Combination therapy of azithromycin with atovaquone is better tolerated

than clindamycin–quinine combinations. The dosing is atovaquone 750 mg orally

every 12 hours and azithromycin 500 mg to 1,000 mg orally on day 1 and 250 mg to

1,000 mg on subsequent days for 7 to 10 days.

32

Increased azithromycin doses of 600

mg to 1,000 mg/day may be used in immunocompromised patients.

3,36 Children should

receive atovaquone 20 mg/kg (maximum, 750 mg dose) every 12 hours and

azithromycin 10 mg/kg (maximum, 500-mg dose) on day 1 and 5 mg/kg (maximum,

250-mg dose) orally thereafter for 7 to 10 days.

3,32

For severe babesial illness, the intravenous clindamycin plus oral quinine should

be given.

32 Dosing recommendations for adults are clindamycin 300 mg to 600 mg IV

every 6 hours plus quinine 650 mg orally every 6 to 8 hours for 7 to 10 days; children

should receive clindamycin 7 to 10 mg/kg (maximum, 600-mg dose) IV every 6 to 8

hours plus quinine 8 mg/kg (maximum, 650 mg dose) orally every 8 hours for 7 to 10

days.

3,32

Antimicrobials should be used in all patients with symptomatic, active babesiosis

once the diagnosis is confirmed by PCR or blood smear, owing to the risk of disease

complications.

34 Antibody-seropositive, symptomatic patients without identifiable

parasites on blood smear or PCR positivity should not be treated. Similarly,

asymptomatic patients should not be treated regardless of serologic results, blood

smear examinations, or PCR findings. A course of treatment should be considered in

asymptomatic patients, however, if these tests are positive and repeat testing

demonstrates persistent parasitemia for more than 3 months.

3,32

Partial or complete red blood cell transfusions may be lifesaving in severe

babesiosis for patients having high-grade parasitemia (10% or more infected

erythrocytes), significant hemolysis, or pulmonary, renal, or hepatic compromise.

3

Rapidly increasing parasitemia leading to massive intravascular hemolysis and renal

failure mandates immediate treatment for this form of the disease. Patients receiving

antibiotic treatment, in particular those with severe or persistent symptoms, should be

evaluated for coinfection with B. burgdorferi or A. phagocytophilum or both.

Babesiosis prevention is the same as for other tick-borne diseases. Asplenic

patients should avoid areas where babesiosis is endemic. To date, no supportive data

for the use of prophylactic antibiotics to prevent babesial infection after a tick bite

are available.

32 Although developed for use in cattle, babesial vaccines are not

available for humans.

THE VIRUSES: COLORADO TICK FEVER, TICKBORNE ENCEPHALITIS, AND OTHER VIRALLY

MEDIATED TICK-BORNE DISEASES

Colorado Tick Fever

VIRUS IDENTIFICATION, TICKS, AND HOST RESERVOIRS

“Mountain fever” has been described since the first immigrants arrived in the Rocky

Mountains. It was later renamed Colorado tick fever (CTF), and the Colorado tick

fever virus (CTFV) was identified as the cause.

CTF is caused by a double-stranded RNA Coltivirus. It is an intraerythrocytic

virus. At least 22 strains of CTFV are known, but antigenic variation among human

strains is low.

33 The virus is an arbovirus because it replicates inside ticks. The

primary nidus

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p. 1728

of infection is thought to be CTFV invasion of hematopoietic progenitor

erythroblasts, and it remains sheltered in mature erythrocytes.

37,38

CTF is a viral illness transmitted by the bite of an infected tick.

37 Although at least

eight tick species have been found to be infected with the virus, adult D. andersoni

ticks are the primary tick vector that transmits CTF to humans.

37,38 D. andersoni feeds

on numerous mammals, but ground squirrels, porcupines, and chipmunks are the

primary reservoirs for CTFV as well as the ticks themselves.

37,38 Transstadial

transmission of CTF virus within the tick ensures it is infected for life.

37

PREVALENCE

CTF is contracted in forested mountain areas at higher elevations of the western

Black Hills and Rocky Mountain regions of the United States and Canada, especially

on the south-facing brush slopes and dry rocky surfaces of mountains east of the

Continental Divide.

37,38 Although CTF can develop from March to October, May

through July are peak incidence months.

4,5

SYMPTOMS

CASE 82-10

QUESTION 1: T.P., a previously healthy 27-year-old native of Atlanta, Georgia, returns from a 1-week latespring camping trip with her friends in the eastern Colorado Rocky Mountains. Four days later, she experiences

fever, chills, headache, myalgias, conjunctivitis, and lethargy. She recalls no tick bites and has no skin rashes.

