Photo- Babesia Organism Inside A Red Blood Cell
People can be infected with more than one tick borne disease organism. One study indicates over half of the Babesiosis patients also have Lyme disease. Hunters, fishermen, park employees, farmers and those spending a lot of time outdoors are more at risk for contracting the disease.
People can have Babesiosis (over 100 known species) and not realize it if symptoms are mild and fleeting. Often though, there can be a sudden onset of symptoms- coming, as described by patients, from "out of no-where".
UPDATE- 12/28/18- Several studies have supported the literature stating ARDS- Accute Respiratory Distress Syndrome- can be linked to Babesiosis.
In a 1984 study a transfusion induced Babesiosis/ARDS patient died from the condition.
In a 2012 study a Babesiosis/ARDS patient was successfully treated, however, six years later in a 2018 study, 3 out of 8 patients with Babesiosis related ARDS also died.
It was also reported in a 2017 study that the "degree of lung injury was severe in the majority, and multi-organ dysfunction was the norm."
Of special note in the 2018 study- "ARDS often followed the initiation of anti-babesia drug therapy". This is reminiscent of what many patients have been reporting for years as part of a severe herx-like reaction.
ARDS has been described multiple times in the scientific literature. Abstracts listed here.
UPDATE- Babesia duncani (aka WA1) has been detected in patients on the west coast (USA) where it was first discovered. However, doctors have been finding WA1 infected patients across the USA and overseas. Some of these patients are also infected with the Babesia microti and other strains.
BOTH strains need to be considered when ordering tests. Babesia duncani is NOT detected using the standard Babesia microti tests. Doctors should initiate treatment immediately and order both the Babesia duncani test along with the Babesia microti test if Babesiosis is suspected. (See testing information below.)
UPDATE- 9/12/14 In Maryland, the WA1 strain (Babesia duncani) is being detected in human patients approximately 5 times more often than the B. microti strain.
Study 2019- Babesiosis- Persistent and chronic infections, relapses, transfusable and serious.
Dr. Daniel Cameron- "Although Lyme disease is the most talked about tick-transmitted disease, Babesia is more common than you might think. In the 2015 issue of Trends in Parasitology, Diuk-Wasser and colleagues report that up to 40% of patients with Lyme disease experienced concurrent Babesiosis.  Source
Exposure to several species of infected ticks is the most common way to contract Babesiosis.
Babesiosis is also known to be transmitted by infected donors to those who have received a blood transfusion or organ transplant. Beginning in the early 1980s, cases of transfusion-transmitted Babesiosis were reported sporadically, but cases have steadily increased in frequency over the past 30 years, with at least 12 fatalities in transfusion recipients diagnosed with Babesiosis.
Babesiosis has also been shown to be transmitted transplacentally or perinatally. Infected infants have developed Babesiosis at 26 days to 5 weeks of age.
Update September 2018- Watch Babesia organisms enter and leave cells on short video clips in this scientific study. (Certainly read the article, with excellent pictures/charts too, but near the bottom of the page they have a section called... Electronic supplementary material... where you can watch Babesia moving in and out of cells.)
Babesiosis Symptoms: (Some are described by patients in their own words.) The parasite that causes Babesiosis invades and then destroys red blood cells. It can cause a malaria-like (relapsing) illness which can become chronic and/or can be fatal (10%- 28% fatality rate).
Symptoms may appear slowly or have a sudden onset, or may take months to years to fully develop. There can be "flares" of symptoms every four to six days, or on an on/off basis. Symptoms can plateau and return full force at a later time. Many people fear the symptoms will never go away.
Symptoms can include dizziness, vertigo, depression, acute respiratory distress syndrome, feelings of being off-balance, chronic cough, intermittent fevers, fatigue that worsens with exercise, severe fatigue, nausea, anxiety, chills, non-typical symptoms related to the head, low back pain, appetite swings, waves of sweats at night that can also occur during the day.
Babesia patients may experience de-ja-vu feelings, mood swings, vision and focusing disturbances and/or eye orbit problems, soreness or pain on the top of the head, sensitivity to light, "weird" feelings (confusion, panic, jittery, nauseated, "got to get out of here" thoughts, light-headed, claustrophobia, etc.) especially in areas with florescent lighting (malls, hospitals, stores, offices, etc.).
