Rocky mountain spotted Fever ( Bacterial Research Project)

Rocky Mountain spotted fever
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Rocky Mountain spotted fever is a disease caused by Rickettsia rickettsii and causes symptoms like high grade fever, rash, myalgia and headache. The disease was so named as it was first detected in Rocky Mountain States. It was first reported by Edward Ernest Maxey in 1989 and Howard Taylor Ricketts found its relation to tick bites thus lending his name to the causative agent.
This paper will deal with the causative agent, mode of transmission and then go on to the epidemiology of the disease. The clinical symptoms, diagnosis and treatment will also be discussed.
Causative Organism
The disease is caused by Rickettsia rickettsii. It is an aerobic organism but is non mobile and is unable to form spores. It belongs to Gram negative coccobacilli category and is unicellular. The cell size varies from 0.3 – 0.5 X 0.8 – 2μm.
R. rickettsii functions as an obligate intracellular parasite and usually demonstrates an endo-symbiotic relationship with cells.
Epidemiology
The disease was initially known as Black Measles because of the spots present on the body. All continents have reported cases of RMSF except Antarctica. The incidence of the disease has been on upswing in the past ten years. Around 6 cases per million were reported in the United States in 2010.
Seasonal Pattern:
Maximum cases of RMSF occur during summer months and the months of June and July show the highest incidence.
At – risk Population
The disease occurs more frequently and is more severe in males, people who are older than 40 years, children less than 10 years, immuno-compromised patients, people who are in close contact with dogs or live near forests.

People of African – American ancestry and those who abuse alcohol are also prime candidates for the disease.
It has been seen that people with glucose – 6 – phosphate dehydrogenase deficiency (G6PD) usually have more complications when infected with RMSF.
Mode of Transmission:
Arthropod Vector
As far as RMSF is concerned, tick acts as both the vector and reservoir for R. rickettsii.
There are various ways by which a tick can be infected with R. rickettsii. Transovarial transmission by a female tick to her eggs can keep the organism alive over generations. If the tick feeds on an infected host then it acquires R. rickettsii from the host while feeding known as trans-stadial transmission. R. rickettsii can also be transmitted via sexual intercourse between male and female species of tick.
Mammals:
Humans and other mammals can be infected with R. rickettsii via tick bite, exposure of broken skin to tick feces or tick fluids. Humans are an accidental host in the life cycle.

Figure 1: Life cycle of R.ricketsii in ticks.
Vector:
In the United States, the American dog tick and Rocky Mountain wood tick are the major vectors of the disease. Dermacentor variabilis or American dog tick are predominantly found in the areas that lie east of the Rocky Mountains. This tick is considered the most common vector that is responsible for causing RMSF in humans.
Dermacentor andersoni or Rocky Mountain wood tick is the variety that is localized to Rocky Mountain States and south-western Canada.
Pathogenesis of R. rickettsii:
Once the organism enters a host its preferred site of action are the endothelial cells in which it induces certain cytoskeletal changes that initiates the process of phagocytosis. Research is ongoing to identify the virulence factors of R. rickettsii and certain proteins like Omp A and Omp B, enzyme Phospholipase A 2 and Actin polymerization are possible candidates.
Sign and Symptoms:
The disease is difficult to diagnose and a high index of suspicion is necessary so that it can be diagnosed at an early stage.
The most defining triad for the disease is a combination of fever, rash and history of tick bite. But, mostly all the three features are not present together leading to a diagnostic dilemma.
The incubation period of the disease varies between 2 – 14 days after tick bite or exposure to infected material. The initial symptoms include fever, headache, nausea and vomiting, abdominal pain.
Rash:
The characteristic rash of RMSF usually develops 2 -5 days after the first fever spike. The rash first involves wrists, forearms, ankles and is in form of macular rash which is non – itchy. Then the rash may develop into a petechial form as the disease progresses further. Only 35 – 60% of patients develop the characteristic petechial rash.
It must also be remembered that approximately 10 – 15% patients never show the presence of a rash during the course of the disease.

