5
Ehrlichia and Anaplasma
An Overview
Human monocytotropic ehrlichiosis was first reported in the United States in 1987, but during the ensuing 20 years it has become the most prevalent life-threatening tick born disease in the US.
N. ISMAIL, K. C. BLOCH, AND J. W. MCBRIDE, “HUMAN EHRLICHIOSIS AND ANAPLASMOSIS”
The incidence is likely underestimated since active surveillance studies performed in HME-endemic areas in Missouri, Tennessee, and Georgia have revealed an incidence 10–100 times higher than reported by passive surveillance.
INSTITUTE OF MEDICINE (U.S.) COMMITTEE ON
LYME DISEASE AND OTHER TICK-BORNE DISEASES,
CRITICAL NEEDS AND GAPS IN UNDERSTANDING
PREVENTION, AMELIORATION, AND RESOLUTION
OF LYME AND OTHER TICK-BORNE DISEASES
Not only are these pathogens new to science, but their maintenance in nature requires the complex interactions of tick vectors and vertebrate hosts that are sensitive to environmental influences that can drive epidemics. . . . Reports of severe and fatal ehrlichiosis . . . will increase as an unavoidable consequence of environmental forces that increase the risk of exposure to these pathogens, coupled with dramatic changes in human demography.
C. D. PADDOCK AND J. E. CHILDS, “EHRLICHIA CHAFFEENSIS”
Ehrlichia and Anaplasma spp. are closely related bacteria that are infecting increasing numbers of people each year. Most people haven’t heard of them, though, including many physicians. They are still relatively new to our human world . . . and our awareness. Like many organisms in the Lyme group, we have barely begun to learn anything about them. As Christopher Paddock and James Childs (2003) comment:
In April 1986, a medical intern scanning the peripheral blood smear of a severely ill man with an unexplained illness observed peculiar intracytoplasmic inclusions in several of the patient’s monocytes. The patient described multiple tick bites sustained approximately 2 weeks earlier during a visit to a rural area in northern Arkansas . . .
It was not until 1991, five years later, that those bacteria were identified as a unique Ehrlichia species, a genus believed at the time to be limited to veterinary infections. As Paddock and Childs continue:
During this interval, surveillance efforts identified several hundred cases of moderate to severe, and occasionally fatal, ehrlichiosis in patients with unexplained illnesses following tick exposures. These findings indicated that ehrlichiosis was a widespread and significant public health problem of increasing but undefined magnitude.
Further research found that those early infections were only the first, shy indicators of a substantial problem. It soon became clear that the infections were widespread and were in fact caused by a number of similar organisms, not just one. As Paddock and Childs continue:
During the 1990s, two additional Ehrlichia spp., Anaplasma (formerly Ehrlichia) phagocytophila (the agent of human granulocytic ehrlichiosis [HGE]) and E. ewingii (a cause of granulocytic ehrlichiosis in dogs), were identified as human pathogens, and these reports greatly expanded the geographic region and the size of the human population at risk for acquiring one of these potentially lethal infections.
Nor were these infections limited to the United States. As researcher Heather Stevenson (2009) observes, “The incidence of ehrlichial species throughout the world has been increasing with recent identification of cases being reported in Mexico (1999), Brazil (2004), Spain (2004), France (2007), Africa (2005), Netherlands (2006), Russia (2001), and Thailand (1997).”
In fact, the more deeply the diseases were examined, the more pervasive they were found to be. New species and genotypes in the genus continue to emerge and species not formerly thought to infect humans in fact do so. Completely unknown 20 years ago, this group of infections is now one of the most serious worldwide. Treatment failures are common and there are few alternatives (in the medical community) to conventional pharmaceuticals when they fail.
THE ANAPLASMATACEAE
The two most common infectious species among the Ehrlichia group of bacteria—and the ones causing the most concern within the Lyme community—are in two different genera, Ehrlichia and Anaplasma. The one most commonly heard of is Ehrlichia chaffeensis, the other is its close cousin Anaplasma phagocytophilum.
