Rickettsiae comprise a group of microorganisms that phylogenetically occupy a position between

bacteria and viruses. The genus Rickettsia is included in the bacterial tribe Rickettsiae, family
Rickettsiaceae, and order Rickettsiales. They are obligate intracellular gram-negative coccobacillary
forms that multiply within eukaryotic cells. Rickettsiae do not stain well with Gram stain, but they take
on a characteristic red color when stained by the Giemsa or Gimenez stain. They have typical gram-
negative cell walls and lack flagella. Their genome is very small, composed of 1-1.5 million bases.
[1, 2]

Rickettsiae are a rather diverse collection of organisms with several differences; this prohibits their
description as a single homogenous group. A general characteristic of rickettsiae is that mammals
and arthropods are natural hosts. Rickettsioses are usually transmitted to humans by arthropods. Q
fever, traditionally described among the rickettsial illnesses until recently, is primarily acquired by
inhalation of contaminated airborne droplets.
[3, 4, 5]

The epidemiology of human diseases caused by rickettsiae is intimately related to the biology of the
vector that transmits it. Rickettsial diseases widely vary in severity from self-limited mild illnesses to
fulminating life-threatening infections.
[4]

Rickettsial illnesses, caused by organisms within the genus of rickettsiae, are recognized and can be
divided into the following 3 biogroups:
[2, 6]

Spotted fever biogroup (15 rickettsioses)
Rocky Mountain spotted fever (RMSF), caused by Rickettsia rickettsii
Rickettsialpox, caused by Rickettsia akari
Boutonneuse fever (ie, Kenya tick-bite fever, African tick typhus, Mediterranean spotted fever, Israeli
spotted fever, Indian tick typhus, Marseilles fever)
Typhus group
These are similar diseases that differ epidemiologically. The causative organisms (Rickettsia
prowazekii and Rickettsia typhi) are similar to those of the spotted fever group but are antigenically
distinct.
Louse-borne (epidemic) typhus
Brill-Zinsser disease (ie, relapsing louse-borne typhus)
Murine (endemic or flea-borne) typhus
Scrub typhus biogroup (Tsutsugamushi disease)
The rickettsial agents of scrub typhus have a single taxonomic name: Orientia
tsutsugamushi. However, these organisms represent a heterogeneous group that strikingly differs
from Rickettsial species of the spotted fever and typhus groups. The 3 major serotypes are Karp,
Gilliam, and Kato.
Other rickettsioses and closely related illnesses
New or reemerging rickettsioses have been described in the last few decades, including tickborne
lymphadenopathy (TIBOLA) and Dermacentor -borne-necrosis-eschar-lymphadenopathy (DEBONEL)
related to Rickettsia slovaca infection, as well as lymphangitis-associated rickettsiosis attributed
to Rickettsia sibriciainfection.
[1]
Recently, a new Rickettsia species, 364D, that causes an eschar-
associated illness was identified in California.
[7]

Ehrlichia organisms (the cause of human monocytic ehrlichiosis and Ehrlichia
ewingii infection), Anaplasmaphagocytophilum (the cause of human granulocytic anaplasmosis),
and Bartonella species (the cause of Catscratch disease, relapsing fever, and Trench fever) are
organisms related to the rickettsiae. They are discussed in separate articles.
Q fever is a disease caused by Coxiella burnetii, which has recently been removed from
the Rickettsiales.
[5]
The disease is described here for comparison with other rickettsioses.
The environmental stability, small size, aerosol transmission, persistence in infected hosts, low
infectious dose and high associated morbidity and mortality have made pathogenic rickettsiae
desirable bioterrorism agents. In fact, R prowazekii and C burnetii have been weaponized. However,
developing rickettsial pathogens as biological weapons has many drawbacks, such as the lack of
direct host-to-host transmission and availability of therapeutic countermeasures against them.
[8]

Pathophysiology
Rickettsiae microorganisms appear to exert their pathologic effects by adhering to and then invading
the endothelial lining of the vasculature within the various organs affected. The adhesins appear to be
outer membrane proteins that allow the rickettsia to be phagocytosed into the host cell. Once inside,
the rickettsial organisms either multiply and accumulate in large numbers before lysing the host cell
(typhus group) or they escape from the cell, damaging its membrane and causing the influx of water
(spotted fever group).
[4]

