Rocky Mountain spotted fever
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|Rocky Mountain spotted fever|
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Rocky Mountain spotted fever (RMSF), also known as blue disease, is the most lethal and most frequently reported rickettsial illness in the United States. It has been diagnosed throughout the Americas. 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). It is distinct from the viral tick-borne infection, Colorado tick fever. The disease is caused by Rickettsia rickettsii, a species of bacterium that is spread to humans by Dermacentor ticks. Initial signs and symptoms of the disease include sudden onset of fever, headache, and muscle pain, followed by development of rash. The disease can be difficult to diagnose in the early stages, and without prompt and appropriate treatment it can be fatal.
The name “Rocky Mountain spotted fever” is something of a misnomer. The disease was first identified in the Rocky Mountain region, but beginning in the 1930s, medical researchers realized that it occurred in many other areas of the United States. It is now recognized that the disease is broadly distributed throughout the contiguous United States and occurs as far north as Canada and as far south as Central America and parts of South America. Between 1981 and 1996, the disease was reported from every state of the United States except for Hawaii, Vermont, Maine, and Alaska.
Rocky Mountain spotted fever remains a serious and potentially life-threatening infectious disease. Despite the availability of effective treatment and advances in medical care, approximately three to five percent of patients who become ill with Rocky Mountain spotted fever 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 during the latter 1940s, as many as 30% of those infected with R. rickettsii died.
Signs and symptoms
Spotted fever can be very difficult to diagnose in its early stages, and even experienced doctors who are familiar with the disease find it hard to detect.
People infected with R. rickettsii usually notice symptoms following an incubation period of one to two weeks after a tick bite. The early clinical presentation of Rocky Mountain spotted fever is nonspecific and may resemble a variety of other infectious and non-infectious diseases.
- Emesis (vomiting)
- Severe headache
- Muscle pain
- Lack of appetite
- Parotitis in some cases (somewhat rare)
Later signs and symptoms:
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. The rash has a centripetal, or "inward" pattern of spread, meaning it begins at the extremities and courses towards the trunk.
The rash first appears two to five days after the onset of fever, and it is often quite subtle. Younger patients usually develop the rash earlier than older patients. Most often the rash begins as small, flat, pink, non-itchy spots (macules) on the wrists, forearms, and ankles. These spots turn pale when pressure is applied and eventually become raised on the skin. The characteristic red, spotted (petechial) rash of Rocky Mountain spotted fever is usually not seen until the sixth day or later after onset of symptoms, but this type of rash occurs in only 35 to 60% of patients with Rocky Mountain spotted fever. The rash involves the palms or soles in as many as 80% of the patients. However, this distribution may not occur until later on in the course of the disease. As many as 15 percent of patients may never develop a rash.
Rocky Mountain spotted fever, like all rickettsial infections, is classified as a zoonosis. Zoonoses are diseases of animals that can be transmitted to humans. Some zoonotic diseases require a vector (e.g., a mosquito, tick, or flea) to 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 vectors of R. rickettsii. Ticks transmit the organism to vertebrates primarily by their bites. Less commonly, infections may occur following exposure to crushed tick tissues, fluids, or tick feces.
A female tick can transmit R. rickettsii to her eggs in a process called transovarial transmission. Ticks can also become infected with R. rickettsii while feeding on blood from the host in either the larval or nymphal stage. After the tick develops into the next stage, the R. rickettsii may be transmitted to the second host during the feeding process. Furthermore, male ticks may transfer R. rickettsii to female ticks through body fluids or spermatozoa during the mating process. These types of transmission represent how generations or life stages of infected ticks are maintained. Once infected, the tick can carry the pathogen for life.
Rickettsiae are transmitted to a vertebrate host through saliva while a tick is feeding. It usually takes about 24 hours of attachment and feeding before the rickettsiae are transmitted to the host. In general, about one to three percent of the tick population carries R. rickettsii, even in areas where the majority of human cases are reported. Therefore, the risk of exposure to a tick carrying R. rickettsii is low.
Vectors include the American dog tick Dermacentor variabilis, Dermacentor andersoni, Rhipicephalus sanguineus, and Amblyomma cajennense. Not all of these are of equal importance, and most are restricted to certain geographic areas.
