RICKETTSIAL AND EHRLICHIAL INFECTIONS (ROCKY MOUNTAIN SPOTTED FEVER AND TYPHUS)

RICKETTSIAL AND EHRLICHIAL INFECTIONS (ROCKY MOUNTAIN SPOTTED FEVER AND TYPHUS)

Current Diagnosis

• The diagnosis of Rocky Mountain spotted fever (RMSF) is typically made clinically. RMSF should be considered in the setting of fever, headache, rash, and a history of probable tick exposure. Thrombocytopenia, hyponatremia, and elevated serum hepatic transaminases are common. A rash is typically present by days 3–5.

• RMSF is usually confirmed by demonstrating a fourfold increase between acute and convalescent serum antibody titers.

• Early evaluation of peripheral blood leukocytes for morulae can confirm the diagnosis of human monocytic ehrlichiosis (HME) or human granulocytic anaplasmosis (HGA). However, this method lacks sensitivity.

• PCR analysis performed within the first 48 hours of presentation and convalescent antibody titers are often required to confirm a diagnosis of HME or HGA.

• Typical findings of HME and HGA include fever, headache, malaise, leukopenia, thrombocytopenia, elevated serum transaminases, and potential exposure to ticks.

Current Therapy

• Given the potential for rapid clinical decline in patients with RMSF, HME, and HGA, initiation of therapy should be based on clinical suspicion and one should not await laboratory confirmation of illness.

• Treatment of choice for RMSF, HME, and HGA is doxycycline (Vibramycin) 100 mg PO or via IV twice daily.

•   For children ≤ 45 kg,1 the recommended doxycycline dose is 2.2 mg/kg given via IV or orally every 12 hours.

• Though optimal duration of therapy has not been well studied, a common treatment course for RMSF is at least 3 days after the patient defervesces (typically 5–7 days of therapy).

• HME and HGA are commonly treated for 5–10 days, or at least 3 days after defervescence.

• Chloramphenicol (Chloromycetin) is the treatment of preference for RMSF in pregnant women and those with adverse reactions to tetracyclines.

• Potential treatment alternatives for HME and HGA include rifampin (Rifadin)2 and chloramphenicol, although patient experience is limited.

1  Not FDA approved for this indication.

2  Not available in the United States.

Rickettsial Infections

RMSF

Rocky Mountain spotted fever (RMSF) is the most serious of the Rickettsial infections found in the United States. If not promptly treated, death can ensue.

Epidemiology

RMSF is caused by Rickettsia rickettsii, a small, gram-negative coccobacillus. The name RMSF can be misleading. Though first described in the Snake River Valley of Idaho in 1896, the greatest density of illness can be found in the south central and southeastern United States (see Figure 1). RMSF can also be found in Canada, Mexico, Central America, and northern portions of South America.

FIGURE 1    Annual reported incidence (per million population)  for RMSF in the United States for 2010 http://www.cdc.gov/rmsf/stats/ (accessed January 4, 2014).

In the United States, R. rickettsii is transmitted primarily by three species of ticks: Dermacentor variabilis (the American dog tick, most common vector in the central and eastern United States), D. andersoni (the Rocky Mountain wood tick, primary vector in the western United States), and Rhipicephalus sanguineus (the brown dog tick, found throughout the United States). R. sanguineus also serves as a vector in Mexico, while Amblyomma cajennense has been found to transmit R. rickettsii in Central and South America. These ticks, and the mammals on which they feed, serve as reservoirs. Therefore, these tickborne infections occur more commonly in the warmer months, when tick activity is greater. R. rickettsii can have a lethal effect on most of its tick vectors, limiting the number that survive to transmit infection to humans. Less than 1% of D. andersoni ticks harbor R. rickettsii.

Pathogenesis

R. rickettsii is transmitted from the tick to humans via a painless bite, which often goes unrecognized. The organism resides in the salivary gland of the tick and is passed during acquisition of a blood meal. R. rickettsii can be transmitted as early as 10 to 24 hours after tick attachment. Tick saliva results in local host immune modulation, assisting bacterial survival. Once injected, the bacteria invade vascular endothelial cells. This obligate intracellular pathogen utilizes the nutrients of the cytosol for proliferation and host cell actin elements to propel the organism through the cytosol, to the surface membrane, and onto adjacent endothelial cells. Small and medium-sized blood vessels are most heavily invaded by this pathogen, with invasion of macrophages, monocytes, and hepatocytes to a lesser degree. Invasion of the endothelium results in a local cell injury resulting from oxidative stress. This endothelial injury results in increased vascular permeability and stimulation of inflammatory cytokines, which can progress to multiorgan failure.