Rickettsiae rely on the cytosol of the host cells for growth. To avoid phagocytosis within the cells, they
secrete phospholipase D and hemolysin C, which disrupt the phagosomal membrane, allowing for
rapid escape.
The most important pathophysiologic effect is increased vascular permeability with consequent
edema, loss of blood volume, hypoalbuminemia, decreased osmotic pressure, and hypotension. On
the other hand, disseminated intravascular coagulation is rare and does not seem to contribute to the
pathophysiology of rickettsiae.
Studies of murine models have demonstrated that rickettsiae are cleared by cytotoxic CD8 cells and
by cytokine-activated rickettsicidal nitrogen and oxygen species. In fact, antibodies do not play an
important role in immunity against pathogenic rickettsia upon fist exposure. Walker provided an
excellent review of this topic.
[1]

RMSF: In RMSF, rickettsiae multiply within the endothelial cells of small blood vessels and then gain
access to the bloodstream after skin inoculation. Focal areas of endothelial proliferation and
perivascular mononuclear cell infiltration cause leakage of intravascular fluid into tissue space.
These vascular lesions can affect all organs; however, they most readily are found in the skin and
adrenals. In the central nervous system and heart, a damaging host response (primarily cell-
mediated) accompanies the vasculitis. The liver is usually affected with portal triaditis. Vascular wall
destruction consumes platelets, causing thrombocytopenia. Multiple factors lead to
hypoalbuminemia (eg, renal loss, decreased intake, hepatic involvement) and hyponatremia (eg,
renal loss, extracellular fluid shifts, cellular exchange of sodium for potassium).
Rickettsialpox: The organism that causes this illness is known to cause angiitis similar to other
rickettsiae. Biopsies, which are rarely needed to establish the diagnosis of rickettsialpox, show
evidence of thrombosis and necrosis of capillaries, as well as perivascular mononuclear cell
infiltration.
Boutonneuse fever: Features of this illness are related to involvement of the vascular structures of
the dermis in a manner similar to that observed in RMSF. Endothelial cells of the capillaries,
venules, and arterioles (ie, small-to-medium sized vessels) in various organs may also become
involved as the organism disseminates.
[9]
Additionally, a few cases of leukocytoclastic vasculitis have
been reported with this infection.
Louse-borne (epidemic) typhus: The pathology is similar to that described for the spotted fever
group of rickettsial diseases. However, typhus group rickettsiae do not stimulate actin-based
mobility and rather extensively multiply and accumulate intracellularly until they burst the endothelial
cell and disseminate into the bloodstream.
Brill-Zinsser disease (ie, relapsing louse-borne typhus): The pathology is similar to that described for
the spotted fever group of rickettsial diseases. However, the organisms appear to lie dormant, most
likely in the cells of the reticuloendothelial system, until they are reactivated by an unknown stressor,
multiply and cause another acute but milder infection.
Murine (endemic or flea-borne) typhus: Pathology is similar to that described for epidemic typhus.
Tsutsugamushi disease (ie, scrub typhus): After invading the host cell and replicating in its
cytoplasm, the Orientia tsutsugamushi exits by budding enveloped by part of the host cell
membrane as it invades adjacent cells. Perivasculitis of small blood vessels occurs similarly to other
rickettsial diseases. Usually, a necrotic inflammatory skin lesion occurs at the mite bite site, and
regional and generalized lymphadenopathy is associated with this infection.
Q fever: In Q fever, the Coxiella organism directly causes disease in various organs. It has been
demonstrated in macrophages in the lungs and in vegetations of the heart valves. Host-mediated
pathogenic mechanisms also appear to play an important role in disease pathogenesis; the disease
causes granulomatous changes in reticuloendothelial organs (granulomatous hepatitis).
Epidemiology
Frequency
United States
RMSF
RMSF is caused by R rickettsii. Now reported in all geographic areas of the United States, RMSF was
first recognized in and thought to be limited to the Rocky Mountain area. Its incidence sharply
declined with the introduction of broad-spectrum antibiotics in the 1950s; the incidence soared again
in the 1960s and peaked in 1981. Incidence has declined since that time. The average annual
incidence from 1997-2002, based on passive surveillance, was 2.2 cases per million population. The
major endemic areas in the United States today include North Carolina, Oklahoma, South Carolina,
Tennessee and Arkansas. More than 90% of patients with RMSF are infected from April through
September. Individuals with frequent exposure to dogs and who reside near wooded areas or areas
with high grass are at an increased risk of infection.
[3, 10, 11]

