Clinical manifestations

Presentation and course

Rocky Mountain spotted fever. In the United States, Dermacentor variabilis (dog tick) is the vector for most cases of Rocky Mountain spotted fever. This tick is found in the Eastern and Central parts of the United States as well as the Pacific Coast. D andersoni (wood tick) is the vector in the Western United States. Rhipicephalus sanguineus (brown dog tick) is a vector in parts of Arizona, Southern California, along the US–Mexico border, and in Mexico (06). Several species of Amblyomma ticks are the vector of Rocky Mountain spotted fever in Mexico and Argentina (06).

Symptoms of Rocky Mountain spotted fever typically begin 3 to 12 days after the bite of an infected tick; the incubation period is shorter in individuals with severe disease (06). Early symptoms of Rocky Mountain spotted fever are nonspecific and include high fever, headache, myalgias, and gastrointestinal symptoms. The characteristic rash begins 2 to 4 days after the onset of fever, but most patients present for care before rash onset; the classic triad of tick bite, rash, and fever is uncommon at first presentation (06). The rash begins as pink, blanching or nonblanching macules on the wrists and ankles and progresses to a maculopapular rash on the torso.

The rash may subsequently become petechial or purpuric. In severe cases, it may be ecchymotic and necrotic, especially in distal areas, including the fingers, toes, nose, ears, and genitals (66). Rash is more common and occurs earlier in the disease course in children than in adults. According to the Tennessee Unexplained Encephalitis Project, the median time to rash after fever onset was 1 day in children and 15.5 days in adults; rash was seen in all children and in only half of the adults (10).

The main neurologic complications of Rocky Mountain spotted fever are meningoencephalitis and cerebral edema (02), and clinical findings include altered mental status, focal abnormalities, increased tone, and reflex abnormalities. Seizures were seen in 42% of patients in the Tennessee Unexplained Encephalitis Project (10). Focal neurologic deficits, including cranial or motor neuropathies, and sudden transient hearing loss have been described (06).

Common laboratory findings in Rocky Mountain spotted fever include thrombocytopenia, anemia, hyponatremia, and increases in serum concentrations of hepatic transaminases, bilirubin, and creatine kinase (66; 06). Peripheral white blood cell concentration may be normal, but there may be an increase in immature granulocytes (06).

Case fatality is 5% to 10% for spotted fever rickettsiosis and is higher for those treated more than 5 days after illness onset (17). In a review of published cases, 4% of patients treated within 5 days of illness onset died compared to 35% who were treated after 5 days (34). In addition to those with delayed treatment, children less than 10 years of age, adults 70 years old or older, and individuals with alcohol use disorder or immunosuppression are at the greatest risk of death from Rocky Mountain spotted fever (21). Persons with G6PD deficiency can have early fulminant disease, leading to death (06).

Long-term complications of Rocky Mountain spotted fever include cognitive impairment; hearing and vision loss; vestibular dysfunction; bowel and bladder abnormalities; speech, motor, and cerebellar dysfunction; and seizures (06). In a study of 80 hospitalized individuals with Rocky Mountain spotted fever in Arizona between 2002 and 2017, 17 (21%) died (26). Fifty-four of 63 survivors were impaired at hospital discharge based on modified Rankin score. Forty patients were interviewed after discharge, and nine of them underwent neurologic examination. Nine (23%) had persistent neurologic deficits, most commonly cognitive impairment. Some individuals with subsequent neurologic sequelae were reportedly normal at hospital discharge. The odds of neurologic sequelae were 19 times higher in patients who initiated doxycycline after day 5 of illness.

Anaplasmosis. Anaplasma phagocytophilum is transmitted by Ixodes scapularis ticks in the Northeast and Midwest United States and by Ixodes pacificus ticks on the West Coast. It is transmitted by I ricinus in Europe and by I persulcatus in Asia. The organism has an affinity for granulocytes, and it may also infect endothelial cells (57). Anaplasma can be transmitted by blood transfusion and organ transplantation, and infection may be more severe in these instances (49). The incubation period is 5 to 14 days (06). Symptoms are nonspecific and mimic those of Rocky Mountain spotted fever, including fever, headache, fatigue, arthralgia, and myalgia. However, contrary to Rocky Mountain spotted fever, rash is not typically seen. Neurologic manifestations are less common in anaplasmosis than in ehrlichiosis (06; 33). Confusion is the most common neurologic manifestation of infection (68). Young and Klein reported a patient who had both anaplasmosis and ehrlichiosis, with encephalopathy and frequent focal seizures (72). Stroke and cerebral vasospasm have been reported (40; 28; 50). Peripheral nervous system involvement, including brachial plexopathy; cranial nerve palsies, including bilateral facial palsy; and demyelinating polyneuropathy have been described in patients with anaplasmosis (33). Because of the overlap in tick vectors, concomitant infections with A phagocytophilum and B burgdorferi or Babesia microti in the United States (65; 33) or concomitant infection with A phagocytophilum and tick-borne encephalitis virus or B garinii in Europe (43; 44) have been reported.

