Rickettsial Diseases

Introduction

Infectious agent

Rickettsial infections are caused by various obligate intracellular bacteria within the order Rickettsiales and genera Rickettsia, Orientia, Anaplasma, Ehrlichia, "Neoehrlichia," and Neorickettsia (Table 4.16.1). Rickettsia spp. have been classically divided into the typhus group and spotted fever group (SFG). Orientia tsutsugamushi and 2 new Orientia species comprise the scrub typhus group. The rickettsial pathogens (and diseases) that travelers are more likely to encounter during travel outside the United States include Ehrlichia species (ehrlichiosis), Rickettsia africae (African tick bite fever), Rickettsia conorii (Mediterranean spotted fever), O. tsutsugamushi (scrub typhus), Anaplasma phagocytophilum (anaplasmosis), Rickettsia rickettsii (known as both Rocky Mountain spotted fever and Brazilian spotted fever), and Rickettsia typhi (known as flea-borne typhus, endemic typhus, and murine typhus). African tick bite fever is the most commonly diagnosed rickettsial disease among international travelers, although Rocky Mountain spotted fever among travelers from Mexico is a growing concern. Many other rickettsial agents cause human infections across the globe, but the true burden of disease and full spectrum of clinical illness are not well understood.

Table 4.16.1: Classification, primary arthropod vector, and host association of rickettsiales known to cause disease in humans

Transmission

Rickettsial pathogens (except for Neorickettsia sennetsu) are transmitted by arthropods such as fleas, lice, mites, and ticks. Most rickettsial pathogens are transmitted by bites from these ectoparasites. For some rickesttsial pathogens, transmission can occur by direct inoculation of infectious fluids or feces from the ectoparasites into bite site(s), abraded skin, or the conjunctiva. Inhaling infectious material can also initiate infection for some of these organisms, but this is uncommon. Although rare, transmission of some rickettsial pathogens has occured through transfusion of infected blood products or organ transplantation.

Vectors that transmit each rickettsial species within the order Rickettsiales are listed in Table 4.16.1. We discuss select rickettsial pathogens and their vectors here.

Epidemiology

All age groups are at risk for rickettsial infections during travel to endemic areas, and both short- and long-term travelers are at risk for infection. The risk of transmission is higher for travelers who participate in outdoor activities, those with close proximity to wild or domestic animals, and during times of the year when the feeding activities of the appropriate vector species and life stage are highest. However, rickettsial infections can occur throughout the year in many parts of the world. Because the incubation period for most rickettsial diseases is 5–10 days, travelers can experience signs and symptoms during their trip or within 1–2 weeks after returning home. The most commonly reported rickettsial diseases in travelers include spotted fevers (African tick bite fever and Mediterranean spotted fever), murine typhus, and scrub typhus. Healthcare professionals should be aware that travelers can also acquire other rickettsioses that are often specific to certain global regions with a diverse range of clinical symptoms. These diseases, including those caused by emerging and newly recognized species, are not well known by many healthcare professionals, and diagnostic testing is not readily available except at specialized laboratories (Table 4.16.1).

Tick-borne spotted fever rickettsioses are the most frequently reported travel-associated rickettsial infections. African tick bite fever, caused by R. africae, is the most commonly reported rickettsial infection acquired during travel and the second-most common cause of fever, after malaria, in travelers returning from Sub-Saharan Africa. Travelers who go on safari—especially those traveling to national parks, game hunters, and ecotourists to Sub-Saharan Africa—are at increased risk for African tick bite fever. Cases commonly occur in clusters among travel groups; the diagnosis of African tick bite fever in a member of a family or tourist group should alert other travelers with similar exposures to seek medical care if they develop signs and symptoms compatible with this disease. R. africae is also endemic to several islands of the West Indies in the Caribbean and imported cases have been described.