Rickettsialpox
In the United States, rickettsialpox most commonly occurs in the Northeast, especially in New York
city. Despite sporadic periodic outbreaks, incidence appears to be declining. The natural host is the
common house mouse (Mus musculus).
Boutonneuse fever
This disease is very rare outside a limited geographical area in the Mediterranean, Africa, and India.
With increased travel and ecotourism in endemic areas, more imported cases of the disease are
described in travelers returning to the United States from Mediterranean regions.
[9]

Louse-borne (epidemic) typhus
This is rare in the United States, but sporadic cases have been reported. The presumed source of
infection is the southern flying squirrel.
Brill-Zinsser disease (ie, relapsing louse-borne typhus)
The distribution of this disease is analogous to louse-borne epidemic typhus. Recently, it has been
rarely reported in the United States, and all cases had acquired the primary infection elsewhere.
[12, 2, 13]

Endemic murine (flea-borne) typhus
This type of typhus is prevalent in urban cities and costal ports where rats are abundant. This is
because it is transmitted rat-to-rat by a rat flea (Xenopsylla cheopis) and transmitted accidentally to
humans by the feces of infected fleas. The cat flea (Ctenocephalides felis) may also serve as a vector
for transmission of this disease to humans. These may be important vectors in Texas and southern
California. Incidence has declined coincident with increased use of insecticides. Cases occur
throughout the year, with peak prevalence from April through June in Texas and during the warm
months of summer and early fall elsewhere.
[12, 14]

Tsutsugamushi disease (ie, scrub typhus)
This is extremely rare outside the southwest Pacific and Southeast Asia.
Q fever
Outbreaks are most common in slaughterhouses, research facilities, and plants, where handling of
animals or their birth products is a source of exposure. Prevalence of Q fever in the United States is
underestimated. Since Q fever became a nationally reportable disease in 1999 in the United States, a
linear increase has been observed in the number of human cases identified (17 cases with onset in
2000 compared with 167 cases with onset in 2007). The incidence of Q fever increased similarly, from
less than 0.1 case per million persons in 2000 to 0.6 case per million persons in 2007.
The surveillance case definition for Q fever was modified in 2008 to revise laboratory criteria for
diagnosis and to allow for the separate reporting of acute and chronic Q fever. During 20082010, the
number of reported cases decreased slightly, relative to 2007, and the incidence rate has decreased
to 0.4 case per million persons. One hundred thirty-one cases of Q fever were reported with onset in
2010; of these, 106 were acute Q fever and 25 were chronic Q fever.
[15]

International
The spotted fever rickettsiae have been found in every continent except Antarctica.
[2]

RMSF: This primarily occurs in the continental United States but has been reported in southern
Canada, Central America, Mexico, and parts of South America. It is rarely seen elsewhere.
[10]

Rickettsialpox: This may be more prevalent worldwide than is reported. It has been identified in
large cities in Russia, South Africa, and Korea.
Boutonneuse fever has demonstrated an increased incidence in Mediterranean countries, such as
Spain, Italy, and Israel. Along with African tickbite fever, these infections have been identified in
Algeria, Malta, Cyprus, Slovenia, Croatia, Kenya, Somalia, South Africa, Ethiopia, India, and
Pakistan, as well as rural Sub-Saharan Africa, the eastern Caribbean, and around the Black Sea.
[4, 9]

Louse-borne (epidemic) typhus: Epidemics have occurred in Europe, Asia, and Africa. African
countries, especially Ethiopia and Nigeria, have reported most of the cases in the last 2 decades.
Brill-Zinsser disease (ie, relapsing louse-borne typhus): This disease follows the epidemiology of
louse-borne epidemic typhus and rarely, if ever, occurs in children because the reactivation usually
occurs decades after primary infection.
Murine (endemic or flea-borne) typhus: This is prevalent in large cities around the world where rats
abound. It has been reported in travelers returning from ports and beach resorts in Asia, Africa and
Europe.
[2]
Human infections with rickettsia contracted after exposure to cat fleas was recently
described in Australia. The fleas involved demonstrated the presense of Rfelis.
[16]

Tsutsugamushi disease (ie, scrub typhus): Cases are usually seen in rural south and southeast
Asia, limited to the geographical area bound by Japan, the Solomon Islands, and Pakistan. It is
estimated that 1 million cases occur each year.
Q fever: This zoonotic disease is observed in humans who come in contact with infected animals in
Australia and Canada, as well as other areas of the world. Incidence figures widely vary.
[5]

