Última actualización:
April 08, 2009
Años publicados: 1989, 1998, 2001, 2009
Rocky Mountain spotted fever (RMSF) is an infectious disease that belongs to a group of diseases known as the spotted fever group rickettsioses. It is caused by infection with the bacterium Rickettsia rickettsii (R. rickettsii), which is usually transmitted by a tick bite. When introduced into the body, the bacterium spreads by the bloodstream or lymphatic vessels and multiplies within and damages certain cells lining the inside of small blood (vascular) vessels (i.e., endothelial cells) as well as vascular smooth muscle cells. Such damage leads to inflammatory changes of affected blood vessels (vasculitis), leakage of fluid from the blood vessels, an abnormal accumulation of fluid in body tissues (edema), and additional abnormalities, resulting in the symptoms and findings associated with the disease.
Approximately two to 14 days after initial infection, early symptoms may include a high fever, severe headaches, muscle pain (myalgia), nausea, vomiting, loss of appetite (anorexia), abdominal pain, and/or features. In addition, in most individuals with RMSF, a distinctive rash develops about three to five days after fever onset. The rash often initially appears on the skin of the wrists and ankles and spreads to involve the palms of the hands, the soles of the feet, the forearms, the trunk, the buttocks, and the neck and facial areas. The rash typically initially consists of small, flat pinkish spots (macules) that eventually become raised (papules) and darker. The lesions usually develop «pin-point» reddish spots (petechia) due to localized bleeding (hemorrhaging) and may merge to form larger hemorrhagic patches. In some severe cases, insufficient oxygenated blood supply to certain tissues may lead to areas of tissue loss (necrosis).
R. rickettsii infection may affect blood vessels, tissues, and organs throughout the body, including the lungs, brain and spinal cord (central nervous system), heart, liver, and kidneys. Associated symptoms and findings may vary, depending upon the specific tissues and organs affected. Without timely, appropriate treatment, individuals with severe disease may develop potentially life-threatening complications due to tissue and organ injury and dysfunction.
As its name indicates, the disease was originally recognized in the Rocky Mountain states. It has since been reported throughout the continental United States as well as Mexico, Canada, Central America, and South America. As noted above, in most cases, infection with the R. rickettsii bacterium results from tick bites. Several different types of ticks serve as «vectors» for the disease, transmitting the R. rickettsii bacterium to humans.
Rocky Mountain spotted fever (RMSF) is considered the most potentially severe form of the spotted fevers. The onset of symptoms typically occurs approximately two to 14 days (with an average of seven days) after having been bitten by a tick carrying the R. rickettsii bacterium. Early symptoms usually include a fever that may reach 103 or 104 degrees Fahrenheit; chills; extreme exhaustion (prostration); muscle pain (myalgia); and severe headaches that are often associated with pain upon moving the eyes and increased sensitivity to light (photophobia). Many also develop nausea, with or without vomiting, and loss of appetite (anorexia). Additional early symptoms may include diarrhea, abdominal tenderness, and abdominal pain. The disease may be difficult to diagnose in early stages since its early symptoms and signs are nonspecific, resembling those associated with many other infectious and non-infectious diseases.
Most affected individuals develop a skin rash between the third to fifth days after onset of fever. Thus, in some instances, the rash may not be present or may be subtle when affected individuals initially seek medical attention. Less commonly, the rash may appear as early as the first day of illness or past five days. In addition, in some rare cases, a rash may never develop («spotless fever»).
In those who do develop a rash, it often initially develops on the wrists and ankles and then spreads to the palms and soles, forearms, neck, face, under the arms (axilla), buttocks, and trunk. Rarely, the rash may be atypical in distribution, beginning on the trunk, being widespread at onset, or remaining limited to one region.
The skin rash typically begins as small, flat pinkish spots (macules) that initially become white (blanch) when pressure is applied. The lesions eventually become raised (papular) and darker and may develop reddish spots (petechia) due to small areas of abnormal bleeding (hemorrhages). With continued disease progression, petechial areas may begin to merge (coalesce) into larger patches that later ulcerate. In severe cases, inadequate oxygenated blood supply to certain tissues (ischemia) may lead to areas of tissue loss and possible decay (gangrene). Particularly susceptible areas may include the ear lobes, the tip of the nose, fingers and/or toes (digits), and/or the scrotum in affected males.
