4,11 Similar to erythromycin, they are less effective in the treatment of Lyme
disease. The combination of a macrolide with lysosomotropic agents, especially
hydroxychloroquine, anecdotally has been suggested to be associated with increased
symptom relief probably related to combined anti-inflammatory activity rather than
direct antimicrobial activity.
3 Doxycycline is well absorbed orally and is less
expensive than parenteral ceftriaxone or cefotaxime. Doxycycline has a long serum
half-life of 18 to 22 hours. In addition, doxycycline penetrates into the cerebrospinal
fluid (CSF) at concentrations of at least 10% of serum levels, even in the absence of
meningeal inflammation. Although not as significant as with tetracycline, doxycycline
can complex with divalent or trivalent cations in the gut, with an associated decrease
in oral absorption. On the other hand, administering doxycycline with food, to
minimize nausea, is recommended.
3 Compared with other tetracyclines, doxycycline
has the least affinity for divalent calcium cations, and oral absorption is reduced by
only 20% if given with milk. The major side effect of doxycycline is phototoxicity,
which is of concern because Lyme disease usually occurs during sunny times of the
year. A less recognized side effect is the risk of doxycycline-induced esophageal
ulceration. Patients should be instructed to never take doxycycline or other
tetracyclines near bedtime and to take the medication while standing up with at least
240 mL of clear fluid, especially with the capsule formulation. Despite less in vitro
activity compared with some β-lactam antibiotics, B. burgdorferi is sufficiently
susceptible to doxycycline, and clinical experience with doxycycline has been very
favorable. In conclusion, doxycycline was a suitable choice for M.K.
repeated for M.K.’s arthritis?
Acute Lyme arthritis occurs from the accumulation of neutrophils, cytokines,
immune complexes, complement, and mononuclear cells induced by the spirochete.
Appropriate antimicrobial treatment of acute Lyme arthritis is usually successful, and
doxycycline, amoxicillin, or cefuroxime axetil is recommended for adult patients,
such as M.K., if there is no clinical evidence of neurologic disease.
Lyme arthritis typically requires 28 days of therapy.
11 A minority subset of patients
may have persistent Lyme arthritis.
It is very unlikely that this is attributable to the
continued presence of B. burgdorferi in the joint, but rather to the patient’s continued
inflammatory response or autoimmunity.
12 Polymerase chain reaction (PCR) testing of
synovial fluid can be considered, and if negative, symptomatic therapies may be
offered rather than repeated antibiotic courses. Such patients often respond well to
synovectomy, suggesting that the presence of synovitis may not be the result of
3,11 However, it should be noted that before the
antibiotic treatment era for Lyme disease, even the most prolonged cases of persistent
Lyme arthritis eventually improved without treatment, although sometimes lasting for
QUESTION 1: E.T., a 57-year-old female, presents to her PCP with symptoms of early neurologic Lyme
E.T. be treated with antibiotics? If so, how long should she be treated?
Although rare, late neurologic complications of Lyme disease may present as
encephalopathy, peripheral neuropathy, or encephalomyelitis.
Borrelia species found in Europe do not strictly overlap with those species found in
the United States, there are no data to support a differential response to antibiotic.
Based on these studies, oral doxycycline can be considered as first-line therapy for
neurologic Lyme disease in Europe and for ambulatory patients with early neurologic
Lyme disease in the United States. An oral antibiotic treatment regimen may suffice in
cases of early neurologic disease, but parenteral regimens are appropriate for severe
In conclusion, E.T. can be treated with doxycycline administered orally and
should be reassessed following treatment.
about it. How should you respond?
Chronic Lyme disease is a confusing term, and most authorities agree that there
may be “Post-Treatment Lyme Disease Syndrome,” (PTLDS).
cause is unknown, most medical experts believe that the lingering symptoms that can
occur are the result of residual damage to tissues and the immune system. Clinical
findings in patients may include fatigue, widespread musculoskeletal pain, cognitive
difficulties, or subjective symptoms of such severity that a substantial reduction in
quality of life has occurred. The subjective symptoms must include an onset within 6
months of the initial Lyme disease diagnosis and persistence for at least 6 months
after completion of antimicrobial therapy. If adherence to a recommended Lyme
treatment regimen is confirmed, the existence of symptomatic, chronic infection by B.
burgdorferi is difficult to confirm. After appropriately targeted antibiotic therapy for
early Lyme disease, treatment failure is exceedingly rare. The organism has not been
shown to develop antibiotic resistance.
