Incidence

Incidence of all 3 of these tickborne illnesses is steadily increasing. In 2014, 1744 cases of babesiosis were reported in the United States, according to the Centers for Disease Control and Prevention (CDC).2 The geographic region and number of cases of babesiosis have steadily increased since it became a reportable illness in 1986.3  More than 4600 cases of babesiosis in New York alone have been reported since 1986, of which 3500 were reported between 2006 and 2015.3 From 2000 to 2008, cases of ehrlichiosis quadrupled from 200 to 961,with 4613 cases reported from 2008 to 2012.4,6

Anaplasmosis is more frequently reported than HME in the United States.  Incidence of anaplasmosis climbed from 348 to 1761 cases between 2000 to 2008, and the reported cases increased 52% between 2009 and 2010.4,7 These numbers likely underestimate the actual incidence of these diseases as many cases are not confirmed by laboratory testing and current surveillance systems, and the majority of patients with these infections remain asymptomatic. Additionally, babesiosis was only reportable for surveillance in 31 states in 2014.2

Distribution of vector-borne disease is determined by complex demographic, environmental, and social factors. For many vector-borne diseases, climate change and warming temperatures make transmission seasons longer or more intense or spread vectors so that disease can emerge in different geographic locations. Expanding deer and tick populations, swelling human population density, urbanization and deforestation, and human activities and recreation in wooded areas with exposure to ticks are surmised to relate to this increasing incidence. Most patients acquire babesiosis, HME, and HGA between May and September with reported spikes in June and July.3,6,7 Approximately 75% of cases of babesiosis are diagnosed from June through August.3 Age groups with high incidence for these 3 diseases are similar; the ranges include persons aged 60 to 69 years, 60 to 64 years, and ≥65 years and older for babesiosis, ehrlichiosis,6 and anaplasmosis, respectively.2,7

Geography

The CDC reports that 90% of cases of babesiosis and anaplasmosis occur in only 7 states with concentrations in the Northeast (Massachusetts, Connecticut, Rhode Island, New York, and New Jersey) and the upper Midwest (Minnesota and Wisconsin).2,3,7 In the Northeast, babesiosis occurs in both inland and coastal areas (ie, Nantucket and Martha’s Vineyard in Massachusetts; Block Island in Rhode Island; and Shelter Island, Fire Island, and eastern Long Island in New York) (Figures 3 and 4). This also corresponds to the known geographic distribution of Lyme disease as all of these diseases share the same Ixodes tick vector. HME is most frequently reported in the Southeastern, South Central, and Mid-Atlantic regions of the United States. Approximately 35% of infections of E chaffeensis were reported in Oklahoma, Missouri, and Arkansas in 20105 (Figure 5).Of note, from 2009 to 2011 a novel Ehrlichia species closely related to E muris in Europe and Asia was identified among patients in the upper Midwest (Wisconsin and Minnesota).4 Since then, more than 67 cases have been identified.6 This epidemiologic shift is important as ehrlichiosis had not been previously described in that geographic area and studies suggest that the tick vector has expanded to include I scapularis.4


Figure 3. Number of reported cases of babesiosis by US county of residence, 2014. Image courtesy of the US Centers for Disease Control and Prevention.

Figure 4. Incidence of anaplasmosis by region in the United States, 2010. Image courtesy of the US Centers for Disease Control and Prevention.

Figure 5. Incidence of ehrlichiosis by region in the United States, 2010. Image courtesy of the US Centers for Disease Control and Prevention.

Coinfection

As many as two-thirds of patients with babesiosis experience concurrent Lyme disease, and one-third experience concurrent HGA.3 One study demonstrated thatthe frequency of ticksinfected with B microti is higher when they feed on mice that are coinfected with B burgdorferi and B microti, rather than with B microti alone.8 In studies of I scapularis from different locales, 2.2% to 26% were coinfected with B burgdorferi and A phagocytophilum; in fact, 3% to 15% of patients in Connecticut and Wisconsin were found to be coinfected.4 Disease concomitance is important to recognize as patients who are coinfected tend to have increased duration and severity of infection, and treatment of B microti is different from the other disorders.9