Suspecting RMSF, her physician prescribes doxycycline. T.P.’s symptoms and fever initially resolve, but 2 days

later her symptoms return. Physical examination at this time reveals a temperature of 39°C. Routine laboratory

tests are normal, although leukopenia is observed with a WBC count of 2,400/μL. Explain how T.P.’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 being bitten.

37,38 The most common initial symptoms are

fever of rapid onset, headache, chills without true rigors, and myalgias.

37 A rash,

which may be petechial, maculopapular, or macular, can occur in 5% to 15% of

patients.

38 About half of patients with fever experience a “biphasic” pattern of fever

and other symptoms, which means they have several days of fever, then improve for

several days, and then have a second period of fever and illness.

37,38 Sequelae are

rare, although fatigue and malaise may last for months.

38 One- to three-week periods

of convalescence are usual. Children, however, experience complications more

frequently than adults. Patients with suspected CTF should defer from donating blood

or bone marrow for at least 6 months after their illness because the virus may stay in

red blood cells for several months and can be passed to others via blood

transfusions.

LABORATORY FINDINGS

Moderate-to-significant leukopenia is the most important finding in CTF. Leukocyte

counts are usually normal on the first day, but decrease to 2,000 to 4,000/μL by the

fifth or sixth day of illness with a lymphocytic predominance.

38

In one-third of

confirmed CTF cases, however, the leukocyte counts remained around 4,500/μL.

Counts return to normal within a week of fever abatement in most cases.

Thrombocytopenia may occur.

37,38 Although the CSF may show a lymphocytic

pleocytosis, this does not distinguish CTF from other causes of

meningoencephalitis.

38

DIAGNOSIS AND TREATMENT

CTF diagnosis can be made serologically, either with IFA staining of erythrocytes,

complement fixation, or ELISA.

37,38 The most sensitive isolation system is

intracerebral injection of infected blood into suckling mice.

37,38 A reverse

transcriptase PCR of specimens can be diagnostic within the first 5 days of illness,

whereas serologic tests are more relevant for diagnosis 2 weeks after symptom

onset.

38 There is no specific treatment available for patients with CTF infection,

which is usually self-limiting. Supportive care should be provided. The best

protection for CTF is tick prevention strategies.

38

TICK-BORNE ENCEPHALITIS (TBE)

Tick-borne encephalitis, a life-threatening neurologic disease, is a growing public

health concern in Europe and Asia as the incidence of TBE virus has significantly

increased in the past decade.

4,34 TBE virus is divided into three subtypes: Central

European (western subtype), Siberian, and Far Eastern (Russian spring–summer or

eastern subtype), and is endemic to central and eastern Europe, Russia, and the Far

East, with some overlap in geography.

4,34

The etiologic agents are spherical, lipid-enveloped RNA viruses in the genus

Flavivirus.

4,39 The western subtype is transmitted to humans by I. ricinus, and the

Siberian and Far Eastern subtypes are transmitted by I. persulcatus, although I. ovatus

is the vector in Japan.

40 A minority of TBE cases have followed the consumption of

infected unpasteurized milk or cheese directly without a tick vector.

39 The main virus

reservoirs are small rodents.

39 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 the virus transovarially and

transstadially.

39 TBE viruses are transmitted from the saliva of an infected tick very

rapidly, within minutes of the bite, so early removal of the tick may not prevent

subsequent encephalitis.

As the disease name implies, the ultimate outcome of the infectious process is

manifested as CNS involvement, with symptoms of aseptic meningitis,

meningoencephalitis, and meningoencephalomyelitis. TBE begins as a febrile

headache with progression to CNS manifestations. There is no antiviral treatment

available and treatment is supportive, including management of any complications.

Two inactivated cell culture-derived preventive human TBE vaccines are available

in Europe, in adult and pediatric formulations (FSME-IMMUN and Encepur).

4 The

adult formulation of FSME-IMMUN is also licensed in Canada. Two other

inactivated TBE vaccines are available in Russia (TBE-Moscow and EncVir). The

reader is referred to the CDC for information regarding vaccination to TBE-endemic

countries.

4

POWASSAN DISEASE

Powassan virus infection is an RNA virus belonging to the genus Flavivirus that is

related to West Nile, St. Louis encephalitis, and tick-borne encephalitis viruses.

4

Powassan disease is now recognized in the United States, Canada, and Russia. In the

United States, approximately 60 cases have been reported in the past decade

primarily from northeastern states and the Great Lakes region. The incubation period

ranges from 1 week to 1 month. Many people who become infected are

asymptomatic. Signs and symptoms of illness can include fever, headache, vomiting,

and malaise. Because the Powassan virus can infect the CNS, progression of disease

to meningoencephalitis with confusion, seizures, and memory loss may occur. There

are currently no vaccines or treatment for Powassan disease. Supportive care should

be provided to patients with suspected disease.

p. 1728

p. 1729

THE TOXINS: TICK PARALYSIS

Tick Paralysis

CASE 82-11

QUESTION 1: C.M., a 7-year-old girl residing in Spokane, Washington, complains to her parents that she

feels weakness in both legs. The next day, her mother notices that C.M. has worsened and immediately takes

her to the pediatrician. The physician finds that C.M has begun experiencing flaccid paralysis in both legs and

the lower trunk, although she is alert and oriented. The pediatrician finds that there is a tick attached to C.M.’s

scalp under her hair and removes it. C.M. is back to full health in 2 days. What happened?

