Other Rickettsia Species

Description of Pathogen

Rickettsia prowazekii is a small, gram-negative, obligately intracellular, rod-shaped bacterium. R. prowazekii possesses a regularly arrayed surface autotransporter protein (OmpB) layer external to the cell envelope that has a peptidoglycan sacculus located between the inner cytoplasmic and lipopolysaccharide-containing outer membrane. It does not possess flagella. Both humoral and cellular immune responses are directed against the surface layer protein and result in protective immunity that is dependent on methylation of lysine residues in this protein. Two other proteins, Adr1 and Adr2, were identified initially as adhesins to host cells, but the latter appears to block complement-mediated killing of R. prowazekii . R. prowazekii grows freely in the cytoplasm of infected host cells and preferentially infects endothelial cells in humans. R. prowazekii is the prototype species of the typhus group (TG), which is differentiated from the more diverse and numerous rickettsial agents in the spotted fever group (SFG) by its lipopolysaccharide (LPS) group antigen and some biologic characteristics. ^, Complete genome sequence comparisons have been proposed as the basis for differentiating species of Rickettsia . ^, Numerous small RNAs have been identified in Rickettsia and proposed to play important regulatory roles in regulation of gene transcription in different environments. Unlike SFG rickettsiae, which can survive and replicate for several days after death of their host cells, TG rickettsiae rapidly die after killing their host cells. However, R. prowazekii can retain high aerosol infectivity and viability in dried louse feces. Similarly, it remains highly infectious after drying in media with high osmolarity and has been weaponized so that it could be used as an agent of bioterrorism. Consequently, R. prowazekii is a “select agent,” possession and distribution of which is tightly regulated in the US and other countries. The threat of such agents to pregnant women and their fetuses has been assessed recently. Genetic variants of R. prowazekii with different geographic distributions are known.

Epidemiology

Classic epidemic typhus is spread from infected to uninfected people by migration of the human body louse ( Pediculus humanus corporis ). ^{, ,} Infected lice defecate during feeding and excrete copious amounts of rickettsiae in their feces. Transmission occurs to non-immune humans when louse fecal material or crushed lice are inoculated into the bite site or skin abrasions or conjunctiva (more rarely), or when they are inhaled. The lice die from the rickettsial infection within 2 weeks but desiccated dead lice and fecal materials may remain infectious for much longer. Epidemic typhus is one of the classic plagues of humankind, having infected and killed millions of people in the preantibiotic era during epidemics until the middle of the 20th century. ^, However, major outbreaks still occur infrequently in sub-Saharan Africa, and sporadic cases continue to be reported from North Africa, Ethiopia, Kenya, Peru, Russia, and the US. Body lice live in clothing; classic epidemic typhus occurs typically in conditions where poverty, famine, and war, frequently accompanied by cold weather, lead to unhygienic conditions favoring louse infestation. Head and pubic lice have not been shown to be significant human vectors for epidemic typhus, although head lice can be infected with R . prowazekii in conditions suitable for transmission to humans. Besides the louse gut, hemocytes of infected lice appear to harbor live rickettsiae.

Humans, in whom organisms persist despite strong humoral and cellular immune responses, are the primary reservoir for R. prowazekii. Formerly infected people can suffer a relapse of typhus, known as Brill-Zinsser disease or recrudescent typhus . ^, The precise factors causing relapses are not well understood, but recrudescence of disease is thought to constitute the source of R. prowazekii that permits initiation of new outbreaks of louse-transmitted typhus. Because infestation with body lice is now uncommon in much of the world, and fewer people who experienced primary epidemic typhus now exist in the population, both primary epidemic typhus and herd immunity have declined throughout the world since the 1970s. Indigenous louse-borne epidemic typhus has not occurred in the US since 1922, but Brill-Zinsser disease occasionally is seen among immigrants from historically endemic foci of epidemic typhus or people infected in concentration camps. Healthcare personnel and military personnel may be at particular risk for infection. The last major outbreak occurred in Burundi and was first detected because of the fatal infection of an evacuated Swiss Red Cross worker.

In 1975, Bozeman and colleagues first reported a sylvatic cycle of R. prowazekii in southern flying squirrels ( Glaucomys volans ) in Florida and Virginia, but it is likely that this reservoir extends through much of the range of this squirrel in the eastern US. R. prowazekii can be transmitted experimentally between flying squirrels by squirrel lice ( Neohaematopinus sciuropteri ) and their fleas ( Orchopeas howardi ). About 40 cases of human sylvatic typhus infections, including several in children, have been reported in the eastern US. ^, Cases usually occur during the winter months when squirrels may enter houses. The mechanism by which disease is transmitted to humans is unclear, and although squirrel fleas occasionally bite humans, it is more likely that aerosolized infected ectoparasite feces are the primary source of infection. The genetic types of R. prowazekii from flying squirrels differ from European and African types. ^,

R. prowazekii has been detected in Hyalomma ticks in Ethiopia and Amblyomma ticks from Mexico. ^, If confirmed, this unusual source may account for sporadic cases of primary epidemic typhus that are not associated with human body lice, infected flying squirrels, or recrudescent typhus.

