Murine typhus

INTRODUCTION — Murine (endemic) typhus is a flea-borne infectious disease caused by Rickettsia typhi. Infection occurs worldwide, with the majority of cases occurring in areas where rats accumulate in large numbers. However, the incidence is difficult to establish since disease can be mild, self-limited, and clinically similar to other causes of rash and fever.

This topic will review the epidemiology, clinical manifestations, diagnosis, and treatment of murine typhus. Discussions of other rickettsial diseases are found in separate reviews. (See "Scrub typhus" and "Other spotted fever group rickettsial infections" and "Epidemic typhus".)

PATHOGEN — R. typhi is a member of the typhus group of rickettsiae that also includes the agent of epidemic typhus, R. prowazekii. These organisms are obligate intracellular, gram-negative bacteria that can only be grown in tissue culture, the cells of experimental animals, or chick embryos. (See "Biology of Rickettsia rickettsii infection".)

TRANSMISSION — Murine typhus is primarily transmitted by the rat flea, Xenopsylla cheopis. Additional vectors include the cat flea, Ctenocephalides felis, and the mouse flea, Leptopsyllia segnis. Fleas remain permanently infected with R. typhi, and their lifespan is not shortened by the presence of rickettsiae. Humans are infected by inoculation of infective flea feces in bite wounds [1].

In addition to serving as hosts for infected fleas, rats may become rickettsemic after contact with an infected flea and thereby transmit the organism to numerous simultaneously feeding fleas. The resultant amplification of rickettsiae may lead to rapid spread of infection to other rats.

House mice, cats, and shrews occasionally serve as hosts to infected fleas. In addition, domestic cats may have serologic evidence of infection with R. typhi in both endemic and nonendemic regions. In one study, cats were also shown to have detectable R. typhi DNA in their blood using molecular methods [2]. (See "Other spotted fever group rickettsial infections".)

EPIDEMIOLOGY — Murine typhus has a worldwide distribution, although the bulk of the large outbreaks described in the literature has been in Southeast Asia, North Africa and the Mediterranean region, and North America [3]. The majority of cases of murine typhus are associated with sites in which rats accumulate in large numbers. However, in suburban locations in the United States, domestic cats, cat fleas, and opossums may maintain a cycle of both R. typhi and Rickettsia felis (a spotted fever group rickettsia that is flea-borne and produces an illness that is clinically indistinguishable from murine typhus) [1].

Murine typhus sporadically occurs on all the inhabited continents, in environments ranging from hot to cold and from humid to semi-arid [4]. There is no seasonal variation in murine typhus in tropical areas, but in temperate regions, the disease is most common in hot, dry periods, such as late summer and early fall [1].

In the United States, murine typhus is occasionally identified in returning travelers [4,5]. Most cases of murine typhus acquired in the United States have been recognized and reported in residents of Texas, California, and Hawaii. As an example, in 2008, there was a report of a cluster of 53 cases of murine typhus in Austin, Texas. In this outbreak, there was thought to be a high density of infection in domestic animals or opossums that may have been responsible for the hyperendemic focus of infection secondarily involving humans. In October 2018, two outbreaks of murine typhus were reported in Los Angeles County [6,7].

However, murine typhus is not reported in surveillance data collected by most state health departments, and it is likely that the disease exists in a much wider geographic area. Murine typhus is almost certainly underdiagnosed, as it is easily mistaken for a viral illness because patients are rarely aware of having had flea bites and because most cases resolve spontaneously. As an example, one serologic study of 513 children from South Texas found that approximately 13 percent of children aged 1 to 17 years had immunoglobulin (Ig)G antibodies reactive to R. typhi, supporting the possibility of undiagnosed infections [8].

Laboratory-acquired murine typhus has also occurred in a few rare instances. This has been seen mostly in research facilities as a result of aerosol exposure or self-inoculation related to handing infected tissues during necropsies or during preparation of experimental vaccines [9].

PATHOLOGY — A limited number of autopsy studies of murine typhus cases have been performed due to the low case fatality rate [10]. The primary pathologic lesion of R. typhi infection is an inflammatory vasculitis characterized by perivascular infiltration of lymphocytes, macrophages, plasma, and mast cells. In rare cases, vasculitis may be accompanied by mural or intimal thrombi in small vessels of the heart, lungs, kidneys, and central nervous system.

