About the Condition

Introduction

• Vector-borne zoonosis caused by intraerythrocytic protozoan parasites of the genus Babesia (a hemoprotozoan parasite) which infect and lyse red blood cells; most often transmitted by the bite of an infected Ixodes scapularis tick:
  • Organism:
    • B. microti (most common)
    • B. duncani
    • B. divergens-like organism
    • B. venatorum
    • B. crassa-like pathogen
  • Vector – Ixodes scapularis 
  • Animal reservoir; Babesia species divide and replicate in the red blood cells (RBCs) of diverse vertebrate hosts, including:
    • White footed mouse – natural
    • Meadow mole – natural
    • Human – accidental

History

• Victor Babes first described the parasite in 1888 in Romanian cattle.¹
• The first human case of babesiosis was reported in 1957, when a splenectomized Yugoslavian herdsmen died of infection with B. divergens.²
• Babesiosis was first documented in the United States in a splenectomized California resident in 1968, followed by a report in 1970 of a previously healthy woman with an intact spleen who developed a nonspecific febrile illness after a tick bite on Nantucket Island, Massachusetts.³
• With additional cases among residents of Nantucket Island, the disease became known as Nantucket fever.

Epidemiology

• More than 2000 cases of babesiosis are reported to the CDC annually.
• Transmission may also occur via:
  • Transplacental route (Vertical transmission leading to congenital babesiosis)
  • Blood transfusion
  • Organ transplant 
• Most cases worldwide caused by B. microti from the northeastern and northern midwestern regions of the United States where the disease is endemic.
• In the United States, 95% of cases occur in seven states in the northeast and upper Midwest:
  • Connecticut
  • Massachusetts
  • Minnesota
  • New Jersey
  • New York
  • Rhode Island
  • Wisconsin
• Most cases occur from late spring through early autumn, when when people are active outdoors and the population of infected ticks attempting to feed is at its greatest (when the vector tick, rodents and deer are in close proximity to humans).

• Incidence of tick-borne diseases in the US is increasing due to multiple factors including:
  • Enlarging deer and tick populations
  • Expanding territory of I. scapularis
  • Greater recognition of these diseases by physicians and the general public
  • Increased prevalence of B. microti in I. scapularis populations
  • Increased proximity between humans and ticks due to rural development
  • Expanded awareness of tick-borne infections
  • Availability of better diagnostic methods
  • Effects of climate change
  • An increasingly immunosuppressed population
• Transfusion-associated babesiosis:
  • The incidence of transfusion-transmitted Babesia has been reported to be about 1.1 cases per million packed red blood cells (RBCs) across the United States.
  • Babesia microti is currently the leading cause of RBC-transfusion-transmitted infections reported to the U.S. Food and Drug Administration (FDA) and the leading infectious cause of transfusion-related deaths reported to the FDA.
  • At present, prospective blood donors are asked to report a history of babesiosis, but no FDA-licensed screening assay for blood donors has been approved.

Pathophysiology

• More than 100 Babesia species infect a wide variety of domestic and wild animals, but only a few infect humans including:
  • Babesia microti (rodent species) – most common cause in the northeastern part of the US
  • Babesia divergens (cattle species) – most common cause in Europe
  • Babesia duncani
  • Babesia venatorum
  • Babesia crassa-like pathogen
• Babesiosis is a zoonotic disease with an enzootic cycle between a tick vector and vertebrate host.
• Humans are accidental hosts and most commonly acquire infection through the bite of an infected tick, usually I. scapularis, which is:
  • The predominant vector for B. microti in the United States.
  • Also known as the deer tick or blacklegged tick.
  • The same tick vector responsible for the transmission of anaplasmosis and Lyme disease.
• Mechanism of infection:
  • When Babesia spp. sporozoites are first injected via a tick bite into the human host, they invade the host red blood cells (RBCs). Babesia does not invade other host cells.
  • Once inside the RBC, the parasite begins a cycle of maturation and growth exhibited by intense intracellular  proliferation (divides approximately every 8 h).
  • Babesia replication occurs by budding (fission), giving rise in sequence to:
    • A parasite form commonly called the ‘figure eight’ form.
    • A tetrad form know as a ‘Maltese Cross’.
  • Resulting daughter merozoites egress from the RBCs, lysing it in the process, and invade other (uninfected) RBCs, perpetuating the intracellular cycle of infection.
• The incubation period for babesiosis is somewhere between 5 and 30 days (longer if transmitted by transfusion).

 