Common laboratory findings in anaplasmosis include leukopenia, thrombocytopenia, and elevated serum levels of hepatic transaminases.

The case fatality rate is 0.3% in anaplasmosis (45). As with spotted fever rickettsioses, the elderly and those with underlying immunocompromise have poorer outcomes and are at the highest risk of death (06).

Ehrlichiosis. Ehrlichia chaffeensis is transmitted by Amblyomma americanum, the lone star tick (06), and this bacterium primarily infects monocytes. Ehrlichia chaffeensis infection is mostly seen in the Southeast, South Central, and mid-Atlantic United States, where the vector is endemic. Anaplasma can also be transmitted by blood transfusion and organ transplantation, and infection may be more severe in these instances (49). The incubation period is 5 to 14 days (06). Clinical symptoms of ehrlichiosis are nonspecific and mimic those of Rocky Mountain spotted fever and anaplasmosis, including fever, myalgia, headache, malaise, arthralgia, and nausea. Maculopapular, petechial, or red rashes are more common in ehrlichiosis than in anaplasmosis; they occur in up to 30% of patients, more commonly in children than in adults (65; 06; 33).

Ehrlichiosis is a more severe disease than anaplasmosis, and neurologic symptoms and signs are more common in ehrlichiosis than in anaplasmosis. Meningitis or meningovasculitis is seen in 20% of patients with ehrlichiosis (27). Other neurologic abnormalities include stupor and coma, hallucinations, seizures, and cranial nerve palsies (27).

Laboratory abnormalities in ehrlichiosis are similar to those of anaplasmosis, including leukopenia, thrombocytopenia, and increased serum concentration of hepatic transaminases.

The case fatality rate is 3% in ehrlichiosis (65). As with spotted fever rickettsioses, the elderly and those with underlying immunocompromise have poorer outcomes and are at the highest risk of death from ehrlichiosis (06). Children less than 10 years old have the highest case fatality rate for ehrlichiosis (06).

African tick bite fever. Rickettsia africae is transmitted by Amblyomma ticks, and it is endemic in sub-Saharan Africa, the Caribbean, and Oceana. It is the most common cause of rickettsial disease in travelers, where it occurs in clusters (37; 20). Clinical symptoms typically develop 5 to 7 days after a tick bite but may take up to 10 days to develop (37). The clinical presentation mimics many of the manifestations of Rocky Mountain spotted fever, including fever, headache, and myalgia. Regional lymphadenitis and aphthous stomatitis may also be seen. Neck muscle pain with subjective stiffness is common, as it is in Rocky Mountain spotted fever (37). Unlike Rocky Mountain spotted fever, one or more inoculation eschars, which are characterized by a black crust surrounded by erythema, are a unique finding. Macular, papular, or vesicular rash near the eschar (37) is seen in about 40% of patients (58). The disease course is generally mild. Neurologic complications include neuropsychiatric symptoms in adults and encephalopathy in infants (58). Subacute neuropathy is described as a complication in a small series (36).

Murine typhus. Murine typhus is most often a mild disease, with gradual onset of fever, myalgia, headache, maculopapular rash, hepatitis, and thrombocytopenia 7 to 14 days after exposure (18). Neurologic complications are uncommon, occurring in about 2% of patients, usually during the second week of illness (62). These include change in mental status, focal neurologic signs, papilledema with or without elevated CSF pressure, seizures, and aseptic meningitis or meningoencephalitis (64). Meningitis and meningoencephalitis can occur in the absence of other symptoms or signs of murine typhus (46). As with other rickettsial diseases, transient hearing loss may be seen (67).

Little information is known about neurologic outcomes after murine typhus. Neurologic deficits are considered rare, even in untreated disease (14).