Mortality/Morbidity
Rickettsial diseases vary in clinical severity according to the virulence of theRickettsia and host
factors, such as age, male gender, and other underlying diseases. The most virulent rickettsiae are R
rickettsii and R prowazekii, which kill a significant portion of infected persons unless the diseases are
sufficiently treated early with an effective antimicrobial agent.
[4, 8]

RMSF: The overall mortality rate is 4%, despite effective antibiotic therapy. This most likely is
caused by delay in the diagnosis and initiation of proper treatment. Patients treated during the first
week of illness have the highest chance of complete recovery; however, if the disease is allowed to
progress to the second week untreated, even optimal therapy progressively becomes less
effective.
[17]
Deficiency of glucose-6-phosphate dehydrogenase (G-6-PD) enzyme is associated with
a high proportion of severe cases of RMSF. This is a rare clinical course that is often fatal within 5
days of onset of illness.
Rickettsialpox: No mortality has occurred from this infection. Morbidity is minimal, as noted in
Clinical.
Boutonneuse fever: This infection generally runs a benign course. Unusual presentations (eg, acute
pancreatitis)
[18]
, rare complications (eg, hemophagocytic lymphohistiocytosis),
[19]
and severe forms of
the disease have been described and fatalities are rare.
[9]

Louse-borne (epidemic) typhus: Mortality rates in untreated cases correlate with the patient's age.
The mortality rate is approximately 10% in young adults but approaches 60-70% in patients older
than 50 years.
Brill-Zinsser disease (ie, relapsing louse-borne typhus): These relapses tend to be milder, shorter,
and less debilitating.
Murine (endemic or flea-borne) typhus: Complications and mortality (1% mortality rate in the United
States) are uncommon.
Tsutsugamushi disease (ie, scrub typhus): The illness usually is mild and self-limited. However, if
left without treatment complications may include pneumonitis, meningoencephalitis, disseminated
intravascular coagulation and renal failure. Fatality rate ranges from 1-35%, depending on the
virulence of the infecting strain, host factors, and institution of proper treatment.
Q fever: Uncomplicated disease is self-limited, lasting for 10-90 days. Complications requiring
hospitalization are rare and may include endocarditis, encephalitis, pneumonia, hepatitis, and
splenomegaly. Rates of hospitalization among Q fever cases reported to the US Centers for
Disease Control and Prevention (CDC) averaged over 50% during 2002-2008. However, it is likely
that mild Q fever infections, which do not require hospitalization, may be more likely to be under-
recognized and therefore under-represented in current national surveillance systems.
[15]
The overall
mortality rate of Q fever is approximately 1%. However, the rate may increase to 30-60% with
complications.
[5]

Race
No specific racial predilection is observed.
Sex
Males appear to be at higher risk for infection with tick-borne rickettsioses. This is likely because of
greater recreational or occupational exposures to tick habitats. However, in some spotted fever
illnesses (eg, Q fever), females seem to be less susceptible to the infection possibly due to a
protective role of female hormones.
[9]

Age
Two thirds of patients with RMSF are aged 15 years or younger.
[4]

Rickettsialpox, boutonneuse fever, epidemic and endemic typhus, and Tsutsugamushi disease affect
all ages.
Q fever occurs in all age group but is more prevalent between age 30-70 years

Early signs and symptoms of these infections are notoriously nonspecific and may mimic benign viral
illnesses, making the diagnosis more difficult. Certain features that aid in making the early diagnosis
of rickettsial diseases include (1) a history of tick bite or exposure, (2) recent travel to endemic areas,
and (3) similar illness in family members, coworkers, or family pets (especially dogs).
Rocky Mountain spotted fever (RMSF)
[20]

Fever, headache, rash, confusion, and myalgia are cardinal features.
Onset may be gradual or abrupt, beginning approximately 1 week (range, 2-14 d) following a bite
from an infected tick. As many as 40% of patients may be unaware of the tick bite, which is usually
painless and may go unnoticed or be easily forgotten.
Headache is usually persistent, intense, and intractable.
Patients may appear toxic, and this usually progresses to mental confusion and delirium.
GI symptoms (eg, abdominal pain and diarrhea) commonly occur during early stages of illness.
Conjunctival injection may also be seen.
Rickettsialpox
[4]

