Rickettsialpox

INTRODUCTION — Rickettsialpox is an uncommon, mite-borne rickettsial disease caused by the agent Rickettsia akari. R. akari was first isolated in 1946 from a patient, mites, and a naturally infected house mouse in Queens, New York [1]. The disease was named rickettsialpox because of its resemblance to chickenpox. The etiologic agent was named R. akari because the causative agent belonged to the genus Rickettsia and because akari is Greek for "mite." R. akari has long been considered a member of the spotted fever group of rickettsiae of which R. rickettsii is the prototype. However, some experts have proposed that R. akari should be considered a member of the transitional group of Rickettsia along with R. australis and R. felis [2]. (See "Biology of Rickettsia rickettsii infection".)

EPIDEMIOLOGY — R. akari is transmitted to the common house mouse (Mus musculus) by the bloodsucking mite Liponyssoides sanguineus (formerly Allodermanyssus sanguineus). The mouse serves as the usual reservoir for the disease, although R. akari has also been detected in Korean voles [3]. L. sanguineus is a small (0.75 to 1.5 mm), colorless arthropod that swells to many times its normal size after a blood meal and becomes bright red in color. L. sanguineus rarely bites humans when mice are plentiful. However, when mouse populations are reduced (eg, by vermin eradication programs), this mite will bite humans and transmit the disease. Although natural infection is thought to occur exclusively by the bite of an infected mite, transmission has occurred in laboratory settings via inhalation of infectious aerosols [4].

Occurrence — Rickettsialpox has been detected in urban areas in New York, Pittsburgh, Cleveland, Boston, as well as Arizona, Utah, South Africa and the Ukraine. Although over 800 cases of rickettsialpox have been reported since the initial description of the infection in 1946, it is widely assumed that this infection is underrecognized and underreported [5,6]. Rickettsialpox has also been described in homeless patients and in persons who use intravenous drugs [7].

Rickettsialpox may have a wider geographic occurrence than previously realized. For example, R. akari was isolated from a 36 year old man from Croatia, an area in which rickettsialpox had not been previously recognized [8]. Similarly, others have speculated that R. akari is widespread in Europe [9,10]. In another report, sera reactive with R. akari antigens were detected among patients from Mexican states of Yucatan and Jalisco who were initially thought to have dengue fever [11]. Another serosurvey done in southern California suggested that R. akari or an akari-like rickettsiae are present in wild rodents in Orange County, California [12]. A single case of rickettsialpox was diagnosed in a man who worked at a suburban golf course in North Carolina [13].

Incubation period — The incubation period for rickettsialpox has not been conclusively established but is thought to range from 10 to 14 days. One patient developed fever nine days after an apparent single exposure to a known focus of infection. In a second, laboratory-acquired case, a primary lesion at the site of inoculation appeared on the seventh day and fever appeared ten days after exposure [14].

CLINICAL MANIFESTATIONS — Rickettsialpox is characterized clinically by a triad of findings which occur in the following order:

●Initial skin lesion at the site of the bite of the infected mite

●Abrupt onset of fever and constitutional symptoms such as chills and myalgia

●A papulovesicular rash

Most cases have each of the features of this triad. The diagnosis should be suspected when these findings occur in the appropriate epidemiologic setting.

Most patients have a mild illness, and full recovery can be seen even without treatment. In one review, only 12 of 144 patients required hospitalization [15]. Fatal rickettsialpox has never been described.

Initial lesion — The initial lesion typically begins as a tiny papule that enlarges to 1 to 1.5 cm as it progressively vesiculates and then subsequently forms a dark black crust or eschar. Eschars develop in the majority (more than 80 to 90 percent) of patients and, in rare cases, there is more than one initial lesion [14,15]. They can appear in virtually any location including the face, extremities, or trunk.

The skin surrounding the initial lesion usually becomes erythematous and regional lymphadenopathy is often present. However, the initial lesion and the surrounding skin are rarely tender or pruritic. As a result, patients are often unaware of the initial lesion, which typically heals in two to three weeks without treatment and leaves a small scar at the site of the eschar.

Biopsy of the initial lesion characteristically reveals epidermal and dermal necrosis with perivascular and periadnexal inflammation. Other findings on pathologic examination of skin biopsies include granulomatous inflammation, perivascular T cell infiltrates, and histiocytosis [16]. In one study of 13 cases of rickettsialpox [5], a lymphocytic vasculitis was described; in addition, fluorescent-antibody testing using anti-R. rickettsii globulin (which cross reacts with R. akari antigens) demonstrated organisms consistent with R. akari in five patients.