Pathophysiology, Clinical Manifestations, and Associated Laboratory Features

In babesiosis, sporozoites are delivered to the dermis within 36 to 72 hours of tick attachment. Therefore, removal of the tick during the first 24 to 36 hours of attachment greatly minimizes risk of transmission, similar to Lyme disease. In a process similar to the actions of protozoa that cause malaria, the Babesia sporozoites migrate to the bloodstream where they invade erythrocytes, mature into merozoites, and lyse the host cell to be released back into the bloodstream to invade new erythrocytes. The host’s splenic macrophages play a critical role in clearing Babesia-infected erythrocytes. Clinical manifestations of babesiosis range from asymptomatic to flu-like symptoms, but patients with asplenia, those aged >50 years, or those with immune system compromise (ie, from HIV/AIDS, malignancy, chemotherapy, radiation, or immunosuppressant therapy) are at risk for severe, life-threatening babesiosis.3,10 The release of merozoites into the circulation stimulates the host’s inflammatory response involving pyrogenic cytokines (ie, tumor necrosis factor-alpha, interleukin-6), which induce symptoms characteristic of a viral-like illness such as fever, chills, diaphoresis, headache, anorexia, myalgia, fatigue, nausea, and vomiting. The lysis of erythrocytes results in hemolytic anemia with associated jaundice, and hemoglobinuria may cause resultant renal injury. This anemia is compounded by Babesia-induced generation of reactive oxygen species, loss of erythrocyte membrane integrity, and opsonization, all of which promote clearance of erythrocytes by splenic macrophages. Hepatosplenomegaly may be noted on physical examination. The same cytokines may contribute to complications associated with severe babesiosis such as acute respiratory distress syndrome and disseminated intravascular coagulation.10 The pathology of babesiosis is reflected in laboratory findings that may include hemolytic anemia with reticulocytosis and unconjugated hyperbilirubinemia, thrombocytopenia, lymphopenia, and elevated aminotransferases.

Ehrlichia speciespreferentially infect peripheral leukocytes, with E chaffeensis associated with human monocytic cells (ie, monocytes and macrophages); infection of neutrophils with E ewingii has been reported. Multiorgan involvement is known to occur, with organisms detected in the spleen, lymph nodes, bone marrow, and peripheral blood. A phagocytophilum preferentially infects granulocytes, particularly neutrophils. HME and HGA typically present as similar acute illnesses; however, a wide spectrum of disease exists from subclinical and self-limited to subacute or chronic infection. It is likely that symptoms are due to the host inflammatory response rather than to direct damage caused by the bacteria.5 Ehrlichia has an incubation period of 1 to 2 weeks, but a shorter period may be seen. In a study of 18 adults with HGA, symptoms appeared an average of 5.5 days after tick bite.4 Constitutional symptoms such as fever, chills, headache, malaise, and myalgia occur in the majority of patients, while nausea, vomiting, arthralgia, and cough occur in 25% to 50%.4,11 In HME, cough and respiratory symptoms are more common in adults than in children.5 A minority of patients (up to 36%) with HME may present approximately 5 days into illness with a nonpruritic, erythematous rash that may be macular, maculopapular, or petechial and is more frequent in children.4,5 Rash is not typical in anaplasmosis. In both HME and HGA, laboratory evaluation demonstrates thrombocytopenia, leukopenia, and increased aminotransferase levels.

Although HME and HGA have similar clinical manifestations, HME is often more serious, with hospitalization occurring in 50% of patients and increased risk of sepsis or shock-like presentations, particularly in immunosuppressed hosts and the elderly.4 Central nervous system  involvement occurs in 20% of patients, and symptoms may progress to acute respiratory distress syndrome  or coagulopathy.5 The CDC reports mortality rates of 1% to 3% in patients who present for medical care of ehrlichiosis.5 In HGA, 5% to 7% of patients require intensive care, and at least 7 deaths associated with delayed diagnosis and treatment and development of opportunistic infections have been identified. In HGA, infection diminishes CD4 and CD8 counts and impairs phagocytosis, antibody responses, neutrophil emigration, and intracellular killing.11 An intact immune system is important for recovery from HGA, and HGA further antagonizes immune dysfunction.11 Other complications of HME and HGA include acute abdominal syndrome, rhabdomyolysis, myocarditis, acute renal failure, and demyelinating polyneuropathies and/or cranial nerve palsies.