Life Cycle

Figure 1: Life cycle of Rocky Mountain Fever

Figure 2: Pathogenesis of the rickettsial agents illustrating unique aspects of their interactions with eukaryotic cells.

Disease Scenario:¹⁹

Figure 3: Rocky Mountain Fever in United Country

The bacteria Rickettsia rickettsii that causes RMSF is transmitted by the dog tick (Dermacentor variabilis) in the eastern United States and by the wood tick (Dermacentor andersoni) in the Rocky Mountain states. On the West Coast, the lone star tick (Amblyomma americanum) also can transmit the RMSF gets its name from the trademark rash it causes small red spots and blotches that begin on the wrists, ankles, palms and soles Rickettsiae are small, Gram-negative bacilli that have evolved in such close association with arthropod hosts that they are adapted to survive within the host cells².

Table 2: Distribution of Rocky Mountain Fever in various Regions

Country/Region	Extrapolated Incidence	Population Estimated Used
Rocky Mountain spotted fever in North America (Extrapolated Statistics)
USA	625	293,655,405
Canada	69	32,507,874
Rocky Mountain spotted fever in Europe (Extrapolated Statistics)
Austria	17	8,174,762
Belgium	22	10,348,276
Britain (United Kingdom)	128	60,270,708 for UK
Czech Republic	2	1,0246,178
Denmark	11	5,413,392
Finland	11	5,214,512
France	128	60,424,213
Greece	22	10,647,529
Germany	175	82,424,609
Iceland	0	293,966
Hungary	21	10,032,375
Liechtenstein	0	33,436
Ireland	8	3,969,558
Italy	123	58,057,477
Luxembourg	0	462,690
Monaco	0	32,270
Netherlands (Holland)	34	16,318,199
Poland	82	38,626,349
Portugal	22	10,524,145
Spain	85	40,280,780
Sweden	19	8,986,400
Switzerland	15	7,450,867
United Kingdom	128	60,270,708
Wales	6	2,918,000
Rocky Mountain spotted fever in the Balkans (Extrapolated Statistics)
Albania	7	3,544,808
Bosnia and Herzegovina	0	407,608
Croatia	9	4,496,869
Macedonia	4	2,040,085
Serbia and Montenegro	23	10,825,900
Rocky Mountain spotted fever in Asia (Extrapolated Statistics)
Bangladesh	300	141,340,476
Bhutan	4	2,185,569
China	2,764	1,298,847,624
East Timor	2	1,019,252
Hong Kong s.a.r.	14	6,855,125
India	2,267	1,065,070,607
Indonesia	507	238,452,952
Japan	271	127,333,002
Laos	12	6,068,117
Macau s.a.r.	0	445,286
Malaysia	50	23,522,482
Mongolia	5	2,751,314
Philippines	183	86,241,697
Papua New Guinea	11	5,420,280
Vietnam	175	82,662,800
Singapore	9	4,353,893
Pakistan	338	159,196,336
North Korea	48	22,697,553
South Korea	102	48,233,760
Sri Lanka	42	19,905,165
Taiwan	48	22,749,838
Thailand	138	64,865,523
Rocky Mountain spotted fever in Eastern Europe (Extrapolated Statistics)
Azerbaijan	16	7,868,385
Belarus	21	10,310,520
Bulgaria	16	7,517,973
Estonia	2	1,341,664
Georgia	9	4,693,892
Kazakhstan	32	15,143,704
Latvia	4	2,306,306
Lithuania	7	3,607,899
Romania	47	22,355,551
Russia	306	143,974,059
Slovakia	11	5,423,567
Slovenia	4	2,011,473
Tajikistan	14	7,011,556
Ukraine	101	47,732,079
Uzbekistan	56	26,410,416
Rocky Mountain spotted fever in Australasian and Southern Pacific (Extrapolated Statistics)
Australia	42	19,913,144
New Zealand	8	3,993,817
Rocky Mountain spotted fever in the Middle East (Extrapolated Statistics)
Afghanistan	60	28,513,677
Egypt	162	76,117,421
Gaza strip	2	1,324,991
Iran	143	67,503,205
Iraq	54	25,374,691
Israel	13	6,199,008
Jordan	11	5,611,202
Kuwait	4	2,257,549
Lebanon	8	3,777,218
Libya	11	5,631,585
Saudi Arabia	54	25,795,938
Syria	38	18,016,874
Turkey	146	68,893,918
United Arab Emirates	5	2,523,915
West Bank	4	2,311,204
Yemen	42	20,024,867
Rocky Mountain spotted fever in South America (Extrapolated Statistics)
Belize	0	272,945
Brazil	391	184,101,109
Chile	33	15,823,957
Colombia	90	42,310,775
Guatemala	30	14,280,596
Mexico	223	104,959,594
Nicaragua	11	5,359,759
Paraguay	13	6,191,368
Peru	58	27,544,305
Puerto Rico	8	3,897,960
Venezuela	53	25,017,387
Rocky Mountain spotted fever in Africa (Extrapolated Statistics)
Angola	23	10,978,552
Botswana	3	1,639,231
Central African Republic	7	3,742,482
Chad	20	9,538,544
Congo Brazzaville	6	2,998,040
Congo kinshasa	124	58,317,030
Ethiopia	151	71,336,571
Ghana	44	20,757,032
Kenya	70	32,982,109
Liberia	7	3,390,635
Niger	24	11,360,538
Nigeria	37	12,5750,356
Rwanda	17	8,238,673
Senegal	23	10,852,147
Sierra leone	12	5,883,889
Somalia	17	8,304,601
Sudan	83	39,148,162
South Africa	94	44,448,470
Swaziland	2	1,169,241
Tanzania	76	36,070,799
Uganda	56	26,390,258
Zambia	23	11,025,690
Zimbabwe	7	1,2671,860

