RICKETTSIARICKETTSIA

HISTORY:HISTORY: Rickettsial infections have played a significant role in the Rickettsial infections have played a significant role in the

history of Western civilization. Epidemic typhus has been history of Western civilization. Epidemic typhus has been known since the 16th century and it has long been known since the 16th century and it has long been associated with famine and war. The outcome of several associated with famine and war. The outcome of several wars was influenced by epidemic typhus. Typhus killed wars was influenced by epidemic typhus. Typhus killed or caused great suffering in over 100,000 people in the or caused great suffering in over 100,000 people in the two World Wars. In spite of its long history, it was not two World Wars. In spite of its long history, it was not until the early part of the 20th century that the causative until the early part of the 20th century that the causative agent was determined. Howard Ricketts described the agent was determined. Howard Ricketts described the causative agent of Rocky Mountain spotted fever and causative agent of Rocky Mountain spotted fever and was able to culture it in laboratory animals. Others then was able to culture it in laboratory animals. Others then realized that the causative agent of epidemic typhus was realized that the causative agent of epidemic typhus was related to the organism that Ricketts described. After the related to the organism that Ricketts described. After the discovery of the importance of arthropod vector in the discovery of the importance of arthropod vector in the spread of typhus, vector control measures were spread of typhus, vector control measures were instituted to control the disease. However, as Hans instituted to control the disease. However, as Hans Zinsser has pointed out, typus is not dead.Zinsser has pointed out, typus is not dead.

INTRODUCTION TO THE INTRODUCTION TO THE RICKETTSIARICKETTSIA

TheThe rickettsia rickettsia are small (0.3-0.5 x 0.8-2.0 um), Gram- are small (0.3-0.5 x 0.8-2.0 um), Gram-negative, aerobic, coccobacilli that are obligate negative, aerobic, coccobacilli that are obligate intracellular parasites of eukaryotic cells. They may reside intracellular parasites of eukaryotic cells. They may reside in the cytoplasm or within the nucleus of the cell that they in the cytoplasm or within the nucleus of the cell that they invade. They divide by binary fission and they metabolize invade. They divide by binary fission and they metabolize host-derived glutamate via  aerobic respiration and the host-derived glutamate via  aerobic respiration and the citric acid (TCA) cycle. They have typical Gram-negative citric acid (TCA) cycle. They have typical Gram-negative cell walls, and they lack flagella. The rickettsia frequently cell walls, and they lack flagella. The rickettsia frequently have a close relationship with arthropod vectors that may have a close relationship with arthropod vectors that may transmit the organism to mammalian hosts. The rickettsia transmit the organism to mammalian hosts. The rickettsia have very small genomes of about 1.0-1.5 million bases. have very small genomes of about 1.0-1.5 million bases.

Rickettsia must be grown in the laboratory by co-Rickettsia must be grown in the laboratory by co-cultivation with eukaryotic cells, and they have not been cultivation with eukaryotic cells, and they have not been grown by in axenic culture. The basis of their obligate grown by in axenic culture. The basis of their obligate relationship with eukaryotic cells has been explained by relationship with eukaryotic cells has been explained by rickettsial possession of "leaky membranes" that require rickettsial possession of "leaky membranes" that require the osmolarity and nutritional environment supplied by an the osmolarity and nutritional environment supplied by an intracellular habitat. intracellular habitat.

NATURAL HISTORY:NATURAL HISTORY: Rocky Mountain spotted fever, like all rickettsial infections, is classified as a Rocky Mountain spotted fever, like all rickettsial infections, is classified as a

zoonosis. zoonosis. ZoonosesZoonoses  are diseases of animals that can be transmitted to humans.   are diseases of animals that can be transmitted to humans. Many zoonotic diseases require a vector (e.g., a mosquito, tick, or mite) in order to Many zoonotic diseases require a vector (e.g., a mosquito, tick, or mite) in order to be transmitted from the animal host to the human host. In the case of Rocky be transmitted from the animal host to the human host. In the case of Rocky Mountain spotted fever, ticks are the natural hosts, serving as both reservoirs and Mountain spotted fever, ticks are the natural hosts, serving as both reservoirs and vectors of vectors of R. rickettsii.R. rickettsii. Ticks transmit the organism to vertebrates primarily by their Ticks transmit the organism to vertebrates primarily by their bite. Less commonly, infections may occur following exposure to crushed tick bite. Less commonly, infections may occur following exposure to crushed tick tissues, fluids, or feces. tissues, fluids, or feces.