Mediterranean spotted fever is a tick-borne illness caused by R. conorii. It is most commonly found throughout the Mediterranean basin region of Europe, Africa, and the Middle East, but cases have also been reported from India and Sub-Saharan Africa. Rocky Mountain spotted fever (also known as Brazilian spotted fever and other local names) is a tick-borne disease caused by R. rickettsii. It occurs throughout much of the Western Hemisphere, and cases are reported from Canada, the United States, Mexico, and many countries of Central and South America, including Argentina, Brazil, Colombia, Costa Rica, and Panama. Clusters of illness may be reported in families or in geographic areas. Contact with dogs in rural and urban settings and outdoor activities such as hiking, hunting, fishing, and camping increase the risk of infection. More recently, Rocky Mountain spotted fever in northern Mexico associated with dogs is an emerging public health concern.

Scrub typhus, caused by Orientia spp., is transmitted by larval stages of trombiculid mites encountered in high grass and brush. Scrub typhus is endemic to Japan, Southeast Asia, Indonesia, eastern Australia, China, the Indian subcontinent, and some regions of south-central Russia. In these regions, more than 1 million cases of scrub typhus occur annually, often in farmers or other occupationally exposed people. Most travel-acquired cases of scrub typhus are reported during visits to rural areas in countries where O. tsutusgamushi is endemic and are associated with outdoor activities such as camping, hiking, and rafting. While urban cases have also been described, the risk to travelers is not well defined. Recently, cases of disease have been described in the United Arab Emirates and Chile that were caused by newly recognized species of Orientia, including "Orientia chuto" and "Orientia chiloensis." There have not been any documented travel-associated cases of infection with these 2 pathogens, but this disease should also be considered in travelers to these regions who present with consistent symptoms.

Flea-borne rickettsial infections, caused by R. typhi and Rickettsia felis, are distributed globally and particularly in and around urban port cities and coastal regions with large rodent populations. Those exposed to flea-infested cats, dogs, or peridomestic rodents while traveling in endemic areas are at increased risk for flea-borne rickettsioses, such as murine typhus (R. typhi) and cat flea rickettsiosis (R. felis). Murine typhus has been reported among travelers returning from Asia, Africa, and the Mediterranean Basin. In the United States, most cases are reported from Hawaii, California, and Texas. Recently, there has been an increase in the number of reported cases of murine typhus in California and Texas. R. felis has been identified in several invertebrate hosts worldwide and has been reported as a cause of febrile illness in people in Africa.

Rickettsialpox, caused by Rickettsia akari, is transmitted by house mouse mites (Liponyssides sanguineus) and circulates in urban centers in Ukraine, South Africa, Korea, the Balkan states, and the United States. Outbreaks of rickettsialpox most often occur after contact with infected peridomestic rodents and their mites, especially during natural die-offs or exterminations of infected rodents. These events cause the mites to seek out new hosts, including humans. Although it is likely that infested urban rodents are the major driver of human cases, R. akari has also been identified in some wild rodent populations.

Louse-borne typhus, also known as epidemic typhus, is caused by Rickettsia prowazekii and is transmitted by the human body louse. While this disease was formerly the cause of large epidemics in urban areas and among soldiers, since 1950 this disease has primarily occurred in refugee camps or among incarcerated populations where limited access to hygienic services leads to increased risk of human body lice. Because body lice spread when clothing or blankets are shared, outbreaks often occur during the colder months. Travelers who provide medical or humanitarian aid to refugee camps and impoverished regions affected by war, famine, or natural disasters are at the highest risk for epidemic typhus. Recent foci of epidemic typhus have been identified in the Andes regions of South America and some parts of Africa (including, but not limited to, Burundi, Ethiopia, and Rwanda). R. prowazekii infections leading to epidemic spread have not occurred in the United States for the past century; however, the native southern flying squirrel is a zoonotic reservoir, and sporadic cases of sylvatic transmission have occurred when these squirrels invaded houses or cabins.

Ehrlichiosis, caused by predominantly by Ehrlichia chaffeensis, Ehrlichia ewingii, and Ehrlichia muris euclairensis, and anaplasmosis, caused predominantly by Anaplasma phagocytophilum, are commonly reported tick-borne infections in the United States. Infections with these organisms, as well as other Ehrlichia spp. and Anaplasma spp., have been reported in Europe, Africa, Asia, and South America. There are limited data on travel-associated cases of ehrlichiosis and anaplasmosis.