After an incubation period of 9-14 days, a red papule develops at the site of the mite bite. The
papule subsequently develops an eschar. The appearance of the latter roughly coincides with the
appearance of fever.
Irregular fluctuating fever (38-41C) occurs and lasts for less than a week. Fever is accompanied by
headache, chills, rigors, profuse sweating, myalgias, and occasionally by rhinorrhea, cough, sore
throat, nausea, vomiting, and abdominal pain.
Boutonneuse fever
Incubation period is usually 6 days (ranges from 1-16 d).
An eschar or cutaneous necrosis caused by rickettsial vasculitis at the tick-bite site of inoculation,
known as tache noire ("black spot"), is pathognomonic. However, it may not be seen in 14-40% of
cases. This lesion heals slowly over 10-20 days without leaving a scar.
The disease has an acute onset with high fever (above 39C), headache, malaise and arthromyalgias.
Headaches are less frequent in children.
[9]
Unusual presentations, such as acute pancreatitis, have
also been described.
[18]

African tick bite fever is similar but has a more timid presentation. It differs from other similar
rickettsioses in that it produces a painful lymphadenopathy, multiple eschars, nuchal myalgia, and,
occasionally, a sparse vesicular rash.
[1, 21]

Louse-borne (epidemic) typhus
The illness has an abrupt onset occurring 1-2 weeks following the bite of an infected louse.
Patients develop fever, intractable headache, and rash. The rash appears on days 4-7 of illness and
spreads from the trunk to the extremities, sparing the face, palms, and soles. The lesions progress
from macules to maculopapules to petechiae.
Conjunctival injection, rales, and delirium commonly occur.
Brill-Zinsser disease (relapsing louse-borne typhus)
Presentation is analogous to primary louse-borne epidemic typhus but is milder.
Murine (endemic or flea-borne) typhus
[12]

Murine typhus is similar to louse-borne typhus but tends to have a milder and shorter course.
Fever is less pronounced and remittent, headache is less severe, and rash is less extensive. The
latter may be absent in approximately 50% of patients.
Tsutsugamushi disease (ie, scrub typhus)
[12]

The incubation period is approximately 1-2 weeks.
In fewer than half of patients, the site of the mite bite develops a necrotic eschar with enlargement of
regional lymph nodes similar to rickettsialpox.
Inquiring about history of travel to the Southwest Pacific or Southeast Asia, where patients almost
exclusively contract this disease is also helpful.
Q fever
[22, 5]

Primary infection is usually asymptomatic. Adults and men are more likely to have symptomatic
infection compared with children and women, respectively.
Incubation period ranges from 2-6 weeks.
Acute Q fever infection usually has an abrupt onset, with fever, intractable headache, chills, myalgia,
cough, and chest pain. The three clinical presentations more commonly observed are flulike
illness, pneumonia, and hepatitis.
Rash is absent in over 90% of cases.
Chronic Q fever infection is less common (1-5%). It may be manifested as endocarditis, chronic or
relapsing multifocal osteomyelitis, chronic hepatitis, chronic vascular infection, endocarditis,
pericarditis, or myocarditis.
[23]
The infection may be insidious, developing months to years following
the acute infection.
Humans contract the disease by inhaling contaminated aerosols when they come in contact with
infected animals or materials contaminated by them. Workers who handle livestock (eg, cattle,
sheep, goats), especially at the time of slaughter or parturition, are at an increased risk of infection.
Human infection also occurs after ingestion of contaminated raw milk.
[5]

Tickborne lymphadenopathy (TIBOLA) and Dermacentor -borne-necrosis-eschar-
lymphadenopathy (DEBONEL)
[1]

An eschar associated with painful cervical lymphadenopathy appears 1 week after a tick bite to the
occipital scalp.
Fever and rash are seldom present.
Patients may develop persistent asthenia and alopecia at the site of the eschar.
Physical
RMSF
Fever reaches 40-41C and, more commonly, has a persistent pattern rather than an oscillating
one.
[20, 4]

Rash starts on the second or third day of the illness. It usually appears peripherally on the wrists and
ankles and spreads to involve the extremities and trunk. Rarely, the rash may be evanescent or
localized to a particular region of the body.
[24]