Constitutional symptoms — Constitutional symptoms typically appear abruptly several days after the initial lesion. Virtually all patients have fever and malaise. Headache is characteristically present and may occasionally be severe enough to suggest infection of the central nervous system, especially if stiff neck is present. The cerebrospinal fluid is typically normal [15]. Individual patients may complain of photophobia, conjunctival injection, sore throat, nausea, or vomiting.

Papulovesicular rash — A generalized skin rash that is the hallmark of rickettsialpox may occur on the same day or from one to nine days after the onset of constitutional symptoms. The rash of rickettsialpox typically begins as a maculopapular eruption that quickly becomes papulovesicular. These lesions then scab and fall off without scarring. Lesions may be numerous or few in number. They can occur on the face, palms, soles and mucous membranes. In some cases the rash remains maculopapular and never becomes papulovesicular [8].

Laboratory findings — Leukopenia is common during the early febrile stage of illness [14,15]. The differential count may reveal a relative lymphocytosis. Hepatitis that resolves coincident with treatment may also occur [17].

DIAGNOSIS — The diagnosis of rickettsialpox can be made through serologic testing or detection of the organism. However, given the limitations of current diagnostics, treatment decisions are often made clinically in a patient with a typical clinical syndrome who lives in an endemic area where L. sanguineus and mice are known or suspected to be present. (See 'Clinical manifestations' above and 'Epidemiology' above and 'Treatment' below.)

Serologic testing — The gold standard for diagnosis of rickettsialpox remains a fourfold rise in convalescent titers of indirect fluorescent antibodies using spotted fever group (SFG) antigens. Such tests are readily available through most state health departments and the Centers for Disease Control and Prevention.

However, serologic analysis is rarely helpful in making treatment decisions for the acutely ill patient given the relatively short course of disease, and the late onset of IgG antibodies coupled with the need for both acute and convalescent serology for confirmation. In addition, these serologic methods cannot reliably distinguish rickettsialpox from other SFG rickettsial infections (including R. rickettsii, R. parkeri, and others) since R. akari cross-reacts with other spotted fever group rickettsiae. (See "Other spotted fever group rickettsial infections".)

A modification of the enzyme-linked immunosorbent assay (ELISA) test utilizing epitope saturation by specific monoclonal antibodies has been developed to serologically confirm the specific species of infective rickettsiae, although this is not yet widely available [18]. Other serology-based diagnostic options include direct immunofluorescence assays that identify rickettsial organisms in paraffin-embedded biopsy tissue from patients with rickettsialpox [19].

Direct methods for diagnosis — During active disease, the diagnosis of rickettsialpox can be confirmed by detection of the organism via immunostaining or polymerase chain reaction (PCR) in a biopsy of an eschar or papulovesicular lesions, or rarely through isolation of the agent from the blood. A real-time multiplex PCR technique has been developed that can specifically identify R. akari in formalin-fixed paraffin-embedded skin biopsy specimens and can distinguish it from R. rickettsii and R. parkeri [20]. However, PCR testing and isolation of the organism are only available in a few large medical centers with specialized laboratory facilities and access to specialized reagents.

DIFFERENTIAL DIAGNOSIS — The most common disease to mimic rickettsialpox is chickenpox. Rickettsialpox can be distinguished from chickenpox by the following characteristics:

●Rickettsialpox usually has a coexistent eschar

●The lesions of chickenpox characteristically appear in crops in contrast to rickettsialpox

●The mature lesion of chickenpox is a vesicle compared to a papulovesicle with a prominent papular component in rickettsialpox

Rickettsialpox can also be confused with other rickettsial diseases, including Mediterranean spotted fever, Queensland tick typhus, African tick bite fever, R. parkeri infection, scrub typhus, infection with R. philipii (the presumed agent of Pacific Coast Fever) [21], and Siberian tick typhus. All of these infections may be associated with eschars, but only Queensland tick typhus and African tick bite fever have rashes that are typically or occasionally vesicular. Furthermore, these illnesses occur in restricted geographic areas and a history of travel or residence in an endemic area can usually be elicited. (See "Other spotted fever group rickettsial infections".)