  Only members of the tick family Only members of the tick family IxodidaeIxodidae (hard ticks) are naturally infected with (hard ticks) are naturally infected with Rickettsia rickettsii.Rickettsia rickettsii. These ticks have four stages in their life cycle: egg, larva, These ticks have four stages in their life cycle: egg, larva, nymph, and adult. After the eggs hatch, each stage must feed once to develop into nymph, and adult. After the eggs hatch, each stage must feed once to develop into the next stage. Both male and female ticks will bite. the next stage. Both male and female ticks will bite.

A female tick can transmit A female tick can transmit R. rickettsiiR. rickettsii to her eggs in a process called transovarial to her eggs in a process called transovarial transmission. Ticks can also become infected with transmission. Ticks can also become infected with R. rickettsiiR. rickettsii while feeding on blood while feeding on blood from the host in either the larval or nymphal stage. After the tick develops into the from the host in either the larval or nymphal stage. After the tick develops into the next stage, next stage, R. rickettsiiR. rickettsii may be transmitted to the second host during the feeding may be transmitted to the second host during the feeding process.  Furthermore, male ticks may transfer process.  Furthermore, male ticks may transfer R. rickettsiiR. rickettsii to female ticks through to female ticks through body fluids or spermatazoa during  mating..  In this manner generations or each life body fluids or spermatazoa during  mating..  In this manner generations or each life stage of infected ticks are maintained. Once infected, the tick can carry the rickettsia stage of infected ticks are maintained. Once infected, the tick can carry the rickettsia for life. for life.

Rickettsiae are transmitted to a vertebrate host through saliva while a tick is 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 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 rickettsiae are transmitted to the host. The risk of exposure to a tick carrying R. R. rickettsiirickettsii is low. Generally, about 1 -3% of the tick population carries is low. Generally, about 1 -3% of the tick population carries R. rickettsii,R. rickettsii, even in areas where the majority of human cases are reported. even in areas where the majority of human cases are reported.

DESCRIPTION AND SIGNIFICANCEDESCRIPTION AND SIGNIFICANCE

RickettsiaRickettsia bacteria are well known pathogens. bacteria are well known pathogens. Rickettsia conoriiRickettsia conorii causes Mediterranean causes Mediterranean spotted fever in humans and is contracted by spotted fever in humans and is contracted by contact with infected brown dog ticks. Other contact with infected brown dog ticks. Other Rickettsia include Rickettsia include Rickettsia prowazekii, Rickettsia prowazekii, which which causes typhus, causes typhus, R. rickettsiiR. rickettsii, which causes , which causes Rocky Mountain spotted fever, and Rocky Mountain spotted fever, and Rickettsia Rickettsia akariakari, which causes rickettsialpox. In addition , which causes rickettsialpox. In addition to this, the genome of to this, the genome of Rickettsia prowazekiiRickettsia prowazekii is is similar to mitochondrial genomes; similar to mitochondrial genomes; phylogenetically, phylogenetically, R. prowazekiiR. prowazekii is more closely is more closely related to the mitochondria than any other related to the mitochondria than any other microbe known thus far. microbe known thus far.

TAXONOMY:TAXONOMY:

GENOME STRUCTUREGENOME STRUCTURE The genome of The genome of Rickettsia prowazekiiRickettsia prowazekii is is

1,111,523 base pairs in length and contains 834 1,111,523 base pairs in length and contains 834 protein-coding genes. It contains no genes for protein-coding genes. It contains no genes for anaerobic glycolysis as well as genes involved anaerobic glycolysis as well as genes involved in the biosynthesis and regulation of in the biosynthesis and regulation of biosynthesis of amino acids and nucleosides in biosynthesis of amino acids and nucleosides in free-living bacteria similar to mitochondrial free-living bacteria similar to mitochondrial genomes. Unlike the mitochondrial genome, genomes. Unlike the mitochondrial genome, however, the genome of however, the genome of R. prowazekii R. prowazekii contains contains a complete set of genes encoding for the a complete set of genes encoding for the tricarboxylic acid cycle and the respiratory-tricarboxylic acid cycle and the respiratory-chain complex. Still, the genomes of chain complex. Still, the genomes of RickettsiaRickettsia as well as the mitochondria are small, highly as well as the mitochondria are small, highly derived, "products of several types of reductive derived, "products of several types of reductive evolution" (Andersson et al. 1998).evolution" (Andersson et al. 1998).