3 For these patients with chronic subjective
symptoms for more than 6 months, repeated or prolonged antibiotic therapy is not
The friend should be encouraged to seek additional diagnostic workup for other
diseases. Even in patients who have had verified Lyme disease, the aches and pains
of daily living they experience appear to be more related to their post-treatment
symptoms than to Lyme disease itself.
QUESTION 1: A family living in a Lyme disease endemic area is concerned regarding their risk for
Although some vector-borne diseases are prevented through vector control, this
has proven difficult for tick-borne diseases because of a lack of efficacy or
environmental concerns with the use of pesticides. Evaluated methods include habitat
destruction by fire, chemical spraying agents such as acaricides to achieve tick
eradication, culling or removal of host deer, or protection of mice from tick
Currently, there are limited vaccines available for tick-borne and mosquito-borne
14 A Lyme disease vaccine for humans is no longer available in the United
States. Citing low demand, the U.S. manufacturer discontinued production in 2002.
Clinical trials are currently underway for candidate Lyme borreliosis vaccines.
The first step in prevention of Lyme disease is personal protection and tick
16,17 Tick repellents may be applied to the skin or clothing. One basic
(IR) 3535 (ethyl butylacetylaminopropionate). The second chemical category of
repellant is the plant-derived oils and synthetics, such as oil of lemon eucalyptus or
PMD (para-menthane-3,8-diol), which is an extract of the leaves of lemon
eucalyptus, Corymbia citriodora, a synthesized version of oil of lemon eucalyptus.
The use of DEET skin repellent has evolved as the standard repellant for mosquito
and tick-borne diseases. In combination with a permethrin clothing, DEET appears to
offer adequate protection. DEET has been tested against Ixodid ticks for repellence
and is more effective than dibutyl phthalate, dimethyl phthalate, pyrethrum, and two
16,17 DEET is generally safe; however, excessive DEET
application has been associated with seizures in children.
however, and if the products are used according to their labeling, the adverse
reaction risk is low, even for children older than 2 months of age.
excessive application is not recommended. It may be prudent to use the lowest
effective concentration of DEET-containing repellents, such as those containing 20%
to 30%. To minimize DEET toxicity, the product should be applied sparingly,
inhalation or introduction into the eyes should be avoided, repellent-treated skin
should be washed when coming inside, use on children’s hands (that are likely to
have contact with the eyes or mouth) should be avoided, and it should be applied
only to intact skin or clothing.
Picaridin was developed in Europe in the 1990s and released in the United States
about 10 years ago. A couple of advantages over DEET include the lack of a
chemical odor and its nonsticky or greasy feel. It is also safe to use on plastics,
whereas DEET may damage certain synthetics including eyeglass frames. IR3535,
originally marketed in the United States as a skin emollient and moisturizer, was then
adopted for use as an insect repellant. Plant-derived IRs, such as oil of lemon
eucalyptus or PMD, have demonstrated efficacy against the tick vectors of Lyme
disease (Ixodes scapularis, Ixodes pacificus) and Rocky Mountain spotted fever
A literature review between 2000 and 2012 on the efficacy of repellants against
various mosquito and tick species noted that there are only limited studies conducted
on tick behavior and repellant efficacy against the tick species Ixodes.
picaridin, IR 3535, and PMD were also reviewed as part of this study. Results of this
study found that the use of IR 3535 provided the longest protection against Ixodes
scapularis, whereas DEET and commercial products containing picaridin or PMD
demonstrated a better response than IR 3535 against Ixodes ricinus.
which environmental exposure to disease-transmitting ticks, biting midges, sandflies,
or blackflies is anticipated, topical repellants containing IR 3535, picaridin, or oil of
eucalyptus (or PMD) would offer better protection than topical DEET alone.
to Chapter 81, Parasitic Infections, Table 81-2, Mosquito Protection Measures for
additional information on insect repellants).