Tick paralysis (tick toxicosis) occurs worldwide in humans and many animals, and

was first described by the explorer Hovell in Australia in 1824.

40 Although 60 tick

species worldwide can produce tick paralysis in animals and humans, it is

predominantly caused in humans by D. andersoni and D. variabilis in North

America.

40

In Australia, Ixodes holocyclus is the culprit.

40

Most human cases occur during the spring and summer in Australia and North

America. In the United States, it is most common in the Pacific Northwest and

adjacent areas of southwestern Canada and in the Rocky Mountain states.

40

In

children, girls are more commonly affected; however, in adults, more men are

affected.

40 Of epidemiologic significance, a young girl’s long hair provides

camouflage for feeding ticks.

40

The cause of tick paralysis is the secretion of a neurotoxin present in the large

salivary glands of female ticks. They must usually be attached to a host for 4 to 5

days before symptoms develop.

40 The toxin affects motor neurons, decreases

acetylcholine release, and may have a mechanistic similarity to botulinum toxin.

40

Paresthesias and symmetric weakness in the lower extremities with motor difficulties

progress to an ascending flaccid paralysis in several hours or days. Cerebral

sensorium is usually spared, pain is absent, and the blood and CSF are normal.

40

If

the tick is not removed, the toxicosis can progress to respiratory paralysis and

death.

40

Initially reported mortality rates of 10% have fallen dramatically with our

modern intensive care units and available respiratory care.

40 A Washington State

case series of 33 patients conducted over the course of 50 years revealed a mortality

rate of 6%, with the last two patients’ deaths occurring in the 1940s.

40 Children are

likely more vulnerable to tick paralysis than adults because the dose of neurotoxin

present per kilogram of body weight is higher.

39 Diagnosis should include a complete

body examination of the skin for the presence of an engorged tick.

39

In North America, tick removal commonly results in complete recovery within

hours to days. In Australia, the disease is more acute, and paralysis may continue to

progress for 2 days after tick removal. Recovery from the disease in Australia may

take several weeks. Treatment is supportive. Antitoxin derived from dogs is the

treatment of choice for animals, but it also has been used occasionally in humans in

Australia with severe tick paralysis.

40 Local experts must determine its use on a caseby-case basis because of the risk of serum sickness or acute allergic reactions.

39

MIXED INFECTIONS

Because the tick vectors and mammalian hosts are the same for babesiosis,

anaplasmosis, and Lyme disease in the northeastern US, all three diseases,

theoretically, could be transmitted to a human from one tick bite. Human coinfection

by the agents of Lyme disease, babesiosis, or anaplasmosis can occur, especially in

endemic areas.

5 Coinfection may alter the natural course for each disease or increase

clinical manifestations, especially flu-like symptoms, in concurrent Lyme disease

with babesiosis or HGA. Because the same tick vector in Europe and Russia can

carry Lyme disease and TBE, dual infection may result in more severe disease.

39

Dual infection may affect the choice of initial antibiotic therapy. For example,

although amoxicillin is sometimes used to treat early Lyme disease, it is not effective

for HGA. Doxycycline, however, is useful in both of these diseases. Thus, some

cases of Lyme disease that were believed to be treatment failures may actually have

been confounded by coinfection. Patients with concurrent Lyme disease and

babesiosis have more symptoms and a longer duration of illness compared with

patients with single infections. When moderate-to-severe Lyme disease is diagnosed,

the possibility of concomitant babesial or anaplasma infection should be considered

in regions where both diseases are endemic. Neutropenia and thrombocytopenia are

associated with anaplasmosis, anemia and thrombocytopenia are associated with

babesiosis, and neither is routinely found in Lyme disease.

5 For patients with Lyme

disease who experience a prolonged flu-like illness that fails to respond to

appropriate antiborrelial therapy in an endemic area, clinicians should consider

testing for babesiosis and anaplasmosis.

5

SUMMARY

Most of the research into tick-borne human disease demonstrates a close historical

relationship of endemic tick-deer-rodent cycles for various microorganisms. Tick-

borne diseases have become increasingly challenging and a serious global problem.

