2

Babesia

An Overview

image

The number of reported cases in humans is rising steadily worldwide. Hitherto unknown zoonotic Babesia spp. are now being reported from geographic areas where babesiosis was not previously known to occur.

A. HILDEBRANDT, J. S. GRAY, AND K. P. HUNFELD,
“HUMAN BABESIOSIS IN EUROPE:
WHAT CLINICIANS NEED TO KNOW”
 

Genetic diversity was very high and infections with multiple genotypes were frequently found for both [Babesia] parasites in outbreak samples.

E. GUILLEMI, P. RUYBAL, V. LIA, ET AL., “MULTI-LOCUS TYPING SCHEME FOR BABESIA BOVIS
AND BABESIA BIGEMINA REVEALS HIGH LEVELS
OF GENETIC VARIABILITY IN STRAINS
FROM NORTHERN ARGENTINA”

Babesia microti, which has long been considered a single species [but is not], demonstrates a high degree of genetic diversity.

A. ZAMOTO-NIIJURA, M. TSUJI, W. QIANG, ET AL., “DETECTION OF TWO ZOONOTIC BABESIA MICROTI LINEAGES, THE HOBETSU AND U.S. LINEAGES,
IN TWO SYMPATRIC TICK SPECIES, IXODES OVATUS AND IXODES PERSULCATUS, RESPECTIVELY, IN JAPAN”

Babesia organisms are protozoa, not bacteria, as everyone surely knows. Still, if you try to find a really usable definition of what protozoa are, and why the differences between bacteria and protozoa matter, you are going to be unhappy. Inevitably you will find yourself reading such linguistic tours de force as this one (from Wikipedia, which has apparently been taken over by inarticulate reductionists). Protozoa, they note, are “organisms formerly classified in the Kingdom Protozoa.” Unsurprisingly unhelpful so far; still, as the authors (insistently) continue:

The species traditionally collectively [“traditionally collectively”?] termed “protozoa” are not closely related to each other, and have only superficial similarities (eukaryotic, unicellular, motile, though with exceptions). The terms “protozoa” (and protist) are usually discouraged in the modern biosciences. However, this terminology is still encountered in medicine. This is partially because of the conservative character of medical classification, and partially due to the necessity of making identifications of organisms based upon appearances and not upon DNA. (Wikipedia, under “protozoan infection,” Jan. 12, 2013)

In other words, he looks like a duck, therefore he is a duck. Nevertheless, if you remain undaunted, and decide to travel deeper into Wikipedia-think by clicking on “Protist,” you get the following descriptive:

Protists are a large and diverse group of eukaryotic microorganisms, which belong to the kingdom Protista. There have been attempts to remove the kingdom from the taxonomy but it is still very much in use. The use of Protoctista is also preferred by various organizations and institutions. Molecular information has also been used to redefine this group in modern taxonomy as diverse and often distantly related phyla. The group of protists is now considered to mean diverse phyla that are not closely related through evolution and have different life cycles, tropic levels, modes of locomotion and cellular structures. Besides their relatively simple levels of organization, the protists do not have much in common. They are unicellular or they are multicellular.

“They are unicellular or they are multicellular”? Alrighty then.

This hasn’t been a lot of help so far, though it does give you an experience of the current state of taxonomy (and science in general) when it comes to the natural world. Taxonomists, in other words . . .

people who are taxing, that is, burdensome, onerous, difficult, laborious, exhausting, grueling, oppressive, rigid, toilsome, wearing, stressful

really are a pain.

And no, it’s not just a Wikipedia problem. This same kind of definitional fog about protozoa, and unfortunately most living organisms, can be found wherever taxonomists reside. So, let’s try again . . .

Babesia organisms are protozoa, like malarial parasites, rather than bacteria (not that I am sure it really matters for our purposes). And according to current taxonometric classifications, bacteria are prokaryotes while protozoa are eukaryotes. (Hmmm, not very enlightening so far but let’s soldier on.)

Protozoa, it turns out, possess a nucleus while bacteria do not. The term prokaryote (which bacteria are) means “pre-nucleus” or rather more exactly “before the nut,” while eukaryote (which protozoa are) means “easily formed nut,” if that helps any.

Taxonomists then would be eukaryotes, that is, easily formed nuts, as in “ insane, unbalanced, a state of mind that prevents normal perception, behavior, or social interaction; seriously mentally ill.”