Physical barriers to ticks, such as wearing protective garments—long pants, and
long-sleeved shirts—tucking shirts into pants and pants into boots, and wearing
closed-toed shoes, prevent infection.
1 Ticks are easier to spot on light-colored
clothing. Checking the body for ticks regularly is recommended; any that are found
should be promptly removed. Avoiding tick habitats is the best protection against
tick-borne diseases. Effective postexposure antibiotic prophylaxis can be
administered in Lyme disease endemic areas after a tick bite.
Relapsing fever, a bacterial infection caused by a variety of Borrelia species, causes
episodes of fever, nausea, headache, and muscle and joint aches. Of the two types of
relapsing fever, tick-borne relapsing fever (TBRF) occurs in the western US and
louse-borne relapsing fever (LBRF) is generally restricted to refugee settings in
developing parts of the world.
or domestic animals and, incidentally, on humans. In North America, three tick
species carry the agents of endemic relapsing fever with apparent strict specificity. In
fact, the names of the responsible Borrelia species have been adopted from the three
tick species that transmit them: Ornithodoros hermsii, Ornithodoros parkeri, and
20 Although the ticks themselves may serve as reservoir hosts,
the Borrelia usually circulate among wild rodents, ticks, and possibly birds.
to Lyme disease, greater worldwide variations of endemic cycles and vectors for
TBRF may exist than in North America.
In North America, relapsing fever is an uncommon disease largely confined to the
geographic distribution of the tick species that harbor the Borrelia. In the United
States, most cases of TBRF have occurred in 14 western states and are caused by B.
5 These ticks are usually found in the remote natural settings of the mountains
and semiarid plains of the far west and Mexico. TBRF can develop when people
visit tick- or rodent-infested cabins or summer homes. While TBRF is spread by
multiple tick species, Ornithodoros hermsii is the tick responsible for most cases in
the United States usually at altitudes of 1,500 to 8,000 feet. The health significance of
O. parkeri and O. turicata transmits its Borrelia at lower altitudes in the Southwest,
where they inhabit caves and the borrows of ground squirrels, prairie dogs, and
Ticks acquire spirochetes from blood feeding on small wild rodents. If high levels of
Borrelia are present in the animal’s blood, large numbers of spirochetes will be
ingested by the tick and reside in the tick’s midgut. During the next few days, the
spirochetes invade the midgut wall, traverse the hemolymph system, and within a few
weeks infect the salivary glands as well as other tick tissues and organs. Females
may develop infected ovaries and transmit Borrelia to offspring in some
Ornithodoros species, but this is rare in O. hermsii.
salivary glands, the spirochetes are poised to invade the tick’s next host.
In contrast to the hard-bodied ticks, these soft ticks feed rapidly, often detaching after
20,21 They feed at night while people are sleeping, and their bite is
usually painless. Therefore, most people are unaware that they have been bitten.
The hallmark of endemic relapsing fever is an abrupt onset of high fever (often
>39°C) after an incubation period of 4 to 18 days.
shaking chills, severe headache, abdominal pain, myalgias, arthralgias, nausea,
vomiting, and malaise. A few cases of acute respiratory distress syndrome have
20 The fever usually breaks in 3 days (range, 12 hours to 17
20 After a variable afebrile period of 3 to 36 days (usually
7 days), cyclic periods of fever and constitutional symptoms reappear. Each febrile
attack progressively diminishes in severity. Three to five relapses typically occur in
Routine laboratory testing is of little value. Moderate anemia and an increased
erythrocyte sedimentation rate (ESR) are common. Leukocyte counts may be normal,
yet moderate-to-severe thrombocytopenia is commonly observed but is considered
nonspecific. The diagnosis of relapsing fever is made by direct observation of the
spirochete on a peripheral blood smear while the patient is febrile.
the smear is enhanced with Wright or Giemsa staining. Few diagnostic laboratories
perform antibody serology tests; however, these tests lack specificity.
of a rash to identify the spirochete is unreliable. Direct culture of the spirochete from
the blood into a special culture medium is the most specific diagnostic tool, but this
is a slow technique confined to research laboratories.