In individuals with RMSF, endothelial cell damage and associated changes may affect blood vessels throughout the body. Therefore, the disease may affect multiple tissues and organ systems, including respiratory, neurologic, heart (cardiac), digestive, and kidney (renal) functioning. Individuals with severe disease may develop life-threatening complications approximately eight to 15 days after onset if prompt, appropriate treatment has not been received. Reports indicate that certain factors may be associated with an increased risk of such complications, including advanced age, male sex, and, possibly, alcohol abuse. In addition, a genetic disorder known as glucose-6-phosphate dehydrogenase (G6PD) deficiency has been associated with rare, fulminant RMSF (see below).
In some affected individuals, there may be extensive infection of the pulmonary circulation, which is the network of blood vessels between the heart and lungs. Endothelial cell injury and leakage of fluid from the blood vessels may lead to abnormal fluid accumulation within lung tissues and air sacs (pulmonary edema). Lung (pulmonary) involvement may be suggested by various symptoms and findings, such as coughing; increasing difficulties breathing (dyspnea); inflammation of the lungs (pneumonia); an abnormal accumulation of fluid between layers of the membrane lining the lungs and chest cavity (pleural effusion); and/or other abnormalities. Some individuals with RMSF may also have cardiac involvement, with inflammation of muscular walls of the heart (myocarditis), potentially leading to disturbances of the normal heart rhythm (dysrhythmias), chest pain, reduced pumping efficiency (heart failure), and/or other findings.
Central nervous system (CNS) involvement may also occur in association with severe cases of RMSF. Vascular injury may lead to inflammation of the brain (encephalitis), which may initially be associated with confusion, listlessness, and/or drowsiness. Symptoms and findings that may suggest progressively severe encephalitis may include restless, disorientation, impaired control of voluntary movements (ataxia), sudden episodes of uncontrolled electrical activity in the brain (seizures), unresponsiveness to surroundings (stupor), and/or coma. Various other neurologic abnormalities have also been reported in severe cases of RMSF. Such symptoms and findings have included hearing loss; abnormal, involuntary, rapid eye movements (nystagmus); a sensation that the environment or one’s body is revolving (vertigo); abnormally increased reflex responses (hyperreflexia); difficulty articulating speech (dysarthria); impairment of certain cranial nerve pairs arising from the brain (cranial nerve palsy); inability to control urination or defecation (incontinence); muscle weakness or paralysis; and/or other abnormalities.
As noted above, many affected individuals may develop certain digestive symptoms, such as nausea, vomiting, diarrhea, and/or abdominal tenderness or pain. In some cases, there may be blood in the contents expelled from the stomach during vomiting and/or in the stools due to abnormal bleeding (hemorrhaging) in the digestive (gastrointestinal [GI]) tract. In severe cases, affected individuals may develop severe hemorrhaging in the upper GI tract.
Some individuals with RMSF may also develop abnormal enlargement of the liver and/or spleen (hepatosplenomegaly). In some cases, infection may result in injury of certain liver (hepatic) cells, leading to abnormalities of liver function; however, reports indicate that liver failure does not result. Some affected individuals may develop abnormal yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), which is thought to be due to both liver cell injury and destruction of red blood cells (hemolysis).
In some cases, sudden (acute) renal failure may occur in association with severe RMSF. Endothelial injury, leakage of fluid from blood vessels, and additional changes may lead to an abnormally decreased volume of blood circulating in the body (hypovolemia) and low blood pressure (hypotension). Such changes may result in reduced filtering of blood by the kidneys (glomeruli filtration); retention of excessive amounts of certain toxic compounds in the blood (prerenal azotemia); and, in severe cases, associated renal failure.
In some cases, additional abnormalities have been reported in association with RMSF. These have included voluntary (skeletal) muscle injury and changes that may reflect eye (ocular) involvement, such as inflammatory changes of certain blood vessels of the retina and swelling of the head of the optic nerve (papilledema).
Fulminant Rocky Mountain Spotted Fever
In rare cases, R. rickettsii infection may cause an unusually rapid onset of severe RMSF, known as fulminant RMSF. Individuals with particular forms of glucose-6-phosphate dehydrogenase (G6PD) deficiency may be prone to developing fulminant RMSF when infected with the R. rickettsii bacterium. G6PD deficiency is an X-linked genetic condition that affects approximately 10 percent of the black male population. It is characterized by deficiency of the enzyme G6PD from the red blood cell membranes. This enzyme plays a crucial role in processing glucose, a simple sugar that is the primary energy source for red blood cells. In those with G6PD deficiency, certain infections, medications, stress, or other factors may trigger sudden (acute) episodes of premature red blood cell destruction (hemolysis), leading to reduced concentrations of the oxygen-carrying component (hemoglobin) in the blood (anemia). In individuals with G6PD deficiency, fulminant RMSF is thought to be related to unknown secondary effects of acute hemolysis on the R. rickettsii infection. In individuals with fulminant RMSF, life-threatening complications may develop within five days after onset.