Bacteria have, instead of a nucleus, a nucleoid where they keep their DNA. (“These are not the nucleiods you are looking for. Move along, move along.”) A nucleoid, it turns out, is a kind of nucleus but it doesn’t have a membrane around it—thus nucleoid. It’s a sort-of nucleus, a baby nucleus, a semi-nucleus, a pretend nucleus. Again, this is not very useful. Hmmmm, maybe then this will work:

Protozoa are bigger, some ten to one hundred times larger than bacteria, so much so that they sometimes feed on bacteria. This is why protozoa were originally considered to be the simplest form of animal (protozoa actually means “first animal”) while bacteria are, well, just bacteria. Hmmmm. Still, if we look deeper, and despite all the definitional posturing by VSP (very serious people), it turns out that the particular protozoa we are concerned with here, that is, Babesia, are more similar to bacteria than these definitions would have us believe. Researchers note:

Due to its origin, this [babesial] organelle has bacterial characteristics, and the metabolic pathways it contains have been shown to be vital for parasite survival. Therefore it can be targeted by bacterial antibiotics which, as has been demonstrated in Plasmodium and Toxoplasma, result in a delayed-death response. Hence, particularly antibiotics that target the bacterial-like protein biosynthesis within the plastid like azithromycin, clindamycin, and tetracycline, are commonly used to treat human babesiosis. (Schnittger et al. 2012)

Ultimately, if you stay with it long enough, you will find out that protozoa, like bacteria, are simply microorganisms that sometimes infect people, and I don’t know why they just can’t say that to begin with.

There are some 30,000 different types of protozoa that have been identified so far in a variety of genera (genuses?). Each protozoal genus has from one to hundreds of different species within it. In the genus Babesia some 110 different species have been found so far. Like many of the Lyme group of infections, members of the Babesia complex, irrespective of what animal they infect, are parasites. They don’t live in the wild but always inside another organism. Like their relatives, the malarial organisms, they colonize (infect) red blood cells (which is why they are sometimes referred to as hemoprotozoans—as if we didn’t need another term and yes, they are sometimes called piroplasmids, too). It is from those cells that they gather the nutrients they need to survive. Babesial organisms infect pretty much everything with red blood cells: mammals, birds, and almost certainly reptiles and amphibians—although no one has spent any time looking for the ones that do. In fact, every mammal species tested has been found to harbor babesial infections, often specific to themselves. That is, lions and tigers and bears (don’t say it) all tend to be infected, usually subclinically, with one babesial organism unique to themselves. Each different than the others. (But as current research is finding, this is not as cut-and-dried as was once thought.)

Babesial parasites have been around for hundreds of millions of years. In fact, genome studies have found that the ancestors of babesial organisms existed inside the early ancestors of ticks. Both evolved together into their current forms; they have had a very long coevolutionary mutualism. As new species of animals emerged from the ecological background of the planet, and as each was fed upon by ticks (or their ancestors), the Babesia protozoa altered their genome to make infection of those new animals possible. Some sources still insist that the various members of the genus only infect specific animals (and specific vectors) and that humans are incidental hosts. However, as leading babesial researchers Schnittger et al. (2012) comment:

Although a single tick species is typically the principal vector of a certain Babesia or Theileria species, this transmission capacity is usually extended to the whole genus. Moreover, often two or even more tick genera can transmit any one piroplasmid species. It has also been reported that a given tick species transmits two or more different piroplasmid species (e.g. Hyalomma a. anatolicum can transmit Babesia sp. Xinjinang, T. annulata, and T. lestoquardi). One vertebrate host may be infected by several different piroplasmid species, and likewise “vertebrate host specificity” is not a reliable taxonomic criterion. Some Babesia spp. have a broad host range.

And, as they go on to say:

During the last decade, it has become clear that B. microti infects a large variety of different hosts worldwide (many different small rodent species; carnivores, such as raccoon, skunk, canine, fox, river otter; macaque; and humans) and does not constitute a single species as previously assumed, but a variety of different species currently referred to as the B. microti-species complex.

