Babesiosis is an acute health-threatening parasitic disease that targets the red blood cells. It is caused by intraerythrocytic parasites belonging to the Babesia genus. These parasites are transmitted primarily through the bite of infected Ixodes ticks. While Babesia is a significant blood parasite, malaria caused by Plasmodium species remains the most prevalent globally. Another name for babesiosis, particularly in veterinary contexts, is “red water fever,” a term referring to the hemoglobinuria seen in infected livestock. The disease is a notable cause of economic loss in regions where livestock is heavily affected.¹
Babesiosis is also recognized as an emerging zoonotic disease in humans, raising increasing public health awareness. Transmission can occur not only through tick bites but also via blood transfusion and, in rare cases, from mother to fetus. Common symptoms in humans include fever, chills, fatigue, and headache, while severe cases may involve complications such as acute respiratory distress syndrome (ARDS), hemolytic anemia, and multi-organ failure, necessitating hospitalization.²³

Life Cycle of the Babesia

The life cycle of Babesia requires two hosts: a definitive invertebrate host (ticks) and an intermediate vertebrate host (humans, rodents, or other animals).

Infection

The life cycle begins when an infected tick feeds on the vertebrate host. During this feed, the ticks transmit Babesia into the host’s bloodstream.

Asexual Reproduction in Vertebrates

Inside the vertebrate host, the parasite invades the erythrocytes through sporozoites excreted in the tick’s saliva. In the erythrocytes, the parasites multiply asexually. The sporozoites develop into trophozoites. This asexual multiplication is named merogamy. The asexual reproduction ends in the formation of merozoites or gametocytes. Merozoites can infect the neighboring red blood cells, and gametocytes develop into gametes.

Sexual Reproduction in invertebrates

The infected vertebrate host serves as a source of Babesia for ticks. When ticks feed on the infected host, they ingest the parasites. The ingested parasites undergo sexual reproduction in the ticks. Sexual reproduction is also called gamogony. Ticks have a four-stage life cycle: egg, larva, nymph, and adult. Each stage requires a blood meal from a different host to advance to the next stage.

Transmission to a New Host

As the ticks bite new hosts, they transmit the parasite again, and the cycle continues. Human infections usually occur during late summer and spring when the tick population is highest.⁴

Life Cycle of Babesia spp. Image Courtesy: Santos, J.H.M., Siddle, H.V., Raza, A. *et al.* Exploring the landscape of *Babesia bovis* vaccines: progress, challenges, and opportunities. *Parasites Vectors* 16, 274 (2023). https://doi.org/10.1186/s13071-023-05885-z

Causes & Transmission of Bebesiosis

Babesia spp. is the causative agent of this infection. Most of the Babesia are pear-shaped, oval or round, and small (1-5 mm long). This zoonotic disease requires hard tick vectors for its transmission.⁵

The most common Babesia species causing human babesiosis include:

Babesia microti: Endemic in the upper Midwest and northeastern United States.
Babesia divergens: Common in Europe, often affecting splenectomized or immunocompromised individuals.
Babesia duncani: Found along the Pacific coast of the United States.
Babesia crassa: Predominantly seen in China.
Babesia venatorum: Present in both Europe and China.⁶

Over 100 Babesia species are known to infect domestic and wild animals, causing significant economic losses in livestock. Common examples include:

Babesia bovis, B. major, and B. divergens: Affect cattle and lead to anemia, fever, and reduced productivity.
Babesia canis: Infects dogs.
Babesia caballi: Infects horses.
Babesia odocoilei: Found in deer.
Babesia microti: Common in rodents.
Babesia felis: Infects cats.⁷

Modes of Transmission

Babesiosis cannot be transmitted from one person to another. Babesia spp. are hemoprotozoan parasites that are transmitted through:

Bites of Ticks

The most common mode of transmission is through the bite of infected hard ticks, primarily Ixodes scapularis (deer tick) in the United States and Ixodes ricinus in Europe. Ticks become infected during blood meals from parasitized hosts and transmit the parasite during subsequent feedings.⁸

Congenital Transmission

Infected mothers can also pass the infection to their babies during pregnancy.

