Recognizing reemerging and recently described rickettsial infections in the United States.
MATERIALS AND METHODS
In order to assess the evolving epidemiology of rickettsial infectious diseases in the US, a descriptive review and analysis of the US scientific literature on rickettsial infectious diseases was conducted. Data sources describing emerging and re-emerging rickettsial diseases in the US were selected by various search engines, 1966-2010. Data sources extracted included case reports, case series, observational and longitudinal studies, active and passive surveillance investigations, and meta-analyses.
The Epidemiology of Rickettsial Infectious Diseases
The rickettsioses are caused by obligate, Gram-negative intracellular bacilli which infect the cytoplasm of endothelial lining cells and other target organ cells. The global epidemiology of the tick-borne, spotted fever causing rickettsiae has dramatically evolved since the transmission cycle of RMSF was first described by Ricketts in 1906 with (1) emerging new strains and diseases (Rickettsia slovaca-associated lymphadenopathy); (2) greater understanding of the highly conserved genome of several related species (R. africae-R. parkeri and the R. conorii subspecies); (3) wider geographic distribution and greater virulence of existing strains (R. rickettsii, R. conorii subspecies, R. australis); (4) unanticipated new tick vectors for some SFs (Rhipicephalus sanguineus for RMSF in the US); (5) cluster outbreaks of the tickborne SF rickettsioses in returning travelers (R. africae, causing African tick bite fever); (6) regional clusters and epidemic cycles of more severe SFs worldwide (RMSF in the US, Mediterranean SF [MSF] in Europe, and Queensland tick typhus [QTT] in Australia); and (7) much improved rapid immunological and molecular techniques now replacing older laboratory diagnostics, such as the Weil-Felix reactions and antibody titers on paired sera. (1-11)
The reasons for such changes in rickettsial SF epidemiology remain unexplained and may include (1) warming temperatures and increasing humidity; (2) more frequent drought-rain cycles; (3) residential development in preferred tick and mite ecosystems; (4) more competent tick and mite vectors given competitive advantages by environmental and genetic changes; (5) more frequent contact between ticks, mites, and humans outdoors and even in summer camp cabins; and (6) international trade and travel quickly and widely distributing arthropod vectors and their preferred animal hosts, especially rodents. (12)
The Microbiology and Pathophysiology of Rickettsial Infectious Diseases
The family Rickettsiaceae contains two genera. First, the genus Rickettsia, which is subdivided into the SF group of more than 20 species and the typhus group with only two species, Rickettsia prowazekii and R. typhi. These are causative pathogens of epidemic and murine (endemic) typhus respectively. Second, the scrub typhus-causing genus Orientia, which only contains one recognized species, Orientia tsutsugamushi. (6) Recently, a new transitional species of rickettsiae, Rickettsia felis transmitted by cat fleas, has been described that shares clinical and phylogenetic characteristics with both the SF and typhus groups. (13) The rickettsiae may be also stratified by transmitting arthropod vectors into the tick-borne SF group; the mite-transmitted rickettsioses, scrub typhus (O. tsutsugamushi) and rickettsialpox (R. akari); the cat flea-transmitted rickettsial infection (R. felis); and the louse (R. prowazekii) and flea-transmitted (R. typhi) typhus group. (6)
[FIGURE 1 OMITTED]
Rickettsiae thrive in arthropod salivary glands and gastrointestinal tracts and are transmitted during blood-feeding or during fecal contamination of intensely pruritic bite site wounds. Some rickettsia may also be transmitted by aerosols containing infected arthropods or their feces. (6) Once injected into the host, rickettsiae are initially distributed regionally via lymphatics with some species causing marked regional lymphadenopathy (Rickettsia slovaca). (6) Within 2 to 14 days (mean, 7 days), rickettsiae are disseminated hematogenously to the vascular endothelial lining cells and other cells of target organs and systems, including the gastrointestinal tract, central nervous system (CNS), lungs, liver, kidneys, and myocardium. (6) Rickettsiae gain entry into the cytoplasm of their host's cells in a Trojan Horse-like manner by using their outer membrane proteins (outer membrane protein A [OmpA] and B [OmpB) to stimulate endocytosis. (6) Once within the phagosomes of endothelial cells, rickettsiae escape to enter the cytosol or nucleus for rapid replication by binary fission, safe from host immune recognition and attack. (6)
