Rocky Mountain Spotted Fever
Rocky Mountain spotted fever is the most severe and most frequently reported rickettsial disease in the United States. In the pre-antibiotic era, 20-25% of previously healthy, infected persons died of the illness. Today, even with antimicrobial agents that are highly effective, 3-5% of persons die mainly because of late or mis-diagnosed infection and delayed or ineffective antimicrobial treatment.
The disease is caused by Rickettsia rickettsii, and the bacteria are spread to humans by ixodid (hard) ticks. The onset of disease follows an infective bite by a week (range 2-14 days), beginning with fever, severe 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 reasons are that up to 40% of patients are unaware of a tick bite, which is painless and may go unnoticed or be forgotten, and that the rash does not usually appear until 3-5 days after onset of illness. To further confound the diagnosis, symptoms such as nausea, vomiting, diarrhea, abdominal pain, and cough may suggest other diagnoses such as enterocolitis, acute surgical abdomen, or pneumonia. The rash typically appears on the ankles and wrists as faint pink 1-5 mm macules that represent a focus of vascular infection and surrounding vasodilation. These lesions may progress to become maculopapular, owing to the leakage of edema fluid from the affected blood vessels, with the development of a hemorrhage (petechia) in the center of the lesions.
Figure 2. Characteristic spotted rash of late-stage Rocky Mountain spotted fever on legs of a patient. (CDC)
Rocky Mountain spotted fever was first recognized in 1896 in the Snake River Valley of Idaho and was originally called "black measles" because of the characteristic rash. It was a dreaded and frequently fatal disease that affected hundreds of people in this area. By the early 1900s, the geographic distribution of the disease in United States was recognized as far north as Washington and Montana and as far south as California, Arizona and New Mexico.
Howard Ricketts was the first to establish the identity of the infectious organism that causes Rocky Mountain spotted fever at the turn of the Twentieth Century. He and others characterized the basic epidemiologic features of the disease, including the role of tick vectors. Studies showed that Rocky Mountain spotted fever is caused by Rickettsia rickettsii, and involves a complex cycle between ticks and mammals. Humans are accidental hosts, but are not involved in the natural transmission cycle of the pathogen.
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, as well as southern Canada, 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- 5% of individuals 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 in the late 1940s, as many as 30% of individuals infected withR. rickettsii died.
Figure 3. Discovery of chloramphenicol and tetracycline antibiotics in the 1940s led to a sharp decline in RMSF-related mortality. Today, doxycycline is the drug of choice for treatment of RMSF. (CDC)
Figure 4. Gimenez stain of tick hemolymph cells infected with R. rickettsii. (CDC)Rickettsia rickettsii, is a very small bacterium that must live inside the cells of its hosts. Consequently, they are difficult to see in tissues by using routine histologic stains and generally require the use of special staining methods.
Natural History
Rocky Mountain spotted fever, like all rickettsial infections, is classified as a zoonosis. Zoonoses 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 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 bite. Less commonly, infections may occur following exposure to crushed tick tissues, fluids, or feces.
Only members of the tick family Ixodidae (hard ticks) are naturally infected withRickettsia rickettsii. 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 the next stage. Both male and female ticks will bite.
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, 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 spermatazoa during mating. In this manner, generations or each life stage of infected ticks are maintained. Once infected, the tick can carry the rickettsiae for life.
Rickettsiae are transmitted to a vertebrate host through saliva while a tick is feeding. It usually takes several hours of attachment and feeding before the rickettsiae are transmitted to the host. The risk of exposure to a tick carrying R. rickettsii is low. Generally, about 1 -3% of the tick population carries R. rickettsii,even in areas where the majority of human cases are reported.
Major Tick Vectors in the United States
There are two major vectors of R. rickettsii in the United States, the American dog tick and the Rocky Mountain wood tick.