Gaffer et al. (2003) as well note that “B. bovis merozoites invade and develop in multiple species in contrast to the host specificity observed in nature.” And as Schnittger et al. (2012) conclude, with their usual gift for understatement, “These findings suggest that our picture of the species that harbor babesia parasites is far from complete.” In fact, it appears that babesial protozoa can infect a much broader range of animals than is currently supposed, essentially anything with red blood cells.

Analysis of piroplasmid genomes has found that there has been frequent switching of their vertebrate hosts over millennia. That is, they can alter their genome under environmental pressure to allow them to infect any life form that possesses red blood cells. They jump species. These organisms have in fact been around for so long that in one form or another they have infected everything they could infect. Long ago they infected dinosaurs, and as mammals emerged, they began to infect them, too. This, of course, includes the primates, of which humans are a member.

Those that specialize in humans tend to be a bit smaller in size than those that infect other mammals (but not always). There are currently twelve species of babesia that are known to infect people. Still, the research on babesial organisms is, as with most of the Lyme group, only a few decades old, so the knowledge base is actually very thin. As researchers look more deeply at the genus, more species that infect people are being discovered. And, to make matters more complex, while there are twelve species that are currently known to infect people, there are scores of different genotypes of those species. In other words, to hide from the human immune system, during infection each species produces offspring that possess slightly different exterior protein structures, i.e., genotypes. So, what you get during infection is, as is the case with most of the Lyme group, an infectious swarm of similar but not identical organisms. This is why successful treatment can sometimes be difficult and why, even after antibiotic treatment, the organisms may remain and disease symptoms recur.

HUMAN INFECTION

Transmission of babesial parasites is primarily by tick bite (with various different ticks carrying different or multiple species of the organisms). Still, infection through transfusions of infected blood are becoming an increasing problem (blood donors are rarely tested for the parasites) and placental transfer from an infected mother to an unborn child has also been documented.

The main endemic areas for infection are the northeast (New Jersey upward), northern California up through Washington State, the geographical area around Wisconsin, and the southeast, with Georgia as the epicenter. For the most part, the usual Lyme-endemic areas.

The majority of clinicians believe that there are only four Babesia species that infect people: Babesia microti, B. duncani, B. divergens, and B. venatorum. But as is common with the Lyme group (and much medical knowledge), that information bears little relation to reality. There are at least twelve currently known: Babesia microti, Babesia duncani (formerly called Babesia WA1), Babesia CA1, CA3, and CA4, Babesia MO1 (also called Babesia divergens-like), Babesia divergens, Babesia venatorum (formerly Babesia EU1), Babesia bigemina, Babesia vinsonii subspecies arupensis, and Babesia KO1 and TW1. (There are also others that have been found, noted by the terms WA2, CA5, CA6. They might be unique species or simply a subtype of, for example, Babesia duncani; the research is still too new to say for sure.)

Each of the species identified by letters such as CA1 and so on are currently named for where they were first identified. In other words, California (CA1, etc.), Missouri (MO1), Europe (EU1), Korea (KO1), and Taiwan (TW1). These species have been found to infect people throughout the world but have not yet been given their own species name. Again, and importantly, each of these species generates multiple genotypes during human infection.

And, irritatingly for determinists, Babesia microti is not just one species. It turns out that it is a group of similar but not identical species. The various B. microti species, like many of the human-infecting Babesia complex, at present only possess casual identifiers. The four primary

B. microti lineages or subtypes (U.S. type, Munich type, Kobe type, and Hobetsu type), which tend to infect people in different regions of the planet, have discrete genome differences. They are, in fact, each unique. Each creates slightly different symptoms and responds slightly differently to pharmaceuticals. They, too, generate multiple genotypes. And it turns out that this is not uncommon. Babesia canis, which normally infects canines, is not in fact a single species either but rather three distinct ones.

Unfortunately, to continue making things difficult, some people (taxonomists with OCD, a well-known subgroup of the genus) are beginning to call babesial organisms piroplasms and the infections they cause piroplasmosis. Piro means “pear-shaped” and plasm essentially means “substance of a living cell.” In essence, a pear-shaped cell. (Scientists like to use big words; when translated most of them are just this mentally simplistic.) While some researchers like to call Babesia “pear-shaped” they are in fact only sometimes pear-shaped, and at other times they are oval, and sometimes round. So, again and with monotonous regularity, not a very useful descriptive.

