Rickettsial Infections Heat Up in the US

The bacteria that cause rickettsial infections are gram-negative, obligate intracellular organisms.¹ Spotted fever rickettsial (SFR) diseases constitute the majority of rickettsial infections in the United States, and all rickettsial infections are notifiable diseases in the US. This means all documented cases must be reported to the local health department.

SFR infections in the US are commonly caused by Rickettsia rickettsii, transmitted by the dog tick (Dermacentor variabilis); Rickettsia parkeri, transmitted by the Gulf Coast tick (Amblyomma maculatum); or Rickettsia akari, transmitted by the bite of an infected mouse mite (Liponyssoides sanguineus).² All rickettsial infections are most prevalent in the warmer summer months (May-August). In the US, Rocky Mountain spotted fever (RMSF), caused by R rickettsii, is the most dangerous of the rickettsial infections. There were more than 5000 cases of RMSF in the US in 2019, slightly lower than the peak in 2017 of more than 6000 cases. However, rates of all rickettsial diseases have steadily increased from 2000 to 2017.³ Individuals older than 40 years and younger than 10 years have the highest risk for acquiring and dying from RMSF, respectively. In 2019, the highest number of SFR cases was seen in individuals 60 years and older.⁴ Fortunately, the fatality rate for RMSF is much lower than in the previous century, before tetracycline antibiotics (the agent of choice) were discovered, but it remains as high as 30% in untreated individuals.^4-6

Other rickettsial infections in the US include anaplasmosis, ehrlichiosis, and typhus. Anaplasmosis is more commonly found in the midwestern and northeast US, and cases have been rising over the past 20 years. Anaplasma phagocytophilum is also transmitted by Ixodes scapularis ticks. The mortality rate for these infections is less than 1%.⁷

There are 3 ehrlichial infections common in the US: Ehrlichia chaffeensis and Ehrlichia ewingii transmitted by the lone star tick (Amblyomma americanum) found in the southeast US from Texas to Delaware, and E muris, more commonly transmitted by the I scapularis tick, with cases being discovered in Wisconsin in 2009. The highest prevalence of ehrlichia is in the Oklahoma, Kansas, Arkansas, and Missouri region, with cases extending east from there. Ehrlichia cases do not seem to be fatal; no cases have been reported to the Centers for Disease Control and Prevention (CDC).⁸ Lastly, typhus is caused by Rickettsia typhi (mouse flea), and Rickettsia prowazekii (lice) in the US, although R prowazekii is relatively uncommon. Typhus caused by R typhi is most commonly found in California, Hawaii, and Texas and the incubation period is 5 to 14 days.⁹ It can lead to hospitalizations but has low mortality.

PATHOPHYSIOLOGY AND TRANSMISSION

Rickettsial infections are transmitted by the bite of an infected vector (eg, lice, ticks, or fleas). In individuals bitten by a tick with one of the SFR species, the disease starts a couple of days after the bite and rapidly progresses. It potentially lead to necrosis of the digits or limbs and the need for amputation.

R prowazekii is transmitted person-to-person via body lice, but other rickettsial infections have rodents as the natural reservoirs.10 R rickettsii and Orientia tsutsugamushi ( found only in Southeast Asia)¹¹ can recur years after the primary infection, despite antibiotic therapy.^12,13

When an individual is bitten by an infected vector, the bacteria travel through the lymphatic system and invade host cells to replicate by fission. They move cell to cell without damaging host cells, but cells are damaged via free radical injury, and there is enzymatic damage to cells that line blood vessels, which leads to leaky vessels. Increased permeability of membrane causes loss of protein, and the inflammatory response (vasculitis) leads to vasodilation, which also increases vascular permeability. This will cause edema and hypovolemia. If the brain or lungs are involved, there is no way to drain the fluid. Death is due to organ failure, often of the liver or kidneys.¹⁴

For individuals with RMSF, within 2 weeks most will experience a spotted rash that starts on the wrists and ankles, which can then spread to palms, soles, and trunk. The rash will become raised, and it may be possible to see petechiae in the center. Without treatment, the mortality rate is approximately 25% but could be as high as 85%. Rates are closer to 5% in those receiving treatment, but delayed treatment can increase the risk of mortality. RMSF disproportionally affects individuals with darker skin, at least in part because providers find it difficult to evaluate rashes on dark-pigmented skin.¹⁵

DIAGNOSIS

The key to diagnosing a rickettsial infection is knowing the patient’s exposure risks. Patients typically present with vague symptoms such as a headache, fever, and/or gastrointestinal upset. These are symptoms that could be mistaken for a variety of other infections if exposure isn’t known. Since the average incubation period for rickettsial infections is approximately 2 to 14 days, individuals who were infected while traveling may not develop symptoms until returning home, adding to the diagnostic challenge.¹⁶