CLINICAL MANIFESTATIONS — Murine typhus is typically a mild illness with an incubation period from 8 to 16 days. The onset of illness is typically abrupt, with largely nonspecific symptoms including rash and fever. However, the classic clinical triad of fever, headache, and rash only occurs in 35 to 49 percent of patients [3,11].

Nonspecific symptoms — Fever, headache, chills, and myalgias are usually prominent early in the illness. Nonspecific gastrointestinal (GI) symptoms, such as nausea, vomiting, abdominal pain, and diarrhea, may also occur at this time.

Children with murine typhus also have headaches and myalgias but are more likely than adults to have abdominal pain and diarrhea [3]. In one series that evaluated 97 children with murine typhus, GI symptoms occurred in 77 percent [11].

Rash — Rash occurs in some patients near the end of the first week of illness. The frequency of rash has ranged from 20 percent in a report from Thailand to 54 percent in a series from Texas [3,12,13].

The rash of murine typhus typically begins as a maculopapular eruption on the trunk and spreads peripherally, sparing the palms and soles [1] (picture 1). However, the pattern of evolution and distribution are sufficiently variable to preclude their use in differential diagnosis.

The rash may be faint and difficult to see, particularly in dark-skinned individuals. As an example, in one study of 180 patients, rash was observed in only 20 percent of Black patients compared with 81 percent of White patients [14]. The rash has a petechial component in less than 10 percent of cases [12,13].

Manifestations of severe disease — The vast majority of patients experience mild illness, but more severe disease (eg, resulting in intensive care unit admission or even death) may develop, especially in untreated individuals [15].

Patients with severe disease may present with neurologic, hepatic, cardiac, renal, and/or pulmonary dysfunction. As examples:

●Renal dysfunction can result from several mechanisms, including decreased renal perfusion (prerenal) and acute interstitial nephritis [16]. Microscopic hematuria and proteinuria may occur in up to one-third of patients [3]. In one review, renal dysfunction was present in one-fourth of cases [13].

●Patients with more severe illness may develop cough and dyspnea. Chest radiographs in such patients may show interstitial infiltrates or changes suggestive of pulmonary edema [13]. Rarely, pleural effusions and even respiratory failure have been described [3].

●Ocular exam may show a variety of abnormalities ranging from exudates to hemorrhages to optic disk or vitreal inflammation. These changes are secondary to the widespread vasculitis that is the hallmark of this disease [17].

●Myocarditis has been rarely reported as a manifestation of murine typhus [18,19] as well as other rickettsial diseases. Relative bradycardia has also been observed, but the overall frequency of cardiac manifestations is unknown [20,21].

●Splenomegaly has been detected in 15 to 20 percent of patients [3], and rare cases of splenic rupture have been reported [1,20,21].

●Mental confusion and focal neurologic symptoms, including facial paralysis, abducens nerve palsy, and meningoencephalitis or meningitis, have rarely been reported [22-24].

●Other rare complications include uveitis, septic shock with multiorgan failure, and hemophagocytic syndromes [3,25].

As in other rickettsial diseases, the presence of glucose-6-phosphate dehydrogenase deficiency (G6PD) and advanced age appear to be host factors associated with severe or fatal disease. The association with G6PD deficiency was first described in an American soldier who developed acute renal failure and severe hemolysis after contracting murine typhus in Vietnam [26]. Several subsequent studies found an association between G6PD deficiency and severe or fulminant Rocky Mountain spotted fever (RMSF) and severe infection with the agent of boutonneuse fever (Rickettsia conorii) [27]. The mechanism of this association between severe rickettsial diseases and the presence of G6PD deficiency has not been conclusively established, but it has been proposed that G6PD-associated hemolysis may somehow aggravate or potentiate rickettsia-induced vasculitis [28].

Laboratory findings — Routine laboratory findings in murine typhus are nonspecific. Thrombocytopenia is a common finding, occurring in 48 percent of patients in one series [13]. The white blood cell count is usually normal, but mild leukocytosis or leukopenia may occur [3]. Hyponatremia, hypoalbuminuria, elevated creatine kinase levels, and abnormal liver function tests are frequently present, although these abnormalities are usually mild [3,13]. Mild cerebrospinal fluid abnormalities consistent with aseptic meningitis may be noted in patients with murine typhus who undergo lumbar puncture [29].