ORGANISM:ORGANISM:

Genus:Genus: RickettsiaRickettsia, , RochalimaeaRochalimaea, , CoxiellaCoxiella

Species:Species: Rickettsia prowazekiiRickettsia prowazekii (epidemic typhus), (epidemic typhus), Rickettsia typhiRickettsia typhi (endemic typhus), (endemic typhus), Rickettsia Rickettsia rickettsiirickettsii (spotted fever), (spotted fever), Rochalimaea quintanaRochalimaea quintana (trench fever), (trench fever), Coxiella burnetiiCoxiella burnetii (Q fever) (Q fever)

RickettsiaRickettsia bacteria are obligate intracellular bacteria are obligate intracellular pathogens that are dependent on entry, growth, and pathogens that are dependent on entry, growth, and replication within the cytoplasm of a eukaryotic host replication within the cytoplasm of a eukaryotic host cell. The host cell then lysis and releases the cell. The host cell then lysis and releases the rickettsial progeny to initiate a new infection cycle. rickettsial progeny to initiate a new infection cycle. The infection generally doesn't result in complete The infection generally doesn't result in complete shutdown of the host machinery. Apparently, shutdown of the host machinery. Apparently, "vigorous host responses" generally clear the "vigorous host responses" generally clear the rickettsial pathogens (Radulovicrickettsial pathogens (Radulovic et al. et al. 2001). 2001). Conversely, the host's immune responses can also Conversely, the host's immune responses can also lead to the persistence of a sub clinical infection even lead to the persistence of a sub clinical infection even years past primary infection and/or antibiotic years past primary infection and/or antibiotic treatment. One theory on how rickettsia survives in treatment. One theory on how rickettsia survives in host cells has to do with the "suppression of the host cells has to do with the "suppression of the antimicrobial activities of the eukaryotic target cells, antimicrobial activities of the eukaryotic target cells, specifically monocytes/macrophages" (Radulovic specifically monocytes/macrophages" (Radulovic et et al.al. 2001). 2001).

CELL STRUCTURE AND CELL STRUCTURE AND METABOLISM:METABOLISM:

EPIDEMIOLOGY:EPIDEMIOLOGY: Epidemic typhus and trench fever are transmitted Epidemic typhus and trench fever are transmitted

from human to human via the louse. from human to human via the louse. Endemic (murine) typhus is primarily maintained Endemic (murine) typhus is primarily maintained

in rodent populations and is transmitted via the in rodent populations and is transmitted via the flea. Humans are an accidental host. flea. Humans are an accidental host.

Spotted fever is found predominantly in animals Spotted fever is found predominantly in animals and is transmitted by the tick. Humans are and is transmitted by the tick. Humans are accidental hosts. Most cases of Rocky Mountain accidental hosts. Most cases of Rocky Mountain spotted fever in the US occur during the summer spotted fever in the US occur during the summer months in North and South Carolina, Kansas and months in North and South Carolina, Kansas and Oklahoma. Oklahoma.

Q fever is found mostly in animals. Humans Q fever is found mostly in animals. Humans acquire disease primarily by inhalation of acquire disease primarily by inhalation of contaminated aerosols. contaminated aerosols.

ECOLOGY:ECOLOGY: RickettsiaRickettsia bacteria are commonly carried by bacteria are commonly carried by

anthropods like ticks, mites, lice, or fleas. Another anthropods like ticks, mites, lice, or fleas. Another way for animals and humans to contract the way for animals and humans to contract the bacteria is through wild rodents that have been bacteria is through wild rodents that have been infected with a infected with a RickettsiaRickettsia bacteria by these louse. bacteria by these louse. Different forms of Different forms of RickettsiaRickettsia and the diseases that and the diseases that they cause can be found all over the world. While they cause can be found all over the world. While some diseases themselves are worldwide, others, some diseases themselves are worldwide, others, such as Oriental spotted fever caused by such as Oriental spotted fever caused by R. R. japonicajaponica in Japan, are localized to one general in Japan, are localized to one general place or area. place or area.

PATHOGENESIS:PATHOGENESIS: Typhus, spotted fever and trench fever are Typhus, spotted fever and trench fever are

transmitted via arthropod vectors; Q fever is acquired transmitted via arthropod vectors; Q fever is acquired via inhalation or ingestion of contaminated milk or via inhalation or ingestion of contaminated milk or food. food.

Within minutes, the bacteria enter host endothelial Within minutes, the bacteria enter host endothelial cells via an induced phagocytosis. The enzyme cells via an induced phagocytosis. The enzyme phospholipase A may help penetration. phospholipase A may help penetration.

Replication of the bacteria causes lysis of the host cell Replication of the bacteria causes lysis of the host cell and consequent spread to other cells. and consequent spread to other cells.

Initial replication occurs at the site of entry producing Initial replication occurs at the site of entry producing a local lesion. This is followed by dissemination via the a local lesion. This is followed by dissemination via the vascular system producing vasculitis and a skin rash. vascular system producing vasculitis and a skin rash. These lesions may become necrotic. These lesions may become necrotic.