Clinical Manifestations and Diagnosis

Up to 40% of patients will be unaware of a tick bite at the time of presentation. RMSF must be considered given the appropriate clinical and laboratory picture. The median incubation period is 7 days, with a range of 2 to 14 days. Classically, one would consider this diagnosis in the setting of fever, headache, rash, and a history of probable tick exposure. However, these clinical findings are often variably present early in the course of the illness. Within the first 3 days, a temperature of > 100 °F occurs in 73%, headache in 71%, and rash in 49%. A rash usually develops within 3 to 5 days of fever onset. As the disease progresses, 99% of those infected will develop a temperature of > 100°F, 91% will develop a headache, and 88% will develop a rash. The rash often presents as maculopapular, but can transition to a petechial exanthem. Gangrenous changes occur much less commonly. Traditionally, many have considered rash involvement of the palms and soles and the “centripetal” rash, progression of rash from wrists and ankles toward the trunk, to be pathognomonic of this infection.

However, disregarding the diagnosis of RMSF in the absence of these findings could prove problematic. Rash involvement of the palms and soles is commonly not present in the first few days of illness, but may appear as the disease progresses in a majority of patients. Similarly, the centripetal rash occurs in a minority of patients. Other common manifestations include malaise, anorexia, generalized myalgia, arthralgia, abdominal pain, nausea, vomiting, and, less commonly, diarrhea. Common laboratory abnormalities include hyponatremia, thrombocytopenia, and elevated serum transaminases.

Diagnosis

When appropriate clinical features and history of tick exposure are present, the diagnosis of RMSF should be considered. Initiation of treatment should not be delayed, awaiting laboratory confirmation. Currently available tests include serologic tests and skin biopsy.

Indirect immunofluorescent antibody tests are the most widely available. Other serologic tests include latex agglutination, complement fixation, and enzyme-linked immunosorbent assays. These assays typically measure both IgM and IgG levels. A single IgM level ≥ 1:64 is considered evidence of recent or current infection.

However, false negative tests can occur during the first 5 days of the illness. For more accurate results, convalescent titers should also be performed 2 to 4 weeks after illness onset. A fourfold increase between acute and convalescent IgG levels would suggest recent illness. IgM levels wane after 3 to 4 months. IgG levels may also diminish after 7 to 8 months, but can remain detectable for many years. These persistently elevated IgG levels can cause some confusion as cross-reactivity to other rickettsia, e.g., R. parkeri (an organism of lesser virulence), can occur.

At the time of presentation, a biopsy of rash-involved skin can be performed with immunohistochemical staining of the specimen. Test specificity is 100%; however, the sensitivity is approximately 70%. The sensitivity also declines quickly following the initiation of therapy.

The sensitivity of the assay and lack of its wide availability limits the usefulness of this test.

Differential Diagnosis

Differential diagnosis could include meningococcemia, leptospirosis, measles, mononucleosis, and certain streptococcal and staphylococcal infections.

Treatment

Given the high mortality rate associated with RMSF, treatment should be initiated early based on clinical suspicion. The drug of choice for nonpregnant individuals is doxycycline (Vibramycin). The recommended dose for patients > 45 kg (adults and children > 8 years of age) is doxycycline 100 mg intravenously (IV) or orally every 12 hours. For patients ≤ 45 kg, the recommended doxycycline dose is 2.2 mg/kg given IV or orally every 12 hours. Chloramphenicol (Chloromycetin) has been used successfully in treating RMSF and is the preferred agent during pregnancy, given the known effects of tetracyclines on fetal bones and teeth.

The optimal duration of therapy is not well defined. It’s recommended to continue therapy at least 3 days after the patient defervesces. Unless suffering from multiorgan injury, most patients will defervesce 2 to 3 days after the initiation of treatment, resulting in a typical treatment course of 5 to 7 days of antibiotics. Short courses of doxycycline in young children (< 8 years of age),1 as outlined above, have not been associated with discoloration of permanent teeth.