Clinical Manifestations

Epidemic typhus is fatal in 10%–50% of untreated patients and is more likely to be clinically severe or fatal in people with concurrent malnourishment or other disease. ^{, ,} Onset of epidemic typhus is abrupt and occurs 7–14 days after exposure, whereas Brill-Zinsser disease can occur >40 years after primary infection. Patients manifest high prostrating fever with severe headache, limb pains, and vomiting. The patient often appears vacant and semi-mute and can have epistaxis and a dry cough. The classical macular or maculopapular, sometimes petechial, rash appears 5–7 days after onset of symptoms; later it becomes purpuric. The exanthem, which may be difficult to see on dark skin, begins on the trunk and spreads to the arms and legs but rarely involves the palms, soles, or face. Constipation is common, and paralytic ileus can occur. Typhus infrequently induces diarrhea or splenomegaly, which helps in its differentiation from typhoid and malaria, respectively. A cough and pneumonia are observed in two-thirds of patients, and nervous system involvement (drowsiness, disorientation, and delirium) is frequent. In severe cases, a meningoencephalitic syndrome occurs with meningismus, tinnitus, and hyperacusis, followed by deafness, dysphoria, agitation, and coma. Thrombocytopenia, jaundice, and abnormal liver function can occur in severe cases. Survivors can experience hemiparesis, acute transverse myelitis, or peripheral neuropathy. Complications include secondary bacterial infections, myocarditis, and peripheral gangrene or venous thromboembolism. Convalescence is rapid and uneventful if appropriate antibiotic therapy is initiated early after onset of disease. Classic epidemic typhus in pediatric patients often is a milder illness and has a lower fatality rate compared with that in adults and elderly people. Intoxication syndrome and cardiovascular and neurologic symptoms usually are less pronounced. Observations from the pre-antibiotic era indicate that epidemic typhus in pregnant women clinically resembles Brill-Zinsser disease with a good prognosis and low mortality; however, spontaneous abortion and premature birth can occur in 20%–50% of pregnant patients.

In contrast to primary epidemic typhus, delirium is rarely noted in recrudescent typhus. Although Brill-Zinsser disease often is considered to be milder than primary disease, exceptions occur. Late in the second week of illness, fever and headache subside abruptly, and patients feel generally well. The clinical presentation of flying squirrel-associated typhus fever also appears to be milder than that observed in louse-borne epidemic typhus. Whether this difference in clinical presentation is related to the different strains associated with sylvatic R. prowazekii or to the relatively good nutrition, health, and supportive care in US cases is unknown.

Clinical diagnosis of epidemic typhus can be difficult because of its resemblance to influenza, typhoid fever, meningococcal meningitis, hemorrhagic fevers, infectious mononucleosis, sepsis, measles, and malaria.

Laboratory Findings and Diagnosis

The white blood cell count frequently is reduced with a relative lymphocytosis during the first week of epidemic typhus, and can be elevated as disease progresses. Eosinophils are decreased or absent during the entire febrile period. Anemia and increased erythrocyte sedimentation rate frequently are detected but return to normal after treatment. Nephritis occurs with azotemia and moderate amounts of albumin and granular casts in urine.

Diagnosis of epidemic typhus generally is suspected because of specific epidemiologic circumstances and clinical findings. Diagnosis of acute epidemic typhus can be made by polymerase chain reaction (PCR) assays for rickettsial DNA or RNA extracted from whole blood or the buffy coat fraction, or biopsies of the rash; PCR is sensitive and specific. ^, Detection of rickettsial DNA in squirrel tissues and ectoparasites provides alternative detection of the etiologic agent. ^, PCR assays, which distinguish typhus infections with R. prowazekii and R. typhi, also are available. More recently, loop-mediated isothermal amplification (LAMP) and recombinase polymerase amplification (RPA) assays for Rickettsia were developed. ^, Immunohistochemical procedures also can be applied to biopsy and ectoparasite samples. However, these procedures are available only in specialty laboratories, and prompt submission and correct handling of samples is essential for agent detection. Isolation is possible from acute phase blood and biopsy samples collected before initiation of antimicrobial therapy in laboratories with access to embryonated chicken eggs, susceptible animals, or antibiotic-free cell cultures. Isolation can require up to several weeks. Isolates of R. prowazekii are differentiated readily from other species of Rickettsia by genetic, biologic, and antigenic criteria.