Blood Transfusions

Transfusion of contaminated blood products, such as red blood cells, whole blood-derived platelets, or frozen deglycerolized blood cells, is also the transmission source of babesiosis.

Organ Transplant

Rarely, babesiosis has been transmitted through solid organ transplants.⁹

Pathogenesis of the Babesia

The pathogenesis of Babesia involves its lifecycle within the host’s red blood cells, leading to significant cellular and systemic effects.
After being deposited in the dermis by an infected tick, Babesia sporozoites enter the bloodstream and invade red blood cells (erythrocytes). Once inside, the parasitophorous vacuole membrane surrounding the parasite dissolves, allowing free access to the host cell’s contents. The free sporozoites differentiate into trophozoites. The trophozoites eventually undergo binary fission. It generates two to four merozoites. The merozoites make a way out to trigger the cell lysis in the host, thus causing anemia. Anemia also occurs from the suppression of erythropoiesis and clearance of uninfected erythrocytes. Additionally, inflammatory cytokines also play a role in the formation of acute cytokines. The resolution of parasitemia necessitates intact adaptive and immune responses. Autoantibodies produced during parasite clearance can amplify prolonged anemia or thrombocytopenia.¹⁰

Symptoms of Babesiosis

The clinical manifestations of this condition usually range from asymptomatic infection to critical disorder that can cause death. Symptoms appear after an incubation period of one to four weeks after a bite from an infected tick. After one to nine months after the blood transfusion, the patients experience a gradual onset of fatigue and malaise in addition to other symptoms.

Common Symptoms

The most common manifestations include:

Fatigue
A very high fever (104 F)
Sweats
Chills
Anorexia
Myalgia
Headache

Less Common Symptoms

These include:

Depression
Emotional liability
Arthralgia
Abdominal pain
Sore throat
Neck stiffness
Nausea
Hyperesthesia
Vomiting
Shortness of breath
Conjunctival infection
Weight loss
Photophobia
Non-productive cough
Hyperesthesia

Laboratory Findings

Other laboratory abnormalities involve:

Elevated levels of liver enzymes,
Elevated reticulocyte count
Severe Hemolytic anemia
Thrombocytopenia
Elevated blood urea
Elevated creatinine levels
Proteinuria

Physical Findings

Physical abnormalities may involve:

Pallor
Jaundice
Hepatomegaly
Splenomegaly

People with malignancy, AIDS/HIV, neonatal prematurity, immunosuppressive therapy, asplenia, immunosuppressive therapy, liver, hematologic, or cardiac comorbidities experience severe symptoms. The most severe complications that can arise in these patients are:

Renal failure
Hemophagocytic lymphohistiocytosis
Disseminated intravascular coagulation
Acute respiratory distress syndrome (ARDS)
Congestive heart failure
Severe anemia
Splenic rupture¹¹

Diagnosis of Babesiosis

Diagnosing babesiosis involves a combination of clinical evaluations, epidemiological factors, and laboratory testing. The primary methods for diagnosing babesiosis include microscopic examination, serology, and molecular techniques.

Symptomatic Evaluation:

The healthcare providers will first look at the symptoms of the condition. The diagnosis should also consider risk factors such as recent travel to endemic areas and exposure to ticks. Fever is the most common finding in a physical exam. The skin can be yellowish or pale. Tenderness in the abdomen, usually at the upper left quadrant, suggests splenomegaly. Unexplained splenomegaly or abdominal pain with increased heart rate raises the possibility of hemoperitoneum and splenic rupture. An erythematous skin lesion is also suggestive of concurrent Lyme disease. Jaundice can also be observed due to petechiae, disseminated intravascular coagulopathy, or hemolysis.¹²

Microscopic Examination:

A more definitive diagnosis can be made through microscopic examination of the Giemsa-stained blood smears. The provider smears a blood sample on a slide, airs dry it, fixes it in methanol, and then stains it. The stained slides are then examined under high magnification (100x oil immersion lens) to detect the presence of Babesia spp. in the erythrocytes. Thin smears provide better morphological details for identifying the parasites. The Babesia trophozoites appear in ring forms, while merozoites often appear pear-shaped and can also be arranged in a tetrad. Thick smears are also informative, but as these parasites are small, they can be missed.¹³

Photomicrograph of a Giemsa stained blood film specimen, which was extracted from an infected human, and which revealed the presence of the hemoprotozoan parasitic organism, Babesia microti, one of the causes of the disease babesiosis. Image courtesy: Public Health Image Library (PHIL), Image ID: 3899.

