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Human ehrlichiosis and anaplasmosis

Human ehrlichiosis and anaplasmosis
Literature review current through: Jan 2024.
This topic last updated: Apr 27, 2023.

INTRODUCTION — The first case of human ehrlichiosis was described in 1986 when a patient became ill with fever, hypotension, confusion, acute renal failure, coagulopathy, and gastrointestinal hemorrhage [1]. The etiologic agent was identified as Ehrlichia chaffeensis, the agent of human monocytic ehrlichiosis (HME). In 1994, Anaplasma phagocytophilum was identified as the agent of human granulocytic anaplasmosis (HGA) [2]. HGA was previously called human granulocytic ehrlichiosis (HGE). These tickborne illnesses are recognized as separate disease entities even though their clinical and laboratory manifestations are similar.

The epidemiology, clinical manifestations, diagnosis, and treatment of human ehrlichiosis and anaplasmosis will be reviewed here. An in-depth overview of the microbiology of ehrlichial organisms and the mechanisms by which they cause disease are discussed elsewhere. (See "Biology of Anaplasmataceae".)

MICROBIOLOGY — Ehrlichiae are obligate intracellular bacteria that grow within membrane-bound vacuoles in human and animal leukocytes (picture 1). The two most important species to infect humans include E. chaffeensis, the causative agent of human monocytic ehrlichiosis (HME), and A. phagocytophilum, the agent of human granulocytic anaplasmosis (HGA). Less commonly, ehrlichiosis is caused by Ehrlichia ewingii, which was discovered in 1999 [3]. (See 'Human monocytic ehrlichiosis' below and 'Human granulocytic anaplasmosis' below and 'E. ewingii infection' below.)

In 2009, a third species of Ehrlichia was identified in four patients from Wisconsin and Minnesota who had fever, malaise, headache, and lymphopenia [4]; more than 100 cases have been subsequently reported [5]. Molecular methods, culture techniques, and serologic testing demonstrated that this species is closely related to Ehrlichia muris, which is found in Eastern Europe and Asia. In 2007, this organism was named E. muris eauclairensis [6].

Another species less commonly seen is Neorickettsia sennetsu, which causes a mild mononucleosis-like illness. Neorickettsial illness has not been reported outside the Far East and Southeast Asia [7].

A more detailed discussion of the taxonomy, phylogeny, and host specificity of these bacteria is presented elsewhere. (See "Biology of Anaplasmataceae".)

EPIDEMIOLOGY — Most cases of human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) occur in the spring and summer months, and many of the epidemiologic features are similar (table 1 and table 2).

Human monocytic ehrlichiosis — Human monocytic ehrlichiosis (HME) is endemic in the southeastern, south-central, and mid-Atlantic regions of the United States (figure 1) [8]. A few cases of HME have been recognized in New England and the Pacific Northwest, and isolated cases have been reported in Europe, Africa, and Mexico [9]. Serologic studies have suggested that E. chaffeensis also occurs in Mexico, Venezuela, Brazil, Chile, Korea, and China. Serologic and molecular testing of vertebrates and humans have also detected E. chaffeensis or a closely related ehrlichial agent in Venezuela, Croatia, Poland, Greece, Italy, and several countries in central Africa [10,11].

The total number of cases of HME reported annually to the United States Centers for Disease Control and Prevention (CDC) quadrupled from 2000 to 2008 and has continued to increase [5,12]. From 2008 to 2012, the incidence of HME was 3.2 cases per million person-years, with wide variations in incidence by state [13]. However, these numbers likely underestimate the actual incidence of the disease, as many cases are not confirmed by laboratory testing and current surveillance systems rely on voluntary reporting by clinicians. Depending on geographic location and exposure history, incidence rates as high as 660 per 100,000 have been reported in outbreak situations, and serologic surveys have shown evidence of asymptomatic infection [14,15]. Tick bites, exposure to wildlife, and golfing have been associated with an increased risk of infection.

Human granulocytic anaplasmosis — The human granulocytic anaplasmosis (HGA) agents Ehrlichia phagocytophila and Ehrlichia equi are now recognized as the same organism, which has been renamed A. phagocytophilum. (See "Biology of Anaplasmataceae".)

HGA is more frequently reported than HME in the United States, with an average reported annual incidence of 6.3 cases per million population from 2008 to 2012 [16]. In the United States, regional estimates of HGA vary significantly by locale, and most reported cases of anaplasmosis are from Vermont, Maine, Rhode Island, Minnesota, Massachusetts, Wisconsin, New Hampshire, and New York (figure 2). The number of cases of HGA reported to the CDC increased more than 12-fold from 2001 to 2011 [17] and continued to rise, reaching 5762 cases reported in the United States during 2017 [18]. These numbers are likely incomplete, as reporting is a passive process and a significant number of cases diagnosed on clinical grounds are not confirmed serologically. In addition, serologic studies of persons with a history of tick bites suggest that many infections are asymptomatic [19].

Infection with HGA is also recognized in Europe and Asia with similar risk factors of tick bite exposure [20-23]. The majority of human cases in Europe have been reported from Central Europe (eg, Slovenia) and Scandinavia (eg, Sweden) [24]. Although numerous studies done in various European countries have shown that A. phagocytophilum is commonly present in rodents, small mammals, and ticks, relatively few human cases of HGA have been recognized, and the course of disease when infection does occur appears to be less severe than that seen in the United States [25]. It is currently unknown if these findings are due to the presence of less pathogenic or nonpathogenic variants of A. phagocytophilum in Europe [21].