Patients with an enteroviral infection may occasionally have an illness that mimics rickettsialpox, but they generally lack eschar and a true vesiculopapular eruption. Rarely, patients with disseminated gonococcal infection have vesiculopustular lesions that superficially resemble the lesions of rickettsialpox; however, these lesions do not form eschars. Rickettsialpox has also been confused with cutaneous anthrax [6]. However, patients with cutaneous anthrax characteristically have local edema out of proportion to the size of the lesions and Gram stain of these lesions should reveal nonsporulating gram-positive rods. (See "Clinical manifestations and diagnosis of anthrax".)

TREATMENT — We recommend treating all patients with suspected rickettsialpox. Although though the disease is usually self-limited, treatment may reduce the duration of symptoms. Given the limitations of current diagnostics, treatment decisions are often based upon typical clinical manifestations in a patient with epidemiologic risk factors. (See 'Epidemiology' above and 'Clinical manifestations' above and 'Diagnosis' above.)

The treatment of choice for rickettsialpox in all patients is doxycycline 200 mg orally as a loading dose and then 100 mg orally every 12 hours until the patient has been afebrile and clinically well for 48 to 72 hours. We administer doxycycline even to pregnant women and young children. Although tetracyclines other than doxycycline are generally contraindicated in these groups, doxycycline has not been associated with serious adverse events in pregnant women or children <8 years old. A more detailed discussion of the use of doxycycline in children and pregnant women is found elsewhere. (See "Treatment of Rocky Mountain spotted fever", section on 'Pregnant women' and "Treatment of Rocky Mountain spotted fever", section on 'Children'.)

The only alternative agent with clinical data to support its use is chloramphenicol. However, since rickettsialpox is typically a mild, self-limited infection, we recommend not treating with this drug given its risk of potential severe adverse reactions.

In a report of 25 patients from a New York City hospital, oxytetracycline, chlortetracycline, or chloramphenicol (at doses of 250 mg orally every six hours) led to resolution of fever and other systemic signs of infection within 48 hours of the institution of therapy in all 25 patients [22]. A similar response was demonstrated in a subsequent report of 13 patients; all of those who were treated with tetracycline became afebrile within 24 hours [5]. Doxycycline was also associated with prompt recovery in an HIV-infected patient with rickettsialpox, despite immunohistochemical staining of biopsied lesions showing relatively large numbers of rickettsiae [23]. A number of novel tetracycline-like agents (tigecycline, eravacycline, and omadacycline) have shown strong activity in vitro against Rickettsial spp and may offer additional effective alternatives, although clinical data on their use is limited [24].

SUMMARY AND RECOMMENDATIONS

●Rickettsialpox is an uncommon, mite-borne rickettsial disease caused by the agent Rickettsia akari. The disease was named rickettsialpox because of its resemblance to chickenpox. (See 'Introduction' above.)

●R. akari is transmitted to the common house mouse by a bloodsucking mite. The mouse serves as the reservoir for the disease. When mouse populations are reduced, this mite will bite humans and transmit the disease. Although natural infection is thought to occur exclusively by the bite of an infected mite, transmission has occurred in laboratory settings via inhalation of infectious aerosols. (See 'Epidemiology' above.)

●The incubation period for rickettsialpox has not been conclusively established, but is thought to range from 10 to 14 days. (See 'Incubation period' above.)

●Rickettsialpox is characterized clinically by a triad of findings including the initial skin lesion at the site of the bite followed by abrupt onset of fever, chills, myalgias and a generalized papulovesicular rash. The initial lesion typically begins as a tiny papule that vesiculates and subsequently forms an eschar. (See 'Clinical manifestations' above.)

●The diagnosis of rickettsialpox is often a clinical one based upon characteristic symptoms and signs. A diagnosis of rickettsialpox can be established retrospectively by documenting a fourfold rise in convalescent titers of complement fixation or indirect fluorescent antibodies using spotted fever group antigens. The diagnosis can also be confirmed by detection of the organism via immunostaining or polymerase chain reaction testing. (See 'Diagnosis' above.)

●The most common disease to mimic rickettsialpox is chickenpox. (See 'Differential diagnosis' above.)

●The treatment of choice for rickettsialpox is doxycycline (200 mg orally as a loading dose and then 100 mg orally every 12 hours) until the patient has been afebrile and clinically well for 48 to 72 hours. (See 'Treatment' above.)