Scientists continue to search for improvements in diagnosing, treating and preventing

tick-borne diseases, as well as controlling the tick populations that transmit

microbes. We will continue to encounter increasing cases of tick-borne human

disease of known or unknown causes. Because patients present frequently with

nonspecific signs and symptoms, a high index of suspicion is crucial to include a

tick-borne illness in the differential diagnosis of those presenting with symptoms

compatible with a tick-borne illness. It is essential to obtain a careful history of

possible tick exposure and consider the epidemiology of infected ticks when

considering the possibility of tick-borne illnesses. It is important to increase

awareness of personal protection strategies and tick avoidance.

ACKNOWLEDGMENT

The authors acknowledge Thomas E. Christian for his past contributions to this

chapter of this text.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Alpern JD et al. Personal protection measures against mosquitoes, ticks, and other arthropods. Med Clin N Am.

2016(100):303–313. (16)

Centers for Disease Control and Prevention. Tickborne Diseases of the United States. A Reference Manual for

Health Care Providers, 3rd ed. 2015. https://www.cdc.gov/lyme/resources/tickbornediseases.pdf.

Accessed January 17, 2017. (5)

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p. 1730

Diaz JH. Chemical and plant-based insect repellents: efficacy, safety, and toxicity. Wilderness Environ Med.

2016;27:153–163. (1)

Mead PS. Epidemiology of Lyme disease. Infect Dis Clin N Am. 2015(29):187–210. (6)

Sanchez E et al. Diagnosis, treatment, and prevention of Lyme disease, Human Granulocytic Anaplasmosis, and

Babesiosis. A review. JAMA. 2016;315(16):1767–1777. (10)

Wormser GP et al. The clinical assessment, treatment, and prevention of Lyme Disease, Human Granulocytic

Anaplasmosis, and Babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.

[published correction appears in Clin Infect Dis. 2007;45(7):941]. Clin Infect Dis. 2006;43:1089–1134. (11)

Key Websites

Centers for Disease Control and Prevention. Tickborne diseases of the U.S.

http://www.cdc.gov/ticks/diseases/. (4)

COMPLETE REFERENCES CHAPTER 82 TICK-BORNE

DISEASES

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2016;27:153.

Anderson JF, Magnarelli LA. Biology of ticks. Infect Dis Clin N Am. 2008;22(2):195, v.

De la Fuente J et al. Overview: Ticks as vectors of pathogens that cause diseases in humans and animals. Front

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Centers for Disease Control and Prevention. Ticks. http://www.cdc.gov/ticks/diseases/. Accessed January 17,

2017.

Centers for Disease Control and Prevention. Tickborne Diseases of the United States. A Reference Manual for

Health Care Providers, 3rd ed. 2015. https://www.cdc.gov/lyme/resources/tickbornediseases.pdf.

Accessed January 17, 2017.

Mead PS. Epidemiology of Lyme disease. Infect Dis Clin N Am. 2015(29):187–210.

Maraspin V, Ruzic-Sablijic E, Strele F. Lyme borreliosis and Borrelia spielmanii. Emerg Infect Dis. 2006;12:1177.

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Theel ES. The past, present, and (possible) future of serologic testing for Lyme disease. J Clin Microbiol.

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Sanchez E et al. Diagnosis, treatment, and prevention of Lyme disease, Human Granulocytic Anaplasmosis, and

Babesiosis. A review. JAMA. 2016;315(16):1767–1777.

Wormser GP et al. The clinical assessment, treatment, and prevention of Lyme Disease, Human Granulocytic

Anaplosmosis, and Babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin

Infect Dis. 2006;43:1089–1134.

Rivera Rivera KB, Blais CM. Tick-borne infections. Hosp Med Clin. 2015;4:489–499.

Hinckley AF et al. Effectiveness of residential acaricides to prevent Lyme and other tick-borne diseases in

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De la Fuente J, Contreras M. Tick vaccines: current status and future directions. Expert Rev Vaccines.

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CLINICAL ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

Anxiety disorders are characterized by anxiety that is out of proportion

to any actual threat and is excessive for the situation or distressing to

the point that it interferes with daily functioning. Both medical and

medication-related factors can cause or exacerbate anxiety.

Case 83-1 (Question 1),

Table 83-2

GENERALIZED ANXIETY DISORDER

Generalized anxiety disorder (GAD) is defined in the Diagnostic and

Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5) as a

chronic state of waxing and waning anxiety that is associated with an

inability to controlsymptoms of anxiety and worry. The severity of

anxiety and the degree of impairment in daily activities are the main

determinants of whether medication should be used to treat GAD.

Case 83-2 (Question 1),

Table 83-3

First-line therapies for the treatment of GAD may include medications

such as venlafaxine, duloxetine, selective serotonin reuptake inhibitors

(SSRIs), buspirone, or benzodiazepines, when a rapid onset is needed.