They represent a rather diverse collection of bacteria and therefore listing characteristics that apply to the entire group is difficult. The common threads that hold the rickettsiae into a group are their epidemiology, their obligate intracellular lifestyle and the laboratory technology required to work with them. In the laboratory, rickettsiae cannot be cultivated on agar plates or in broth, but only in viable eukaryotic host cells (e.g., in cell culture, embryonated eggs, or susceptible animals). The exception, which shows the artificial nature of using obligate intracellular parasitism as a defining phenotypic characteristic, is Bartonella (Rochalimaea) quintana, which is cultivable axenically, but was traditionally considered as a rickettsia³. The diversity of rickettsiae is demonstrated in the variety of specific intracellular locations where they live and the remarkable differences in their major outer membrane proteins and genetic relatedness. An example of extreme adaptation is that the metabolic activity of Coxiella burnetii is greatly increased in the acidic environment of the phagolysosome, which is a harsh location for survival for most other organisms. Obligate intracellular parasitism among bacteria is not unique to rickettsiae. Chlamydiae also have evolved to occupy an intracellular niche and numerous bacteria (e.g., Mycobacteria, Legionella, Salmonella, Shigella, Francisella and Brucella) are facultative intracellular parasites. In contrast with chlamydiae, all rickettsiae can synthesize ATP. Coxiella burnetii is the only rickettsia that appears to have a developmental cycle. Rocky Mountain spotted fever and Mediterranean spotted fever are rickettsial infections primarily of endothelial cells that normally have a potent anticoagulant function. As a result of endothelial cell infection and injury, the hemostatic system is perturbed and shows changes that vary widely from a minor reduction in the platelet count (frequently) to severe coagulopathies, such as deep venous thrombosis and disseminated intravascular coagulation (rarely). Changes favoring a hypercoagulable state include endothelial injury and release of procoagulant components, activation of the coagulation cascade with thrombin generation, platelet activation, increased antifibrinolytic factors, consumption of natural anticoagulants and possibly high levels of coagulation-promoting cytokines. Yet, most studies have been performed on endothelial cell cultures that provide nonphysiologic, reductionistic, experimental conditions. The lack of flow, platelets and WBCs makes these experiments far from simulating the response of endothelial cells in the human body ⁴.

Figure 4: Laboratory methods used in confirming a diagnosis of rickettsial infection.