These Borrelia have not demonstrated antibiotic resistance. Successful treatment
regimens usually include a 7- to 10-day course of antibiotics.
mg every 6 hours for 10 days) is the preferred regimen. Erythromycin is an effective
alternative at a dose of 500 mg (or 12.5 mg/kg) every 6 hours for 10 days. For
individuals experiencing central nervous system (CNS) involvement, ceftriaxone (2
g/day for 10–14 days) is preferred. Hospitalization and administration of IV
antibiotics may be required in severely ill patients.
QUESTION 1: T.J. is a 49-year-old man who visits his PCP with a sudden onset of high fever, severe
and outdoor activities are consistent with areas with prior outbreaks where relapsing fever has been
respiration rate. What do these symptoms represent? Is this an adverse drug reaction?
Up to 54% of patients with relapsing fever experience a reaction, a Jarisch–
Herxheimer reaction, to the first dose of antibiotic (see Chapter 72 Sexually
It may occur in LBRF, TBRF, and in other spirochetal
diseases such as syphilis or Lyme disease.
3 The dramatic reaction consists of a rise
in temperature, chills, myalgias, tachycardia, hypotension, increased respiratory rate,
20 Treatment of the reaction consists of supportive care. Severe
reactions may require hospitalization for vital sign monitoring and management of
hypovolemia. Although this is a reaction to the administration of an antibiotic drug, it
is not an allergic response, and the antibiotic should be continued.
CASE 82-6, QUESTION 2: T.J. continues with antibiotic therapy and his symptom resolves. Given his
typically present and what treatment options are available?
Borrelia miyamotoi is a bacterial species that is closely related to the bacteria that
cause TBRF and distantly related to Borrelia burgdorferi that causes Lyme disease.
While first identified in 1995 in ticks from Japan, B. miyamotoi has been detected in
two species of North American ticks, the black-legged or deer tick (I. scapularis) and
the western black-legged tick (I. pacificus). The first human cases of infection were
identified in Russia and described in 2011, followed by the first recognized cases in
northeastern United States in 2013.
22 To date, there are less than 60 well-documented
cases of B. miyamotoi in the United States. Because ticks are also known to transmit
several diseases, including Lyme disease, anaplasmosis, and babesiosis, researchers
and healthcare providers need to learn more about the transmission and signs and
Patients with B. miyamotoi infection generally experience nonspecific symptoms
such as fever, chills, headache, myalgia, and arthralgia.
rash was an uncommon finding, with only 4 out of 51 patients experiencing a rash.
The blood tests that are used for Lyme disease are not helpful in the diagnosis of B.
miyamotoi infections. Currently, the PCR tests that detect DNA from the organism or
antibody-based tests are used for confirmatory diagnosis. Patients with B. miyamotoi
have been successfully treated with a 2 to 4 week of doxycycline, and amoxicillin
and ceftriaxone have also been used. Borrelia miyamotoi disease will continue to be
evaluated, and it may be an emerging tick-borne infection in the northeastern region
SOUTHERN TICK-ASSOCIATED RASH ILLNESS (STARI)
Amblyomma americanum (the lone star tick) is found throughout the southeast and
south-central US and along the Atlantic coast as far north as Maine, and its territory
4 The lone star tick aggressively bites humans in the southern states, as
opposed to I. scapularis ticks.
5,24 Spirochetes detected by microscopy and culture
have been found in 1% to 5% of lone star ticks and are named Borrelia lonestari.
B. lonestari and B. burgdorferi, however, were ruled out as the cause of EM -like
skin lesions known as STARI in one Missouri investigation.
the agent of this Lyme-like illness, although exhaustive, have been unsuccessful.
causative agent of STARI has not yet been confirmed. There are differences in the
appearance and content of the rashes of STARI and the EM of Lyme disease. For
example, Lyme EM rashes show an abundance of plasma cells contrasted with a
predominantly lymphocytic infiltrate seen in STARI.
G.T.’s diagnosis was based on symptoms, geographic location, and tick bite
information. Because the cause of STARI is unknown, no diagnostic tests are
available, nor is it known if antibiotic treatment is necessary or beneficial for
patients. However, because STARI resembles Lyme disease, limited data support
treating STARI with regimens similar to those used for Lyme disease.
doxycycline may be given for 10 to 30 days, with longer durations reserved for
evidence of dissemination beyond the rash, such as fever, severe headache,
lymphadenopathy, or multiple rashes.