Both of these organisms are in the family Anaplasmataceae, the members of which are bacteria, not protozoa (thank god). They are part of the Proteobacteria phylum (meaning a tribe or clan—the next level up from a family), all of whom are Gram-negative bacteria. Gram-negative bacteria (so called because they refuse to take a Gram stain—I can’t help but like them for that), as opposed to Gram-positive, have a double cell wall, making them less susceptible to antibacterial and environmental damage. Medically, the Gram-negative group tend to be tougher to treat.
Unfortunately, due to the spread of infectious taxonomitis among scientists and researchers, the taxonomy of this family and genera is in flux. (Something that is apparently true for every life form on this planet.) Until 2001, the genus Ehrlichia appeared well defined; nevertheless, as taxonomitis spread further among the human population, it, too, suffered meddling. The Ehrlichia group has now been split into three closely related but very distinct genera: Ehrlichia, Anaplasma, and Neorickettsia. All are still in the Anaplasmataceae family. Other genera in that family include Aegyptianella (known to only infect birds at this point), Wolbachia (which does infect people), and a very new (as of 2013), sixth genus, Neoehrlichia, that also infects people from time to time.
Neorickettsia, Neoehrlichia, and Wolbachia
Neorickettsia has four species (so far) within it, all transmitted by trematodes in fish. The known species are N. sennetsu (infects people, four genotypes of this species exist), N. risticii (Potomac horse fever, infects horses), N. helminthoeca (salmon poisoning disease, infects dogs), and N. elokominica (salmon poisoning disease, infects dogs, bears, racoons, and ferrets). N. sennetsu is believed (though not confirmed) to only be carried by trematodes in fish, the usual source of infection. It is generally contracted by eating undercooked fish and is primarily found in Japan and Malaysia. (I am not going to deal with it in this book.)
The new genus, Neoehrlichia, contains one member so far, N. mikurensis (which I am not going to cover herein). It is considered an emerging pathogen for people in Europe, Asia, and Africa. Similarly to Ehrlichia ruminantium, these bacteria tend to infect the endothelium, especially in the liver and spleen.
The Wolbachia (and no, I am not going to deal with these either) infect a wide range of insects, including nematodes, mosquitoes, and, occasionally, ticks. Up to 70 percent of all insects are considered to be potential hosts for the organisms. The primary diseases caused by this genus in humans are elephantiasis and river blindness (generally in Africa) and, in dogs, heartworm.
The Ehrlichia Genus
The Ehrlichia, as of 2014, contains seven species known to researchers: E. canis, E. ewingii, E. chaffeensis, E. muris, E. ruminantium, E. mineirensis (a new species found in 2011 in Brazil that blends genome structures from both E. canis and E. chaffeensis), and a new species with some similarities to E. muris (but not yet formally named) that was discovered to be infecting people in the Wisconsin/Minnesota area in 2009. (Hence its temporary designation as Ehrlichia muris-like or EML.) Five of the species are known to infect people, the exceptions being E. muris and E. mineirensis. However (just an FYI), people with antibodies to E. muris have been found in Japan, indicating previous infection by that species. Many researchers (and physicians) still insist that E. ruminantium does not infect people. However, a number of peer-review journals reveal it to be an emerging pathogen in Africa, especially in children. It is almost invariably fatal. (As is usual in the United States, the CDC information on the organisms, and the diseases they cause, is unreliable.)
Like most of the Lyme group, the Ehrlichia genus is undergoing rapid genetic alteration in response to environmental pressures. Each ehrlichial species has been found to generate multiple genotypes; at least 21 different genetic variants of E. chaffeensis have been identified to date. This is beginning to alter how the organisms in this genus are referred to. For example, because of the continuing emergence of new and distinct genotypes among E. muris and E. canis, some researchers now refer to these species as the E. muris group and the E.canis group. (A new, possibly human-infectious member of the E. canis group, for example, is Ehrlichia sp. AvBat discovered in France in 2010.) Because of this, it is probably more accurate to refer to E. chaffeensis, as well, as the E. chaffeensis group.