Typically, the lesions are small (1-5 mm), blanching, erythematous macules that may progress to
maculopapules and petechiae.
Skin necrosis is rare. In as many as 20% of cases, patients may not develop a rash (spotless RMSF),
but this should not delay institution of proper therapy based on historical and clinical data.
Signs of meningoencephalitis and coma may follow delirium.
Meningismus may accompany the disease but is not necessarily associated with abnormal
cerebrospinal fluid (CSF) findings (eg, minor elevation of CSF lymphocyte count). Other neurologic
findings may include cortical blindness, seizures, central deafness, ataxia, paralysis, and cranial
palsies.
Cardiac involvement frequently occurs. Adequate monitoring and workup are necessary to exclude
arrhythmias and congestive cardiac failure.
Pulmonary manifestations may range from atelectasis to infiltrates or pulmonary edema.
Myalgia is a common feature and usually manifests as thigh or calf tenderness.
Retinal disease (i.e., edema, papilledema, cotton wool exudates, hemorrhages, retinal artery
occlusion) occurs more commonly than uveitis or iritis.
Enlargement of the liver or spleen is infrequent.
Rickettsialpox
Regional lymph nodes at the area of the primary eschar typically become enlarged.
A macular rash develops within several days of the onset of fever. The lesions then develop into
vesicular maculopapules over a few days. The rash is distributed on the face, neck, trunk, and
extremities and easily may be confused with the rash of varicella, especially in adult patients (hence,
the name). In addition to the exanthem, the disease also may involve the mucus membranes, causing
an enanthem. The pox usually heals within 2-3 weeks without scarring.
In addition to the exanthem, the disease also may involve the mucus membranes, causing an
enanthem.
Boutonneuse fever
Generalized myalgia occurs, and even myositis can be demonstrated.
Eschars can be often found in the trunk, arms and legs of cases. In young children they are frequently
found on the scalp in a retroauricular area.
A rash appears on days 3-5 after the fever onset. It spreads from the extremities to the trunk, neck,
palms, and soles within 36 hours. It usually spares the face.
[9]

The lesions progress from macular to maculopapular and may persist for 2-3 weeks.
Atypical cutaneous findings may occur in a few patients and 1-4% of cases never develop a rash.
Cervical adenopathy may be found in 33-75% of affected children.
Patients with African tickbite fever usually have a lower incidence of rash. It is usually vesicular and
sparser than in Boutonneuse fever. Also, multiple eschars and prominent regional lymphadenopathy
are present.
[21]

Other manifestations and complications are similar to those seen in patients with RMSF.
Louse-borne (epidemic) typhus
[12]

A rash appears on days 4-7 of illness and spreads from the trunk to the extremities, sparing the
face, palms, and soles. Initially the rash may be concentrated in the axilla.
The lesions progress from macules to maculopapules to petechiae.
Uncommonly, complications such as gangrene, pericarditis, myocarditis, pleural effusion, and
pneumonia may occur.
In severe cases, meningoencephalitis and delirium with fatal cardiac and renal failure may ensue.
Brill-Zinsser disease (ie, relapsing louse-borne typhus)
This is analogous to primary louse-borne epidemic typhus. The rash is usually milder and resolves
faster.
Murine (endemic or flea-borne) typhus
It is similar to louse-borne typhus but tends to have a milder and shorter course.
The rash is less extensive. Unlike RMSF, the rash usually spreads from the trunk to the extremities.
Tsutsugamushi disease (ie, scrub typhus)
Unlike in other rickettsial diseases, generalized lymphadenopathy is a common feature (80%) of scrub
typhus. It develops concomitantly with other manifestations, such as fever, headache, and rash.
[12]

The rash, which occurs 1-3 weeks following exposure to the vector, is frequently truncal and has a
short duration. In 50% of cases, patients have an inoculation eschar.
Hepatosplenomegaly, ocular pain, and conjunctival injection are relatively common.
Other less common manifestations include deafness, tinnitus, myocarditis, atypical pneumonia, and
adult respiratory distress syndrome.
Q fever
[22]

Pneumonitis occurs in more than half of patients. Cough is usually nonproductive and physical
findings may not be pronounced.
Radiography may reveal a wide variety of pathologic findings, ranging from multiple segmental
opacities to pleural effusion, lobar consolidation, or linear atelectasis.
Hepatitis presents with a fever and silent elevation of liver enzymes (transaminases).
Hepatosplenomegaly may be present.
[5]

Chronic Q fever infection must be excluded in patients with multifocal osteomyelitis, especially if a
history of exposure to farm animals is noted.
[23]

Causes
RMSF
This disease is caused by R rickettsii.
[1, 6]

