The first symptoms of Rocky Mountain spotted fever (RMSF) typically begin 2-14 days after the bite of an infected tick. A tick bite is usually painless and about half of the people who develop RMSF do not remember being bitten. The disease frequently begins as a sudden onset of fever and headache and most people visit a healthcare provider during the first few days of symptoms. Because early symptoms may be non-specific, several visits may occur before the diagnosis of RMSF is made and correct treatment begins. The following is a list of symptoms commonly seen with this disease, however, it is important to note that few people with the disease will develop all symptoms, and the number and combination of symptoms varies greatly from person to person. 
 
 - Fever  
 - Rash (occurs 2-5 days after fever, may be absent in some cases; see below) 
 - Headache  
 - Nausea  
 - Vomiting  
 - Abdominal pain (may mimic appendicitis or other causes of acute abdominal pain)  
 - Muscle pain  
 - Lack of appetite  
 - Conjunctival injection (red eyes)  
 
                
RMSF is a serious illness that can be fatal in the first eight days of symptoms if not treated correctly, even in previously healthy people. The progression of the disease varies greatly. Patients who are treated early may recover quickly on outpatient medication, while those who experience a more severe course may require intravenous antibiotics, prolonged hospitalization or intensive care. 
                
 
Rash 
                
While most people with RMSF (90%) have some type of rash during the course of illness, some people do not develop the rash until late in the disease process, after treatment should have already begun.  Approximately 10% of RMSF patients never develop a rash. It is important for physicians to consider RMSF if other signs and symptoms support a diagnosis, even if a rash is not present. 
                
A classic case of RMSF involves a rash that first appears 2-5 days after the onset of fever as small, flat, pink, non-itchy spots (macules) on the wrists, forearms, and ankles and spreads to include the trunk and sometimes the palms and soles.  Often the rash varies from this description and people who fail to develop a rash, or develop an atypical rash, are at increased risk of being misdiagnosed. 
                
The red to purple, spotted (petechial) rash of RMSF is usually not seen until the sixth day or later after onset of symptoms and occurs in 35-60% of patients with the infection. This is a sign of progression to severe disease, and every attempt should be made to begin treatment before petechiae develop. 
                
Figure 1a and 1b: Examples of an early-stage rash in an RMSF patient. 
 
  
   
     
    
   
  
  
   
     
    
   
  
 
 
   
  
 
                
  
 
                
 
Long-term Health Problems 
                
Patients who had a particularly severe infection requiring prolonged hospitalization may have long-term health problems caused by this disease. Rickettsia rickettsii infects the endothelial cells that line the blood vessels. The damage that occurs in the blood vessels results in a disease process called a "vasculitis", and bleeding or clotting in the brain or other vital organs may occur. Loss of fluid from damaged vessels can result in loss of circulation to the extremities and damaged fingers, toes or even limbs may ultimately need to be amputated. Patients who suffer this kind of severe vasculitis in the first two weeks of illness may also be left with permanent long-term health problems such as profound neurological deficits, or damage to internal organs. Those who do not have this kind of vascular damage in the initial stages of the disease typically recover fully within several days to months. 
                
 
Infection in Children 
                
Children with RMSF infection may experience nausea, vomiting, and loss of appetite. Children are less likely to report a headache, but more likely to develop an early rash than adults. Other frequently observed signs and symptoms in children with RMSF are abdominal pain, altered mental status, and conjunctival injection. Occasionally, symptoms like cough, sore throat, and diarrhea may be seen, and can lead to misdiagnosis. 
                
For more in-depth information about signs and symptoms of RMSF, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm 
                
 
Physician Diagnosis 
                
There are several aspects of 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. Also, information about the presence of symptoms such as fever and rash may be helpful. The healthcare provider may also look at routine blood tests, such as a complete blood cell count or a chemistry panel. Clues such as a low platelet count (thrombocytopenia), low sodium levels (hyponatremia), or elevated liver enzyme levels are often helpful predictors of RMSF but may not be present in all patients. After a suspect diagnosis is made on clinical suspicion and treatment has begun, specialized laboratory testing should be used to confirm the diagnosis of RMSF. 
  
  
   
  
 
                
 
Laboratory Confirmation 
                
R. rickettsii infects the endothelial cells that line blood vessels, and does not circulate in large numbers in the blood unless the patient has progressed to a very severe phase of infection. For this reason, blood specimens (whole blood, serum) are not always useful for detection of the organism through polymerase chain reaction (PCR) or culture. If the patient has a rash, PCR or immunohistochemical (IHC) staining can be performed on a skin biopsy taken from the rash site. This test can often deliver a rapid result. These tests have good sensitivity (70%) when applied to tissue specimens collected during the acute phase of illness and before antibiotic treatment has been started, but a negative result should not be used to guide treatment decisions. PCR, culture, and IHC can also be applied to autopsy specimens (liver, spleen, kidney, etc) collected after a patient dies. Culture of R. rickettsii is only available at specialized laboratories; routine hospital blood cultures cannot detect R. rickettsii. 
                
