Etiology

Murine typhus is caused by R. typhi, a rickettsia transmitted from infected fleas to rats, other rodents, or opossums and back to fleas. Transovarial transmission (passage of the organism from infected fleas to their progeny) in fleas is inefficient. Transmission depends on distribution by the flea to uninfected mammals that become transiently rickettsemic and transmit the organism to uninfected fleas.

Rickettsia felis is a novel agent species identified as a cause of a murine typhus-like illness worldwide. This new rickettsia is genetically a member of a transitional Rickettsia group and is capable of highly efficient transovarial transmission in cat fleas. This organism is found in cat fleas obtained from areas endemic for murine typhus in the USA and increasingly worldwide.

Epidemiology

Murine typhus has a worldwide distribution and occurs especially in warm coastal ports, where it is maintained in a cycle involving rat fleas (Xenopsylla cheopis) and rats (Rattus species). Peak incidence occurs when rat populations are highest during spring, summer, and fall. In the USA, the disease is most prevalent in south Texas and southern California, although seroprevalence studies among children indicate a higher than anticipated rate of infection broadly across the southeast and south-central USA, expanding the endemic areas in which pediatricians must be alert for this infection. In the coastal areas of south Texas, the disease is seen predominantly from March through June and is associated with opossums, cats, and cat fleas (Ctenocephalides felis).

Transmission

R. typhi normally cycles between rodents or mid-size animals such as opossums and their fleas. Human acquisition of murine typhus occurs when rickettsiae-infected flea feces contaminate flea bite wounds.

Pathology and Pathogenesis

R. typhi is a vasculotropic rickettsia that causes disease in a manner similar to R. rickettsii (Chapter 220.1). R. typhi organisms in flea feces deposited on the skin as part of the flea feeding reflex are inoculated into the pruritic flea bite wound. After an interval for local proliferation, the rickettsiae spread systemically to infect the endothelium in many tissues. As with spotted fever group rickettsiae, typhus group rickettsiae infect endothelial cells, but unlike the spotted fever group rickettsiae, they polymerize intracellular actin poorly, have limited intracellular mobility, and probably cause cellular injury by mechanical lysis after accumulating in large numbers within the endothelial cell cytoplasm. Intracellular infection leads to endothelial cell damage, recruitment of inflammatory cells, and vasculitis. The inflammatory cell infiltrates bring in a number of effector cells, including macrophages that produce proinflammatory cytokines, and CD4, CD8, and natural killer lymphocytes, which can produce immune cytokines such as interferon-γ or participate in cell-mediated cytotoxic responses. Intracellular rickettsial proliferation of typhus group rickettsiae is inhibited by cytokine-mediated mechanisms and nitric oxide–dependent and –independent mechanisms.

Pathologic findings include systemic vasculitis in response to rickettsiae within endothelial cells. This manifests as interstitial pneumonitis, meningoencephalitis, interstitial nephritis, myocarditis, and mild hepatitis with periportal lymphohistiocytic infiltrates. As vasculitis and inflammatory damage accumulate, multiorgan damage can ensue.

Clinical Manifestations

Murine typhus is a moderately severe infection that is similar to other vasculotropic rickettsioses. The incubation period varies from 1 to 2 wk. The initial presentation is often nonspecific, and fever of undetermined origin is the most common presentation. Pediatric patients exhibit the typically important clues for murine typhus somewhat less often than for the other vasculotropic rickettsioses, including rash (48-80%), myalgias (29-57%), vomiting (29-45%), cough (15-40%), headache (19-77%), and diarrhea or abdominal pain (10-40%). Lymphadenopathy and hepatosplenomegaly are reported often among children with murine typhus in Europe. Although neurologic involvement is a common finding in adults with murine typhus, photophobia, confusion, stupor, coma, seizures, meningismus, and ataxia are seen in <17% of hospitalized children and <6% of infected children treated as outpatients. A petechial rash is observed only in ≤13% of children, and the usual appearance is that of macules or maculopapules distributed on the trunk and extremities. The rash can involve both the soles and palms.

Laboratory Findings

Although nonspecific, laboratory findings that may be helpful include mild leukopenia (36-40%) with a moderate left shift, mild to marked thrombocytopenia (43-60%), hyponatremia (20-66%), hypoalbuminemia (46-87%), and elevated aspartate aminotransferase (82%) and alanine aminotransferase (38%). Elevations in serum urea nitrogen are usually due to prerenal mechanisms.

Diagnosis and Differential Diagnosis

As for other vasculotropic rickettsioses, delays in diagnosis and therapy are associated with increased morbidity and mortality; thus, diagnosis must be based on clinical suspicion. Occasionally, patients present with findings suggesting pharyngitis, bronchitis, hepatitis, gastroenteritis, or sepsis; thus, the differential diagnosis may be extensive.

Confirmation of the diagnosis is usually accomplished by comparing acute and convalescent-phase antibody titers obtained with the indirect fluorescent antibody assay. Research tools now being evaluated include polymerase chain reaction amplification of rickettsial nucleic acids in acute-phase blood, rickettsial culture by the centrifugation-assisted shell vial assay, and immunohistology on skin biopsy.

Treatment

Therapy for murine typhus includes tetracyclines or chloramphenicol, similar to treatment for Rocky Mountain spotted fever. No controlled trials of other antimicrobial agents have been performed. Ciprofloxacin has been used effectively to treat murine typhus, but treatment failures have been reported. In vitro experiments suggest that minimal inhibitory concentrations of azithromycin and clarithromycin for R. typhi should be easily achieved.

