Continuing Education Activity

Anaplasma phagocytophilum is a gram-negative intracellular bacteria that causes an acute febrile illness known as anaplasmosis or human granulocytic anaplasmosis (HGA). Anaplasmosis generally presents with nonspecific symptoms such as fever, chills, malaise, headache, and myalgia. On rare occasions, a rash may be present. Patients may also report nonspecific gastrointestinal or respiratory symptoms. A minority of patients will develop life-threatening complications. This activity examines when this condition should be considered on differential diagnosis and how to properly evaluate for it. This activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Identify the most common etiology of anaplasmosis.
• Describe the history and physical exam findings typically seen in patients with anaplasmosis.
• Summarize the treatment options available for anaplasmosis.
• Employ interprofessional team strategies for improving care coordination to improve the management of anaplasmosis and improve outcomes.

Introduction

Anaplasma phagocytophilum is an obligate gram-negative, intracellular bacterium that causes an acute febrile illness known as anaplasmosis or human granulocytic anaplasmosis (HGA). The organism is genetically related to rickettsia and is transmitted by Ixodes scapularis in the northeast United States and by Ixodes pacificus in California. The vector also transmits other organisms responsible for diseases such as Lyme, babesiosis, ehrlichioses and Powassan encephalitis. Anaplasmosis was formerly named human granulocytic ehrlichiosis (HGE). In 2001, the organism was reassigned to the genus Anaplasma. Cases of anaplasmosis have been identified worldwide; in the United States, it is mostly reported in the upper Midwest and the Northeast. Disease activity has also been reported in Northern Europe and Southeast Asia.[1][2][3][4]

Anaplasmosis generally presents with nonspecific symptoms such as fever, chills, malaise, headache, and myalgias. On rare occasions, a rash may be present. The patient may also report nonspecific gastrointestinal (GI) or respiratory symptoms. A low number of patients manifest with life-threatening complications. Immunosuppressed patients are more likely to get hospitalized and have a higher risk of suffering from severe complications. Occasionally, co-infection with other tick-borne organisms (Anaplasma, Lyme, and Babesia) occurs given that Ixodes ticks are the common vector.

Anaplasmosis is diagnosed by culture, histopathology, PCR, or serology. The presence of intracytoplasmic aggregates of Anaplasma in peripheral blood neutrophils can be diagnostic in 20% to 80% of symptomatic patients. First-line treatment is doxycycline 100 mg orally, twice daily administered for 14 to 21 days or at least 3 days after defervescence.

Etiology

An obligate gram-negative intracellular bacterium causes anaplasmosis. Ixodes ticks transmit Anaplasma phagocytophilum. The main reservoir is the white-footed mouse, Peromyscus leucopus; however, a broad range of wild and domestic mammals have been identified as reservoirs.[5][6]

Epidemiology

Anaplasmosis was first reported in 1994 by Chen et al. (J Clin Micro 1994;32(3):589-595). The latest CDC estimate for 2016 reported cases is 4151 cases (https://www.cdc.gov/anaplasmosis/stats/index.html accessed June 27, 2018). In the 10 year period between 2000 through 2010, cases increased from 346 to 1761 with estimates of 1.4 to 6.1 cases per million. Cross-sectional seroprevalence studies have demonstrated that up to 15% of the population in northwest Wisconsin; 1% Connecticut habitants and US military personnel; 17% of Slovenians; and 12% of the population of Sweden's Koster Islands have positive antibodies for Anaplasma phagocytophilum without a history of clinical manifestations. This suggests that infection is frequently subclinical.

Anaplasmosis occurs at any age in both genders; however, it is more frequent in men over the age of 40 years. Men are at higher risk of getting infection compared to women, with a 1.4 fold higher likelihood. The case fatality rate is usually less than 1%.

Anaplasmosis is found worldwide, particularly in the northeast United States, northern Europe, and Southeast Asia (has been reported in China, Mongolia, and Korea). The disease is transmitted by the bites of nymphal or adult Ixodes ticks. The species varies according to the region where the infection is transmitted. In the Eastern and the Midwestern United States, the vector is the Ixodes scapularis tick commonly known as the black-legged or deer tick; whereas in the Western United States, the tick vector is Ixodes pacificus. Other important tick vectors are Ixodes ricinus in West Europe and Ixodes persulcatus in Asia. It is important to point out that Ixodes ticks are commonly coinfected with other organisms and can transmit Lyme disease, Babesia, Ehrlichia, Rickettsia, and Powassan virus.

The reservoir for Anaplasma phagocytophilum includes domestic and wild mammals. In North America, it includes the white-footed mouse, Peromyscus leucopus, whereas in the Eastern United States, the reservoir is the white-tailed deer. Other mammals also identified as reservoirs include squirrels, voles, wood rats, white-tailed deer, red deer, and roe deer. Larval ticks acquire the bacterium after feeding on small mammals which were previously infected by nymphal ticks. After infection, the white-footed mouse develops immunity to the organism which decreases transmission.

