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Diagnosis and Treatment of Four Tickborne Diseases

Lyme disease, Ehrlichiosis, Anaplasmosis and Babesiosis

Infectious Disease and Emergency Medicine

Continuing Medical Education

Eligible for CME Credit


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Larva, Nymph, adult male and female Ixodes scapularis ticks AKA blacklegged or deer ticks
[1] (L to R) Larva, Nymph, adult male and female Ixodes scapularis ticks (AKA blacklegged or deer ticks) on a dime


This article explores the diagnosis and treatment of four tick borne illnesses: Lyme disease, ehrlichiosis, anaplasmosis and babesiosis. Diagnosis can be challenging, as the tick bite may not have been noticed, clinical symptoms may be non-specific, and laboratory confirmation of infection can be problematic, especially early in the course of these diseases. At times clinicians may need to treat on clinical suspicion alone.

map of Anaplasmosis, Babesiosis, Lyme, and Ehrlichiosis ticks

Lyme Disease

Although there are only about 30,000 cases of Lyme disease reported to the CDC per year, the CDC estimates the actual total is about 476,000 cases per year in the United States.[2]


As can be seen on the map below, most cases of Lyme disease occur in the Mid-Atlantic states, New England and the Midwest, although there is significant distribution around the country. The geographic distribution of the three other tickborne infections under discussion can also be seen below.


Tick Life Cycle and Infection Transmission


Lyme disease is a tick transmitted disease, with protean manifestations, usually caused by the spirochete, Borrelia burgdorferi, although it can rarely be caused by Borrelia mayonii.


Ticks go through four life stages: egg, six-legged larva, eight-legged nymph, and adult. After hatching from the eggs, ticks must eat blood to survive. Ticks can take up to 3 years to complete their full life cycle, although the Ixodes scapularis tick, also known as the blacklegged or deer tick, that typically spreads Lyme disease has a 2-year life cycle. Most nymph infections occur in the spring and summer, with adult tick caused infections typically occurring during the cooler months. Nymph ticks are much harder to detect, as they are typically less than 2 mm in size, and may be more likely to feed unnoticed, as opposed to an adult tick.[4] For Lyme disease to occur, the tick needs to be attached for a significant time, typically 36-48 hours before an infection can be transmitted.[5] The more engorged the tick the higher the likelihood of an infection being transmitted.


Most tick bites do not result in Lyme disease infections. In some studies, only 2% to 3% of people bitten by ticks in endemic areas actually contract Lyme disease.[6,7]

Ixodes scapularis life and feeding cycle[4]
Ixodes scapularis life and feeding cycle[4]

Ticks can detect an animal’s breath and sense body odors, heat, moisture, and vibrations. Ticks can’t fly or jump, but many tick species wait in a position known as “questing” on well walked paths. When questing, ticks hold onto leaves and grass by their third and fourth pair of legs and keep their first pair of legs outstretched. When a host brushes by the tick, it climbs aboard, and either attaches quickly or goes looking for places where the skin is thinner.


Ticks transmit pathogens that cause disease through the process of feeding. When the tick finds a feeding spot, it grasps the skin and cuts into the surface. The tick then inserts its feeding tube, which may have barbs to help keep the tick in place. Many species also secrete a substance that keeps them firmly attached to the host during the meal. Tick saliva contains an anesthetic like substance, to prevent the host from feeling the attached tick. A tick will then suck the host’s blood slowly for several days. If the host animal has a bloodborne infection, the tick can ingest the pathogens and become infective. If the tick’s saliva contains a pathogen, it may enter the host animal during feeding causing an infection. After feeding, most ticks will drop off the host and move on to the next life stage.[4]



tick sizes
[4]

How to Remove a Tick

Never crush a tick with your fingers. Use fine-tipped tweezers to grasp the tick as close to the skin’s surface as possible. Pull upward with steady, even pressure. Don’t twist or jerk the tick, as this can cause the mouth-parts to break off and remain in the skin. If this happens, remove the mouth-parts with tweezers if they are easily removable. If a significant debridement is necessary, most sources recommend leaving the mouth parts in place. After removing the tick, thoroughly clean the bite area with rubbing alcohol or soap and water. Dispose of a live tick by putting it in alcohol, placing it in a sealed bag or container, wrapping it tightly in tape, or flushing it down the toilet.