Psychotherapy, such as cognitive behavioral therapy (CBT), can also be

used alone or in combination with medications. Specific treatment for

GAD should be chosen based on prior therapy, comorbid psychiatric

disorders, pharmacokinetic drug properties, desired onset of effect, and

patient preference.

Case 83-2 (Questions 2, 3),

Tables 83-4, 83-5, 83-6, 83-8

When beginning treatment with benzodiazepines for GAD, patients

should be educated about possible adverse effects, dependence liability,

and drug–drug interactions. Possible effects on pregnancy,

teratogenicity, and breast-feeding should also be discussed.

Case 83-2 (Questions 4, 5),

Case 83-3 (Question 1),

Case 83-4 (Questions 1, 2),

Case 83-5 (Question 1),

Case 83-6 (Questions 1–3),

Table 83-7

Patients beginning treatment with SSRIs, venlafaxine, or duloxetine

should be counseled regarding possible adverse effects that may occur

early in treatment, as well as those that may occur later and display a

more chronic time course. Additionally, all patients being treated with

medications for GAD should be counseled regarding the duration of

drug therapy.

Case 83-2 (Question 6)

PANIC DISORDER

Panic disorder is characterized by short episodes of intense fear,

associated with perceived physicalsymptoms such as increased heart

rate or respiration, gastrointestinal disturbance, tremor, or feelings of

disassociation with the physical body that are often not diagnosed or

misdiagnosed because they are attributed by the patient to a medical

illness.

Case 83-7 (Question 1),

Table 83-9

Therapy for panic disorder includes CBT, medications (SSRIs,

venlafaxine, TCAs, or benzodiazepines), or combination therapy. The

expected short-term adverse effects such as jitteriness should prompt

using a lower initial medication dose and be discussed with the patient.

Case 83-7 (Questions 2–4),

Table 83-5

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SOCIAL ANXIETY AND SPECIFIC PHOBIAS

Both social anxiety and specific phobias involve fears that are excessive

and lead to avoidance behaviors to minimize fear. Social anxiety

involves a generalized and intense anxiety involving social interactions,

whereas specific phobias involve intense fear associated with specific

objects or situations (e.g., spiders or elevators). SSRIs are first-line

treatments for social anxiety, whereas psychotherapy is the primary

treatment of specific phobias.

Case 83-8 (Questions 1–3),

Tables 83-5, 83-10

POST-TRAUMATIC STRESS DISORDER AND ACUTE STRESS

DISORDER

Post-traumatic stress disorder (PTSD) and acute stress disorder occur in

persons who have experienced a severely distressing traumatic event.

Re-experiencing symptoms, avoidance, hyperarousal, and negative

alterations in cognition and mood cause considerable psychological

distress, as well as impairment in occupational functioning and personal

relationships in PTSD.

Case 83-9 (Question 1),

Table 83-11

Medications, primarily SSRIs, and CBT are used to treat PTSD.

Adjunctive treatment for psychiatric comorbidities such as depression or

sleep is often indicated. Treatment goals include reducing the core

symptoms of PTSD and improving patient functioning.

Case 83-9 (Questions 2, 3),

Table 83-5

OBSESSIVE–COMPULSIVE DISORDER

Obsessive–compulsive disorder (OCD) is characterized by chronic

obsessions and/or compulsions. Obsessions and compulsions can be

extremely disabling and usually consume at least an hour a day. OCD

can be treated with medications (SSRIs, clomipramine, or venlafaxine),

psychotherapy (CBT with or without exposure therapy), or combined

modalities for optimal therapy. Despite combination therapy, up to 40%

of patients may continue to experience disabling symptoms.

Case 83-10 (Questions 1–5),

Table 83-5

Owing to incomplete remission of symptoms with monotherapy in many

patients suffering from OCD, augmentation strategies involving the

combination of antidepressants or adjunctive antipsychotics may be

considered with vigilant monitoring for increased adverse effects and

drug–drug interactions.

Case 83-11 (Questions 1–3)

Anxiety can be described as an uncomfortable feeling of vague fear or apprehension

accompanied by characteristic physical sensations. It is a normal reaction to a

perceived threat to one’s physical or psychological well-being. Anxiety is normally

provoked by stress and involves activation of neurobiologic systems that, when

activated, contribute to self-preservation. It involves two basic components: mental

features (e.g., worry, fear, difficulty concentrating) and physical symptoms (e.g.,

racing heart, shortness of breath, trembling, pacing). Certain medical illnesses (e.g.,

pheochromocytoma or hyperthyroidism) and/or medications (e.g., sympathomimetics)

can result in both the physical and psychological manifestations of anxiety. However,

when the anxiety is attributable to an external cause such as a medical illness or a

medication, the anxiety abates when the physiological cause is removed.