The time-honored recommended treatment for murine typhus is doxycycline (4 mg/kg/day divided every 12 hr PO or IV, maximum 200 mg/day). Alternative regimens include tetracycline (25-50 mg/kg/day divided every 6 hr PO, maximum 2 g/day) or chloramphenicol (50-100 mg/kg/day divided every 6 hr IV, maximum 4 g/day). Therapy should be continued for a minimum of 5 days and until the patient has been afebrile for at least 3 days to avoid relapse, especially in patients treated early.

Supportive Care

Although disease is usually mild, 7% of children with murine typhus require intensive care to manage complications such as meningoencephalitis or a disseminated intravascular coagulation–like condition. As for other rickettsial infections with significant systemic vascular injury, careful hemodynamic management is mandatory to avoid pulmonary or cerebral edema.

Complications

Complications of murine typhus in pediatric patients are uncommon; however, relapse, stupor, facial edema, dehydration, splenic rupture, and meningoencephalitis are reported. Predominance of abdominal pain has led to surgical exploration to exclude a perforated viscus.

Prevention

Control of murine typhus was dependent on elimination of the flea reservoir and control of flea hosts, and this remains important. However, with the recognition of cat fleas as potentially significant reservoirs and vectors, the presence of these flea vectors and their mammalian hosts in suburban and urban areas where close human exposures occur will probably pose increasingly difficult control problems. It is not known with certainty if infection confers protective immunity; reinfection appears to be rare.

Etiology

Humans are considered the principal or only reservoir of R. prowazekii, the causative agent of epidemic or louse-borne typhus and its recrudescent form, Brill-Zinsser disease. Another reservoir exists in flying squirrels and their ectoparasites in a sylvatic cycle with small rodents. R. prowazekii is the most pathogenic member of the genus Rickettsia and multiplies to very large intracellular quantities before rupture of infected endothelial cells.

Epidemiology

The infection is characteristically seen in winter or spring and especially during times of poor hygienic practices associated with crowding, war, famine, extreme poverty, and civil strife. A cause of some sporadic cases of a mild, typhus-like illness in the USA has been confirmed as R. prowazekii; such cases are associated with exposure to flying squirrels harboring infected lice or fleas. R. prowazekii organisms isolated from these squirrels appear to be genetically similar to isolates obtained during typical outbreaks.

Most cases of louse-borne typhus in the developed world are sporadic, but outbreaks have been identified in Africa (Ethiopia, Nigeria, and Burundi), Mexico, Central America, South America, Eastern Europe, Afghanistan, Russia, northern India, and China within the past 25 years. Following the Burundi Civil War in 1993, 35,000-100,000 cases of epidemic typhus were diagnosed in displaced refugees, resulting in an estimated 6,000 deaths.

Transmission

Human body lice (Pediculus humanus corporis) become infected by feeding on rickettsemic persons. The ingested rickettsiae infect the midgut epithelial cells of the lice and are passed into the feces, which in turn is introduced into a susceptible human host through abrasions or perforations in the skin, through the conjunctivae, or rarely through inhalation after drying in clothing, bedding, or furniture.

Clinical Manifestations

Louse-borne typhus can be mild or severe in children. The incubation period is usually <14 days. The typical clinical manifestations include fever, severe headache, abdominal tenderness, and rash in most patients, as well as chills (82%), myalgias (70%), arthralgias (70%), anorexia (48%), nonproductive cough (38%), dizziness (35%), photophobia (33%), nausea (32%), abdominal pain (30%), tinnitus (23%), constipation (23%) meningismus (17%), visual disturbances (15%), vomiting (10%), and diarrhea (7%). However, investigation of recent African outbreaks has shown a lower incidence of rash (25%) and a high incidence of delirium (81%) and cough associated with pneumonitis (70%). The rash is initially pink or erythematous and blanches. In 1/3 of patients, red, nonblanching macules and petechiae appear predominantly on the trunk. Infections identified during the preantibiotic era typically produced a variety of central nervous system findings, including delirium (48%), coma (6%), and seizures (1%). Estimates of case fatality rates range between 3.8% and 20% in outbreaks.

Brill-Zinsser disease is an unusual form of typhus that becomes recrudescent months to years after the primary infection, thus rarely affecting children. When rickettsemic, these infected patients can transmit the agent to lice, potentially providing the initial event that triggers an outbreak if hygienic conditions permit.

Treatment

Recommended treatment regimens for louse-borne or sylvatic typhus are identical to those used for murine typhus. The treatment of choice is doxycycline (4 mg/kg/day divided every 12 hr PO or IV, maximum 200 mg/day). Alternative treatments include tetracycline (25-50 mg/kg/day divided every 6 hr PO, maximum 2 g/day) or chloramphenicol (50-100 mg/kg/day divided every 6 hr IV, maximum 4 g/day). Therapy should be continued for a minimum of 5 days and until the patient has been afebrile for at least 3 days to avoid relapse, especially in patients treated early. Good evidence exists that doxycycline as a single 200 mg oral dose (4.4 mg/kg if <45 kg) is also efficacious.

Prevention

Immediate destruction of vectors with an insecticide is important in the control of an epidemic. Lice live in clothing rather than on the skin; thus, searches for ectoparasties should include examination of clothes. For epidemic typhus, antibiotic therapy and delousing measures interrupt transmission, reduce the prevalence of infection in the human reservoir, and diminish the impact of an outbreak. Dust containing excreta from infected lice is stable and capable of transmitting typhus, and care must be taken to prevent its inhalation. Infection confers solid protective immunity. However, recrudescence can occur years later with Brill-Zinsser disease, implying that immunity is nonsterile.