Methods for tick removal that have been tried, but are not recommended include; applying a hot match or nail to the tick, covering the tick with petroleum jelly, nail polish, alcohol or gasoline, using injected or topical lidocaine, or passing a suture needle through the tick.[8,9]


Tick Removal Technique
Tick Removal Technique[8]

Should You Send the Removed Tick for Laboratory Testing?

It may be helpful diagnostically to identify which tick a patient has been bitten by, either with identification by the clinician, or sending the tick to a laboratory for identification.[10,11]


Testing if a tick is carrying B. burgdorferi is not recommended, for the following reasons:

  • Positive results showing that the tick contains a disease-causing organism do not necessarily mean that it caused an infection.

  • Negative results can lead to false assurance, as the patient may have unknowingly been bitten by another infected tick as well.

  • Clinical symptoms will typically occur prior to the test results returning.

  • Laboratories that conduct tick testing are not required to have the same standards of quality control used by clinical diagnostic laboratories, potentially leading to misdiagnosis.[10]

Lyme Disease Testing

Testing for Lyme disease is both complicated, and potentially inaccurate. Currently a 2-tier antibody assay method is the recommended testing method. This has a sensitivity of only 30%–40% during the typical 30-day window period of early infection, while the antibody response is developing. The 2-tier method does have a 70%–100% sensitivity for disseminated disease. Specificity of 2-tier testing is >95% during all stages of Lyme disease.[12]



In 2-tier Lyme disease antibody testing, a screening test is done either using an enzyme immunoassay or immunofluorescence assay. If the screening test is negative another diagnosis should be considered, or the test may have been done during the 30-day antibody window period, before enough antibody has been produced to be detected, and repeat testing may be needed later on. If the screening test is positive or equivocal, immunoglobulin G(IgG) and or immunoglobulin M(IgM) western blot tests are confirmative. If symptoms are less than 30 days both IgG and IgM western blot tests are recommended, with IgM being the acute phase antibody first produced, and IgG the later phase and longer lasting antibody. Theoretically, if symptoms have been present for over 30 days only the IgG western blot is needed, but most labs routinely test for both.[14]


The western blot is an immunoassay that allows visualization of Borrelia antibodies in specific bands. The IgM western blot is considered positive if two of three antibody bands measured are positive. An IgG western blot is positive if five of the ten antibody bands measured are positive. It is important to avoid interpreting fewer bands as evidence of infection because some of the antibodies tested for are cross-reactive with non-Borrelial antigens. Therefore, presence of one IgM band or less than five IgG bands does not indicate an overall positive result. Overinterpreting a small number of antibody bands leads to reduced specificity and potential misdiagnosis.[10,12]


Polymerase chain reaction(PCR) testing can provide highly specific evidence of B. burgdorferi nucleic acid in synovial fluid, skin biopsy tissue, blood, and cerebral spinal fluid(CSF). However, its clinical utility is limited by low sensitivity, particularly for blood and CSF samples. Studies of PCR on blood have found that its high specificity is outweighed by its lack of clinical sensitivity and potential for contamination, and as a result, PCR testing of blood or CSF for Lyme disease is not recommended.[12]


For CSF infections, obtaining simultaneous samples of CSF and serum for determination of anti-Borrelia antibodies allows for calculation of the CSF:serum antibody index. This test can differentiate between intrathecal synthesis versus passive diffusion of specific anti-Borrelia antibodies into the CSF.[10,13]

Because B.burgdorferi is a slow-growing organism and current culturing methods are labor-intensive and have poor sensitivity, culture is generally not recommended. Routine hospital blood cultures will not grow B.burgdorferi.[10]


It is not recommended to perform Lyme disease testing in asymptomatic patients after a tick bite, as an infection may be too early to detect, and even if delayed testing is done 4-6 weeks later there is insufficient evidence that patients with asymptomatic seropositivity should receive antibiotic therapy.[10]


Symptoms of Early Lyme Disease[15]

  • Possible symptoms of early Lyme disease include fever, chills, headache, fatigue, muscle and joint aches, and swollen lymph nodes.