Clinical presentation

• Clinical manifestations of babesiosis range from asymptomatic infection to fulminating disease resulting in death (fatality rate of 6–21%).
• Symptoms are gradual in onset and are typically non-specific and constitutional, including:
  • Fatigue
  • Generalized weakness and malaise
  • Abdominal pain
  • Nausea and vomiting
  • Photophobia
  • Anorexia
  • Headache
  • Myalgia
  • Diaphoresis
  • Shaking chills
  • Hematuria (depending on the degree of hemolysis)
  • Jaundice (depending on the degree of hemolysis)
  • Less common symptoms:
    • Arthralgia
    • Emotional liability and depression
    • Hyperesthesia
    • Neck stiffness
    • Sore throat
    • Conjunctival injection
    • Photophobia
    • Shortness of breath
    • Non-productive cough
• Physical examination may reveal:
  • Fever
  • Pallor and/or jaundice
  • Tachycardia or bradycardia
  • Hepatosplenomegaly 
• Laboratory findings include:
  • Mild to moderately severe hemolytic anemia
  • Thrombocytopenia
  • Elevated reticulocyte count
  • Elevated liver enzyme levels
• Severe complications may develop in up to 57% of immunocompromised patients and include:
  • Acute respiratory distress syndrome (ARDS)
  • Disseminated intravascular coagulation (DIC)
  • Liver failure
  • Renal failure
  • Hemophagocytic lymphohistiocytosis (HLH)
• Risk factors for severe disease include:
  • Asplenia
  • increased age (older than 50 years of age)
  • Immunocompromised state, for example:
    • HIV
    • Malignancy
    • Organ transplant
    • History of immunomodulating agents
  • Autoimmune disorders
• Of the cases reported to the CDC between 2011 and 2015 and from whom data were available, about half were 
  hospitalized at least overnight and about one-third experienced one or more complications.

 

Hematologic manifestations of Babesia:

• Hematologic abnormalities are common in symptomatic cases.
•  Platelets
  • Thrombocytopenia:
    • May be caused by:
      • Hypersplenism
      • Disseminated intravascular coagulation (DIC) (in severe cases)
      • Immune-mediated destruction of platelets
• Red blood cells
  • Anemia
    • Caused by hemolysis, secondary to:
      • Egress of the parasites from infected RBCs and subsequent irreparable damage to the RBC membranes (the primary mechanism).
      • Autoimmune hemolysis through several mechanisms, including:
        • Deposition of cross-reacting microbial antigens
        • Adsorption of immune complexes and complement
        • Deregulation of immune tolerance provoked by active infection
  • White blood cells
    • Lymphopenia is a common finding among patients with babesiosis:
      • In one study, 76.5% with babesiosis had lymphopenia.
    • Neutropenia:
      • One study showed that neutropenia may occur in more than 50% of infants with congenital babesiosis and in around one-third of adults with this infection (in absence of co-infection with Anaplasma).

From: Clin Infect Dis. 2001 Apr 15;32(8):1117-25.

 

Diagnosis

• Suspect diagnosis in a patient:
  • With tick exposure in an endemic area
  • Who presents with unexplained nonspecific symptoms such as:
    • Fever
    • Fatigue
    • Chills
    • Sweats
    • Headache
    • Myalgia
    • Arthralgia
    • Anorexia
  • Laboratory features including:
    • Thrombocytopenia
    • Hemolytic anemia
    • Elevation of liver enzyme levels.
• Confirm diagnosis by light microscopic visualization of Babesia parasites on Giemsa- or Wright-stained thin blood smears:
  • Thin smears are the gold standard for the diagnosis of infection.
  • The diagnostic sensitivity and specificity of light microscopy are highly dependent on the proficiency of the examiner.
  • In the immunocompetent host, parasitemia can be hard to detect on a peripheral blood smear given that it rarely exceeds 5%, in comparison to the asplenic patient where parasitemia may amount up to 85%.
  • One review stated: “Thick blood smears are not recommended because B microti and B duncani parasites are small organisms (diameter <3 μm) that may be missed”.
• Nucleic acid-based methods:
  • Real-time quantitative PCR or conventional PCR.
  • The detection limit of PCR is usually 50 parasites per ml, while that of light microscopy is approximately 0.001% parasitemia, which is around 5000 infected erythrocytes per mL.
• Serology:
  • Serologic testing for IgM/IgG antibodies by indirect immunofluorescent assay can be performed, but seropositivity per se does not indicate active infection.
  • The diagnosis of acute babesiosis cannot be confirmed solely by the presence of Babesia antibody in a serum sample collected at a single time point.
  • Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis
    and Management of Babesiosis:
    • For diagnostic confirmation of acute babesiosis, we recommend peripheral blood smear examination or polymerase chain reaction (PCR) rather than antibody testing (strong recommendation, moderate-quality evidence). Comment: The diagnosis of babesiosis should be based on epidemiological risk factors and clinical evidence, and confirmed by blood smear examination or PCR

Treatment

• Anti-Babesia treatment
  • Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis
    and Management of Babesiosis:
    • We recommend treating babesiosis with the combination of atovaquone plus azithromycin or the combination of clindamycin plus quinine (strong recommendation, moderate-quality evidence). Comment: Atovaquone plus azithromycin is the preferred antimicrobial combination for patients experiencing babesiosis, while clindamycin plus quinine is the alternative choice. The duration of treatment is 7 to 10 days in immunocompetent patients but often is extended when the patient is immunocompromised

• RBC exchange, for cases with:
  • High parasitemia (defined as 10% of RBCs being infected)
  • Severe hemolysis/anemia
  • Renal, hepatic, or pulmonary compromise
  • Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis
    and Management of Babesiosis:
    • In selected patients with severe babesiosis, we suggest exchange transfusion using red blood cells (weak recommendation, low-quality evidence). Comment: Exchange transfusion may be considered for patients with high-grade parasitemia (>10%) or who have any one or more of the following: severe hemolytic anemia and/or severe pulmonary, renal, or hepatic compromise. Expert consultation with a transfusion services physician or hematologist in conjunction with an infectious diseases specialist is strongly advised.
  • 2019 American Society for Apheresis guideline: