AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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.

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 usually are transmitted to humans by arthropods. An exception is Q fever, which is transmitted by airborne droplets.

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

Eighteen rickettsioses, caused by organisms within the genus of rickettsiae, are recognized and can be divided into the following 3 biogroups:

• 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, 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 heterogenous 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
• • Q fever is a rickettsial disease caused by Coxiella burnetii.
  • Ehrlichia organisms (the cause of human monocytic ehrlichiosis and Ehrlichia ewingii infection), Anaplasma phagocytophilum (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.
  • 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 sibricia infection.

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).

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 CNS 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 in various organs may also become involved as the organism disseminates. 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).

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.
• 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.
• 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.
• 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.
• 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.

International

The spotted fever rickettsiae have been found in every continent except Antarctica.

• 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.
• 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 tick–bite fever, these infections have been identified in Kenya, Somalia, South Africa, Ethiopia, India, and Pakistan, as well as rural Sub-saharan Africa and the eastern Caribbean.
• 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.
• 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 rickettsial disease is observed in humans who come in contact with infected animals in Australia and Canada, as well as other areas of the world.

Mortality/Morbidity

Rickettsial diseases vary in clinical severity according to the virulence of the Rickettsia 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.

• 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. 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, and fatalities are rare.
• 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 1-2 weeks. The mortality rate is approximately 1%. Complications are rare but may increase the mortality rate to 30-60%.

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.

Age

• RMSF: Two thirds of patients are aged 15 years or younger.
• Rickettsialpox, boutonneuse fever, epidemic and endemic typhus, Tsutsugamushi disease, and Q fever affect all ages.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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)
• • 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.
  • Gastrointestinal symptoms (eg, abdominal pain and diarrhea) commonly occur during early stages of illness.
  • Conjunctival injection may also be seen.
• Rickettsialpox
• • 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 (38-41°C) 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 varies from 6-10 days.
  • 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 is seen in only half of patients. This lesion heals slowly over 10-20 days without leaving a scar.
  • The disease has an acute onset with fever, headache, and malaise.
  • 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.
• 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
• • 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)
• • 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.
  • It is helpful to inquire about history of travel to the Southwest Pacific or Southeast Asia, where patients almost exclusively contract this disease.
• Q fever
• • 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.
  • Characteristically, rash is absent.
  • Chronic Q fever infection is less common. It may be manifested as endocarditis, chronic or relapsing multifocal osteomyelitis, chronic hepatitis, chronic vascular infection, pericarditis, or myocarditis.
  • 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.
• TIBOLA and DEBONEL
• • 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 40-41°C and, more commonly, has a persistent pattern rather than an oscillating one.
  • 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.
  • 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 (ie, 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.
  • A rash appears on days 3-5 of the illness. It spreads from the extremities to the trunk, neck, face, palms, and soles within 36 hours.
  • The lesions progress from macular to maculopapular and may persist for 2-3 weeks.
  • Atypical cutaneous findings may occur in a few patients.
  • Patients with African tick–bite 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.
  • Other manifestations and complications are similar to those seen in patients with RMSF.
• Louse-borne (epidemic) typhus
• • 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.
  • 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
• • Pneumonitis occurs in more than half of patients.
  • Physical findings may not be pronounced; however, radiographs may demonstrate a wide variety of pathologic findings ranging from multiple segmental opacities to pleural effusion, lobar consolidation, or linear atelectasis.
  • Hepatosplenomegaly is a common finding; it usually is accompanied with elevation of liver enzymes.
  • Chronic Q fever infection must be excluded in patients with multifocal osteomyelitis, especially if a history of exposure to farm animals is noted.