Virulence is probably due to many factors including Virulence is probably due to many factors including release of endotoxin, the production of immune release of endotoxin, the production of immune complexes and hypersensitivity reactions. complexes and hypersensitivity reactions.

Attachment of rickettsiae to the surface of an Attachment of rickettsiae to the surface of an endothelial cell is followed by their entry into the endothelial cell is followed by their entry into the cell via rickettsia- induced phagocytosis. cell via rickettsia- induced phagocytosis. Following phagocytosis, the phagosome Following phagocytosis, the phagosome membrane (arrow) is lost and the rickettsiae membrane (arrow) is lost and the rickettsiae escape into the host cell cytoplasm.escape into the host cell cytoplasm.

Following release from the phagosomes, Following release from the phagosomes, rickettsiae grow free in the cytoplasm of rickettsiae grow free in the cytoplasm of cultured cells, dividing by binary fission cultured cells, dividing by binary fission (seen at arrows). The inset photo (seen at arrows). The inset photo highlights the outer and inner membranes highlights the outer and inner membranes of rickettsia. of rickettsia.

Rickettsiae are propelled through the Rickettsiae are propelled through the host cell cytoplasm by stimulating the host cell cytoplasm by stimulating the polymerization of host cell F-actin, polymerization of host cell F-actin, seen in the comet-like 'tail' (arrow). seen in the comet-like 'tail' (arrow).

Propulsion by F-actin into long host cell Propulsion by F-actin into long host cell projections known as filopodia projections known as filopodia precedes the release of rickettsiae precedes the release of rickettsiae from the cell surface or their spread to from the cell surface or their spread to adjacent endothelial cells.adjacent endothelial cells.

Growth of rickettsiae (arrows) in the Growth of rickettsiae (arrows) in the endothelium results in damage to vascular endothelium results in damage to vascular integrity and thus the leakage of fluid into a integrity and thus the leakage of fluid into a vital organ such as the brain. The vital organ such as the brain. The accumulation of fluid (edema) in the accumulation of fluid (edema) in the perivascular space (asterisks) may result in perivascular space (asterisks) may result in clinical encephalitis. clinical encephalitis.

Gamma interferon and tumor necrosis factor Gamma interferon and tumor necrosis factor alpha, substances secreted by host immune cells, alpha, substances secreted by host immune cells, "activate" the infected endothelial cell to kill "activate" the infected endothelial cell to kill intracellular rickettsiae via the creation of intracellular rickettsiae via the creation of autophagosomes. Later, fusion of lysosomes with autophagosomes. Later, fusion of lysosomes with autophagosomes results in the digestion of dying autophagosomes results in the digestion of dying rickettsiarickettsia

SIGNS AND SIGNS AND SYMPTOMS:SYMPTOMS:

R. rickettsiiR. rickettsii  infects the cells lining blood vessels throughout the body,   infects the cells lining blood vessels throughout the body, severe manifestations of this disease may involve the respiratory severe manifestations of this disease may involve the respiratory system, central nervous system, gastrointestinal system, or renal system, central nervous system, gastrointestinal system, or renal system. Host factors associated with severe or fatal Rocky Mountain system. Host factors associated with severe or fatal Rocky Mountain spotted fever include advanced age, male sex, African-American race, spotted fever include advanced age, male sex, African-American race, chronic alcohol abuse, and glucose-6-phosphate dehydrogenase chronic alcohol abuse, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. African-American male population; deficiency of this (G6PD) deficiency. African-American male population; deficiency of this enzyme is associated with a high proportion of severe cases of Rocky enzyme is associated with a high proportion of severe cases of Rocky Mountain spotted fever.  This is a rare clinical course that is often fatal Mountain spotted fever.  This is a rare clinical course that is often fatal within 5 days of onset of illness. within 5 days of onset of illness.

Long-term health problems following acute Rocky Mountain spotted Long-term health problems following acute Rocky Mountain spotted fever infection include partial paralysis of the lower extremities, fever infection include partial paralysis of the lower extremities, gangrene requiring amputation of fingers, toes, or arms or legs, gangrene requiring amputation of fingers, toes, or arms or legs, hearing loss, loss of bowel or bladder control, movement disorders, hearing loss, loss of bowel or bladder control, movement disorders, and language disorders. These complications are most frequent in and language disorders. These complications are most frequent in persons recovering from severe, life-threatening disease, often persons recovering from severe, life-threatening disease, often following lengthy hospitalizations. The most important following lengthy hospitalizations. The most important pathophysiologic effect is increased vascular permeability with pathophysiologic effect is increased vascular permeability with consequent edema, loss of blood volume, hypoalbuminemia, consequent edema, loss of blood volume, hypoalbuminemia, decreased osmotic pressure, and hypotension. These effects can be decreased osmotic pressure, and hypotension. These effects can be life threatening resulting in pulmonary edema and adult respiratory life threatening resulting in pulmonary edema and adult respiratory distress syndrome, shock, or acute tubular necrosis. distress syndrome, shock, or acute tubular necrosis.