The American dog tick (Dermacentor variabilis) is widely distributed east of the Rocky Mountains and also occurs in limited areas along the Pacific Coast. Dogs and medium-sized mammals are the preferred hosts of adult D. variabilis,although it feeds on other large mammals, including humans. This tick is the most commonly identified species responsible for transmitting R. rickettsii to humans.
Figure 5. American dog tick (Dermacentor variabilis). (CDC)
Figure 6. Approximate distribution of the American dog tick. (CDC)
The Rocky Mountain wood tick (Dermacentor andersoni) is found in the Rocky Mountain states and in southwestern Canada. The life cycle of this tick may require up to 2 to 3 years for completion. Adult ticks feed primarily on large mammals. Larvae and nymphs feed on small rodents.
Figure 7. Rocky Mountain wood tick (Dermacentor andersoni). (CDC)
Figure 8. Approximate distribution of the Rocky Mountain wood tick. (CDC)
Figure 9b. Reported cases of Rocky Mountain spotted fever in the United States, 1997-2002.According to CDC's annual Summary of Notifiable Diseases, in 2002 - 1104 cases were reported; 2003 - 1091 cases; 2004 - 1713 cases; 2005 - 1936 cases; 2006 - 2288 cases. The number of reported cases by county in the United States in 2006 is shown in Figure 9c below.
Figure 9c. Reported cases of Rocky Mountain spotted fever in the United States, 2006. (CDC)
Figure 10. Seasonal distribution of reported cases of Rocky Mountain spotted fever, 1993-1996. (CDC)
Signs and Symptoms
Rocky Mountain spotted fever can be very difficult to diagnose in its early stages, even among experienced physicians who are familiar with the disease. Patients infected with R. rickettsii generally visit a physician in the first week of their illness, following an incubation period of about 5-10 days 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.
Initial symptoms may include fever, nausea, vomiting, severe headache, muscle pain, and lack of appetite. Later signs and symptoms include rash, abdominal pain, joint pain and diarrhea.
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 first appears 2-5 days after the onset of fever and is often not present or may be very subtle when the patient is initially seen by a physician. Younger patients usually develop the rash earlier than older patients. Most often it begins as small, flat, pink, non-itchy spots (macules) on the wrists, forearms, and ankles (Figure 13). 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, and this type of rash occurs in only 35% to 60% of patients with Rocky Mountain spotted fever (Figure 14). The rash involves the palms or soles in as many as 50% to 80% of patients; however, this distribution may not occur until later in the course of the disease. As many as 10% to 15% of patients may never develop a rash.
Figure 13. Early (macular) rash on sole of foot. (CDC)
Figure 14. Late (petechial) rash on palm and forearm. (CDC)
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 renal system. 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. Deficiency of G6PD is a sex-linked genetic condition affecting approximately 12% of the U.S. African-American male population; deficiency of this 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 within 5 days of onset of illness.
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.
Laboratory Diagnosis
There is no widely available laboratory assay that provides rapid confirmation of early Rocky Mountain spotted fever. Treatment decisions must be based on epidemiologic and clinical clues, and should never be delayed while waiting for confirmation by laboratory results.
Serologic assays are the most widely available and frequently used methods for confirming cases of Rocky Mountain spotted fever. The indirect immunofluorescence assay (IFA) is generally considered the reference standard in Rocky Mountain spotted fever serology and is the test currently used by CDC and most state public health laboratories (Figure 15).
Figure 15. IFA reaction of a positive human serum on Rickettsia rickettsii grown in chicken yolk sacs, 400X. (CDC)
IFA can be used to detect either IgG or IgM antibodies. Blood samples taken early (acute) and late (convalescent) in the disease are the preferred specimens for evaluation. Most patients demonstrate increased IgM titers by the end of the first week of illness. Diagnostic levels of IgG antibody generally do not appear until 7-10 days after the onset of illness. It is important to consider the amount of time it takes for antibodies to appear when ordering laboratory tests, especially because most patients visit their physician relatively early in the course of the illness, before diagnostic antibody levels may be present. The value of testing two sequential serum or plasma samples together to show a rising antibody level is considerably more important in confirming acute infection with rickettsial agents because antibody titers may persist in some patients for years after the original exposure.
