OVERVIEW: What every practitioner needs to know

Why might you consider the diagnosis of ehrlichiosis or anaplasmosis in your patient? What should you expect to find?

The symptoms of both ehrlichiosis (HME) and anaplasmosis are non-specific. Fever, headache and myalgia are usually present in both infections and may be the only symptoms. Organ involvement, including gastrointestinal (GI) symptoms (nausea, vomiting or diarrhea), acute respiratory distress syndrome (ARDS), and central nervous system (CNS) symptoms suggesting meningitis or encephalitis may occasionally be present. These more localized symptoms are more likely to occur with HME than with HGA. Ehrlichiosis is generally the more severe infection of the two, and patients may appear to be septic.
Physical findings are usually not helpful in distinguishing these infections from each other or from other similar infections. A generalized rash that may be scarlatiniform, maculopapular or petechial may develop in approximately 60% of children with ehrlichiosis. However, rashes are usually not present at the time of presentation and are much less common in adults than in children. Anaplasmosis rarely causes rash in either adults or children (<10% of cases).

How did the patient develop ehrlichiosis or anaplasmosis? What was the primary source from which the infection spread?

These infections are acquired by a tick bite within 14 days of the onset of illness. A history of tick bite is helpful but may be absent, particularly with HGA. These infections should be considered in persons whose history includes outdoor activities in an area where tick transmission is known to occur, whether or not there is a history of tick bite.
The geographic distribution of these diseases is dictated by the distribution of the tick vectors that carry them:

Anaplasma phagocytophilum is transmitted by Ixodes scapularis, the same tick responsible for Lyme disease. Consequently, the distribution of human infection parallels that of Lyme Disease, with most cases occurring in the Upper Atlantic Coast and in areas of Wisconsin and Minnesota.
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There are three species of Ehrlichia now known to infect humans: Ehrlichia chaffeensis (>90% of cases), E. ewingii (<10% of cases), and a rare, unnamed species currently designated as E. muris-like (EML). The first two species are transmitted by the Lone Star tick (Amblyomma americanum). The distribution of these ticks is less restricted than that of Ixodes, but most of the infections occur in the Southeastern U.S. extending to the Great Plains. Thirty-five percent of all reported cases occur in just 3 states: Missouri, Oklahoma and Arkansas.

EML is thought to be transmitted by Ixodes ticks and appears to be geographically restricted to the Minnesota and Wisconsin areas associated with Lyme disease transmission.

Which individuals are of greater risk of developing ehrlichiosis or anaplasmosis?

Men are more commonly affected than women, presumably due to the greater likelihood of recreational and occupational exposure. Both diseases are more common in the summer and fall than during winter months; the transmission period is dictated by the local climate. Serological studies suggest a high incidence of asymptomatic infection. However, individuals who are immunosuppressed or have HIV infection are less likely to have an asymptomatic infection after sustaining a tick bite and may have more severe manifestations of infection.
Epidemiological risk factors include:

Outdoor activities, occupational or recreational

Travel or residence in an area of known transmission

Male gender

Beware: there are other diseases that can mimic ehrlichiosis or anaplasmosis:

HME and HGA should be included in the differential diagnosis of acute, undifferentiated fever. Since the list of diseases responsible for this presentation is extensive, the astute clinician will include HME or HGA as possible diagnoses when any of the following conditions occur:

Known tick bite within 3 weeks of the onset of symptoms

Travel to an endemic area within 3 weeks

Residence in an endemic area with outdoor exposure

Presence of laboratory abnormalities consistent with these diagnoses. Without at least one of these clues, the diagnosis is likely to be extremely challenging.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Peripheral WBC with platelet and differential count: thrombocytopenia in more than 90%; leukopenia in about half of the patients.
Liver function tests: elevation of transaminases in most patients.

The above tests are those that are most likely to give useful information leading to a presumptive diagnosis of ehrlichiosis or anaplasmosis. However, the non-specific nature of the presentation in most cases will usually warrant other tests to rule out alternative diagnoses, e.g., blood cultures, urinalysis, urine culture, chest X-ray.