Causes

• RMSF
• • This disease is caused by R rickettsii.
  • 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 East along the Pacific coast and central United States, and the Lone Star tick (Amblyomma americanum) in some southern areas.
  • From 2002-2004, cases of RMSF reported from rural Arizona by Demma and colleagues were attributed to exposure to the common brown dog tick (Rhipicephalus sanguineus).² This represents a change from the typical vectors for this disease.
  • 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 the majority of 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).
• 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.
• Boutonneuse fever
• • This disease is a tick-borne infection caused by Rickettsia conorii (the cause of Mediterranean spotted fever), Rickettsia africae (the cause of African tick–bite fever), or R slovaca, which are obligate intracellular organisms transmitted to humans by various ticks, depending on the geographical location.
  • Contact with dogs 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 it is related to the reactivation of the organism from a poorly defined latent state.
• Murine (endemic or flea-borne) typhus
• • This disease is caused primarily 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) also may transmit the disease.
• 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
• • This acute illness, caused by C burnetii, was first described in the late 1930s.
  • Unlike other human rickettsial infections, it is a zoonosis transmitted from diseased animals to humans by the aerosol route.
  • 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Typhoid fever
Infectious mononucleosis
Enteroviral infections
Idiopathic thrombocytopenic purpura
Drug reaction
Chronic granulomatous bone lesions: These could be caused by Mycobacteria, Bartonella, Francisella, Brucella, and Nocardia species. These should be considered in the differential diagnosis for chronic recurrent multifocal osteomyelitis, in addition to chronic Q fever infection.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Rickettsiae are not evident on blood smear findings and do not stain with most conventional stains.
• No rapid laboratory tests are available to diagnose rickettsial diseases early in the course of illness.
• • Serologic assays that demonstrate antibodies to rickettsial antigens (eg, indirect immunoflourescence, complement fixation, indirect hemagglutination, latex fixation, enzyme immunoassay, microagglutination) are preferable to the nonspecific and insensitive Weil-Felix test based on the cross-reactive antigens of Proteus vulgaris strains. Serologic findings usually take 10-12 days to become positive. The value of testing 2 sequential serum or plasma samples together to show a rising antibody level is considerably more important in confirming acute infection with rickettsial agents because antibody titers may persist in some patients for years after the original exposure.
  • Immunoflourescence assay (IFA) is currently considered to be the reference serological method. However, it cannot determine the causative agent to the species level.
  • Polymerase chain reaction (PCR) to detect rickettsiae in blood or tissue provides promise for early diagnosis. PCR testing and immunohistochemical staining of skin specimen obtained by performing a biopsy may help confirm the clinical diagnosis in patients with rash (high expertise is usually needed to interpret the biopsy result). However, serology remains the mainstay of diagnosis because these other tests are expensive and less available to clinicians.
  • Rickettsial isolation in culture is unnecessary, laborious, and hazardous to laboratory personnel.
• Rocky Mountain spotted fever (RMSF)
• • Serology is the mainstay to confirm diagnosis.
  • Another approach to RMSF diagnostics is immunostaining whereby a skin biopsy of the rash from an infected patient is tested prior to therapy or within the first 48 hours after antibiotic therapy has been started. This test's utility remains highly operator-dependent.
  • Other tests, such as PCR, are rather expensive and not readily available.
  • Nonspecific laboratory findings, such as thrombocytopenia, leukopenia, and mild hyponatremia, may give helpful clues to the treating physician.
  • If cerebrospinal fluid is examined, pleocytosis (generally <100 cells/μL) is typically observed with polymorphonuclear or lymphocyte predominance, moderately elevated protein levels (100-200 mg/dL), and normal glucose levels.
• Rickettsialpox
• • As with other rickettsial infections, diagnosis is clinical and may be confirmed by serology.
  • The Weil-Felix test is not useful because R akari does not produce Weil-Felix agglutinins.
  • R akari has a soluble antigen that cross-reacts with R rickettsii (the cause of RMSF) and other spotted fever groups of rickettsiae.
• Boutonneuse fever
• • Serologic laboratory confirmation (complement fixation, microagglutination, western blot, indirect immunofluorescent tests) usually provides support for the diagnosis made on clinical and epidemiologic grounds. Additionally, a latex agglutination test for detection of antibodies to R conorii that is both specific and sensitive now can be performed in specialized laboratories.
  • R conorii has been detected from the tache noire by restriction fragment length polymorphism (RFLP) and by PCR.
• Louse-borne (epidemic) typhus
• • Serologic laboratory confirmatory tests are available as in RMSF. Patients initially have an IgM response followed by production of immunoglobulin G (IgG) antibodies.
  • However, a significant antigenic crossing exists between this Rickettsia organism and those of the spotted fever group.
  • PCR promises to be a rapid diagnostic test but is expensive and not yet widely available.
• Brill-Zinsser disease (ie, relapsing louse-borne typhus): Laboratory studies are similar to those for primary louse-borne epidemic typhus. However, patients develop an anamnestic immune response whereby only IgG is produced.
• Murine (endemic or flea-borne) typhus:
• • Laboratory studies are analogous to those mentioned for epidemic louse-borne typhus.
  • Additionally, a mild-to-moderate elevation of serum aspartate aminotransferase (AST) level is present in approximately 90% of patients. Other indices of hepatocellular injury (alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase) are often also elevated.
• Tsutsugamushi disease (ie, scrub typhus)
• • Serologic testing using specific methods (eg, immunofluorescence antibody test, indirect immunoperoxidase test, enzyme immunoassay) is superior to the Weil-Felix reaction.
  • However, these tests are cumbersome and only available in a few special laboratories.
• Q fever
• • In addition to clinical and epidemiologic features, serology (eg, immunofluorescence, complement fixation, enzyme immunoassay) remains the mainstay of diagnosis in acute and chronic illnesses.
  • As with other rickettsiae, attempts to isolate the organism are biohazardous and unnecessary.
  • PCR may be used; however, it remains less available and more expensive than serology.
  • Chronic Q fever endocarditis is diagnosed by demonstration of high antibody IgG and immunoglobulin A (IgA) titers against C burnetii in patients with signs of endocarditis whose blood cultures contain no organisms.