The group of infectious diseases known as spotted fevers (i.e., spotted fever group rickettsioses), including Rocky Mountain spotted fever (RMSF), are caused by bacteria belonging to the «Rickettsiae» family. RMSF is caused by a bacterium called Rickettsia rickettsii (R. rickettsii), named after its discoverer, Howard T. Ricketts. As noted above, the disease is usually transmitted to humans via a tick bite. In many cases, the R. rickettsii bacterium is transmitted from infected ticks to their offspring; in other instances, uninfected ticks may become carriers (i.e., vectors) by feeding on infected mammals (e.g., rodents or dogs).
Rarely, RMSF may be transmitted due to exposure to infected tick tissues. For example, such exposure may occur when removing an infected tick from a person or pet, particularly if the engorged tick is crushed between the fingers. There have also been reports in which laboratory workers have been infected due to inhaling droplets from solutions containing the bacterium (i.e., resulting from accidental formation of aerosolized infectious specimens). However, according to the medical literature, it is important to note that direct person-to-person airborne transmission does not occur.
Upon entering the body, usually via the skin, the R. rickettsii bacterium spreads through blood (vascular) or lymphatic vessels. (The lymphatic system functions as part of the immune system, helping to protect the body against infection and disease. It consists of a network of tubular channels known as lymph vessels that branch into all bodily regions, including the skin. The lymph vessels drain a thin watery fluid called lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and the infection-fighting white blood cells known as lymphocytes.)
The R. rickettsii bacterium characteristically invades, multiples within, and directly damages cells lining the inside of small blood vessels (i.e., endothelial cells) as well as involuntary (smooth) muscle cells within these vessels. Such damage may lead to an inflammatory response; increased permeability of blood vessels (vascular permeability*); and increased accumulations of blood cells involved in blood clotting (i.e., platelets) within affected areas, with an associated depletion in the numbers of circulating platelets in the bloodstream (thrombocytopenia). (*Vascular permeability indicates the degree to which the blood vessel wall structure allows blood elements and waste products to pass through.)
Some have speculated that the tissue and organ injury in RMSF may be due to the widespread development of obstructive blood clots (thromboses) within blood vessels, leading to a decreased supply of oxygenated blood to certain tissues (ischemia) and associated, localized areas of tissue death (necrosis). However, evidence suggests that such organ injury and dysfunction is primarily due to increased vascular permeability, with resulting leakage of fluid from blood vessels; abnormal accumulation of fluid in body tissues (edema); bleeding (hemorrhaging); a low volume of blood circulating in the body (hypovolemia); low blood pressure (hypotension); and insufficient blood supply to certain organs or tissues (ischemia). Reports indicate that widespread, obstructive blood clotting within vessels (occlusive vascular thrombosis) and associated reduction in the elements involved in clotting (i.e., disseminated intravascular coagulation) occur only rarely in RMSF.
As noted above, in affected individuals with G6PD deficiency, fulminant RMSF is thought to result from certain unknown effects of acute, premature red blood cell destruction (hemolysis) on the progression of R. rickettsii infection. (For more information on G6PD deficiency, choose «glucose-6-phosphate dehydrogenase» as your search term in the Rare Disease Database.)
Rocky Mountain spotted fever (RMSF) was first described in the late 1800s in Idaho. The disease was initially recognized as existing in only the Rocky Mountain (western) area of the United States. However, beginning in the 1930s, the disease was noted in other regions of the country. Currently, the frequency of the disease is higher in the west south-central region and the South Atlantic states than in the Rocky Mountain states. RMSF has been reported in almost every state as well as other countries, including Canada, Mexico, Brazil, Columbia, Costa Rica, and Panama.
Most cases of RMSF occur between April to September, when outdoor activities are most frequent. However, some cases may occur in winter, particularly in the southern states. RMSF is most commonly seen in wooded areas or those with high grasses (i.e., within rural and suburban regions), although the disease has also been reported in urban areas. The frequency of reported cases is highest in children younger than age 15 years and others who participate in recreational or occupational activities in tick-infested areas. In addition, males are more commonly affected than females. Individuals who live in such regions and who have frequent exposure to dogs may also have an increased risk. Evidence indicates that up to one-third of individuals diagnosed with RMSF do not remember having experienced a recent tick bite or tick contact.