The genetic recombination that is occurring among these bacteria and the presence of such a large number of distinct genotypes makes pharmaceutical treatment more difficult and failures more common. (There is a reason they call these second-generation or stealth pathogens.) The Ehrlichia are, in fact, a potent emerging pathogenic group and more extensive spread throughout the human community is inevitable. Researchers at Columbia University comment:
Since that [first report of a human infection in 1987], the number of case reports has grown fairly steadily and currently stands at around 500 per year. Although ehrlichiosis is a nationally reportable disease, reporting is passive, and the true incidence of Ehrlichia infection is thus assumed to be significantly higher. This suspicion is bolstered by the high rates of background seroprevalence (~12–15%) in endemic areas, a finding that also indicates that many infections are mild and self-limiting or asymptomatic. (Columbia University Medical Center, n.d.)
In fact, in-depth research indicates that the true incidence is anywhere from 10 to 100 times greater than reported infections. In other words, at minimum 5,000 infections are occurring per year and perhaps as many as 50,000. Since the majority of infections are self-limiting, most people just think they are having a bout of the flu.
The Anaplasma Genus
The Anaplasma group includes at least eight species: A. marginale, A. centrale, A. mesaeterum, A. ovis, A. platys, A. bovis, A. caudatum, and A. phagocytophilum, though there are probably many more. (Two unnamed species were recently identified in African elands.) Most of these organisms infect red blood cells (though A. platys infects platelets). A. phagocytophilum, the primary organism that infects people, instead infects white blood cells, not red.
The other Anaplasma species can sometimes infect people (A. ovis is an example). These infections are (herbally) treated similarly to babesiosis and with the same pharmaceuticals used for ehrlichiosis, i.e., doxycycline. (And, no, I am not going to deal with these other Anaplasma here either.)
As with ehrlichial infections, anaplasmosis is relatively new to physicians. The first case of infection by A. phagocytophilum was not encountered until 1990 (in Wisconsin . . . again). While thought at first to be a newly emerging Ehrlichia species, after examination the bacteria were found to possess distinct differences. A deeper look found them to be very similar to two known veterinary pathogens, Ehrlichia equi and E. phagocytophila. After a lot of DNA analysis, the three pathogens were eventually determined to be one organism and combined under one rubric as Anaplasma phagocytophilum. Despite its later discovery, cases of anaplasmosis now outnumber those of ehrlichiosis in the United States.
Similarly to the Ehrlichia, anaplasmal organisms are undergoing tremendous genetic recombination; over 130 genotypes of A. marginale have been described so far. A. phagocytophilum also shows a massive tendency to create new genotypes; the bacteria possess a high capacity for genetic diversity.
TRANSMISSION
Both Ehrlichia chaffeensis and Anaplasma phagocytophilum are transmitted by ticks, most commonly hard ticks. Unfortunately, as with most of the Lyme group, little research has been done on soft ticks (or other arthropods) as a vector. This, it turns out, is in fact a problem, since soft-tick transmission does occur in mammals and, in consequence, may occur in people.
Ehrlichia spp. have been found in soft ticks such as Argas vespertilionis (as have various Borrelia and Rickettsia) and transmission to mammals (bats) has been documented. As Socolovschi et al. (2012) note, “The findings from our study have repercussions for public health in many parts of Europe, Asia, and Africa because A. vespertilionis ticks have a wide geographic range and may bite humans.” In fact, that species of soft tick, as they comment, “can be highly aggressive toward humans” and infections from soft-tick bites (with symptoms similar to those from the Lyme group) have been documented in people—though no analysis of the infectious agents was performed.
There is emerging evidence that Ehrlichia and Anaplasma may be transmitted by fleas. Both organisms are commonly found in cats and dogs (up to 60 percent of those tested in some studies) and are widespread in foxes and other wild mammals. Testing of fleas from pathogen-positive species has found them to be infected by both types of bacteria. Studies of dogs and their owners in a number of locations has found that some owners are seropositive for the same Ehrlichia canis genotype as that of their dogs, indicating that transmission occurred from the pet to the owner. Whether such transmission is via fleas or direct has not yet been determined. Again, the research on these organisms is very new.