Another approach to Rocky Mountain spotted fever diagnostics is immunostaining. This method is used by taking a skin biopsy of the rash from an infected patient prior to therapy or within the first 48 hours after antibiotic therapy has been started. Because rickettsiae are focally distributed in lesions of Rocky Mountain spotted fever, this test may not always detect the agent. Even in laboratories with expertise in performing this test, the sensitivity is only about 70% on biopsied tissues. This assay may also be used to test tissues obtained at autopsy and has been used to confirm Rocky Mountain spotted fever in otherwise unexplained deaths (Figure 16). Immunostaining for spotted fever group rickettsiae is offered by the CDC, a few state health departments, and some university-based hospitals and commercial laboratories in the United States.
Figure 16. Red structures indicate immunohistological staining of Rickettsia rickettsii in endothelial cells of a blood vessel from a patient with fatal RMSF. (CDC)
Treatment
Appropriate antibiotic treatment should be initiated immediately when there is a suspicion of Rocky Mountain spotted fever on the basis of clinical and epidemiologic findings. Treatment should not be delayed until laboratory confirmation is obtained.
If the patient is treated within the first 4-5 days of the disease, fever generally subsides within 24-72 hours after treatment with an appropriate antibiotic (usually a tetracycline). In fact, failure to respond to a tetracycline antibiotic argues against a diagnosis of RMSF. Severely ill patients may require longer periods before their fever resolves, especially if they have experienced damage to multiple organ systems. Prophylactic therapy in non-ill patients who have had recent tick bites is not recommended and may, in fact, only delay the onset of disease.
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 lb.]) is the drug of choice for patients with Rocky Mountain spotted fever. Therapy is continued for at least 3 days after fever subsides and until there is unequivocal evidence of clinical improvement, generally for a minimum total course of 5 to 10 days. Severe or complicated disease may require longer treatment courses. Doxycycline is also the preferred drug for patients with ehrlichiosis, another tick-transmitted infection with signs and symptoms that may resemble Rocky Mountain spotted fever.
Tetracyclines are usually not the preferred drug for use in pregnant women because of risks associated with malformation of teeth and bones in unborn children. Chloramphenicol is an alternative drug that can be used to treat Rocky Mountain spotted fever; however, this drug may be associated with a wide range of side effects including aplastic anemia, and may require careful monitoring of blood levels.
Prevention and Control
Limiting exposure to ticks is the most effective way to reduce the likelihood of Rocky Mountain spotted fever infection. In persons exposed to tick-infested habitats, prompt careful inspection and removal of crawling or attached ticks is an important method of preventing disease. It may take several hours of attachment before organisms are transmitted from the tick to the host.
Currently, no licensed vaccine is available for Rocky Mountain spotted fever.
It is unreasonable to assume that a person can completely eliminate activities that may result in tick exposure. Therefore, prevention measures should be aimed at personal protection. CDC recommends the following prevention measures:
-Wear light-colored clothing to allow you to see ticks that are crawling on your clothing.
-Tuck your pants legs into your socks so that ticks cannot crawl up the inside of your pants legs.
-Apply repellents to discourage tick attachment. Repellents containing permethrin can be sprayed on boots and clothing, and will last for several days. Repellents containing DEET (diethyltoluamide) can be applied to the skin, but will last only a few hours before reapplication is necessary. Use DEET with caution on children. Application of large amounts of DEET on children has been associated with adverse reactions.
-Conduct a body check upon return from potentially tick-infested areas by searching your entire body for ticks. Use a hand-held or full-length mirror to view all parts of your body.
-Remove any tick you find on your body. Parents should check their children for ticks, especially in the hair, when returning from potentially tick-infested areas. Additionally, ticks may be carried into the household on clothing and pets. Both should be examined carefully.