Diagnostic tests may include immunofluorescence assays (IFAs), which detect IgG and IgM. These are very sensitive and specific for detection of antibodies early in the course of the disease (> 7 days after exposure) but are expensive and require training to perform. IFAs may not be available in areas with less access to health care technology. The same is true for the enzyme-linked immunosorbent assay (ELISA), although this method does allow for screening of many samples at once. Both IFA and ELISA can have cross-reactivity among rickettsiae species.16 In addition, E chaffeensis and E ewingii cannot be distinguished from each other with serologic testing.¹⁷ Molecular testing in the form of polymerase chain reaction is another promising diagnostic tool that can provide more rapid results than serology or culture.¹⁷

The future of diagnosis may include whole-genome sequencing, which is highly sensitive and specific and can detect more species than current technology allows.¹⁷

PREVENTION

Individuals and pets should be checked for ticks after being outside. No vaccine is currently available for any rickettsial infections. A vaccine was attempted in the 1920s, however, it was time-consuming to create and only led to a milder disease in those exposed, rather than preventing disease. A subsequent vaccine produced in chicken egg embryos also was ineffective at preventing disease, but it did result in a less severe illness in those who did become infected. A live attenuated vaccine using human R prowazekii was developed during World War II but 14% of those vaccinated developed the disease despite the vaccine showing long-lasting immunity.¹⁸

At this time, avoiding vectors—ticks, fleas, and lice—is the most important method of prevention. To avoid typhus, individuals should not reside in crowded areas, when possible. Maintaining distance from animal reservoirs is also important. Awareness of the risk of specific infections in a region can help travelers or immigrants to that region prepare properly.

TREATMENT

Because rickettsiae are obligate intracellular organisms, antibiotics that achieve intracellular concentrations are needed for effective treatment. Tetracycline-type antibiotics are the most effective and preferred treatment agents for rickettsial diseases. There have been historical concerns about using tetracyclines in children younger than 8 years for fear of staining the teeth or weakening the tooth enamel.⁶ Tetracyclines are lifesaving drugs in the case of SFR and are recommended even for children. More recent research into the adverse effects has shown that short courses of the drugs are unlikely to cause any harm to children.¹⁹

FUTURE OF RICKETTSIAL INFECTIONS

Increasing temperatures as a result of climate change can increase the survival and active periods for ticks that transmit rickettsial infections. This may increase the prevalence of ticks in areas where they are already established, as well as increase their habitable environments and allow for increased activity. Climate changes also affect ticks’ reproduction rates and the reservoirs for these organisms (often rodents). Prolonged warm seasons may lead to human hosts being in the outdoors for longer portions of the year as well.20,21 Mass migration, due to changes in climate that affect agriculture and livability of certain regions, also can have an impact on the spread of infectious diseases.²² Overcrowding, which is seen in some refugee camps, can lead to the spread of louse-borne typhus, which travels person to person.

As climate changes, we will see shifts in the distribution of these pathogens, as they expand into currently uninhabitable regions. For example, it is proposed that anaplasmosis, babesiosis, and ehrlichiosis will expand northward from their current endemic regions in the northeast into and beyond Rhode Island.²³ Lyme disease has already spread from the Northeast US into Canada, and increasing temperatures are cited as the main influence. Lyme disease is proposed to spread farther northward as the climate changes and northern latitudes become increasingly warmer. In addition, as warmer temperatures begin earlier in the year, people may be more likely to encounter ticks because they will be able to be outdoors for an extended period of time.²⁴

Lastly, R prowazekii also is considered a suitable agent for biowarfare. It was developed into an aerosolized version as a biologic weapon in the 1930s by the Soviet Union and was tested as a biowarfare agent.¹⁸ Although categorized as a category B biologic agent by the CDC, to date it has not been used in biowarfare.²⁵

Although rickettsial infections usually are limited to specific regions, it is important for all health care providers to be aware of the presenting signs and symptoms, as well as the risk factors a patient may have. Luckily, the treatment for all rickettsial infections is simple with a tetracycline antibiotic.