Ehrlichia Transmission
Ehrlichia chaffeensis is, most commonly, transmitted by two tick species in the United States. The first, Amblyomma americanum, the Lone Star tick, ranges from west-central Texas, north to Iowa, and eastward in a broad range spanning the southeastern United States. It extends, as well, northward along the Atlantic coast through the coastal areas of New England. These particular ticks are relatively nonspecific in their feeding habits (they bite anything at all when they are hungry) and are, as researchers put it, “notorious” for their aggressive behavior when hungry. Studies in 15 states have found that between 5 and 15 percent of all A. americanum ticks tested are positive for ehrlichial bacteria.
Ixodes scapularis, the other major vector, has nearly the same range though it extends farther north into Michigan, Wisconsin, Minnesota, and Canada. Ixodes ticks such as this one are common carriers of Lyme-group infections. For example, Ixodes pacificus (the Western black-legged tick) is responsible for many of the Lyme-group infections in the western United States while Ixodes ricinus (the castor bean tick) spreads the group throughout Europe, Iceland, Russia, North Africa, and the Middle East. All members of this genus carry ehrlichial organisms and can spread the disease.
Nevertheless, ehrlichial tranmission is not limited to that genus; many other species of hard ticks are known to carry the organisms. They have been found throughout the various, most common genera of hard ticks: Amblyomma, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, and Rhipicephalus. These genera are common worldwide; so is ehrlichiosis.
Ehrlichial organisms have also been transmitted through transfusion and organ transplantation. Blood transfusion transmission is considered to be an increasingly serious problem as the organism is not generally (in 2014) tested for. Eleven percent of blood donors in New York State have tested positive for Ehrlichia, as have 3.5 percent in Connecticut, and 0.5 percent in Wisconsin.
Previous infection seems to be the norm throughout Lyme-endemic areas as antibodies to ehrlichial organisms are rather common. Studies have found that 0.4 percent of tested adults in northern California have positive antibodies to ehrlichial organisms, as do 3.4 percent in New York State, and 15 percent in Wisconsin. However, even these figures could be too low, as Ismail et al. (2010) note:
The true incidence of human infection with E. chaffeensis is likely to be much higher [than current estimates and studies show], as two-thirds of the infections are either asymptomatic or minimally symptomatic. A seroprevalence study found that 20% of the children residing in endemic areas had detectable antibody to E. chaffeensis, without prior history of clinical disease.
Anaplasmal bacteria have been transmitted through a wider range of routes (see below) than are currently known for the ehrlichial. Suspicion exists that these other routes of transmission are occurring for the Ehrlichia genus as well.
Anaplasma Transmission
Anaplasma phagocytophilum is most commonly transmitted by Ixodes scapularis in the northeast United States; however, as with Ehrlichia chaffeensis the range of genera (and species) that can, and do, carry the organism is much broader. Specifically: Ixodes, Dermacentor, Rhipicephalus, Haemaphysalis, and Amblyomma genera have all been found to harbor the bacteria. (As an aside, similarly to the babesial protozoa, the A. phagocytophilum bacteria induce the expression of an antifreeze glycoprotein in all ticks infected by them. This enhances the ticks’ ability to survive cold winters.)
In Europe the main vector for A. phagocytophilum is Ixodes ricinus. In southern Europe, northern Africa, and India it is Rhipicephalus sanguineus. In eastern Europe and Asia it is Ixodes persulcatus. Ixodes pacificus carries it in the western United States and Canada. And still other species in the genus Haemaphysalis carry the bacteria in Japan, India, Russia, China, Korea, Thailand, and North America. Anaplasmal organisms can infect Lone Star ticks but appear to do so with much less frequency than Ehrlichia.
As with ehrlichial infections, anaplasmosis is often asymptomatic or merely presents as a minor case of the flu. Studies in Europe have found that up to 15 percent of the general populace have antibodies to the bacteria; on the island of Crete it is 24 percent. Seroprevalence studies in the United States show high rates as well, as much as 15 percent in Wisconsin.