Laboratory Tests:

Some routine laboratory tests can help in diagnosing the condition. These tests include:

Complete Blood Count (CBC)

A complete CBC will reveal low hematocrit, low hemoglobin, an elevated reticulocyte, a low platelet count, and a low red blood cell count. Elevated lactate dehydrogenase and low haptoglobin levels are consistent with hemolytic anemia. Neutropenia also occurs in some patients. The leukocyte count is usually normal to slightly decreased. However, in severe cases, the examiner may also observe elevated bilirubin and liver enzymes.¹⁴

Urinalysis

The presence of hematuria, proteinuria, hemoglobinuria, and excessive urobilinogen will confirm the infection. Additionally, the high levels of serum creatinine and urea nitrogen will also indicate renal compromise.¹⁵

Immunological Testing:

Healthcare providers use immunological techniques to detect antibodies.

Indirect Fluorescent Antibody Test (IFAT)

IFAT recognizes parasitic antigens by serum antibodies. This method uses fluorochrome anti-Ig antibodies to detect bound antibodies. IFAT holds 93.1% sensitivity and 88.9% specificity for the detection.¹⁶

Enzyme-linked Immunosorbent Assay (ELISA)

ELISA detects the antibodies against Babesia in the serum. It can process a large number of samples at a time to save time. It has a higher specificity (97.4%) than IFAT. This test can identify ongoing infection and can monitor a high parasitic load. The other advantages of ELISA include the non-subjectivity and simplicity of the technique.¹⁷

Immunochromatography

Immunochromatography is also a rapid diagnostic test to detect antibodies to specific antigens. It requires a small amount of serum and uses specific antibodies and test strips. It is an easy, rapid, and simple test, and its cost is lower than that of other techniques. This process requires only 15 minutes to complete.

Molecular Techniques:

Molecular techniques target nucleic acids and are generally used in conditions when immunological methods cannot be employed. Such conditions include acute or chronic infection and also when antibodies do not exist. In addition, molecular methods seem to be more specific and sensitive compared to immunological methods. The most frequently used approach for field diagnosis of babesiosis is the Polymerase chain reaction (PCR).

PCR

PCR can detect low parasitemia effectively. It is particularly beneficial because the identification is more accurate when microscopy cannot identify the parasites. PCR provides better results for distinguishing Babesia spp and is definitive when conventional microscopy is unsatisfactory.¹⁸

Loop-Mediated Isothermal Amplification (LAMP)

LAMP, or Loop-Mediated Amplification, is a relatively young method of nucleic acid-based diagnostics. This method gives the result within a short period and has high sensitivity without requiring sophisticated instruments. For delamination, LAMP only calls for an ordinary water bath for the slide. The results are quite visible and one can read them with plain naked eye sight. Therefore, LAMP is a rapid, easy-to-perform, and inexpensive method of DNA amplification.¹⁹

Treatment & Management of Babesiosis

Babesiosis therapy and approaches for control are considered depending on the disease’s stage, the species causing the infection, and the immunocompetency of the host. The following part of the article will provide comprehensive information on the available methods that may help to cure babesiosis.

Mild to Moderate Babesiosis

In children, the first-line treatment option is atovaquone 750 mg/ 12 hours. The recommended dose of azithromycin is 500 mg /day. Quinine sulfate 650 mg per dose and clindamycin 600 mg per dose is an alternative option for children.
The first-line treatment for babesiosis in adults involves the use of atovaquone together with azithromycin. Atovaquone recommended dosage is 750 mg per 12 hours. The recommended dose of azithromycin is 50 mg/ day and then 250mg/ day. The symptoms of babesiosis usually start resolving within one of the treatments. Clindamycin, along with quinine, is an alternative treatment option for babesiosis. A 650 mg dose of quinine and 600 mg dose of clindamycin, 600 mg after every eight hours, is recommended.²⁰