  • A small bump or redness at the site of a tick bite that occurs immediately and resembles a mosquito bite is common. This generally goes away in 1-2 days and is not a sign of Lyme disease.

  • The erythema migrans rash occurs in approximately 70 to 80 percent of infected persons. It begins at the site of a tick bite after an average delay of 7 days but onset can range from 3 to 30 days. It typically has a bullseye appearance, but may present with central sparing or complete central involvement.[15A]


Possible Signs and Symptoms of Disseminated Lyme Disease[15]


Musculoskeletal/Rheumatological

  • Intermittent pain in tendons, muscles, joints, and bones

  • Arthritis with severe joint pain and swelling, particularly the knees and other large joints.

  • Baker’s cyst

Neurologic

  • Bell’s palsy or other cranial neuropathies

  • Headache, meningitis, or rarely encephalitis

  • Motor and sensory radiculoneuropathy, mononeuritis multiplex

  • Problems with short-term memory and cognitive problems

Cardiac

  • Lyme carditis- leading to heart block, myocarditis, or pericarditis

Dermatologic

  • Multiple erythema migrans lesions

Multiple truncal erythema migrans lesions
Multiple truncal erythema migrans lesions [17]

  • Acrodermatitis chronica atrophicans

    • A rash that can potentially be seen in chronic Lyme disease, especially on the dorsal surfaces of the hands, feet, knees, and elbows. Initially the rash is erythematous, followed by discoloration, inflammation and potentially skin atrophy.

Acrodermatitis chronica atrophicans of the hand
Acrodermatitis chronica atrophicans of the hand [18]
  • Borrelial lymphocytoma

    • Borrelial lymphocytoma is an uncommon manifestation of early disseminated Lyme disease reported only in Europe, possibly due to infection by other Borrelia strains more common there. It is a bluish-red nodular swelling that typically occurs on the ear lobe in children, or on the breast in adults.

Borrelial lymphocytoma of the earlobe
Borrelial lymphocytoma of the earlobe [19]

Recommended Treatment for Lyme Disease Antibiotic Prophylaxis

Prophylactic antibiotic therapy is recommended for adults and children within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal or low risk.


One meta-analysis concluded that there was a 2.2% chance of getting Lyme disease in untreated patients, compared to 0.2% infection rate in the antibiotic prophylaxis group.[21] A prospective study of prophylactic antibiotics after tick bites found a 3.2% infection rate in the placebo group and a 0.4% infection rate in the antibiotic prophylaxis group.[22]


A tick bite is considered to be high-risk only if it meets these three criteria:

  1. The tick bite was from an identified Ixodes vector species.

  2. The tick bite occurred in a highly endemic area

  3. The tick was attached for ≥36 hours. The duration of tick attachment is an important predictor of subsequent Lyme disease. Unfed or flat recently attached ticks do not pose a significant risk for Lyme disease. The likelihood of transmission increases with the duration of attachment and the majority of transmission occurs after 36–48 hours of attachment.[10]


Nymphal Blacklegged Tick After Feeding
Nymphal Blacklegged Tick After Feeding [22]

For high-risk tick bites in all age groups, a single dose of oral doxycycline within 72 hours of tick removal is recommended. Doxycycline is given as a single oral dose, 200 mg for adults and 4.4 mg/kg (up to a maximum dose of 200 mg) for children. There is no study of the efficacy of doxycycline in children under 12 years of age and the parents should understand that monitoring for symptoms and signs is important.