Prevention

Prevention of RMSF and other rickettsial infections can be very challenging, because the tick bites are often painless and frequently go unnoticed. When working or living in areas of high tick density, use of repellants, such as 20% to 30% DEET (N, N-diethyl-m-toluamide) on skin or permethrin on clothing, can provide some benefit. In addition, daily self-examination for ticks is important. If a tick is found attached to the skin, fine-tipped tweezers can be used to grasp the tick as close to the skin surface as possible. The tick is pulled upward with steady pressure. Early detection and removal within the first several hours of attachment may prevent transmission of the pathogen. Given that < 1% of ticks are colonized with R. rickettsii, prophylactic antibiotics are not required following a tick bite. However, one should seek medical attention and consider therapy for RMSF if fever, headache, or other common symptoms develop within 2 weeks of the tick bite.

Other Rickettsial Organisms

In addition to R. rickettsii, there are many other members of the spotted fever group (SFG) rickettsioses. These include R. conorii (southern Europe, Africa), R. africae (sub-Saharan Africa, West Indies), R. australis (eastern Australia) and R. parkeri (southeast United States), to name a few. R. parkeri infection is transmitted by the Gulf Coast tick (A. maculatum). Similar to RMSF, R. parkeri infection can present with a fever, a headache, myalgia, and a rash. Unlike RMSF, an eschar at the site of the tick bite is commonly noted. Rash can include macules, papules, pustules, and, less commonly, petechiae. Laboratory abnormalities commonly include mild leukopenia, elevated liver transaminases, and total bilirubin. There is significant antibody cross- reactivity with other members of the SFG. Thus, some cases are misdiagnosed as RMSF. Typhus group rickettsial infections include R. prowazekii and R. typhi. R. prowazekii is louseborne infection most commonly encountered in Africa. R. typhi, the cause of “murine typhus,” is transmitted by the oriental rat flea. This infection is seen uncommonly in the United States, but is more common in Asia, Africa, and southern Europe.

Ehrlichial Infections

Ehrlichiosis is a term to define infections caused by bacteria in the family Anaplasmatacea, primarily comprised of the genera Ehrlichia and Anaplasma. The genus Ehrlichia was named after the German-born physician Paul Ehrlich in 1937. However, human ehrlichiosis was not identified until 1986. Since then, many additional species have been identified. In total, three species from the genus Ehrlichia and one species in the genus Anaplasma have been found to cause human disease in the United States. These include A. phagocytophilum, E. chafeensis, E. ewingii, and E. muris-like. Our focus will remain on the two most prevalent diseases, human monocytic ehrlichiosis (HME), caused by E.chafeensis, and human granulocytic anaplasmosis (HGA), caused by A. phagocytophilum.

Epidemiology

Ehrlichia and Anaplasma are small (0.5–1.5 µm) gram-negative organisms. E. chaffeensis is primarily transmitted by A. americanum (lone star tick), but has been identified in Ixodes pacficus and D. variabilis. Consistent with the location of A. americanum ticks, HME is commonly found in the Midwest, southeastern, and Atlantic states. E. chaffeensis has been detected in 2.6% and 9.8% of lone star ticks in Tennessee and Missouri, respectively. A. phagocytophilum, the cause of HGA, is transmitted by I. scapularis ticks in the northern Midwest and eastern United States and by I. pacificus in the western United States.

These Ixodes ticks are vectors for pathogens that cause Lyme disease and babesiosis, thus making co-infection a concern in those diagnosed with HGA. As with other tickborne zoonoses, HME and HGA are more commonly acquired during warmer months, when ticks are more active. Vertebrates, such as the white-tailed deer, are reservoirs for both E. chaffeensis and A. phagocytophilum.

Pathogenesis

Following inoculation, these small organisms spread initially via the lymphatic system to regional nodes, followed by hematogenous dissemination. E. chaffeensis invade primarily monocytes and macrophages, and less commonly lymphocytes. These infected monocytes can be found within the peripheral blood, bone marrow, CSF, lymphatic system, and most major organs. In a similar fashion, A. phagocytophilum disseminate throughout the body, eventually invading neutrophils, band cells, and possibly endothelial

Clinical Manifestations and Diagnosis

The onset of symptoms of HGA and HME occurs 5 to 21 days after inoculation from an infected tick. Both typically present as an undifferentiated febrile illness, marked by fever, chills, headache, malaise, myalgia, and arthralgia. Additional symptoms, particularly in HME, may include abdominal pain, nausea, vomiting, cough, and a nonspecific rash. Key elements in diagnosing HME or HGA include fever, thrombocytopenia, leukopenia, elevated serum transaminases, and exposure to a tick endemic region. Patients can present with varying levels of acuity, and rates of complications can vary, depending on the diagnosis. Individuals with HME can develop septic shock and are more likely to develop CNS manifestations (meningitis or meningoencephalitis). In HGA, patients are less likely to develop septic shock but more likely to develop peripheral neuropathies. Diagnosis can be made by examination of the peripheral smear, evaluating for intracytoplasmic collections of organisms, called morulae, within monocytes (HME) or neutrophils (HGA).