The Spotted Fever Group Rickettsial Infections
The SF group rickettsioses, most of which are transmitted by ticks, share many common features in clinical presentations, including (1) incubation periods of approximately one week; (2) flu-like prodromes of high fever, fatigue, headache, myalgia, arthralgia, nausea, vomiting, and abdominal pain (that may mimic acute appendicitis in RMSF); (3) spotty rashes within three to five days of fever onset; and (4) necrotic eschars at tick-bite sites. Some SF rickettsial diseases may be "spotless" with no rashes, including RMSF in 10-15% of cases, complicating early differential diagnosis. (6) The tick-borne rickettsial infections that can cause spotty rashes include R. rickettsii (RMSF), R. conorii (MSF), R. australis (QTT), and R. africae/R. parkeri (African/North American tick bite fever) in about 50% of cases. (1, 9-11) The tickborne rickettsial infections that are associated with one or more necrotic eschars at tick-bite sites include R. conorii, R. australis, R. africae/R. parkeri, R. japonica, R. slovaca, R. aeschlimannii, R. felis, and R. honei. (1,9-11) The SF rickettsioses may vary in severity from causing multi-system organ failure (RMSF, MSF), to painful lymphadenopathy (R. africae/R. parkeri, R. slovaca), to central nervous system (CNS) involvement (R. felis), to mild or subclinical disease (R. aeschlimannii). (6,8,9)
Despite its confusing name, RMSF occurs in a distinct latitudinal band in the southeastern US, stretching from the panhandle of Oklahoma in the West to the Atlantic coast of North Carolina. After an average incubation period of one week, RMSF starts with a flu-like, febrile prodrome followed by a characteristic maculopapular, evolving-to-petechial rash in 85-90% of cases in three to five days (Figure 1). (2) The pathognomonic rash starts distally on the wrists and ankles and then spreads centripetally up the limbs (Figure 1). The pathophysiological mechanisms of petechial rashes and target organ system damage (CNS, lungs, heart) in all of the SF rickettsioses include vascular endothelial cell damage by microbial replication, vascular inflammation (vasculitis), and increased widespread vascular permeability, which may result in hypovolemic shock, oliguric pre-renal failure from acute tubular necrosis, cerebral edema, adult respiratory distress syndrome (ARDS), noncardiogenic pulmonary edema, myocardial dysfunction, congestive heart failure, and cardiogenic pulmonary edema. (6) Distal, digital skin necrosis may occur in severe cases of RMSF and QTT from vascular hypoperfusion (Figure 2). (6, 10) Cardiac vasculitis may manifest as myocarditis with intraventricular conduction blocks. Aside from petechial rash and thrombocytopenia, other hemorrhagic manifestations in RMSF and other SFs are relatively rare. (6, 9, 10) CNS complications in RMSF and other severe SF infections may include ataxia, photophobia, transient deafness, focal neurologic deficits, meningismus, meningoencephalitis, seizures, confusion, and coma. Pulmonary complications may include cough, alveolar infiltrates, interstitial pneumonitis, pleural effusions, pulmonary edema, and ARDS. (6, 8-10)
Rickettsia parkeri and Maculatum Disease in the Southern United States
Rickettsia parkeri, the causative agent of disease, was initially isolated from the Gulf Coast tick, Amblyomma maculatum, in 1937. (11) Although phylogenetically related to Rickettsia africae, the causative agent of African tick-bite fever in Sub-Saharan Africa, R. parkeri, was, until recently, felt to be non-pathogenic in man in the US. (9, 11) Figure 3 depicts a heralding eschar on the shin from the bite of a tick infected with R. parkeri.
In 2004, Paddock and co-authors investigated a case of tick-bite fever in Virginia associated with multiple eschars that resembled African tick-bite fever. It was misdiagnosed as mite-transmitted rickettsialpox and treated successfully with doxycycline. (14) Polymerase chain reaction (PCR) analysis of biopsies from tick-bite eschars ruled out RMSF and rickettsialpox (R. akari) and identified R. parkeri as the causative agent. (14) The authors concluded that R. parkeri was an often unrecognized cause of a mild tick-transmitted febrile illness accompanied by multiple eschars, maculopapular rash, regional lymphadenopathy, and transient leukopenia and transaminitis that closely resembled African tick-bite fever and responded rapidly to antibiotic therapy with oral doxycycline. (14) In addition, the authors and other investigators have now concluded that because of the extensive antibody cross-reactivity among rickettsial SF-group antigens, previous cases of R. parkeri infection may have been misdiagnosed as RMSF or rickettsialpox. (14, 15)
[FIGURE 2 OMITTED]
In 2007, Sumner and co-authors serologically reconfirmed cases of Maculatum disease or infections with R. parkeri in patients in both Virginia and Mississippi and detected R. parkeri infection by DNA PCR in Gulf Coast ticks (Amblyomma maculatum) in Georgia, Florida, Mississippi, Kentucky, Oklahoma, and South Carolina. (16) The authors concluded that (1) Gulf Coast ticks were indeed transmitting R. parkeri throughout the Gulf South and that (2) Maculatum disease was frequently misdiagnosed as other tick-borne rickettsial infectious diseases, primarily RMSF, due to immunological cross-reactivity on routine serological assays. (16) The authors recommended differentiation of R. parkeri from R. rickettsii infections and confirmation of R. parkeri infections by Western blot analysis with the 120-kD protein of R. parkeri or by PCR techniques. (16)
The Diagnosis and Treatment of Rickettsial Spotted Fever Group Infections
A history of tick bites, bite site eschars, fever, maculopapular rashes, and painful regional lymphadenopathy will help to establish the correct diagnosis, especially in the absence of adequate molecular diagnostic laboratory services. The precise laboratory diagnosis of tick-borne riskettsial SFs may be established by microbiological isolation of the causative organisms from skin biopsies or blood cultures; nonspecific immunofluorescent antibody tests that often cross-react with many SF antigens; other immunocytological techniques to demonstrate intracellular rickettsiae; and PCR to identify and to speciate rickettsial DNA or RNA.
Antibiotic treatment mainstays for the tick-borne rickettsial SFs remain the tetracyclines for most cases and chloramphenicol for severe multi-system diseases and during pregnancy. (6) Although the quinolones, azithromycin, and clarithromycin may be as effective as tetracyclines and chloramphenicol in the treatment of some SFs, they are not recommended for initial therapy. (6) Although short, one to two-day courses of doxycycline have been reported to be as successful as 10-day courses in some SF infections (MSF, cat flea SF). Such treatment strategies have not been tested in randomized controlled trials in other SF infections and are also not recommended. (6) Most authorities now recommend that doxycycline, chloramphenicol, or ciprofloxacin for tetracycline-allergic patients be continued for a minimum or seven days or until the patient has been afebrile for at least 72 hours and is improving clinically. (6)
The Mite-Transmitted Rickettsial Infections
Only biting larvae of Asian scrub typhus chiggers (Leptotrombidium species) transmit scrub typhus caused by Orientia tsutsugamushi (formerly Rickettsia tsutsugamushi); and only biting house mouse mites (Liponyssoides sanguineus) transmit rickettsialpox caused by Rickettsia akari. Scrub typhus chiggers are the main environmental reservoirs of O. tsutsugamushi in tropical endemic regions, with much smaller secondary reservoirs in wild rodents. (6) Common house mice are the zoonotic reservoirs of R. akari, not only in crowded urban apartment buildings in large US cities but also in mice-infested buildings in more rural locations worldwide, including the southern US. (15) Mite-transmitted scrub typhus and rickettsialpox present similarly. Fortunately, both infections respond to treatment with oral tetracycline, oral doxycycline, or intravenous chloramphenicol, which is not recommended, except in life-threatening infections, due to its bone marrow toxicity. (20)
[FIGURE 3 OMITTED]
Rickettsialpox in the United States
The house mouse mite, Liponyssoides sanguineus, maintains a rickettsial zoonosis in its preferred house mouse (Mus musculus) reservoir and can transmit rickettsialpox caused by Rickettsia akari through bites. (15) Although initially described in clusters in crowded apartment buildings in large US cities, including New York, Boston, Cleveland, Philadelphia, and Pittsburgh, rickettsialpox has now been reported in rural areas of the southern US (North Carolina) and eastern Europe. (15) Many experts now feel that rickettsialpox is underreported and distributed in silent sylvan cycles worldwide. (15) The incubation period and initial clinical manifestations of rickettsialpox mirror those of scrub typhus with eschar formation at the bite site within 10-12 days, followed by fever, chills, severe headache, conjunctival injection, and truncal maculopapular then vesicular rash. (15) Unlike scrub typhus, hearing loss does not occur and regional lymphadenopathy is also uncommon. (15) Unlike scrub typhus, complications are rare but may include thrombocytopenia and interstitial pneumonia. (15)