E. ewingii infection — In 1999, E. ewingii, the agent of canine granulocytic ehrlichiosis, was found to cause disease in humans. Several of these cases occurred in Missouri, an area endemic for E. chaffeensis, and the clinical features of illness in these patients were initially confused with those of HME [3]. Subsequently, however, sequencing of isolates distinguished the organism in these cases from E. chaffeensis.

From 2008 to 2012, 55 cases of E. ewingii infection were reported, with an incidence ratio of 0.04 cases per million person-years [13]. Human E. ewingii infection is likely to be widely distributed throughout the south-central and southeastern United States as the vector for this disease (Amblyomma americanum, the "lone star" tick) is found throughout this wide geographic area. Most human E. ewingii infections have been recognized in immunocompromised patients [26]. It is likely that some cases of E. ewingii infection are misdiagnosed as HME since the most commonly used serologic tests for convalescent antibodies to Ehrlichia do not distinguish between E. ewingii and E. chaffeensis infection [3].

E. muris eauclairensis — E. muris eauclairensis infection is uncommon and has only been described in patients from Minnesota and Wisconsin. It is transmitted by Ixodes scapularis, the same tick that transmits A. phagocytophilum, Lyme disease, babesiosis, and Powassan virus. Its principal host is Peromyscus leucopus, the white-footed mouse [5]. The clinical features of this illness resemble E. chaffeensis infection (see 'Clinical manifestations' below). In a series of 69 patients, 27 percent had immunocompromising conditions [27].

TRANSMISSION

Tick vectors — The distribution of vector tick species dictates the epidemiology of human monocytic ehrlichiosis (HME), human granulocytic anaplasmosis (HGA), and other tickborne illnesses, and is partially overlapping in the United States (figure 3).

HME – The principal vector of E. chaffeensis (agent of human monocytic ehrlichiosis [HME]) is the lone star tick (Amblyomma americanum) (picture 2). Other ticks such as Amblyomma maculatum, Dermacentor variabilis, and Ixodes pacificus have occasionally been found to contain E. chaffeensis DNA, but their role in transmission is either minor or unlikely.

Surveys of A. americanum ticks have shown rates of infection ranging from 0 to 27 percent; these wide ranges have been noted not only from different geographic locations, but also from the same location sampled at different times [11]. The tick vectors of E. chaffeensis in South America, Asia, and Africa have not been firmly identified [11]. Epidemiologic studies suggest that the tick vector for the novel species E. muris eauclairensis, identified in Wisconsin and Minnesota in 2009, is I. scapularis [4].

HGA – In the northeastern and midwestern regions of the United States, A. phagocytophilum (agent of human granulocytic anaplasmosis [HGA]) is transmitted by I. scapularis (picture 3), the tick that is also the vector of E. muris eauclairensis, Lyme disease, babesiosis, and Powassan virus [28] (see 'Coinfection with other tickborne illnesses' below). I. pacificus (picture 4), the western black-legged tick, is the primary vector of HGA in the western United States, and Ixodes ricinus is the primary vector in much of Europe [19].

Animal reservoirs — White-tail deer are the principal animal reservoir for E. chaffeensis, and deer and the white-footed mouse are the principal animal hosts for A. phagocytophilum [29]. Although E. chaffeensis infection has been noted in coyotes and goats, their role in the epidemiology of HME remains to be determined [11,30-32].

Other modes of transmission — Although HME and HGA are primarily tickborne diseases, Ehrlichia and Anaplasma transmission have been reported to occur through transfusion of blood, leuko-reduced red cells, and platelets [33-37]. E. chaffeensis has also been reported after solid organ transplantation, although most of these cases were probably acquired post-transplant from tick bites rather than donor-derived [38-40]. Transmission by other means has also been suggested, such as maternal-child transmission [41] and transmission through direct contact with slaughtered deer [42].

CLINICAL MANIFESTATIONS

Adults — Both human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) typically present as an acute illness; however, there is a wide spectrum of disease ranging from subclinical and self-limited to subacute and prolonged. While many clinical manifestations overlap, HME infections are more likely to be severe and require hospitalization compared with HGA [13,16]. Most published data relate to infection in adults.

Ehrlichial diseases generally have an incubation period of one to two weeks, but a shorter period may be seen. In a study of 18 adults with HGA, for example, symptoms appeared an average of 5.5 days after a tick bite was noted [43].

For those who develop symptoms, the clinical manifestations of HGA and HME can vary from mild to severe.

Most patients are febrile, but clinically mild or inapparent infection probably occurs. In studies of transfusion-related disease, the donors implicated as the source of transmission were asymptomatic [34-36].

Nonspecific symptoms such as malaise, myalgia, headache, and chills occur in over two-thirds of cases, while nausea, vomiting, arthralgias, and cough occur in 25 to 50 percent.

Older patients and those with comorbid illnesses or immunosuppressive conditions such as HIV appear to have more severe infections [33]. (See 'Immunocompromised hosts' below and 'Morbidity and mortality' below.)