Rocky Mountain spotted fever is the most severe and most frequently reported rickettsial disease in the United States. In the pre-antibiotic era, 20-25% of previously healthy, infected persons died of the illness. Today, even with antimicrobial agents that are highly effective, 3-5% of persons die mainly because of late or mis-diagnosed infection and delayed or ineffective antimicrobial treatment.
The disease is caused by Rickettsia rickettsii, and the bacteria are spread to humans by ixodid (hard) ticks. The onset of disease follows an infective bite by a week (range 2-14 days), beginning with fever, severe 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 reasons are that up to 40% of patients are unaware of a tick bite, which is painless and may go unnoticed or be forgotten, and that the rash does not usually appear until 3-5 days after onset of illness. To further confound the diagnosis, symptoms such as nausea, vomiting, diarrhea, abdominal pain, and cough may suggest other diagnoses such as enterocolitis, acute surgical abdomen, or pneumonia. The rash typically appears on the ankles and wrists as faint pink 1-5 mm macules that represent a focus of vascular infection and surrounding vasodilation. These lesions may progress to become maculopapular, owing to the leakage of edema fluid from the affected blood vessels, with the development of a hemorrhage (petechia) in the center of the lesions.
Figure 2. Characteristic spotted rash of late-stage Rocky Mountain spotted fever on legs of a patient. (CDC)
Rocky Mountain spotted fever was first recognized in 1896 in the Snake River Valley of Idaho and was originally called "black measles" because of the characteristic rash. It was a dreaded and frequently fatal disease that affected hundreds of people in this area. By the early 1900s, the geographic distribution of the disease in United States was recognized as far north as Washington and Montana and as far south as California, Arizona and New Mexico.
Howard Ricketts was the first to establish the identity of the infectious organism that causes Rocky Mountain spotted fever at the turn of the Twentieth Century. He and others characterized the basic epidemiologic features of the disease, including the role of tick vectors. Studies showed that Rocky Mountain spotted fever is caused by Rickettsia rickettsii, and involves a complex cycle between ticks and mammals. Humans are accidental hosts, but are not involved in the natural transmission cycle of the pathogen.
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, as well as southern Canada, 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- 5% of individuals 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 in the late 1940s, as many as 30% of individuals infected withR. rickettsii died.
Figure 3. Discovery of chloramphenicol and tetracycline antibiotics in the 1940s led to a sharp decline in RMSF-related mortality. Today, doxycycline is the drug of choice for treatment of RMSF. (CDC)
Figure 4. Gimenez stain of tick hemolymph cells infected with R. rickettsii. (CDC)Rickettsia rickettsii, is a very small bacterium that must live inside the cells of its hosts. Consequently, they are difficult to see in tissues by using routine histologic stains and generally require the use of special staining methods.
In humans, Rickettsia rickettsii live and multiply primarily within cells that line small- to medium-sized blood vessels. Spotted fever group rickettsiae can grow in the nucleus or in the cytoplasm of the host cell. Once inside the host the rickettsiae multiply, resulting in damage and death of these cells. This causes blood to leak through tiny holes in vessel walls into adjacent tissues. This process causes the rash that is traditionally associated with Rocky Mountain spotted fever and causes damage to organs and tissues.
Rocky Mountain spotted fever, like all rickettsial infections, is classified as a zoonosis. Zoonoses 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 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 bite. Less commonly, infections may occur following exposure to crushed tick tissues, fluids, or feces.
Only members of the tick family Ixodidae (hard ticks) are naturally infected withRickettsia rickettsii. 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 the next stage. Both male and female ticks will bite.
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, 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 spermatazoa during mating. In this manner, generations or each life stage of infected ticks are maintained. Once infected, the tick can carry the rickettsiae for life.
Rickettsiae are transmitted to a vertebrate host through saliva while a tick is feeding. It usually takes several hours of attachment and feeding before the rickettsiae are transmitted to the host. The risk of exposure to a tick carrying R. rickettsii is low. Generally, about 1 -3% of the tick population carries R. rickettsii,even in areas where the majority of human cases are reported.