Several different types of hard-shelled ticks serve as «vectors» for the disease, carrying and transmitting the R. rickettsii bacterium to humans. A vector is any organism that may transmit a particular infectious agent, such as a bacterium or virus, to another organism. The primary vector for RMSF within the eastern two-thirds of the United States and the far west is the American dog tick (Dermacentor variabilis). The Rocky Mountain wood tick (Dermacentor andersoni) is the principal vector in the western United States and is also found in southwestern Canada. Other prevalent vectors include the brown dog tick (Rhipicephalus sanguineus) in Mexico and another species (Amblyomma cajennense) in Central and South America.
According to the results of specialized blood studies (i.e., serologic assays) conducted among those residing in or exposed to tick-infested regions, some suggest that some individuals may develop antibodies in response to R. rickettsii infection without experiencing symptoms typically associated with RMSF (asymptomatic or subclinical infection). (Antibodies are specialized proteins that are an important part of the body’s immune system. They are produced by certain white blood cells in response to typically foreign proteins [antigens], helping the body to neutralize or destroy invading microorganisms or other antigens.) However, researchers have questioned some of the methods used during such studies as well as whether the bacterium triggering the antibody response was indeed R. rickettsii rather than another rickettsial or other bacterium. Thus, it remains unclear whether subclinical infections occur with the R. rickettsii bacterium.
As mentioned above, risk factors for severe RMSF include male sex, advanced age, and alcoholism. In addition, rare, fulminant RMSF is most frequently seen in black males with G6PD deficiency.
Because its early symptoms and findings may be similar to those associated with many other infectious and non-infectious diseases, Rocky Mountain spotted fever (RMSF) may be difficult to diagnose in its early stages. The classic "triad" of the disease is fever, rash, and a history of tick bite. However, rash often is not present when affected individuals initially seek medical attention. In addition, as noted above, some do not recall recent tick exposure.
According to the medical literature, a diagnosis of RMSF should be considered in any individual who has developed sudden unexplained high fever, severe headache, and extreme exhaustion (prostration) and who has recently been exposed to or resides in tick-infested regions, particularly in the spring or summer months. In addition, the appearance of a faint pinkish rash on the wrists and ankles subsequent to fever onset should suggest RMSF as a diagnosis. However, it is important to note that the initial skin rash may be overlooked in some cases and, again, that some affected individuals may not develop a rash during the course of R. rickettsii infection.
In addition to a thorough clinical evaluation, specialized laboratory tests play an important role in helping to determine a diagnosis of RMSF and identifying specific abnormalities potentially associated with the infection. The findings revealed by certain laboratory tests may vary, depending upon the stage of the disease and the specific tissues and organ systems affected.
For most affected individuals, during early stages of the disease, blood tests reveal that white blood cells are within normal levels. However, in some cases, the white blood cell count may be abnormally low or elevated. Abnormal laboratory findings that may be suggestive of RMSF as a possible diagnosis include low levels of circulating blood platelets (thrombocytopenia); elevated levels of certain liver enzymes; and low levels of sodium in the blood (hyponatremia). (The latter may result due to inappropriate secretion of the antidiuretic hormone [ADH] in reaction to hypovolemia; ADH acts on the kidneys to increase their reabsorption of water into the blood to maintain optimal water levels in the body.. As just noted, thrombocytopenia is a common finding; however, in only rare cases of RMSF, testing may reveal an abnormal reduction in certain additional elements (e.g., fibrinogen) that play a role in blood clotting (coagulation) due to their involvement in coagulation within blood vessels throughout the body (disseminated intravascular coagulation).
Confirming the presence of the R. rickettsii bacterium is essential in making a firm diagnosis of RMSF. A diagnosis may be confirmed by specialized laboratory procedures in which the R. rickettsii bacterium is isolated from an affected individual's blood and cultivated (e.g., in cell culture). However, few laboratories undertake such diagnostic procedures.
In most cases, specialized laboratory tests conducted on blood serum (serologic assays) are used to confirm a diagnosis of R. rickettsii infection. (Blood serum is the clear fluid that separates from blood on clotting. It contains no blood cells nor the protein that helps blood clotting [fibrinogen]; it does contain glucose, various antibodies, and other proteins.. Indirect immunofluorescence assay (IFA) is the serologic test that is most commonly used and considered the most specific and sensitive for confirming RMSF. With IFA, specific antibodies are labeled with special fluorescent dyes and a microscope that projects ultraviolet light is used, enabling researchers to observe antibody response to certain microorganisms. Diagnostic rises in antibody response to the R. rickettsii bacterium usually are not detected until approximately seven to 14 days after the disease's onset, with peak antibody levels typically occurring at about two to three weeks. Therefore, diagnostic antibody levels typically are not present within the initial five days of symptoms, when antibiotic therapy should be begun (see "Treatment" below). (In addition, individuals who receive treatment within 48 hours after symptom onset may have a reduced antibody response.)
