Endemic Typhus

                                                    by Munawar Sultana                                                     

Name of disease: Murine Typhus (Endemic)

Etiologic agents: Rickettsia typhi, and R. felis (formerly called the ELB agent).1, 3, 12

Reservoirs: rats, opussums, domestic cats, 2 raccoons, and skunks. 3

Transmission: Murine typhus is a zoonotic disease that is transmitted by arthropod vectors. Transmission of R. typhi occurs through the rat flea Xenopsylla cheopsis, and the rat louse, Polyplax spinulosa. 3 R. felis is transmitted by the cat flea Ctenocephalides felis (the cat flea inhabits cats, opussums, raccoons and skunks). 3 The classic rodent-flea cycle involves rats (Rattus rattus and R. norvegicus) and their fleas (X. cheopsis), but in certain areas (Texas), the opussum- cat flea cycle is more common. The etiologic agents, R. typhi and R. felis, both have been reported in opussums and their fleas. 13 The Rickettsiae are highly adapted to their arthropod vector host, and have co-evolved with the vector (symbiotic relationship). 13

The transmission cycle involves the transfer of pathogen from an animal reservoir into the flea vector along with a blood meal (the blood of the animal has the pathogen). After gaining entry into the vector, the pathogen grows inside the midgut epithelial cells, and is excreted in the feces.3, 5 Transmission to the human host generally occurs when the feces of the flea is rubbed into the bite area, or any other cut/abrasion on the skin of the host. Transmission may also occur by inhalation of dried flea feces, or by rubbing of the flea feces on mucus membranes such as conjunctiva .2, 3

General characteristics: Rickettsia typhi, an obligate intracellular parasite, is a gram-negative, aerobic, coccobacillus belonging to the family Rickettsiaceae (order Rickettsiales, Class Alphaproteobacteria, Phylum Proteobacteria).4, 10 It is much smaller in size (0.3µm to 1.0µm) than other gram-negative bacteria. 7 It grows within host cells by metabolizing glutamate. 4 Rickettsiae cannot be cultured axenically. They can be grown in cell culture, embryonated eggs, or in experimental animals.4

Key tests for identification: Routine histological staining methods cannot be used to identify Rickettsiae. They can be observed only by special staining techniques (Giemsa or Gimenez staining techniques).6 Isolation of the pathogen by culture can be done during the acute stage of illness. 1 However, culture of organisms is generally not undertaken, instead serological tests are often used.7 Biopsy of skin lesions for the purpose of Immunofluorescence Assay or Immunohistological staining may help to diagnose the disease, but cannot confirm the etiologic agent. 6, 7 Laboratory tests that are usually performed for confirming the pathogen (by detecting antibodies against R. typhi) are Indirect Fluorescent Antibody (IFA) assay, solid phase immunoassay, latex agglutination, Complement Fixation (CF), and PCR. 3, 5, 6, 9 However, serologic response to R. typhi antigen may be delayed by more than a week until the patient mounts a considerable immune response.6

Historical Information:

·         An American microbiologist, Hans Zinsser (1878 – 1940), developed a vaccine (made of killed rickettsiae) against Typhus in 1934. 4

·         The family Rickettsiaceae is named after the American pathologist, Howard Taylor Ricketts (1871 – 1910) who discovered the Rickettsia sp. that caused Rocky Mountain Spotted Fever, and Epidemic Typhus. 8

Signs and Symptoms: The clinical signs and symptoms that are manifested about 1 to 2 weeks after infection include fever, headache, nausea, and muscle pain. 5, 6, 7, 11 A rash (maculopapular or petechial) may be observed on the trunk, axilla, and other parts of the body, except the face, palms, and soles. 6, 7 Preliminary diagnosis of the disease is often made based on clinical signs and symptoms, along with epidemiological characteristics such as the patient’s occupation and surroundings, and exposure to reservoirs and vectors. 6, 7, 9 A fourfold increase in antibody titer, or a single convalescent titer of ≥ 128 is indicative of the disease. 3, 9

Microbial virulence mechanisms and pathogenesis:

After the rickettsiae gain entry into the human body, they spread through the blood and attach to the vascular endothelium of various organs of the body such as skin, gastrointestinal tract, liver, kidney, heart, lungs, and brain by means of adhesins (ligands on the outer membrane).7 Adherence to the endothelial cells stimulates phagocytosis, but the pathogen subsequently escapes from the phagosome (before it fuses with a lysosome), into the cytoplasm. 4, 7, 10 Escape from the phagosome may be facilitated through the action of an enzyme, phospholipase A2. 4, The pathogen multiplies rapidly in the cytoplasm (by binary fission), as a result of which the cell bursts or undergoes lysis, releasing the pathogens to invade other cells.4, 7, 11 The enzymes phospholipase D, and hemolysin C, secreted by the pathogen, are reported to be involved in the lysis of cells. 11