DIAGNOSIS — An otherwise undifferentiated febrile illness, especially in a patient with a rash, thrombocytopenia, or mildly elevated liver function tests (LFTs), should raise suspicion for murine typhus or another rickettsial disease that can mimic typhus in the appropriate epidemiologic setting. However, no reliable diagnostic laboratory test in the early phase of illness is available. Thus, our approach to diagnosis is as follows:

●The initial diagnosis (and decision to treat) is based on typical clinical and laboratory findings developing in a patient with potential exposure to fleas or known flea-bearing hosts (eg, rats, cats, dogs, opossums, etc). However, it is important to note that most patients do not remember a fleabite or contact with rodents. (See 'Clinical manifestations' above and 'Epidemiology' above and 'Transmission' above.)

●In patients with a suspected diagnosis of murine typhus, the diagnosis should be confirmed serologically with an indirect fluorescent antibody (IFA) test after a course of empiric therapy. (See 'Treatment' below.)

A diagnosis of murine typhus can be established by a fourfold antibody rise in IgG titer between acute and convalescent serum samples (taken at least two weeks apart). IgM assays for R. typhi also offer reasonable specificity in acute illness but are hampered by variable sensitivity, and thus absence of detectable IgM should not be used to rule out acute disease [30]. The IFA test is available through all state health department laboratories.

It is important to note that R. typhi can cross-react with R. prowazekii, the agent of epidemic typhus, and with a variety of spotted fever group antigens, including those from R. felis and Rickettsia rickettsii. Western blot testing and cross-adsorption studies can often help determine the infecting rickettsia if necessary, although these techniques require specialized laboratories, and such testing is expensive and time consuming [8,31].

●Polymerase chain reaction (PCR)-based tests can also be used to confirm the diagnosis of murine typhus. These techniques have been used successfully on blood, plasma, and tissue samples but are not widely available in routine clinical practice and can suffer from poor sensitivity due to low levels of rickettsemia that vary by stage of illness, receipt of appropriate therapy, and other factors [1,32,33]. More recently, next generation sequencing (NGS) of microbial cell-free DNA has also been demonstrated to identify cases of infection with Rickettsia typhi in the United States [34]. Other types of diagnostic tests that are less commonly used include rickettsial cultures of blood and skin biopsy with direct fluorescent antibody staining [35].

In regions where laboratory diagnostic facilities are limited or nonexistent, it is often not practical to confirm the diagnosis of murine typhus and distinguish it from other endemic rickettsial and non-rickettsial diseases, such as dengue and leptospirosis. This is a particularly common dilemma in patients during the early phases of illness in regions where these diseases are all common, especially in patients with fever, myalgias, and headache who lack characteristic skin rashes or lesions. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of a syndrome that includes fever, headache, myalgias, and rash is extremely broad and can include viral, spirochetal, rickettsial, and other bacterial infections, as well as non-infectious etiologies (eg, drug reactions or Kawasaki disease [36]). A careful history that assesses for exposures to animals, as well as travel to certain geographic regions, may increase a provider's suspicion for diagnosing murine typhus. As examples:

●Viral infections – Viral etiologies should be considered in the differential diagnosis of a patient presenting with a nonspecific febrile illness that includes fever, headache, myalgias, and/or rash. These include rubella, measles, Epstein Barr virus, coxsackievirus, echovirus, Zika, dengue, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [37,38]. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention" and "Rubella" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" and "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Zika virus infection: An overview" and "COVID-19: Clinical features".)

In returning travelers, murine typhus is often confused with dengue and Zika virus infection, as all three illnesses occur in tropical regions, commonly present as fever with nonspecific flu-like symptoms (eg, myalgias and headaches), and are often associated with thrombocytopenia, rash, and sometimes petechiae. However, there are some differences in the clinical manifestations and pattern of laboratory abnormalities that may help the clinician differentiate these infections [5,39]. As an example, in one small study, patients with dengue had lower neutrophil counts and C-reactive protein levels and were less likely to have hepatitis, compared with those who had typhus [5]. In another study comparing dengue and typhus, patients with murine typhus were more likely to have fevers of ≥8 days, C-reactive protein levels >31.9 mg/L, platelet counts >63,000, and an absence of bone pain and bleeding [39].