Sennetsu fever, caused by Neorickettsia sennetsu, occurs in Japan, Malaysia, Thailand, and other parts of Southeast Asia. This disease can be contracted from eating raw fish infested with neorickettsiae-infected flukes.

Clinical presentation

The symptoms of rickettsial infections are non-specific and can be difficult to diagnose, even for healthcare professionals with experience treating these diseases. Classically, symptoms include the "rickettsial triad" of fever, headache, and rash, but these symptoms are variably present and this triad is not a reliable means of diagnosis. Clinical presentations vary with the causative agent and patient. Symptoms common to many rickettsial diseases include fever, headache, malaise, rash, nausea, or vomiting, which typically occur within 1 week of infection. Many rickettsioses are accompanied by a maculopapular, vesicular, or petechial rash, or sometimes a dark necrotic lesion, known as an eschar, at the site of the tick or mite bite.

Although most rickettsial diseases cause mild to moderate illness, some have the potential to cause life-threatening infection. Rocky Mountain spotted fever, scrub typhus, Mediterranean spotted fever, murine typhus, and epidemic typhus can be life-threatening, particularly if administration of appropriate antibiotics is delayed. Prompt treatment with tetracycline-class antibiotics (most commonly doxycycline) is essential. Early treatment saves lives and prevents long-term sequelae. Early clinical symptoms of rickettsial diseases often present with similar signs and symptoms to other tropical diseases and can have similar geographical distribution and seasonality.

Rocky Mountain spotted fever is the most severe spotted fever rickettsiosis. Initial symptoms include fever, headache, nausea, and abdominal pain that can rapidly progress to septic shock and even death. A maculopapular or petechial rash is commonly reported, although this rash may not occur until late in the illness course, and eschars are rarely seen. Case fatality rates of 20%–40% are seen among patients for whom antibiotic treatment is delayed. Mediterranean spotted fever can also be life-threatening and should be suspected in patients with fever, rash, and eschar after recent travel to North Africa or the Mediterranean basin. African tick bite fever is typically milder than other spotted fever group rickettsioses. It should be suspected in a patient who presents with fever, headache, myalgia, and an eschar after recent travel to Sub-Saharan Africa or the Caribbean. Regional lymphadenopathy is also common in patients with African tick bite fever. Many patients may not remember a tick bite and not all will present with eschars. Although African tick bite fever is typically mild, recovery is faster with appropriate treatment.

Scrub typhus presents with fever, headache, and myalgia; lymphadenopathy, respiratory symptoms, encephalitis, and eschars may also occur. The respiratory sympoms are present in approximately two-thirds of patients, and severity ranges from mild cough to acute respiratory distress syndrome. This disease should be suspected in travelers returning from endemic areas. Scrub typhus can be fatal if not treated appropriately.

Patients with murine typhus usually present with a moderately severe but often otherwise non-specific febrile illness; approximately half of patients will develop a maculopapular rash, generally appearing on the trunk. The fever can persist for up to 2 weeks in the absence of treatment. Although generally less severe than diseases such as Rocky Mountain spotted fever or scrub typhus, patients can develop organ failure or other manifestations requiring hospitalization, and death can occur in some cases.

Ehrlichiosis and anaplasmosis also present as a non-specific febrile illness, although they are less commonly reported in travelers. Cytopenias, particularly leukopenia and thrombocytopenia, are common and should heighten suspicion for these diseases. Other clinical signs and symptoms are similar to other rickettsioses. Rash may be seen in some children with ehrlichiosis, but rash is not a feature of anaplasmosis.

Sennetsu fever presents with fever, weakness, lymphadenopathy, and hepatosplenomegaly, and the symptoms can resemble infectious mononucleosis. Although this disease is rarely reported in endemic regions, serologic evidence suggests that it may be an underrecognized cause of fever in these regions.

