Approach

Ehrlichiosis and anaplasmosis have a broad differential due to multisystemic involvement and the absence of specific clinical features.[64]​​[65] A presumptive diagnosis can be made in all patients with potential tick exposure/demonstrated tick bite combined with fever of abrupt onset, characteristic constitutional symptoms, leukopenia and/or thrombocytopenia, and elevated LFTs. Definitive diagnosis is confirmed by serology studies or polymerase chain reaction (PCR). A high index of suspicion is required for diagnosis of infection, even in endemic areas.[66]

Ehrlichiosis and anaplasmosis are nationally notifiable diseases, and healthcare providers should notify local health departments, which in turn notify the State Health Department. The CDC is notified through the National Electronic Telecommunications System for Surveillance.

History

Potential tick exposure (e.g., outdoor activities in endemic areas during active tick months) and demonstrated tick bite within 14 days before onset of symptoms are key risk factors supporting a suspicion of any tick-borne disease. However, it is important to note that many patients do not have any recollection of a tick bite and therefore, lack of a tick bite history cannot exclude diagnosis in patients with signs, symptoms, and investigation results consistent with tick-borne illness.

[Figure caption and citation for the preceding image starts]: Tick bite at later stage with central necrosis (dark area around tick bite) surrounded by a markedly erythematous areaCourtesy of Lucas Blanton, MD [Citation ends].com.bmj.content.model.Caption@385fa085

Infection typically presents as an acute illness; the incubation time is 1 to 2 weeks after tick bite. Some patients may be asymptomatic, although this is rare, especially in adults. Infection tends to be more severe in patients over 60 years of age.[16][61][62][63]

Fever of abrupt onset in combination with other constitutional symptoms such as rigors, myalgia, malaise, headache, arthralgia, or nausea is the most common presentation. Diagnosis should be considered in any patient with abrupt onset fever and a potential tick exposure. Less common presentations include nonspecific symptoms such as abdominal pain, vomiting, diarrhea, cough, dyspnea, and rash. Rash is more common in children than in adults. [Figure caption and citation for the preceding image starts]: Erythematous macular rash involving the lower extremity in a pediatric case of human monocytotropic/monocytic ehrlichiosisCourtesy of Edwin Masters, MD [Citation ends].com.bmj.content.model.Caption@72bb0e93

Neurologic symptoms such as stiff neck, photophobia, and confusion are rare.

Human granulocytotropic/granulocytic anaplasmosis (HGA) can coexist with Lyme disease, babesiosis, and tick-borne encephalitis.

Severe manifestations, such as hemophagocytic lymphohistiocytosis (HLH), a rare and potentially fatal immunologic syndrome, have also been reported in ehrlichiosis.[13][14]​ Signs and symptoms include hepatosplenomegaly, fever, and rash.

Physical exam

Typically, there are no findings on physical exam; however, a small round erythematous lesion with or without a small necrotic dark center may be seen on the skin (tick bite). Patients with human monocytotropic/monocytic ehrlichiosis (HME) may develop lymphadenopathy, hepatomegaly (more common in children), jaundice, or splenomegaly; however, this is rare. Central nervous system complications such as stupor, seizures, or coma are also rare but more common in HME than in HGA. Signs of candidiasis, cytomegalovirus infection, and aspergillosis may be seen in severe cases of HME and HGA. It is not fully understood why these patients are more susceptible but it is thought the acute infection with HME or HGA results in a level of immunosuppression.

Laboratory tests

CBC, peripheral blood smear, and LFTs should be ordered initially. Leukopenia with absolute and relative lymphopenia is common during the first week of the disease and is usually associated with thrombocytopenia; however, normal counts do not rule out the diagnosis. Cytoplasmic morulae are seen on blood smear, although this has not yet been observed in patients with Ehrlichia muriseauclairensis (formerly known as Ehrlichia muris-like agent, EMLA). Although this is a recommended investigation, detection of morulae is considered insensitive as a diagnostic test in immunocompetent patients. However, in clinical experience, in immunocompromised patients, a peripheral blood smear examination performed by an experienced hematologist may confirm the diagnosis more quickly.[67] Anemia is less frequent. LFTs are usually mildly to moderately elevated. Marked absolute and relative rebound lymphocytoses are seen during the second week of illness.[68]

If LFTs are elevated and leukopenia and thrombocytopenia are present, this is very strong evidence for diagnosis. In the presence of strong suspicion, presumptive treatment would be started even if these tests are normal. Specific laboratory tests may then be pursued including serology or PCR testing. Specimens for diagnostic confirmatory tests should ideally be obtained before the patient receives the first dose of antibiotics.