There can be disturbances in autonomic nervous system, vasculitis, concusion-like symptoms, an overstimulation of the brain, enhanced senses (everything is more intense), headaches (often pressure headaches- often behind the eyes- can feel like head is in a vise), focal vasculitis, exaggerated startle responses and headaches that feel like you are experiencing moving sensations.
Malaise, feeling "unstable", personality changes, feeling as if in a "fog", numb spots on head, drenching night sweats, delayed responses to questions, memory and cognitive disorders, muscle pains, irritability, temperature intolerance, racing heart and/or irregular heart beat (often worse at night) and breathing difficulties (air hunger- need to sigh and take a deep breath) are possible symptoms.
Patients with Babesiosis may also experience orthostatic hypotension, various uncomfortable feelings, episodes of vomiting, suicidal thoughts, panic disorder, hypercoaguable states (thick blood), mild to very severe insomnia and obsessive compulsive disorder (OCD).
They may have wrist and hand pain, dehydration or swelling, pain in feet/ankles, bleeding tendencies, acute respiratory distress syndrome, severe fluctuation of temperature, unexplained weight gain or loss, dark colored urine (blood in urine), anemia, swollen spleen (can rupture in some cases), enlarged liver, attention deficit disorder (ADD), vivid dreams and nightmares, congestive heart failure, respiratory failure, renal failure, bruising, jaundice, pulmonary edema, myocardial infarction, anorexia, evidence of shock and encephalopathy.
Symptoms can range from mild to severe. They can limit a persons ability to do everyday chores, their jobs and they can negatively affect their life in general. Driving, playing sports, operating machinery, walking a straight line, grocery shopping, attending family functions, being in a room with more than one person speaking and even cooking a meal may become difficult, if not impossible.
Some feel Babesiosis is more dangerous than Lyme disease. To see more information on symptoms, please refer to Dr. James Schaller’s Checklists for Bartonella, Babesia and Lyme Disease by clicking here.
Most doctors are not familiar with the diagnosis, wide range of symptoms or treatment of Babesiosis (and they really SHOULD be). To find a health care professional educated in diagnosing and treating Babesiosis and other tick borne diseases please go to www.LymeDoc.org for lists of professionals by state.
A specialty field of medical professionals, chiropractic neurologists, have been helpful for many people when addressing the symptoms of Babesiosis. They can help relieve the "off-balance" feelings and other neuro-brain related symptoms. To find a chiropractic neurologist in your area see the "Alternative" page at www.LymeDoc.org
*Update- Supplementation with glutathione and glutamine can increase the number of Babesia parasites and if used it should be started slowly to prevent a sudden increase in symptoms and anxiety.
*Update- Babesia can be found in biofilms. Source
*Update- Chronic Babesia infections can cause multiple symptoms and enhance the severity of Lyme, but patients may not present with detectable hemolysis (rupture or destruction of red blood cells). In more severe infections there is persistent, but very low grade hemolysis which can lead to iron deficiency over time. Think of Babesiosis for an iron-deficient patient with no obvious sources of blood loss.
*Update- Babesia infections can raise carbon monoxide levels which in turn can add to or even cause environmental sensitivities. This is an often overlooked clue to the presence of this bug.
Babesia Testing: Babesia tests, like Lyme tests, are unable to detect the infection in all patients. Therefore, you should treat the patient, not the test. Many experienced doctors will diagnose and treat patients based on exposure, history and symptoms due to the failure of many tests to detect the infection.
Note that standard blood smears are only sensitive for diagnosis during the first two weeks of infection.
There has been an increasing number of additional Babesia and Babesia-like agents discovered in the United States, Europe and Asia, including CA-1, MO-1, EU-1, KO-1, and TW-1.
The Babesia organism is rarely detected in blood smears.
It is recommended doctors run multiple tests to improve the chance of detecting a Babesia infection.