Damage to endothelial cells contributes to the pathophysiology of the disease. Pathophysiological effects include increased vascular permeability leading to edema and low blood volume, hypoalbuminemia (low albumin levels in blood serum), hypotension, and reduced perfusion of different organs followed by organ dysfunction.7, 11

Treatment:

Treatment is usually initiated based on clinical diagnosis. Delay in treatment may prolong the disease and lead to hospitalization of affected individuals. 1, 2, 9 Confirmation of disease is done later based on laboratory tests (acute stage serum does not contain antibodies to pathogen). Antibiotic treatment with Tetracyclines (especially Doxycycline), and chloramphenicol is effective.1, 10, 11 Doxycycline acts by blocking protein synthesis (binds to 30S ribosomal subunits) in the pathogen, 6 and dosage for adults is 200 mg daily for 3 – 14 days (2.2 mg/kg body weight per dose, twice a day (oral/intravenous), for children weighing < 100 lbs). 1

Most cases of murine typhus that are diagnosed early, and treated with antibiotics recover quickly (usually afebrile within 3 days) indicating positive prognosis.3, 6 Complications may occur due to delayed diagnosis, and severity of disease may be observed in elderly patients. 3 The mortality rate for treated patients ranges from 1 to 4%. 6

Prevention:

Currently vaccines are not available for preventing the disease.1 Due to the presence of long lasting immunity in individuals after a single attack of the disease, 2. 3 7 there is potential scope for vaccine development.7 Prevention measures basically include control of vector (fleas) and the reservoir host (mostly rodents) 1, 7, 9 Reducing exposure to fleas and animal reservoirs in endemic areas has also been suggested 1, 9

Current Outbreaks (Local and Global):

Murine Typhus disease is reported to occur in tropical and sub-tropical areas worldwide. 1 In the United States, the disease is endemic in certain areas of California, Hawaii, and Texas 9. During the 1940’s, 2000 to 5000 disease cases (especially in Southeastern and Gulf coast states) were reported annually, but incidence of the disease has declined due to rat control measures. 14 There was a recent outbreak of murine typhus (involving R. typhi) in the Austin area during March to October, 2008, and 33 confirmed cases were reported to the CDC. 9 In 2006, six cases of Murine Typhus were reported in California. 17 In 2002, there was an outbreak in Hawaii, where 47 cases were reported. 15 Earlier to this, there was an outbreak in the Texas area during 1981-1982, when 49 cases were reported.14

With respect to the current outbreak of the disease worldwide, a recent outbreak of Murine Typhus occurred in Nepal, in 2001, where 50% of 756 disease cases were found to have antibodies against R. typhi confirmed by PCR. 19 There was an outbreak in Portugal in 1996, and several cases showed the presence of antibodies to R.typhi.16 In 1978, there was an outbreak of this disease in Kuwait, and 254 cases were reported by the World Health Organization. 18

References:

1. Adjemian, Jennifer, Marina E. Eremeeva, and Gregory A. Dasch. “Rickettsial (spotted and typhus fevers) and related infections (Anaplasmosis and Ehrlichiosis).” Centers for Disease Control and Prevention. 3 September 2010. National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention. 2 Dec. 2010.

http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-5/rickettsial-and-related-infections.aspx

 

2. “Murine Typhus.” Texas Department of State Health Services. 11 Feb. 2010. Zoonosis Control Branch (Infectious Disease Control Unit), Texas Department of State Health Services. 2 Dec. 2010.

http://www.dshs.state.tx.us/idcu/disease/murine_typhus/information/

 

3. Baxter, John, D. “The Typhus Group.” Clinics in Dermatology. 14.3 (1996):271-278. Web. 5 Dec. 2010.

http://www.sciencedirect.com.ezproxy.lib.utexas.edu/science?_ob=ArticleListURL&_method=list&_ArticleListID=1568577287&_sort=r&_st=13&view=c&_acct=C000059713&_version=1&_urlVersion=0&_userid=108429&md5=2f98c6b5ea1e6dafa3bb6ef7736cc7a7&searchtype=a

 

4. Todar, Kenneth. “Rickettsial diseases, including Typhus and Rocky Mountain Spotted Fever.”Todar’s Online Textbook of Bacteriology. 2009. Todar’s Online Textbook of Bacteriology. 2 Dec. 2010.