DISEASES:DISEASES: SFG rickettsioses often manifest regional SFG rickettsioses often manifest regional

lymphadenopathy in the drainage of the eschar, lymphadenopathy in the drainage of the eschar, suggesting that rickettsiae may spread via suggesting that rickettsiae may spread via lymphatic vessels from the tick bite inoculation lymphatic vessels from the tick bite inoculation site early in the infection. Rickettsiae spread site early in the infection. Rickettsiae spread throughout the body and infect mainly throughout the body and infect mainly endothelial cells, establishing many foci of endothelial cells, establishing many foci of contiguous infected blood vessel-lining cells. contiguous infected blood vessel-lining cells. Injury in these local sites causes vascular damage Injury in these local sites causes vascular damage manifesting as rash, interstitial pneumonia, manifesting as rash, interstitial pneumonia, encephalitis, interstitial nephritis, and interstitial encephalitis, interstitial nephritis, and interstitial myocarditis, as well as lesions in the liver, myocarditis, as well as lesions in the liver, gastrointestinal wall, pancreas, and potemtially gastrointestinal wall, pancreas, and potemtially any vascularized tissue of the body. any vascularized tissue of the body.

DIAGNOSIS:DIAGNOSIS: Clinical:Clinical: These diseases present as febrile illnesses These diseases present as febrile illnesses

after exposure to arthropods or animal hosts or aerosols after exposure to arthropods or animal hosts or aerosols in endemic areas and are easily misdiagnosed. A delay in endemic areas and are easily misdiagnosed. A delay in diagnosis may be partly responsible for the high in diagnosis may be partly responsible for the high mortality from Spotted fever. The spread of the rash is mortality from Spotted fever. The spread of the rash is often characteristic: spread from the trunk to the often characteristic: spread from the trunk to the extremities (centrifugal) is typical for typhus; spread extremities (centrifugal) is typical for typhus; spread from the extremities to the trunk (centripetal) is typical from the extremities to the trunk (centripetal) is typical for spotted fever. for spotted fever.

Laboratory: Laboratory: Serologic assays are the most widely Serologic assays are the most widely available and frequently used methods for confirming available and frequently used methods for confirming cases of Rocky Mountain spotted fever. The indirect cases of Rocky Mountain spotted fever. The indirect immunofluorescence assay (IFA) is generally considered immunofluorescence assay (IFA) is generally considered the reference standard in Rocky Mountain spotted fever the reference standard in Rocky Mountain spotted fever serology and is the test currently used by CDC and most serology and is the test currently used by CDC and most state public health laboratories. IFA can be used to state public health laboratories. IFA can be used to detect either IgG or IgM antibodies. detect either IgG or IgM antibodies.

CONTROL:CONTROL:

Sanitary:Sanitary: Arthropod and rodent Arthropod and rodent control are possible but difficult.control are possible but difficult.

Immunological:Immunological: No vaccines are No vaccines are currently available.currently available.

Chemotherapeutic:Chemotherapeutic: Tetracycline or Tetracycline or chloramphenicol are drugs of choice.chloramphenicol are drugs of choice.

Prevent any contact with louse as Prevent any contact with louse as can as possible.can as possible.

TREATMENT:TREATMENT: Doxycycline (100 mg every 12 hours for adults or 4 mg/kg body Doxycycline (100 mg every 12 hours for adults or 4 mg/kg body

weight per day in two divided doses for children under 45 kg [100 weight per day in two divided doses for children under 45 kg [100 lbs]) is the drug of choice for patients with Rocky Mountain lbs]) is the drug of choice for patients with Rocky Mountain spotted fever. Therapy is continued for at least 3 days after fever spotted fever. Therapy is continued for at least 3 days after fever subsides and until there is unnequivocal evidence of clinical subsides and until there is unnequivocal evidence of clinical improvement, generally for a minimum total course of 5 to 10 improvement, generally for a minimum total course of 5 to 10 days. Severe or complicated disease may require longer treatment days. Severe or complicated disease may require longer treatment courses. Doxycycline is also the preferred drug for patients with courses. Doxycycline is also the preferred drug for patients with ehrlichiosis, another tick-transmitted infection with signs and ehrlichiosis, another tick-transmitted infection with signs and symptoms that may resemble Rocky Mountain spotted fever. symptoms that may resemble Rocky Mountain spotted fever.