Results that confirm the diagnosis

Patients suspected of having either ehrlichiosis or anaplasmosis should be treated empirically on suspicion. Diagnostic tests may confirm the diagnosis but they are not timely and should not be used as a criterion to administer treatment.
Examination of a peripheral blood smear for morulae: The presence of membrane-bound vesicles filled with organisms (morulae) in leukocytes is diagnostic. They are seen in neutrophils in about half of the patient with HGA, but are seen in <20% of patients with ehrlichiosis. Morulae of E. chaffeensis are typically seen in circulating monocytes; E. ewingii is usually associated with neutrophils. Obviously, recognizing these inclusions requires an experienced microscopist, so the sensitivity and specificity of the test is operator-specific (see Figure 1 and Figure 2).
Serology: This is the most widely used confirmatory test. Antibody levels are usually NOT elevated during the first week of illness, so paired samples (acute and 2-3 week convalescent antibody titers) are most useful.
PCR: PCR is the most useful diagnostic test during the first week of infection. However, the sensitivity and specificity of PCR is the range of 60 – 90%, so negative PCR is therefore not a sufficient cause to withdraw empirical therapy.
Immunohistochemistry: Requires having a specific labeled antibody on hand and a biopsy or autopsy specimen to examine. Not timely or practical in most clinical settings.
Culture: Requires tissue culture. Not timely or practical in most clinical settings.

Ehrlichia chaffeensis morula in a monocyte. Source: http://www.cdc.gov/anaplasmosis/symptoms/index.html.

Anaplasma phagocytophilum morula in an immature granulocyte. Source: http://www.cdc.gov/anaplasmosis/symptoms/index.html.

What imaging studies will be helpful in making or excluding the diagnosis of ehrlichiosis or anaplasmosis?

There are no imaging tests that are routinely and specifically necessary for diagnosis or management. Diagnostic studies should be ordered in response to specific symptoms or signs, e.g., chest X-ray or computed tomography (CT) scan with cough or hypoxia, cerebrospinal fluid (CSF) examination in response to altered mental status or meningeal signs. Since Ehrlichia or Anaplasma infection are usually part of a larger differential diagnosis, diagnostic studies are most likely to be ordered to rule-in or rule-out other possible cause of the febrile illness.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has ehrlichiosis or anaplasmosis, what therapies should you initiate immediately?

Doxycycline should be started promptly on suspicion of ehrlichiosis, anaplasmosis, or suspected tick-borne rickettsiae. Withholding this treatment pending a confirmatory diagnosis is associated with a poorer prognosis. Doxycycline is the drug of choice for both adults (100 mg orally every 12 hours) and children (if <100 kg, 2.2 mg/kg orally every 12 hours) for 7-14 days.

Key principles of therapy: Since Ehrlichia spp. and Anaplasma phagocytophilum. are members of the order Rickettsiales, they are uniformly sensitive to tetracyclines. As with infection by the human pathogens in the Rickettsia group, early (usually presumptive) treatment with doxycycline or tetracycline is the key principle of therapy.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

The drug of choice for all Ehrlichia and Anaplasma infections is doxycycline (or other tetracyclines). Antibiotic resistance is not known to be an issue. Consequently, the selection of treatment is complicated not by the choice of drug but by the use of the drug in patient groups in which tetracyclines are not usually used, e.g., during pregnancy (see Table I).

Table I.

Antimicrobial	Inhibitory	Bactericidal
Doxycycline(drug of choice)	Excellent	Excellent
Rifampin	Good	Usually
ChloramphenicolGentamicin	Weak	Minimal or none
FluoroquinolonesBeta-lactamsCarbepenemsTrimethoprim-sulfamethoxasoleClindamycinErythromycinAzithromycin	Little or none	None

IDSA recommendations for treatment of human granulocytic anaplasmosis

There are no formal IDSA recommendations for HME treatment, but the HGA recommendations should be equally applicable (see Table II).

Table II.n

Treatment recommendations of Ehrlichia and Anaplasmosis

2. Next list other key therapeutic modalities.

Usual supportive care accompanies antibiotic therapy in hospitalized patients.

Moderate-to-severe complications may occur in up to 1/3 of adults who are hospitalized with HME. Complications tend to occur more often in immunocompromised patients (e.g., HIV) and the elderly. Reported complications include:

Meningoencephalitis

ARDS

Toxic-shock-like disorder

Hemophagocytic lymphohistiocystosis (HLH)

Disseminated intravascular coagulation (DIC)

