Rocky Mountain spotted fever

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Rocky Mountain spotted fever is the most severe and most frequently reported rickettsial illness in the United States. Some synonyms for Rocky Mountain spotted fever in other countries include “tick typhus,” “Tobia fever” (Colombia), “São Paulo fever” or “febre maculosa” (Brazil), and “fiebre manchada” (Mexico). The disease is caused by Rickettsia rickettsii, a species of bacteria that is spread to humans by Ixodid ticks (Dermacentor). Initial signs and symptoms of the disease include sudden onset of fever, headache, and muscle pain, followed by development of a rash. The disease can be difficult to diagnose in the early stages, and without prompt and appropriate treatment it can be fatal. ^[1] The name Rocky Mountain spotted fever is somewhat of a misnomer. Beginning in the 1930s, it became clear that this disease occurred in many areas of the United States other than the Rocky Mountain region. It is now recognized that this disease is broadly distributed throughout the continental United States, and occurs as far north as Canada and as far south as Central America, Mexico, and parts of South America. Between 1981 and 1996, this disease was reported from every U.S. state except Hawaii, Vermont, Maine, and Alaska. Rocky Mountain spotted fever remains a serious and potentially life-threatening infectious disease today. Despite the availability of effective treatment and advances in medical care, approximately 3% to 5% of individuals who become ill with Rocky Mountain spotted fever still die from the infection. However, effective antibiotic therapy has dramatically reduced the number of deaths caused by Rocky Mountain spotted fever; before the discovery of tetracycline and chloramphenicol in the late 1940s, as many as 30% of persons infected with R. rickettsii died. ^[1]

Rocky Mountain spotted fever was first recognized in 1896 in the Snake River Valley of Idaho and was originally called black measles. For a vast part of American history, the rash was dreaded as a frequently fatal disease in this endemic region. By the early 1900s, the recognized geographic distribution of this disease grew to encompass parts of the United States as far north as Washington and Montana and as far south as California, Arizona, and New Mexico. ^[2] After much anticipation and failure to cure the disease, there was finally a breakthrough in 1922. In Western Montana (1922) an Assistant Surgeon, R.R. Spencer, inoculated himself with a mixture of mush ticks and carboxylic acids to which later began the development of a vaccine for the disease. ^[3]

There is currently no classification system established for Rocky Mountain spotted fever.

Rocky Mountain spotted fever is caused by a bacterial organism of the Rickettsia genus known as Rickettsia rickettsii. The organism is a Gram-negative bacteria, ranging in sizes between 0.2 x 0.5 micrometers to 0.3 x 2.0 micrometers. Rickettsia rickettsii is non-spore forming, non- motile, and varies in shape. Early in it’s life cycle, Rickettsia rickettsii survives within an invertebrate host. The invertebrate host may then transmit the organism through blood meals, open skin, and breakages in mucous barriers. ^[4] The disease is most often transmitted through arthropod vectors, especially the hard tick- Ixodidae family. Rickettsia rickettsii requires an invertebrate vector and vertebrate host. Humans are considered an accidental host within the R. rickettsii life cycle. The organism has evolved a set of strategic mechanisms in order to evade the human immune system. Infection begin with an induced phagocytosis of the organism into an endothelial host cell. Usually endothelial cells are not phagocytic, however R. rickettsii is able to induce changes to the overall cytoskeleton of the cell. Invasion goes largely unnoticed, enabling the organism to avoid lysosomal fusion and an escape into the cytoplasm for future reproduction. ^[5]

Since the 1920’s the United States Center for Disease Control and Prevention has deemed Rocky Mountain spotted fever as a reportable disease. RMSF cases were most often reported within the Rocky Mountain region, although recent data reveals that the disease is widespread throughout the United States. Areas that currently harbor the majority of RMSF infections are Oklahoma, Tennessee, and Arkansas. The disease has also been reported throughout the Western Hemisphere. ^[6] Incidents are highest among children the between the ages of 5-9 years and adults between the ages of 40-64 years. Fatality rates are also higher among these groups, with the highest fatality rate in the elderly at 60 years or more. In terms of demographics, Rocky Mountain spotted fever has been reported at higher rates among males, especially of White and Native American descent. ^[7]

The primary risk factors associated with Rocky Mountain spotted fever are exposure to endemic environment and the time of that exposure. Wood Ticks have been identified as the primary vector of Rocky Mountain spotted fever infections, thus being bitten in an endemic area may result in the contraction of the disease.