Tetracycline are usually not the preferred drug for use in pregnant Tetracycline are usually not the preferred drug for use in pregnant women because of risks associated with malformation of teeth and women because of risks associated with malformation of teeth and bones in unborn children. Chloramphenicol is an alternative drug bones in unborn children. Chloramphenicol is an alternative drug that can be used to treat Rocky Mountain spotted fever; however, that can be used to treat Rocky Mountain spotted fever; however, this drug may be associated with a wide range of side effects this drug may be associated with a wide range of side effects including aplastic anemia,  and may require careful monitoring of including aplastic anemia,  and may require careful monitoring of blood levels. blood levels.

Currently, no licensed vaccine is available for Rocky Mountain Currently, no licensed vaccine is available for Rocky Mountain spotted fever. spotted fever.

Rickettsia Rickettsii Rickettsia Rickettsii (Rocky Mountain Spotted (Rocky Mountain Spotted

Fever)Fever) Epidemiology - Rocky Mountain spotted fever is the most Epidemiology - Rocky Mountain spotted fever is the most common rickettsial disease in the United States with 400-common rickettsial disease in the United States with 400-700 cases occurring annually.700 cases occurring annually.

Clinical syndromes - Rocky Mountain spotted fever begins Clinical syndromes - Rocky Mountain spotted fever begins with the abrupt onset of fever, chills headache and with the abrupt onset of fever, chills headache and myalgia usually 2-12 days after the tick bite. Patients may myalgia usually 2-12 days after the tick bite. Patients may not recall being bitten by a tick. Rash usually (90% of not recall being bitten by a tick. Rash usually (90% of cases) appears 2-3 days later. The rash begins on the cases) appears 2-3 days later. The rash begins on the hands and feet and spreads centripetally towards the hands and feet and spreads centripetally towards the trunk. Rash on the palms and soles is common. Initially the trunk. Rash on the palms and soles is common. Initially the rash is maculopapular but in the later stages may become rash is maculopapular but in the later stages may become petechial and hemorrhagicpetechial and hemorrhagic

Complications from widespread vasculitis can include Complications from widespread vasculitis can include gastrointestinal symptoms, respiratory failure, seizures, gastrointestinal symptoms, respiratory failure, seizures, coma and acute renal failure. Complications occur most coma and acute renal failure. Complications occur most frequently in cases in which the rash does not develop, frequently in cases in which the rash does not develop, since treatment is usually delayed. Mortality rate in since treatment is usually delayed. Mortality rate in untreated patients is 20%.untreated patients is 20%.

Red structures indicate Red structures indicate immunohistological immunohistological

staining of Rickettsia staining of Rickettsia rickettsii in endothelial rickettsii in endothelial cells of a blood vessel cells of a blood vessel

from a patient with fatal from a patient with fatal RMSF CDCRMSF CDC

IFA reaction of a IFA reaction of a positive human serum positive human serum on Rickettsia rickettsii on Rickettsia rickettsii grown in chicken yolk grown in chicken yolk sacs, 400X  CDC sacs, 400X  CDC

Rickettsia Akari Rickettsia Akari (Rickettsialpox)(Rickettsialpox)

Epidemiology - Epidemiology - R. akariR. akari Is found in the United States and Is found in the United States and sporadic infection occur. The vector is a mouse mite and sporadic infection occur. The vector is a mouse mite and the reservoirs are mites and mice. In mites the bacteria the reservoirs are mites and mice. In mites the bacteria are maintained by transovarian transmission. Humans are maintained by transovarian transmission. Humans are accidentally infected.are accidentally infected.

Clinical syndromes - Rickettsialpox is typically a mild Clinical syndromes - Rickettsialpox is typically a mild disease that has two phases. In the first phase a papule disease that has two phases. In the first phase a papule develops at the site of the mite bite and quickly develops at the site of the mite bite and quickly ulcerates and forms an ulcerates and forms an eschareschar. This initial phase occurs . This initial phase occurs approximately 1 week after the bite. After an incubation approximately 1 week after the bite. After an incubation time of 7-24 days the second phase of the disease time of 7-24 days the second phase of the disease occurs. This phase is characterized by sudden onset of occurs. This phase is characterized by sudden onset of fever, chills headache and myalgia and is followed 2 to 3 fever, chills headache and myalgia and is followed 2 to 3 days later with a generalized rash. The rash is days later with a generalized rash. The rash is papulovesicular and crust over in the later stages. The papulovesicular and crust over in the later stages. The pox heal with in 2 to 3 weeks without scarring. Fatalities pox heal with in 2 to 3 weeks without scarring. Fatalities are rare.are rare.

