A male patient in his 70s presents to the emergency department with a 5-day history of fever, malaise, and confusion. His symptoms began after a trip to his cottage located 100 km outside Ottawa, Ont. He had spent time outdoors in brushy areas but has no known tick bites. He has no clear source of infection and no respiratory symptoms, abdominal pain, urinary symptoms, or contacts who are ill. Bloodwork reveals marked leukopenia, thrombocytopenia, elevated transaminase levels, and elevated creatinine levels. Despite several days of empiric broad-spectrum antibiotic therapy, the patient’s fever and laboratory test result abnormalities persist and the source of infection remains unclear. How would you approach this patient?

A PubMed search was conducted between October 2024 and March 2025 for relevant articles with no time restrictions using the search terms anaplasmosis and tick-borne illness. References of the articles resulting from the search were also reviewed. Articles highlighting data from Canadian studies were prioritized. Most available data came from case reports, case series, epidemiologic studies, and systematic reviews. Prospective studies and randomized controlled trials were largely absent. Additional information was sourced from Canadian and United States government health agency reports. The level of evidence cited ranged from level II to level III.

Tick-borne illnesses are becoming increasingly prevalent in Canada. Anaplasmosis, an emerging infection transmitted by the same vectors as Lyme disease, is an underrecognized but growing public health concern. Its nonspecific presentation often leads to diagnostic delays, underscoring the need for greater clinical awareness. This review provides an approach to recognizing, diagnosing, and managing patients with anaplasmosis.

Transmission and epidemiology. Anaplasmosis, also known as human granulocytic anaplasmosis, is a tick-borne infection of granulocytes caused by the intracellular bacterium Anaplasma phagocytophilum.1 In North America anaplasmosis is transmitted through the bite of infected blacklegged ticks (Ixodes scapularis) or western blacklegged ticks (Ixodes pacificus). These tick vectors may also carry other pathogens including Borrelia burgdorferi (which causes Lyme disease), Babesia species (babesiosis), and Powassan virus.

In North America anaplasmosis is primarily endemic in the midwestern and northeastern United States, where it has been a nationally reportable disease since 1999.2 Historically, anaplasmosis has been a rare condition in Canada, with few sporadic cases reported. However, due to climate change and other ecological factors, tick populations are growing in both numbers and range.3,4 One study conducted in Ontario in 2016 estimated the range of tick populations is expanding northward at approximately 46 kilometres per year.3 In 2024 Health Canada designated anaplasmosis a nationally reportable disease.5

The geographic distribution of anaplasmosis is similar to that of established blacklegged tick populations, which corresponds to areas with high risk of Lyme disease (Figure 1).6 Human cases of anaplasmosis have primarily been reported in Ontario, Quebec, New Brunswick, Nova Scotia, and Manitoba, although a few cases have also been reported in Alberta.7-13 Between May 2023 and July 2024 more than 514 cases were reported in Nova Scotia.10 In 2023 there were 40 reported cases of anaplasmosis in Ontario.7 Previous reports from Ontario and Quebec described regional clusters of up to 25 cases within a single transmission season, highlighting the emergence of localized outbreaks in high-risk areas.8,9 The incidence of anaplasmosis is expected to rise as environmental change continues to drive the expansion of tick populations.

Areas of Canada with documented Lyme disease risk, 2023: Modified September 12, 2024.

Infections can occur at any time of year, but most cases occur between April and November. The first peak of cases occurs between June and July when nymphal ticks are most active, and a second smaller peak occurs between October and November when adult ticks are most active.2,7

Clinical features. The presentation and severity of anaplasmosis vary. While most patients with anaplasmosis have either asymptomatic or mild cases, some develop severe infections.14-16 Symptoms typically occur between 5 and 21 days after a tick bite and commonly present as a febrile illness with nonspecific symptoms of headache, arthralgias, myalgias, and malaise.1,15,16 The overlap of these symptoms with other infectious conditions requires primary care physicians to maintain a high index of suspicion for anaplasmosis and other tick-borne illnesses. Important risk factors on history include recent tick exposure, travel to tick-endemic areas, or outdoor activities in woody or brushy areas.14,15 Lack of a known tick bite does not exclude the possibility of anaplasmosis, as many patients may not recall having tick bites.16

Rash is an uncommon feature of anaplasmosis, occurring in approximately 6% to 14% of cases.16,17 Morphology of rashes in reported cases is diverse, including maculopapular, erythematous, and petechial rashes.17 Anaplasmosis lacks any pathognomonic rash, which can contribute to delays in identification.