Person-to-person transmission of anaplasmal organisms has been documented: 1) to hospital staff via contact with patient blood; 2) through respiratory secretions to family members; and 3) to hospital patients through blood transfusion and bone marrow transfer. Developing infants in the womb have contracted the disease from their mothers and, in one instance, transmission through breast milk is suspected. Transmission to hunters while cleaning carcasses, via deer blood, is strongly suspected in three cases.
HUMAN INFECTION AND SYMPTOMS
Despite the fact that most genera of hard ticks can carry these organisms, infections in the United States tend to congregate in certain geographic locations. Most human infection with E. chaffeensis (commonly known as human monocytic ehrlichiosis or HME) occurs in the south, south-central, and southeast states. Infection with Anaplasma phagocytophilum (known as human granulocytic anaplasmosis or HGA) occurs primarily in the northeast and north states. E. ewingii infection (known as human ewingii ehrlichiosis or HEE) is, at this point, still relatively rare. (Similarly to A. phagocytophilum, Ehrlichia ewingii infects neutrophils rather than monocytes. Treatment would be the same as that for anaplasmosis.) The majority of infections tend to be self-limiting, mimicking a bout of the flu. Onset generally occurs within 5 to 21 days after tick bite. Most people do not seek treatment and the disease tends to clear on its own. A few people develop a relapsing form of the disease or can’t clear it and seek medical help. HME and HGA, as researchers comment,
have similar clinical presentations including fever, headache, leukopenia, thrombocytopenia and elevated liver enzymes. Symptoms typically begin a median of 9 days following tick bite, with the majority of patients seeking medical attention within the first 4 days of treatment. (Ismail et al. 2010)
Still, there are some significant differences. HME is more common in the south and southeast, HGA more common in the typical Lyme-endemic areas of the country. HME is generally a bit more serious; some 48 percent of those infected need hospitalization with around 17 percent experiencing life-threatening complications. More people with HME infections have serious neurological symptoms than those with HGA and it is more commonly fatal (about 3 percent total). Around 36 percent of those with anapasmal infections are hospitalized, and less than 1 percent die. While HGA is, in general, a more benign disease, both HGA and HME can, under some circumstances, progress to a fatal septic shock type of infection.
Once the bacteria enter the host tissues, they are spread by the blood and lymph system throughout the body. Infected cells seek out protected niches in fixed macrophages in numerous sites, including the bone marrow, spleen, lymph nodes, and hepatic sinusoids. There are varying populations also to be found in the meninges, brain, lungs, kidneys, GI tract, and heart.
Infections with either organism can be followed by a subclinical phase that lasts months or even years. The subclinical phase can become chronic, with recurrent mild or severe episodes of the initial primary symptoms.
HME
HME infections are more common throughout the South and Southeast and in Texas, Missouri, Kentucky, Tennessee, North Carolina, and Arkansas. The bacteria actively infect several specific white blood cell types, most commonly monocytes and macrophages, hence the infection’s designation as human monocytic ehrlichiosis. Still, the bacteria can infect a much wider range of cells if they wish: lymphocytes, atypical lymphocytes, promyelocytes, metamyelocytes, endothelial cells, eosinophils, and neutrophils. The general symptoms accompanying HME (and their relative percentages in those infected) are:
| Fever | 97% |
| Headache | 81% |
| Myalgia | 68% |
| Nausea | 48% |
| Arthralgia | 41% |
| Vomiting | 37% |
| Rash | 36% |
| Cough | 26% |
| Pharyngitis | 26% |
| Diarrhea | 25% |
| Lymphadenopathy | 25% |
| Abdominal pain | 22% |
| Confusion | 20% |
Chills, shaking, night sweats, and low back pain are commonly reported. Skin eruptions occur more frequently in children than in adults, with around 66 percent exhibiting them. Rashes can be maculopapular (a flat red rash with small raised bumps), petechial (pinpoint round spots—red, brown, or purple—on the skin due to bleeding just under the surface), or a diffuse erythroderma (patchy red blotches with scaling); it is rarely on the face, palms, or soles of the feet. Abdominal pain can sometimes be so severe it mimics appendicitis. Men are more often infected than women (no one knows why, but there is a joke in there somewhere), generally by a 2:1 ratio.
