Rickettsialpox

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Background

Rickettsialpox is a mild, self-limited, zoonotic febrile illness characterized by eschar formation at the location of a mite bite, followed by the onset of systemic symptoms and a more generalized papulovesicular rash. The causative agent is Rickettsia akari, a member of the spotted-fever group of rickettsiae.[1, 2]

Pathophysiology

R akari is an obligate intracellular gram-negative coccobacillus. Its vector is the colorless mite Liponyssoides sanguineus (formerly Allodermanyssus sanguineus), which is found on mice (most commonly the house mouse [Mus musculus]) and other rodents. These hosts serve as the reservoir for the disease. A sanguineus will bite humans when murine hosts are scarce. About 7-10 days after the painless bite, a papular skin lesion appears at the bite location and becomes vesicular with a surrounding area of erythema. An eschar forms and slowly heals. About 3-7 days after the initial skin lesion develops, patients may suddenly develop high-grade fever, chills, headaches, and myalgias with subsequent development of a sparse generalized papulovesicular rash.

Rickettsialpox is mild and self-limited and usually persists for about a week.

Epidemiology

Frequency

United States

Rickettsialpox occurs primarily in urban areas, where the density of mites, mice, and humans is high. Huebner et al first isolated and named rickettsialpox in 1946 in New York City.[3]

Rickettsialpox has been reported primarily in the northeastern and midwest United States (Boston, Mass; West Hartford, Conn; Philadelphia, Pa; Pittsburgh, Pa; and Cleveland, Ohio). Cases have also been reported in North Carolina, Arkansas, and Utah.[4, 5, 6] R akari–like organisms have also been identified in wild rodents in Orange County, California.[7]

Although the prevalence of confirmed cases is very low, several reports suggest the disease is more common than previously thought. Serologic evidence of rickettsialpox exposure was found in 16% of 631 intravenous drug users in inner-city Baltimore, MD, and in 9% of 204 intravenous drug users in Harlem, NY.[8, 9] In addition, between 2001 and 2003, the number of clinical samples submitted to the Centers for Disease Control and Prevention (CDC) increased following the anthrax bioterror attack, reflecting an increased awareness of eschar-associated febrile illness.[10] Prior to this, these clinical syndromes may have been misdiagnosed, or perhaps the infected persons did not seek medical attention. Consequently, rickettsialpox is widely believed to be an underrecognized and underreported clinical entity.

In 2007, about 14 cases of rickettsialpox were reported New York City (a rate of approximately 1.7 cases per 1,000,000 persons). Case reports increased in of 2001 and continued in 2002, following the anthrax attacks in New York City, New Jersey, Washington, D.C., and Florida.[11]

International

Internationally, rickettsialpox has been described in South Africa, Costa Rica, France, Italy, Turkey, Croatia, the Ukraine, Russia, and Korea.[4, 12, 13]

A case report from 2012 described the first case of rickettsialpox in the Netherlands wherein the patient did not have any contact with mice or other animals and the cause of transmission unclear.[14] There have been case reports of rickettsialpox in Mexico and suspected cases identified by serologic assays in Albania, Bosnia Herzegovina, Central African Republic, France, Germany, and Turkey.[15]

Mortality/Morbidity

Rickettsialpox is a benign, self-limited disease. No fatalities have been reported. The incubation period varies from 10-21 days. Rickettsialpox usually resolves within 14-21 days; however, headache and lassitude may persist for another 1-2 weeks.

Sex

Rickettsialpox has no sexual predilection.

Age

Rickettsialpox has no age predilection. It has been reported in patients aged 6 months to 72 years.

History

Following a mite bite, R akari proliferates locally in the skin. After 7-10 days, a firm, red papule 1-1.5 cm in diameter appears; in a few days, it vesiculates with a surrounding area of erythema. The lesion then ulcerates, forms an eschar, and slowly heals.

About 3-7 days after the appearance of the skin lesion, rickettsialpox may manifest as a sudden onset of high fever, chills, sore throat, rigor and profuse sweating, myalgias (especially backache), anorexia, and photophobia. Untreated, fever may last a week. Vertigo, conjunctival injection, cough, rhinorrhea, nausea, and vomiting sometimes occur. Headaches and neck stiffness may be severe. Regional lymphadenopathy at the draining site of the eschar is common, and generalized lymphadenopathy has also been reported. Lymphangitis is not a feature of rickettsialpox.

Approximately 2-3 days after the onset of systemic symptoms, the generalized papulovesicular rash of rickettsialpox erupts. This can involves palms and soles and is occasionally accompanied by an oropharyngeal enanthem. This rash typically lasts a week.

Physical

Patients with rickettsialpox may have high fever fluctuating between 101-104ºF.

The maculopapulovesicular exanthema is usually composed of 20-40 lesions but may range from 5-100. Features are as follows:

At the time of presentation, an eschar is present in at least 95% of affected individuals. The mite bite is painless and begins as an erythematous papule, which develops into a tense vesicle that ruptures to form a dark crust with surrounding induration. More than one eschar may be present. Features are as follows:

Causes

Rickettsialpox is caused by R akari and was first described in 1946.

Rickettsialpox is sporadically observed in many urban centers of the United States. The bloodsucking mite L sanguineus is the vector, and mice (typically M musculus) and other rodents are the reservoir.

When murine hosts are scarce, A sanguineus will bite humans.

No human-to-human transmission occurs.

Laboratory Studies

Routine laboratory test results are nonspecific for rickettsialpox, but leukopenia with relative lymphocytosis and mild proteinuria are common. Thrombocytopenia is also a frequently reported finding.