Imaging Studies

• Chest radiography may be required in patients with severe illness or pulmonary manifestations, especially in patients with RMSF and Q fever.
• Other imaging studies may be necessary, depending on the severity of organ involvement and development of complications.

Procedures

• A lumbar puncture and other procedures may be needed to exclude other possible etiologies.

Histologic Findings

• Evidence of vasculitis, angiitis, and perivascular mononuclear cell infiltration may be evident in involved organs.
• Chronic Q fever infection of the skeletal system causes the formation of granulomatous lesions.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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.

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.

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, ofloxacin, and pefloxacin, may be effective in the treatment of certain rickettsioses. 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.

Supportive therapy

Thrombocytopenia, hypoalbuminemia, hypotension, and coagulation defects require supportive management. Hyponatremia is best managed with maintenance fluids or even modest fluid restriction. Controversy exists as to whether or not steroids are helpful in shortening the febrile period in Rocky Mountain spotted fever (RMSF).

• 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.
• 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: Duration of therapy has not been definitively established.
• 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.
• Q fever: Acute disease responds to tetracyclines or chloramphenicol; relapses are rare. In general, chronic Q fever infections require prolonged courses of antimicrobial therapy. In cases of endocarditis caused by chronic Q fever, the appropriate drug and duration of therapy is unknown. Additionally, combination therapy (eg, quinolones, tetracyclines, doxycycline, chloramphenicol, lincomycin, rifampin) has produced variable results.

Consultations

• Infectious disease subspecialists play a vital role in diagnosis confirmation, management, and exclusion of other illnesses on the differential.
• Other subspecialists may be consulted, depending on the course of the illness (eg, cardiologist, pulmonologist, nephrologist, intensivist).

Diet

No dietary restriction is required in uncomplicated rickettsial infections.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Adequate antibiotic therapy initiated early is highly effective and associated with the best outcomes.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients may require hospitalization only if they are clinically unstable or have developed complications.

Transfer

• Rickettsial infections with severe complications may require transfer to tertiary care facilities.

Deterrence/Prevention

Personal avoidance of ticks (wearing proper clothing and use of repellants) remains an integral part of protection against rickettsial infections. In case of bites, prompt removal of ticks might prove extremely beneficial in prevention of infection. Attempting to control the tick reservoir is not usually feasible. Use of antibiotics following tick exposure is not currently indicated to prevent rickettsial infection.