Epidemiology:

Coxiella burnetii infects a wide variety of ticks, domestic livestock and other wild and domestic mammals and birds throughout the world. Most human infections follow exposure to heavily infected birth products of sheep, goats and cattle, as occurs on farms, in research laboratories and in abattoirs. Coxiella burnetii is also shed in milk, urine and feces of infected animals. Animals probably become infected by aerosol and by the bite of any of the 40 species of ticks that carry the organisms ⁹. Scrub typhus occurs where chiggers infected with virulent rickettsial strains feed upon humans. Leptotrombidium deliense and other mites are found particularly in areas where regrowth of scrub vegetation harbors the Rattus species that are hosts for the mites. Some of these foci are quite small and have been referred to as mite islands ¹⁰. Because tsutsugamushi is transmitted transovarially from one generation of mites to the next, these dangerous areas tend to persist for as long as the ecologic conditions, including scrub vegetation, persist. Truly one of the neglected diseases, scrub typhus occurs over a vast area, including Japan, China, the Philippines, New Guinea, Indonesia, other islands of the southwest Pacific Ocean, southeastern Asia, northern Australia, India, Sri Lanka, Pakistan, Russia and Korea¹¹. Recognized in western countries mainly because of large numbers of infections of military personnel during World War II and the Vietnam War, scrub typhus perennially affects native populations. Reinfection and undiagnosed infections are highly prevalent. Mortality ranges from 0 to 35 percent and has not been correlated with any specific factor¹².

The clinical gravity of Rocky Mountain spotted fever is due to severe damage to blood vessels by R rickettsii. This organism is unusual among rickettsiae in its ability to spread and invade vascular smooth muscle cells as well as endothelium ¹³. Damage to the blood vessels in the skin in locations of the rash leads to visible hemorrhages in one-half of all infected persons. Attempted plugging of vascular wall destruction consumes platelets, with consequent thrombocytopenia also affecting approximately one-half of the patients ¹⁴.

Pathogenesis:

Rickettsia and Orientia species are transmitted by the bite of infected ticks or mites or by the feces of infected lice or fleas. From the portal of entry in the skin, rickettsiae spread via the bloodstream to infect the endothelium and sometimes the vascular smooth muscle cells. Rickettsia species enter their target cells, multiply by binary fission in the cytosol and damage heavily parasitized cells directly. Rickettsiae are transmitted to humans by the bite of infected ticks and mites and by the feces of infected lice and fleas. They enter via the skin and spread through the bloodstream to infect vascular endothelium in the skin, brain, lungs, heart, kidneys, liver, gastrointestinal tract and other organs ¹⁵. Rickettsial attachment to the endothelial cell membrane induces phagocytosis, soon followed by escape from the phagosome into the cytosol Rickettsiae divide inside the cell. Rickettsia prowazekii remains inside the apparently healthy host cell until massive quantities of intracellular rickettsiae accumulate and the host cell bursts, releasing the organisms ¹⁶. In contrast, R rickettsii leaves the host cell via long, thin cell projections (filopodia) after a few cycles of binary fission. Hence, relatively few R rickettsii organisms accumulate inside any particular cell and rickettsial infection spreads rapidly to involve many other cells. Perhaps because of the numerous times the host cell membrane is traversed, there is an influx of water that is initially sequestered in cisternae of cytopathically dilated rough endoplasmic reticulum in the cells more heavily infected with R rickettsii¹⁷.

The bursting of endothelial cells infected with R prowazekii is a dramatic pathologic event. The mechanism is unclear, although phospholipase activity, possibly of rickettsial origin, has been suggested. Injury to endothelium and vascular smooth muscle cells infected by R rickettsii seems to be caused directly by the rickettsiae, possibly through the activity of a rickettsial phospholipase or rickettsial protease or through free-radical peroxidation of host cell membranes. Host immune, inflammatory and coagulation systems are activated and appear to benefit the patient. Cytokines and inflammatory mediators account for an undefined part of the clinical signs. Rickettsial lipopolysaccharide is biologically relatively nontoxic and does not appear to cause the pathogenic effects of these rickettsial diseases. The pathologic effects of these rickettsial diseases originate from the multifocal areas of endothelial injury with loss of intravascular fluid into tissue spaces (edema), resultant low blood volume, reduced perfusion of the organs and disordered function of the tissues with damaged blood vessels (e.g., encephalitis, pneumonitis and hemorrhagic rash). Human Q fever follows inhalation of aerosol particles derived from heavily infected placentas of sheep, goats, cattle and other mammals. Coxiella burnetii proliferates in the lungs, causing atypical pneumonia in some patients. Hematogenous spread occurs, particularly to the liver, bone marrow and spleen. The disease varies widely in severity, including asymptomatic, acute, subacute, or chronic febrile disease, granulomatous liver disease and chronic infection of the heart valves. The target cells are macrophages in the lungs, liver, bone marrow, spleen, heart valves and other organs. Coxiella burnetii is phagocytosed by Kupffer cells and other macrophages and divides by binary fission within phagolysosomes ¹⁸.Apparently it is minimally harmful to the infected macrophages. Different strains have genetic and phenotypic diversity. The lipopolysaccharides are relatively nonendotoxic. Host-mediated pathogenic mechanisms appear to be important, especially immune and inflammatory reactions, such as T-lymphocyte-mediated granuloma formation ¹⁸.

