Introduction

Babesiosis is a tick-borne parasitic disease currently considered an emerging infectious disease. It is caused by protozoan parasites of the genus Babiesia, which infect red blood cells and are transmitted to humans through the bite of an infected Ixodes scapularis tick. It can also be acquired through blood transfusions, vertically or organ transplantation.

The diagnosis of the disease can prove to be quite challenging due to the nonspecific symptoms it causes that can easily be attributed to other disease entities. There is also potential for co-infection with other tick-borne diseases.

This article will discuss the clinical presentation of babesiosis, methods of diagnosing babesiosis and its differential diagnoses.

Epidemiology

Babesia infection is most commonly seen in the northern midwestern and northeastern United States. It can also be found throughout the world in certain parts of Europe, Asia, Africa, and South America. In 2018, there were over 2000 cases of babesiosis reported in the United States.¹

Babesia microti is the most common species responsible for human infection in the United States, while Babesia divergens are more prevalent in Europe. Other species known to infect humans include B. duncani, B. divergens, B. venatorum, and B. crassa.

The prevalence of babesiosis has increased over the past twenty years.² However, the exact number of those affected is unknown due to the subclinical nature of presentation for most patients which is responsible for many undiagnosed cases.

Risk factors

• Outdoor activities such as hiking
• Advanced age
• Neonates 
• Immunosuppressants 
• HIV infection 
• Cancer
• Autoimmune disease
• Corticosteroid use
• Congestive heart failure

Clinical presentation

The clinical manifestations of babesiosis can vary from asymptomatic infection to severe, life-threatening illness in those who are immunocompromised, elderly or asplenic.

Infection with B. microti in healthy individuals may result in subclinical infection, going undetected while B. divergens often infect those who are immunocompromised and result in more severe manifestations.

The symptoms vary depending on disease severity and they include:

• Fever
• Diaphoresis
• Chills
• Myalgia
• Nausea
• Vomiting
• Athralgia
• Fatigue
• Malaise
• Abdominal pain
• Altered sensorium
• Shortness of breath
• Photophobia
• Haemolytic anemia
• Thrombocytopenia 

Severe cases may present with organ failure, including acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and renal failure.

Diagnostic methods

Accurate diagnosis of babesiosis involves a combination of a high index of clinical suspicion, microscopic examination, molecular techniques, and serological tests.

Blood smear examination

The gold standard for diagnosing babesiosis is the microscopic examination of a Giemsa or Wright-stained peripheral blood smear. Babesia parasites appear as ring forms inside the blood cells, resembling Plasmodium species, which causes malaria. 

Tetrads (Maltese cross formations) are pathognomonic but not always observed. However, the parasitemia level is typically lower in babesiosis compared to malaria.

Molecular testing

Polymerase Chain Reaction (PCR) is a highly sensitive and specific method for detecting Babesia DNA in blood samples. It is especially useful in cases with low parasitemia levels, where blood smears might be negative. PCR can also identify the species of Babesia, which can aid in epidemiological studies and targeted treatment.

Serologic testing

Serological tests, such as indirect immunofluorescent antibody (IFA) assays, can detect antibodies against Babesia antigens. These tests are useful for confirming recent or past infections, especially in cases with low parasitemia or after treatment has started. However, they are less useful for acute diagnosis due to the time required for antibody production.

Other laboratory findings

Additional laboratory findings in babesiosis may include:

• Hemolytic anaemia (low haemoglobin, increased reticulocyte count)
• Elevated liver enzymes (ALT, AST)
• Elevated bilirubin levels
• Thrombocytopenia, also known as lower than normal number of platelets
• Elevated lactate dehydrogenase (LDH)
• Deranged blood urea nitrogen
• Elevated creatinine

Differential diagnosis

The differential diagnosis of babesiosis includes other infectious and non-infectious diseases that can present with similar clinical and laboratory features:

Malaria

Malaria, caused by Plasmodium species, shares many clinical and microscopic features with babesiosis. Both babesiosis and malaria present with fever, chills, and hemolytic anaemia. Travel history, exposure risk, and geographic location are critical in distinguishing the two. 

Blood smear examination is key to differentiating the two, as malaria parasites have distinct morphologies and may display schizonts and gametocytes, which are not seen in babesiosis. PCR and serology can aid in differentiating babesiosis from malaria.

Anaplasmosis

Human granulocytic anaplasmosis (HGA), caused by Anaplasma phagocytophilum, is also transmitted by the Ixodes tick. It can present with similar symptoms, including fever, myalgia, leukopenia and thrombocytopenia. PCR and serology can help distinguish anaplasmosis from babesiosis.