Rash, which can be macular, maculopapular, or rarely petechial, occurs in a minority of patients [44]. In one review, rash was noted in 36 percent of 211 cases of HME [45]. Rash is rarer in HGA infection, occurring in only 1 of 41 patients in one report [46]. Some experts caution that when rash is present, alternative etiologies of rash should be considered. For example, the presence of classic erythema migrans rash should raise the possibility of infection or coinfection with Borrelia burgdorferi. Similarly, diffuse maculopapular, petechial, or vasculitic rash is more typical of Rocky Mountain spotted fever (RMSF) or other illnesses [19]. (See "Clinical manifestations of Lyme disease in adults", section on 'Erythema migrans' and "Clinical manifestations of Lyme disease in adults", section on 'Cutaneous findings' and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Rash'.)

Neurologic symptoms, including mental status changes, stiff neck, clonus, and meningoencephalitis, can be present in up to 20 percent of ehrlichiosis cases but are not as commonly reported in anaplasmosis. In a retrospective review of 57 individuals with confirmed Ehrlichia, 15 (26 percent) had neurologic findings that prompted cerebrospinal fluid (CSF) analysis. Eight of the samples were abnormal, and the most common abnormalities were lymphocytic pleocytosis and elevated protein levels [47]. In a separate case report of ehrlichial meningitis, characteristic inclusions compatible with Ehrlichia morulae were seen within mononuclear cells in the CSF [48].

Some patients present subacutely with unexplained fever, and fever can persist for up to two months in the absence of therapy [44,49]. In one study, 6 of 41 cases of HME recognized at a medical center in Missouri during a four-year span had protracted fever ranging in duration from 17 to 51 days [49]. Another report described an untreated patient with HGA in whom A. phagocytophilum DNA was detected 21 days after the onset of symptoms despite the presence of high antibody titers [50].

A case of rapidly progressive myocarditis due to E. chaffeensis infection, leading to the death of a previously healthy 15-year-old girl, has been reported [51].

More detailed discussions of the complications that can result from HME and HGA infection are found below. (See 'Complications' below and 'Morbidity and mortality' below.)

Children — Data in children with ehrlichiosis have largely consisted of case reports and small series. A report from the Tick-Borne Infections in Children Study Group evaluated 32 children with HME in the "tick belt" of the southeastern United States [52]. The major disease manifestations were fever in all patients; headache, myalgia, and rash (66 to 69 percent); and nausea/vomiting, altered mental status, and lymphadenopathy (47 to 56 percent). The triad of fever, headache, and rash was present in 48 percent. These findings are similar to those in adults. In this report, a minority of the children had severe disease. Seven (22 percent) were admitted to the intensive care unit, four of whom required ventilatory and hemodynamic support.

Anaplasmosis is rarely reported in children. In one small series of nine patients, children with HGA frequently presented with fever, headache, and malaise; children appeared to be more likely than adults to complain of abdominal pain [53].

Pregnant women — Data are limited on the effect of HME and HGA in pregnancy. In one case series of six pregnant women with HGA, all had mild disease [54]. However, another report described a pregnant woman with HGA who spontaneously aborted her child while being treated for HGA [55].

Perinatal transmission of HGA has been described in case reports [41,54,56]. Performing polymerase chain reaction (PCR) on blood from the neonate should be considered if HGA or HME is diagnosed in the mother during pregnancy. (See 'Polymerase chain reaction' below.)

Immunocompromised hosts — Severe disease has been reported in patients with factors leading to impaired immunity, such as advanced age, immunosuppression, chronic illness, and malignancy [19,57,58]. (See 'Morbidity and mortality' below.)

Laboratory findings — A variety of laboratory abnormalities occur in HME and HGA infections. The most common, occurring in 50 to 90 percent of patients, are leukopenia (often accompanied by a left shift), thrombocytopenia, and elevated plasma levels of aminotransferases (transaminases), lactate dehydrogenase, and alkaline phosphatase [46,52,59]. Nonhemolytic anemia and an elevated plasma creatinine also may be seen. Lab findings consistent with hemolytic anemia should prompt consideration of Babesia infection or coinfection in the appropriate epidemiologic setting. (See "Babesiosis: Clinical manifestations and diagnosis".)

Leukopenia in patients with HGA can be caused by lymphopenia or neutropenia. Lymphopenia tends to occur in the early stages of infection, followed by lymphocytosis with atypical lymphocytes [43]. In contrast, the initial neutrophil count in patients with HGA is inversely related to the duration of symptoms before treatment is begun. In one study, for example, neutropenia was seen in three of four patients who had HGA for more than four days versus only one of nine patients with a shorter duration of illness [43].

Thrombocytopenia was observed more often than leukopenia in a retrospective study of 144 patients with HGA [60]. This study also included matched controls with other acute febrile illnesses, and the risk of having ehrlichiosis in this group of patients varied inversely with granulocyte and platelet counts. The number of band neutrophils was also increased in most patients with HGA from the time of onset through the eighth day of illness. The authors emphasized that automated differential counting of leukocytes may not separate band neutrophils from segmented neutrophils or detect morulae, and they stressed the important point that a manual differential count should be ordered if ehrlichiosis is suspected.

Changes in the CSF can be seen in patients in whom a lumbar puncture is performed because of neurologic symptoms. In one report, for example, lymphocytic pleocytosis and elevated CSF protein levels were found in 21 of 38 patients with E. chaffeensis infection [47]. In contrast, patients with HGA who have neurologic symptoms typically have relatively normal CSF [33].