OTHER BACTERIAL DISEASES: TULAREMIA
In 1911, George W. McCoy and Charles W. Chapin from the US Public Health
Service investigated a plague-like disease in wild ground squirrels harvested in
Tulare County, California, and discovered the infectious etiology of tularemia.
bacterium is a small, pleomorphic, catalase-positive, nonmotile, aerobic,
nonencapsulated, gram-negative coccobacillus now named Francisella tularensis in
honor of Edward Francis for his fieldwork and contributions to tularemia research.
He proposed the terminology tularemia because the disease is associated with
Although tularemia is found worldwide, it occurs primarily in the Northern
22 The important reservoir hosts for F. tularensis are wild rabbits, ticks,
25 The North American tick vectors are Dermacentor variabilis (dog
tick), Amblyomma americanum (lone star tick), and Dermacentor andersoni (wood
tick). Tick-borne tularemia occurs most often in the spring and summer, matching the
4 Before 1950, most human cases of the disease developed
from direct contact with infected animals, usually hares or rabbits, and tularemia
cases that occurred in the fall or winter were usually associated with hunting season
exposure. Tick bite transmission, however, now accounts for more than half of
tularemia cases west of the Mississippi River in the United States. In summer months,
tick or fly bites appear to be the main mode of transmission of tularemia to humans.
Other animals, such as domestic cats, are susceptible to tularemia and are known to
have transmitted tularemia to humans.
4 Tularemia outbreaks have also occurred
among hamsters purchased from pet shops. Individuals should be careful when
handling any sick or dead animal. Other modes of transmission include ingestion of,
or contact with, infected meat, water, or soil; inhalation of aerosolized bacteria; or
bites from infected animals, mosquitoes, or deerflies.
transmission has not been reported.
The clinical manifestations of tularemia are related to the mode of transmission,
patient characteristics, and bacterial subspecies causing infection.
types of tularemia presentation have been identified: ulceroglandular, glandular,
typhoidal, oculoglandular, oropharyngeal, and pneumonic. The last three forms were
presumably not tick-borne, reflecting alternative avenues of transmission. Today, the
clinical manifestations fall into two main groups: ulceroglandular and typhoidal.
Ulceroglandular is the most common form of tularemia, accounting for
25 Sixty percent of ulceroglandular cases are
characterized by an ulcer that forms at the site of entry, usually on the lower
extremities, perineum, buttocks, or trunk from arthropods that tend to bite the lower
extremities or on the upper extremities from mammalian bites.
firm, erythematous papule that ulcerates and heals over the course of several weeks.
It is accompanied by regional, painful lymphadenopathy, usually inguinal or femoral.
Typhoidal tularemia, occurring in approximately 25% of cases, is characterized by
fever, chills, headache, debilitation, abdominal pain, and prostration. Fever and
chills are common with all forms of tularemia.
After exposure to the bacteria and an incubation period of 4 to 5 days, patients
become ill with a sudden onset of fever, chills, headache, cough, arthralgias,
myalgias, fatigue, and malaise. The severity of symptoms is quite variable, ranging
from a mild, limited disease (probably type B tularemia) to rare cases of septic
shock (probably type A tularemia). A hallmark manifestation is a high fever without
an accompanying increase in pulse, or pulse–temperature disparity.
complications are mild hepatitis, secondary pneumonia, and pharyngitis. With
antibiotic treatment of uncomplicated tularemia, mortality rates are only 1% to 3%.
Increased morbidity and mortality are seen in the more rare typhoidal forms.
most lethal form of tularemia is from pulmonary infection.
standard precautions are all that is required when caring for tularemia-infected
patients because they are not a source for secondary infection. However, any
suspected outbreaks should be reported and investigated.
Tularemia can be difficult to diagnose as routine laboratory testing is of little help in
establishing a diagnosis and is limited to the demonstration of an antibody response
to the bacteria. Because an antibody response to the illness requires 10 to 14
days for detection, treatment is usually empiric. The diagnosis is based on clinical
suspicion from the epidemiologic history and the presence of compatible findings.