Acute renal failure

Myocarditis

Gastrointestinal bleeding

Hepatitis

Rhabdomyolysis

Pancreatitis

Most of these complications may also occur with anaplasmosis, but with lesser frequency.
In uncomplicated infections, the response to therapy is typically rapid (defervescence in 24-48 hours). Failure to defervesce should lead to a reconsideration of the diagnosis.
Approximately half of all patients suspected of having one of these infections are admitted to the hospital. The case-fatality rate is 3% for ehrlichiosis and 0.5-1.0% for anaplasmosis.
Risk factors for complicated, extensive or fatal infection include:

Advanced age

Immunosuppression

HIV (especially with CD4 lymphocyte count <200/ml)

Monoclonal gammopathy-asplenia

Add what-if scenarios here:

If a patient in the endemic region for ehrlichiosis develops a petechial rash, consider Rocky Mountain Spotted Fever as an alternative diagnosis. Ehrlichiosis has been known to cause a petechial rash, but not one involving the palms and soles. The distinction between the infections is more academic than practical, since both infections are effectively treated with doxycycline. Other diagnostic considerations might include: meningococcemia, group A streptococcal infection in children, overwhelming pneumococcal (or other) sepsis in an asplenic individual and atypical enteroviral infections.
A patient in an endemic region for anaplasmosis may also have concomitant Lyme disease or (much less likely) babesiosis. Testing for these entities should also be ordered. Also note that patients treated with rifampin are not covered for concomitant Lyme disease. If co-infection with Lyme is detected, treatment specific to the stage of Lyme disease should be added to the regimen.

The geographic distribution of cases is determined by the distribution of ticks. Two species of these pathogens (Ehrlichia chaffeensis and E. ewingii) are transmitted primarily by the bite of Amblyomma americanum (the Lone Star Tick). E. chaffeensis may also be transmitted by Dermacentor variabilis (the American Dog Tick).

Anaplasma phagocytophilum is transmitted by Ixodes scapularis, the vector of Lyme disease, on the East Coast of the U.S. and Upper Midwest, and I. pacificus on the West Coast. The geographic distribution of these ticks species in the continental U.S. are shown in Figure 3 and Figure 4. EML is also transmitted by Ixodes ticks, but has so far been seen only in the mid-western areas of Lyme transmission.

Distribution of Amblyomma americanum and Dermacentro variabilis ticks in the continental U.S.

Distribution of Ixodes spp. tick vectors in the continental U.S.

Human Ehrlichiosis

The estimated incidence rate of ehrlichiosis in the U.S. was about 2.5 per million residents in 2010. However, an analysis of 4,613 cases between 2008 and 2012 suggests that a more recent estimate of the incidence rate of E. chaffeensis is 3.2 per million person-yrs. The highest incidence rates are in persons over the age of 50, but this could reflect an ascertainment bias, since the older age groups are also more likely to have more severe infection. The incidence rates vary dramatically between endemic and non-endemic states. Incidence rates in Oklahoma, Missouri, Virginia, and Arkansas ranged between 19.4 – 30.9 per million person-yrs; whereas the incidence rate in 6 Western U.S. states was 0. Most of the cases occur between May and September, but infections acquired in the southern states may have a more extended season because of the warmer climate for tick feeding. The rate of hospitalization for the E. chaffeensis cases was 57%; the overall case-fatality rate was 1% but was 4% in children <5 years of age. There were 55 cases of E. ewingii (Incidence Rate= 0.04 per million person-yrs.). Seventy-seven per cent of these cases were hospitalized; there were no deaths.

Human Anaplasmosis

The estimated incidence of anaplasmosis in the U.S. was about 6.1 per million residents in 2010. A repeat study of cases between 2008-2012 suggested a national incidence rate of 6.3 per million person-yrs. However, the rates in Minnesota and Wisconsin were 97.3 and 79.1 per million person-yrs., respectively. Eighty-eight per cent of the reported cases arise in only 6 U.S. states (New York, Connecticut, Rhode Island, Massachusetts, Wisconsin, and Minnesota.). Active surveillance for human disease in a region around Lyme, Connecticut showed incidence rates as high as 24-51 per 100,000 residents per year. Most of the infections occur between May and November, with the peak month being June. As with ehrlichiosis, the highest incidence rates occur in persons over 50 years of age. In the endemic states, from 10-50% of the captured Ixodes ticks carry Anaplasma spp. In addition, since Amblyomma americanum are also found in southern New England, 8-12% of these ticks have been found to carry E. chaffeensis as well.