Rickettsia rickettsii (abbreviated as R. rickettsii) is a unicellular, Gram-negative coccobacillus (plural coccobacilli) that is native to the New World. It belongs to the spotted fever group (SFG) of Rickettsia and is most commonly known as the causative agent of Rocky Mountain spotted fever (RMSF). By nature, R. rickettsii is an obligate intracellular parasite that survive by an endosymbiotic relationship with other cells. ^[7] R. rickettsii is a non-motile, non-spore forming aerobic organism. Cells are typically 0.3–0.5 × 0.8–2.0 μm in size. They lack a distinct nucleus and membrane bound organelles. Their outer membrane is composed mostly of lipopolysaccharides. RMSF is transmitted by the bite of an infected tick while feeding on warm-blooded animals, including humans. Humans are considered to be accidental hosts in the Rickettsia–tick life cycle and are not required to maintain the rickettsiae in nature.^[8]

Rocky Mountain spotted fever (RMSF) must be differentiated from other diseases that cause fever, headaches, muscle pain, and rash. In virtually all cases, RMSF presents with a rash. When trying to differentiate RMSF from other infections, it should be noted that there has been a rare case in which RMSF has presented itself without the typical rash. Examples of misdiagnosed, rickettsiae caused, diseases include typhus-spotted fevers and Ehrlichiosis. Other misdiagnoses include pox diseases and acne.When diagnosing Rocky Mountain spotted fever it’s important to account for patient history such as exposure to endemic regions and a history of tick bites. Although immunofluorescence assays, polymerase chain reactions, and immuno-staining remain the most effective ways of determining a RMSF infection.

If left untreated patients with Rocky Mountain spotted fever will undergo three developmental stages of infection. The early stages of infection begin within 2-14 days of inoculation by an infected tick and present themselves as a fever, nausea, vomiting, and a severe headache. Late stage progression of symptoms will result in a maculopapular rash, abdominal and joint pain. Further progression of the disease, if left untreated, will result in the following complications; gangrene, pulmonary complications, ARDS, cerebral edema as well as other long term complications. Ultimately, if Rocky Mountain spotted fever progresses entirely untreated, it will conclude in the patient’s death. With a fatality rate as high as 87%, without antibiotic intervention. ^{[9] [7]}

The classic triad of findings for this disease are fever, rash, and history of tick bite. However, this combination is often not identified when the patient initially presents for care. Early onset symptoms typically associated with Rocky Mountain spotted fever include fever, nausea, vomiting, and headache. Abnormal laboratory findings seen in patients with Rocky Mountain spotted fever may include thrombocytopenia, hyponatremia, or elevated liver enzyme levels.

There are several aspects of Rocky Mountain spotted fever (RMSF) that make it challenging for healthcare providers to diagnose and treat. The symptoms of RMSF vary from patient to patient and can easily resemble other, more common diseases. Treatment for this disease is most effective at preventing death if started in the first five days of symptoms. Diagnostic tests for this disease, especially tests based on the detection of antibodies, will frequently appear negative in the first 7-10 days of illness. Due to the complexities of this disease and the limitations of currently available diagnostic tests, there is no test available at this time that can provide a conclusive result in time to make important decisions about treatment.For this reason healthcare providers must use their judgment to treat patients based on clinical suspicion alone. Healthcare providers may find important information in the patient’s history and physical examination that may aid clinical suspicion. Information such as recent tick bites, exposure to high grass and tick-infested areas, contact with dogs, similar illnesses in family members or pets, or history of recent travel to areas of high incidence can be helpful in making the diagnosis.

A diagnosis of Rocky Mountain spotted fever is based on a combination of clinical signs and symptoms and specialized confirmatory laboratory tests. Other common laboratory findings suggestive of Rocky Mountain spotted fever include thrombocytopenia, hyponatremia, and elevated liver enzyme levels. There are three tests which are predominantly used for the diagnosis of RMSF, immunofluorescence assay (IFA), polymerase chain reaction (PCR), and immuno-staining. IFA is considered to be the “gold standard” in testing for the disease. It’s important to consider that the most effective treatment for RMSF occurs when diagnosis and medical therapy begins within the first 5 days, early symptoms. Unfortunately however IFA can’t usually detect IgG antibodies until 7-10 days of illness. Thus it is of utmost importance to successfully diagnose and begin medical therapy initially, even prior to confirmation by lab testing. ^[1]

A chest x-ray may be helpful in the diagnosis of Rocky Mountain spotted fever. Findings on a chest x-ray indicating pulmonary edema may be suggestive of a Rocky Mountain spotted fever infection.

There are no further diagnostic studies associated with Rocky Mountain spotted fever.

The mainstay of therapy for Rocky Mountain spotted fever is doxycycline. Pharmacologic therapy for Rocky Mountain spotted fever includes either Doxycycline or Chloramphenicol.