Epidemic typhus. Epidemic typhus is characterized by 1 to 3 days of malaise, followed by abrupt onset of fever, severe headache, maculopapular or petechial rash, myalgia, hepatitis, and thrombocytopenia 8 to 16 days after exposure (18). Patients with epidemic typhus frequently have neurologic complications, including seizures, confusion, delirium, and coma (52; 05). Meningitis or meningoencephalitis may occur (47). Deafness is common, but it is often reversible (30). Symptoms and signs are generally less severe in infection associated with exposure to flying squirrels and in Brill-Zinsser disease.

Mortality of epidemic typhus is greatest in those over 60 years of age (05). Little information is known about neurologic outcomes after epidemic typhus. In a study from Ethiopia, adverse neurologic outcomes after epidemic typhus were rare (52).

Scrub typhus. Scrub typhus can range in severity from mild to severe, depending on the infecting strain. Abrupt onset of fever and chills, headache, myalgia, lymphadenopathy, altered mental status, and thrombocytopenia and abnormal levels of liver transaminases, bilirubin, and creatinine are seen 7 or more days after exposure. One or more eschars at the sites of chigger bites may be seen. A macular or maculopapular rash may develop in up to 50% of patients (05; (18).

A wide variety of neurologic abnormalities have been attributed to scrub typhus, including acute and reversible hearing loss (04). A prospective study of 189 patients with scrub typhus in Southern India identified headache, altered sensorium, and seizures as the most common neurologic symptoms or signs; 39 individuals had aseptic meningitis (09). Scrub typhus is a common cause of meningoencephalitis in endemic areas. In two large prospective studies of children with clinically defined meningoencephalitis or acute encephalitis syndrome in Southern India, about 24% had scrub typhus (03; 23). Similarly, in a study of 254 patients of all ages with bacterial or fungal CNS infections in Laos, O tsutsugamushi was responsible for 12% (25).

Little information is known about neurologic outcomes after scrub typhus. The median mortality of treated scrub typhus is 1.4%, but mortality is higher in those with CNS involvement (25). One study showed that 90% of children with scrub typhus meningoencephalitis had good overall performance at discharge (03).

Biological basis

Etiology and pathogenesis

The gram-negative Rickettsiales, which include Rickettsia species, Anaplasma phagocytophilum, Ehrlichia chaffeensis, and Orientia tsutsugamushi are obligate intracellular pathogens. They have reduced genomes, having lost the genes required to live outside of host cells (60). They grow and replicate in endothelial and vascular smooth muscle cell cytoplasm and cause a lymphohistiocytic vasculitis (37; 19). The infection is cytopathic, which can cause capillary leakage and systemic volume depletion.

A phagocytophilum and E chaffeensis have two intracellular forms: dense core cells and reticulate cells. Dense core cells are infectious and transform into reticulate cells that reside inside a membrane vacuole in the host cell. These vacuoles filled with bacteria are the morulae characteristic of infection. Unlike rickettsia, A phagocytophilum, E chaffeensis, and O tsutsugamushi lack lipopolysaccharide and peptidoglycan, which helps them to evade host innate immune responses (33; 24).

Interaction with target cells, be it vascular endothelium or leukocytes, leads to the secretion of proinflammatory cytokines and chemokines and recruitment of inflammatory cells. This inflammation is the main driver of pathogenicity (37; 60; 39). Excessive macrophage activation may lead to secondary hematophagocytic lymphohistiocytosis (HLH) in patients with anaplasmosis and ehrlichiosis, which may resolve with antibiotic therapy alone (51; 61). Although this complication is uncommon in anaplasmosis, it may occur in at least 16% of individuals with ehrlichiosis (51; 13). Hematophagocytic lymphohistiocytosis is reported in individuals with spotted fever rickettsiosis (32), as well as murine typhus (31) and scrub typhus (70).

Epidemiology

Murine typhus occurs worldwide. Most cases of murine typhus in the United States occur in California, Hawaii, and Texas.

Louseborne epidemic typhus is uncommon in resource-rich settings, but outbreaks continue to occur worldwide where there is war, famine, displacement, and crowding. In the United States, cases of epidemic typhus are described in individuals exposed to flying squirrels and their nests.

Scrub typhus is endemic in Asia and the Western Pacific, with recent spread to the Middle East, South America, and Africa.