Complications — The complications of HME and HGA infections include seizures, coma, and renal and respiratory failure. Cardiac complications can also occur, including heart failure in previously healthy patients, (with or without electrocardiographic or chemical evidence of myocarditis) [61], and pericardial effusions leading to tamponade [62]. In addition, a septic or toxic shock-like illness may occur in patients with severe HME or HGA infections [63].

Other complications include:

Secondary infections – HGA infection can be complicated by serious and even fatal opportunistic infections, including herpes simplex esophagitis, invasive aspergillosis, and candidiasis [63,64].

Hemophagocytic lymphohistiocytosis – While rare, there have also been an increasing number of reports of patients with HME or HGA infections who developed hemophagocytic lymphohistiocytosis (HLH) [40,65]. HLH can be fulminant and difficult to treat. Underlying HME or HGA should be treated if it is suspected to have triggered HLH [66-68]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Post-infectious complications – Demyelinating polyneuropathy and brachial plexopathy have been temporally linked with HGA infections [69,70].

Coinfection with other tickborne illnesses — Because individual ticks can carry multiple different pathogens, humans can simultaneously acquire more than one infection after a single tick bite.

Coinfections with HGA – In addition to A. phagocytophilum, the I. scapularis tick is also the vector for B. burgdorferi (the agent of Lyme disease) and Babesia, and humans have become simultaneously infected with a combination of these organisms after a single tick bite. In studies of I. scapularis ticks from different locales, 2 to 26 percent of ticks were coinfected with B. burgdorferi and A. phagocytophilum [28,71]; in Connecticut and Wisconsin, concurrent HGA and Lyme disease may occur in as many as 3 to 15 percent of patients with tickborne infection [72].

Clinical features that should raise suspicion for possible concomitant Lyme disease include erythema migrans rash, neurologic symptoms (such as Bell palsy), and cardiac rhythm abnormalities. Hemolytic anemia or intraerythrocytic parasitic inclusions on peripheral blood smear should raise suspicion for Babesia coinfection. (See "Clinical manifestations of Lyme disease in adults", section on 'Early disseminated disease' and "Babesiosis: Clinical manifestations and diagnosis".)

Other pathogens that can be carried by I. scapularis include E. muris eauclairensis, other Borrelia species (eg, B. miyamotoi), and Powassan virus. These are discussed elsewhere. (See "Borrelia miyamotoi infection" and "Arthropod-borne encephalitides", section on 'Powassan virus'.)

Coinfections with HME – Patients with HME do not typically have concurrent tickborne infections, although simultaneous bites from ticks of multiple species may lead to coinfection [73].

Morbidity and mortality — Overall, more than 50 percent of reported cases require hospitalization [13,74]. However, case fatality rates for both HME and HGA have declined as reported cases have increased over the past decade. Estimated mortality rates range from 1.0 to 2.7 percent for HME and are around 0.3 percent for HGA [13,16,59,75]. Secondary opportunistic infections (likely due to leukopenia) such as fungal pneumonia are common in patients who die [46].

Ehrlichiosis may be particularly life-threatening in immunocompromised patients. In a review of 21 patients with HIV coinfection, 6 of 13 died and several other patients had severe illnesses including respiratory failure, gastrointestinal hemorrhage, and fungal superinfections [44]. Severe disease, including hemophagocytic lymphohistiocytosis, can occur in solid organ transplant recipients [39,40,76,77]. One report of 23 cases of HME in this population found that organ failure occurred in all patients, and six patients (25 percent) died [76].

Outcome data are more limited in children. In a review of 32 children with HME, there were no deaths, but three had significant neurologic deficits at discharge [52]. (See 'Children' above.)

DIAGNOSIS

Clinical suspicion — A presumptive diagnosis of human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) can be made in patients who have a compatible systemic febrile illness with appropriate epidemiologic exposures and no clear alternative explanation. As an example, outdoor exposure in an endemic area during spring or summer months coupled with a febrile illness and isolated leukopenia and/or thrombocytopenia provides strong circumstantial evidence for the diagnosis of ehrlichiosis. (See 'Epidemiology' above and 'Clinical manifestations' above.)

The diagnosis should be considered even in those with a history of HGA or HME since prior infection may not confer long-lasting immunity. One patient experienced two episodes of HGA spaced two years apart [78].

Given the potential for rapid progression to serious illness, we agree with the Centers for Disease Control and Prevention (CDC) guidance that antimicrobial treatment should be administered as soon as infection is clinically suspected [79]. Delaying treatment can lead to increased morbidity and mortality. (See 'General principles' below.)

Confirming the diagnosis — As stated above, we suggest treating for HME or HGA as soon as the diagnosis is suspected. The results of testing should not delay treatment.

Approach to testing — When HME or HGA is suspected, we send blood samples for HME or HGA polymerase chain reaction (PCR), HME or HGA serology, and a blood smear. In areas endemic for both HME and HGA, separate PCR and serologic tests should be sent for each organism.

PCR is widely used and is able to provide diagnostic results during the acute setting. Importantly, a positive PCR result confirms infection, but a negative result does not definitively rule out disease. (See 'Polymerase chain reaction' below.)