A diagnosis of rickettsialpox is usually confirmed with a combination of clinical, epidemiological, and serological testing. In the presence of compatible illness in the context of mite exposure, perform serologic tests for antibodies to the spotted-fever group of rickettsiae. If possible, send a biopsy specimen for direct fluorescent antibody (DFA) testing, culture, and polymerase chain reaction (PCR). Sensitivity of the DFA is better for the eschar site than for secondary papulovesicular lesions.

Weil-Felix test findings are negative.

If acute titer results are negative, obtain convalescent sera after 6-8 weeks.

Other Tests

Organism culture, immunohistochemical staining, protein gel electrophoresis, and molecular analysis via PCR may be performed, usually at the reference laboratory level.[18] A newer multiplex real-time PCR of skin biopsy specimens has been shown to yield higher sensitivity in the diagnosis of rickettsialpox.[19]

Giemsa stains of tissue specimens may reveal extremely small coccobacillary intracellular bacteria.

Histologic Findings

Skin biopsies are not routinely obtained to confirm a diagnosis of rickettsialpox. If collected, biopsy samples show epidermal infiltration by mononuclear cells and necrosis of the dermis and epidermis. Inflammation around blood vessels with thrombi and extravasation of red blood cells may also be observed. Vacuolar degeneration of basal cell layers is consistently present.

Medical Care

Rickettsialpox is a self-limited disease; however, antibiotics hasten defervescence and provide relief of other systemic symptoms. A presumptive diagnosis of rickettsialpox can be made based on high clinical suspicion in the correct geographic context, and empiric antimicrobial therapy can be appropriately prescribed. The treatment of choice is doxycycline 100 mg administered orally twice daily until the patient has clinically recovered for approximately 48 hours. Usually, 5-7 days is sufficient. Supportive and symptomatic therapy may also be provided.

Consultations

If antibiotics cause no response within 48 hours, seek an alternate diagnosis.

Medication Summary

A brief course of a tetracycline antibiotic is recommended. Quinolones may also be considered. Chloramphenicol is an alternate treatment but is not usually recommended because of substantial toxicity.

Doxycycline (Bio-Tab, Doryx, Vibramycin, Doxy)

Clinical Context:  Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Deterrence/Prevention

Measures aimed at controlling rodent population and their mite ectoparasites should be instituted.

No human-to-human transmission occurs.

No vaccine is available.

Prognosis

Prognosis is excellent.

Rickettsialpox is usually a self-limited disease.

No fatalities have been reported.

Despite cross-reactivity with other members of the spotted-fever group, cross-immunity to other agents is not conferred upon recovery from rickettsialpox.

Author

Pradeep Kumar Mada, MD, MRCP(UK), Fellow, Division of Infectious Disease, Louisiana State University School of Medicine in Shreveport

Disclosure: Nothing to disclose.

Coauthor(s)

Mohammad J Alam, MD, Assistant Professor of Medicine, Departments of Internal Medicine, Infectious Disease, and Emergency Medicine, University Health, Louisiana State University School of Medicine in Shreveport; Affiliate Staff Physician, Department of Internal Medicine (Infectious Disease), Schumpert Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Charles V Sanders, MD, Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center

Disclosure: Received royalty from Baxter International for other.

Chief Editor

Mark R Wallace, MD, FACP, FIDSA, Infectious Disease Physician, Skagit Valley Hospital, Skagit Regional Health

Disclosure: Nothing to disclose.

Additional Contributors

Chi Hiong U Go, MD, Assistant Professor, Department of Internal Medicine, Texas Tech University Health Science Center at Odessa

Disclosure: Nothing to disclose.

Fred A Lopez, MD, Associate Professor and Vice Chair, Department of Medicine, Assistant Dean for Student Affairs, Louisiana State University School of Medicine

Disclosure: Nothing to disclose.

Julie A Ake, MD, Fellow, Infectious Disease Service, Walter Reed Army Medical Center

Disclosure: Nothing to disclose.

Timothy J Whitman, DO, Consulting Staff, Department of Infectious Disease, National Naval Medical Center

Disclosure: Nothing to disclose.

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Disease Rash/Eschar Generalized Rash Clinical Features Geography
Rickettsialpox secondary to R akari infectionA red papule with a vesicle in the center dries and forms a black eschar with surrounding induration. Multiple eschars are possible.The papulovesicular rash is usually on the trunk and extremities; the palms, soles, and oral mucosa may also be involved.The papule precedes the febrile illness and mild systemic symptoms. Regional lymphadenopathy may develop.See Frequency
Chickenpox secondary to varicella zoster infectionThe papule turns into a vesicle on an erythematous base and resembles a "dew drop on a rose petal."The rash begins on the head and progresses to the trunk, arms, and then legs; vesicles are present in all stages.It is common in children. No black eschar is present.Worldwide
Mediterranean spotted fever secondary to Rickettsia conorii infectionAt the site of a tick bite, a single eschar with a red halo forms.The rash is generalized, involves the palms and soles, and is often maculopapular, occasionally petechial.Fever, headache, myalgias may develop. The onset is abrupt. The disease may be severe in context of comorbidity.North Africa, Middle East, Southern Europe
African tick bite fever secondary to R africae infectionSingle or multiple eschars with regional lymphadenopathyA scant generalized rash, vesicular or maculopapular, may be present. Conversely, the rash may be absent.Fever, headache, myalgias, regional lymphadenopathy; associated with reports of subacute neuropathySub-Saharan Africa, Caribbean
Human spotted fever secondary to R parkeri infectionSingle or multiple eschars develop from erythematous papules.Scant nonpruritic papulesFever, headache, myalgias, arthralgiasUnited States
Scrub typhus secondary to Orientia tsutsugamushi infectionA vesicle or black scab appears on an erythematous base at the bite site.Vesicles are usually on the trunk or extremities.The rash fades within a few days; pneumonitis is common.Asia-Pacific rim