Ticks are the vectors of ehrlichiosis and anaplasmosis, but they are not a reservoir (as they are for Rocky Mountain Spotted Fever). This is because these pathogens are not transmitted transovarially in ticks, i.e., mother ticks do not pass the infections to the progeny via their eggs. The infection is passed transstadially, i.e., from one stage of metamorphosis to the next. The practical consequence of this arrangement for the epidemiology is that the tick that transmits the infection to a human must first feed on an infected reservoir animal before it will be infectious to a human in its next metamorphic stage. For example, an Ixodes scapularis nymph can infect a human if it took a meal from the reservoir mouse during the previous season.

It is known from animal studies that A. phagocytophilum is transmitted from an infected tick to a mammal host only after the tick has been attached and feeding for 24-48 hours. The act of feeding presumably triggers the replication of the infecting organism and its secretion in the tick saliva. It is assumed that Ehrlichia are transmitted in a similar manner. The consequence of this delayed transmission is that early tick removal can interrupt the transmission of the infection, as is also the case for Lyme disease.

Ehrlichiosis: In Tennessee, a seroprevalence study showed that 12.5% of residents had antibodies to E. chaffeensis.
Anaplasmosis: In Wisconsin, a seroprevalence study showed that 14.9% of residents without a history of tick bite had antibodies to Anaplasma phagocytophilum.

All of these infections are zoonoses. There are numerous ehrlichia and anaplasmas that are exclusive pathogens of animals and do not infect humans. Some are significant veterinary pathogens. The relationships of the human pathogens to animals are shown in Table III.

Table III.n

Causes of Human Ehrlichiosis and Anaplasmosis

What pathogens are responsible for this disease?

Table III. Causes of Human Ehrlichiosis and Anaplasmosis

Ehrlichiae and anaplasmas are obligate intracellular pathogens and can only be propagated in living cells.

After injection of the pathogen into the bloodstream by the infecting tick, ehrlichia and anaplasma enter the targeted leukocytes via an endocytic pathway. They are contained within a membrane-bound endosome within the host cell. The endosome matures with respect to the inclusion of certain late endosomal markers on the membrane, but it is not acidified normally. The pathway of the infected endosome does not fuse lysosomes, and it presumably allows the organisms to acquire nutrients and replicate within the cell. These endosomes packed with organisms create the appearance of morula in the cell that are of diagnostic value when they are seen in stained blood smears.

In many patients (particularly the immunocompromised), the severity of illness correlates with the magnitude of the bacteremia and the numbers of morula-containing cells. However, this is not always the case, and fatal cases have occurred without detectable morula in the blood or bone marrow. In severe disease, lymphohistiocytic infiltrates may occur without damage to blood vessels or thrombosis. Focal necrosis has been observed in the liver, spleen, and lymph nodes. Diffuse hemorrhages may involve multiple tissues. Alveolar hemorrhage or damage may occur in the lung along with interstitial pneumonitis and edema.

It is assumed that cell-mediated immunity is required to clear this intracellular infection. An effective immune response consists of the generation of Ehrlichia-specific IFN-gamma-producing CD4 cells, cytotoxic CD8 cells, and Ehrlichia-specific antibodies. Experiments in inbred mice clarify the relative importance of these elements. Inbred mice that lack TLR-4 have delayed clearance of the pathogen, and strains that lack MHC class II molecules cannot clear it at all. This suggests that CD4 lymphocytes are needed to clear the infection, a proposition that is consistent with the observation of severe, uncontrolled infection in patients with AIDS.

A history of tick bite is helpful when present, but the report of a bite in a febrile patient is likely to be associated with the size of the biting tick. Amblyomma americanum is a much larger tick than Ixodes scapularis, and a bite by an adult is much less likely to be overlooked. In contrast, nymphal Ixodes ticks are easily mistaken for blemishes, particularly in the older patients whose skin is more likely to have pigmented spots that help to obscure the nymphal tick. Consequently, tick bite histories are more common in areas of endemic HME than in the regions where HGA is acquired.

Prevention of tick bites is the best way to avoid these diseases. Certainly, the early removal of ticks after attachment can reduce the likelihood of transmission, but this is not as certain to be beneficial as the avoidance of tick attachment altogether. Protective clothing and repellants are key. Clothing can be sprayed with permethrin-based products such as Permanone^® to prevent ticks from accessing clothing. Application of DEET to exposed areas of the skin is effective as are some derivatives of eucalyptus oil.