A different species, Anaplasma capra, has been detected in Northern China. This organism infects goats, and approximately 6% of individuals with a history of tick bites have evidence of infection detected by PCR studies. These patients presented with a febrile illness, the presence of rash, or an eschar was variable.

Infection can also be transmitted during a blood transfusion. Even though this is a rare form of transmission, the diagnosis should be considered in patients with symptomatic clinical presentation and a history of a blood transfusion.

Pathophysiology

Anaplasma phagocytophilum is an obligate intracellular bacteria that survives and propagates within the host cell and can evade neutrophil antimicrobial functions. A. phagocytophilum infection is acquired through a tick bite and disseminates to the bone marrow and spleen.  A. phagocytophilum can selectively survive and multiply within cytoplasmic vacuoles of polymorphonuclear cells. It affects the progenitors of myeloid and monocytic lineages, and it is seen in neutrophils in peripheral blood and tissue. The presence of Anaplasma in neutrophils induces proinflammatory responses leading to neutrophil deactivation, and the release of cytokines promotes neutrophil degranulation. Interleukin-10, IL12, and IFN-gamma are among the cytokines released which contribute to continuous tissue injury. IFN-gamma is primarily produced by innate immune NK and NKT cells as well as CD8 T lymphocytes. The development of tissue injury prevents neutrophils from exerting effective antimicrobial response. These cytokine-driven mechanisms as a response to infection explain the clinical manifestations associated with human granulocytic anaplasmosis.  Clinical cases may present with fever, pancytopenia, liver dysfunction or more severe manifestations such as shock or organ failure.

In animal models, A. phagocytophilum infection-induced IFN-gamma production which also activates macrophages and increases inflammatory tissue injury. Further, Anaplasma also can inhibit the fusion of lysosomes with the cytoplasmic vacuoles and inhibiting signaling pathways responsible for respiratory burst. Other effects of Anaplasma include downregulation of phagocyte oxidase activity, delay in apoptosis, ineffective binding to and transmigration of activated endothelium, and inhibition of phagocytosis.

Histopathology

Microscopic examination of peripheral blood smear shows characteristic intracytoplasmic aggregates in neutrophils called morulae. This finding is detected 25% to 75% of the time in patients that have not begun therapy. The sensitivity of peripheral smear for diagnosis is higher during the first week of infection.

Microscopic examination of lymphoid organs such as the liver, spleen, bone marrow, and lymph nodes in patients with HGA shows changes in mononuclear phagocytes. Lung injury may also occur secondary to the systemic inflammatory response. Pathology examination in animal and human models demonstrate normocellular or hypercellular bone marrow, phagocytized erythrocytes, and hepatic apoptosis. Other tissue findings in patients with organ damage are periportal lymphohistiocytic infiltrates, focal splenic necrosis, mild interstitial pneumonitis, and pulmonary hemorrhage.

History and Physical

Anaplasma phagocytophilum has an incubation period of 1 to 2 weeks. Most infections are probably subclinical. Clinical manifestations range from mild to severe and include fever, malaise, myalgias, and headache. Less than 50% of cases present with nausea, vomiting, diarrhea, cough, arthralgias, stiff neck, and confusion.

Physical exam findings include fever, diffuse muscle tenderness, and in patients coinfected with Borrelia burgdorferi, a rash may be seen; however, a rash is uncommon and is identified in approximately 10% of cases. Also, patients coinfected with Rocky Mountain Spotted Fever (RMSF) or Lyme disease may present with a rash.

Approximately one-third to one-half of symptomatic cases require hospitalizations due to the severe presentation, and 3% to 7% have life-threatening complications. These severe manifestations include respiratory insufficiency, septic shock, multiorgan failure, rhabdomyolysis, and opportunistic infections.

The involvement of the central nervous system is rare in HGA, with meningoencephalitis occurring in 1% of the cases. However, manifestations of peripheral nervous system involvement include brachial plexopathy, cranial nerve palsies, demyelinating polyneuropathy, and bilateral facial nerve palsy. Neurologic function recovery may take several months.[7][8][9][10]

Evaluation

Given the potential for life-threatening complications associated with anaplasmosis, therapy must be instituted as soon as possible if a patient presents with signs and symptoms compatible with infection and in the right epidemiologic setting. Therapy for presumptive diagnosis should be initiated while waiting for laboratory confirmation.