Serology

  • Immunofluorescence antibody assay is the most definitive, widely available test for HME and HGA and is based on detection of a rise in antibodies against Ehrlichia chaffeensis or Anaplasma phagocytophilum in serum.[62][69]​​[70][71][72][73]​​​[74]​​[75]​​[76][77][78][79]​​

  • Paired samples should be obtained during the acute and convalescent phases (i.e., 2-4 weeks later) to demonstrate rising antibody titers. A fourfold or greater increase in antibody titre is diagnostic.[68]

  • Serology cannot be used for diagnosis of human ewingii ehrlichiosis (HEE) due to extensive cross-reactive antibodies with E chaffeensis.

PCR

  • Detection of bacterial DNA/RNA from peripheral blood/tissue specimens using primers targeting a specific ehrlichial gene is the most definitive diagnostic finding for HME and HGA during the acute phase of the disease, when the patient is febrile and symptomatic.[16][17][19][24][58][62][72][80][81]​​[82][83][84][85][86][87]

  • PCR using primers specific for E ewingii is the only method available for diagnosing HEE;​E ewingii is not culturable and serologic cross-reactions with E chaffeensis are extensive.[4][88]

Other tests used to confirm diagnosis include Western immunoblotting, culture, and immunohistochemistry; however, these tests are not routinely used.

Coinfections

Infections with Borrelia spp. and Babesia spp. can occur simultaneously or sequentially in cases of HGA due to the presence of the first 2 pathogens in Ixodes ticks.[89][90][91][92][93] In the northeast and upper midwest areas of the US, the vector is Ixodes scapularis, whereas in the western part of the country the vector is I pacificus. The incidence of borreliosis and babesiosis is lower in the latter.[89]

The natural reservoir for all 3 pathogens is the white-footed mouse (Peromyscus leucopus), whereas deer (Odocoileus virginianus or white-tailed deer) are the definitive hosts of these tick vectors. Coinfections in Europe and eastern Europe/Asia also occur but the vectors are I ricinus and I persulcatus, respectively.[26]

The presence of more than 1 of these pathogens in the vectors varies greatly depending on the geographic area studied.[89][94] The pathogens responsible for borreliosis in the US and Europe include B burgdorferi sensu stricto, B garini (higher frequency of neurologic disease), and B afzelii. The latter 2 are more prevalent in Europe.[26][95][96] As for babesiosis, most infections in the US are caused by B microti (northeast and midwest). B duncaniand the unnamed species CA-1 occur toward the west coast of the US, while MO-1 occurs in Missouri.[89][97][98] In Europe, the main pathogen is B divergens.[26]

Diagnoses of coinfections should rely on direct methods such as microscopic visualization of the pathogen (spirochetes seen by silver stains from skin biopsies, PCR, or culture in patients with borreliosis; intraerythrocitic parasites visualized in peripheral blood smears and PCR in cases of babesiosis; and microscopic visualization of intracellular morulae in polymorphonuclear leukocytes from peripheral blood smears, PCR, or culture in cases of HGA).[95] Serologic methods should be avoided for diagnosis of coinfections due to high rate of antibodies against these agents in highly endemic areas. However, evidence of rising antibodies in samples taken 2 to 4 weeks apart strongly suggest the presence of an acute infection by any of those pathogens. Clinically, the diagnosis of B burgdorferi infections is relatively easy if the classic skin manifestations are present such as erythema migrans or annular rash. However, both HGA and babesiosis present as undifferentiated febrile illnesses with no distinguishing features to differentiate them from each other or other nonspecific febrile illnesses including tick-borne diseases such as Rocky Mountain spotted fever and tick-borne encephalitis (caused by flaviviruses). The clinical manifestations of both Lyme disease and babesiosis are usually more severe when compared with infections that occur separately.[89][90]

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