Rickettsia ProwazekiiRickettsia Prowazekii (Epidemic Typhus Or Louse-(Epidemic Typhus Or Louse-

borne Typhus)borne Typhus) Unlike the other rickettsial diseases, humans are the primary Unlike the other rickettsial diseases, humans are the primary reservoir for reservoir for R. prowazekiiR. prowazekii. Epidemic typhus occurs among . Epidemic typhus occurs among people living in crowded , unsanitary conditions such as those people living in crowded , unsanitary conditions such as those found in wars, famine and natural disasters. Transovarian found in wars, famine and natural disasters. Transovarian transmission in the louse does not occur since lice die several transmission in the louse does not occur since lice die several weeks after being infected. weeks after being infected.

Clinical syndromes:Clinical syndromes: a. a. Epidemic typhusEpidemic typhus is characterized by sudden onset of fever, is characterized by sudden onset of fever,

chills, headache chills, headache myalgiamyalgia and and arthralgiaarthralgia, after an average , after an average incubation period of 8 days. Approximately 7 days later a rash incubation period of 8 days. Approximately 7 days later a rash develops in most patients. The rash is maculopapular but can be develops in most patients. The rash is maculopapular but can be petechial or hemorrhagic. In contrast to the rash seen with Rocky petechial or hemorrhagic. In contrast to the rash seen with Rocky Mountain spotted fever, the rash in epidemic typhus develops on Mountain spotted fever, the rash in epidemic typhus develops on the trunk first and spreads to the extremities (centrifugal the trunk first and spreads to the extremities (centrifugal spread). Complications include: myocarditis, stupor and delirium. spread). Complications include: myocarditis, stupor and delirium. The name typhus comes from the Greek for "smoke" The name typhus comes from the Greek for "smoke" underscoring the fact that stupor and delirium often complicate underscoring the fact that stupor and delirium often complicate the disease. Recovery may take several months. The mortality the disease. Recovery may take several months. The mortality rate varies but can be quite high (60-70%) in some epidemics.rate varies but can be quite high (60-70%) in some epidemics.

b. b. Brill-Zinsser diseaseBrill-Zinsser disease is recrudescent epidemic typhus. It is recrudescent epidemic typhus. It occurs decades after the initial infection. In the United occurs decades after the initial infection. In the United States it is most commonly seen in those who were exposed States it is most commonly seen in those who were exposed to epidemic typhus in World War II. The clinical course of the to epidemic typhus in World War II. The clinical course of the disease is similar to epidemic typhus but is milder and disease is similar to epidemic typhus but is milder and recovery is faster. The skin rash is rarely seen. Diagnosis is recovery is faster. The skin rash is rarely seen. Diagnosis is made on the basis of a fever with unknown origin and a made on the basis of a fever with unknown origin and a history of previous exposure to epidemic typhus.history of previous exposure to epidemic typhus.

Laboratory diagnosis - Diagnosis should be made on clinical Laboratory diagnosis - Diagnosis should be made on clinical findings and treatment should begin before laboratory findings and treatment should begin before laboratory confirmation. Weil-Felix antibodies are produced but the test confirmation. Weil-Felix antibodies are produced but the test is not recommended. Serology is the primary laboratory test is not recommended. Serology is the primary laboratory test used for diagnosis of used for diagnosis of R. prowazekiiR. prowazekii. Indirect fluorescent . Indirect fluorescent antibody tests and latex agglutination tests are available. antibody tests and latex agglutination tests are available. Patients with epidemic typhus initially have an IgM response Patients with epidemic typhus initially have an IgM response followed by IgG antibodies whereas patients with Brill-followed by IgG antibodies whereas patients with Brill-Zinsser disease initially have an anamnestic IgG response. Zinsser disease initially have an anamnestic IgG response. Isolation of the organism is possible but dangerous.Isolation of the organism is possible but dangerous.

Rickettsia Typhi Rickettsia Typhi (Murine Or Endemic (Murine Or Endemic

Typhus)Typhus) Epidemiology - Rats are the primary reservoir for the Epidemiology - Rats are the primary reservoir for the

disease which is transmitted by the rat flea vector. The disease which is transmitted by the rat flea vector. The normal cycle is rat to flea to rat and humans are normal cycle is rat to flea to rat and humans are accidentally infected. Since there is no transovarian accidentally infected. Since there is no transovarian transfer in the flea the flea is not a reservoir for the transfer in the flea the flea is not a reservoir for the disease. The cat flea can also be a vector for the disease in disease. The cat flea can also be a vector for the disease in the United States. The bacteria are in the flea feces and the United States. The bacteria are in the flea feces and are inoculated into abraded skin by scratching the area are inoculated into abraded skin by scratching the area irritated by the bite.irritated by the bite.