Major Tick Vectors in the United States
There are two major vectors of R. rickettsii in the United States, the American dog tick and the Rocky Mountain wood tick.
The American dog tick (Dermacentor variabilis) is widely distributed east of the Rocky Mountains and also occurs in limited areas along the Pacific Coast. Dogs and medium-sized mammals are the preferred hosts of adult D. variabilis,although it feeds on other large mammals, including humans. This tick is the most commonly identified species responsible for transmitting R. rickettsii to humans.
Figure 5. American dog tick (Dermacentor variabilis). (CDC)
Figure 6. Approximate distribution of the American dog tick. (CDC)
The Rocky Mountain wood tick (Dermacentor andersoni) is found in the Rocky Mountain states and in southwestern Canada. The life cycle of this tick may require up to 2 to 3 years for completion. Adult ticks feed primarily on large mammals. Larvae and nymphs feed on small rodents.
Figure 7. Rocky Mountain wood tick (Dermacentor andersoni). (CDC)
Figure 8. Approximate distribution of the Rocky Mountain wood tick. (CDC)
Other tick species have been shown to be naturally infected with R. rickettsii, but these species are likely to play only a minor role in the ecology of R. rickettsii.
Epidemiology
Rocky Mountain spotted fever has been a notifiable disease in the United States since the 1920s. In the last 50 years, approximately 250-2288 cases of Rocky Mountain spotted fever have been reported annually, although it is likely that many more cases go unreported. Between 2002 and 2006, the number of reported cases doubled.
Figure 9a. Reported cases of Rocky Mountain spotted fever in the United States, 1942-1996. CDC compiles the number of cases reported by the state health departments. (CDC)
Rocky Mountain spotted fever has been a notifiable disease in the United States since the 1920s. In the last 50 years, approximately 250-2288 cases of Rocky Mountain spotted fever have been reported annually, although it is likely that many more cases go unreported. Between 2002 and 2006, the number of reported cases doubled.
Figure 9a. Reported cases of Rocky Mountain spotted fever in the United States, 1942-1996. CDC compiles the number of cases reported by the state health departments. (CDC)
Figure 9b. Reported cases of Rocky Mountain spotted fever in the United States, 1997-2002.According to CDC's annual Summary of Notifiable Diseases, in 2002 - 1104 cases were reported; 2003 - 1091 cases; 2004 - 1713 cases; 2005 - 1936 cases; 2006 - 2288 cases. The number of reported cases by county in the United States in 2006 is shown in Figure 9c below.
Figure 9c. Reported cases of Rocky Mountain spotted fever in the United States, 2006. (CDC)
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.
Figure 10. Seasonal distribution of reported cases of Rocky Mountain spotted fever, 1993-1996. (CDC)
Over half of Rocky Mountain spotted fever infections are reported from the south-Atlantic region of the United States (Delaware, Maryland, Washington D.C., Virginia, West Virginia, North Carolina, South Carolina, Georgia, and Florida). Infection also occurs in other parts of the United States, namely the Pacific region (Washington, Oregon, and California) and west south-central (Arkansas, Louisiana, Oklahoma, and Texas) region.
The states with the highest incidences of Rocky Mountain spotted fever are North Carolina and Oklahoma. These two states combined accounted for 35% of the total number of U.S. cases reported to CDC during 1993 through 1996. Although Rocky Mountain spotted fever was first identified in the Rocky Mountain states, actually less than 3% of the U.S. cases were reported from that area during the same interval (1993-1996).
Figure 11. Number of reported cases of Rocky Mountain spotted fever by state and region, 1994-1998. (CDC)
Certain individuals are at higher risk of disease. The frequency of reported cases of Rocky Mountain spotted fever is highest among males, Caucasians, and children. Two-thirds of the Rocky Mountain spotted fever cases occur in children under the age of 15 years, with the peak age being 5 to 9 years old (see Figure 12). 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.