There are three types of piroplasms (it seems): organisms in the genera Babesia, Theileria, and Cytauxzoon. But there is a lot of infighting going on among researchers. Some taxonomists, inevitably, are now insisting that Babesia microti is not a Babesia but belongs among the Theileria, hence you may see Babesia microti also referred to as Theileria microti. (This is why no one likes taxonomists.) Other researchers disagree, and with reams of genetic data trailing behind them, they snicker, point to their data, and make geek jokes.

Two theoretical physicists are lost at the top of a mountain.

Still other taxonomists are (of course) insisting that some of the Theileria are really Babesia.

Physicist one pulls out a map and peruses it for a while, then says, “Hey, I know where we are!”

The arguments are heated and unrelenting. (Fisticuffs at eleven.) Cytauxzoon, however, has so far been left alone (there is only one, so not much to fight over).

Physicist two says, “Okay then, where are we?”
Physicist one points and says, “You see that
mountain over there?”
“Yes.”
“Well, that’s where we are!”

Uh, oh, I feel another rant coming on.

image

Tiny Rant

Monological Antipathies

The problem is that most scientists don’t know much about the real, living world. They don’t spend much time in it and, to make things worse, their paradigm is inaccurate; it’s much too simplistic. These organisms do not fit into, as Buckminster Fuller once put it, monological descriptions of Universe. In other words, there is no one-picture answer to either the Earth or organisms this complex. The Lyme group of microorganisms are called stealth pathogens for a reason. They are highly sensitive nonlinear life forms with tremendous genetic flexibility, a flexibility that has been honed over billions of years. They perform unique and highly sophisticated functions within the ecological network of the planet. As Lynn Margulis once put it, “They have lots better things to do than sit around figuring out how to make us sick.” (Even if a few of them do so from time to time.) Hence, when reductive researchers approach organisms with this kind of complexity, they are often at a loss. There is in fact no one word that can be used to describe an organism that is sometimes pear-shaped, sometimes oval, sometimes round; sometimes has one genetic structure, sometimes another; sometimes infects this mammal, sometimes that one; and sometimes responds to this antibiotic, while sometimes not.

The Lyme group, along with other resistant bacteria, are forcing a truer picture of the world into our awareness, whether we wish it or not. Younger researchers (those not so firmly embedded within a reductive framework) are beginning to let go of their presuppositions and look at what is right in front of them. They are finding that the simplistic descriptives that fill medical texts are very much inaccurate compared to what they are seeing. For example . . .

On one hand, piroplasms can be distinguished into two groups by their diameter: theileria and small babesia, and large babesia parasites. However, species identification can be hampered due to developmental changes in the form and size of parasitic stages in the erythrocyte [red blood cell], and due to the observation that some piroplasmid species may differ in form and size when infecting different vertebrate hosts. (Schnittger et al. 2012)

In other words, the organisms can alter their physical form depending on the habitat within which they find themselves; they are genetically responsive to any alterations in their environment. To put it another way, any environmental pressure can stimulate alterations in their genome. And among environmental pressures are such things as vaccinations against Babesia (in cattle), antibiotics (and their prevalence in water supplies and soil), and ecological disruption (such as cutting of forests and people inhabiting formerly undeveloped habitat). The various babesial species also engage in highly prolific genetic exchanges between themselves (and other bacteria), which enhances the emergence of unique genotypes. Thus . . .

In one study, 31 cattle were examined over a six-month period. Of the 31 animals, 20 showed babesial genotype alterations. Within those 20 cattle, 28 different genotypes were found. New genotype innovation was continual. The researchers note:

Genetic exchange is frequent in Babesia as well as in Theileria parasites, and it may have the following significance with respect to disease control. First, drug resistance, if it occurs, will most likely spread rapidly in the entire population. Second, inter-genetic recombination between and intra-genetic recombination within polymorphic surface antigen-coding genes should highly promote the diversity of the parasite surface and its surface antigens. This may result in continuous creation of immune escape variants in a given parasite population, advocate vaccine breakthroughs, and complicate vaccine development. (Schnittger et al. 2012)

In fact, both resistant forms and vaccine breakthroughs have already occurred and are becoming problematic. And it is well recognized among most medical researchers that immune escape variants (that is, the immune system can’t “see” them) are common in a substantial number of people who are infected with the organisms. Babesial organisms, it turns out, are so adaptable that the same species may take on forms that make them unrecognizable from one host to the next. This, inevitably, screws up successful diagnosis . . . and simplistic mental approaches to the organisms.