In some cases, if affected individuals develop a rash, small samples of skin tissue may be removed (biopsied) and microscopically examined (e.g., via direct immunofluorescence or immunoenzyme staining) before antibiotic therapy is initiated or within the first 48 hours of such therapy, potentially confirming RMSF during acute illness. However, because the bacteria are locally distributed within the skin lesions, this diagnostic method may not detect R. rickettsii in all patients (i.e., 70 percent sensitivity). In addition, it is not as widely available as IFA.
Treatment
Evidence indicates that beginning treatment within the first five days of symptoms is essential, since delaying therapy carries an increased risk of life-threatening complications. Thus, appropriate antibiotic therapy should be begun immediately when a diagnosis of RMSF is clinically suspected and should not be delayed until definitive laboratory findings are available.
The treatment of choice for both children and most adults is administration of the antibiotic tetracycline doxycycline. Although tetracycline agents can cause teeth staining in young children, the risk is minimal with a short course of doxycycline. Therapy with the antibiotic agent chloramphenicol is recommended for women who are pregnant (due to the potential effects of tetracycline agents on fetal bone development) and as an alternative for other patients who are unable to receive tetracycline antibiotics (e.g., due to allergy). Antibiotic therapy for RMSF is usually administered for five to seven days, continuing for at least three days after the fever abates. If an affected individual is treated with appropriate antibiotic therapy within the first three to five days of illness, the fever usually subsides within two to three days. However, for those who are severely ill, the fever may take longer to subside on appropriate antibiotic therapy.
In many cases, antibiotic medications may be given by mouth (orally). However, when affected individuals are experiencing nausea or vomiting or are seriously ill, medications may be administered by infusion through veins (intravenously).
Individuals who are severely ill require hospitalization and intensive supportive care. Such measures include careful administration of fluids and monitoring of blood flow (hemodynamics) to obtain appropriate restoration of fluid content without causing abnormal fluid accumulation within lung tissues and air spaces (pulmonary edema) due to increased vascular permeability. Seriously ill individuals who have low levels of circulating oxygen in the blood (hypoxemia) may require the use of a machine to deliver oxygen to the lungs (mechanical ventilation). In some cases, acute kidney failure may necessitate hemodialysis, a procedure in which excess waste products are removed from the blood by filtering the blood through a machine. Transfusion of red blood cells may be required for those who have abnormally low levels of the oxygen-carrying component of red blood cells (anemia) or who experience severe bleeding (hemorrhaging). In some cases, severely reduced levels of circulating blood platelets (thrombocytopenia) and hemorrhaging may necessitate platelet transfusions. In addition, individuals with neurologic involvement who experience seizures may require the administration of medications that prevent or help to control such seizure episodes (anticonvulsants). In extremely severe cases of restricted oxygenated blood supply to certain tissues (ischemia) and associated tissue loss and decay (gangrene), certain affected areas (e.g., fingers, toes, limbs) may need to be surgically removed (amputated).
Those who receive appropriate, timely treatment generally have a complete recovery. However, a small percentage of those with severe RMSF may have long-term health problems following the disease, such as hearing loss, muscle weakness or partial paralysis of one side of the body (hemiparesis), incontinence, and/or other abnormalities. Other treatment for this disease is symptomatic and supportive.
Prevention
Individuals who will be exposed to areas with high numbers of tick vectors for the R. rickettsii bacterium (e.g., fields, wooded or marsh areas, etc.) should consider taking certain steps to prevent infection. Such steps include using appropriate tick repellents; wearing long-sleeved shirts, long pants, and hats; wearing light-colored clothing to make ticks more visible; and tucking pants into socks or boots. In addition, it is important to carefully check clothing and the body (including scalp, pubic, and underarm hair) after being in such locations. If engorged ticks are discovered, they must be removed with caution, such as with the use of fine-tipped tweezers. They should not be crushed between the fingers, since this has been associated with disease transmission.
Preventive (prophylactic) antibiotic therapy is not advised for individuals with known tick bites. However, such individuals should immediately seek medical attention should they develop any generalized symptoms, particularly fever and headache, within the two weeks following the recent tick bite.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
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