●Other rickettsial diseases – It may also be difficult to distinguish the different rickettsial diseases from one another [40]. R. felis infection, for example, may mimic the clinical features of murine typhus, and the two illnesses may produce similar convalescent serologic responses. In areas such as Thailand and Taiwan, murine and scrub typhus are both endemic, and although rare, patients may manifest concurrent infections with R. typhi and Orientia tsutsugamushi [41]. The clinical manifestations of other rickettsial infections are reviewed elsewhere. (See "Other spotted fever group rickettsial infections" and "Scrub typhus".)

●Bacterial diseases – Certain bacterial diseases can present with fever and rash. As an example, these clinical manifestations can be seen in the setting of disseminated gonorrhea or meningococcal infections, as well as certain spirochetal infections (eg, leptospirosis, syphilis, Lyme disease). (See "Disseminated gonococcal infection" and "Clinical manifestations of meningococcal infection" and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV" and "Clinical manifestations of Lyme disease in adults".)

More detailed discussions of fever and rash, including the evaluation of fever in the returning traveler, are found elsewhere. (See "Fever and rash in the immunocompetent patient" and "Fever and rash in patients with HIV" and "Evaluation of fever in the returning traveler" and "Drug eruptions".)

TREATMENT

Indications — We recommend empiric treatment for all patients in whom a diagnosis of murine typhus is suspected. Although spontaneous recovery generally occurs within two weeks in untreated patients, rare fatalities have been reported [12,13,42]. In addition, antibiotics significantly shorten the duration of illness [12,43].

In a systematic review with available treatment data on 1135 patients, time to defervescence was 1.5 to 4 days in patients who received a tetracycline-containing regimen versus 12 to 21 days in untreated patients [3]. In a subsequent retrospective study of 213 children in South Texas, the mean duration of hospitalization was significantly shorter when therapy was started within 24 hours of admission (2.7 versus 4.1 days) [43].

Regimen selection

Preferred regimen — We recommend doxycycline as the preferred agent for the treatment of murine typhus:

●The dose of doxycycline for adults should be 100 mg orally twice daily. The dose of doxycycline for children who weigh <45.4 kg (100 pounds) is 2.2 mg/kg twice per day (maximum daily dose 200 mg). Children who weigh ≥45.4 kg (100 pounds) should receive the adult dose.

Several observational studies support the use of doxycycline for the treatment of murine typhus [43-46]. In addition, doxycycline has been found to have greater efficacy than azithromycin in a prospective randomized trial of patients with uncomplicated murine typhus [47]. In this trial, which included 216 patients from Laos with murine typhus diagnosed using a rapid test (approximately 75 percent confirmed by serology), patients received either doxycycline (200 mg loading dose followed by 100 mg twice daily for a total duration of three or seven days), or azithromycin (500 mg loading dose followed by 250 mg daily for a total duration of three days). The duration of fever was significantly longer in patients who received azithromycin (48 versus 34 to 36 hours). In addition, patients who received azithromycin were significantly more likely to have treatment failure, defined as fever >37.5°C after ≥72 hours on treatment without clinical improvement or with development of severe disease (23 versus 3 percent for patients receiving azithromycin or doxycycline, respectively).

●The optimal duration of therapy for murine typhus has not been established. We suggest that patients be treated for at least 48 hours after defervescence or for seven days, whichever is longer.

Treatment regimens with doxycycline, from as little as a single dose to 10 days of therapy, have all been reported to show some efficacy [12,44,47]. In the randomized trial described above, there was a consistent trend towards more rapid resolution of disease and fewer relapses with seven days versus three days of doxycycline [47].

Combination therapy has not been shown to offer any additional benefit to doxycycline alone [46].

Alternative regimens — In the setting of an absolute contraindication to doxycycline, other regimens can be considered. However, data suggest that these other regimens are associated with a longer duration of fever and more frequent relapse [44-47].

Alternative regimens include:

●Azithromycin – Second-line therapy for most subjects should be azithromycin. This regimen is better studied for scrub typhus, but there is some experience with murine typhus, which is described in the study above [47]. In that study, the dose of azithromycin used in adults was 500 mg on day 1 followed by 250 mg daily for two additional days.

●Chloramphenicol – Chloramphenicol can be considered as a third-line agent (12.5 mg/kg every six hours [maximum 4 grams per day]; treatment should be continued for at least seven days) [1,45-47].

●Ciprofloxacin – There are some case reports that suggest ciprofloxacin may have some efficacy for murine typhus [46,48], but fluoroquinolones should only be used as a last resort for treatment of murine typhus, since there is the least amount of experience with this agent. In addition, there are insufficient data to make definitive recommendations regarding the optimal dose and duration.