Antibody tests from Quest Lab (includes two strains) and PCR tests from IGeneX Lab in CA for Babesiosis are useful if positive, but a negative result does not rule out the disease.
"It [PCR] may be useful in monitoring the infection, though it cannot differentiate between acute or active forms of babesiosis and chronic forms of the disease." Source
Galaxy Lab- Galaxy Lab tests for at least 47 species of Bartonella, Ehrlichia, Rickettsia (spotted fevers) and Babesia. See which species are tested for each genus HERE.
Try to have blood drawn for testing early in the week so it is not delayed in transport and does not sit in the lab or elsewhere over the weekend.
Some advanced experts use indirect laboratory testing such as VEGF, TNF-a, IL-6, IL-1B, ECP, and sudden drops in MSH (LabCorp) or natural killer cell numbers such as CD57, CD56, CD3 and CD4 in response to a malaria or Babesia medication.
Some feel increased symptoms caused by patients being prescribed low doses of pure Babesia medications is highly suspicious for Babesia.
If someone has an "out-of-range" RDW reading (red-cell distribution width) on a standard CBC blood test, Babesiosis should be suspected.
QUOTE- "Until recently, it was thought that B. microti was found in the Eastern U.S. while B. duncani was prevalent in the Western U.S. However, this is no longer the case, as both species have expanded their range. While B. duncani was once called WA-1 because it originated in Washington state, it’s since been found in California and Oregon, as well as in the Eastern USA. B. microti, on the other hand, has been found all over the U.S., as well as in Switzerland.
Because of these changes in endemicity, it’s crucial that physicians test for both B. microti and B. duncani even if the patient lives outside of those species’ primary regions. If you receive a negative Babesia test for one species, you may still be infected with another species." Source
Babesia Treatment: A combination of Atovaquone/Mepron, 2-4 teaspoons per day (1-2 teaspoons, 2x per day) with Zithromax or Biaxin, is a common treatment for Babesiosis. This combination is reported to have less serious side effects than quinine and clindamyacin.
Eating fatty foods (bacon, ice cream, etc) while taking Mepron has been reported to increase absorption of the drug.
Some experts feel for Mepron to work you have to push the dose- 1 teaspoon for 5 months minimum (some say 9 months minimum)- and it must be taken with a large amount of fat. In absorption studies the test subjects had 23g of fat with each dose. Healthy fats could be yogurt, cheese, or 2 tablespoons of olive oil on a salad. (Personally I like ice cream and bacon which I don't normally get to eat otherwise.)
Artemesinin SOD (Researched Nutritionals) can be used, but as with all artemesia products there must be a regular break in treatment- typically 3 weeks on and one week off.
Cryptolepis, green tea egcg (epigallocatechin gallate) and sida can be added to the treatment protocol.
The cost to treat Babesiosis with Mepron/Zithromax can range from approximately $1,800- $3,600 per month. If you have little or no insurance and have a modest net income, $30,000 as a single person or $40,000 as a couple, or less, you may qualify for free Mepron or Malarone through the Bridges to Access program. You can learn more about the program by clicking here.
Recently a generic for Mepron came on the market. Prices vary greatly so please contact different sources to determine the best prices. Patients have reported the ITunes App has been helpful in locating pharmacies in their area with the lowest prices. To learn more about the App, click here.
The duration of treatment has recently been increased to a minimum of 5 months, often requiring 9 months to eradicate the organisms in early cases. In some patients recovery was not seen until five years into treatment and relapses are fairly common.
*Update- June 2015- a recent report from Australia provided a possible reason for the relapses or recurrences of the disease (in animals) ... "parasitised erythrocytes were few or undetectable in peripheral blood samples but were sequestered in large numbers within small vessels of visceral organs, particularly in the kidney and brain, associated with distinctive clusters of extraerythrocytic organisms."
*Update- September 2016- Study showing Babesia parasites are NOT cleared by red blood cell exchange. Link Here.
Medications such as Coartem, Malarone and Artesunate are also used to treat Babesiosis in some cases, especially when patients develop Mepron resistance or have a strain that does not respond.
Some physicians feel other anti-malarials or antibiotics may play a role in removing residual Babesia, and others feel improvements are seen once Lyme is being killed.