The indirect immunofluorescence assay (IFA) is the current gold standard for serologic diagnosis of epidemic typhus. Diagnosis is based on a fourfold rise in immunoglobulin G (IgG) antibody titers between acute and convalescent paired sera to R. prowazekii antigen or a high single titer of antibody with compatible clinical symptoms. Other serologic procedures for the specific detection of TG antibodies include enzyme immunoassay (EIA), complement fixation, latex agglutination, dipsticks, and chromatographic flow assays. Commercial testing usually employs IFA or EIA methods. Brill-Zinsser disease elicits low IgM and greater IgG responses than primary epidemic typhus. The nonspecific Weil-Felix febrile agglutination test, which detects IgM antibodies to a typhus cross-reactive LPS epitope found in Proteus OX19 antigen, is not used in the US but is sometimes employed in other countries. Serologic cross-reactions can occur between TG and SFG of Rickettsia, and IgM antibodies can react with some Legionella and Proteus spp. Cross-absorption of sera for IFA testing or Western blotting analysis differentiates epidemic and murine typhus and excludes other cross-reactions.

Treatment

Treatment must be instituted before the diagnosis of epidemic typhus is confirmed by laboratory testing. Tetracyclines and chloramphenicol are effective against all forms of typhus infections, whereas ciprofloxacin and azithromycin have failed in the treatment of primary disease and Brill-Zinsser disease, respectively. ^{, ,} Doxycycline is the preferred treatment for adults and children of all ages. ^, Dosage is 4 mg/kg/day (maximal dose, 200 mg/day), given orally or intravenously, divided into doses every 12 hours for 7–10 days. A single dose of 200 mg of doxycycline orally for adults and 100 mg for children is efficient in the control of epidemics where continuous patient management can be difficult. Chloramphenicol (50 mg/kg/day divided into doses every 6 hours for children for 7–10 days) also is effective; however, the use of chloramphenicol has been associated with increased risk for fatal outcome and relapses in Rocky Mountain spotted fever and typhus. Marked improvement with defervescence should be apparent within 48 hours after initiating treatment, but other symptoms can persist for up to 1 week. Rickettsial methionine aminopeptidase has shown promise as a target for new therapeutics.

Prevention and Control

Sporadic cases of Brill-Zinsser disease can occur in the US, primarily among immigrants from areas endemic for epidemic typhus, but they pose little risk for spread except from individuals infested with body lice. Head lice have never been associated with outbreaks of epidemic typhus. No licensed vaccine is available. Exclusion of flying squirrels and their nests from domiciles to prevent concomitant exposure to their ectoparasites, use of pyrethrin-containing insecticides, and decontamination of infested clothing by washing with detergent at high temperatures are recommended for prevention and control.

Description of Pathogen and Epidemiology

Rickettsia typhi is a member of the TG of rickettsiae and closely resembles the other member of that group, R. prowazekii, in its genetic, biologic, and immunologic properties. ^{, , , ,} R. typhi replicates to higher titers in embryonated chicken eggs and is more infectious for laboratory mice and guinea pigs than R. prowazekii, but it is not regulated as a “select agent” in the US. Genetic analyses of R. typhi strains from the US, Africa, and Asia suggest the organism was distributed worldwide with rats by human activity from its origin in Southeast Asia and exhibits only small differences in pathogenicity and virulence. ^, R. typhi is the best model organism for the genus Rickettsia for investigations of protein functions and immunological responses because of its reduced genome size, greatest growth, and lethality for mice. Immunological studies have helped to elucidate the relative importance of CD4 and CD8 T cells, neutrophils, macrophages, NK cells, and cytokines in protective responses. ^,

Commensal rats of the genus Rattus are the primary zoonotic reservoirs for R. typhi . ^, The oriental rat flea ( Xenopsylla cheopis ) is the classic vector that transmits murine typhus to humans but six genera and seven species of flea, including the cat flea ( Ctenocephalides felis ), have been found to be naturally infected with R. typhi . Cats and peridomestic opossums infested with cat fleas have been implicated in the maintenance of R. typhi in the US; however, murine typhus from this source likely is rare. ^, Fleas are infected for life after feeding on R. typhi -infected rodents. The fleas shed organisms in their feces, and humans become infected through contact between flea feces and abraded skin, or possibly through inhalation of fecal material. Besides rats, fleas may be an important reservoir of R. typhi because they can transmit the organism transovarially to their progeny. Recent studies in Mexico have suggested a role for the tick Rhipicephalus sanguineus and dogs for maintenance of R. typhi . ^,