●Novel tetracycline-like agents (omadacycline, tigecycline and eravacycline) show activity against R. typhi in vitro and thus may have some efficacy, but there are currently no meaningful clinical data to directly support their use [49].

In addition to being less effective than doxycycline, some of the alternative agents may have an increased risk of adverse reactions. As examples, chloramphenicol has been associated with aplastic anemia, and quinolones and macrolides have been associated with QT prolongation.

Response to therapy — Patients typically defervesce rapidly on doxycycline (mean 35 hours; range 4 to 66 hours in the trial described above) [47]. Fevers that persist beyond this point despite adequate doxycycline therapy should raise suspicion of an alternate or concomitant diagnosis.

Considerations during pregnancy — We administer doxycycline to pregnant women with murine typhus. Rickettsial infections convey a high risk for adverse pregnancy outcomes [50]. Thus, we utilize the most efficacious intervention available, which in this setting is doxycycline. (See 'Preferred regimen' above.)

In addition, although most tetracyclines are contraindicated in pregnancy because of the risk of hepatotoxicity in the mother [51] and adverse effects on fetal bone and teeth [52,53], these events are extremely rare with doxycycline. Observational studies support the relative safety of doxycycline compared with older tetracyclines in both pregnancy and in children [54,55]. As an example, one systematic review showed no correlation between the use of doxycycline during pregnancy and teratogenic effects or dental staining in children [54].

SUMMARY AND RECOMMENDATIONS

●Microbiology – Murine (endemic) typhus is a flea-borne infectious disease caused by Rickettsia typhi. R. typhi is a member of the typhus group of rickettsiae that also includes the agent of epidemic typhus, R. prowazekii. (See 'Introduction' above and 'Pathogen' above.)

●Vector and transmission – Infection is primarily transmitted by the rat flea, Xenopsylla cheopis, although fleas from other common animals (eg, cats, dogs, opossums, and others) can transmit disease as well. Humans are infected by inoculation of infective flea feces within bite wounds. (See 'Transmission' above.)

●Epidemiology – Infection occurs worldwide, with the majority of cases occurring in areas where rats accumulate in large numbers. In the United States, most cases of murine typhus have been recognized and reported in Texas, California, and Hawaii. Overall incidence is difficult to establish since clinical presentations are nonspecific and can be mild and self-limited. (See 'Epidemiology' above.)

●Clinical manifestations

•Typical presentation – Murine typhus is typically a mild illness with an incubation period from 8 to 16 days. The onset of illness is usually abrupt, with nonspecific symptoms followed by fever, a maculopapular rash, and headache. (See 'Clinical manifestations' above.)

•Atypical severe disease – Signs and symptoms of hepatic, cardiac, renal, neurologic, and pulmonary dysfunction can occur in severe cases. The presence of glucose-6-phosphate dehydrogenase deficiency (G6PD) and advanced age appear to be associated with severe or fatal disease. (See 'Manifestations of severe disease' above.)

•Laboratory findings – Routine laboratory findings in murine typhus are nonspecific. Thrombocytopenia is a common finding, occurring in approximately half of patients. (See 'Laboratory findings' above.)

●Diagnosis – The initial diagnosis (and decision to treat) is usually based upon typical clinical findings developing in an appropriate epidemiologic setting. The diagnosis is usually confirmed serologically with paired acute and convalescent indirect fluorescent antibody (IFA) tests. (See 'Diagnosis' above.)

●Antibiotic selection – For patients with suspected murine typhus, we recommend treatment with doxycycline (Grade 1B). Although spontaneous recovery generally occurs within two weeks in untreated patients, rare fatalities have been reported, and antibiotics significantly shorten the duration of illness. Alternative regimens (eg, azithromycin, chloramphenicol, quinolones) also appear to shorten the duration of symptoms, but there is less experience with these agents compared with doxycycline, and they are associated with a longer duration of fever, more frequent relapses, and potentially an increased risk of toxicity. (See 'Treatment' above.)

●Duration of therapy – Patients typically defervesce rapidly on doxycycline. We suggest that patients be treated with doxycycline for at least 48 hours after defervescence or for seven days, whichever is longer (Grade 2C). (See 'Preferred regimen' above and 'Response to therapy' above.)