Excerpt from Rocky Mountain Spotted Fever

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Background

All rickettsioses are classified as zoonoses with arthropods as the natural host. The rickettsiae organisms causing the spotted fever group of diseases are tick-borne with transovarial and transstadial passage. Humans are accidental hosts.

Rocky Mountain spotted fever (RMSF) is the most commonly reported rickettsial disease. It is caused by the obligate intracellular pathogen, Rickettsia rickettsii. Initial descriptions of the disease, then referred to as "black measles," date back to 1896 in the Snake River Valley of Idaho. Not until the early 1900s did Howard T. Ricketts (who ironically died of the rickettsial disease, typhus, in 1910) identify the causative agent, while the geographic distribution of the disease grew throughout the midwest region of the country. Contrary to its name, the disease has been reported throughout the United States, with the exceptions of Maine and Vermont.

Despite advances in health care and effective treatment options, RMSF remains a killer for a small percentage of those affected. As a prevalent and potentially fatal infection, RMSF is an important condition to recognize, especially because of the difficult clinical diagnosis and the lack of a variety of sensitive and specific diagnostic tests available in the acute stage.

Pathophysiology

Endothelial cells are important components of vessel walls that function to provide vascular tone, angiogenesis, and proper inflammatory responses and to aid in normal hemostasis. Because of the tropism of R rickettsii for the endothelium, the organism spreads centripetally, cell to cell via filopodia propulsion, resulting in injury to the microcirculation (small-to-medium–sized vessels) of various organ systems with little host response. The organism is able to replicate within the nucleus or cytoplasm of host cells. R rickettsii attaches to and invades the vascular endothelial and smooth muscle cells of many organs, including the brain, liver, skin, lungs, kidneys, and gastrointestinal tract, which may lead to major complications.

The pulmonary interstitial pneumonia, which may complicate RMSF, may be the direct result of pulmonary microcirculation vasculitis. Similarly, vascular injury–induced myocardial edema has emerged as the likely cause of myocarditis occurring with RMSF. Portal triaditis and vasculitis have been found in liver specimens during postmortem examination. Vascular injury of the pancreas and the gastrointestinal tract, including the stomach, the small intestine, and the colon, may result in nausea, vomiting, diarrhea, and abdominal cramping. The emergence of such common and nonspecific gastrointestinal symptoms early in the disease may lead to diagnostic confusion.

Infected endothelial cells display an activated phenotype causing hemostatic system changes that may result in severe coagulopathies. Up-regulation of gene expression for proinflammatory and procoagulation proteins occurs. Activation of the coagulation cascade with thrombin production, platelet activation, increased antifibrinolytic factors, and anticoagulant factor consumption leads to a hypercoagulable state. Note that most patients with RMSF will have thrombocytopenia and abnormal liver function test results as a consequence of these system disruptions. Infected endothelial cells also generate oxygen free radicals. Leaking of blood through vessel walls into adjacent tissue creates the rash for which RMSF is known.

Frequency

United States

RMSF is the most common fatal tick-borne disease in the United States. Approximately 1253 cases occurred from 1993-1996, which calculates to an annual incidence of 2.2 cases per million persons. Although RMSF has been a reportable illness with data compiled by the US Centers for Disease Control and Prevention (CDC) since the 1920s, the number of cases may be grossly underreported considering some infections with R rickettsii may be subclinical. Approximately 45-52% of confirmed cases come from the South Atlantic region of the United States, with Oklahoma, Tennessee, North Carolina, and South Carolina ranking highest. Of note, the Rocky Mountain states have only contributed to approximately 3% of total reported cases in recent years. Approximately 90% of cases occur between April and September.

International

Canada, Mexico, Central America, Colombia, and Brazil are all areas with widespread infection by R rickettsii; however, the vectors differ. The principal vector in South America is Amblyomma cajennense, whereas Rhipicephalus sanguineous is the primary vector in Mexico and Central America. Dermacentor variabilis (American dog tick) and Dermacentor andersoni (Rocky Mountain wood tick) are widely spread throughout the United States, while only the latter predominates in Canada.

Mortality/Morbidity

In general, males, whites, and children are the groups mostly likely to be afflicted. Although the incidence is lowest for the population older than 70 years, the case-fatality rate of 9% is the highest. It is lowest among adults aged 40-49 years at 0.6%. The overall annual case-fatality rate is 1.1-4.9%. Although it is a nationally surveyed illness, this number may be an underrepresentation because discrepancies exist between independent sources of RMSF mortality data. With appropriate treatment, the mortality rate ranges from 3-5%. Without treatment, and prior to the advent of tetracycline and chloramphenicol, the mortality rate was as high as 30%. If antibiotic therapy is delayed for more than 5 days from symptom onset, the case-fatality ratio is 3-4 times higher.

Race

Although whites are more likely to become affected with the disease, the mortality rate among African Americans is higher compared with whites. This may be due, in part, to the high percentage (22-66%) of dark-skinned individuals who do not experience a rash when infected with R rickettsii. The lack of a rash has been associated with mortality, possibly because of the delay in diagnosis and treatment. In addition, approximately 10% of American black males have from glucose-6-phosphate dehydrogenase deficiency, the presence of which has been linked to a more severe course of illness and fatality from RMSF.

Sex

Males have a higher incidence and higher rate of more severe disease compared with females.

Age

Children aged 5-9 years have the highest incidence in the United States. An estimated 3.3 cases per million occur in this age group, whereas only 1.4 cases per million occur in people older than 70 years.

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