The most frequent neurological problems are meningitis and meningoencephalitis. Around 20 percent of those infected have more extensive central nervous system involvement; in severe cases seizures and coma can occur. Cranial nerve palsy is sometimes reported, almost always after antimicrobial therapy (successful or not—this is one of the common side effects of antibiotics with this disease). Long-term problems in children include cognitive delays, fine motor impairment, and persistent foot drop. In adults, self-reported neurocognitive deficits are moderately common. Delays in treatment are associated with more pulmonary complications, transfer to intensive care, and longer duration of treatment.
During severe disease, interstitial pneumonia, hepatic dysfunction, aseptic meningitis, and hemorrhages can occur. This can lead, in fatal disease, to a toxic shock–like syndrome, severe tissue damage, and ultimately multisystem organ failure. The liver is the most impacted of all the organs, though the spleen, lungs, and kidneys can be similarly impacted.
Severe infections occur most readily in those over 50, those with immune disease (HIV), and those on immunosuppressive drugs. Still, the immunocompetent are frequently reported to experience severe HME. As with most of the Lyme group the severity of infection is directly proportional to the health of the immune system.
HGA
Anaplasmal organisms generally infect polymorphonuclear leukocytes (neutrophils), a different type of white blood cell than that infected during HME. These white blood cells have granules or secretory vesicles inside them so they are sometimes referred to as neutrophil granulocytes, hence the disease’s designation as human granulocytic anaplasmosis or HGA. (However, the bacteria do infect other cells, e.g., neutrophil and monocyte progenitors in bone marrow such as CD34+ and CD14+ cells, endothelial cells, fibroblasts, eosinophils, and mononuclear phagocytes.) Although infection with these bacteria does occur throughout the United States, it is most common in the upper midwestern and northeastern states and northern California. Most infections are reported in New York, Connecticut, New Jersey, Rhode Island, and Wisconsin (again). Nearly all infections are with one specific species, Anaplasma phagocytophilum (though other Anaplasma species—an A. ovis variant, for example—can sometimes infect people). The symptoms of HGA infections, again, are similar to those of HME:
| Fever | 97% |
| Headache | 81% |
| Myalgia | 68% |
| Nausea | 48% |
| Arthralgia | 41% |
| Vomiting | 37% |
| Cough | 26% |
| Pharyngitis | 26% |
| Diarrhea | 25% |
| Lymphadenopathy | 25% |
| Abdominal pain | 22% |
| Confusion | 20% |
| Rash | 6% |
As with HME, men are much more likely to be infected than women (also again, no one knows why) by a ratio (again) of 2:1 (sexism). The usual symptoms of infection are flu-like, nonspecific febrile illness accompanied by high-grade fever, rigors, generalized myalgias, severe headache, chills, dizziness, malaise, and fatigue. As with ehrlichiosis, leukopenia (low white blood cell count), thrombocytopenia (decreased platelet count, blood does not clot properly, easy bruising), and elevations in transaminases are common during HGA infections. Central nervous system involvement is much less common than with HME (less than 1 percent of those infected); however, peripheral nervous system impacts are often reported. Such peripheral manifestations include brachial plexopathy, cranial nerve palsies, demyelinating polyneuropathy, and bilateral facial nerve palsy. It often takes several months for the conditions to improve. Less common symptoms are anorexia, arthralgias, nausea, unproductive cough, and rash.
During severe infections prolonged fever, hepatitis, cholestasis, myocarditis and cardiomegaly (abnormal enlargement of the heart), interstitial pneumonitis, adult respiratory distress syndrome, acute renal failure, gastrointestinal bleeding, rhabdomyolysis (muscle cell destruction), respiratory insufficiency, intravascular coagulation, seizures, and coma have all been noted. In fatal disease a toxic shock–like syndrome occurs, accompanied by severe tissue damage and ultimately multisystem organ failure. The bone marrow, red blood cells, liver, spleen and lymph system, and lungs are the most commonly impacted organs and tissues.
As with HME, severe infections occur most readily in those over 50, those with immune disease (HIV), and those on immunosuppressive drugs. Still, the immunocompetent are frequently reported to experience severe infections of HME. As with most of the Lyme group the severity of infection is directly proportional to the health of the immune system.
DIAGNOSIS
Diagnosis of HME and HGA is often difficult due to the relative newness of the organisms to physicians—misdiagnosis is common. Both conditions generally present at early onset with fever, headache, myalgia, and malaise. The usual flu-like symptom picture.
Despite the commonness of misdiagnosis, both HME and HGA infections possess a fairly unique, and rather definitive, profile, specifically: 90 percent of infections show elevated AST and 84 percent elevated ALT. Thrombocytopenia occurs in 73 percent, leukopenia in 72 percent, and anemia in 55 percent.
In other words, if a patient presents with flu-like symptoms accompanied by two or more of elevated liver enzymes, thrombocytopenia, leukopenia, and anemia, differential diagnosis indicates either HGA or HME.
Among children a mild hyponatremia (low sodium levels in the blood) occurs in around 50 percent.
Acute infections can be accompanied by a number of abnormalities depending on the organ involved. Specifically: increased creatinine, lactate dehydrogenase, creatine phosphokinase, and amylase levels; electrolyte abnormalities such as hypocalcemia, hypomagnesemia, and hypophosphatemia; prolonged prothrombin times; increased levels of fibrin degradation products; metabolic acidosis; hypotension; disseminated intravascular coagulopathy; adrenal insufficiency; myocardial dysfunction; and hepatic and renal failure.
The clinical symptoms for hospitalization include immune impairment, pain requiring management, confusion, abnormal spinal fluid, infiltrates on chest radiographs, hypotension, shock, or acute organ failure.
As an initial diagnostic finding, history of tick exposure is often inconclusive since many people don’t notice the tick bite. And other than initial flu-like symptoms, early infection has few signs. As well, a reliance on residence in an endemic area is inconclusive and should not be definitively relied upon. Infection can occur in nearly every state in the United States. Hence . . .
It is malpractice for a physician to definitively state that a person cannot possibly be infected with a pathogen from the Lyme group because of where they live, especially if this is followed by the physician’s refusal to test after testing is specifically requested. Unfortunately, scores of people report having had this experience with their physicians. Most of them subsequently suffered years of progressively worsening illness that could have been avoided by competent medical care.
A note to those who are ill: remember, you are paying them, they are not paying you. In other words, physicians, despite their reluctance to recognize the fact, work for you; you do not work for them. You are not lucky to have gotten an appointment, they are lucky that you made one. You are the one that is ill; they are there to serve you and they need to be reminded of that, every day of their careers. Do not allow them to redefine the relationship otherwise.
TESTING
The most common diagnostic tests are the following.
Blood Smears
Microscopic examination of Wright’s, Diff-Quik, or Giemsa stains of peripheral blood smears. These look for dark staining morulae (bacterial inclusions) within either monocytes and neutrophils. Unfortunately, very low bacterial burdens are common during these infections. In many instances only 0.1 to 0.2 percent of cells may be infected, which would demand the inspection of 500 to 1,000 cells to find one containing the bacteria. As Thomas, Dumler, and Carlyon (2009) comment:
A limitation of this assay is that it requires a well-trained microscopist. For instance, prolonged examination is often required to accurately detect A. phagocytophilum morulae, as they can be present in less than 0.1% of neutrophils.