References

1. Walker DH. Rickettsiae. In: Baron S, ed. Medical Microbiology. 4th ed. University of Texas Medical Branch at Galveston; 1996. Accessed June 1, 2022. http://www.ncbi.nlm.nih.gov/books/NBK7624/

2. Rickettsialpox. NYC Health. Accessed May 31, 2022. https://www1.nyc.gov/site/doh/health/health-topics/rickettsialpox.page

3. Ehrlichiosis: epidemiology and statistics. CDC. August 4, 2021. Accessed May 27, 2022. https://www.cdc.gov/ehrlichiosis/stats/index.html

4. RMSF: Epidemiology and statistics. CDC. August 3, 2021. Accessed May 27, 2022. https://www.cdc.gov/rmsf/stats/index.html

5. Fill MMA, Moncayo AC, Bloch KC, Dunn JR, Schaffner W, Jones TF. Evaluation of a spotted fever group Rickettsia public health surveillance system in Tennessee. Am J Trop Med Hyg. 2017;97(3):789-794. doi:10.4269/ajtmh.16-0765

6. Research on doxycycline and tooth staining. CDC. February 19, 2019. Accessed May 31, 2022. https://www.cdc.gov/rmsf/doxycycline/index.html

7. Anaplasmosis: epidemiology and statistics. CDC. August 6, 2021. Accessed May 27, 2022. https://www.cdc.gov/anaplasmosis/stats/index.html

8. Ehrlichiosis: epidemiology and statistics. CDC. August 4, 2021. Accessed May 31, 2022. https://www.cdc.gov/ehrlichiosis/stats/index.html

9. Typhus. Virginia Department of Health. December 2018. Accessed May 31, 2022. https://www.vdh.virginia.gov/epidemiology/epidemiology-fact-sheets/typhus/

10. Osterloh A. The neglected challenge: vaccination against rickettsiae. PLoS Negl Trop Dis. 2020;14(10):e0008704. doi:10.1371/journal.pntd.0008704

11. Chakraborty S, Sarma N. Scrub typhus: an emerging threat. Indian J Dermatol. 2017;62(5):478-485. doi:10.4103/ijd.IJD_388_17

12. Parola P, Raoult D. Tropical rickettsioses. Clin Dermatol. 2006;24(3):191-200. doi:10.1016/j.clindermatol.2005.11.007

13. Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev. 1997;10(4):694-719. doi:10.1128/CMR.10.4.694

14. Sahni A, Fang R, Sahni S, Walker DH. Pathogenesis of rickettsial diseases: pathogenic and immune mechanisms of an endotheliotropic infection. Annu Rev Pathol. 2019;14:127-152. doi:10.1146/annurev-pathmechdis-012418-012800

15. Lester JC, Taylor SC, Chren MM. Under-representation of skin of colour in dermatology images: not just an educational issue. Br J Dermatol. 2019;180(6):1521-1522. doi:10.1111/bjd.17608

16. Husin NA, AbuBakar S, Khoo JJ. Current tools for the diagnosis and detection of spotted fever group Rickettsia. Acta Trop. 2021;218:105887. doi:10.1016/j.actatropica.2021.105887

17. Abdad MY, Abou Abdallah R, Fournier PE, Stenos J, Vasoo S. A concise review of the epidemiology and diagnostics of rickettsioses: Rickettsia and Orientia spp. J Clin Microbiol. 2018;56(8):e01728-17. doi:10.1128/JCM.01728-17

18. Walker DH. The realities of biodefense vaccines against Rickettsia. Vaccine. 2009;27(suppl 4):D52-55. doi:10.1016/j.vaccine.2009.07.045

19. Todd SR, Dahlgren FS, Traeger MS, et al. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever. J Pediatr. 2015;166(5):1246-1251. doi:10.1016/j.jpeds.2015.02.015

20. Bouchard C, Dibernardo A, Koffi J, Wood H, Leighton PA, Lindsay LR. N Increased risk of tick-borne diseases with climate and environmental changes. Can Commun Dis Rep Releve Mal Transm Au Can. 2019;45(4):83-89. doi:10.14745/ccdr.v45i04a02

21. El-Sayed A, Kamel M. Climatic changes and their role in emergence and re-emergence of diseases. Environ Sci Pollut Res Int. 2020;27(18):22336-22352. doi:10.1007/s11356-020-08896-w

22. Coates SJ, Norton SA. The effects of climate change on infectious diseases with cutaneous manifestations. Int J Womens Dermatol. 2021;7(1):8-16. doi:10.1016/j.ijwd.2020.07.005

23. Jannelle Couret PhD, M. E. M., and B. S. N. Jason Garrett. Potential Effects of Climate Change on tick-borne diseases in Rhode Island. Rhode Island Medical Journal 104.9 (2021): 29-33.

24. Bouchard C, Dibernardo A, Koffi J, Wood H, Leighton PA, Lindsay LR. N Increased risk of tick-borne diseases with climate and environmental changes. Can Commun Dis Rep. 2019;45(4):83-89. Published 2019 Apr 4. doi:10.14745/ccdr.v45i04a02

25. Bioterrorism agents/diseases. CDC. May 15, 2019. Accessed May 31, 2022. https://emergency.cdc.gov/agent/agentlist-category.asp