Extrapolation of Incidence Rate for Rocky Mountain spotted fever to Countries and Regions:

The following table attempts to extrapolate the above incidence rate for Rocky Mountain spotted fever to the populations of various countries and regions. As discussed above, these incidence extrapolations for Rocky Mountain spotted fever are only estimates and may have limited relevance to the actual incidence of Rocky Mountain spotted fever in any region

Transmission:

Rocky Mountain spotted fever, ticks are the natural hosts, serving as both reservoirs and vectors of R. rickettsii. Ticks transmit the organism to vertebrates primarily by their bite. Less commonly, infections may occur following exposure to crushed tick tissues, fluids, or tick feces.Only members of the tick family Ixodidae (hard ticks) are naturally infected with Rickettsia rickettsii. These ticks have four stages in their life cycle: egg, larva, nymph and adult. After the eggs hatch, each stage must feed once to develop into the next stage. Both male and female ticks will bite ²⁰.A female tick can transmit R. rickettsii to her eggs in a process called transovarial transmission. Ticks can also become infected with R. rickettsii while feeding on blood from the host in either the larval or nymphal stage. After the tick develops into the next stage, the R. rickettsii may be transmitted to the second host during the feeding process. Furthermore, male ticks may transfer R. rickettsii to female ticks through body fluids or spermatazoa during the mating process ²¹. These types of transmission represent how generations or life stages of infected ticks are maintained. Once infected, the tick can carry the pathogen for life.Rickettsiae is transmitted to a vertebrate host through saliva while a tick is feeding. It usually takes several hours of attachment and feeding before the rickettsiae are transmitted to the host. The risk of exposure to a tick carrying R. rickettsii is low. In general, about 1%-3% of the tick population carries R. rickettsii, even in areas where the majority of human cases are reportedRocky Mountain spotted fever is found throughout the United States, except in Maine, Alaska and Hawaii. Despite the name, few cases are reported from the Rocky Mountain region. Most cases occur in the southeastern United States.Rocky Mountain spotted fever is spread by the American dog tick, the lone-star tick and the wood tick, all of which like to live in wooded areas and tall, grassy fields ²². The disease is most common in the spring and summer when these ticks are active, but it can occur anytime during the year when the weather is warm.This acute, infectious disease is transmitted by ticks. The distinguishing feature is a characteristic rash. With early treatment, most children recover fully and develop permanent immunity. Untreated, however, the disease can be severe. Early medical intervention is thus essential.Rocky Mountain spotted fever, a life-threatening tick-transmittedinfection, is the most prevalent rickettsiosis in the UnitedStates. This zoonosis is firmly entrenched in the tick host,which maintains the rickettsiae in nature by transovarian transmission.Although the incidence of disease fluctuates in various regionsand nationwide, the problems of a deceptively difficult clinicaldiagnosis and little microbiologic diagnostic effort persist ²³.

Diagnosis:

Diagnosis of rickettsial infections is often difficult. The clinical signs and symptoms (e.g., fever, headache, nausea, vomiting and muscle aches) resemble many other diseases during the early stages when antibiotic treatment is most effective. A history of exposure to the appropriate vector tick, louse, flea, or mite is helpful but cannot be relied upon. Observation of a rash, which usually appears on or after day 3 of illness, should suggest the possibility of a rickettsial infection but, of course, may occur in many other diseases also. Knowledge of the seasonal and geographic epidemiology of rickettsioses is useful, but is inconclusive for the individual patient ²⁴. Except for epidemic louse-borne typhus, rickettsial diseases strike mostly as isolated single cases in any particular neighborhood. Therefore, clinico-epidemiologic diagnosis is ultimately a matter of suspicion, empirical treatment and later laboratory confirmation of the specific diagnosis. Because rickettsiae are both fastidious and hazardous, few laboratories undertake their isolation and diagnostic identification. Some laboratories are able to identify rickettsiae by immunohistology in skin biopsies as a timely, acute diagnostic procedure, but to establish the diagnosis physicians usually rely on serologic demonstration of the development of antibodies to rickettsial antigens in serum collected after the patient has recovered. Currently, assays that demonstrate antibodies to rickettsial antigens themselves (e.g., the indirect fluorescence antibody test or latex agglutination) are preferable to the nonspecific, insensitive Weil-Felix test that is based on the cross-reactive antigens of OX-19 and OX-2 strains of Proteus vulgaris ²⁵.

