Rickettsial Infection

Etiology

Rickettsial infections are caused by a variety of obligate intracellular bacteria in the genus Rickettsia and are grouped into one of four categories: spotted fever group, typhus group, ancestral group, and transitional group.[3] Rickettsia rickettsii causes Rocky Mountain spotted fever, the most severe and most well-known of the rickettsial infections in North America.[4] However, it is important to recognize that other species are common in other parts of the world, including Rickettsia africae, the cause of African tick bite fever in sub-Saharan Africa, and Rickettsia conorii which causes Mediterranean spotted fever in Europe and North Africa. Rickettsia prowazekii and Rickettsia typhi present as typhus syndromes. Researchers continue to discover new species of Rickettsia as molecular techniques advance.[5]

Epidemiology

Rickettsia is typically vector-borne, transmitted by ticks, body lice, mites, and fleas.[6] In most cases, humans are thought to be accidental hosts. The transmitting ticks vary depending on the region and organism, with Dermacentor variabilis (American dog tick), Dermacentor andersoni (Rocky Mountain wood tick), and Amblyomma americanum (Lone Star tick) associated with most cases of Rocky Mountain spotted fever in the United States. Alternatively, Amblyomma cajennense has been associated with spotted fever in South America and Amblyomma hebraeum or Amblyomma variegatum in South Africa.[7] Because of the association with ticks and other vectors, infections with rickettsiae are more common during warmer months and in people exposed to outdoor activities. Epidemic typhus, R. prowazekii, is transmitted by body lice and is associated with crowded conditions and poor hygiene. Murine typhus (R. typhi) is most commonly reported in tropical and subtropical areas and is associated with flea bites.[8]

Pathophysiology

Rickettsia preferentially infects the vascular endothelial cells lining the small and medium vessels throughout the body, causing the systemic symptoms and high mortality seen with these infections. The infection of endothelial cells leads to disseminated inflammation, loss of barrier function, and altered vascular permeability throughout the body.[6] Consequently, those infected develop fever, myalgias, central nervous system symptoms such as a headache and confusion, rash, and cardiovascular instability. Mortality can occur in severe cases of infection. The mechanisms involved in the rapid entry of the organism into the cell and the downregulation of immune pathways allowing for persistence of infection are being studied to identify new therapeutic targets.

History and Physical

Patients typically present with symptoms four to ten days after exposure to the Rickettsia species via a flea or tick bite. Symptoms classically include the triad of fever, headache, and a petechial or maculopapular rash. Symptoms also may include lymphadenopathy, central nervous system changes such as confusion and nuchal rigidity, an eschar at the inoculation site, myalgias and arthralgias, hepatitis, vomiting, and cardiovascular instability.[9] It is important to have a high index of suspicion for rickettsial infection when patients present with these "influenza-like" symptoms during the summer months, regardless of known tick or insect exposure (the tick or insect exposure may be brief and unnoticed by the patient).[10] Importantly, the classic triad of symptoms is largely consistent across Rickettsia species, although clinical judgment as to a specific etiology can be refined based on geographic exposure and specific symptoms. A detailed history of travel and outdoor exposure is essential in diagnosing the specific cause of these symptoms.

Evaluation

Currently, most rickettsial infections are diagnosed based on serologic response, such as IgG and IgM to R. rickettsiae, in conjunction with a high degree of clinical suspicion. While rickettsia can be cultured in a microbiology laboratory, this approach is not often used for clinical diagnosis because the technique is difficult and requires a high level of biosafety containment due to the risk of exposure. Other diagnostic options include molecular tests, such as PCR, in some centers and skin biopsy.[11] In addition to suggestive or positive serologic tests, patients with rickettsial infections can have thrombocytopenia, hyponatremia, and cerebrospinal fluid pleocytosis. On a peripheral white blood cell count, it is important to note that this may be elevated, normal, or low and thus may not help to rule out rickettsial infection. A high index of suspicion is crucial given the high morbidity and mortality associated with rickettsial infection and the potential for negative serologic testing early in the course of illness. Negative tests should not preclude treatment if the clinical suspicion for rickettsial infection is high.[12]

Treatment / Management

The drug of choice for treating rickettsial infections is doxycycline, with the dosing and length of therapy depending on the specific causative organism. In the case of allergy and severe disease, chloramphenicol is an option. In milder disease, macrolides such as clarithromycin can be considered. Fluoroquinolones have been associated with worse outcomes and are not recommended for the treatment of rickettsial disease. It is important to note that in severe rickettsial disease, such as Rocky Mountain spotted fever, mortality rates are as high as 20 to 30% without prompt antibiotic treatment. Additionally, while doxycycline is not routinely utilized in children younger than 8 years of age, it is indicated for certain rickettsial infections in this age group due to the high mortality associated with the severe rickettsial disease. Thus, treatment should not be delayed while awaiting confirmatory laboratory testing in a patient with a suspected rickettsial infection.[13]

Differential Diagnosis

• Dengue

• Emergent management of malaria

• Group A streptococcal infection

• Kawasaki disease

• Leptospirosis

• Measles

• Meningococcal infection

• Pediatric rubella

• Pediatric syphilis

• Pediatric toxic shock syndrome

• Vasculitis and thrombophlebitis

Prognosis

Rickettsial infections vary in severity based on the virulence of the Rickettsia species and host factors, such as the degree of immunocompetence. R rickettsii and R prowazekii are considered the most virulent species and are associated with significant mortality if the infected individual is not diagnosed and treated early. For example, patients with Rocky Mountain spotted fever have mortality rates are as high as 30% without prompt diagnosis and antibiotic treatment. Appropriate antibiotics started in the first week of the patient's illness are very effective and are associated with excellent outcomes.[13]

Complications

As with prognosis, complications depend on the Rickettsia species and host factors. If a patient receives a prompt diagnosis and proper treatment, complications are uncommon. Possible long-term sequelae include gangrene, hearing loss, bowel or bladder incontinence, and partial paralysis of the lower extremities.[5]