Loading doses with some medications can cause severe symptoms in the beginning of treatment and this method is not advised. Instead, starting with low doses may allow less debris and less added inflammation. The doses can be raised as the negative effects disappear.
>>> WARNING- MEPRON BLUES <<<
This is a condition that often occurs after starting treatment for Babesiosis and can continue or come and go during treatment (sometimes on a 3 week to monthly basis). Patient can suddenly become severely depressed, even suicidal.
Additionally, symptoms of Babesiosis can at first increase many times over rather than decrease as would typically be expected.
It is important to know IT WILL GO AWAY & YOU WILL GET BETTER!
Some of the terms used by patients to describe what has been dubbed the "Mepron Blues"...
Depression- can be deep and dark
Down feelings and sadness
Wanting to die
Extreme flares of pain
Flares of current symptoms
Not feeling like yourself
Dragging around trying to accomplish anything
Crying all the time
Wanting to just lay in bed
Make the world go away
Feelings of doom
Out of touch
Out of body feeling
Not in touch with self
If you experience any of these symptoms please contact your doctor. If you are feeling suicidal please contact the Suicide Hotline. Many patients have and reported it really helped!
Suicide Hotline 1-800-273-8255
Artemisinin has been rejected by all international major malaria organizations as a treatment as of 2014, and was replaced with artesunate in combination with a synthetic anti-malarial medication.
Since Babesia is far harder to kill than malaria, some experts feel using artemisinin, a rejected synthetic form of sweet wormwood or Artemisia that is no longer promoted in malaria care, is unwise. Babesia relapses are fairly common, but do not appear to be caused by a slime protective layer coating the organisms, which is commonly found in bacteria and fungal infections.
In summary, artemisinin is reported to not be as affective as other treatments and can still (rarely) produce some severe side effects. However, if a patient feels worse in the first few days on this medicine, they should inform their doctor. If ear pain is not involved it might be a sign you just killed some Babesia.
Many other medications exist that are proposed to augment the bodies ability to remove Babesia. Some include beta blockers, heparin and perhaps most importantly, quality blood thinners or clot prevention agents-- both natural and synthetic options exist.
Some experts feel Babesia is far more deadly than Lyme disease, and a clot is one way patients are harmed. A TIA, stroke or heart attack in a Lyme patient or someone in a high exposure area should be examined closely for clotting time with a D-Dimer test, PT/PTT and attention to how long you bleed--under one minute is far too fast. Many new lab tests exist to examine clotting function and samples are avaialable at all large national labs.
Cucurmin, an anti-malerial herbal, is reported to improve babesia treatment, and two possible optimal forms may be Enhansa and BCM-95, but we defer this to your health care provider.
Heparin inhibits the growth of babesia and has been shown to eliminate the infection by covering/coating the outer area of red blood cells, preventing the parasites from entering individual cells. (When adrenal function is low, response to treatment can be negatively affected.)
Cryptoleptis is another herbal option that has been noted to help patients who relapse when anti-malerials fail or for those who need milder treatment that can still hinder babesia reproduction and action.
Re-treatment or long term treatment is often needed in chronic or long-standing cases.
PLEASE REMEMBER- Patients may experience a worsening of the symptoms while treating babesiosis (reported in some to be during the first two weeks or later). Once this worsening occurs a few times, the patient should enter into a more stable recovery phase, although with each dose increase you may also notice more symptoms.
SPECIAL NOTE- this worsening is often accompanied by what patients have dubbed the "Mepron Blues", which can be a deepening depression, emotional instability, insomnia, rages, aches and an increase in anxiety levels. More information about the Mepron Blues is above.
After an infectious tick bite (babesia organisms found in salivary glands and guts of ticks), Babesia parasites invade red blood cells.
There are more than 100 known species of Babesia that can infect various small mammals, primates, rats and gerbils. The first Babesia species was discovered in 1888 by Victor Babes, a Romanian pathologist in whose honor the organisms were subsequently named.
Researchers continue to describe new babesial species affecting humans, such as MO1, which was associated with the first reported case of Babesiosis acquired in the state of Missouri. It is unclear where to classify MO-1.