Rocky Mountain spotted fever. As of 2010, cases of Rocky Mountain spotted fever in the United States are reported under the category of spotted fever rickettsiosis because commonly available serological tests cannot distinguish between Rocky Mountain spotted fever and other rickettsial diseases that cause a similar illness (63). The reporting of all cases of rickettsial disease in the United States is passive, and its limitations should be acknowledged. Specifically, serological confirmation is required. A study using data from University of North Carolina Health showed that only 10% of individuals with suspected spotted fever group rickettsiosis underwent requisite acute and convalescent serological testing (see diagnostic workup below) (12). A study published in 2011 showed that the rate of reported Rocky Mountain spotted fever was as much as 11-fold higher in Native Americans than in whites (22). However, the odds of reporting Rocky Mountain spotted fever in Native Americans was almost 8-fold lower than in whites, likely reflecting limited access to health care and serological testing.

Limitations of surveillance aside, the number of reported cases of spotted fever rickettsiosis has increased over time (07; 17). However, the case fatality rate has decreased, perhaps because of the inclusion of spotted fever rickettsiosis infections caused by less virulent organisms compared to R rickettsii. Most cases are reported from April to September (06). The highest incidence of spotted fever rickettsiosis is in 60 to 69 year olds. The most recent data show that over half of the cases in the United States are reported from Arkansas, Missouri, and North Carolina (17). Spotted fever rickettsioses are endemic in several Native American communities in Arizona (06), where delays in diagnosis have likely led to high mortality (55). Similarly, a large outbreak of Rocky Mountain Spotted Fever is ongoing in Mexicali, Mexico, and surrounding regions, which primarily impacts low-income individuals (73). Recent increases in infections in Southern California have particularly impacted individuals who describe themselves as Hispanic or Latino and are likely related to the outbreak at the United States–Mexico border (41). The CDC issued a health advisory on December 8, 2023, regarding severe and fatal Rocky Mountain spotted fever in individuals who had traveled to Tecate, Mexico, which highlights the high fatality rate of Rocky Mountain spotted fever in Mexico.

Anaplasmosis. Anaplasmosis was first seen in Switzerland and in Slovenia in 1997. It is now widespread in Europe and is seen in Russia, China, and South Korea (45). Anaplasmosis has been reportable in the United States since 1999, and the number of cases has successively increased since then (15). Although cases are reported year-round, most occur in the summer, which corresponds to when the nymphal ticks are active. In the United States, anaplasmosis is most often reported in the upper Midwest and northeastern states. Cases are most commonly reported in men and in persons over 40 years of age (15).

Ehrlichiosis. As of 2008, cases of E chaffeensis infection are separately reportable to the United States Centers for Disease Control and Prevention. Although cases are reported throughout the year, most occur during the summer, with a peak in June and July. In the United States, E chaffeensis infections occur most frequently in the South Central and Eastern United States (16).

African tick bite fever. African tick bite fever is endemic in sub-Saharan Africa, the Caribbean, and Oceania. An estimated 3.6 billion people are at risk for infection with R africae (74).

Murine typhus. Murine typhus is caused by R typhi. Humans acquire infection by inoculating infected flea feces into the area of a flea bite, abraded skin, or mucous membranes or by inhalation of dust containing infected flea feces. Historically the Oriental rat flea is considered the vector, but in the United States the cat flea, found on cats, dogs, rats, and opossums, is the vector. Murine typhus occurs worldwide. A study from Laos showed that murine typhus was one of the three most common causes of bacterial CNS infections; the other two were leptospirosis and scrub typhus (25). Most cases of murine typhus in the United States occur in California, Hawaii, and Texas (01). Murine typhus is no longer a reportable disease in the United States.

Epidemic typhus. Epidemic typhus is caused by R prowazekii. Humans acquire infection by inoculating infected human body lice or their feces into non-intact skin, conjunctiva or mucous membranes, or by inhalation of dust containing infected louse feces. Although louseborne epidemic typhus is historically important with isolated outbreaks in crowded unsanitary settings, particularly during World War I, it is now an uncommon disease in resource-rich settings. Nonetheless, outbreaks continue to occur worldwide (54). In the United States, cases of epidemic typhus have been described in individuals exposed to flying squirrels and their nests (53). Epidemic typhus is no longer a reportable disease in the United States.

Scrub typhus. Scrub typhus is primarily caused by O tsutsugamushi. It is transmitted to humans by the bite of the parasitic larval chigger stage of Leptotrombidium mites. The organism is endemic in Asia and the Western Pacific, with recent spread to the Middle East, South America, and Africa (71). Surveillance data suggest that the incidence of scrub typhus is increasing, with both rural and urban populations affected (71).