Serology can also provide a definitive diagnosis, but its clinical utility in the acute setting is limited. If PCR is negative and suspicion for HME or HGA remains, we submit a second serologic test two to four weeks later to make a diagnosis; a fourfold rise in the antibody titers between the acute and convalescent tests can confirm the diagnosis. Accuracy and interpretation of these microbiologic tests are described further below. (See 'Serology' below.)

Microscopic examination of a blood smear can sometimes provide rapid confirmation of the diagnosis. Although sensitivity for this test is lower than that of PCR, it is highly specific and can provide the most rapid results. Obtaining a smear of the buffy coat in blood can improve sensitivity, but buffy coat examination is labor intensive for the laboratory and is not frequently performed. (See 'Blood smears' below.)

Polymerase chain reaction — Polymerase chain reaction (PCR)-based testing can detect HME and HGA infections early in the course of illness. Tests are widely available from multiple commercial labs, as well as the CDC and some state public health laboratories.

PCR assays for HME and HGA have excellent sensitivity and specificity during the first week of illness [79]. Sensitivity and specificity vary from laboratory to laboratory, but have been reported to be as high as 95 to 100 percent [80-83].

However, the PCR test may be negative despite infection, particularly in specific situations:

PCR tests sent more than one week after onset of symptoms are less reliable [79].

Because PCR assays detect single species, a PCR test for A. phagocytophilum does not detect Ehrlichia species, and vice versa. Furthermore, a PCR test for E. chaffeensis may not detect E. ewingii, E. muris eauclairensis, or other Ehrlichia spp [4]. If multiple species are suspected, individual tests for each suspected organism should be ordered. Many laboratories provide PCR panels that can detect multiple organisms simultaneously.

Samples obtained from patients on antibiotic therapy may have false-negative PCR results [84]. Some data suggest that PCR sensitivity falls within 48 hours of administration of appropriate antibiotics [79].

Serology — Serologic tests measure specific immunoglobulin (Ig)M and IgG antibody levels against HME and HGA.

To diagnose HME or HGA by serologic testing, one blood sample should be obtained upon presentation (ie, an acute sample) and a second sample should be obtained two to four weeks after the first antibody test is sent (ie, a convalescent sample). We agree with CDC guidance that a definitive diagnosis requires at least a fourfold change in the IgG titer between the acute and convalescent stage [85]. To confirm an infection, most labs require at least one of the IgG titers to be at least 1:64 to 1:80 [86].

Serologic tests are available from multiple commercial laboratories and most state public health laboratories. Laboratories use different methodologies to perform serologic tests, but IgG indirect fluorescent antibody assays (IFA) are the historical reference standard for HME or HGA.

Paired serologic tests for IgG have been estimated to be 80 to 86 percent sensitive if ordered and interpreted correctly [87,88].

Like PCR tests, serologic tests can be negative despite active infection, particularly in specific situations:

Early in the clinical course, serologic tests are often negative because antibodies often do not reach detectable levels within the first week of illness. Patients with negative initial serology can be confirmed to have disease if a subsequent convalescent sample shows a significant conversion from undetectable to a positive titer, as described above.

Tests for the wrong organism can cause negative results because serologic tests that detect E. chaffeensis (the cause of HME) do not reliably detect HGA, and vice versa. Therefore, in areas endemic for both HME and HGA, a serologic test should be sent for each organism. In contrast, most serologic tests for E. chaffeensis do detect multiple Ehrlichia species due to cross-reactivity [12,59,86,89].

Antibiotic treatment can abort IgM and IgG production, which may prevent fourfold rises in convalescent titers [88].

Unlike PCR, serologic tests can be positive in the absence of ongoing infection, particularly in specific situations:

Patients with past HME or HGA infections can have persistently positive IgG results, often past one year [46,90]. As described above, correct timing of acute and convalescent titers can differentiate past from acute infection.

Single positive IgG antibody titers should not be used to make a definitive diagnosis of acute or recent infection, regardless of whether the sample was drawn in the acute phase or the convalescent phase. As an example, in a case report of an individual with two HGA infections two years apart, the IgG titer at the time of reinfection was the same as that measured 13 months after the first infection (1:80); the diagnosis was definitively made by a significant rise in the convalescent titer [78].

Like IgG, single positive IgM antibody titers should not be used to make a definitive diagnosis of acute or recent infection. IgM antibody tests are frequently offered by commercial labs, but they are significantly less specific than IgG titers and thus do not necessarily indicate acute or past infection [33].

Blood smears — In patients with HME or HGA, intracytoplasmic inclusions called morulae can sometimes be seen on a blood smear. When seen in the right clinical setting, they definitively confirm the diagnosis. If available at an institution, performing a buffy coat examination of a blood smear from centrifuged blood can increase the likelihood of finding morulae.

In patients with HGA, morulae are detected in the neutrophils (picture 1). Reported frequency varies between 20 and 80 percent. One report found obvious morulae in the peripheral smear in 28 of 35 (80 percent) patients with laboratory-confirmed HGA infection [46]. Another study of 141 patients with HGA from the upper Midwest and New York found that 86 (61 percent) had morulae visualized in neutrophils [60].

In individuals with HME, morulae are detected in the mononuclear cells. They are identified less commonly, in approximately 1 to 20 percent of patients (figure 4) [84,86,91,92].

Other diagnostic tests — Other diagnostic tests are rarely used.