The most potent risk factor in the development of Rocky Mountain spotted fever is exposure to infected ticks. Therefore proper prevention is achieved by emphasizing personal protection from ticks when traveling through a tick-infested habitats. Other risk factors include race, age, and seasonal variation.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Rocky Mountain spotted fever was first recognized in 1896 in the Snake River Valley of Idaho and was originally called black measles. For a great part of American history, the rash was dreaded as a frequently fatal disease in this endemic region. By the early 1900s, the recognized geographic distribution of this disease grew to encompass parts of the United States as far north as Washington and Montana and as far south as California, Arizona, and New Mexico. ^[1] After much anticipation and failure to cure the disease, there was finally a breakthrough in 1922. In Western Montana (1922) an Assistant Surgeon, R.R. Spencer, inoculated himself with a mixture of mush ticks and carboxylic acids to which later began the development of a vaccine for the disease. ^[2]

• Rocky Mountain spotted fever was first recognized in 1896 in the Snake River Valley of Idaho and was originally called black measles.
• It was a dreaded and frequently fatal disease that affected hundreds of people in this area.
• By the early 1900s, the recognized geographic distribution of this disease grew to encompass parts of the United States as far north as Washington and Montana and as far south as California, Arizona, and New Mexico. ^{[3] [2]}

• Howard T. Ricketts was the first to establish the identity of the infectious organism that causes Rocky Mountain spotted fever.
• He and others characterized the basic epidemiological features of the disease, including the role of tick vectors.
• Their studies found that Rocky Mountain spotted fever is caused by a tick borne, gram-negative coccobacillus that was named Rickettsia rickettsii,
• This species is maintained in nature by a complex cycle involving ticks and mammals; humans are considered to be accidental hosts and are not involved in the natural transmission cycle of this pathogen.
• Dr. Ricketts died of typhus (another rickettsial disease) in Mexico in 1910, shortly after completing his studies on Rocky Mountain spotted fever.^[2]</nowiki> ^[3]

• Research reawakened in 1922 in western Montana — in the Bitter Root Valley; Hamilton, Montana — after the governor’s daughter and son-in-law died of the fever.
• Past assistant surgeon R.R. Spencer of the hygienic laboratory of the US Public Health Service was ordered to the region and led a research team at an abandoned local schoolhouse.
• In 1924, Spencer inoculated himself with a large dose of ground wood ticks and weak carbolic acid. The vaccine was effective.
• Three of the researchers involved in the project, Gettinger, Cowan and Kerlee, would all die from the fever during their research efforts.

• Much of the early research was conducted at Rocky Mountain Laboratories, which is the source of the name of the condition. ^{[1] [3]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ilan Dock, B.S.

There is currently no classification system established for Rocky Mountain spotted fever.

There is currently no classification system established for Rocky Mountain spotted fever.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Rocky Mountain spotted fever is caused by a bacterial organism of the Rickettsia genus known as Rickettsia ricketsii. The organism is a Gram-negative bacteria, ranging in sizes between 0.2 x 0.5 micrometers to 0.3 x 2.0 micrometers. Rickettsia ricketsii is non-spore forming, non- motile, and varies in shape. Early in it’s life cycle, Rickettsia ricketsii survives within an invertebrate host. The invertebrate host may then transmit the organism through blood meals, open skin, and breakages in mucous barriers. ^[1] The disease is most often transmitted through arthropod vectors, especially the hard tick- Ixodidae family. Rickettsia ricketsii requires an invertebrate vector and vertebrate host. Humans are considered an accidental host within the R. ricketsii life cycle. The organism has evolved a set of strategic mechanisms in order to evade the human immune system. Infection begins with an induced phagocytosis of the organism into an endothelial host cell. Usually endothelial cells are not phagocytic, however R. ricketsii is able to induce changes to the overall cytoskeleton of the cell. Invasion goes largely unnoticed, enabling the organism to avoid lysosomal fusion and an escape into the cytoplasm for future reproduction. ^[2]

• Rocky Mountain spotted fever is caused by Rickettsia rickettsii, a small bacterium that grows inside the cells of its hosts.
• These bacteria range in size from 0.2 x 0.5 μm to 0.3 x 2 μm.
• The bacteria is a pleomorphic Gram-negative coccobacillus organism. ^[3]
• Cell wall and lipopolysaccharide resembles those of the average gram-negative bacteria. ^[3]
• They are difficult to see in tissues by using routine histologic stains and generally require the use of special staining methods.
• In the human body, rickettsiae live and multiply primarily within cells that line small- to medium-sized blood vessels.
• Spotted fever group rickettsiae can grow in the cytoplasm or in the nucleus of the host cell.
• Once inside the host, the rickettsiae multiply, resulting in damage and death to these cells.
• This causes blood to leak through tiny holes in vessel walls into adjacent tissues.
• In turn, the leakage process causes the rash that is traditionally associated with Rocky Mountain spotted fever and also causes damage to organs and tissues. ^[1]

The life cycle of Rickettsia rickettsii is considered to be a complex one. Survival is dependent on both an invertebrate vector, (the hard tick- Family Ixodidae) and a vertebrate host (including mice, dogs, rabbits). Humans are considered to be accidental vectors and are not essential in the rickettsial cycle. In addition, a sequence of events occur between both hosts in the successful transmission of rickettsial disease.

Rickettsia rickettsii mostly affects canines and humans.

• Three arthropod vectors in the United States have been identified in transmitting R. rickettsii to humans, causing the potentially fatal disease Rocky Mountain spotted fever. The American Dog Tick (Dermacentor variabilis), the Rocky Mountain Wood Tick (Dermacentor andersoni), and the Brown Dog Tick (Rhipicephalus sanguineus) can acquire Rickettsia rickettsii in a number of different ways.

• First, an uninfected tick can become infected when feeding on the blood of an infected mammalian host in the larval or nymph stages, a mode of transmission called transstadial transmission. Once a tick becomes infected with this pathogen, they are infected for life.
• Both the American dog tick and the Rocky Mountain Wood Tick serve as long-term reservoirs for Rickettsia rickettsii, in which the organism resides in the tick posterior diverticulae of the midgut, the small intestine and the ovaries.

• Due to its confinement in the midgut and small intestine, it is possible for mammals, including humans, to contract rickettsial disease from open skin/wound contact with the feces of the organism. In addition, an infected male tick can transmit the organism to an uninfected female during mating.
• Once infected, the female tick can transmit the infection to her offspring, in a process known as transovarial transmission. ^[2]

• An uninfected mammal can become infected with Rickettsia rickettsii when eating food that contains the feces of the infected tick. They can also be infected through the bite of an infected tick.

• Humans acquire Rickettsia rickettsii infection from infected vectors. After getting bitten by an infected tick, rickettsiae are transmitted to the bloodstream by tick salivary secretions or, as mentioned previously, through contamination of broken skin by an infected vector’s feces.

• All these modes of transmission ensure the survival of Rickettsia. ^[4]

• R. rickettsii have evolved a number of strategical mechanisms or virulence factors that allow them to evade the host immune system and successfully infect the host. ^[2]
• R. rickettsii invades the endothelial cells that line the blood vessels. Endothelial cells are not phagocytic in nature; however, after attachment to the host cell surface, the pathogen causes changes in the host cell cytoskeleton that induces phagocytosis. They are able to avoid lysosomal fusion and oxidative burst by escaping from the phagosome into the cytoplasm where they multiply and spread.
• This invasion can cause significant endothelial damage that can lead to end organ failure, DIC, and even death.

• OmpA (rOmp) and Omp B (rOmp) have been identified as rickettsial outer surface proteins and are implicated in adherence of the bacterium to the host cell.
• The genes that encode these two surface proteins are designated as ompA and ompB, respectively.

• rOmp B is the predominant surface membrane protein in R. rickettsii; Policastro et al., identified the rOmpA to rOmpB ratio to be 1:9 (1994).^[5]
• While the surface proteins of the bacterium have been identified, the host cell protein receptor(s) have not.

• Entry into the host cell is mediated by a Type 4 secretion system’ (T4SS) which is found in all Rickettsiae.
• The T4SS apparatus is a tunnel-shaped structure that is embedded in the bacterial inner membrane and extends to the outer membrane. At least 12 or more proteins help form the tunnel-like apparatus.
• Once adherence to the host cell is established, the T4SS of Rickettsiae recruits substrates to the bottom of the apparatus, activating the complex via an ATP-dependent process that results in the direct transfer of the bacterium’s DNA and other proteins into the host cell.

• Invasion of the host endothelial cell immediately triggers phagocytosis, where the rickettsiae escape from the phagosome and into the cytosol where replication takes place. Although the escape from the phagosome is not well understood, it is thought to be mediated by phospholipase A2 activity.

• In the cytosol, the virulence factor Sca2 (Surface Cell Antigen 2) and the protein RickA form an actin tail that provides motility.
• RickA is thought to be responsible for directing the actin-based motility in R. rickettsii.
• RickA has been shown to activate the Arp2/3 complex in vitro, but “R. raoulti” expresses RickA and does not have acting-based motility.^[6]
• The Sca2 virulence factor has been shown to be essential for actin tail formation in “R.rickettsii” Listeria. Comparisons of actin motility mechanisms appears to be independently evolved in Listeria, Shigella, and Rickettsia.