Development of a vaccine for ehrlichiae has been hampered by genetic diversity in its outer membrane proteins. Recent experiments in mice have shown that immunization with the P28 outer membrane protein of E. chaffeensis results in durable T and B cell responses that confer protection against challenge. Whether this immunogen can be exploited for an effective human vaccine is still an open question.

Prophylactic antibiotic therapy after a tick bite is not recommended as a routine strategy.

Wormser, GP, Dattwyler, RJ, Shapiro, ED. “The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 43. 2006. pp. 1089-1134. (Includes a discussion of the rationale for treatment of anaplasmosis in different treatment groups and rating of available evidence.)

Biggs, HM, Behravesh, CB, Bradley, KK. “Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis – United States: a practical guide for physicians and other health-care and public health professionals”. MMWR Recommendations and Reports. vol. 65. 2016. pp. 1-44. (Includes CDC recommendations for diagnosis and treatment of tickborne diseases in general and with specific sections devoted to Ehrlichia and Anaplasma.)

Rand, JV, Tarasen, AJ, Kumar, J. “Intracytopplasmic granulocytic morulae counts on confirmed cases of ehrlichiosis/anaplasmosis in the Northeast”. Am J Clin Pathol. vol. 141. 2014. pp. 683-86. (Fourteen cases of anaplasmosis diagnosed by PCR or serology had peripheral smears examined. 11 (78.6%) were deemed positive for morulae by counting 100 granulocytes. When 200 granulocytes were examined, all 14 cases were diagnosed.)

Maurin, M, Bakken, JS, Dumler, JS. “Antibiotic susceptibilities of () strains from various geographic areas in the United States”. Antimicrob Ag Chemother. vol. 47. 2003. pp. 413-415. (A representative study of antibiotic susceptibility using HL-60 cells to cultivate the isolates. This study demonstrates the dramatic superiority of doxycycline over most other antibiotics in vitro and provides added justification for considering it the drug of choice.)

Dumler, JS, Madigan, JE, Pusterla, N, Bakken, JS. “Ehrlichiosis in humans: epidemiology, clinical presentation, diagnosis, and treatment”. Clin Infect Dis. vol. 45. 2007. pp. S45S51(Large study of the clinical features and complications of 471 casses of monocytic ehrlichiosis and 700 cases of granulocytic anaplasmosis.)

Hamburg, BJ, Storch, GA, Micek, ST, Kollef, MH. “Importance of early treatment with doxycycline in human ehrlichiosis”. Medicine. vol. 87. 2008. pp. 53-60. (A retrospective cohort analysis of PCR-positive patients at Barnes-Jewish Hospital in St. Louis that analyzes the clinical impact of treatment within 24 hours of hospital admission versus delayed onset of therapy.)

Paddock, CD, Folk, SM, Shore, GM. “Infections with and in persons coinfected with human immunodeficiency virus”. Clin Infect Dis. vol. 33. 2001. pp. 1586-1594. (In this study, all 6 fatalities among the 20 in this study were caused by E. chaffeensis and all fatalities occurred in patients with CD4 lymphocyte counts <200/mm3. Only 2 of the 4 patients with E. ewingii were hospitalized, suggesting a lesser virulence of the latter pathogen.)

Ratnasamy, N, Everett, ED, Roland, WE. “Central nervous system manifestation of human ehrlichiosis”. Clin Infect Dis. vol. 23. 1996. pp. 314-319. (A review of 21 patients from the University of Missouri Hospital and elsewhere who had CNS manifestation and CSF examination – a brief compendium of experience that may be helpful for practitioners who perform lumbar punctures in this setting.)

Johnsom, DKH, Schiffman, EK, David, JP. “Human infection with Ehrlichia muris-like pathogen, United States, 2007-2013”. Emerg Inf Dis. vol. 21. 2015. pp. 1794-99. (The only analysis of 69 cases diagnosis and characterized by PCR and serology. The annual number of cases detected increased in every year of the study. This study showed that morulae were not seen in any of the positive cases, possibly accounting to the delayed recognition of the Ehrlichia species.)

ICD-10-CM codes

A77.41: Ehrlichia chaffeensis

Converts directly to: 2015 ICD-9-CM 082.41 Ehrlichia chaffeensis

A77.49: Ehrlichiosis, other

Converts directly to: 2015 ICD-9-CM 082.49 Other ehrlichiosis

A77.40: Ehrlichiosis, unspecified (includes anaplasmosis)

Converts directly to: 2015 ICD-9-CM 082.40 ehrlichiosis, unspecified

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Ehrlichia and Anaplasma