A Transitional Group Rickettsial Infection: Cat Flea-Transmitted Rickettsiosis as an Emerging Global Threat
In 1990, Adams and co-investigators described a new rickettsia-like organism resembling R. typhi in the cytoplasm of midgut cells in cat fleas obtained from El Labs, a biological laboratory supply company in Soquel, California. (17) The new organism was initially named the ELB agent after the biological supply company, and early phylogenetic analysis suggested that the new organism belonged to the typhus group due to shared absence of the gene encoding for OmpA. (18,19) Further molecular characterization of the organism's genome by Bouyer et al in 2001, however, provided conclusive evidence that the OmpA protein in R. felis was not completely absent, but only truncated due to premature stop codons in its sequence. (20) These findings led Gillespie and colleagues to propose R. felis as a member of a new transitional group of rickettsiae phylogenetically positioned between the SF group (with OmpA) and the typhus group (without OmpA). (13) By 2002, cat fleas (Ctenocephalides felis) infected with R. felis were reported in the US, Brazil, and Mexico. (21-25)
In a 2008 meta-analysis of potential flea vectors and mammalian hosts infected with R. felis worldwide during 1992-2007, Perez-Osorio and co-authors described R. felis infections in several flea species, including dog (C. canis) and rat (Xenopsylla cheopsis) fleas, and in a variety of domestic and wild animal ectoparasite hosts, including cats, dogs, horses, sheep, goats, gerbils, monkeys, opossums, hedgehogs, and rodents. (26) The authors reached the following conclusions regarding the new rickettsial species: (1) R. felis infections have now been reported to occur throughout the world in fleas, mammals, and humans. (26) (2) Although R. felis infections have been found in several species of fleas and a few other ectoparasites (ixodid ticks), cat fleas are the predominant vectors because only these insect vectors are able to maintain R. felis infections in their progeny through transovarian and transstadial transmission. (26) (3) The clinical features of R. felis infections in humans resemble those of both SF and typhus group rickettsiae, as well as dengue and leptospirosis. Such similarities could precipitate diagnostic dilemmas, especially in areas with limited molecular diagnostic capabilities, and lead to improper antibiotic therapy of potentially fatal infections. (26) (4) The global distribution of infected cat fleas and the presence of R. felis in ectoparasites infesting such a diverse range of wild and domesticated mammalian hosts make R. felis a significant, emerging global threat to world health. (26)
The first human infection with R. felis was reported in the US in 1994 with manifestations resembling murine typhus and including high fever, myalgias, and maculopapular rash. (27) In 2000, Zavala-Velaquez and co-investigators in Mexico described three more cases of R. felis infections in patients having contact with fleas or animals known to be infested with fleas. (28) These cases more closely resembled SF rickettsial infections with high fevers, headaches, arthralgias, myalgias, eschars, rashes, and evidence of CNS involvement with photophobia, hearing loss, and meningismus. (28) In 2002, Richter and colleagues reported the first case of autochthonous R. felis infections in Europe in a German couple documented by PCR, demonstrating that R. felis infections were not confined to the Americas. (29) Following the European cases, other human cases have been reported throughout the world in more than 20 countries on five continents. (26)
In summary, R. felis transitional group rickettsial infections can occur anywhere in the world and cause serious multi-system infections; produce cross-reacting antibodies to other rickettsiae; are best diagnosed by molecular techniques, such as PCR, rather than by serology; and should be treated immediately with oral or intravenous doxycycline (100 mg po bid x 7-10 days, or at least for 72 hours after fever resolves). (26) R. felis infections have likely been underestimated over the years and misdiagnosed as dengue, malaria, leptospirosis, typhus, or other rickettsial infections, especially sylvatic or murine (R. typhi) typhus in the US.
The Typhus Group Rickettsial Infections
Only two pathogenic rickettsial species are classified in the typhus group: (1) Rickettsia prowazekii, the causative pathogen of human body louse-borne epidemic typhus and its milder recrudescence (Brill-Zinsser disease), and flying squirrel-associated epidemic or sylvatic typhus in the eastern US; and (2) Rickettsia typhi, the causative pathogen of murine (endemic) typhus worldwide.