• The actin tail in R. rickettsii is both longer and provides a straighter trajectory due the production of linear actin filaments.^[7] The actin-based motility of R. rickettsii allows swift, unidirectional movement across the cytoplasm into adjacent cells, promoting cell to cell spread.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Since the 1920’s the United States Center for Disease Control and Prevention has deemed Rocky Mountain spotted fever (RMSF) as a reportable disease. RMSF cases were most often reported within the Rocky Mountain region, although recent data reveals that the disease is widespread throughout the United States. Areas that currently harbor the majority of RMSF infections are Oklahoma, Tennessee, and Arkansas. The disease has also been reported throughout the Western Hemisphere. ^[1] Incidence is highest among children the between the ages of 5-9 years and adults between the ages of 40-64 years. Fatality rates are also higher among these groups, with the highest fatality rate in the elderly at 60 years or more. In terms of demographics, Rocky Mountain spotted fever has been reported at higher rates among males, especially of White and Native American descent. ^[2]

• Rocky Mountain spotted fever has been a reportable disease in the United States since the 1920s.
• In the last 50 years, approximately 250-1200 cases of Rocky Mountain spotted fever have been reported annually, although it is likely that many more cases go unreported.
• CDC compiles the number of cases reported by the state health departments.
• To ensure standardization of reporting across the country, CDC advises that a consistent case definition be used by all states. ^[1]

• Over 90% of patients with Rocky Mountain spotted fever are infected during April through September.
• This period is the season for increased numbers of adult and nymphal Dermacentor ticks.
• A history of tick bite or exposure to tick-infested habitats is reported in approximately 60% of all cases of Rocky Mountain spotted fever.^[1]

• RMSF cases have been reported throughout most of the contiguous United States, five states (North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri) account for over 60% of RMSF cases. The primary tick responsible for R. rickettsii in these states is the American dog tick (Dermacentor variabilis Dermacentor andersoni).
• In eastern Arizona, RMSF cases have recently been identified in an area where the disease had not been previously seen. Through 2009, over 90 cases had been reported, and approximately 10% of the people diagnosed with the disease in this part of the state have died. The tick responsible for transmission of R. rickettii in Arizona is the brown dog tick (Rhipicephalus sanguineus), which is found on dogs and around people’s homes.
• Almost all of the cases occurred within communities with a large number of free-roaming dogs.^[1]
• Other incidences have recently been reported in portions of California, the Northwest (Washington, and Oregon), and in portions of the Southwest (Arizona, Texas, and New Mexico.)

• Incidence rate is highest among children between the ages of less than 10 years of age, particularly 5-9, and adults between the ages of 40-64. ^[2]
• Children ages 0-9 and adults ages 60 or higher are at a higher risk of fatality.^[1]

• The frequency of reported cases of Rocky Mountain spotted fever is highest among males, particularly of Caucasian and American Indian descent.
• Two-thirds of the Rocky Mountain spotted fever cases occur in children.
• Individuals with frequent exposure to dogs and who reside near wooded areas or areas with high grass may also be at increased risk of infection. ^[2]

• Incidences of Rocky Mountain spotted fever are most prominent in the Western hemisphere.
• Infections have been documented in portions of Argentina, Brazil, Colombia, Costa Rica, Mexico, and Panama.
• Some synonyms for Rocky Mountain spotted fever in other countries include tick typhus, Tobia fever(Colombia), São Paulo fever, fiebre maculosa (Brazil), and fiebre manchada (Mexico).
• Closely related organisms cause other types of spotted fevers in other parts of the world.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

The primary risk factors associated with Rocky Mountain spotted fever are exposure to endemic environment and the time of that exposure. Wood Ticks have been identified as the primary vector of Rocky Mountain spotted fever infections, thus being bitten in an endemic area may result in the contraction of the disease.

• Individuals with frequent exposure to dogs and who reside near wooded areas or areas with high grass may also be at increased risk of infection.

