Rickettsial infection

Rickettsial infections are caused by a variety of obligate intracellular bacteria in the genus Rickettsia and are grouped into one of four categories: the spotted fever group rickettsiae, typhus group rickettsiae, the ancestral group, and the transitional group ¹. Rickettsia species cause Rocky Mountain spotted fever, rickettsialpox, other spotted fevers, epidemic typhus, and murine typhus. Orientia (formerly Rickettsia) tsutsugamushi causes scrub typhus. Rickettsia rickettsii causes Rocky Mountain Spotted Fever, the most severe and most well known of the rickettsial infections in North America. 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 ².

While the clinical presentations of rickettsial infection are similar, the causative species and epidemiology can vary depending on the region. It is important to recognize both the typical symptoms and the epidemiology of a given region to correctly diagnose and treat these infections promptly, as they can be associated with significant morbidity and mortality ³.

Rickettsia is a group of vector-borne organisms that cause acute febrile illnesses throughout the world. Patients present with febrile exanthems and visceral involvement; symptoms may include nausea, vomiting, abdominal pain, encephalitis, hypotension, acute renal failure, and respiratory distress. Rickettsiae include the genera Rickettsiae, Ehrlichia, Orientia, and Coxiella ⁴. The genus Rickettsia is included in the bacterial tribe Rickettsiae, family Rickettsiaceae, and order Rickettsiales. Rickettsia are obligate intracellular Gram-negative coccobacillary bacteria that multiply within eukaryotic cells in ticks, lice, fleas, mites, chiggers, and mammals ⁴. Rickettsiae do not stain well with Gram stain, but they take on a characteristic red color when stained by the Giemsa or Gimenez stain. They have typical gram-negative cell walls and lack flagella. Their genome is very small, composed of 1-1.5 million bases ⁵.

Spotted fever rickettsiae (15 rickettsioses)

• Rocky Mountain spotted fever, caused by Rickettsia rickettsii
• Rickettsialpox, caused by Rickettsia akari
• Boutonneuse fever (ie, Kenya tick-bite fever, African tick typhus, Mediterranean spotted fever, Israeli spotted fever, Indian tick typhus, Marseilles fever)

Typhus group rickettsiae

These are similar diseases that differ epidemiologically. The causative organisms (Rickettsia prowazekii and Rickettsia typhi) are similar to those of the spotted fever group but are antigenically distinct.

• Louse-borne (epidemic) typhus
• Brill-Zinsser disease (ie, relapsing louse-borne typhus)
• Murine (endemic or flea-borne) typhus

Scrub typhus biogroup (Tsutsugamushi disease)

The rickettsial agents of scrub typhus have a single taxonomic name: Orientia tsutsugamushi. However, these organisms represent a heterogeneous group that strikingly differs from Rickettsial species of the spotted fever and typhus groups. The 3 major serotypes are Karp, Gilliam, and Kato.

Other rickettsioses and closely related illnesses

• New or reemerging rickettsioses have been described in the last few decades, including tickborne lymphadenopathy and Dermacentor -borne-necrosis-eschar-lymphadenopathy related to Rickettsia slovaca infection, as well as lymphangitis-associated rickettsiosis attributed to Rickettsia sibricia infection ⁵. Recently, a new Rickettsia species, 364D, that causes an eschar-associated illness was identified in California ⁶.
• Ehrlichia organisms (the cause of human monocytic ehrlichiosis and Ehrlichia ewingii infection), Anaplasmaphagocytophilum (the cause of human granulocytic anaplasmosis), and Bartonella species (the cause of Catscratch disease, relapsing fever, and Trench fever) are organisms related to the rickettsiae.

Rickettsial infection causes

Rickettsia is typically vector-borne, transmitted by ticks, body lice, and fleas. In most cases, humans are thought to be accidental hosts ¹. 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. Because of the association with ticks and other vectors, infections with Rickettsiae are more common during warmer months and in people exposed to the outdoor and outdoor activities. Epidemic typhus, Rickettsia prowazekii, is transmitted by body lice and associated with crowded conditions and poor hygiene. Murine typhus (Rickettsia typhi) is most commonly reported in tropical and subtropical areas and is associated with flea bites ⁷.

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 diseases. The infection of endothelial cells leads to disseminated inflammation, loss of barrier function and altered vascular permeability throughout the body. This leads to the fever, myalgias, central nervous system symptoms such as a headache and confusion, rash, and cardiovascular instability that can be seen in patients with rickettsial infection, as well as leading to mortality in severe cases. The mechanisms involved in the rapid entry of the organisms into the cell and the downregulation of immune pathways allowing for persistence of infection are being studied to identify new therapeutic targets in these illnesses.

Rickettsial infection prevention

Prevention of Rickettsial infection relies on avoidance of exposure to tick and flea bites, particularly when residing or traveling to endemic areas. There is currently not a vaccine for prevention of Rocky Mountain Spotted Fever or other Rickettsial infections and antibiotic prophylaxis is not routinely recommended in the United States. Careful checks for insects after outdoor activities and use of long-sleeved clothing and insect repellant are all advised to a minimum the risk of rickettsial infection.

Preventing tick bites

Tick exposure can occur year-round, but ticks are most active during warmer months (April-September). Know which ticks are most common in your area.