A few cases of HME have been diagnosed by immunohistochemical staining of bone marrow tissue or autopsy tissue from spleen, lymph nodes, liver, or lung for ehrlichial antigens [93-95].

Routine blood cultures cannot detect the organisms. Culturing the organisms is extremely difficult, so culture has no meaningful role in the diagnosis of HME or HGA. Until 1995, only two isolates of E. chaffeensis had been recovered from humans; in both cases, the process required over 30 days of cultivation [59]. The isolation of A. phagocytophilum from three patients has also been accomplished using a cell culture system derived from human promyelocytic leukemia cells [62]. (See "Biology of Anaplasmataceae".)

Evaluation for coinfections — Patients with suspected HGA should be evaluated for other infections that are transmitted by the same I. scapularis tick (eg, Lyme, babesiosis), if suspected (see 'Coinfection with other tickborne illnesses' above). This is especially important for babesiosis because standard treatment for HGA (doxycycline) would not be effective for babesiosis. Diagnostic testing for Lyme and babesiosis is discussed elsewhere. (See "Diagnosis of Lyme disease", section on 'Approach to diagnosis' and "Babesiosis: Clinical manifestations and diagnosis", section on 'Clinical approach'.)

Patients with HME typically do not have coinfections.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) is broad and includes both infectious and noninfectious etiologies. In addition, coinfection with other tickborne infections should be considered. The clinical presentation can help to narrow the differential diagnosis:

Individuals with severe sepsis or septic shock – Severe sepsis and septic shock from other bacterial infections can mimic severe HME and HGA infections. Examples include bacteremia, acute cholangitis, community-acquired pneumonia, urosepsis, and meningoencephalitis. For these patients, broad-spectrum antimicrobial therapy, including treatment for HME or HGA, should be started until a definitive microbiologic diagnosis is made. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Empiric antibiotic therapy (first hour)'.)

Individuals with fever plus leukopenia, thrombocytopenia, and/or abnormal aminotransferases – Infections with lab findings that mimic HME and HGA include mononucleosis-like illnesses caused by Epstein-Barr virus, cytomegalovirus, and acute HIV. Other viruses can cause similar syndromes, including viral hepatitides like hepatitis A, B, and C.

Other arthropod infections should also be considered. Rocky Mountain spotted fever (RMSF) has a similar clinical presentation to HME and HGA except RMSF is much more likely to have an associated rash. Babesiosis can have similar symptoms and lab findings as HME and HGA, except patients with babesiosis also have evidence of hemolytic anemia or intracytoplasmic parasitic inclusions on blood smears; the presence of Babesia infection does not rule out coinfection with Anaplasma, as discussed above. (See 'Coinfection with other tickborne illnesses' above.)

Noninfectious illnesses can present with fever and lab findings consistent with HME and HGA. Such conditions include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), hemophagocytic lymphohistiocytosis (HLH), and hematologic malignancy. Drug reactions can also mimic these findings, including reactions to trimethoprim-sulfamethoxazole and chemotherapeutic agents.

TREATMENT

Indications — Treatment should be initiated in all symptomatic patients suspected of having ehrlichiosis or anaplasmosis. Human ehrlichiosis can be a serious disease with significant morbidity, particularly if appropriate antibiotics are delayed. (See 'Morbidity and mortality' above.)

For patients who present with severe sepsis or septic shock, broad-spectrum antibiotic therapy is also typically used until the diagnosis of human monocytic ehrlichiosis (HME) or human granulocytic anaplasmosis (HGA) is confirmed. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Initial resuscitative therapy'.)

Some patients have subclinical or undiagnosed illness, and make a full recovery without treatment. There is no evidence that untreated ehrlichiosis produces longer-term symptoms such as those reported after some cases of Lyme disease.

Treatment regimens

General principles — There have been no controlled trials examining the efficacy of antimicrobial therapy in either HME or HGA. Treatment recommendations are based on clinical case series and in vitro data.

The drug of choice for all patients is doxycycline. This is also the preferred therapy for many other tickborne infections (eg, Rocky Mountain spotted fever [RMSF]) that can be confused with HGA and HME. (See 'Differential diagnosis' above.)

Seven to 10 days of therapy is commonly recommended, and relapses have not been described with this treatment duration [33].

Special considerations for pregnant women and those with concurrent tickborne infections are discussed below. (See 'Pregnancy' below and 'Patients with concurrent tickborne infection (coinfection)' below.)

Although most experience is with tetracyclines, if an alternative agent is used, we generally prefer rifampin due to reports of successful outcomes using this agent [19,33,96-98]. However, there is a general lack of consensus on this issue given a paucity of data for second-line agents. Chloramphenicol also appears to be effective, but it can be associated with significant hematologic toxicity and is not available in most pharmacies in the United States. A more detailed discussion of chloramphenicol is found elsewhere. (See "Treatment of Rocky Mountain spotted fever", section on 'Chloramphenicol'.)