• Over half of the cases occur in the South Atlantic region of the United States (Delaware, Maryland, Washington D.C., Virginia, West Virginia, North Carolina, South Carolina, Georgia, and Florida).
• The highest incidence rates have been found in North Carolina and Oklahoma.
• Although this disease was first discovered and recognized in the Rocky Mountain area, relatively few cases are reported from that area today. ^[1]

• Rocky Mountain spotted fever is a seasonal disease and occurs throughout the United States during the months of April through September. ^[2]

• The frequency of reported cases of Rocky Mountain spotted fever is highest among males, particularly of Caucasian and American Indian descent.
• Incidence rate is highest among children between the ages of less than 10 years of age, particularly 5-9, and adults between the ages of 40-64. ^[3]
• Children ages 0-9 and adults ages 60 or higher are at a higher risk of fatality.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Rickettsia rickettsii (abbreviated as R. rickettsii) is a unicellular, Gram-negative coccobacillus (plural coccobacilli) that is native to the New World. It belongs to the spotted fever group (SFG) of Rickettsia and is most commonly known as the causative agent of Rocky Mountain spotted fever (RMSF). By nature, R. rickettsii is an obligate intracellular parasite that survive by an endosymbiotic relationship with other cells. ^[1]

R. rickettsii is a non-motile, non-spore forming aerobic organism. Cells are typically 0.3–0.5 × 0.8–2.0 μm in size. They lack a distinct nucleus and membrane bound organelles. Their outer membrane is composed mostly of lipopolysaccharides.

Rocky Mountain spotted fever (RMSF) is transmitted by the bite of an infected tick while feeding on warm-blooded animals, including humans. Humans are considered to be accidental hosts in the Rickettsia–tick life cycle and are not required to maintain the rickettsiae in nature.^[2]

• Rocky Mountain spotted fever first emerged in the Idaho Valley in 1896. At that time, not much information was known about the disease; it was originally called Black Measles because patients had a characteristic spotted rash appearance throughout their body. ^[3]
• Howard Ricketts (1871–1910) was an American pathologist and infectious disease researcher who was the first to identify and study the organism that causes Rocky Mountain spotted fever. He received his undergraduate degree in zoology from the University of Nebraska and his medical degree from Northwestern University School of Medicine.
• Ricketts completed his internship at Cook County Hospital in Chicago, IL, followed by a fellowship in pathology and cutaneous diseases at Rush Medical College.
• In 1902, Ricketts became the associate professor of pathology at the University of Chicago. The trademark rash, which first appeared in the Idaho Valley, now began to slowly emerge in the Bitterroot Valley region, a highly influential area in western Montana and had an 80–90% mortality rate. ^[4]

• During his tenure as associate professor, Ricketts was funded and recruited by the University of Chicago, the State of Montana, and the American Medical Association to conduct research on Rocky Mountain spotted fever.
• Ricketts research entailed interviewing victims of the disease and collecting and studying infected animals. He was also known to inject himself with pathogens to measure its effects.
• Days after isolating the organism that he believed to cause typhus, he died. It was speculated that his death was likely caused from an insect bite. ^[3]
• S. Burt Wolbach is credited for the first detailed description of the etiologic agent in 1919.
• He clearly recognized it as an intracellular bacterium which was seen most frequently in endothelial cells.
• Wolbach was struck by the fact that in the tick, and also in mammalian cells, the microorganism was intranuclear.
• The nucleus was often completely filled with minute particles and often was distended. Although Wolbach recognized its similarity to the agent of typhus and tsutsugamushi fever (scrub typhus), he did not regard the designation ‘rickettsia’ as appropriate. He proposed the name Dermacentroxenus rickettsi. Dr. Emile Brumpt felt that the etiologic agent of RMSF, despite some uncertainty about its properties, belonged in the genus Rickettsia and in 1922 proposed the name Rickettsia rickettsii.^[3]

• The life cycle of Rickettsia rickettsii is considered to be a complex one.
• Survival is dependent on both an invertebrate vector, (the hard tick- Family Ixodidae) and a vertebrate host (including mice, dogs, rabbits).
• Humans are considered to be accidental vectors and are not essential in the rickettsial cycle.
• In addition, a sequence of events occur between both hosts in the successful transmission of rickettsial disease.
• (Rickettsia rickettsii mostly affects canines and humans.) ^[6]

• Three arthropod vectors in the United States have been identified in transmitting R. rickettsii to humans, causing the potentially fatal disease Rocky Mountain spotted fever. The American Dog Tick (Dermacentor variabilis), the Rocky Mountain Wood Tick (Dermacentor andersoni), and the Brown Dog Tick (Rhipicephalus sanguineus) can acquire Rickettsia rickettsii in a number of different ways.

• First, an uninfected tick can become infected when feeding on the blood of an infected mammalian host in the larval or nymph stages, a mode of transmission called transstadial transmission. Once a tick becomes infected with this pathogen, they are infected for life. Both the American dog tick and the Rocky Mountain Wood Tick serve as long-term reservoirs for Rickettsia rickettsii, in which the organism resides in the tick posterior diverticulae of the midgut, the small intestine and the ovaries.