Despite desires to the contrary, a simple, and useful, descriptive of the organisms is very hard to create. Babesia do have a core identity but the organisms’ physical expression is highly variable. Their gene structure (genotype) is in constant flux, giving rise to multiple phenotypes (physical and behavioral forms). This means that they can truly be unrecognizable from one host to the next, even if you do manage to see them under a microscope.

There seem to be only three constants: they are parasitic microorganisms, they are primarily transmitted by ticks, they infect red blood cells, inside of which they (primarily) reproduce.

image

SYMPTOMS OF INFECTION

As with many microorganism infections, most people are and remain asymptomatic; that is, they have the parasites in their blood but show no symptoms. This is most commonly because their immune function is healthy. The human and the babesial organisms become relatively stress-free joint tenants in the body. (It is this group of people who often donate infected blood. People receiving the blood, if their immune function is low, are at risk of a symptomatic infection.) However, if immune function in the asymptomatic falls for any reason the organism can, and often does, begin to cause problems.

For others, once infected, they merely experience a bout of the “flu.” (The “flu” we think we have is often not the flu but can be nearly any infection at all; it is just what many infections feel like at onset.) After a week or two the “flu” is gone and the person feels fine once more. This group of people sometimes then become asymptomatic carriers themselves. (Other times, the organism actually is eradicated from the body.) And again, if immune function falls later on in their lives, the disease can bloom once more. Generally, symptoms arise one to four weeks after a tick bite, though up to nine weeks has been reported. Here is the symptom breakdown among those who show symptoms.

SymptomOutpatientsInpatients
Fever68 %89 %
Fatigue78 %79 %
Chills39 %68 %
Sweats41 %56 %
Headache75 %32 %
Myalgia37 %32 %
Anorexia24 %24 %
Cough17 %23 %
Arthralgia31 %17 %
Nausea22 %9 %
   

The symptoms for those who successfully process the disease on their own mostly consist of the general aches and pains, low-grade fever, fatigue, and chills that accompany “the flu.” For those who need hospitalization, the symptom picture is generally more severe, especially the fever, fatigue, chills, and sweats. Malaise, abdominal pain, and diarrhea, though not included in the chart, may also occur among both groups.

As with malaria, a relapsing form of the infection is common. The disease appears to be a simple flu, and the person recovers, then relapses months later, recovers, relapses, and so on ad nauseum. This is moderately common among those with Lyme-group infections, especially with Babesia.

To be more specific: all babesial infections commonly present with malaise and fatigue followed by intermittent fever accompanied by (one or more of the following) chills, sweats, general pallor, mild hepatosplenomegaly (liver and/or spleen enlargement and/or pain), headache, lightheadedness, arthralgia, myalgia, anorexia, cough, vomiting, nausea, GI tract problems, depression, and/or emotional lability. In some the illness may last weeks to months; prolonged recovery can last more than a year.

In those in whom the disease becomes more severe, fever may increase to 105°F, shaking chills are common, and hepatosplenomegaly (liver and spleen inflammation and damage) increases. Other symptoms include noncardiogenic pulmonary edema, hypotension, hemolysis (ruptured blood cells), jaundice, hemoglobinuria (hemoglobin in the urine), dark urine, proteinuria (excess protein in the urine), mild neutropenia (low numbers of neutrophils in the blood), leukopenia (low numbers of leukocytes in the blood), atypical lymphocytosis (an increase in lymphocytes in the blood), thrombocytopenia (abnormally low levels of platelets in the blood), retinal infarcts (a blockage of the central retinal artery leading to sudden vision loss), anemia, ecchymoses (a kind of bruising that spontaneously occurs on the skin from ruptured blood vessels), petechia (small red or purple spots on the body caused by hemorrhage in small blood capillaries), and hyperesthesia (abnormal sensitivity to sensory inputs). Hepatic transaminases may become elevated. The lymph nodes rarely become enlarged.

Neurological problems can occur in some people, in part from decreased red blood cell presence in the brain and subsequent damage to various areas of the organ caused by intravascular coagulation and endothelial cell damage. The brain capillaries can become packed with parasitized erythrocytes, interfering with proper blood flow to differing regions of the brain, with resultant problems in mental functioning. Stroke can occur if coagulation is severe.