Clinical syndromes - The symptoms of fever, chills Clinical syndromes - The symptoms of fever, chills headache and myalgia appear abruptly 1-2 weeks after headache and myalgia appear abruptly 1-2 weeks after infection. A rash develops in many but not all cases. The infection. A rash develops in many but not all cases. The rash begins on the trunk and spreads to the extremities, rash begins on the trunk and spreads to the extremities, unlike the rash seen in Rocky Mountain spotted fever. The unlike the rash seen in Rocky Mountain spotted fever. The disease is mild and resolves within 3 weeks even if disease is mild and resolves within 3 weeks even if untreated.untreated.

Laboratory diagnosis - A serological indirect fluorescent Laboratory diagnosis - A serological indirect fluorescent antibody test is used to detect antibodies to antibody test is used to detect antibodies to R. typhiR. typhi..

Orientia (Rickettsia)  Orientia (Rickettsia)  Tsutsugamushi (Scrub Tsutsugamushi (Scrub

Typhus)Typhus) Epidemiology - Scrub typhus occurs in Asia, Epidemiology - Scrub typhus occurs in Asia, Australia and the Pacific Islands. The disease is Australia and the Pacific Islands. The disease is transmitted to humans by the chiggers, the larval transmitted to humans by the chiggers, the larval form of a mite. The mite is both the reservoir and form of a mite. The mite is both the reservoir and the vector and passes the bacteria transovarially. the vector and passes the bacteria transovarially. Rodents can also act as a reservoir. The normal Rodents can also act as a reservoir. The normal cycle is mite to rodent to mite; humans are cycle is mite to rodent to mite; humans are accidentally infected.accidentally infected.

Clinical syndromes - The disease is characterized Clinical syndromes - The disease is characterized by sudden onset of fever, chills headache and by sudden onset of fever, chills headache and myalgia 1 -3 weeks after contracting the bacteria. myalgia 1 -3 weeks after contracting the bacteria. A maculopapular rash develops 2 -3 days later . A maculopapular rash develops 2 -3 days later . The rash appears first on the trunk and spreads The rash appears first on the trunk and spreads to the extremities (centrifugal spread). Mortality to the extremities (centrifugal spread). Mortality rate in outbreaks are variable.rate in outbreaks are variable.

Coxiella Burnetii (Q Fever)Coxiella Burnetii (Q Fever)[Q For Query][Q For Query]

Pathogenesis and immunityPathogenesis and immunity   Infection occurs by inhalation of airborne Infection occurs by inhalation of airborne

particles. The organism multiplies in the lungs particles. The organism multiplies in the lungs and is disseminated to other organs. and is disseminated to other organs. Pneumonia and granulomatous hepatitis are Pneumonia and granulomatous hepatitis are observed in patients with severe infections. In observed in patients with severe infections. In chronic disease immune complexes may play chronic disease immune complexes may play a role in pathogenesis. Phase variation occurs a role in pathogenesis. Phase variation occurs in the LPS of in the LPS of C. burnetiiC. burnetii. In acute disease . In acute disease antibodies are produced against the phase II antibodies are produced against the phase II antigen. In chronically infected patients antigen. In chronically infected patients antibodies to both phase I and phase II antibodies to both phase I and phase II antigens are observed. Cellular immunity is antigens are observed. Cellular immunity is important in recovery from the disease.important in recovery from the disease.

CLINICAL CLINICAL SYNDROMESSYNDROMES

The disease can be mild and asymptomatic The disease can be mild and asymptomatic and is often undiagnosed. The disease can be and is often undiagnosed. The disease can be acute or chronic. In acute Q fever the patient acute or chronic. In acute Q fever the patient presents with headache fever, chills and presents with headache fever, chills and myalgia. Respiratory symptoms are usually myalgia. Respiratory symptoms are usually mild ("atypical pneumonia"). Hepatomegaly mild ("atypical pneumonia"). Hepatomegaly and splenomegaly may be observed. and splenomegaly may be observed. Granulomas can be seen in histological Granulomas can be seen in histological section of most patients with Q fever. Chronic section of most patients with Q fever. Chronic Q fever typically presents as endocarditis Q fever typically presents as endocarditis generally on a damaged heart valve. generally on a damaged heart valve. Prognosis of chronic Q fever is not good.Prognosis of chronic Q fever is not good.