Severe Babesiosis

Adults require a regimen of oral atovaquone 750 mg every 12 hours and intravenous azithromycin 500 mg once a day in severe cases. It is the most effective drug combination. The alternative option is oral quinine sulfate 650 mg every eight hours plus intravenous clindamycin 600 mg every six hours.
To treat severe cases in children, the first line of treatment is atovaquone 750 mg per dose plus 500 mg of intravenous azithromycin per day.²¹
Antibiotic therapy requires seven to ten days. Additionally, immunocompromised patients might not respond sufficiently to standard antibiotic therapy. These patients may require transfusion of erythrocytes. This process requires removing the patient’s erythrocytes and replacing them with the donor’s erythrocytes.
After treatment, the healthcare providers should monitor the susceptible patients who are at risk of potential complications.²²

Complications

Treatment regimens of babesiosis often result in mild to severe complications. These complications include:

Diarrhea
Vertigo
Tinnitus
Decreased hearing
Rash

Severe complications include:

QT prolongation
Cardiac arrhythmia²³

Prevention of Babesiosis

Following are the tips for effective prevention from babesiosis:

Avoid visiting areas known for high tick populations. These include grassy, brushy, and wooded areas where deer and rodents thrive.
Wear appropriate attire. Try to wear light-colored clothes to spot ticks easily.
Tuck your pants into socks to avoid ticks crawling into your pants.
In endemic areas, clothes treated with permethrin provide an additional layer of protection.
Use insect repellents on exposed skin.
After spending some time outdoors, thoroughly check yourself for ticks. You can seek help from a friend to check for the ticks. Pay special attention to the hidden areas.
• Take a shower within two hours of being outdoors. It will help wash off unattached ticks.
Modify your landscape. Keep grass trimmed and short. Remove leaf litter and brush piles where ticks may reside.
Use recommended insect control products on your pets. Check them regularly for ticks after keeping them outdoors for some time.
Beware of the signs of babesiosis and seek medical attention if you develop symptoms after being in the tick-infected area.
Support local initiatives aimed at educating communities about tick-borne infection, prevention strategies, and safe outdoor practices.
The most significant preventive measure is to protect the blood supply. Transmission of babesiosis through blood transfusion is a serious threat. People living in endemic areas should be prevented from donating blood if they have a history of babesiosis. However, this approach is inadequate, as many infections are asymptomatic.
Screening of blood donors for pathogen exposure is the most common preventive measure. This method should be a must in endemic regions to decrease the risk of transfusion-mediated babesiosis.
Pathogen inactivation can also successfully prevent transfusion-transmitted infection.

Babesiosis versus Lyme

Lyme and babesiosis are both tick-borne illnesses caused by different pathogens but transmitted by the same tick species. The key differences between the two conditions are given in the table below.

Feature	Babesiosis	Lyme
Pathogen	Babesia spp.	Borrelia burgdorferi
Incubation Period	One to four weeks after a tick bite	3 to 30 days after the tick bite
Symptoms	Fever Chills Nausea Loss of appetite Dark urine Jaundice Shortness of breath	Circular bull eye rash around the tick bite Tiredness Neck stiffness Joint pain Memory problems Heart problems.
Risks	It can be life-threatening in immunocompromised patients.	Generally not life-threatening, but can lead to chronic symptoms.
Diagnosis	Blood smear examination, serology, and PCR	Clinical evaluation and serology, western blot for confirmation.
Treatment	Combination of antibiotics or antiparasitics	Antibiotics

Final Remarks

Babesiosis represents a growing public health concern, particularly in endemic regions where tick populations are more prevalent. The symptoms are non-specific and closely match with other conditions. The severity of the disorder is recognized in the United States. In the U.S., routine testing for blood donations for Babesia is carried out, and there is a need for improved testing. The present antibiotic therapies are effective in the majority of the cases. However, immunocompromised patients require prolonged or more aggressive treatments. Continued research into active treatment and vaccines with robust public health initiatives should be focused on education and prevention, which are crucial for managing the disease and protecting the population at risk.

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Babesiosis: Understanding the Tick-Borne Disease

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