Tick vectors of RMSF include the Rocky Mountain wood tick (Dermacentor andersoni) in the Western
United States and Canada; the American dog tick (Dermacentor variabilis) in the Eastern United
States, along the US Pacific coast, and in the central United States; and the Lone Star tick
(Amblyomma americanum) in some southern areas.
[3]
Examples of the ticks are shown in the images
below.
This photo shows the relative sizes of the adult forms of Ixodes scapularis
(right) and Dermacentor variabilis (left). These ticks are shown next to a common match for scale. I scapularis is also
referred to as Ixodes dammini. Photo by Darlyne Murawski; reproduced with permission.
This photo is of an adult female, Amblyomma americanum, and a nymphal form
of the same species (shown next to a common match for scale). Photo by Darlyne Murawski; reproduced with
permission.
From 2002-2004, cases of RMSF reported from rural Arizona by Demma and colleagues were
attributed to exposure to the common brown dog tick (Rhipicephalussanguineus).
[25]
This represents a
change from the typical vectors for this disease.
Expansions in tick populations can introduce rickettsial agents to new geographic areas and
previously unrecognized rickettsiae -vector-human host relationships continue to evolve and be
described.
[26]
Research from Germany identified a possible role for migratory birds in the distribution of
emerging tick-borne pathogens including Rickettsiae.
[27]

Rickettsiae multiply within ticks and pass to the next generation transovarially.
Rickettsiae are transmitted to a vertebrate host through saliva while a tick is feeding. It usually takes
several hours of attachment and feeding before the rickettsiae are transmitted to the host. The risk of
exposure to a tick carrying R rickettsii is low. Generally, about 1-3% of the tick population carries R
rickettsii, even in areas where most human cases are reported.
Recognized or potential tick-borne spotted fever group rickettsial pathogens in the United States,
other than R rickettsii include R akari, Rickettsia felis, Rickettsia parkeri, Rickettsia amblyomii,
Rickettsia rhipicephali, and various unnamed serotypes (eg, Tillmook, 364-D).
[28]

Rickettsialpox
It is caused by R akari, a member of the spotted fever group of Rickettsiae.
The disease is distinguishable from other rickettsial infections by the presence of an eschar at the site
of the mouse mite (Liponyssoides sanguineus) bite, a vesiculopustular eruption, and the absence of
Weil-Felix agglutinins.
The house mouse (Mus musculus) is the natural host of the mite transmitting rickettsialpox in the
United States. Other rodents have been associated with the disease in other parts of the world.
[6]

Boutonneuse fever
This disease is a tick-borne infection caused by various subspecies of Rickettsia conorii complex (R
conorii conorii is the cause of Mediterranean spotted fever; R conorii israelensis is the cause of Israeli
spotted fever; R conorii caspica is the cause of Astrakhan spotted fever; and R conorii indica is the
cause of Indian tick typhus) , Rickettsia africae (the cause of African tickbite fever) , or R
slovaca,which are obligate intracellular organisms transmitted to humans by various ticks, depending
on the geographical location.
[9]

Contact with dogs carrying infected ticks appears to be the important risk factor for human infection.
Louse-borne (epidemic) typhus
This disease is caused by R prowazekii.
It is transmitted to humans by lice (ie, Pediculus humanus). Humans are the primary reservoir for R
prowazekii.
Brill-Zinsser disease (ie, relapsing louse-borne typhus)
The rickettsial cause is the same but is related to the reactivation of the organism from a poorly
defined latent state.
Murine (endemic or flea-borne) typhus
This disease is primarily caused by R typhi (Rickettsia mooseri) and R felis,which share a large
antigenic moiety with R prowazekii.
It is transmitted from rat-to-rat by a rat flea (X cheopis) and accidentally to humans by the feces of
infected fleas.
The cat flea (C felis) can also transmit the disease.
[16]

Tsutsugamushi disease (ie, scrub typhus)
This disease is caused by O tsutsugamushi, which has a remarkable antigenic heterogeneity.
It is transmitted to humans by the larval form of trombiculid mites (ie, chiggers) that live and breed in
the soil and scrub vegetation. The mite is both the reservoir and the vector that passes the bacteria
transovarially. Rodents are also reservoirs. Humans are accidentally infected.
Q fever
The name derives from "Query Fever," given in 1935 following an outbreak of febrile illness in an
abattoir in Australia. The disease is caused by C burnetii, a short, Gram negative, strictly intracellular
bacterium.
Originally classified in the order Rickettsiales, C burnetii has since been placed
(with Legionella and Francisella) into the gamma subdivision of the Proteobacteria on the basis of
sequences of the 16SrDNA encoding genes.
[5]

Unlike human rickettsial infections, it is a zoonosis transmitted from diseased animals to humans by
the aerosol route or ingestion of raw milk.
Animals commonly infected include domestic livestock, especially cattle, sheep, and goats, as well as
rodents, marsupials (in Australia), and cats (in Canada).
Ticks play a very minor role, if any, in transmission of the disease to humans; however, they transmit
the disease to rodents and domestic animals.
C burnetii is a resilient organism that remains latent in infected hosts (eg, domestic livestock) until it is
activated by a physiologic stressor, such as parturition. It then multiplies and contaminates the
animals' surroundings, where it remains a potential source of infection for months. It is considered by
the Center for Disease Control and Prevention (CDC) a potential agent of bioterrorism (class B).
[6, 5]

