Rocky Mountain spotted fever 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.

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.

History

Rocky Mountain spotted fever first emerged in the Idaho Valley in 1896. At that time, not much information was known about the disease; it was originally called Black Measles because patients had a characteristic spotted rash appearance throughout their body.

Howard Ricketts (1871–1910) was an American pathologist and infectious disease researcher who was the first to identify and study the organism that causes Rocky Mountain spotted fever. He received his undergraduate degree in zoology from the University of Nebraska and his medical degree from Northwestern University School of Medicine. Ricketts completed his internship at Cook County Hospital in Chicago, IL, followed by a fellowship in pathology and cutaneous diseases at Rush Medical College.

In 1902, Ricketts became the associate professor of pathology at the University of Chicago. The trademark rash, which first appeared in the Idaho Valley, now began to slowly emerge in the Bitterroot Valley region, a highly influential area in western Montana and had an 80–90% mortality rate. During his tenure as associate professor, Ricketts was funded and recruited by the University of Chicago, the State of Montana, and the American Medical Association to conduct research on Rocky Mountain spotted fever.

His research entailed interviewing victims of the disease and collecting and studying infected animals. He was also known to inject himself with pathogens to measure its effects.

Ricketts was also known for his research on typhus, which was very similar to spotted fever. Ironically, days after isolating the organism that he believed to cause typhus, he died. It was speculated that his death was likely caused from an insect bite.

S. Burt Wolbach is credited for the first detailed description of the etiologic agent in 1919. He clearly recognized it as an intracellular bacterium which was seen most frequently in endothelial cells. He was struck by the fact that in the tick, and also in mammalian cells, the microorganism was intranuclear. The nucleus was often completely filled with minute particles and often was distended. Although Wolbach recognized its similarity to the agent of typhus and tsutsugamushi fever (scrub typhus), he did not regard the designation 'rickettsia' as appropriate. He proposed the name Dermacentroxenus rickettsi. Dr. Emile Brumpt felt that the etiologic agent of RMSF, despite some uncertainty about its properties, belonged in the genus Rickettsia and in 1922 proposed the name Rickettsia rickettsii.

Pathogen life cycle

The life cycle of Rickettsia rickettsii is considered to be a complex one. Survival is dependent on both an invertebrate vector, (the hard tick- Family Ixodidae) and a vertebrate host (including mice, dogs, rabbits). Humans are considered to be accidental vectors and are not essential in the rickettsial cycle. In addition, a sequence of events occur between both hosts in the successful transmission of rickettsial disease.

Rickettsia rickettsii mostly affects canines and humans.

Transmission in arthropod vectors

Three arthropod vectors in the United States have been identified in transmitting R. rickettsii to humans, causing the potentially fatal disease Rocky Mountain Spotted Fever. The American dog tick (Dermacentor variabilis), the Rocky Mountain Wood Tick (Dermacentor andersoni), and the Brown dog tick (Rhipicephalus sanguineus) can acquire Rickettsia rickettsii in a number of different ways.

First, an uninfected tick can become infected when feeding on the blood of an infected mammalian host in the larval or nymph stages, a mode of transmission called transstadial transmission. Once a tick becomes infected with this pathogen, they are infected for life. Both the American dog tick and the Rocky Mountain wood tick serve as long-term reservoirs for Rickettsia rickettsii, in which the organism resides in the tick posterior diverticulae of the midgut, the small intestine and the ovaries.

Due to its confinement in the midgut and small intestine, it is possible for mammals, including humans, to contract rickettsial disease from open skin/wound contact with the feces of the organism. In addition, an infected male tick can transmit the organism to an uninfected female during mating. Once infected, the female tick can transmit the infection to her offspring, in a process known as transovarial transmission.

Transmission in mammals

An uninfected mammal can become infected with Rickettsia rickettsii when eating food that contains the feces of the infected tick. They can also be infected through the bite of an infected tick.

Humans acquire Rickettsia rickettsii infection from infected vectors. After getting bitten by an infected tick, rickettsiae are transmitted to the bloodstream by tick salivary secretions or, as mentioned previously, through contamination of broken skin by infected vector feces.

All these modes of transmission ensures the survival of Rickettsia in nature.

R. rickettsii have evolved a number of strategical mechanisms or virulence factors that allow them to evade the host immune system and successfully infect the host.

Epidemiology

The name Rocky Mountain spotted fever is somewhat of a misnomer. Cases of Rocky Mountain spotted fever have been reported in every continent except Antarctica, and in every state in the U.S. except for Alaska, and Hawaii.

Approximately 90% of all infections occur within the months of April to September, the time period in which adult and nymphal ticks are the highest. The areas of the U.S. with the greatest reported cases of RMSF are the mid to south Atlantic states, including DE, MD, DC, VA, WV, NC, SC.

It is estimated that approximately 1200 or more new cases of RMSF will present on a yearly basis.

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.

References