The standard serology for Babesia microti will not detect these species and many other new species and strains in the public genetic data bases. Health care professionals should order tests for multiple strains when available.
PCR testing varies a great deal between labs, and is usually less sensitive than antibody testing. Some practitioners have used 2-3 low dose malaria medications and found the debris of Babesia increases positive PCR or DNA tests for Babesia.
Transfusion-associated Babesiosis, transplacental, perinatal and congenital Babesiosis have also been described and have caused severe illness and death in fetuses and patients.
Dosing for Babesia in children typically starts at 62.5 mg. Mepron. Dr. C
After a transfusion with infected blood, the incubation period can be up to nine weeks. The risk factors for the recipient have included donors who have had exposure in endemic areas. Transfusion transmittal is increasing and blood banks have concerns that asymptomatic donors are increasing in numbers.
The typical incubation period of Babesiosis varies from 5 to 33 days; however, most patients do not recall tick exposure. The correlation between the level of the serology titer and the severity of symptoms is poor, and tests may be false-negative in many cases.
If Babesiosis is suspected, treatment should begin immediately to prevent the worsening of symptoms and should continue until all symptoms have been cleared.
Congenital Transmission of Babesiosis
2018- "...2 infants with congenital babesiosis born to mothers with prepartum Lyme disease..."
2015- "Four ... of five infants with congenital babesiosis whose neutrophil count was reported were neutropenic."
2010- "Congenital babesiosis in a four-week-old female infant"
2009- "... third congenital case of babesiosis in a 26-day-old infant; transmission was determined on the basis of a blood smear from the infant (15% parasitemia) and serologic results from the infant and mother."
2006- "Neonatal babesiosis: case report and review of the literature"
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September 3, 2021
I’ve read this long and detailed study several times and went back to grab some quotes I felt were most important (shared below). Of course, reading the entire article could reveal more information that may be of interest to you.
Babesia microti: Pathogen Genomics, Genetic Variability, Immunodominant Antigens, and Pathogenesis
Link to full study
QUOTES- (bold sections by me)
In the same study, parasite variants containing amino acid substitutions in the rp14, a subunit of riboendonuclease, were associated with relapsing disease.
Based on the available whole genome wide sequence data, a 25 single nucleotide polymorphism (SNP) barcode was subsequently developed that supported the previous findings and identified two distinct B. microti lineages in the northeastern and midwestern United States (Baniecki et al., 2019).
Their results showed that in the northeastern United States, B. microti was strongly structured into three highly differentiated genetic clusters. Interestingly, analyses of the apicoplast genome indicated that in the Northeast, the current genetic diversity in B microti dates back 46,000 years with evidence of population expansion in the past 1,000 years (Carpi et al., 2016).
Their results also showed the presence of three distinct B. microti population structures with each dominated by a single ancestral type (Goethert et al., 2018). The authors concluded that B. microti parasites prevalent in the northeastern United States have expanded from a common ancestral origin(s) on the mainland and not from Nantucket or other islands off the New England mainland where babesiosis was first reported to be endemic.
It remains to be determined whether these closely related but different genetic groups are associated with different clinical severity.
Among the 3568 protein coding genes, 205 genes carried a total of 257 amino acid altering mutations, 27 of which contained nearly all mutations (Silva et al., 2016). It is possible that these surface expressed antigens are major immune targets and subjected to antigen variation that allows the parasite to escape host immunological surveillance and establish long term chronic infection.
These results are surprising because the mice used in the study were major histocompatibility (MHC) compatible. Some immunoreactive antigens continued to elicit antibody responses beyond day 125 following initial infection.
Consistent with this data, confocal microscopy studies showed that two of these antigens were expressed on the surface of infected erythrocytes, raising the possibility of their role as cytoadherence antigens.
This is reminiscent of other apicomplexan surface proteins such as the rifin-like and the var/DBL1 superfamilies in P. falciparum, and the vir/yir superfamilies in Plasmodium vivax/P. yoelii (Anantharaman et al., 2007). Future studies are needed to determine whether any of these antigens expressed on the surface of B. microti-infected red blood cells contribute to an immune escape mechanism that leads to persistent infections in animals and humans.