Determination of the presence of infection relies on the microscopist. However, they often miss the inclusions, not only because of low parasite density, but also because the inclusions are similar to many common intracellular inclusions and blood smear artifacts. This can include such things as crystal stain artifacts, bacterial contamination of the stain solutions, Döhle bodies, and toxic granulation and platelets overlying leukocytes. As Dawson et al. (2001) comment, “These obligate intracellular bacteria are extremely difficult to detect upon routine examination of blood smears or hematoxylin and eosin (HE)-stained tissues.” As they continue, “We often failed to identify morulae unequivocally in HE-stained sections where antigen, as determined by IHC, was abundant. Therefore, routine HE staining should not be used to exclude a diagnosis.”
Sensitivity for this approach to testing is highest during the first week of infection—again a problem, as symptoms may not show for up to three weeks.
PCR Assay
PCR assay runs 60 to 85 percent effective for ehrlichial organisms and 70 to 90 percent accurate for anaplasmal. This is the best test for both HME and HGA. Unfortunately, there is a limited availability of rapid diagnostic tests such as PCR for these diseases so many physicians do not utilize it.
Serological Testing (IFA)
Serological testing (IFA) for antibodies is a common testing approach, but both IgG and IgM are negative in as many as 80 percent of people during the first week of infection. As Dawson et al. (2001) comment, “Many, if not most, E. chaffeensis-infected patients who present early in the course of the disease may be missed by serologic methods due to lack of detectable antibody.” Additionally, there is a fairly high rate of false positives, usually from cross-reactive antibodies. Failure to seroconvert occurs in a number of instances due to immune impairment. Early treatment with tetracyclines can abrogate the antibody responses.
Immunohistochemistry (IHC)
Immunohistochemistry or IHC is a rarely used test (for these bacteria) that acts to detect antigens in cells in tissue sections. It looks for antibodies that are bound to antigens in tissues. IHC is, in fact, a very good diagnostic test for both anaplasmal and ehrlichial infections. As Dawson et al. (2001) comment,
All tissue blocks from all cases were positive for IHC, establishing the IHC technique as a sensitive diagnostic tool. Similarly, a recently published IHC study demonstrated that the granulocytotropic ehrlichiosis agent infects many tissues. The greatest number of [them] were seen in the spleen, lung, and liver [and bone marrow]. . . . E. chaffeensis antigens were consistently seen in mononuclear phagocytotic cells in the spleen, lymph nodes, bone marrow, lung, and liver.”
Tissue samples from the spleen, lymph nodes, bone marrow, and liver are, as they note, “excellent tissues for confirmation” of infection by these agents.
The most effective diagnostic approach is differential diagnosis accompanied by all four tests.
TREATMENT
Ehrlichial and anaplasmal bacteria are resistant to most antibiotics: aminoglycosides (gentamicin), fluoroquinolones (cipro), beta-lactams (penicillins), macrolides and ketolides (erythromycin and telithromycin), and sulfa-containing drugs (co-trimoxazole). They do respond well to tetracyclines, especially doxycycline (100 mg 2x daily for 10 to 14 days, or 30 days, or for 3 days postfever according to various sources). Note: Ehrlichial bacteria have been reisolated from both blood and tissues in animals after doxycycline treatment that was of too short a duration, i.e., less than 14 days. This is why a number of journal papers now recommend a minimum of 30 days of treatment with at least 3 days of postfever intake.
If doxycycline can’t be used, rifampin (300 mg 2x daily for 10 to 14 days, or 30 days, or 3 days postfever, same sources) is an effective alternative. Chloramphenicol has also been used successfully in a few cases despite the fact that in vitro testing appears to show it to be ineffective. Levofloxacin has shown effectiveness in vitro but mixed results in practice. Its use in at least one case merely suppressed the bacteria; it did not clear them. Some evidence exists that a combination of doxycycline and chloroquine stimulates a much more rapid and healthier recovery from infection. Paclitaxel has also been found to be active in preventing monocyte penetration by ehrlichial species.
Note: Corticosteroid treatment during undiagnosed HME or those subsequently infected by the bacteria is associated with a much greater risk of mortality. There is also some evidence that infection with either of these organisms concomitant with statin use may, in some circumstances, stimulate rhabdomyolysis-induced acute kidney injury.