Lyme Disease

Lyme disease, caused by Borrelia burgdorferi, may co-occur with babesiosis due to their shared tick vector, the Ixodes tick. Lyme disease often presents with fever, fatigue, myalgia, erythema migrans (bull’s eye rash) and arthralgia. The low number of white and red blood cells, also known as leukopenia and erythrocytopenia, are notably absent in this condition. To confirm the diagnosis, serologic testing and PCR can prove useful.

Ehrlichiosis

Human monocytic ehrlichiosis (HME), caused by Ehrlichia chaffeensis presents with fever, headache, and leukopenia. Coinfections of babesiosis with ehrlichiosis are rare because ehrlichiosis is transmitted by Dermacentor ticks rather than Ixodes ticks. 

These may be diagnosed through Wright stains of peripheral blood smears or buffy-coat preparations that demonstrate regularly-stained cytoplasmic inclusions in monocytes or, less commonly, lymphocytes, which are mulberry-shaped and are called morulae. 

Increased Ehrlichia titers with an IgG titer of 1:64 or greater are suggestive of Ehrlichia infection, and a four-fold or greater change in antibody titers on immunofluorescent antibody (IFA) testing measured two to four weeks apart is diagnostic of ehrlichiosis.

Rocky mountain spotted fever

Similar to ehrlichiosis, this is transmitted by Dermacentor ticks. The two conditions are differentiated by the distinctive rash of Rocky Mountain Spotted Fever (RMSF). Common findings in this condition include increased levels of serum transaminases, the presence of hemolytic anaemia, leukopenia, splenomegaly and relative bradycardia. 

Hemolytic disorders

Hemolytic anaemia in babesiosis can be mistaken for autoimmune hemolytic anaemia. Direct antiglobulin testing (Coombs test) can help differentiate between the two, as it is typically positive in autoimmune hemolytic anaemia and negative in babesiosis.

Other hemolytic disorders such as hereditary spherocytosis, and glucose-6-phosphate dehydrogenase (G6PD) deficiency, should also be considered in the differential diagnosis. Laboratory tests, including enzyme assays, and genetic testing, can help identify these conditions.

Viral illnesses

Influenza, Ebstein-Barr virus and other viral infections can mimic babesiosis with symptoms like fever, fatigue, and myalgia. Viral serologies for antibody titres and PCR testing can help differentiate these conditions.

Other illnesses

Other conditions which may be mistaken for babesiosis include typhoid fever, Q fever, and Colorado Tick Fever.

Management and treatment

If a patient is otherwise healthy and asymptomatic, no treatment is required. Most of the otherwise healthy patients infected by B. microti appear to have a mild illness and recover without specific treatment.

However, for symptomatic patients, the Infectious Diseases Society of America (IDSA) recommends starting symptomatic patients on a combination treatment regimen of atovaquone and azithromycin (first line) or a combination of clindamycin and quinine (alternative therapy). It is recommended that a seven-to-ten-day course is given.

For highly immunocompromised patients, treatment may be required for at least 6 consecutive weeks or longer. It may be necessary to start with a regimen recommended for hospitalised patients, followed by a regimen recommended for ambulatory patients. Immunocompromised patients require close clinical and laboratory follow-up⁵.

Supportive care 

Exchange blood transfusion may be offered to patients who are severely ill with high parasite counts and haemolysis. They may also require monitoring in the intensive care unit (ICU).

They should be monitored continuously for the resolution of symptoms. Serial blood smears should be conducted to monitor the parasite count and determine the effectiveness of the therapy. 

Additionally, serial complete blood counts should also be taken to assess for recovery and recovery of the anaemia, leukopenia and thrombocytopenia.

Prevention

Babesiosis can be best prevented by avoiding ticks as there is currently no vaccine for the disease. Preventive measures¹ for tick bites include:

• Use of tick repellants
• Wearing socks and long-sleeved shirts
• Performing self-checks for the presence of ticks

Summary

Accurate diagnosis of babesiosis involves a combination of clinical suspicion, microscopic examination, molecular techniques, and serological tests. Differentiating babesiosis from other infectious and non-infectious causes of febrile illness and hemolytic anaemia is essential for appropriate treatment and management. Understanding the epidemiology, transmission, and risk factors of babesiosis can aid in prevention and early detection, ultimately reducing the morbidity and mortality associated with this tick-borne disease.