During very severe infections, further complications may arise: severe acute respiratory distress syndrome, disseminated intravascular coagulation, acute kidney injury, organ failure (renal, heart, liver), splenic rupture, septic shock, coma, and death.

Those most at risk for severe disease are those without a spleen, the elderly (over 50), and the immunocompromised. As an example of the importance of the spleen during a Babesia infection: parasitemia (organism numbers) in those with a spleen runs around 5 percent, but in those without spleens it’s 85 percent. As Babesia specialist Peter Krause, MD, observes, the spleen “helps to clear organisms in the blood that shouldn’t be there. It produces antibodies that attack the protozoans, which are then gobbled up by macrophages, and it acts like a sieve, screening out Babesia-infected red blood cells, which are too big to get through and back into circulation” (Brody 2012). For some people, during severe infection, the spleen is so strongly affected that it may rupture.

Because the spleen performs an essential function during the body’s response to babesial infection and because of the heavy impact on its functioning, it must be supported during treatment. (Removal of the spleen is often performed after splenic rupture. Because that patient population tends to live in Babesia-endemic areas, future infections are very dangerous. The spleen should not be removed unless it absolutely must be. And yes, splenic rupture can be, and has been, successfully treated without spleen removal.)

General mortality among those who are hospitalized due to babesial infection is about 5 percent, among those who are immunocompromised about 10 percent, and among those who have no spleen 21 percent.

Infection rates are increasing in endemic areas (as studies over the decades from 1990 to 2010 have shown) and are spreading outward from those centers. Over a 10-year period researchers found that infections on Block Island (off the coast of Rhode Island) were increasing substantially, from minimal levels when the study began to nearly the same levels as Lyme infection by the study’s end. Sixty percent of the children tested, at one time or another, were found to be symptomatic, as were 81 percent of the adults. The rest of those tested were infected but asymptomatic. The children experienced the same range of symptoms as adults; they just recovered faster and better due to their better immune health.

DIAGNOSIS

As with Lyme disease, many physicians refuse to entertain the thought that a Babesia infection is present if someone has not traveled to what is considered an endemic area within the past four to nine weeks. The organism, however, is rapidly spreading into what are considered non-endemic areas. And because Babesia are regularly transmitted through blood transfusions the disease commonly appears in atypical and non-endemic areas.

The poor medical understanding of Babesia, the numerous species and multiple genotypes that can be found during infection, and the variety of different shapes the organisms take on make clear diagnosis difficult. To make matters worse, diagnostic tests are often unreliable, poorly administered or read, and not sensitive to the wide range of species and genotypes now known to exist.

Simplistically, during a tick bite, some tick saliva and babesial parasites are injected into the bloodstream of the new host. The organisms use the compounds in the tick saliva to facilitate their entry and bypass immune responses. Once in the bloodstream they immediately infect red blood cells, then begin to divide inside those cells. They usually form two or four new babesial organisms inside those cells, depending on the babesial species. When mature, these burst out of the red blood cells, killing them, and infect new cells (which is why anemia, shortness of breath, and fatigue are so common in the condition). A few of the microorganisms do not divide but remain inside red blood cells in order to be picked up by ticks during feeding and thus spread to new hosts.

Blood Smear Analysis

The primary approach to diagnosing a babesial infection has been to microscopically examine the red blood cells (blood smear analysis) and literally look at the structure of the reproducing babesial cells. (During blood smear analysis, daughter cells, free in the blood, are also examined.) Many Babesia (the smaller ones) form what is called a Maltese cross, similar to a plus sign. Once seen inside the blood cells, the diagnosis is certain. Larger forms, when replicating inside cells, form two daughter cells that resemble two pears hanging together (hence the name piroplasmosis). Still, as Schnittger et al. (2012) comment, relying on that is problematic; the organisms don’t always form these shapes and some Babesia form other patterns during reproduction. Specifically, they note that “corresponding to their size classification, all small Babesia as well as all Theileria parasites divide into four merozoite daughter cells (a maltese cross formation), while large Babesia bud into two merozoite daughter cells. However . . . exceptions do occur.”