During RMSF infection, a patient’s immune system develops antibodies to R. rickettsii, with detectable antibody titers usually observed by 7-10 days after illness onset. It is important to note that antibodies are not detectable in the first week of illness in 85% of patients, and a negative test during this time does not rule out RMSF as a cause of illness. 
                
The gold standard serologic test for diagnosis of RMSF is the indirect immunofluorescence assay (IFA) with R. rickettsii antigen, performed on two paired serum samples to demonstrate a significant (four-fold) rise in antibody titers. The first sample should be taken as early in the disease as possible, preferably in the first week of symptoms, and the second sample should be taken 2 to 4 weeks later. In most RMSF cases, the first IgG IFA titer is typically low or negative, and the second typically shows a significant (fourfold) increase in IgG antibody levels. IgM antibodies usually rise at the same time as IgG near the end of the first week of illness and remain elevated for months or even years. Also, IgM antibodies are less specific than IgG antibodies and more likely to result in a false positive. For these reasons, physicians requesting IgM serologic titers should also request a concurrent IgG titer. 
                
Both IgM and IgG levels may remain elevated for months or longer after the disease has resolved, or may be detected in persons who were previously exposed to antigenically related organisms. Up to 10% of currently healthy people in some areas may have elevated antibody titers due to past exposure to R. rickettsii or similar organisms. Therefore, if only one sample is tested it can be difficult to interpret, whereas two paired samples taken weeks apart demonstrating a significant (four-fold) rise in antibody titer provide the best evidence for a correct diagnosis of RMSF. For more in-depth information about testing, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm 
                
 
Treatment 
                
Doxycycline is the first line treatment for adults and children of all ages and should be initiated immediately whenever RMSF is suspected.  
                
Use of antibiotics other than doxycycline is associated with a higher risk of fatal outcome. Treatment is most effective at preventing death if doxycycline is started in the first 5 days of symptoms. Therefore, treatment must be based on clinical suspicion alone and should always begin before laboratory results return or symptoms of severe disease, such as petechiae, develop. 
                
If the patient is treated within the first 5 days of the disease, fever generally subsides within 24-72 hours. In fact, failure to respond to doxycycline suggests that the patient’s condition might not be RMSF. Severely ill patients may require longer periods before their fever resolves, especially if they have experienced damage to multiple organ systems. Resistance to doxcycline or relapses in symptoms after the completion of the recommended course of treatment have not been documented. 
                
Recommended Dosage
Doxycycline is the first line treatment for adults and children of all ages: 
 
 - Adults: 100 mg every 12 hours 
 - Children under 45 kg (100 lbs): 2.2 mg/kg body weight given twice a day 
 
                
Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement. Standard duration of treatment is 7-14 days. 
Treating Children 
                
The use of doxycycline to treat suspected RMSF in children is standard practice recommended by both CDC and the AAP Committee on Infectious Diseases. Use of antibiotics other than doxycycline increases the risk of patient death. Unlike older tetracyclines, the recommended dose and duration of medication needed to treat RMSF has not been shown to cause staining of permanent teeth, even when five courses are given before the age of eight. Healthcare providers should use doxycycline as the first-line treatment for suspected Rocky Mountain spotted fever in patients of all ages. 
Other Treatments 
                
In cases of life threatening allergies to doxycycline and in some pregnant patients for whom the clinical course of RMSF appears mild, chloramphenicol may be considered as an alternative antibiotic. Oral forumulations of chloramphenicol are not available in the United States, and use of this drug carries the potential for other adverse risks, such as aplastic anemia and Grey baby syndrome. Furthermore, the risk for fatal outcome is elevated in patients who are treated with chloramphenicol compared to those treated with doxycycline. Other antibiotics, including broad spectrum antibiotics are not effective against R. rickettsii, and the use of sulfa drugs may worsen infection. 
Prophylaxis (Preventive Treatment) 
                
Antibiotic treatment following a tick bite is not recommended as a means to prevent RMSF. There is no evidence this practice is effective, and may simply delay onset of disease. Instead, persons who experience a tick bite should be alert for symptoms suggestive of tickborne illness and consult a physician if fever, rash, or other symptoms of concern develop. 
                
For more in-depth information about treatment, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm 
                
 
Other Considerations 
                
The clinical presentation for RMSF can also resemble other tickborne diseases, such as ehrlichiosis and anaplasmosis. Similar to RMSF, these infections respond well to treatment with doxycycline. Healthcare providers should order diagnostic tests for additional agents if the clinical history and geographic association warrant. For more in-depth about other similar tickborne diseases, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm