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Introduction

Rocky Mountain Spotted Fever (RMSF) is caused by Rickettsia ricketsii bacteria and is transmitted to humans by two primary tick vectors: the American dog tick, dermacentor variabilis, the brown dog tick, rhipicephalus sanguineus, and the Rocky Mountain wood tick, dermacentor andersoni. It is the most severe rickettsiosis of the United States with mortality rates as high as 30% in untreated cases.

Despite the name of the disease, Rocky Mountain Spotted Fever is actually most common in the south Atlantic and south central parts of the United States. The CDC reports 300-1200 cases per year with a seasonal peak in the late spring and summer. The disease is most common in children, particularly those ages 5-9.

RMSF cases occur throughout the United States but are most commonly reported from North Carolina, Tennessee, Missouri, Arkansas and Oklahoma.

In 2003 there were outbreaks of RMSF on several Indian reservations. The rate of infection reached 150 times the national average and caused 19 deaths. The outbreak was attributed to the large population of free roaming dogs. These dogs carried the brown dog tick which is an important vector for the disease.

They were able to respond to this outbreak by treating over 500 homes with pesticides that target ticks and placing long-acting tick collars on over 1000 dogs. Afterwards ticks were found on only 1% of the dogs with collars versus 69% of the untreated dogs. These measures helped reduce RMSF infection by 43% on these Indian reservations.

RMSF cases in the United States

Risk factors

In 2009 the reporting definition of Rocky Mountain Spotted Fever was broadened to include other Spotted Fever Rickettsiosis. Using these new criteria the number of cases increased from 1.7 cases per million to 14.2 cases per million over a period of 12 years.

People who spend time outdoors, dog owners and native Americans who live on reservations are at higher risk of contracting a rickettsial disease. Children are also at risk because they’re lower to the ground and are more likely to partake in risk behavior such as playing in tall grass and going off trail during a hike.

Signs & Symptoms

Symptoms of Rocky Mountain Spotted Fever appear 3-12 days after infection and include fever, severe headache, myalgia, nausea and yellowing of the skin or eyes. In patients with central nervous system involvement confusion, seizures, dizziness and coma may develop. Late in the disease course half of the patients will develop a rash, with small red spots starting on the hands and feet and extending inward toward the trunk over time.

Rocky Mountain Spotted Fever can affect the respiratory system, the gastrointestinal system, kidneys and/or heart and can lead to a variety of serious or fatal complications. Today about 5-10% of the RMSF cases results in death. Most of the fatalities occur in the very young and very old due to delayed diagnosis and treatment.

Early illness

High fever

Headache (children are less likely to report a headache than adults)

Myalgia

Malaise

In children you see more often edema involving the dorsum of the hands. White blood cell counts, platelets and electrolytes tend to fall within normal limits during early illness.

2-4 days after the onset of illness

Abdominal pain

Nausea

Vomiting

Cough

Rash

Worsening myalgia

Laboratory diagnostics may show elevated liver enzymes or low platelets. Less than half of the patients develop a rash during the first 3 days after the onset of fever.

Late onset rash is a risk factor for fatal outcome. The rash is characterized by small flat pink macules on the wrists, forearms, ankles and spreads to include the trunk and sometimes the palms and soles. Clinicians should never wait with treatment for a rash to appear.

5-7 days after onset of illness

High fever

Worsening abdominal pain

Worsening respiratory status

The rash becomes petechial and more widespread. These symptoms are a reflection of the widespread vasculitis caused by Rocky Mountain Spotted Fever.

Laboratory tests reflect worsening low platelets, elevated liver enzymes and electrolyte abnormalities such as hyponatremia.

After 7 days of illness

Diffuse purpura

Necrosis of digits

Septic shock

Renal failure

Pulmonary edema

Cerebral edema

Altered mental status

Coma

People who survive late illness can experience severe sequela such as necrosis necessitating amputation, persistent neurologic deficits and permanent organ damage.

Rocky Mountain Spotted Fever Rash

Diagnosis

RMSF provides a diagnostic challenge for healthcare providers because early symptoms are often similar to other febrile illnesses and yet decision to treat is based on clinical diagnosis. The sudden onset of fever and headache at the beginning of illness prompts most people to visit a healthcare provider in the first few days of symptoms. Most deaths occur in the first 8 days of illness clinical consideration and early treatment during these initial encounters is critical to prevent severe disease and death.

Diagnosis must often be made on the basis of the history and physical exam because the available lab tests are neither rapid nor sensitive enough and prompt treatment of RMSF is critical to a positive outcome. This can be challenging because many patients don’t recall a tick bite.

Serology is used to confirm the diagnosis after treatment has been initiated. It requires a four-fold or greater rise in IgG antibody titer. Acute serum samples should be taken in the first week of illness or while exhibiting symptoms. The convalescent serum samples should be taken 2-4 weeks later. A single serology result cannot confirm RMSF infection.

PCR assays are also used to detect Rocky Mountain Spotted Fever in whole blood or tissue during the first week of illness. Positive PCR results indicate the presence of rickettsia rickettsii bacteria. Rickettsias circulate in low numbers in the blood stream early in infection and a negative PCR cannot definitively rule out infection with RMSF. But PCR’s for the infection are still not widely available.

Treatment

Treatment is most effective at preventing death and severe disease when it is started within the first 5 days of symptoms and never wait for the rash to begin treatment.

Doxycycline is the recommended treatment for RMSF in all age groups including children under 8 years. With the standard dose and duration of treatment there is no evidence that doxycycline causes teeth staining. It is most effective at preventing severe disease when started within 5 days of illness.

The use of antibiotics other than doxycycline is associated with higher risk of fatality. Minimum duration of treatment is 5-7 days or at least 3 days after the fever subsides and until there is evidence of clinical improvement. Severe cases may require intravenous administration or longer treatment duration.

Prophylactic use of doxycycline following a tick bite is not recommended to prevent RMSF. It may confound or delay presentation of the disease and therefore makes it more difficult to make a correct diagnosis.

Other Ricketsias

New tickborne ricketsial diseases continue to be recognized. Rickettsia parkeri and Rickettsia philipii are two examples of this. Rickettsia Helvetica is thought to be the “Swiss agent” that Willy Burgdorfer, the discoverer of the Lyme disease spirochete, wrote about in his personal papers about his work. These rickettsial diseases often share similar clinical features yet are epidemiologically and etiologically distinct.

Rickettsia parkeri is found along the Gulf Coast and Rickettsia philipii is found along the West Coast. The spotted rash is not a common clinical finding patients that are infected with these rickettsial organisms but there will frequently develop an eschar, or necrotic area at the site of the tick bite. These other rickettsial infections usually result in mild illness of headache, myalgias, fever and swollen lymph nodes that may go undiagnosed.

Eschar

Rickettsias in Europe

In Europe tickborne rickettsial infections are mainly caused by Rickettsia conorri, the causative agent for Fièvre Boutonneus. Fièvre Boutonneus is endemic in countries surrounding the Mediterranean Sea and it therefor also called Mediterranean spotted fever. It is transmitted by the dog tick, Rhipicephalus sanguineus.

After an incubation period of 7 days the disease manifests with chills, fever, muscular and articular pains, severe headache and photophobia. The location of the bite form a black, ulcerous crust called a tache noire. At day 4 a widespread maculopapular rash appears which can become petechial over time.

In Europe the disease is treated with doxycycline, macrolides and/or fluoroquinolones. But doxycycline remains the preferred treatment.

Anaplasma

Anaplasmosis is caused by Anaplasma phagocytophilum, a small, intracellular bacterium that invades neutrophils, the most abundant type of white blood cell in humans. They form bacterial microcolonies within these cells and disturb their function in the body. Most of the damage is thought to be caused by inflammatory processes.

The signs and symptoms of Anaplasma infection can range from asymptomatic to fatal disease. Symptoms appear 5 to 10 days after the tick bite and include fever, chills, headache and muscle aches. Nausea, cough and arthralgia’s can also occur. Nervous system involvement can occur, most often in the form of peripheral neuropathy causing numbness and tingling.

Blood tests may reveal a low number of white blood cells, low platelets and elevated liver enzymes. These abnormalities usually resolve by the second week of symptoms so absence of these abnormalities does not preclude anaplasmosis.