Murine typhus has been diagnosed throughout the world but is reported most frequently from warmer climates and coastal areas where Rattus and fleas flourish. Typically, seaports, coastal areas, and the major commercial arteries are disease-endemic sites. ^, During the 1930s and 1940s, approximately 2000–5000 cases of murine typhus were documented annually in the US. ^{, ,} After World War II, flea and rodent control programs caused a precipitous drop in the number of reported cases. The current prevalence and distribution of murine typhus in the US are unclear; infection has been reported most commonly from focal areas in California, Texas, and Hawaii. ^{, ,} Both sporadic cases and small outbreaks can occur. Disease can be imported by travelers returning to the US from southern Europe, Asia, and Africa. ^, People experiencing homelessness also are at risk for murine typhus. According to the World Health Organization, half of the travel-associated cases of murine typhus were diagnosed in August and September, and most tourists were returning from Africa and Southeast Asia. Epidemiologic studies have helped to elucidate underlying demographic risk factors contributing to transmission of murine typhus in different habitats around the world.

Clinical Manifestations

Murine typhus manifests with fever, chills, headache, and myalgia. ^, Although the disease generally is mild, up to 10% of adults require intensive care with mortality approaching 4% for untreated cases. Most cases of murine typhus in the US occur in adults, but children are infected frequently in many parts of the world. ^, Three large studies of cases of murine typhus in children aged <16 years from Texas provide the most complete clinical pediatric data available for the US. ^{, ,} Fever occurred in all patients 8–16 days after exposure; headaches occurred in 76% with frontal distribution and dengue-like intensity. Rash occurred in 63% with a median onset at 6 days of illness, whereas the triad of rash, fever, and headache was found in only 49% of patients. Rash is generally macular (50%) or maculopapular (25%), and less frequently was erythematous, petechial, or papular. Although flea bites were reported in only 34% of patients, potential patient contact with animals that likely were flea infested was found in 85% of the cases.

Nausea and vomiting occur during the early stage of illness in almost all infected adults. In contrast, in children, gastrointestinal tract symptoms occurred in 27%–46%, and pharyngitis, lymphadenopathy, and cough in 15%–20%. Pneumonitis, stupor, conjunctivitis, or photophobia occurred in only 5%–12% of children. Splenomegaly and hepatomegaly were not common in this series but have been described previously in populations in the tropics. Neurologic findings appear to be more common in adults (15%−45% in different studies) than in children.

Most patients with murine typhus are hospitalized, and many patients have signs of sepsis and shock. Murine typhus causes a systemic vasculitis, and multiorgan complications can include meningitis, meningoencephalitis, facial paralysis and paraparesis, hearing loss, ocular abnormalities including multifocal retinitis and Perinaud oculoglandular syndrome, splenic rupture, myocarditis, myositis, renal failure, and acute respiratory failure. ^{, , , ,} There are published reports of murine typhus being confused with COVID-19, Kawasaki disease, a brain tumor, glucose-6-phosphate dehydrogenase deficiency, and severe fever with thrombocytopenia syndrome. Cases presenting with fatal central nervous system inflammation, renal failure, fatal hemophagocytic lymphohistiocytosis, acute thrombocytopenia, and status epilepticus have been described.

Laboratory Findings and Diagnosis

Laboratory findings are nonspecifically abnormal in murine typhus in children. In the Texas case series, 81% had high erythrocyte sedimentation rate, 77% had a left shift in differential leukocyte count, 68% had absolute neutropenia, and 51% had absolute lymphopenia. Serum hepatic enzyme levels were measured infrequently but generally were abnormal. Serum electrolyte changes included hyponatremia (58%), hypokalemia (21%), and elevated serum creatinine (21%). C-reactive protein, procalcitonin, serum aspartate transaminase levels and white blood cells were elevated, and their decline correlated with defervescence following doxycycline treatment.

Although patients in pediatric case series can be confirmed serologically by IFA, diagnostic titers are present in only 15% of patients at 7 days and 62% by 14 days after onset of illness. More than 28 days are required for all patients to exhibit diagnostic titers. Serologic tests for murine typhus use R. typhi antigen and detect cross-reactive antibodies that usually are elicited during both epidemic and murine typhus infections but less frequently in SFG infections. ^{, ,} Antibody cross-absorption studies often are necessary to clearly distinguish murine and epidemic typhus. Differential serology to distinguish R. typhi from Rickettsia felis also may be necessary. ^{, , ,} Molecular tests that readily discriminate R. typhi , R. prowazekii, and R. felis are available. ^{, ,} Shell vial isolation of R. typhi has been evaluated and correlates well with PCR positive clinical samples. ^, Because fleas have high-density infections with R. typhi , PCR and immunologic detection of the agent in fleas are effective assays. ^,