The two major vectors of R. rickettsii in the United States are the American dog tick and the Rocky Mountain wood tick. American dog ticks are widely distributed east of the Rocky Mountains and they also occur in limited areas along the Pacific Coast. Dogs and medium-sized mammals are the preferred hosts of an adult American dog ticks, although it feeds readily on other large mammals, including human beings. This tick is the most commonly identified species responsible for transmitting R. rickettsii to humans. Rocky Mountain wood ticks (Dermacentor andersoni) are found in the Rocky Mountain states and in southwestern Canada. The life cycle of this tick may require up to three years for its completion. The adult ticks feed primarily on large mammals. The larvae and nymphs feed on small rodents.
Other tick species have been shown to be naturally infected with R. rickettsii or serve as experimental vectors in the laboratory. These species are likely to play only a minor role in the ecology of R. rickettsii.
Mechanism of pathogenicity
Entry into host
Rickettsia rickettsii can be transmitted to human hosts through the bite of an infected tick. As with other bacterium transmitted via ticks, the process generally requires a period of attachment of 4 to 6 hours. However, in some cases a Rickettsia rickettsii infection has been contracted by contact with tick tissues or fluids. Then, the bacteria induce their internalization into host cells via a receptor-mediated invasion mechanism.
Researchers believe that this mechanism is similar to that of Rickettsia conorii. This species of Rickettsia uses an abundant cell surface protein called OmpB to attach to a host cell membrane protein called Ku70. It has previously been reported that Ku70 migrates to the host cell surface in the presence of "Rickettsia". Then, Ku70 is ubiquitinated by c-Cbl, an E3 ubiquitin ligase. This triggers a cascade of signal transduction events resulting in the recruitment of Arp2/3 complex. CDC42, protein tyrosine kinase, phosphoinositide 3-kinase, and Src-family kinases then activate Arp2/3. This causes the alteration of local host cytoskeletal actin at the entry site as part of a zipper mechanism. Then, the bacteria is phagocytosized by the host cell and enveloped by a phagosome.
Studies have suggested that rOmpB is involved in this process of adhesion and invasion. Both rOmpA and rOmpB are members of a family of surface cell antigens (Sca) which are autotransporter proteins; they act as ligands for the Omp proteins and are found throughout the rickettsiae.
Escape from the phagosome and then the host cell
The cytosol of the host cell contains nutrients, adenosine triphosphate, amino acids, and nucleotides which are used by the bacteria for growth. For this reason, as well as to avoid phagolysosomal fusion and death, rickettsiae must escape from the phagosome. To escape from the phagosome, the bacteria secrete phospholipase D and hemolysin C. This causes disruption of the phagosomal membrane and allows the bacteria to escape. Following generation time in the cytoplasm of the host cells, the bacteria utilizes actin based motility to move through the cytosol.
RickA, expressed on the rickettsial surface, activates Arp2/3 and causes actin polymerization. The rickettsiae use the actin to propel themselves throughout the cytosol to the surface of the host cell. This causes the host cell membrane to be deformed outward and then it invaginates into the adjacent cell. The bacteria are then able to spread from cell to cell.
Consequences of infection
Rickettsia rickettsii migrate to vital organs such as the brain, skin, and the heart following infection. The subsequent binary replication causes perforation of the vessel walls within the host cells. Bacteria inflict damage bacteria resulting in hyperplasia and then apoptosis of the infected cell.
People can develop permanent disabilities including "cognitive deficits, ataxia, hemiparesis, blindness, deafness, or amputation following gangrene".
Abnormal laboratory findings seen in patients with Rocky Mountain spotted fever may include a low platelet count, low blood sodium concentration, or elevated liver enzyme levels. Serology testing and skin biopsy are considered to be the best methods of diagnosis. Although immunofluorescent antibody assays are considered some of the best serology tests available, most antibodies that fight against R. rickettsii are undetectable on serology tests the first seven days after infection.
Differentialdiagnosis includes dengue, leptospirosis, and, most recently, chikungunya and Zika virus infections.
Appropriate antibiotic treatment should be started immediately when there is a suspicion of Rocky Mountain spotted fever on the basis of clinical and epidemiological findings. Treatment should not be delayed until laboratory confirmation is obtained. In fact, failure to respond to a tetracycline argues against a diagnosis of Rocky Mountain spotted fever. Severely ill patients may require longer periods before their fever resolves, especially if they have experienced damage to multiple organ systems. Preventive therapy in healthy patients who have had recent tick bites is not recommended and may, in fact, only delay the onset of disease.