Unfortunately, this is a relatively insensitive assay, with morula found typically in < 10% of patients. Peripheral smear is more useful in diagnosing HGA, with morula visible in 25% to 75% of cases. In contrast, PCR detection of the pathogen is much better, with sensitivities ranging between 60% to 85% (HME) and 67% to 90% (HGA). However, in both the peripheral smear and PCR assay, the sensitivity of the test will quickly decline following initiation of therapy. The diagnosis can also be made by the demonstration of a fourfold change in antibody titers during convalescence; with repeat antibody titers acquired 2 to 4 weeks after symptom onset. A single elevated titer ≥ 1:64 may represent an acute infection. However, IgG antibodies may persist for months to years after an infection, thus complicating the interpretation of the assay. Therefore, acute and convalescent titers are recommended in making a diagnosis.

Treatment

As the severity of illness in both HME and HGA can progress quite quickly, initiation of treatment should not be delayed while awaiting laboratory confirmation. The treatment of choice for ehrlichiosis is doxycycline (Vibramycin).2 The recommended dose for patients > 45 kg (adults and children > 8 years of age) is doxycycline 100 mg IV or orally every 12 hours. For those ≤ 45 kg,1 the recommended doxycycline dose is 2.2 mg/kg given IV or orally every 12 hours.

Following treatment with doxycycline, a prompt response usually ensues, with marked clinical improvement typically noted within 24 to 48 hours. Absence of such response should lend to consideration of other diagnoses. There is little data to support the routine use of alternative antibiotics. Limited numbers of pediatric and pregnant HGA patients have been treated successfully with rifampin (Rifadin).2In vitro data does not support the use of chloramphenicol, β- lactams, cephalosporins, macrolides, and aminoglycosides. Though levofloxacin (Levaquin)2 has shown some in vitro activity against A. phagocytophilum, one case report demonstrated a failure of this antibiotic to treat HGA. In addition, fluoroquinolones appear to have poor in vitro activity against E. chaffeensis. The optimal duration of therapy is unknown. A typical course of doxycycline is 5 to 10 days, given at least 3 days after defervescence, which typically occurs within 48 hours of initiation of therapy.

References

1.     Belman A.L. Tick-borne diseases. Semin Pediatr Neurol. 1999;6:249–266.

2.    Chen L.F., Sexton D.J. What’s new in Rocky Mountain spotted fever? Infect Dis Clin North Am. 2008;22:415–432.

3.     Dantas-Torres F. Biology and ecology of the brown dog tick, Rhipicephalus sanguineus. Parasit Vectors. 2010;3:1–11.

4.    Dumler J.S., Madigan J.E., Pusterla N., et al. Ehrlichioses in humans: Epidemiology, clinical presentation, diagnosis, and treatment. Clin Infect Dis. 2007;45(Suppl. 1):S45–S51.

5.     Helmick C.G., Bernard K.W., D’Angelo L.J. Rocky Mountain spotted fever: Clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis. 1984;150:480–488.

6.      Mansueto P., Vitale G., Cascio A., et al. New insight into immunity and immunopathology of Rickettsial diseases. Clin Dev Immunol. 2012;2012:1–26.

7.    Niebylski M.L., Peacock M.G., Schwan T.G. Lethal effect of Rickettsia rickettsii on its tick vector (Dermacentor andersoni). Appl Environ Microbiol. 1999;65:773–778.

8.    Paddock C.D., Finley R.W., Wright C.S., et al. Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever. Clin Infect Dis. 2008;47:1188–1196.

9.     Salinas L.J., Greenfield R.A., Little S.E., et al. Tickborne infections in the southern United States. Am J Med Sci. 2010;340:194–201.

10.     Thomas R.J., Dumler J.S., Carlyon J.A. Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis. Expert Rev Anti Infect Ther. 2009;7:709–722.

11.    Woodward T.E. Rocky Mountain spotted fever: Epidemiological and early clinical signs are keys to treatment and reduced mortality. J Infect Dis. 1984;150:465–468.

12.       Woods C.R. Rocky Mountain spotted fever in children. Pediatr Clin North Am. 2013;60:455–470.

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