Before you go outdoors

• Know where to expect ticks. Ticks live in grassy, brushy, or wooded areas, or even on animals. Spending time outside walking your dog, camping, gardening, or hunting could bring you in close contact with ticks. Many people get ticks in their own yard or neighborhood.
• Treat clothing and gear with products containing 0.5% permethrin. Permethrin can be used to treat boots, clothing and camping gear and remain protective through several washings. Alternatively, you can buy permethrin-treated clothing and gear.
• Use Environmental Protection Agency (EPA)-registered insect repellents (https://www.epa.gov/insect-repellents) containing DEET, picaridin, IR3535, Oil of Lemon Eucalyptus (OLE), para-menthane-diol (PMD), or 2-undecanone. EPA’s helpful search tool (https://www.epa.gov/insect-repellents/find-repellent-right-you) can help you find the product that best suits your needs. Always follow product instructions. Do not use products containing OLE or PMD on children under 3 years old.
• Avoid Contact with Ticks
  • Avoid wooded and brushy areas with high grass and leaf litter.
  • Walk in the center of trails.

After you come indoors

• Check your clothing for ticks. Ticks may be carried into the house on clothing. Any ticks that are found should be removed. Tumble dry clothes in a dryer on high heat for 10 minutes to kill ticks on dry clothing after you come indoors. If the clothes are damp, additional time may be needed. If the clothes require washing first, hot water is recommended. Cold and medium temperature water will not kill ticks.
• Examine gear and pets. Ticks can ride into the home on clothing and pets, then attach to a person later, so carefully examine pets, coats, and daypacks.
• Shower soon after being outdoors. Showering within two hours of coming indoors has been shown to reduce your risk of getting Lyme disease and may be effective in reducing the risk of other tickborne diseases. Showering may help wash off unattached ticks and it is a good opportunity to do a tick check.

Check your body for ticks after being outdoors. Conduct a full body check upon return from potentially tick-infested areas, including your own backyard. Use a hand-held or full-length mirror to view all parts of your body. Check these parts of your body and your child’s body for ticks:

• Under the arms
• In and around the ears
• Inside belly button
• Back of the knees
• In and around the hair
• Between the legs
• Around the waist

Rickettsial infection symptoms

Patients typically present with symptoms four to ten days after exposure to the Rickettsia via a flea or tick bite. Symptoms classically include the triad of fever, headache, and a petechial or maculopapular rash. Symptoms may also include lymphadenopathy, central nervous system changes such as confusion or nuchal rigidity, an eschar at the inoculation site, myalgias and arthralgias, hepatitis, vomiting, and cardiovascular instability. 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, as the tick or insect exposure may be brief and unnoticed by the patient. Importantly, the classic triad of symptoms is largely consistent across rickettsial species, although clinical judgments as to specific etiologies can be refined based on geographic exposure and specific symptoms. A detailed history of travel and other outdoor exposure is essential in diagnosing the specific cause of these symptoms.

Rickettsial infection diagnosis

Currently, most rickettsial infections are diagnosed based on serologic responses, such as IgG and IgM to R. rickettsiae, in conjunction with a high degree of clinical suspicion. While rickettsia can be cultured in the microbiology laboratory, this approach is not often used for clinical diagnosis as 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. In addition to suggestive or positive serologic tests, patients with rickettsial infections may also 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 testing should not preclude treatment if the clinical scenario is suggestive of rickettsial infection due to symptoms and exposure history.

Rickettsial infection treatment

The drug of choice for Rickettsial infections is doxycycline, with the dosing and length of therapy dependent on the specific causative organism ¹. In the case of allergy and severe disease, chloramphenicol may also be an option. In milder disease, macrolides such as clarithromycin may also be considered. Fluoroquinolones have been associated with worsened outcomes and are not recommended for the treatment of rickettsial disease. It is important to note than 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 age 8, 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 suspected rickettsial infection.

References

1. Snowden J, King KC. Rickettsial Infection. [Updated 2019 Jun 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431127
2. Dehhaghi M, Kazemi Shariat Panahi H, Holmes EC, Hudson BJ, Schloeffel R, Guillemin GJ. Human Tick-Borne Diseases in Australia. Front Cell Infect Microbiol. 2019;9:3.
3. Adem PV. Emerging and re-emerging rickettsial infections. Semin Diagn Pathol. 2019 May;36(3):146-151.
4. Walker DH. Rickettsiae. In: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 38. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7624
5. Walker DH. Rickettsiae and rickettsial infections: the current state of knowledge. Clin Infect Dis. 2007 Jul 15. 45 Suppl 1:S39-44.
6. Johnston SH, Glaser CA, Padgett K, Wadford DA, Espinosa A, Espinosa N, et al. Rickettsia spp. 364D causing a cluster of eschar-associated illness, California. Pediatr Infect Dis J. 2013 Sep. 32 (9):1036-9.
7. Khamesipour F, Dida GO, Anyona DN, Razavi SM, Rakhshandehroo E. Tick-borne zoonoses in the Order Rickettsiales and Legionellales in Iran: A systematic review. PLoS Negl Trop Dis. 2018 Sep;12(9):e0006722