Differential Diagnoses
Dengue
Kawasaki Disease
Leptospirosis
Malaria
Measles
Meningococcal Infections
Rubella
Streptococcal Infection, Group A
Syphilis
Toxic Shock Syndrome
Vasculitis and Thrombophlebitis

Specific therapy
Adequate antibiotic therapy initiated early in the first week of illness is highly effective and is
associated with the best outcome. Fever usually subsides within 24-72 hours after starting antibiotic
therapy. If fever fails to subside with the use of a suitable antibiotic, the diagnosis of rickettsial disease
should be reconsidered. Treatment may be terminated 2-3 days after the patient is afebrile and at
least 10 days of therapy has been given.
[32]

Doxycycline is the drug of choice; it is preferred over other tetracyclines for treatment of rickettsial
infections and, at such low dose and short duration, is rarely associated with staining of teeth in
children younger than 8 years.
[33, 9]

Chloramphenicol may be used as an alternative. However, it is rarely used in the United States
because of its potential bone marrow toxicity.
Recent data from Europe suggest that fluoroquinolones, such as ciprofloxacin and ofloxacin, may be
effective in the treatment of certain rickettsioses.
[17, 5]
However quinolones, which are not FDA
approved for use in children younger than 18 years, have been associated with clinical failures
despite good in vitro activity.
Sulfonamides were found to have a harmful effect either by delaying the institution of proper
antimicrobial therapy or by directly stimulating growth of the organisms. They are contraindicated in
rickettsial infections.
[4, 32]

Supportive therapy
Thrombocytopenia, hypoalbuminemia, hypotension, and coagulation defects require supportive
management. Hyponatremia is best managed with maintenance fluids or even modest fluid restriction.
Whether or not steroids are helpful in shortening the febrile period in Rocky Mountain spotted fever
(RMSF) is controversial.
[1, 34]

RMSF: Antibiotic treatment may be terminated 2-3 days after the patient is afebrile and at least 10
days of therapy has been given. Longer courses may be required in complicated illness.
[32]

Rickettsialpox: Antibiotics are the mainstay of treatment. However, in infants and young children
with mild illness, antibiotics may be withheld because the infection is self-limited.
Boutonneuse fever: Doxycycline remains the drug of first choice; however, the newer macrolide may
be of interest.
[9]
Improvement usually occurs within 48 hours of therapy. Duration of therapy has not
been definitively established; however, recommendations state that antibiotic treatment should
continue for 24 hours after fever has abated.
Louse-borne (epidemic) typhus: Treatment is analogous to that of RMSF. The use of insecticides
and pediculicides (eg, lindane, crotamiton, malathion) can be highly effective in reducing louse
infestation and may serve as important adjuncts to specific therapy in curtailing louse-borne typhus
epidemics.
Brill-Zinsser disease (ie, relapsing louse-borne typhus): Treatment is analogous to that of RMSF.
Murine (endemic or flea-borne) typhus: A single dose of doxycycline is the treatment of choice for
this disease. Other tetracyclines and chloramphenicol are also effective agents. The control of rat
fleas with insecticides followed by control of rat populations with rodenticides is an important adjunct
measure to combat the spread of this disease.
Tsutsugamushi disease (ie, scrub typhus): Antibiotic treatment with tetracyclines or
chloramphenicol, similar to that of the spotted fever group, is recommended. However, sporadic
short antibiotic courses of doxycycline or chloramphenicol may be required to prevent relapses.
[33]

Q fever
o Acute disease responds to tetracyclines or chloramphenicol. Fluoroquinolones and the newer
macrolides (eg, azithromycin) have also been used successfully for treatment of acute infection.
Generally, relapses are rare.
[5]

o Chronic Q fever infections, on the other hand, require prolonged courses of antimicrobial therapy.
In cases of endocarditis caused by chronic Q fever, combination therapy with hydroxychloroquine
and doxycycline is the preferred treatment. Duration of therapy is 18-36 months depending on the
serologic response. Several alternative combination regimens (eg, a fluoroquinolone with
doxycycline or rifampin with doxycycline) have been proposed but not adequately studied yet.
[23, 5]