The customary serologic test demonstrates F. tularensis antibody agglutination.
Although a single-tube agglutination test with a titer of 1:160 or more (or 1:128 or
more using a microagglutination study) in a suspected case is highly suggestive of a
tularemia diagnosis, a fourfold or greater rise in titers between the acute and
convalescent stages 2 weeks apart is diagnostic.
detectable antibodies may persist for many years.
Antibiotic treatment options for tularemia have included streptomycin, gentamicin,
doxycycline, and ciprofloxacin. Streptomycin was historically the drug of choice for
tularemia, but it is often unavailable commercially. Some clinicians believe that
gentamicin is the best alternative aminoglycoside for the treatment of nonmeningitic
tularemia. Its advantages compared with streptomycin include lower minimal
inhibitory concentrations (MICs), less vestibular toxicity, and wider commercial
availability. Although considered comparable in efficacy to streptomycin, gentamicin
has been associated with increased treatment failure and relapse. Tobramycin is
inferior to gentamicin or streptomycin and should not be used.
In many of the reported studies of antimicrobial therapy for tularemia, short
courses of treatment were used. To prevent tularemia from worsening or relapsing,
longer regimens (10–14 days) should be used, especially in more severe cases.
Jarisch–Herxheimer reactions can occur with antibiotic treatment of tularemia.
Antibiotic prophylaxis for people exposed to those with tularemia is not
recommended, but prophylactic antibiotics might be used for suspected bioterrorism
attacks of tularemia. Acute febrile illness with pneumonia and other signs of infection
occur 3 to 5 days after exposure to airborne tularemia organisms from an
intentionally set weapon. No tularemia vaccines are available in the United States. A
partially protective one was developed in the former Soviet Union but was only used
for at-risk personnel such as for certain laboratory workers.
measures, as discussed for Lyme disease, should be used when spending time
THE RICKETTSIA: ROCKY MOUNTAIN SPOTTED
FEVER, RICKETTSIA PARKERI INFECTION,
EHRLICHIOSIS, AND ANAPLASMOSIS
Rocky Mountain Spotted Fever (RMSF)
Rocky Mountain spotted fever is the most prevalent and virulent rickettsial disease in
the United States. As early as 1872, RMSF infected white settlers of the Northwest
and it may have been prevalent in Native Americans of the region before that time. It
was first described in residents of the Bitterroot, Snake, and Boise river valleys of
Montana and Idaho in the late 1800s. Howard Ricketts discovered the causative
agent, Rickettsia rickettsii, in 1908.
26 The rickettsia is a small (0.3 × 1 μm),
pleomorphic, weakly gram-negative, obligate intracellular coccobacillus that can
survive only briefly outside of a host.
RMSF is found throughout North America, including the United States, Canada, and
Mexico, and in parts of Central and South America.
outside of the Western Hemisphere. The term “Rocky Mountain spotted fever” is
actually a misnomer because the disease has shifted eastward from the Rocky
Mountain states, and the greatest incidence of RMSF now occurs in North and South
Carolina, Virginia, Oklahoma, Arkansas, and Tennessee.
arise from tick exposure in rural or suburban locations, although rare outbreaks in
urban environments have occurred.
The prevalence of RMSF is highest in children with 5 to 9 years of age.
peak prevalence is seen in men older than 60 years. Risk factors include male sex,
residence in wooded areas, and exposure to tick-infected dogs. RMSF, like other
tick-borne diseases, is highly seasonal, with greatest incidence in late spring and
In the east, south, and west coasts of the United States, the tick vector for RMSF has
been identified as the dog tick, Dermacentor variabilis.
states, the wood tick, D. andersoni, is the vector.
In Mexico, the tick vectors are
Rhipicephalus sanguineus and Amblyomma cajennense, with the latter also being
responsible in Central and South America.
24 The brown dog tick, R. sanguineus, has
been identified as a new tick vector for RMSF in a defined area of Arizona.
Dermacentor ticks feed on humans only during their adult stage.