1

If the anxiety is not the result of an external cause, is out of proportion to the actual

threat, or persists beyond the presence of the threat, it may be classified as an anxiety

disorder. Pathologic anxiety should be differentiated according to whether it occurs

(a) as a primary anxiety disorder, (b) as a secondary anxiety disorder owing to

medical causes or substances, (c) in response to acute stress (e.g., loss of a loved

one, marital or financial problems), or (d) as a symptom associated with other

psychiatric disorders to guide optimal treatment.

1

Classification and Diagnosis of Anxiety Disorders

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)

classifies primary anxiety disorders into seven types: generalized anxiety disorder

(GAD), panic disorder, phobic disorders (including specific and social anxiety

disorder), separation anxiety disorder, selective mutism, and agoraphobia.

1

Obsessive–compulsive disorder (OCD) and post-traumatic stress disorder (PTSD)

are classified under new headings in DSM-5. Each disorder involves an unhealthy

level of anxiety, but the characteristic type and severity of symptoms, course of

illness, and efficacy of drug and nondrug treatments vary indicating underlying

biologic differences. The DSM-5 secondary anxiety disorders include “anxiety

disorder due to a general medical condition” and “substance/medication-induced

anxiety disorder.”

1 Anxiety disorders often present in addition to other psychiatric

disorders, such as mood disorders. Both are associated with dysregulations in the

limbic system and, therefore, share similar symptoms, including fatigue, impaired

concentration, restlessness, difficulties with sleep, and somatic symptoms, although

mood disorders have a prominent mood factor.

2

Neurobiology of Anxiety

The limbic system, which is involved in emotion, learning, and memory, is composed

of a set of structures integral to behavior, including the hippocampus and the

amygdala. Hippocampal brain circuits are essential for conversion of short-term to

long-term memory and for spatial memory, whereas the amygdala circuits are

involved with emotion and its expression. A neurocircuit arising from the output

pathways of the amygdala is believed to mediate fear and anxiety

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responses in humans.

3 Dysregulated or exaggerated output through various amygdalarelated circuits may be a common element underlying the different anxiety disorders,

but the specific type of dysfunction probably differs among the various disorders. If it

is assumed a dysregulation of the stress response is the basis of anxiety disorders,

then the genesis of anxiety is probably related primarily to interactions between

neural pathways in and between the limbic system structures, the sympathetic nervous

system, and the hypothalamic–pituitary–adrenocortical (HPA) axis.

2,4 Many

neurotransmitter and neuroendocrine systems interact to modulate the actions of the

limbic pathways, including the monoamine neurotransmitters, epinephrine and

norepinephrine (NE); corticotrophin-releasing hormone (CRH); the indoleamine,

serotonin (5-HT); the inhibitory amino acid, γ-aminobutyric acid (GABA); the

excitatory amino acid, glutamate; and the neuropeptides, cholecystokinin (CCK),

neuropeptide Y, and substance P.

3,5 As such, the genes from which these products are

derived and regulated are an active area of research. Furthermore, epigenetic

mechanisms are being investigated to explore the complex relationship between

gene–environment interactions.

6

Interaction of the Hypothalamic–Pituitary–

Adrenocortical, Noradrenergic, and Serotonergic

Systems

In the event of an acute threat, a fear stimulus is transmitted via the thalamus to the

amygdala, which then projects to both the hypothalamus and the brainstem. This

results in the peripheral reactions such as increased heart rate and heart stroke

volume, and vasodilation of blood vessels carrying blood to the muscles. This is

accompanied by a release of NE by the locus coeruleus (LC), the main nidus of NE

cell bodies in the brain. Central release of NE results in vigilance, arousal, the

ability to focus attention on the threat, and symptoms of anxiety (e.g., tachycardia,

tremor, sweating). NE innervation of the hippocampus results in an increased state of

memory formation, whereas innervation of the amygdala potentiates the formation of

aversive memories.

4 Normally, this is important in allowing us to encode emotionally

laden memories, but when overactive, it may result in a constant state of arousal and

hypervigilance.

During a perceived threat, CRH is released in the hypothalamus, and it activates

the anterior pituitary to release adrenocorticotropic hormone (ACTH). This

stimulates the release of glucocorticoid steroids from the adrenal cortex. Although

short-term elevation of glucocorticoids allows the body to adapt to a stressful

situation by supporting HPA activation and mobilizing energy stores, prolonged

elevation of the same glucocorticoids impairs neural plasticity and may even result in

neuronal death. When CRH is infused into the LC in rodents, it causes anxiety-like

behaviors.

2,4,7

Although the inhibitory neurotransmitter 5-HT is involved in stress reactions, its

role is not entirely clear. Serotonin has roles in sleep, appetite, memory, impulsivity,

sexual behavior, mood, motor function, and seems to decrease aggressive behavior.