The benefit of tetracyclines was illustrated in a study of 237 patients with HME, in which 3 of 49 outpatients (6.1 percent) treated only with tetracycline required hospitalization, compared with 35 of 38 patients (92 percent) who were treated with antibiotics other than tetracycline or chloramphenicol [45]. Among hospitalized patients, recovery was faster for those initially treated with tetracycline (median 16 days) or chloramphenicol (median 12 days) than for those initially treated with other antibiotics (median 27 days); furthermore, severe illness or death was more probable in patients who did not receive tetracycline or chloramphenicol until eight days or more after the onset of symptoms (odds ratio 4.38; 95% CI 1.36-14.0). The benefit of early therapy was supported in a subsequent study, in which delayed therapy was associated with an increased rate of transfer to the intensive care unit, mechanical ventilation, longer hospital stay, and a longer length of illness [99].

Similar results are seen in patients with HGA. In one study, for example, 2 of 12 patients died; the other 10 improved rapidly after the administration of doxycycline, with defervescence occurring within 48 hours after initiation of treatment [100]. In another report, all 18 patients with HGA who were treated with doxycycline had resolution of fever within 48 hours of starting therapy. The four patients with E. ewingii also responded to treatment with doxycycline, including three receiving immunosuppressive therapy for other conditions [3].

There is only a limited amount of retrospectively collected clinical data on the comparative efficacy of tetracyclines (most commonly doxycycline) and chloramphenicol in the treatment of HME. In one study of hospitalized patients with this disorder, those treated with doxycycline defervesced one day sooner than those treated with chloramphenicol (two versus three days) [44]. This study and in vitro data have led some experts to recommend doxycycline as the treatment of choice even in children [59].

While there are no documented cases of tetracycline resistance in these diseases, some patients have a prolonged course and do not respond well to therapy. In a case report, persistent infection with E. chaffeensis was documented in a man who died 68 days after initial hospitalization for his acute illness [101]. Despite treatment with tetracycline and chloramphenicol, E. chaffeensis morulae were found in samples of his bone marrow on day 18 and at post-mortem. Most reported cases of prolonged illness involved patients with varying degrees of immunosuppression, who may be at higher risk for severe outcomes. (See 'Morbidity and mortality' above.)

In one in vitro study, levofloxacin (minimum inhibitory concentration [MIC] ranging from 0.06 to 0.5 mcg/mL) was active against eight strains of A. phagocytophilum isolated from various geographic areas of the United States [96]. However, there is limited clinical experience with this agent, and relapse of infection has been described in at least one patient with HGA infection treated with levofloxacin [102].

Adults — Doxycycline can be given either orally or intravenously at a dose of 100 mg twice daily. We agree with published recommendations that doxycycline be continued for 10 days or for three to five days after defervescence, whichever is longer [31,57]. Special considerations in pregnant women are discussed below. (See 'Pregnancy' below.)

Patients who have intolerance or allergy to tetracyclines can be treated with rifampin (300 mg twice daily) for 7 to 10 days, but careful follow-up and monitoring of such patients is recommended, as there are only a few case reports on the efficacy of this agent [19,33,96-98].

Children — Children should be treated with doxycycline (4.4 mg/kg per day, divided every 12 hours, intravenously or orally; maximum 100 mg/dose) [103]. Treatment should continue for at least three days after defervescence. In general, the duration of treatment is 7 to 14 days.

Doxycycline can be used regardless of age. Although some tetracyclines can cause dental staining in children <8 years of age, the risk of such staining with doxycycline is minimal if a short course of therapy is administered. The American Academy of Pediatrics supports use of doxycycline for ≤21 days in children of all ages [104].

Rifampin therapy (10 mg/kg twice per day, maximum 300 mg per dose) for 7 to 10 days can be given as an alternative to doxycycline for treatment of ehrlichiosis and anaplasmosis, but children treated with this agent should be carefully monitored to ensure clinical resolution of disease [57]. Successful treatment of HGA with rifampin has been reported in two children, but clinical experience is limited [105].

Special considerations

Pregnancy — At present, no guidelines exist for the treatment of HME or HGA in pregnancy. We suggest doxycycline rather than an alternative antibiotic, since there is most experience with this agent. In addition, case reports support that doxycycline can been used successfully and safely in pregnant women with HME or HGA [54,106].

Although older tetracyclines are relatively contraindicated in pregnancy because of the risk of hepatotoxicity in the mother [86] and adverse effects on fetal bone and teeth [107,108], 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 [109,110]. As an example, in a systematic review, there was no correlation between the use of doxycycline during pregnancy and teratogenic effects or dental staining in children [109].

An alternative to doxycycline in pregnant women is rifampin. Rifampin is both active and bactericidal against HGA in vitro [96,111] and has been effective in small numbers of pregnant women with HGA [33,54,97].

The risk of perinatal transmission is discussed above. (See 'Pregnant women' above.)

Patients with concurrent tickborne infection (coinfection) — Patients infected with HGA who are suspected to have potential coinfection with other tickborne pathogens such as B. burgdorferi, B. miyamotoi, and Babesia microti should receive empiric treatment for all suspected infections until a definitive microbiologic diagnosis is made. Clinical findings that suggest coinfection are described above. (See 'Coinfection with other tickborne illnesses' above.)

Borrelia burgdorferi and other Borrelia species Doxycycline regimens of at least 10 days will treat coinfection with B. burgdorferi (ie, Lyme disease) if it is early in its course (as is the case with coinfection), as well as B. miyamotoi. By contrast, rifampin is not effective against Borrelia spp, so another antibiotic should be added to rifampin when Borrelia coinfection is suspected. (See "Treatment of Lyme disease" and "Borrelia miyamotoi infection", section on 'Treatment'.)

