Rocky Mountain spotted fever overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Overview

Rocky Mountain spotted fever is the most severe and most frequently reported rickettsial illness in the United States, and 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 should not be confused with the viral tick-borne infection, Colorado tick fever.

The disease is caused by Rickettsia rickettsii, a species of bacteria that is spread to humans by ixodid ticks (Dermacentor). Initial signs and symptoms of the disease include sudden onset of fever, headache, and muscle pain, followed by development of a 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 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, and occurs as far north as Canada and as far south as 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% to 5% of individuals who become ill with Rocky Mountain spotted fever still 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 persons infected with R. rickettsii died.

Historical Perspective

Rocky Mountain spotted fever was first recognized in 1896 in the Snake River Valley of Idaho and was originally called “black measles." For a great part of American history, the rash was dreaded as a frequently fatal disease in this endemic region. By the early 1900s, the recognized geographic distribution of this disease grew to encompass parts of the United States as far north as Washington and Montana and as far south as California, Arizona, and New Mexico. After much anticipation and failure to cure the disease, there was finally a breakthrough in 1922. In Western Montana (1922) an Assistant Surgeon, R.R. Spencer, inoculated himself with a mixture of mush ticks and carboxylic acids to which later began the development of a vaccine for the disease.

Classification

There is currently no classification system established for Rocky Mountain Spotted Fever.

Pathophysiology

Rocky Mountain Fever is caused by a bacterial organism of the Rickettsia genus known as Rickettsia ricketsii. The organism is a Gram-negative bacteria, ranging in sizes between 0.2 x 0.5 micrometers to 0.3 x 2.0 micrometers. Rickettsia ricketsii is non-spore forming, non- motile, and varies in shape. Early in it's life cycle, Rickettsia ricketsii survives within an invertebrate host. The invertebrate host may then transmit the organism through blood meals, open skin, and breakages in mucous barriers. The disease is most often transmitted through arthropod vectors, especially the hard tick- Ixodidae family. Rickettsia ricketsii requires an invertebrate vector and vertebrate host. Humans are considered an accidental host within the R. ricketsii life cycle. The organism has evolved a set of strategic mechanisms in order to evade the human immune system. Infection begin with an induced phagocytosis of the organism into an endothelial host cell. Usually endothelial cells are not phagocytic, however R. ricketsii is able to induce changes to the overall cytoskeleton of the cell. Invasion goes largely unnoticed, enabling the organism to avoid lysosomal fusion and an escape into the cytoplasm for future reproduction.

Epidemiology & Demographics

Incidents of Rocky Mountain Spotted Fever date back to the earlier history of the United States. Since the 1920's the United States Center for Disease Control and Prevention has deemed Rocky Mountain Spotted Fever as a reportable disease. RMSF cases were most often reported within the Rocky Mountain region, although recent data reveals that the disease is widespread throughout the United States. Areas that currently harbor the majority of RMSF infections are Oklahoma, Tennessee, and Arkansas. The disease has also been reported throughout the Western Hemisphere.

Incidents are highest among children the between the ages of 5-9 years and adults between the ages of 40-64 years. Fatality rates are also higher among these groups, with the highest fatality rate in the elderly at 60 years or more. In terms of demographics, Rocky Mountain Spotted Fever has been reported at higher rates among males, especially of White and Native American descent.

Risk Factors

The primary risk factors associated with Rocky Mountain Spotted Fever are exposure to endemic environment and the time of that exposure. Wood Ticks have been identified as the primary vector of rocky mountain spotted fever infections, thus being bitten in an endemic area may result in the contraction of the disease.

Causes

Rickettsia rickettsii (abbreviated as R. rickettsii) is a unicellular, Gram-negative coccobacillus (plural coccobacilli) that is native to the New World. It belongs to the spotted fever group (SFG) of Rickettsia and is most commonly known as the causative agent of Rocky Mountain spotted fever (RMSF). By nature, R. rickettsii is an obligate intracellular parasite that survive by an endosymbiotic relationship with other cells.

R. rickettsii is a non-motile, non-spore forming aerobic organism. Cells are typically 0.3–0.5 × 0.8–2.0 μm in size. They lack a distinct nucleus and membrane bound organelles. Their outer membrane is composed mostly of lipopolysaccharides.

RMSF is transmitted by the bite of an infected tick while feeding on warm-blooded animals, including humans. Humans are considered to be accidental hosts in the Rickettsia–tick life cycle and are not required to maintain the rickettsiae in nature.