Flying Squirrel-Associated Epidemic Typhus in the Eastern United States, 1976-2006
In louse-borne typhus epidemics, humans in cold, crowded, and unsanitary living conditions serve as the major reservoir for R. prowazekii. The only other known reservoir for R. prowazekii documented in the US has been in southern flying squirrels (Glaucomys volans) or contact with their nests, secretions, dander, or ectoparasites (fleas or lice). (30, 31) Since 1976, there have been more than 40 cases of PCR-confirmed R.prowazekii typhus in the eastern US, with all cases characterized by fever, chills, headache, myalgia, arthralgia, nausea, abdominal pain, and a variety of neurological manifestations ranging from photophobia to ataxia, aphasia, and confusion. (30, 31) All patients recovered rapidly following treatment with doxycycline; contact with flying squirrels or their nests was documented in most cases. (30, 31)
Murine Typhus in the Southwestern United States
The classical vector for R. typhi-caused murine typhus worldwide has been the rat flea (Xenopsylla cheopsis), which maintains R. typhi within its own species by transmitting infection congenitally to its progeny (transovarian transmission) and horizontally from infected flea to rat (Rattus spp.) to uninfected flea. When infected rat fleas bite humans, their rickettsiae-laden feces are scratched into very pruritic bite wound sites. In a recent reversal of disease ecology in the southwestern US (especially Texas), murine typhus is now maintained in a new reservoir, opossums, and transmitted from infected opossums to man by several flea species, including rodent and cat fleas. (32)
Cat fleas are frequently infected with either R. typhi or R. felis. (33,34) As a result, human cases of R. felis rickettsiosis are often underreported or misdiagnosed as murine typhus due to serological cross-reactions, especially in regions with limited molecular diagnostic capabilities. (35) Since typhus and transitional group rickettsial infections are potentially fatal, most authorities recommend empirical treatment with doxycycline based on clinical presentations and epidemiological features while awaiting rickettsial species confirmation by PCR at state and federal public health laboratories. (35)
The Prevention and Control of Ectoparasite-borne Rickettsioses
There are a number of effective strategies that can be used in the prevention and control of ectoparasite-borne infectious diseases, including immunization, personal protective measures, landscape management, and wildlife management. There are no available immunizations for the tick, mite, flea, or body louse-transmitted rickettsial infections in the US.
Prophylactic antibiotics following presumed ixodid tick bites with eschars have been recommended for the primary prevention of some tick-borne infections. A randomized clinical trial found that a single 200 mg dose of doxycycline administered within 72 hours of a tick bite was 87% effective in preventing Lyme disease. (37) In addition, doxycycline, 200 mg po daily, may provide effective chemoprophylaxis for scrub typhus in endemic areas of the tropics. (36)
Personal protective measures to prevent ectoparasite-transmitted diseases include wearing appropriate clothing, using insect repellants, and performing regular tick and other ectoparasite checks. Wearing long pants tucked into socks, long-sleeved shirts, and light-colored clothing can aide in keeping insects off of the skin and in making them easier to spot on clothing. Impregnating clothing with permethrin, routinely performed by the military on maneuvers, is a highly effective repellant against ticks and other insects. The topical application of insect repellants containing 20-50% formulations of N, N-diethyl-meta-toluamide (DEET), or 19-20% picardin directly on the skin is another effective and recommended measure. Following disasters and population displacements, epidemics of louse-borne typhus have been curtailed by delousing with lindane powder, washing clothes in hot water, and applying 1% permethrin powder to bedding and the inner and outer seams of clothing at six-week intervals. (36)
Most patients who develop ectoparasite-borne infections will not recall insect bites, as these diseases are often transmitted by diminutive nymphal insects. Nevertheless, insect localization and removal as soon as possible, preferably within 36 hours, remain recommended strategies to prevent ixodid tickborne rickettsial diseases. Ticks should always be removed with forceps (or tweezers), not fingers (as squishing ticks can transmit several tickborne diseases across dermal barriers or create infectious aerosols), and in contiguity with their feeding mouthparts, rather than burning ticks with spent matches or painting embedded ticks with adhesives or nail polishes.
Recent environmental changes and human behaviors now place humans, wild and domestic animal reservoirs, and ectoparasitic insect vectors of rickettsial infections together outdoors for longer periods in warming ecosystems worldwide. Such ecosystems support vector breeding, blood-feeding, and rickettsial disease transmission among new mammalian reservoirs, such as flying squirrels for epidemic typhus and opossums for murine typhus. Better prevention and treatment strategies for ectoparasite-borne rickettsial diseases are indicated now before the small and highly conserved genomes of the ectoparasite-transmitted rickettsial diseases re-assort their nucleic acids with their new ectoparasite vectors and vertebrate hosts and develop antimicrobial resistances (especially to tetracyclines) or superpathogen capabilities either by nature's own design or man's pursuit of biological terror weapons.
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James H. Diaz, MD, MPH & TM, DrPH, FACPM
Dr. Diaz is a Professor of Public Health and Preventive Medicine, Program Head of the Environmental and Occupational Health Sciences School of Public Health at Louisiana State University Health Sciences Center in New Orleans. In addition, he is Professor of Anesthesiology/Critical Care Medicine in the School of Medicine at LSUHSC-NO.
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|Author:||Diaz, James H.|
|Publication:||The Journal of the Louisiana State Medical Society|
|Date:||Nov 1, 2011|
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