The site of most 5-HT cell bodies in the brain is the raphe nuclei. There is

considerable interconnectivity between the raphe nuclei and the LC, and they tend to

mutually inhibit one another. Under normal circumstances, 5-HT connections from the

hippocampus decrease activity in the amygdala, which would dampen fear and

anxiety responses. However, under conditions of stress, the LC accelerates firing,

inhibits the raphe nuclei firing, and increases CRH release—all of which sensitize

the limbic system and cause arousal and sensitivity to memory of any stressful or

aversive stimuli. This primes the system to a state of arousal to deal with the threat.

2

Although the specific etiology of anxiety is only hypothesized, the current use of

treatments activating the 5-HT system, or other inhibitory systems such as the GABA

system, supports the hypothesis.

Epidemiology and Clinical Significance of Anxiety

Disorders

As a group, anxiety disorders are the most common psychiatric illnesses.

Epidemiologic surveys indicate 13% to 28% of Americans suffer from an anxiety

disorder at some time in their lives, with similar prevalences in other parts of the

world.

8,9 Anxiety disorders are more common in women than in men.

9

Today, most anxiety disorders can be successfully treated with medications,

cognitive or behavioral therapies, or combinations thereof. However, less than onethird of those affected seek help, and many who do are not properly diagnosed.

9 Most

medical care for anxiety disorders is rendered in nonpsychiatric settings. Patients

commonly present to primary-care providers complaining of physical symptoms that

cannot be medically explained, leading to progression of the anxiety disorder. A

significant portion of patients with anxiety does not believe in taking medication for

emotional problems; others remain untreated because of an inappropriate diagnosis.

10

Because anxiety is a feeling with which everyone is familiar, there is a tendency to

trivialize the impact it can have on a sufferer’s functioning and quality of life. An

increased understanding about pathologic anxiety is needed in society and healthcare

professionals, in particular, so that people seek and receive appropriate treatment. A

list of consumer and professional resources for information about anxiety disorders

and treatment can be found in Table 83-1.

Clinical Assessment and Differential Diagnosis of

Anxiety

CASE 83-1

QUESTION 1: R.R., a 49-year-old woman, complains to her physician of having trouble sleeping, feeling tired

and nervous, and worrying constantly. R.R. was divorced 2 years ago, and she retained custody of their 15-

year-old daughter. Since her divorce, R.R. has returned to work as a nurse, but she worries constantly that she

will not be able to earn enough money to support herself and her daughter. She has hypertension, asthma, and

seasonal allergies for which she is prescribed hydrochlorothiazide 12.5 mg/day, losartan 50 mg/day, montelukast

10 mg/day, albuterol 1-2 puffs every 4-6 hours as needed (PRN) wheezing and shortness of breath, and

pantoprazole 40 mg/day. She also takes over-the-counter (OTC) loratadine 10 mg/day and pseudoephedrine 60

mg every 4 to 6 hours PRN for allergies, naproxen 200 mg every 8 to 12 hours PRN for occasional back pain,

and polyethylene glycol 17 g daily PRN for constipation. R.R. drinks three or four cups of coffee each morning

and one or two glasses of wine four nights each week to help her calm down when she has had a stressful day.

She denies any history of psychiatric illness but states she has always been a “worrier.” What factors should be

considered in the clinical assessment and differential diagnosis of R.R.’s symptoms of anxiety?

A diagnostic decision tree such as that in Figure 83-1 can be used to assist the

clinician in differentiating among various causes of anxiety and different anxiety

disorders. According to DSM-5 criteria for primary anxiety disorders, the symptoms

should not be secondary to any medical (drug or disease) causes (Table 83-2).

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Table 83-1

Resource Organizations for Anxiety Disorders

Anxiety Coach

Website: www.anxietycoach.com

Anxiety Disorders Association of America

Website: www.adaa.org

Freedom From Fear

Website: www.freedomfromfear.org

International OCD Foundation

Website: www.iocdf.org

Mental Health America

Website: www.nmha.org/

National Alliance on Mental Illness

Website: www.nami.org

PTSD Gateway

Website: www.ptsdinfo.org

SECONDARY CAUSES OF ANXIETY

A diagnosis of anxiety disorder attributable to a general medical condition is

warranted when symptoms are believed to be the direct physiologic consequence of a

medical condition.

1 A complete physical and laboratory workup, with a thorough

medical and psychiatric history, is needed to exclude reversible causes before a

primary anxiety disorder diagnosis is considered. Because new onset of anxiety

disorders in elderly persons is rare, this can often be attributed to some medical or

substance-related cause. The presence of anxiety may complicate the medical picture

and have a negative impact on the course of illness. Also, it should be noted R.R. is

49 years old, and the median age for onset of menopause is 52 years. Although not a

medical illness, menopausal symptoms also may include sleep disturbances and

mood swings.