By applying a combination of nanotechnology and mass spectroscopy (MS), Magni et al. (2019) have generated a proteome profile of intraerythrocytic B. microti parasites during acute phase infection in hamsters. They have identified ∼500 proteins with assigned functions, such as transport, carbohydrate and energy metabolism, signaling transport, mobility and invasion, and immune response. This proteome database could be exploited for novel diagnostic and vaccine targets and better understanding of parasite biology, host immunity, and pathogenesis.
Three clinical patterns of human babesiosis have been described: acute symptomatic disease which may be mild, moderate or severe, acute asymptomatic infection, and persistent infection (Vannier et al., 2008; Vannier and Krause, 2012).
Acute asymptomatic infection is the most common clinical presentation. Asymptomatic infection occurs in about 20% of adults and is characterized by low parasitemia. Persistent infection follows acute symptomatic or asymptomatic infection and may last as long as 2 years (Krause et al., 1998, 2007; Raffalli and Wormser, 2016).
Several mechanisms may account for the severity of acute B. microti infection: an aberrant immune response that include excessive pro-inflammatory cytokine release, erythrocyte cytoadherence, persistent infection, and hemolytic anemia.
It is well recognized that immune responses that help protect the host against invading pathogens can also contribute to severe disease (Yokota, 2003; Huang et al., 2005). Over production of several pro-inflammatory cytokines during an array of infections is often associated with acute inflammation and tissue damage in the microenvironment of the lungs and other organs (Rubenfeld et al., 2005).
The phenomenon of hyperimmune immune responsiveness leading to excessive cytokine production has been termed “cytokine storm” and is attributed to the most severe pathogenic consequences of infections such as SARS-CoV-2 infection (Fajgenbaum and June, 2020). Key cytokines involved in cytokine storm are TNF-α, IFN-γ, IL-1, IL-6, and IL-18. The major immune cell types involved are neutrophils, macrophages and NK cells.
Cytokine storm has been implicated in severe disease complications in babesiosis (Clark and Jacobson, 1998; Hemmer et al., 2000; Krause et al., 2007). Excessive TNF-α and IL-1 production by macrophages, Th1 lymphocytes, and other cells in response to high parasitemia, decreases capillary integrity and can cause multi-organ dysfunction, including ARDS (Hemmer et al., 2000). When the effect is more widespread with loss of intravascular fluid, hypotension and shock may result.
Increased nitric oxide production following TNF-α and IL-1 release can help eradicate microbial pathogens but also cause tissue damage (Aguilar-Delfin et al., 2001; Vannier et al., 2015; Djokic et al., 2018). Elevated blood concentrations of TNF-α have been associated with the expression of adherence molecules ICAM-1 and VCAM-1 in vascular epithelium and with cerebral malaria in children (World Health Organization (WHO)., 2000; Krause et al., 2007).
The genomic underpinnings of cytokine storm have just begun to be elucidated. The dynamic of cytokine production leading to cytokine storm is complex and balanced by a number of factors, including proinflammatory cytokines and their cognate soluble receptor or inhibitors and the production of anti-inflammatory cytokines such as IL-10 (Tisoncik et al., 2012).
Other mechanisms that influence cytokine-mediated regulation of severe disease include the association of TNF-α promoter polymorphisms (G-238A and G-308A) with susceptibility to diseases as diverse as systemic lupus erythematous and P. falciparum malaria (Mahto et al., 2019), as well as epigenetic regulation of cytokine storm in COVID-19 patients (Sawalha et al., 2020). Carefully designed transcriptome and cytokine profiling studies in severe babesiosis patients and in chronic asymptomatic Babesia infections would help to identify the molecular factors that lead to severe disease with fatal consequences in susceptible individuals. Such studies may help to develop immunotherapies that could ameliorate the most severe B. microti complications, such as hemolytic anemia, ARDS and kidney damage in babesiosis patients.