Dermacentor ticks may be infected while feeding on small mammals that have
sufficient rickettsemia for transmission, such as chipmunks, ground squirrels, cotton
rats, snowshoe hares, and meadow voles. Dogs are not considered reservoirs for R.
rickettsii but are susceptible to RMSF and may introduce infected ticks into
26,27 Adult ticks transmit the rickettsia transovarially to their progeny with
high efficiency and establish newly infected tick lines. If the rickettsia burden is large
in the adult tick, however, it may cause tick death, thereby reducing infected tick
lines. Therefore, there must be nontick reservoirs, as mentioned previously, to
develop newly infected tick generational lines; otherwise, RMSF would slowly
disappear. In summary, ticks are both vectors and hosts for R. rickettsii.
are dead-end accidental hosts of R. rickettsii.
DISEASE COURSE, SYMPTOMS, AND FATALITIES
Rickettsia rickettsii is usually transmitted to humans from an infected tick bite.
organism can also gain access to humans through broken skin if an infected tick is
being crushed with bare fingers, and such crushing may generate infectious aerosols
that might be inhaled. Conjunctival contact with infected tick tissues or feces
provides another route for rickettsial entry. Contaminated blood transfusions and
needle stick injuries have also transmitted R. rickettsii.
After introduction of the organisms into the body, the rickettsia spread
hematogenously with a predilection for the vascular endothelium, especially in
capillaries and medium-sized blood vessels.
27 During an incubation period of 2 to 14
days, induced phagocytosis allows rickettsial entry into endothelial cells, where they
replicate by binary fission in the cytoplasm and nuclei of infected cells. This induces
a generalized vasculitis leading to activation of clotting factors, capillary leakage,
and microinfarctions in various organs.
26 Exotoxins are not secreted by rickettsia;
however, they do induce oxidative and peroxidative damage to host cell membranes,
In severe infections, hypotension and intravascular
coagulation may coexist and culminate in cell, tissue, or organ destruction.
Dehydration is an early sign of RMSF, followed by increased vascular
permeability, edema, decreased plasma volume, hypoproteinemia, reduced serum
oncotic pressure, and prerenal azotemia. RMSF is a multisystem disease, but a
major focus of the disease. If the brain or lungs are severely infected, death can
ensue. An increased severity of illness is associated with edema, particularly in
children, and hypoalbuminemia. Hypotension is present in 17% of patients and
hyponatremia in 56%. Extensive infection of the pulmonary microvascular
endothelium can cause noncardiogenic pulmonary edema.
A common finding in RMSF is myalgia (72%–83%) or muscular tenderness,
which are manifestations of skeletal muscle necrosis. Striking creatinine kinase
elevations have been described. Thrombocytopenia resulting from consumption of
platelets during intravascular coagulation processes occurs in 35% to 52% of
patients. True disseminated intravascular coagulation with attendant
hypofibrinogenemia is exceptional, however, even in severe or fatal cases.
loss or hemolysis in some may cause anemia, which is seen in 30% of patients and
reflects blood vessel damage. Fatalities usually occur 8 to 15 days after illness onset
if no treatment is given or is delayed. Long-term sequelae from severe forms of
RMSF can include partial paralysis of the lower extremities, gangrene of extremities
requiring amputation, deafness or hearing loss, incontinence, and movement or
speech disorders, but these occur in a minority of patients who receive prompt
“Fulminant” RMSF is best defined as a disease with a rapidly fatal course with
death occurring in approximately 5 days. This form of disease is characterized by an
early onset of neurologic signs and late or absent skin rash; it is highly associated
with glucose-6-phosphate dehydrogenase deficiency, advanced age, male sex, and
In the pre-antibiotic era, RMSF mortality rates were
as high as 30%, but they have fallen to 5% in antibiotic-treated cases today.
The classically defined triad of RMSF symptoms at initial presentation is fever,
rash, and headache, but this is found in only up to 5% of cases during the first 3 days
of illness and up to approximately 60% of cases 2 weeks after exposure.
RMSF skin rash typically begins 2 to 4 days after fever onset as pink, 1- to 5-mm
blanchable macules that later become papules.
It begins on the ankles, wrists, and
forearms, and soon thereafter involves the palms or soles. It then spreads to the arms,
thighs, and trunk, and typically evolves into a petechial exanthem. The utility of these
findings in the differential diagnosis is limited because rash may be absent, transient,
or late; it may never become petechial, or it may have an unusual distribution.