Medical illness is associated with higher rates of anxiety compared with the

general population.

11

In some cases, the anxiety is physically induced by the medical

condition, but reactional anxiety may also occur when faced with a medical illness.

Successful management of the medical condition often relieves associated anxiety,

but short-term anxiety treatment may be beneficial.

When evaluating for possible causes of anxiety, it is also important to consider all

medications a person is taking, including OTC drugs such as cough and cold

preparations.

12 A diagnosis of substance-induced anxiety disorder is warranted when

anxiety symptoms occur in relation to substance intoxication or withdrawal or when

medication use causes the symptoms. Among the medications R.R. is taking,

pseudoephedrine might be contributing to her anxiety. Other medications that can

cause anxiety are listed in Table 83-2. Psychoactive substance abuse, withdrawal

from central nervous system (CNS) depressants (e.g., alcohol, barbiturates,

benzodiazepines), excessive caffeine intake, and nicotine withdrawal may go

unrecognized as underlying precipitants of anxiety. R.R.’s current pattern of alcohol

use, although not excessive, may become problematic if she uses alcohol to selfmedicate her anxiety symptoms.

Although anxiety symptoms are the hallmark characteristic of anxiety disorders, it

is not unique to this diagnostic category. Virtually any psychiatric illness may present

with these symptoms. If anxiety symptoms occur only in relation to another

psychiatric disorder, then a separate anxiety disorder diagnosis is precluded. Anxiety

in these cases may be alleviated with successful treatment of the primary psychiatric

disorder. For example, R.R.’s difficulties with fatigue and sleeping may be target

symptoms of either anxiety or depression, or possibly both. However, individuals

with other psychiatric disorders can also have a primary anxiety disorder. In fact,

comorbidity with anxiety disorders is the rule rather than the exception, particularly

for depression.

7,13 Concurrent anxiety and depression are associated with greater

disability, poorer treatment outcomes, and higher suicide rates than either depression

or anxiety alone.

Anxiety in response to life stressors may be severe and functionally detrimental,

but could be considered appropriate for the circumstances. Usually, this type of

anxiety is self-limiting and brief, subsiding over days to weeks as the person adapts

to the new situation. If the person has no history of an anxiety disorder and the

symptoms last only a few months, a diagnosis of adjustment disorder with anxious

mood may be appropriate. If the symptoms are severe and continue for a prolonged

period, a primary anxiety disorder may be present. The initial onset of a chronic

anxiety disorder often occurs during a stressful period. Short-term or intermittent

therapy with anxiolytic medication or counseling can be extremely beneficial in

helping persons cope during times of acute stress. In contrast, management of primary

anxiety disorders usually requires more extended treatment.

In summary, the factors in R.R.’s case warranting further investigation before a

primary anxiety disorder diagnosis can be made include her medical illness (asthma),

possible onset of menopause, her use of pseudoephedrine and caffeine, and her

adjustment to the recent life changes (divorce, returning to work, becoming a single

mother). These factors need to be addressed and treated, if possible, before a

diagnosis of an anxiety disorder can be applied and appropriately managed.

GENERALIZED ANXIETY DISORDER

Epidemiology and Clinical Course

Generalized anxiety disorder is one of the most common anxiety disorders, with a

lifetime prevalence of about 9% and is twice as common in women than in men.

1,14

Onset is usually gradual and may be associated with increased life stressors. GAD

usually begins between the mid-teens and mid-50s and the median age of onset is 30

years.

9,14 As such, GAD presents the latest of all anxiety disorders.

1 Whites are more

likely to report anxiety symptoms than Asians, Hispanics, and African Americans.

15

The typical course of GAD is described as being chronic and recurrent, but much is

unknown about the long-term course of illness. Without treatment, it appears that less

than half of GAD cases undergo remission.

Most people with GAD have at least one other psychiatric disorder. Common

comorbid disorders include panic or social anxiety disorder, simple phobia, OCD,

and major depressive disorder.

8 Lastly, evidence suggests that GAD itself may be a

risk factor for suicidal ideation, particularly among women, even when comorbid

substance abuse and depression are considered.

16

Diagnostic Criteria

GAD is characterized by excessive anxiety and worry about life issues for 6 months

or longer.

1 The patient usually has great difficulty controlling the worry, which is

accompanied by at least three of the associated symptoms listed in Table 83-3.

Although some physical symptoms are similar between GAD and other anxiety

disorders, if the anxiety is related solely to another anxiety disorder (e.g., obsession

with germs, fear of social situations), a diagnosis of GAD is not warranted.

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Figure 83-1 Diagnostic decision tree for anxiety disorders. GAD, generalized anxiety disorder; OCD, obsessive–

compulsive disorder; PTSD, post-traumatic stress disorder.

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