Prevention ^{29, 30, 31}

Figure 5: Removing a tick attached to the skin using fine-tipped tweez

1. Use fine-tipped tweezers or shield your fingers with a tissue, paper towel, or rubber gloves. When possible, persons should avoid removing ticks with bare hands.

2. Grasp the tick as close to the skin surface as possible and pull upward with steady, even pressure. Do not twist or jerk the tick; this may cause the mouthparts to break off and remain in the skin.

3. Do not squeeze, crush, or puncture the body of the tick because its fluids (saliva, body fluids and gut contents) may contain infectious organisms.

4. After removing the tick, thoroughly disinfect the bite site and wash your hands with soap and water.

5. Save the tick for identification in case you become ill. This may help your doctor make an accurate diagnosis. Place the tick in a plastic bag and put it in your freezer. Write the date of the bite on a piece of paper with a pencil and place it in the bag.

6. No vaccine is available to protect humans against Rocky Mountain spotted fever. The best way to avoid getting the disease is to avoid areas such as the woods or fields where ticks are found. If this is not possible, you can reduce your risk by taking these precautions.

7. Control the tick population on your property. Keep pets tick-free. Mow grass often in yards and outside fences.

8. During outside activities in wooded areas and around tall grass, wear long sleeves and long pants tucked into socks.

9. Use insecticides to repel or kill ticks. Repellents containing the compound DEET can be used on exposed skin except for the face, but they do not kill ticks and are not 100% effective in discouraging ticks from biting. Products containing permethrin kill ticks, but they cannot be used on the skin -- only on clothing. When using any of these chemicals, follow label directions carefully. Be especially cautious when using them on children.

10. After outdoor activities, check yourself for ticks and have a "buddy" check you, too. Check body areas where ticks are commonly found: behind the knees, between the fingers and toes, under the arms, in and behind the ears and on the neck, hairline and top of the head. Check places where clothing presses on skin.

11. Remove attached ticks immediately. Removing a tick before it has been attached for more than 4 hours greatly reduces the risk of infection. Use tweezers and grab as closely to the skin as possible. Do not handle ticks with bare hands. Do not try to remove ticks by squeezing them, coating them with petroleum jelly, or burning them with a match.

12. After removing the tick, thoroughly disinfect the bite site and wash your hands. See or call a doctor if you think that tick parts may remain in your skin. If you get a fever, headache, rash, or nausea within 2 weeks of a possible tick bite or exposure, see a doctor right away.

Treatment:

Appropriate antibiotic treatment should be initiated immediately when there is a suspicion of Rocky Mountain spotted fever on the basis of clinical and epidemiologic findings. Treatment should not be delayed until laboratory confirmation is obtained²⁶. If the patient is treated within the first 4-5 days of the disease, fever generally subsides within 24-72 hours after treatment with an appropriate antibiotic (usually a tetracycline). In fact, failure to respond to a tetracycline antibiotic argues against a diagnosis of RMSF. Severely ill patients may require longer periods before their fever resolves, especially if they have experienced damage to multiple organ systems. Prophylactic therapy in non-ill patients who have had recent tick bites is not recommended and may, in fact, only delay the onset of disease. Doxycycline (100 mg every 12 hours for adults or 4 mg/kg body weight per day in two divided doses for children under 45 kg [100 lb.]) is the drug of choice for patients with Rocky Mountain spotted fever. Therapy is continued for at least 3 days after fever subsides and until there is unequivocal evidence of clinical improvement, generally for a minimum total course of 5 to 10 days. Severe or complicated disease may require longer treatment courses. Doxycycline is also the preferred drug for patients with ehrlichiosis, another tick-transmitted infection with signs and symptoms that may resemble Rocky Mountain spotted fever²⁷. Tetracyclines are usually not the preferred drug for use in pregnant women because of risks associated with malformation of teeth and bones in unborn children. Chloramphenicol is an alternative drug that can be used to treat Rocky Mountain spotted fever; however, this drug may be associated with a wide range of side effects including aplastic anemia and may require careful monitoring of blood ²⁸.