Diagnostic problems also arise using this procedure because the organisms are often present in the blood in extremely low levels; as few as 1 percent of the red blood cells may be infected. (And even so, symptoms can be severe.) Case studies are common in which people are admitted to a hospital with signs of infection but no parasites are noted in blood smears. These studies regularly contain comments such as “There were no blood parasites or schistocytes noted on blood smears performed at that time. Over the next two months, the patient remained on the increased dose of steroids, but had worsening of his anemia and rising values of serum lactate dehydrogenase, suggesting a hemolytic process” (Lubin et al. 2011). It was another month, after symptoms refused to resolve, before protozoa were found in blood smears of that particular patient. (In this instance, the babesial parasites were transmitted via stem cell transplantation.)

Added complications of blood smear diagnosis include: 1) Babesia and malarial parasites may at times be indistinguishable from each other; and 2) blood smear readings generally cannot differentiate between different species or genotypes.

Polymerase Chain Reaction (PCR)

Rapid real-time PCR is perhaps the best of all the tests for babesial organisms, especially when combined with blood smear analysis. A “tick panel” is often the best approach as it can test for Babesia, Ehrlichia, Anaplasma, and Borrelia at the same time. PCR tests are increasing in their sensitivity to the various babesial species though there is not yet one that can test for all those that may infect people.

Indirect Fluorescence Assay (IFA)

IFA is considered to be the third best test to use; however, it possesses a number of problems that make it suspect. The primary problem is that it tests for antibodies in the blood and antibodies do not always appear during the early stages of infection. False negative and false positive results are common. Positive diagnosis from various laboratories has been found to range from 69 to 100 percent in accuracy, from 88 to 96 percent in sensitivity, and from 90 to 100 percent in specificity (for the species tested). Of the IFA tests used, IgM is the most reliable as a diagnostic.

Indirect Enzyme-Linked
Immunosorbent Assay (ELISA)

Relatively useless, nevertheless still sometimes used.

The best diagnostic approach is considered to be symptom picture combined with blood smear analysis and PCR. Researchers Chan et al. (2013) comment:

Accurate diagnosis of various tick-borne diseases is problematic, due to similar clinical manifestations. Currently available serological tests are neither cost-effective, nor sensitive or specific for diagnosis of infections by these three pathogens [Borrelia, Anaplasma, Babesia] transmitted by ticks, especially at early stage of infection. . . . A. phagocytophilum and B. microti infect white and red blood cells, respectively, but are not easily detectable in blood. This offers additional risk since they can also be transmitted through blood transfusions and potentially vertically from mother to infant. The presence of Babesia species is usually visualized by microscopic examination after Giemsa staining; however, it is frequently overlooked, because of the infection of less than 1% of erythrocytes or due to hemolysis during the sample transport. . . . PCR has been found to be more sensitive for its detection.

PHARMACEUTICAL TREATMENT

Pharmaceutical treatment does work for many people. However, both genotypic variation and increasing resistance are causing more failures among the pharmaceutically inclined. One of the main causes of resistance is the use of antibabesial drugs in farm animals. Babesial infections are a common, and serious, problem in cattle throughout the world. In consequence many ranchers include antibabesial drugs in animal feed to try to prevent infection. As researchers note, “The indiscriminate use of anti-Babesia prophylactic agents, including the administration of the drug at sub-lethal blood levels to animals, can produce the development of drug resistant parasites” (Mosqueda et al. 2012). And in fact, it has. Thus, physicians are seeing more treatment failures in general practice.

The standard treatment for people is atovaquone, 750 mg orally twice daily, plus azithromycin. Dosage for the latter is 500 to 1,000 mg on the first day, and 250 to 1,000 mg on subsequent days. Both drugs usually are given for 7 to 10 days. Resistance to this combination has been reported in the literature.

Some people utilize an older treatment approach, especially if the first approach fails. This is the use of clindamycin (600 mg orally three times daily, or by IV four times daily) plus quinine (650 mg orally three times daily). The combination is, again, usually given for 7 to 10 days. This combination is generally used for the more severely ill, but is, however, frequently associated with unpleasant side effects: tinnitus, vertigo, and GI tract upset. The combination often fails when used in those without a spleen, those with HIV, or those on corticosteroid therapy. Resistance to this combination has also been reported in the literature.