• Rocky Mountain spotted fever (RMSF): Various vaccines have been developed; however, they have not yet been proven efficacious or safe to recommend for routine use in patients. A recently improved killed chicken embryo vaccine has shown that it may provide partial protection against RMSF and ameliorate the illness when it occurs.
• Rickettsialpox: Avoidance of contact with and control of house mouse infestations is important to prevent acquisition of infection.
• Boutonneuse fever: Natural immunity occurs following infection. Effective vaccines are not yet available.
• Typhus group (epidemic and endemic typhus): Delousing of individuals and use of insecticides to treat clothing are effective preventive measures against the spread of louse-borne typhus. Killed vaccines that are no longer available in the United States were shown to reduce mortality rates but were not effective in prevention of disease.
• Brill-Zinsser disease (ie, relapsing louse-borne typhus): This is analogous to primary louse-borne epidemic typhus.
• Murine (endemic or flea-borne) typhus: Prevention is primarily by controlling the flea and rat populations. Insecticides should be used before rodenticides to prevent rat fleas from seeking alternate hosts if rats are no longer available. As with louse-borne typhus, a vaccine is no longer available in the United States.
• Tsutsugamushi disease (ie, scrub typhus): Prevention can be achieved by vector control or chemoprophylaxis. The agent of choice for chemoprophylaxis is doxycycline, given as a weekly dose started before exposure to infection and continued for 6 weeks postexposure.
• Q fever: Q fever vaccines are under development and not yet available for clinical use. Control of disease in domestic animal population has been difficult because animals that have no detectable antibodies to C burnetii still shed the organism at parturition. Q fever outbreaks in research laboratories using animals (especially sheep) can be prevented by instituting proper control measures designed to protect the environment from fomite and aerosol transmission.

Complications

• RMSF: Complications are uncommon, especially if patients receive proper treatment. Acute complications may include a superimposed bronchopneumonia and congestive heart failure (caused by fluid overload). Long-term health problems following acute RMSF infection include partial paralysis of the lower extremities; gangrene requiring amputation of fingers, toes, arms, or legs; hearing loss; loss of bowel or bladder control; movement disorders; and language disorders. These rare complications are usually seen in severely affected individuals.
• Rickettsialpox: This is usually a self-limited disease with no complications.
• Boutonneuse fever: Similarly to RMSF, the disease occasionally may follow a malignant and rapidly fatal course with multiorgan failure, encephalopathy, and coagulopathy.
• Louse-borne (epidemic) typhus: Complications are uncommon but include gangrene, parotitis, otitis, myopericarditis, pneumonia, and pleurisy.
• Brill-Zinsser disease (ie, relapsing louse-borne typhus): Complications are similar to the primary illness; however, relapses usually are less severe.
• Murine (endemic or flea-borne) typhus: Complications are similar to those observed in louse-borne typhus and are uncommon.
• Tsutsugamushi disease (scrub typhus): Complications are generally uncommon. Deafness, atypical pneumonia, disease similar to adult respiratory distress syndrome, myocarditis, and disseminated intravascular coagulopathy have been reported.
• Q fever: Complications include chronic Q fever, endocarditis, myocarditis, meningoencephalitis, glomerulonephritis, and syndrome of inappropriate antidiuretic hormone (SIADH).

Prognosis

• RMSF
  • The overall mortality rate without specific therapy is approximately 25%; however, the mortality rates are higher for men, elderly persons, and black men with G-6-PD deficiency.
  • In the United States, the overall mortality rate currently is 5-7%.
  • Fatalities are mainly caused by delay in diagnosis and treatment.
  • Solid immunity usually follows recovery from RMSF.
• Rickettsialpox
  • Rickettsialpox is usually self-limited.
  • Deaths have not been reported.
• Boutonneuse fever
  • Boutonneuse fever generally runs a benign course.
  • Very rarely, it may follow a rapidly fatal course in otherwise healthy children.
• Louse-borne (epidemic) typhus
• • The mortality rate in untreated cases correlates with the patient's age.
  • Mortality may be uncommon in children younger than 12 years, but rates rise to as high as 60-70% in individuals older than 50 years.
  • Most patients who recover develop immunity.
• Brill-Zinsser disease (ie, relapsing louse-borne typhus): This is analogous to primary louse-borne epidemic typhus, except that patients who recover do not develop immunity.
• Murine (endemic or flea-borne) typhus: This is usually a mild illness without significant sequelae.
• Tsutsugamushi disease (ie, scrub typhus)
• • Fatalities are rare with use of antibiotics.
  • The heterogeneity of scrub typhus strains accounts for the frequent reinfections.
  • Sporadic short courses of doxycycline or chloramphenicol may be required to prevent relapses.
• Q fever
  • Patients with uncomplicated Q fever recover within 1-2 months without sequelae.
  • The mortality rate is less than 1%.
  • On the other hand, complicated cases have a higher rate of permanent disabilities and fatalities.

Patient Education

• Education of patient population regarding effective avoidance of ticks is highly important.
• Physician education is also important to promote early diagnosis and proper treatment.
• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Use of sulfonamides, which usually have a harmful effect and are contraindicated in rickettsial infections

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Oct 12, 2007