Common laboratory findings of anaplasmosis include thrombocytopenia, leukopenia, and mild transaminitis.15,17,18 Severe or fatal infections, although less common, are more likely to develop in patients who are older, are immunocompromised, have multiple comorbidities, or experience delays in diagnosis and treatment.14,16 Previously reported severe complications of anaplasmosis include septic shock, acute respiratory distress syndrome, acute renal failure, and heart failure.1,17

Diagnosis. Definitive diagnosis is made with either polymerase chain reaction (PCR) or serologic testing. PCR amplification testing has high specificity and sensitivity during the early, acute phase of infection.18,19 Whole blood is the preferred specimen for PCR testing when available given the intracellular nature of A phagocytophilum infection. Serum-based PCR testing has 85% to 96% sensitivity compared with whole blood–based PCR testing.20 Sensitivity of PCR testing markedly decreases if antibiotics are administered before sample collection. Positive criteria for serologic testing require a 4-fold increase in immunoglobulin G titres from paired serum samples collected 2 to 4 weeks apart, with the first sample taken during the acute phase of illness.18 Serologic testing may yield negative results when performed during the acute phase of infection. A single elevated immunoglobulin G titre result is insufficient to confirm active infection given that antibodies from prior exposures may remain elevated for several years following infection.16

While PCR and serologic testing are considered definitive, results are often not available in a timely manner and access to testing may not be readily available in all regions of Canada. For example, PCR testing is currently available only through the National Microbiology Laboratory, which has a turnaround time of 21 days.21 Peripheral blood smears may be examined for intracytoplasmic inclusions within granulocytes (termed morulae). While the presence of morulae is specific and highly suggestive of anaplasmosis, this finding has low sensitivity; thus, their absence should not rule out the diagnosis.19 When present in conjunction with thrombocytopenia, morulae provide a useful early diagnostic clue that can support clinicians in initiating empiric therapy before confirmatory test results are available. Clearly indicating clinical suspicion of a tickborne illness when ordering blood films and other laboratory tests may prompt laboratory personnel to look more closely for features of anaplasmosis, improving the sensitivity of blood smear findings.

Differential diagnosis. When evaluating patients with nonspecific febrile illness and history of tick exposure, the differential diagnosis for anaplasmosis should include other tick-borne illnesses such as Lyme disease, babesiosis, tularemia, and Powassan virus infection.

Unlike those with anaplasmosis, patients with Lyme disease may present with an erythema migrans (bull’s-eye) rash at the site of the tick bite. Patients with babesiosis also commonly present with febrile illness but often have findings of hemolytic anemia in their bloodwork.22,23 Focal neurologic manifestations are rare in patients with anaplasmosis1; therefore, the presence of neurologic deficits should prompt consideration of alternative diagnoses or possible co-infection. In contrast, patients infected with Powassan virus can progress to neurologic manifestations such as meningitis and encephalitis.24Table 1 provides a summary of common and distinguishing features.1,2,5,22-26

Comparison of anaplasmosis, Lyme disease, babesiosis, and Powassan virus infection characteristics

Co-infections of anaplasmosis and other tick-borne illnesses such as Lyme disease and babesiosis often occur, given that I scapularis and I pacificus ticks are common vectors. The most common co-infection is Lyme disease.15

Treatment. Most patients with anaplasmosis typically have mild or even subclinical cases; some patients may recover spontaneously without treatment.16 However, a small proportion of patients may develop serious or fatal outcomes. Given possible delays and early false-negative test results, empiric treatment before diagnostic confirmation is recommended in patients with suspected anaplasmosis, as delayed treatment may increase the risk of complications (grade II evidence).14,23,27 First-line antibiotic treatment for adults is 100 mg of doxycycline twice daily (orally or intravenously) for 10 days (grade III evidence).14,23,27 For children weighing less than 45 kg (100 lb), the recommended dose of doxycycline is 2.2 mg/kg twice daily (orally or intravenously) (grade III evidence).14 Studies evaluating the optimal treatment duration for patients with anaplasmosis are lacking. A 10- to 14-day course of antibiotics is often selected, as this duration is sufficient to treat co-infection with Lyme disease.27,28 Patients with anaplasmosis typically show rapid clinical improvement and defervescence within 24 to 48 hours after antibiotic initiation.17,23 If clinical improvement is not seen beyond 48 hours after antibiotic initiation, alternative diagnoses should be considered (grade III evidence).23,27

Surveillance data from the United States collected between 2000 and 2012 indicated hospitalization and case fatality rates of 31% and 0.3%, respectively.29 A systematic review of global data published in 2024 reported a case fatality rate of 3%, with most of these cases being in patients older than 50 with medical comorbidities. Notably, half of these patients with fatal cases did not receive appropriate antibiotic therapy.17