Figure 12. Average annual incidence of Rocky Mountain spotted fever by age group, 1993-1996. (CDC)
Rocky Mountain spotted fever can be very difficult to diagnose in its early stages, even among experienced physicians who are familiar with the disease. Patients infected with R. rickettsii generally visit a physician in the first week of their illness, following an incubation period of about 5-10 days 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.
Initial symptoms may include fever, nausea, vomiting, severe headache, muscle pain, and lack of appetite. Later signs and symptoms include rash, abdominal pain, joint pain and diarrhea.
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 first appears 2-5 days after the onset of fever and is often not present or may be very subtle when the patient is initially seen by a physician. Younger patients usually develop the rash earlier than older patients. Most often it begins as small, flat, pink, non-itchy spots (macules) on the wrists, forearms, and ankles (Figure 13). 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, and this type of rash occurs in only 35% to 60% of patients with Rocky Mountain spotted fever (Figure 14). The rash involves the palms or soles in as many as 50% to 80% of patients; however, this distribution may not occur until later in the course of the disease. As many as 10% to 15% of patients may never develop a rash.
Figure 13. Early (macular) rash on sole of foot. (CDC)
Figure 14. Late (petechial) rash on palm and forearm. (CDC)
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 renal system. 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. Deficiency of G6PD is a sex-linked genetic condition affecting approximately 12% of the U.S. African-American male population; deficiency of this 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 within 5 days of onset of illness.
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.
Laboratory Diagnosis
There is no widely available laboratory assay that provides rapid confirmation of early Rocky Mountain spotted fever. Treatment decisions must be based on epidemiologic and clinical clues, and should never be delayed while waiting for confirmation by laboratory results.
Serologic assays are the most widely available and frequently used methods for confirming cases of Rocky Mountain spotted fever. The indirect immunofluorescence assay (IFA) is generally considered the reference standard in Rocky Mountain spotted fever serology and is the test currently used by CDC and most state public health laboratories (Figure 15).
Figure 15. IFA reaction of a positive human serum on Rickettsia rickettsii grown in chicken yolk sacs, 400X. (CDC)
IFA can be used to detect either IgG or IgM antibodies. Blood samples taken early (acute) and late (convalescent) in the disease are the preferred specimens for evaluation. Most patients demonstrate increased IgM titers by the end of the first week of illness. Diagnostic levels of IgG antibody generally do not appear until 7-10 days after the onset of illness. It is important to consider the amount of time it takes for antibodies to appear when ordering laboratory tests, especially because most patients visit their physician relatively early in the course of the illness, before diagnostic antibody levels may be present. The value of testing two sequential serum or plasma samples together to show a rising antibody level is considerably more important in confirming acute infection with rickettsial agents because antibody titers may persist in some patients for years after the original exposure.
Another approach to Rocky Mountain spotted fever diagnostics is immunostaining. This method is used by taking a skin biopsy of the rash from an infected patient prior to therapy or within the first 48 hours after antibiotic therapy has been started. Because rickettsiae are focally distributed in lesions of Rocky Mountain spotted fever, this test may not always detect the agent. Even in laboratories with expertise in performing this test, the sensitivity is only about 70% on biopsied tissues. This assay may also be used to test tissues obtained at autopsy and has been used to confirm Rocky Mountain spotted fever in otherwise unexplained deaths (Figure 16). Immunostaining for spotted fever group rickettsiae is offered by the CDC, a few state health departments, and some university-based hospitals and commercial laboratories in the United States.
Figure 16. Red structures indicate immunohistological staining of Rickettsia rickettsii in endothelial cells of a blood vessel from a patient with fatal RMSF. (CDC)
Treatment
Appropriate antibiotic treatment should be initiated immediately when there is a suspicion of Rocky Mountain spotted fever on the basis of clinical and epidemiologic findings. Treatment should not be delayed until laboratory confirmation is obtained.