Prevention

There are currently no vaccines for the entities discussed in this article. Prevention measures include the avoidance of vectors by physical and chemical means.

Differential diagnosis

Confusing conditions

The differential diagnosis of rickettsioses is very broad (06). The primary consideration is bacterial sepsis, particularly meningococcemia. Other considerations include measles, secondary syphilis, idiopathic thrombocytopenic purpura, leptospirosis, infectious mononucleosis, viral encephalitis, tuberculous meningitis, babesiosis, HIV, and Lyme disease. The differential diagnosis for African tick bite fever, murine typhus, and scrub typhus also includes malaria, typhoid, dengue, chikungunya, and other tropical fevers.

Diagnostic workup

Diagnosis primarily relies on clinical findings, and empiric therapy should be initiated if rickettsial or related infection is suspected, without waiting for laboratory confirmation. Diagnostic tests include examination of a Wright or Giemsa-stained smear of blood; bone marrow or CSF for morulae in ehrlichiosis and anaplasmosis; acute and convalescent IgG serology; polymerase chain reaction testing of whole blood, cerebrospinal fluid, or tissue (especially for the rickettsioses), including the eschar of African tick bite fever and scrub typhus; and immunohistochemical staining of tissue. Although possible, culture is rarely performed.

Polymerase chain reaction is the preferred test because it can provide species-specific results quickly. Polymerase chain reaction should be performed in the first week of illness, ideally before or within 48 hours of antibiotic administration, when the yield is highest.

Immunofluorescent serological tests (IFAs) are used later in illness because they are more likely to be positive 2 to 4 weeks after the onset of symptoms. IgG antibodies are more specific than IgM antibodies, and a single reactive or nonreactive test is not diagnostic. The best way to use serological assays is to test together acute and convalescent serum samples collected 2 to 4 weeks apart. IFA serological tests cross-react within and between the spotted fever and typhus group organisms, and speciation is generally only available in reference laboratories (63).

In Rocky Mountain spotted fever, CSF may show very mild mononuclear pleocytosis and slightly elevated protein. Occasionally, the CSF glucose concentration may be low (10). Cerebrospinal fluid abnormalities are identified in 60% of patients with ehrlichiosis who have neurologic abnormalities, most commonly a mild (< 100 cells/ul) lymphocytic pleocytosis, although CSF cells may be neutrophils in 23% of individuals (27; 33). Morulae may uncommonly be identified in CSF monocytes (33). CSF findings consistent with aseptic meningitis can also be seen in epidemic typhus and scrub typhus. In addition to PCR, CSF IgM may be useful for diagnosing scrub typhus meningitis (03).

Neuroimaging in Rocky Mountain spotted fever may show meningeal enhancement, cerebral infarctions, cerebral edema, or prominent perivascular spaces (08). A “starry sky” appearance on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted magnetic resonance images is described primarily in children with Rocky Mountain spotted fever but may also be seen in adults (35). This imaging finding is likely due to small perivascular and deep white matter infarcts (42; 11; 10; 35).

Management

Doxycycline is the treatment of choice for all patients with rickettsial and related diseases, regardless of age or pregnancy, and it should be given empirically in the appropriate clinical setting without waiting for laboratory confirmation. Moreover, a 1988 report of Rocky Mountain spotted fever acquired in the Bronx in New York, a nonendemic area, serves as a reminder that rickettsial disease should be suspected in any patient with an unexplained febrile illness given the ease of treatment and the risk of a poor outcome if treatment is delayed (59).

Recommended doxycycline dosages are 100 mg every 12 hours for adults and 2.2 mg/kg body weight twice a day for children under 45 kg up to a maximum of 100 mg every 12 hours. Doxycycline administration should continue until at least 3 days after fever resolves and clinical improvement is achieved, generally for 7 to 10 days (06; 15; 16; 17; 18) Azithromycin, rifampin, and chloramphenicol are also effective treatments for scrub typhus and could be considered in the setting of severe tetracycline allergy. Rifampin should be considered as a second-line option after exclusion of a diagnosis of tuberculosis (29). Given the possible adverse events associated with chloramphenicol, it should likely also not be considered a first-line option. Treatment should be given for 10 days in patients with anaplasmosis because of the likelihood of concomitant B burgdorferi infection (06).

Special considerations

Pregnancy

Doxycycline is the first-line treatment for suspected rickettsial and related diseases in pregnant patients and in children. See Management for more information. In the case of life-threatening tetracycline allergy, desensitization should be considered.