CONCLUSION:

Rocky Mountain spotted fever is a disease caused by the bacterium Rickettsia rickettsii which is spread to humans by ticks. Symptoms include the sudden onset of fever, headache and muscle pain followed by the development of a rash.Involvement of multiple organs is also possible because of haematogenous spread. No vaccine is available to protect humans against Rocky Mountain spotted fever but tetracycline, Doxycycline and Chloramphenicol could be useful in controlling the symptoms. The best way to avoid getting the disease is to avoid areas such as the woods or fields where ticks are found. Prevention measures should be aimed at personal protection. Human infections are prevented by control of the vector and reservoir hosts. Massive delousing with insecticide can abort an epidemic of Rocky Mountain spotted fever .

REFERENCE:

1. Helmick CG, Bernard KW, D'Angelo LJ. Rocky Mountain spotted fever: clinical, laboratory and epidemiological features of 262 cases. J Infect Dis. 1984 Oct;150(4):480- 482.

2. Kirkland KB, Marcom PK, Sexton DJ, Dumler JS, Walker DH. Rocky Mountain spotted fever complicated by gangrene: report of six cases and review. Clin Infect Dis. 1993 May; 16(5):629-34.

3. Centers for Disease Control and Prevention. Rocky Mountain spotted fever web site.

4. Sexton DJ, Corey GR. Rocky Mountain "spotless" and "almost spotless" fever: a wolf in sheep's clothing. Clin Infect Dis. 1992 Sep; 15(3):439-48. Abstract

5. Lee N, Ip M, Wong B, et al. Risk factors associated with life-threatening rickettsial infections. Am J Trop Med Hyg 2008 Jun; 78(6):973-8. Abstract

6. Chapman AS, Bakken JS, Folk SM, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses and anaplasmosis -- United States. MMWR. 2006 Mar 31; 55(RR04); 1-27.

7. CDC. Rocky Mountain spotted fever. Prevention and Control.

8. Adal KA, Cockerell CJ, Petri WA: Cat scratch disease, bacillary angiomatosis, and other infections due to Rochalimaea. N Engl J Med, 1994, 330:1509-1515.

9. Drancourt M, Mainardi JL, Brouqui P, et al. Bartonella (Rochalimaea) quintana endocarditis in three homeless men. N Engl J Med , 1995,332:419-423

10. Fishbein DB, Dawson JE, Robinson LE: Human ehrlichiosis in the United States, 1985 to 1990. Ann Int Med, 1994, 120:736-743.

11. Ricketts HT. A micro-organism which apparently has a specific relationship to Rocky Mountain spotted fever. JAMA 1909;52:379–380

12. Hechemy KE, Paretsky D and Walker DH, Mallavia (eds): Rickettsiology: Current Issues and Perspectives. NY Acad Sci, New York, 1990, Vol 590, 124-132.

13. Kaplowitz LG, Fischer JJ, Sparling PF: Rocky Mountain spotted fever: a clinical dilemma. Curr Clin Top Infect Dis, , 1981 2:89-90.

14. Marrie TJ: Q Fever,The Disease. CRC Press, Boca Raton, FL. 1990McDade JE. Newhouse VF: Natural history of Rickettsia rickettsii. Annu Rev Microbiol, 1986 40:287

15. McDade JE, Shepard CC, Redus MA, et al. Evidence of Rickettsia prowazekii infections in the United States. Am J Trop Med Hyg, 1981, 29:277-279.

16. Moulder JW (ed): Intracellular Parasitism. CRC Press, Boca Raton, FL, 1989, 165-169.

17. Walker DH (ed): Biology of Rickettsial Disease. Vols I and II. CRC Press, Boca Raton, FL, 1988, 245-248.

18. Williams WJ, Radulovic S, Dasch GA, et al. Clin Infec Dis , 1994,19:93-99

19. Kirk JL, Fine DP, Sexton DJ, Muchmore HG. Rocky Mountain spotted fever: a clinical review based on 48 confirmed cases, 1994, 199-203.