If the patient is treated within the first 4-5 days of the disease, fever generally subsides within 24-72 hours after treatment with an appropriate antibiotic (usually a tetracycline). In fact, failure to respond to a tetracycline antibiotic argues against a diagnosis of RMSF. Severely ill patients may require longer periods before their fever resolves, especially if they have experienced damage to multiple organ systems. Prophylactic therapy in non-ill patients who have had recent tick bites is not recommended and may, in fact, only delay the onset of disease.
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 lb.]) is the drug of choice for patients with Rocky Mountain spotted fever. Therapy is continued for at least 3 days after fever subsides and until there is unequivocal evidence of clinical improvement, generally for a minimum total course of 5 to 10 days. Severe or complicated disease may require longer treatment courses. Doxycycline is also the preferred drug for patients with ehrlichiosis, another tick-transmitted infection with signs and symptoms that may resemble Rocky Mountain spotted fever.
Tetracyclines are usually not the preferred drug for use in pregnant women because of risks associated with malformation of teeth and bones in unborn children. Chloramphenicol is an alternative drug that can be used to treat Rocky Mountain spotted fever; however, this drug may be associated with a wide range of side effects including aplastic anemia, and may require careful monitoring of blood levels.
Prevention and Control
Limiting exposure to ticks is the most effective way to reduce the likelihood of Rocky Mountain spotted fever infection. In persons exposed to tick-infested habitats, prompt careful inspection and removal of crawling or attached ticks is an important method of preventing disease. It may take several hours of attachment before organisms are transmitted from the tick to the host.
Currently, no licensed vaccine is available for Rocky Mountain spotted fever.
It is unreasonable to assume that a person can completely eliminate activities that may result in tick exposure. Therefore, prevention measures should be aimed at personal protection. CDC recommends the following prevention measures:
-Wear light-colored clothing to allow you to see ticks that are crawling on your clothing.
-Tuck your pants legs into your socks so that ticks cannot crawl up the inside of your pants legs.
-Apply repellents to discourage tick attachment. Repellents containing permethrin can be sprayed on boots and clothing, and will last for several days. Repellents containing DEET (diethyltoluamide) can be applied to the skin, but will last only a few hours before reapplication is necessary. Use DEET with caution on children. Application of large amounts of DEET on children has been associated with adverse reactions.
-Conduct a body check upon return from potentially tick-infested areas by searching your entire body for ticks. Use a hand-held or full-length mirror to view all parts of your body.
-Remove any tick you find on your body. Parents should check their children for ticks, especially in the hair, when returning from potentially tick-infested areas. Additionally, ticks may be carried into the household on clothing and pets. Both should be examined carefully.
Tick Control
Strategies to reduce populations of vector ticks through area-wide application of acaricides (chemicals that will kill ticks and mites) and control of tick habitats (e.g., leaf litter and brush) have been effective in small-scale trials. New methods being developed include applying acaricides to rodents by using baited tubes, boxes, and feeding stations in areas where these pathogens are endemic. Biological control with fungi, parasitic nematodes, and parasitic wasps may play alternate roles in integrated tick control efforts. Community-based, integrated, tick-management strategies may prove to be an effective public health response to reduce the incidence of tick-borne infections. However, limiting exposure to ticks is currently the most effective method of prevention.
Strategies to reduce populations of vector ticks through area-wide application of acaricides (chemicals that will kill ticks and mites) and control of tick habitats (e.g., leaf litter and brush) have been effective in small-scale trials. New methods being developed include applying acaricides to rodents by using baited tubes, boxes, and feeding stations in areas where these pathogens are endemic. Biological control with fungi, parasitic nematodes, and parasitic wasps may play alternate roles in integrated tick control efforts. Community-based, integrated, tick-management strategies may prove to be an effective public health response to reduce the incidence of tick-borne infections. However, limiting exposure to ticks is currently the most effective method of prevention.
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