Very early disease may be detected by PCR but a negative result does not rule it out. Laboratory technicians can examine a blood smear to look for microscopic evidence of micro colonies in the white blood cells but they are detected in only 20% of cases at this stage of the disease.

Serologic testing is useful to confirm the diagnosis of anaplasmosis after 7-10 days of infection. The most common method is IFA of IgM and IgG antibodies against anaplasma phagocytophilum.

In patients that present with acute febrile illness after a tick bite that is suggestive of anaplasmosis should be threated empirically with antibiotics. Laboratory testing is important for confirmation but antibiotic therapy should not be delayed until that confirmation is acquired as delay in treatment can result in severe illness and death.

Doxycycline is the recommended treatment in patients of all ages including children under 8 years. The treatment duration is 10-14 days given the possibility of coinfection with Borrelia burgdorferi. Response to treatment is rapid if the patient remains febrile for 48 hours after the onset of treatment the diagnosis should be revisited.

Ehrlichia

The organisms that most often cause human ehrlichiosis are Ehrlichia chaffeensis and Ehrlichia ewingii. Both are transmitted to humans by lone star ticks rather than deer ticks. E. chaffeensis infects monocytes, a type of white blood cell and is therefore referred to as human monocytic ehrlichiosis while E. ewingii infects neutrophil granulocytes and is called human ewingii ehrlichiosis.

Although they invade different host cells they seem to produce similar symptoms in humans. Symptoms develop 1-2 weeks after the tick bite and most patients will have fever, chills, a severe headache and myalgias. Less common symptoms include nausea, vomiting and confusion.

Most cases of ehrlichiosis are uncomplicated but it is a potentially serious disease. Hospitalization is needed in 40-50% of symptomatic patients and sometimes has a fatal outcome. Patients with a compromised immune system are at greatest risk.

Blood tests may reveal low white blood cell counts, low platelets and elevated liver enzymes. PCR is 60-85% sensitive for E. chaffeensis. The sensitivity for E. ewingii is unknown but it is also the only definitive diagnostic test.

Changes in antibody titers detected by IFA can confirm infection but is not useful during acute illness when treatment decisions must be made. IgG antibodies can remain high for years after infection and false positive results can be caused by other conditions including Lyme disease, Rocky Mountain Spotted Fever and Q-fever.

Doxycycline is again the recommended treatment. Duration of therapy is at least 5-7 days. In severe cases doxycycline is given intravenously and treatment is often extended. Treatment should be continued in all patients for at least 3-5 days after the fever subsides and until clinical improvement is noted.

Table of rickettsias

Group Disease Agent Distribution Anaplasma Human granulocytic anaplasmosis Anaplasma phagocytophilum United States, worldwide Ehrlichia Human monocytic ehrlichiosis Ehrlichia chaffeensis United States, worldwide Ehrlichiosis Ehrlichia muris North America, Europe, Asia Ehrlichiosis Ehrlichia ewingii North America Neoehrlichia Human neoehrlichiosis Neoehrlichia mikurensis Europe, Asia Spotted Fever Rickettsiosis Rickettsia aeschlimannii South Africa, Morocco, Mediterranean Sea African tick-bite fever R. africae Africa, West India Queensland tick typhus R. australis Australia Mediterranean spotted fever R. conorii South Europe, South/West Asia, Africa, India Far Eastern spotted fever R. heilongjiangensis Middle East, Russia, China, East Asia Aneruptive fever R. helvetica Europe, Asia Flinders Island spotted fever,

Thai tick typhus R. honei

R. marmionii Australia, Thailand Japanese spotted fever R. japonica Japan Mediterranean spotted fever-like disease R. massiliae France, Greece, Spain, Portugal, Switserland, Sicily, Central Africa, Mali Mediterranean spotted fever-like illness R. monacensis Europe, North Africa Spotted fever

Maculatum infection R. parkeri East/South America Pacific Coast Tick Fever R. philipii North California, Pacific Coast Tickborne lymphadenopathy R. raoultii Europe, Asia Rocky Mountain spotted fever R. rickettsii North, Central and South America North Asian tick typhus

Siberian tick typhus R. sibirica Russia, China, Mongolia Lymphangitis-associated rickettsiosis R. sibirica mongolotimonae South France, Portugal, China, Africa Tickborne lymphadenopathy R. slovaca South/East Europe, Asia