• Due to its confinement in the midgut and small intestine, it is possible for mammals, including humans, to contract rickettsial disease from open skin/wound contact with the feces of the organism. In addition, an infected male tick can transmit the organism to an uninfected female during mating. Once infected, the female tick can transmit the infection to her offspring, in a process known as transovarial transmission. ^[7]

• An uninfected mammal can become infected with Rickettsia rickettsii when eating food that contains the feces of the infected tick. They can also be infected through the bite of an infected tick.

• Humans acquire Rickettsia rickettsii infection from infected vectors. After getting bitten by an infected tick, rickettsiae are transmitted to the bloodstream by tick salivary secretions or, as mentioned previously, through contamination of broken skin by an infected vector’s feces.

• All these modes of transmission ensures the survival of Rickettsia in nature.

• R. rickettsii have evolved a number of strategical mechanisms or virulence factors that allow them to evade the host immune system and successfully infect the host. ^[7]

• R. rickettsii invades the endothelial cells that line the blood vessels. Endothelial cells are not phagocytic in nature; however, after attachment to the host cell surface, the pathogen causes changes in the host cell cytoskeleton that induces phagocytosis. They are able to avoid lysosomal fusion and oxidative burst by escaping from the phagosome into the cytoplasm where they multiply and spread.

• Over the years, different virulence factors have been identified in R. rickettsii.

• OmpA (rOmp) and Omp B (rOmp) have been identified as rickettsial outer surface proteins and are implicated in adherence of the bacterium to the host cell. The genes that encode these two surface proteins are designated as ompA and ompB, respectively.

• rOmp B is the predominant surface membrane protein in R. rickettsii; Policastro et al., identified the rOmpA to rOmpB ratio to be 1:9 (1994).^[8] While the surface proteins of the bacterium have been identified, the host cell protein receptor(s) have not.

• Entry into the host cell is mediated by a Type 4 secretion system’ (T4SS) which is found in all Rickettsiae. The organization of the T4SS apparatus is a rather elaborate one; it is a tunnel-shaped structure that is embedded in the bacterial inner membrane and extends to the outer membrane. At least 12 or more proteins help form the tunnel-like apparatus.
• Once adherence to the host cell is established, the T4SS of Rickettsiae recruits substrates to the bottom of the apparatus, activating the complex via an ATP-dependent process that results in the direct transfer of the bacterium’s DNA and other proteins into the host cell.

• Invasion of the host endothelial cell immediately triggers phagocytosis, where the rickettsiae escape from the phagosome and into the cytosol where replication takes place. Although the escape from the phagosome is not well understood, it is thought to be mediated by phospholipase A2 activity.

• In the cytosol, the virulence factor Sca2 (Surface Cell Antigen 2) and the protein RickA form an actin tail that provides motility.
• RickA is thought to be responsible for directing the actin-based motility in R. rickettsii.
• RickA has been shown to activate the Arp2/3 complex in vitro, but R. raoulti expresses RickA and does not have acting-based motility.^[9]
• The Sca2 virulence factor has been shown to be essential for actin tail formation in “R.rickettsii” Listeria. Comparisons of actin motility mechanisms appears to be independently evolved in Listeria, Shigella, and Rickettsia.

• The actin tail in R. rickettsii is both longer and provides a straighter trajectory due the production of linear actin filaments.^[10]
• The actin-based motility of R. rickettsii allows swift movement across the cytoplasm into adjacent cells, promoting cell to cell spread.
• Endothelial cell damage caused by R. rickettsii can lead to end organ failure, DIC, and even death.

• In vivo studies reveal that Rickettsia rickettsii invade endothelial lining of small to medium vessels in the human host, causing vascular permeability. When tested in vitro, it is shown that the bacterium infects every kind of cell of the mammalian host.

• The name Rocky Mountain spotted fever is somewhat of a misnomer. Cases of Rocky Mountain spotted fever have been reported in every continent except Antarctica, and in every state in the U.S. except for Alaska, and Hawaii.

• Approximately 90% of all infections occur within the months of April to September, the time period in which adult and nymphal ticks are the highest. The areas of the U.S. with the greatest reported cases of RMSF are the mid to south Atlantic states, including DE, MD, DC, VA, WV, NC, SC.

• It is estimated that approximately 1200 or more new cases of RMSF will present on a yearly basis. ^[11]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Michael Maddaleni, B.S.; João André Alves Silva, M.D. [2]; Ilan Dock, B.S.