Differentiating Rocky Mountain Spotted Fever from Other Diseases

Rocky Mountain Spotted Fever must be differentiated from other diseases that cause fever, headaches, muscle pain, and rash. In virtually all cases, Rocky Mountain spotted fever presents with a rash. When trying to differentiate RMSF from other infections, it should be noted that there has been a rare case in which RMSF has presented itself without the typical rash. Examples of misdiagnosed, rickettsiae caused, diseases include typhus-spotted fevers and Ehrlichiosis. Other misdiagnoses include pox diseases and acne.When diagnosing Rocky Mountain spotted fever it's important to account for patient history such as exposure to endemic regions and a history of tick bites. Although immunofluorescence assays, polymerase chain reactions, and immuno-staining remain the most effective ways of determining a Rocky Mountain Spotted Fever infection.

Natural History, Complications & Prognosis

If left untreated patients with Rocky Mountain Spotted Fever will undergo three developmental stages of infection. The early stages of infection begin within 2-14 days of inoculation by an infected tick and present themselves as a fever, nausea, vomiting, and a severe headache. Late stage progression of symptoms will result in a maculopapular rash, abdominal and joint pain. Further progression of the disease, if left untreated, will result in the following complications; gangrene, pulmonary complications, ARDS, cerebral edema as well as other long term complications. Ultimately, if Rocky Mountain Spotted Fever progresses entirely untreated, it will conclude in the patient's death. With a fatality rate as high as 87%, without antibiotic intervention.

History & 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. Early onset symptoms typically associated with Rocky Mountain Spotted Fever include fever, nausea, vomiting, and headache. Abnormal laboratory findings seen in patients with Rocky Mountain spotted fever may include thrombocytopenia, hyponatremia, or elevated liver enzyme levels.

Clinical manifestations

Early-stage lesions of RMSF

The Centers for Disease Control and Prevention states that the diagnosis of RMSF must be made based on the clinical signs and symptoms of the patient and later confirmed using specialized laboratory tests. However, the diagnosis of RMSF is often missed due to its non-specific onset. The clinical signs and symptoms that a patient may experience could appear and may be misdiagnosed as other diseases even by the most experienced physician.

Initial signs and symptoms

• During the initial stages of the disease, the patient will experience fever, nausea, vomiting, and loss of appetite.

Rash

• The classic RMSF rash occurs in about 90% of patients and develops 2 to 5 days after the onset of fever.
• The characteristic rash appear as small, flat pink macules that develop peripherally on the patient's body, such as the wrists, forearms, ankles, and feet.
• During the course of the disease, the rash will take on a more darkened red to purple spotted appearance and a more generalized distribution.

Late signs and symptoms

Diarrhea, abdominal and joint pain, and pinpoint reddish lesions (petechiae) are observed during the late stages of the disease.

Long-term implications

Patients with severe infections may require hospitalization. They may become thrombocytopenic, hyponatremic, experience elevated liver enzymes, and other more pronounced symptoms. It is not uncommon for severe cases to involve the respiratory system, central nervous system, gastrointestinal system or the renal system. This disease is worst for elderly patients, males, African-Americans, alcoholics, and patients with G6PD deficiency.

Diagnosis and treatment

Physician diagnosis

A proper physician's diagnosis is crucial during the early stages of RMSF. However, due to the fact that the signs and symptoms are very non-specific at onset, RMSF can often be misdiagnosed. For this reason, it is vital for a physician to treat the patient based on suspicion alone.

Laboratory confirmation

Rocky Mountain Spotted Fever is often diagnosed using an indirect immunofluorescence assay (IFA), which is considered the reference standard by the Centers for Disease Control and Prevention (CDC). The IFA will detect an increase in IgG or IgM antibodies.

A more specific lab test used in diagnosing RMSF is polymerase chain reaction or PCR which can detect the presence of rickettiae DNA.

Immunohistochemical (IHC) staining is another diagnostic approach where a skin biopsy is taken of the spotted rash; however, sensitivity is only 70%.

Antibiotics

Doxycycline and Chloramphenicol are the most common drugs of choice for reducing the symptoms associated with RMSF. When it is suspected that a patient may have RMSF, it is crucial that antibiotic therapy be administered promptly. Failure to receive antibiotic therapy, especially during the initial stages of the disease, may lead to end-organ failure (heart, kidney, lungs, meningitis, brain damage, shock, and even death.