Diagnosis

Timely diagnosis and initiation of appropriate antibiotic therapy for rickettsial infections rely on clinical recognition and an appropriate epidemiological context. There are limited diagnostic modalities available, particularly during acute illness. Serologic testing provides retrospective confirmation of rickettisal infection and is most interpretable when acute- and convalescent-phase serum samples are compared. In these circumstances, a ≥4-fold rise in antibody titer between paired specimens taken 2–4 weeks apart (some infections require more than 28 days to develop a seroconversion) in indirect immunofluorescence antibody (IFA) assays is diagnostic. Commercial laboratories offer some serologic testing for rickettsioses, anaplasmosis, ehrlichiosis, and scrub typhus. Testing is available through CDC for serologic tests using rickettsial antigens not routinely available through commercial laboratories. Because of cross-reactivity of antigens, some antibodies may react in group-targeted serology, limiting identification to the group or genus rather than species-specific level.

During acute illness, PCR assays and immunohistochemical analyses may be helpful for diagnosing many of these diseases, but the clinical utility of diagnostic results is highly dependent upon the type and timing of specimen submitted. If an eschar is present, a swab or biopsy sample of the eschar can be evaluated by PCR to provide a species-specific diagnosis. PCR evaluation of eschar specimens is sensitive and realiable and should be pursued, but not all rickettsial infections are associated with eschars. Biopsy specimens of rash lesions or whole blood specimens can also be evaluated by PCR assays, but these specimens are generally less sensitive than samples derived from an eschar due to the relatively lower concentration of rickettsial DNA in blood and biopsy specimens compared to eschar swabs. Blood is often positive by PCR only after the disease has progressed significantly and the patient is severely ill.

If ehrlichiosis or anaplasmosis is suspected, PCR performed using whole blood provides the best diagnostic test while symptomatic. A buffy coat may provide presumptive evidence of infection if examined to identify characteristic intraleukocytic morulae, but this is a specialized test requiring trained operators and may not be widely available.

Ehrlichiosis, anaplasmosis, and spotted fever rickettsiosis (including African tick bite fever) are nationally notifiable diseases in the United States, including those diagnosed as imported cases.

Treatment

Doxycycline is the treatment of choice for all rickettsial infections (100 mg by mouth twice daily for a minimum of 5–7 days; or 2.2 mg/kg by mouth twice daily for children <45 kg). Treatment of patients with possible rickettsioses should be started as soon as the disease is suspected. Initiation of treatment should never be withheld pending confirmatory testing because certain infections can be rapidly progressive and early treatment reduces morbidity and mortality. Immediate empiric treatment with a tetracycline is recommended for patients of all ages. Recent data have shown that there is no evidence to support discoloration of dental enamel in children <8 years of age taking short courses of doxycycline. There are limited available data to support the efficacy of other antibiotics for rickettsial infections. Chloramphenicol may be an alternative in some cases of rickettsial infection, such as persons with tetracycline allergies or tetracycline intolerance or pregnant women, but its use is associated with higher case fatality rate, particularly for Rocky Mountain spotted fever. In some areas, tetracycline-resistant scrub typhus has been reported and azithromycin may be an effective alternative. For severe cases of scrub typhus, the combination of intravenous azithromycin and doxycycline may lead to more rapid resolution of fever. Limited clinical experience has shown that A. phagocytophilum and R. africae infections respond to treatment with rifampin, which may be an alternate drug for some pregnant or doxycycline-intolerant patients. Expert advice from an infectious disease specialist should be sought if alternative treatments are being considered.

Prevention

No vaccine is available for preventing rickettsial infections. Antibiotics are not recommended for prophylaxis of rickettsial diseases and should not be given to asymptomatic people following suspected exposure.

Travelers should minimize exposure to potentially infectious arthropods (including lice, fleas, ticks, mites) and close contact with animal hosts (particularly rodents, free-roaming dogs, and wildlife). Travelers can reduce their risk of infection by using approved insect or tick repellents on skin and clothing, performing self-examination after visits to vector-infested areas, and wearing protective clothing. These precautions are especially important for people with underlying immunosuppressive conditions because they may be more susceptible to severe disease (for more detailed information, see Mosquitoes, Ticks, and Other Arthropods chapter).

Acknowledgments

The following author contributed to the previous version of this chapter: Christopher Paddock.