Figure 2: Characteristic rash of RMSF.
Course of the Disease:
The disease can be fatal if the treatment is not begun in the initial stages. The best outcomes are seen when treatment is initiated within 5 days of onset of symptoms.
R. rickettsii attacks endothelial cells lining blood vessels and leads to vasculitis, it can cause bleeding or development of clots in any part of the body. If patients are not treated timely and severe vasculitis develops then it is possible that they may develop permanent neurological deficits and if circulation to a limb is impaired then they might have to experience the trauma of an amputation.
Diagnosis:
The diagnosis of RMSF is a test of the clinical acumen of physicians. Since, patients present with different signs and symptoms and often do not provide any history related to tick bite or tick exposure, it becomes extremely difficult for treating doctors to connect all the pieces of the puzzle and make the correct diagnosis (Masters et al., 2003).
It becomes extremely important for physicians to keep RMSF as a differential in any undiagnosed case with symptoms like fever, headache, rash and the doctor should specifically question the patient about possible contact with ticks.
Laboratory Tests:
A complete blood count will show decreased platelets, hyponatremia and raised hepatic enzymes are also present in some patients.
Specialized Tests:
It takes around 7 – 10 days after the onset of disease for antibodies to develop in the body of a patient. These antibodies can then be detected using specialized tests.
According to CDC, the diagnostic test of choice for RMSF is indirect immuno-fluorescence assay (IFA) with R. rickettsii antigen. This test is performed on two samples, one taken in the initial stage of the disease and the second around 2 – 4 weeks after the first sample. In case of RMSF, there is a significant rise in IgG in the second sample, a fourfold rise is considered diagnostic.
Since, IFA can diagnose the disease only at later stage, in some patients with rash a PCR or immuno-histochemical staining (IHC) can be done on a sample obtained from skin biopsy. This test has 70% sensitivity in the early stages of the disease but a negative test does not exclude the disease.
Treatment:
Drug of choice is Doxycycline
The dosage is:
In adults the drug must be given in a dose of 100mg two times a day and for children (with body weight of less than 45kgs), the dose is 4mg/ kg body weight in 2 divided doses.
The drug should be given for at least 72 hours after the patient becomes afebrile and the total duration of treatment is usually 7 – 14 days.
Certain concerns have been voiced regarding use of doxycycline in children but both CDC and AAP recommend the use of drug without any reservations. In case of allergies to doxycycline, Chloramphenicol may be used as an alternative drug but its dangerous side effects like aplastic anemia do not make this drug suitable for routine treatment (Traub and Cummins, 2011).
Case Study:
A patient aged 7 years was admitted with complaints of high grade fever, nausea, vomiting and stomach ache for the past 2 days. The patient was treated as a case of acute gastroenteritis, given symptomatic treatment and discharged. She was readmitted after 4 days with complaints of fever, loss of appetite, photophobia and myalgia. She also had an erythmatous petechial rash on trunk, arms, legs and soles along with palpable liver and spleen.
Blood tests were ordered and showed leucocytosis, reduced platelets and raised serum AST and ALT. the patient was given doxycycline and shifted to a pediatric ICU but succumbed to her illness (Eremeeva et al., 2003). Autopsy specimens demonstrated positive indirect immuno-fluorescence test.
One month after the death of the child, her sister aged three also developed similar signs and symptoms. She was immediately started on doxycycline and improved.
Both children had a history of playing in grass and had a pet which at times had ticks.
Conclusion:
Rocky Mountain spotted fever is a zoonotic disease caused by R.ricketsii. Ticks play an important role in the pathogenesis of the disease. The symptoms of the disease are such that it is difficult to diagnose and at times this may lead to delayed initiation of treatment. Clinical features should dictate the treatment in case of suspected RMSF; treatment should not be withheld till results of investigations are achieved. Doxycycline is the drug of choice in all age groups and shows best results when administered within 5 days of onset of the disease.

Reference
Eremeeva ME, Klemt RM, Santucci-Domotor LA, Silverman DJ, Dasch GA. (2003). Genetic analysis of isolates of Rickettsia rickettsii that differ in virulence. Ann N Y Acad Sci. 990:717-722.
Masters EJ, Olson GS, Weiner SJ, Paddock CD. (2003). Rocky Mountain spotted fever: a clinician’s dilemma. Arch. Intern. Med. 163 (7): 769–74.
Traub SJ, Cummins GA. (2011).Tick-borne diseases. In: Auerbach PS. Wilderness Medicine. 6th ed. Philadelphia, Pa.: Elsevier Mosby. Chapter: 51.