Residence within red blood cells offers some protection for Babesia against host immune factors but Babesia infected erythrocytes are recognized and removed in the spleen. Cytoadherence of Babesia-infected erythrocytes to vascular endothelium is thought to allow the pathogen to complete its life cycle, leave the erythrocyte briefly, and infect another red blood cell without ever traversing the spleen. Excessive Babesia-induced erythrocyte adherence may contribute to babesiosis complications.
Babesia-induced red cell cytoadherence has been associated with B. bovis and B. duncani induced pathology (Clark et al., 2006a; Usmani-Brown et al., 2013; Allred, 2019). B. bovis strains with increased cytoadherence activity in vitro have increased virulence in cattle (O’Connor et al., 1999). When parasitemia is high in B. bovis-infected cattle, a large number of infected red blood cells may adhere to small capillaries in the brain, causing vascular obstruction, anoxia and death of neurons.
This is associated with the same stroke syndrome that is seen with cerebral malaria. Cytoadherence also has been associated with lung injury in B. duncani infected hamsters and mice (Dao and Eberhard, 1996; Hemmer et al., 1999, 2000; Krause et al., 2007), as well as renal injury in B. bovis-infected cattle (Patarroyo et al., 1982; Everitt et al., 1986). It remains unclear whether B. microti induces red blood cell cytoadherence. Vascular stasis and blockage has been demonstrated in the retina of a human patient infected with B. microti but another single case study failed to demonstrate evidence of B. microti-infected red blood cell cytoadherence to vascular endothelium in the brain of a comatose patient (Ortiz and Eagle, 1982; Clark et al., 2006b; Ortiz et al., 2020).
These surface proteins mediate infected erythrocyte adherence to vascular endothelium, which make Babesia and Plasmodia less accessible to attack by host immune cells (Allred and Al-Khedery, 2006; Krause et al., 2007). In a recent study, several adherence proteins have been found on the surface of B. microti-infected red blood cells in laboratory mice (Verma et al., 2020). These findings support the possibility that B. microti-induced cytoadherence may contribute to disease complications.
Persistence of infection is critical for the survival of Babesia as they rely on transfer between rodent host and tick vector. Once infected, both the primary host (Peromyscus leucopus) and tick vector (I. scapularis) remain infected for life, increasing the chance of transfer of infection from one to the other.
The same mechanism(s) that ensure persistence of infection in wildlife are likely to be operative in humans as they too experience persistent infection for months, even though they are dead end hosts (Spielman et al., 1981; Telford and Spielman, 1993; Krause et al., 1998; Moritz et al., 2016).
At least three mechanisms are thought to contribute to persistence: intraerythrocytic location, cytoadherence, and regulation of parasite release from the erythrocyte.
The intraerythrocytic location of Babesia protect them against host immune factors. Cytoadherence of Babesia-infected erythrocytes to vascular endothelium avoids splenic destruction of Babesia. Variable parasite release from the erythrocyte also contributes to persistent Babesia infection. The work of Lobo and colleagues has shown that the intraerythrocytic life cycle of B. divergens is flexible and that egress from the erythrocyte can occur rather quickly after red blood cell invasion or later in infection. Once established within the red blood cell, early egress from erythrocytes would be favored when there is a strong need to expand the population, as occurs early in infection. Later egress following several cell divisions is more likely when infection is well established and the intravascular environment becomes hostile due to host immune activation and antimicrobial therapy (Lobo et al., 2019).
It only takes a few infected erythrocytes to support persistence of infection in a host, which helps explain the recrudescence of infection that can occur in immunocompromised hosts despite low level parasitemia after prolonged (6 weeks or longer) antimicrobial therapy (Krause et al., 2008).
The clinical consequences of persistent infection include relapsing disease in immunocompromised individuals and transfer of Babesia to blood transfusion recipients following donation from an asymptomatic infected blood donor. A prospective follow-up study of 46 babesiosis patients demonstrated that B. microti parasitemia can persist for months with or without anti-B. microti therapy (Krause et al., 1998).