Laboratory testing of peripheral blood usually shows leukopenia and thrombocytopenia. Transaminases can be elevated in up to 70% of the cases. In patients who develop severe disease, laboratory abnormalities correlate with organ damage. Elevated creatinine, lactate dehydrogenase, creatine phosphokinase, and amylase can be seen with or without electrolyte imbalances and metabolic acidosis. Significant hypotension, disseminated intravascular coagulation, hepatic, renal failure, adrenal insufficiency and myocardial dysfunction can be observed. For those patients with central nervous system manifestations, CSF analysis shows lymphocytic pleocytosis and moderate protein elevation.

Diagnosis of human granulocytic anaplasmosis can be confirmed using several methods. These include serologic testing, identification of characteristic morulae in peripheral blood, detection of DNA by PCR, bacterial detection on the tissue by immunohistochemistry, or isolation by culture. Detection of DNA by PCR has a sensitivity of 67% to 90% and specificity of 60% to 85% and offers the advantage of rapid turn around time. A 4-fold increase in serologic titers is considered positive.

Immunohistochemical staining techniques can be used on bone marrow, spleen, lymph nodes, liver, and lung tissue specimens.

Treatment / Management

Doxycycline is the first-line treatment for anaplasmosis in adult and pediatric cases. A 14-day to the 21-day course is recommended or continuation of antibiotics for a minimum of 3 days after defervescence. For patients co-infected with Lyme disease (known or suspected), therapy should be continued for 10 days.

To prevent tooth discoloration, pediatric patients younger than 8 years of age co-infected with Borrelia burgdorferi should remain on doxycycline until they have been afebrile for 3 days. They should then switch to an active agent against the pathogen, for example, amoxicillin or cefuroxime, for the remainder of the 14-day course.

Of note, if a patient does not show signs of clinical improvement after 3 days of doxycycline therapy, the patient should be evaluated and treated for possible Babesia infection.

Differential Diagnosis

Differential diagnosis of anaplasmosis includes human monocytotropic ehrlichiosis (HME), Rocky Mountain spotted fever, relapsing fever, tularemia, Lyme disease, Colorado tick fever, and babesiosis.

Similar to anaplasmosis, HME presents with nonspecific symptoms such as fever, headache, myalgias, and headaches. Also, Ixodes ticks are the responsible vector for disease transmission. Clinical cases of HME present with thrombocytopenia, leukopenia, and elevated liver enzymes. Peripheral smear examination (looking for the presence of morulae in monocytes), PCR, serology, culture, or identification in tissue samples confirms the diagnosis.

In those patients with a history of tick bite or outdoor exposure, other diagnoses to consider are Rocky Mountain spotted fever, relapsing fever, tularemia, Lyme disease, Colorado tick fever, and babesiosis.

Lyme disease has a characteristic rash (bulls-eye rash) and can be differentiated with specific ELISA and Western Blot testing.

Colorado tick fever is transmitted by a different tick (Dermacentor), whereas, relapsing fever is transmitted by lice and soft-bodied ticks (Ornithodoros). Tick-borne relapsing fever is characterized by recurrent febrile episodes lasting 1 to 3 days flanked by afebrile periods that could last up to 14 days. Relapsing fever is diagnosed by identifying spirochetes from peripheral blood smears or by PCR.

Babesiosis can be diagnosed by identifying intraerythrocytic ring forms of the parasite which occasionally looks like a "maltese cross" on a peripheral blood smear exam. Tularemia has a different clinical presentation than anaplasmosis including skin ulceration, lymphadenopathy, and severe respiratory symptoms.

Complications

A rare but severe complication of HGA is the development of hemophagocytic lymphohistiocytosis (HLH) due to activated macrophages and lymphocytes that lack normal downregulation, thus exacerbating the tissue damage resulting from excessive inflammation.

Pearls and Other Issues

Doxycycline is the drug of choice but the patient should be admitted if there are signs of toxicity and organ dysfunction. Anecdotal reports indicate that delay in treatment is associated with a poor outcome.

Infection with Anaplasma phagocytophilum can be prevented by avoidance of tick bites in endemic areas as well as by immediate removal of attached ticks. Immediate and complete removal of attached ticks is highly recommended given that the tick must be attached for 4 to 24 hours to transmit infection. It is also recommended to apply a repellent such as N, N-Diethyl-meta-toluamide (DEET) to the skin, and wear light-colored clothing that makes it easier for individuals to identify the ticks. For individuals at risk of getting exposed to tick bites, such as when they are engaging in outdoor activities, it is recommended that they inspect their skin, hair, and clothing for ticks when returning from possible infested areas.

Enhancing Healthcare Team Outcomes

Anaplasmosis can present with life-threatening complications and is best managed by an interprofessional team that consists of an infectious disease expert, internist, laboratory specialist, hematologist, nephrologist, and an intensivist. The patient must be treated as soon as the disorder is suspected.