Babesia microti None of the agents used to treat anaplasmosis are effective for Babesia, so a specific regimen is needed if concurrent babesiosis is suspected or diagnosed. (See "Babesiosis: Treatment and prevention".)

PREVENTION — The best way to prevent infection with A. phagocytophilum and E. chaffeensis is through the use of tick repellants, such as DEET (N,N-diethyl-3-methylbenzamide, previously called N,N-diethyl-m-toluamide) or permethrin, and prompt examination for and removal of ticks. Other strategies include bathing after outdoor activities in areas where ticks are abundant, placing clothes in dryers for a short time after outdoor activities, wearing protective white clothing, and simply avoiding areas where ticks are abundant. Tick control in domestic animals (eg, dogs, cats) may also be helpful [112,113].

Antibiotic therapy with doxycycline after a tick bite is not recommended to prevent ehrlichiosis and anaplasmosis, despite the fact that 5 to 15 percent of lone star ticks may be infected with E. chaffeensis and 10 to 50 percent of I. scapularis ticks may be infected with A. phagocytophilum in endemic areas [86]. Instead, patients with tick bites should be told to report any symptoms compatible with infection in the two weeks following a bite. The use of antibiotics to prevent Lyme disease is discussed elsewhere. (See "Evaluation of a tick bite for possible Lyme disease", section on 'Antimicrobial prophylaxis'.)

There are no licensed vaccines for ehrlichiosis or anaplasmosis. Animal studies suggest that it may take 24 hours following tick attachment to transmit A. phagocytophilum infection [114]. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tick-borne infections (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, and Rocky Mountain spotted fever)".)

SUMMARY AND RECOMMENDATIONS

Microbiology Although similar in clinical presentation, diagnosis, and treatment, human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) are caused by different organisms. HME is caused by Ehrlichia species, most commonly E. chaffeensis. HGA is caused by Anaplasma phagocytophilum. (See 'Microbiology' above.)

Epidemiology HME is transmitted by the lone star tick (Amblyomma americanum) and is endemic in the southeastern, south-central, and mid-Atlantic United States. HGA is transmitted by the Ixodes scapularis tick and is endemic in Minnesota, Wisconsin, and the northeastern region of the United States. Cases have also been reported from other parts of the world. (See 'Epidemiology' above.)

Clinical manifestations HME and HGA have similar clinical manifestations, ranging from mild illness to septic shock. Severe disease is more common with HME infection and in immunocompromised individuals. (See 'Clinical manifestations' above.)

Onset of illness is usually within one to two weeks of the tick bite.

Typical symptoms include fever, malaise, myalgia, and headache.

Typical laboratory findings include leukopenia, thrombocytopenia, and transaminitis.

Diagnosis In endemic areas, a presumptive clinical diagnosis of HME or HGA can be made in patients who present with a typical febrile illness and outdoor exposure. As soon as either is suspected, we send blood samples for polymerase chain reaction (PCR) testing, a blood smear, and serology for the suspected species. (See 'Diagnosis' above.)

A positive PCR test strongly supports the diagnosis of HME or HGA, but a negative result does not rule out disease, particularly after the first week of illness.

A single positive serologic test does not confirm the diagnosis of HME or HGA. If HME or HGA infection is suspected despite a negative PCR, we send a second convalescent serologic test two to four weeks later. A fourfold difference between acute and convalescent IgG titers is confirmatory. IgM titers have questionable utility in the diagnosis of HME or HGA.

If seen on blood smear in the right clinical setting, intracytoplasmic inclusions called morulae (picture 1) definitively confirm the diagnosis.

Treatment As soon as HME or HGA is suspected, empiric treatment should be initiated. For patients with severe sepsis or septic shock, broad-spectrum antimicrobials should be added until the diagnosis of HME or HGA is confirmed. (See 'Indications' above.)

For treatment of HME or HGA in nonpregnant adults and children, we recommend doxycycline rather than a nontetracycline agent (Grade 1B). Although some tetracyclines can cause dental staining in children <8 years of age, the risk of such staining with doxycycline is minimal if a short course of therapy is administered. Rifampin is an alternative for individuals who cannot take doxycycline (eg, severe allergy). (See 'Adults' above and 'Children' above.)

For treatment of HME or HGA in pregnant individuals, we also suggest doxycycline rather than rifampin (Grade 2C). Although most tetracyclines are contraindicated in pregnancy because of the risk of hepatotoxicity in the mother and adverse effects on fetal bone and teeth, these are extremely rare with doxycycline. (See 'Pregnancy' above.)

Treatment should be continued for at least three days after defervescence. In adults, the minimum duration is 10 days. For children, there is no minimum duration, but most patients require 7 to 14 days of treatment. (See 'Adults' above and 'Children' above.)

For patients with HGA in whom coinfection is suspected, 10 days of doxycycline is sufficient to treat most cases of early Lyme disease or infection with B. miyamotoi. An additional regimen is needed for babesiosis coinfection. (See 'Patients with concurrent tickborne infection (coinfection)' above.)

Prevention Preventive measures include the use of tick repellants and prompt examination and removal of ticks after exposure to tick-infested environments. (See 'Prevention' above and "Prevention of Lyme disease".)

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Topic 7907 Version 25.0

References

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