http://www.textbookofbacteriology.net/Rickettsia.html

 

5. Mayer, Gene. “Rickettsia, Orientia, Ehrlichia, Anaplasma, Coxiella, and Bartonella.” Microbiology and Immunology Online. 15 April 2010. Microbiology and Immunology Online, University of South Carolina School of Medicine. 2. Dec. 2010. http://pathmicro.med.sc.edu/mayer/ricketsia.htm

 

6. Okulicz, Jason, F., Mark S. Rasnake, Eric A. Hansen, and Burke A. Cunha. “Typhus.” Emedicine/Medscape. 18 Sep. 2008. Emedicine/Medscape. 2 Dec. 2010.

http://emedicine.medscape.com/article/231374-diagnosis

 

7. Baron, Samuel, ed. Medical Microbiology. Galveston: University of Texas Medical Branch at Galveston, 1996. 3 Dec. 2010. http://www.ncbi.nlm.nih.gov/books/NBK8270/

 

8. “Howard T. Ricketts,” Encyclopedia Brittanica. 2010. Encyclopedia Brittanica Online. 3 Dec. 2010. http://www.britannica.com/EBchecked/topic/502939/Howard-T-Ricketts

 

9. Adjemian, Jennifer, Sharyn Parks, Kristina McElroy, Jill Campbell, Marin E. Eremeeva, William L. Nicholson, Jennifer McQuiston, and Jeffery Taylor. “ Murine Typhus in Austin, Texas, USA, 2008.” Emerging Infectious Diseases 16.3 (2010): 412-417. Web. 3 Dec. 2010. http://www.cdc.gov/eid/content/16/3/412.htm

 

10. Tortora, Gerard J., Berdell R. Funke, and Christine L. Case. Microbiology: An Introduction. New York: Benjamin Cummings, 2010. Print.

 

11. Rathore, Mobeen, H, and Nizar F. Maraqa. “Rickettsial Infection.” Emedicine/Medscape.11 May 2009. Emedicine/Medscape. 5 Dec. 2010. http://emedicine.medscape.com/article/968385-overview

 

12. “Bacteria genomes – Rickettsia felis.” European Bioinformatics Institute. 2010. European Bioinformatics Institute. 5 Dec. 2010. http://www.ebi.ac.uk/2can/genomes/bacteria/Rickettsia_felis.html

 

13. Azad, Abdu, F., and Charles B. Beard. “Rickettsial pathogens and their arthropod vectors.” Emerging Infectious Diseases 4.2 (1998). Web. 6 Dec. 2010.

http://www.cdc.gov/ncidod/eid/vol4no2/ascii/aza.txt

 

14. “Outbreak of Murine Typhus – Texas.” Morbidity and Mortality Weekly Report 32.9 (1983): 131-132.Web. 6.Dec. 2010 http://www.cdc.gov/mmwr/preview/mmwrhtml/00001270.htm

 

15. “Murine Typhus – Hawaii 2002.” Morbidity and Mortality Weekly Report 52.50 (2003): 1224 – 1226. Web. 6. Dec. 2010. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5250a2.htm

 

16. “Vector-borne human infections of Europe.” World Health Organization. 2004. World Health Organization (Europe). 6 Dec. 2007 http://www.euro.who.int/__data/assets/pdf_file/0008/98765/e82481.pdf

 

17. “Investigation of a Murine Typhus outbreak in a Metropolitan area.” American Public Health Association. 2007. American Public Health Association. 6 Dec. 2010.

 

18. Al-Awadi, Abdul Rahman, Nouri Al-Kazemi, Gaffar Ezzat, Alfred J. Saah, Charles Shepard, Talaat Zaghloul, and Beatriz Gherdian. “Murine Typhus in Kuwait in 1978.” Bulletin of the World Health Organization 60.2 (1982): 283 – 289. Web. 6. Dec. 2010. http://whqlibdoc.who.int/bulletin/1982/Vol60-No2/bulletin_1982_60%282%29_283-289.pdf

 

19. Zimmerman, Mark, D., David R. Murdoch, Patrick J. Rosmaszl, Buddha Basnyat, Christopher W. Woods, Allen R. Richards, Ram Hari Belbase, David A. Hammer, Trevor P. Anderson, and L. Barth Reller. “Murine Typhus and Febrile Illness, Nepal.” Emerging Infectious Diseases 14.10 (2008). Web. 6 Dec. 2010. http://www.cdc.gov/eid/content/14/10/1656.htm