Rocky Mountain spotted fever (RMSF) must be differentiated from other diseases that cause fever, headaches, muscle pain, and rash. In virtually all cases, RMSF presents with a rash. When trying to differentiate RMSF from other infections, it should be noted that there has been a rare case in which RMSF has presented itself without the typical rash. Examples of misdiagnosed, rickettsiae caused, diseases include typhus-spotted fevers and Ehrlichiosis. Other misdiagnoses include pox diseases and acne.When diagnosing Rocky Mountain spotted fever it’s important to account for patient history such as exposure to endemic regions and a history of tick bites. Although immunofluorescence assays, polymerase chain reactions, and immuno-staining remain the most effective ways of determining a RMSF infection.

Examples of diseases that may be misdiagnosed for Rocky Mountain spotted fever are found in the table below:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

If left untreated patients with Rocky Mountain spotted fever will undergo three developmental stages of infection. The early stages of infection begin within 2-14 days of inoculation by an infected tick and present themselves as a fever, nausea, vomiting, and a severe headache. Late stage progression of symptoms will result in a maculopapular rash, abdominal and joint pain. Further progression of the disease, if left untreated, will result in the following complications; gangrene, pulmonary complications, ARDS, cerebral edema as well as other long term complications. Ultimately, if Rocky Mountain spotted fever progresses entirely untreated, it will conclude in the patient’s death. With a fatality rate as high as 87%, without antibiotic intervention. ^{[1] [2]}

Rocky Mountain spotted fever patients will progress from early symptoms to late symptoms and possible chronic conditions, as well as death, if left untreated. The infection begins with inoculation of the disease from an infected tick. Once inoculated, the organism Rickettsia rickettsii will incubate for 2- 14 days. As the incubation period concludes early onset symptoms will begin, these symptoms are listed below.

• Fever
• Vomiting
• Nausea
• Severe headache
• Muscular soreness and pain
• Anorexia
• Rash (within may appear within 2-5 days of fever onset.)^[1]

Treatment is most effective if an antibiotic therapy is administered at this point. As the disease progresses, treatment loses effectiveness, thus it is of utmost importance to diagnose and begin treatment early on. Most individuals who begin treatment will usually clear the infection.

After the first three days of early onset symptoms, other symptoms will progress. These symptoms are described as late stage symptoms and will include the characteristic rash that is commonly associated with Rocky Mountain spotted fever. Not all patients will have the same clinical presentation of the disease. Particularly, the rash is present within the majority of infected patients, yet 10-15% of patients may never develop the characteristic spotted rash. If the infection progresses in severity, patients will be hospitalized at this point. Late stage symptoms may be observed below.

• Maculopapular rash
• Diarrhea
• Abdominal pain
• Joint pain

With proper treatment and antibiotic therapy, most patients will have cleared the infection. However, if left untreated or improperly diagnosed, Rocky Mountain spotted fever will progress further and may involve chronic complications or severe tissue damage as well as death. Complications and chronic conditions associated with untreated development of Rocky Mountain spotted fever are found below.

• Gangrene
• ARDS
• Myocarditis
• Acute renal failure
• Meningoencephalitis
• Pulmonary hemorrhaging
• Pulmonary edema
• Cerebral edema
• Death ^[1]

• Meningitis
• Brain damage
• Clotting problems
• Heart failure
• Kidney failure
• Lung failure
• Adult respiratory distress syndrome
• Pneumonitis (lung inflammation)
• Encephalitis
• Noncardiogenic pulmonary edema
• Cardiac arrythmia
• Impaired blood clotting
• Skin necrosis
• Gastrointestinal bleeding
• Shock^[3][4]

• Paralysis of lower extremities
• Impaired bladder function
• Impaired bowel function
• Gangrene and amputation
• Hearing impairment
• Movement and speech disorders^[3]
• These complications are most frequent in persons recovering from severe, life-threatening disease, often following lengthy hospitalizations. ^[5]

• The prognosis is usually good for patients suffering from a Rocky Mountain spotted fever infection.
• Factors that might contribute to a poor prognosis are infections within children 0-9, especially 5-9, and adults over 60 years of age. With a higher rate of fatality within these groups.
• Other host factors associated with severe or fatal Rocky Mountain spotted fever include advanced age, male sex, African-American race, chronic alcohol abuse, and

glucose-6-phosphate dehydrogenase (G6PD) deficiency.

• It should be noted that although the prognosis is usually good, RMSF is a severe illness and many infected patients will be hospitalized.
• The mortality rate is approximately 20% if untreated and 5% if treated properly. ^[2]
• Infection with R. rickettsii may provide long lasting immunity against re-infection.
• Previous infection with Rocky Mountain spotted fever should not deter persons from practicing good tick-preventive measures or visiting a physician if signs and symptoms consistent with Rocky Mountain spotted fever occur, especially following a tick bite, as other diseases may also be transmitted by ticks. ^[6]