As for most tick-borne diseases, confirmatory serologic analysis is not particularly
useful in early diagnosis of disease. The initial diagnosis is made based on clinical
signs and symptoms and medical history. Because RMSF can be a severe or even
fatal illness, antirickettsial treatment should begin immediately to prevent morbidity
26,27 R. rickettsii is difficult to culture. Immunohistologic demonstration
of R. rickettsii in biopsy specimens of rash lesions is the only approach that can yield
diagnostic results in a timely manner, but this approach is applicable only to those
presenting with a skin rash, and these tests are not readily available.
The best serologic test for RMSF is the indirect immunofluorescence assay (IFA)
test, but antibodies typically appear only after 10 to 14 days.
laboratory abnormalities of RMSF disease include a normal leukocyte count with a
shift to the left, hyponatremia, thrombocytopenia, elevated serum transaminases or
creatinine kinase, and CSF pleocytosis. These findings are observed late in the
disease course, however, and are not helpful in early disease recognition.
Clinical findings and history are essential to early diagnosis and successful
treatment. Therapy must precede laboratory confirmation of RMSF.
tick-exposed person with a rash, RMSF should be considered. RMSF should be
strongly considered in febrile children, adolescents, or men older than 60 years of
days of symptom onset increases the mortality rates from 5% to 22%.
Doxycycline should be initiated immediately as first-line treatment for RMSF in both
adults and children whenever RMSF is suspected. The recommended treatment is
doxycycline 100 mg every 12 hours for children under 45 kg (100 lbs): 2.2 mg/kg
body weight given twice a day. The standard duration of treatment is 7 to 14 days,
including at least 3 days after the temperature has normalized.
doxycycline to treat suspected RMSF in children is standard practice by the CDC and
the American Academy of Pediatrics (AAP) Committee on Infectious Diseases as the
use of alternative antibiotics increases the risk of death. Contraindications to
doxycycline use include history of severe hypersensitivity reactions to tetracyclines,
and in some pregnant patients in which the case of RMSF seems mild,
chloramphenicol may be considered as an alternative antibiotic.
formulations of chloramphenicol are not available in the United States, and there are
severe risks of adverse of effects with this agent, including gray baby syndrome and
26 The erythromycins, penicillins, sulfonamides, aminoglycosides,
and cephalosporins are not effective for RMSF, and sulfa drugs may worsen
A crucial component in the management of RMSF is appropriate supportive care.
Those with severe disease should be hospitalized and managed with hemodynamic,
renal, pulmonary, and fluid support as needed.
In addition to the same guidelines for prevention of Lyme disease, keeping pets free
of ticks can reduce exposure. Ticks must not be crushed in a way that might introduce
rickettsia into cutaneous lesions, mucous membranes, or the conjunctiva. No RMSF
26 Antirickettsial antibiotic prophylaxis after a tick bite is not
warranted as there is no evidence that this approach is effective and it may delay the
Spotted Fever Group Rickettsia (SFGR)
In addition to Rickettsia rickettsii, the agent of RMSF, many other rickettsial
pathogens have been recognized and grouped broadly as “Spotted Fever group
In the United States, these pathogens include Rickettsia parkeri
and Rickettsia 364D, and internationally, there is a growing number of tick-borne
SFGR that are pathogenic to humans.
4,30 Doxycycline treatment is effective and is the
antibiotic of choice for tick-borne SFGR infections.
SPECIES IDENTIFICATION, TICK VECTORS, AND DISEASE HOSTS
Though ehrlichiosis and anaplasmosis are transmitted by two different species of
ticks and generally occur in different regions of the United States, patients may have a
similar clinical presentation.
4,5 The term “ehrlichiosis” may be more broadly applied
to different infections, including Ehrlichia chaffeensis and Ehrlichia ewingii, which
are transmitted by the lone star tick generally in the southeastern and south-central
US, from the eastern seaboard extending westward to Texas. A third species,
provisionally called Ehrlichia muris-like (EML), was identified among patients in
the upper Midwest; however, the tick responsible for transmitting
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