Doxycycline (a tetracycline) (for adults at 100 milligrams every 12 hours, or for children under 45 kg (99 lb) at 4 mg/kg of body weight per day in two divided doses) is the drug of choice for patients with Rocky Mountain spotted fever, being one of the only instances doxycycline is used in children. Treatment should be continued for at least three days after the fever subsides, and until there is unequivocal evidence of clinical improvement. This will be generally for a minimum time of five to ten days. Severe or complicated outbreaks may require longer treatment courses. Doxycycline/ tetracycline is also the preferred drug for patients with ehrlichiosis, another tick-transmitted infection with signs and symptoms that may resemble those of Rocky Mountain spotted fever.
Chloramphenicol is an alternative drug that can be used to treat Rocky Mountain spotted fever, specifically in pregnancy. However, this drug may be associated with a wide range of side effects, and careful monitoring of blood levels can be required.
Rocky Mountain spotted fever can be a very severe illness and patients often require hospitalization. Because R. rickettsii infects the cells lining blood vessels throughout the body, severe manifestations of this disease may involve the respiratory system, central nervous system, gastrointestinal system, or kidneys.
Long-term health problems following acute Rocky Mountain spotted fever infection include partial paralysis of the lower extremities, gangrene requiring amputation of fingers, toes, or arms or legs, hearing loss, loss of bowel or bladder control, movement disorders, and language disorders. These complications are most frequent in persons recovering from severe, life-threatening disease, often following lengthy hospitalizations
Host factors associated with severe or fatal Rocky Mountain spotted fever include advanced age, male sex, African or Caribbean background, chronic alcohol abuse, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Deficiency of G6PD is a genetic condition affecting about 12 percent of the Afro-American male population. Deficiency in this enzyme is associated with a high proportion of severe cases of Rocky Mountain spotted fever. This is a rare clinical complication that is often fatal within five days of the onset of the disease.
In the early 1940´s, outbreaks were described in the Mexican states of Sinaloa, Sonora, Durango, and Coahuila driven by dogs and Rhipicephalus sanguineus sensu lato, the brown dog tick.  Over the ensuing 100 years case fatality rates were 30%-80%. In 2015, there was an abrupt rise in Sonora cases with 80 fatal cases. From 2003 to 2016, cases increased to 1394 with 247 deaths.
History and cultural references
Rocky Mountain spotted fever (or "black measles" because of its characteristic rash) was recognized in the early 1800's, and in the last 10 years of the 1800's (1890 - 1900) it became very common, especially in the Bitterroot Valley of Montana. Though it would be decades before scientists discovered the tick as the carrier of the disease, in as early as 1866, Doctor John B. Buker (establishing a practice in Missoula, MT) noticed a tick embedded in the skin of one of his patients. His notes were later studied as part of later research. 
In 1901, Dr. A. F. Longeway was appointed to solve "the black measles problem" in Montana. He in turn enlisted his friend, Dr. Earl Strain to help him. Strain suspected that the illness was from ticks. In 1906, Howard T. Ricketts was the first to establish the identity of the infectious organism (the organism smaller than a bacterium and larger than a virus) that causes this disease. 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 Rickettsia rickettsii. Ricketts died of typhus (another rickettsial disease) in Mexico in 1910, shortly after completing his studies on Rocky Mountain spotted fever.
Prior to 1922, Doctors McCray and McClintic both died while doing research on Rocky Mountain spotted fever, as did an aide of Noguchi Hideyo at the Rockefeller Institute. McCalla and Brerton also did early research into Rocky Mountain spotted fever.
Research began in 1922 in western Montana, in the Bitterroot Valley around Hamilton, Montana, after the Governor's daughter and his son-in-law died of the fever. However, prior to that, in 1917, Dr. Lumford Fricks introduced herds of sheep into the Bitterroot Valley. His hypothesis was that the sheep would eat the tall grasses where ticks lived and bred.  Past Assistant Surgeon R.R. Spencer of the Hygienic Laboratory of the U.S. Public Health Service was ordered to the region, and he led a research team at an abandoned schoolhouse through about 1924. On May 19, 1924, he put a large dose of mashed wood ticks, from lot 2351B, and some weak carbolic acid into his arm by injection. This vaccine worked. Spencer was assisted by R. R. Parker, Bill Gettinger, Henry Cowan, Henry Greenup, Elmer Greenup, Gene Hughes, Salsbury, Kerlee, and others, of whom Gettinger, Cowan and Kerlee died of Rocky Mountain spotted fever.
Much of the early research was conducted at Rocky Mountain Laboratories a part of the National Institute of Allergy and Infectious Diseases.
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- "Rocky Mountain spotted fever". Centers for Disease Control.