20. Williams WJ, Radulovic S, Dasch GA, et al. Clin Infec Dis,1994,19:93-99.

21. Wolbach SB, Todd JL, Palfrey FW: Etiology and Pathology of Typhus, 2002, 235-239.

22. The League of Red Cross Societies Harvard Press, Cambridge, Mass, 1922

23. Audy JR (ed): Red Mites and Typhus. University Press, New York, 1968, 285-290.

24. Bakken JS, Dumler JS, Chen S-M, et al. Human granulocytic ehrlichiosis in the upper Midwest United States. A new species emerging? JAMA 272:212-218, 199

25. Brouqui P, Dumler JS, Raoult D: Immunohistologic demonstration of Coxiella burnetii in the valves of patients with Q fever endocarditis. Am J Med,1994, 97:451-453

26. Rowland LP. Bacterial infections. In: Merritt’s Textbook of Neurology.8th ed. Philadelphia: Lea and Febiger, 1989:78–80

27. Miller JQ, Price TR. Involvement of the brain in Rocky Mountain spotted fever. South Med J 1972; 65:437–439.

28. Hornay LF, Walker DH. Meningoencephalitis as a major manifestation of Rocky Mountain spotted fever. South Med J 1988; 81:915–918.

29. Von Lichtenberg F. Viral, chlamydia, rickettsial and bacterial diseases. In: Cotran RS, Kumar V, Robbins SL, eds. Robbins’Pathologic Basis of Disease. Philadelphia: Saunders, 1989:330–333.

30. Benhammou B, Balafiej A, Mikou N. Mediterranean boutonneuse fever disclosed by severe neurological involvement. Arch Fr Pediatr 1991; 48:635–636.

31. Brooks RG, Licitra CM, Peacock MG. Encephalitis caused by Coxiella burnetii. Ann Neurol 1986; 20:91–93.

Received on 08.10.2009

Accepted on 18.11.2009

Research J. Pharmacology and Pharmacodynamics 1(3) Nov - Dec. 2009; 104-110

1896	In the Snake River Valley of Idaho and was originally called “black measles” because of the characteristic rash ⁵.
1900	The recognized geographic distribution of this disease grew to encompass parts of the United States as far north as Washington and Montana and as far south as California, Arizona and New Mexico⁶.
1910	Tragically and ironically Dr. Ricketts died of typhus (another rickettsial disease) in Mexico, shortly after completing his remarkable studies on Rocky Mountain spotted fever ⁵.
1920	Rocky Mountain spotted fever has been a notifiable disease in the United States.
1993-1996	These two states combined accounted for 35% of the total number of U.S. cases reported to CDC.
2002 -2006	Approximately 250-2288 cases of Rocky Mountain spotted fever have been reported annually, although it is likely that many more cases gounreported. Between 2002 and 2006, the number of reported cases doubled ⁶.
2006	Over 90% of patients with Rocky Mountain spotted fever are infected during April through September. This period is the season for increased numbers of adult and Nymphal dermacentor ticks. A history of tick bite or exposure to tick-infested habitats is reported in approximately 60% of all cases of Rocky Mountain spotted fever ⁷.
1993-1996	Over half of Rocky Mountain spotted fever infections are reported from the south-Atlantic region of the United States (Delaware, Maryland, Washington D.C., Virginia, West Virginia, North Carolina, South Carolina, Georgia and Florida). Infection also occurs in other parts of the United States, namely the Pacific region⁸.

General Symptom	Eye symptoms, Mouth and throat, Hearing and EAR symptoms, Joint symptoms, Heart symptoms, Skin symptoms, Digestive symptoms, Urinary symptoms.
Mental health symptoms	Depressive symptoms, Anxity symptoms
Women’s health symptoms	Pregnancy symptoms, Menopause symptoms, Female sexual symptoms, Menstrual irregularities, Breast symptoms, Vaginal symptoms,
Children’s health symptoms	Sleep symptoms, Throat symptoms, Ear symptoms, Speech symptoms, Skin symptoms, Sleep apnea, Adenoind disorder, Asthma, Urinary tract infection
Men’s health symptoms	Male sexual symptoms, Balding and hair loss, Balding and hair loss, Erectile disorder, Penile condition
Chronic disease	Cancer, Diabetese, Heart disease
Disease categories	Autoimmune disease, Eye disorder

Prevention 29, 30, 31

Prevention ^{29, 30, 31}