Asymptomatic infection persisted even longer in a group of patients who had mild B. microti infection and were not treated because of concern about side effects of clindamycin and quinine, the only effective therapy available at the time of the study. In these cases, parasitemia duration was 7–27 months. Only one of the 46 previously healthy patients had recrudescence of infection and that occurred 27 months after initial diagnosis (Krause et al., 1998).
In contrast, recrudescence is more common in highly immunocompromised patients, especially those with defective antibody production (Krause et al., 2008). Prolonged Babesia disease has been described in immunocompromised hosts, with relapsing symptoms lasting up to 9 months and parasitemia continuing for more than 2 years (Krause et al., 2008; Raffalli and Wormser, 2016; Allred, 2019; Bloch et al., 2019). These patients are markedly immunocompromised with underlying diagnoses that include HIV/AIDS, malignancy, and asplenia. A retrospective case series of consecutively enrolled babesiosis patients who failed to respond to standard anti-Babesia antibiotic therapy also demonstrated that patients with these immunosuppressive conditions experienced persistent and relapsing babesiosis (Krause et al., 2008).
Interestingly, 10 of the 14 patients in this series suffered from B cell lymphoma and had been treated with Rituximab, an anti-B cell monoclonal antibody. These data suggest that an impaired anti-Babesia antibody response, along with generalized immunosuppression, prevents clearance of B. microti infection.
Long term antibiotic therapy of at least 6 weeks with at least 2 weeks of negative blood smears, rather than the standard 7–10 days, was required to resolve infection in these severely immunocompromised patients. Severe and persistent B. microti infection has been associated with advanced age in a mouse model and in humans (Vannier et al., 2004; Vannier and Krause, 2012).
Lack of knowledge of the mechanisms of persistence of parasitemia in asymptomatic carriers, and the intraerythrocytic characteristics of the parasite, present unique challenges in identifying Babesia infection in blood donors. While the minimum infectious dose to transmit Babesia in humans is not known, results from a mouse model suggest that as few as 10–100 infected RBC are sufficient to establish fulminant blood stage infection (Bakkour et al., 2018).
In more recent years, results from prospective studies in large cohorts of blood donors conducted under the Investigational New Drug protocols have shed light on the prevalence of B. microti infections in asymptomatic healthy adults in endemic areas and non-endemic states (Levin et al., 2016; Moritz et al., 2016; Tonnetti et al., 2020).
After invasion of erythrocytes, B. microti multiply by binary fission, resulting in two to four daughter cells (merozoites). Rupture of erythrocytes that occurs with merozoite release is associated with fever, anemia, jaundice, hemoglobinemia, hemoglobinuria, tissue hypoxia, and renal insufficiency (Vannier and Krause, 2012; Vannier et al., 2015).
Synchronous release leads to paroxysms of fever interspersed with periods of apparent wellness, whereas non-synchronous release results in a more continuous pattern of fever. Because non-infectious hemolytic processes do not cause fever, additional factors associated with the lysis of the red cell are thought to result in febrile episodes. Hemolytic anemia with hypoxia has been implicated in exacerbation of congestive heart failure. Red cell membrane debris may lead to sequestration, vascular stasis, and functional impairment in the kidney and possibly other organs. Renal impairment is commonly noted, including renal failure in about 5% of babesiosis patients (Persing et al., 1995; Hatcher et al., 2001).
Hemolytic anemia due to production of autoantibodies 2–4 weeks after the diagnosis of babesiosis has been described in a subset of asplenic patients who had no previous history of autoimmunity (Woolley et al., 2017). The genetic aspects of the severity of babesiosis-induced hemolytic anemia and hypercoagulability have not been investigated.
Finally, genomic studies should help in the development of novel treatment options. These include new drugs and/or biologics such as monoclonal antibodies that are urgently needed for treatment of those patients experiencing severe babesiosis in whom standard anti-Babesia antibiotics are not effective.
Recommended Book on Babesia- Dr. James Schaller's Health Care Professional's Guide Book to the Treatment and Diagnosis of Human Babesiosis, which can be purchased online through Amazon.com
Babesiosis diagnosis and treatment ideas in a video featuring Dr. Horowitz can be seen by clicking here.
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Last Update- September 2021Lucy Barnes- AfterTheBite@gmail.com