In those who are immunocompromised, no one treatment approach has been found to be effective and pharmaceutical treatment for a minimum of six weeks with an additional two weeks of treatment after the last positive blood smear has been found to be essential.

The literature contains reports of people “successfully” treated with pharmaceuticals whose blood showed no organisms who nevertheless were still infected and experienced relapsing episodes of infection. As Krause et al. (1998) comment, “Although treatment with clindamycin and quinine reduces the duration of parasitemia, infection may still persist and recrudesce and side effects are common.”

Numerous studies are indicating that a longer treatment duration than 7 to 10 days is necessary, in general six to eight weeks. As an example: Atovaquone administered for 7 days to dogs infected with B. gibsoni initially cleared the parasites. However they reappeared in blood smears 33 days later. The recurring parasites were more strongly resistant to the drug during the second antibacterial treatment. This same outcome has been reported in dogs when using an atovaquone/ azithromycin combination. As well, a rather large percentage of people treated for 7 to 10 days with either of these drug combinations have been found to experience a reemergence of the disease. As researchers comment:

In a prospective study, DNA evidence of parasitemia persisted after 7 days of treatment in approximately 40% of subjects who received azithromycin plus atovaquone and in approximately 50% of subjects who were treated with clindamycin plus quinine. (Florescu et al. 2008)

In the case of the man infected through stem cell transplantation, once he was correctly diagnosed, he was treated with azithromycin and atovaquone. His symptoms improved but did not resolve; blood smear showed the continued presence of parasites, though reduced in number. After two months on the protocol symptoms worsened, with increasing hemolysis and persistent parasitemia. He was switched to clindamycin and quinine for the usual 7- to 10-day treatment. Infection cleared and he was discharged from the hospital. He was readmitted one month later, again with worsening symptoms. This time he was given both pharmaceutical protocols. After 7 days, with significant symptom resolution, he was discharged but left on the combined protocol for another six weeks. Clindamycin/quinine was discontinued due to side effects; he remained on azithromycin/atovaquone for an additional six weeks. It was only then that PCR failed to detect babesial infection. The necessity for such lengthy treatment times, again, is common in approximately half of the infected. Failure to treat for longer than 7 to 10 days risks disease recurrence, often with worsening symptoms, including death. For example, Florescu et al. (2008) report the death of a woman, aged 75, who was hospitalized with symptoms of fever, fatigue, and night sweats and was treated with the usual 7- to 10-day regimen.

Upon initial examination her spleen was enlarged, and lower leg edema and anemia were present. Ceftazidime, filgrastim, and epoietin alfa were administered prophylactically before diagnosis. Blood smears for malaria and babesiosis were negative. Due to persistent anemia and fever, after 25 days of hospitalization additional blood smears were taken. Babesial protozoa were found. Initial treatment was with azithromycin and atovaquone and then altered to clindamycin, quinine, and doxycycline. After 7 days symptoms resolved and blood smear was negative, and after 3 more days of treatment she was discharged. Ten days later she was readmitted with similar but more severe symptoms. Blood smears showed babesial infection. Treatment was resumed but the organisms did not respond to any drug course utilized. Severe lung edema, sepsis, and multiorgan failure followed over the next six weeks until death occurred.

The opinion of researchers who reviewed that case is that a longer duration of therapy would have prevented a recrudescence of the disease. However, due to CDC guidelines only a 7- to 10-day course of therapy was pursued. As the researchers note, “In this case relapse was most likely associated with delayed clearance of parasitemia, which has been observed in a substantial portion of treated patients” (Florescu et al. 2008).

Given that some 40 to 50 percent of those treated with the standard pharmaceutical regimens show relapses, a more responsible treatment regimen would entail at minimum 30 days of drug therapy.

OTHER USEFUL DRUGS

Heparin is emerging as a possible adjunct to the common pharmaceutical treatments for Babesia infection. For severe babesiosis it should be considered, especially during infection with cerebral impacts. It has a number of relevant actions for treating the disease. It inhibits blood coagulation, suppresses replication of the parasites, and significantly decreases the penetration of red blood cells by the organisms. Heparin has been successfully used in the treatment of cerebral malaria infections and found to be effective in vitro and in vivo for Babesia. Also of note:

In those in whom infection is severe, a complete transfusion of the blood has been used, sometimes successfully.