Doxycycline is contraindicated in pregnancy, and the recommendation for tick bites during pregnancy most commonly is watchful waiting and treating if Lyme disease occurs, rather than using prophylaxis. Amoxicillin in a 10-day course might work for prophylaxis in the pregnant patient, but is not recommended because the frequency of adverse reactions is higher than the Lyme disease cases it prevents.[23] The latest Lyme disease prophylaxis during pregnancy recommendation of 3 different professional societies, which includes the Infectious Diseases Society of America is this: “Because of uncertainty about the safety of doxycycline in pregnancy, we advise pregnant women to have an informed discussion with their physicians about the risks, benefits, and uncertainties of antibiotic treatment versus observation.”[10]


Please note that while amoxicillin and cefuroxime are not recommended currently for prophylaxis, due to a lack of data, they can be used for treatment of early Lyme disease.


Recommended Treatment of Erythema Migrans Rash/Early Lyme Disease


Doxycycline, amoxicillin, or cefuroxime are recommended as treatment for erythema migrans rash/early Lyme disease. The dosage and duration are listed in the table below.


NOTE: For people intolerant of amoxicillin, doxycycline, and cefuroxime, the macrolides azithromycin, clarithromycin, or erythromycin may be used, although they have a lower efficacy. People treated with macrolides should be closely monitored to ensure that symptoms resolve.

[24]


Additional considerations for treating erythema migrans rash/early Lyme disease include:

  • In the pregnant patient or woman who wants to continue breast feeding, amoxicillin would be the first drug of choice.

  • In infants and children, amoxicillin or cefuroxime can be used to avoid the use of doxycycline.[10]

  • If azithromycin is used, the indicated duration is 5–10 days, with a 7-day course being the most common one prescribed most commonly [10].

  • In patients with acrodermatitis chronica atrophicans, oral antibiotic therapy for 21–28 days is recommended.[12]

  • In patients with borrelial lymphocytoma, oral antibiotic therapy for 14 days is recommended.[10]

  • Coinfection should be investigated in patients who have a persistent fever while on antibiotic treatment for Lyme disease. If fever persists despite treatment with doxycycline, Babesia microti infection is an important consideration.[10]

For more information on the CDC recommended antibiotic regimes for Lyme carditis/heart block, arthritis or neurologic Lyme disease, some of which may require intravenous antibiotics as initial therapy, go to this link; https://www.cdc.gov/lyme/treatment/index.html . For more information on the specific treatment of Lyme disease complications, such as heart block, go to this link; https://www.idsociety.org/practice-guideline/lyme-disease/ .


Post-Treatment Lyme Disease

Although most cases of Lyme disease can be cured with a 10-day to 4-week course of oral antibiotics, patients can sometimes have symptoms of pain, fatigue, or difficulty thinking that lasts for more than 6 months after they finish treatment, called Post-Treatment Lyme Disease Syndrome (PTLDS). It has been hypothesized that the syndrome is caused by an autoantibody response. There is no proven treatment for PTLDS, and studies have found that prolonged antibiotic treatment works no better than patients who received placebo. Patients with PTLDS usually get better over time, but it can take many months to feel completely well.[10,25]


Ehrlichiosis


Ehrlichiosis is caused by three bacteria, Ehrlichia chaffeensis, Ehrlichia ewingii, or Ehrlichia muris eauclairensis. The majority of reported cases are due to infection with E. chaffeensis. E. chaffeensis and E. ewingii are carried by the lone star tick, Amblyomma americanum, found primarily in the south-central and eastern United States. E. muris eauclairensis is carried by the blacklegged tick, Ixodes scapularis, but despite this tick’s wide distribution has only been reported in Wisconsin and Minnesota.[26] In 2018, there were 1,799 cases of E. chaffeensis reported to the CDC. The other Ehrlichia infections are much rarer, with only 218 cases of E. ewingii ehrlichiosis reported to CDC from 2008–2018, and about 115 cases of ehrlichiosis caused by E. muris eauclairensis reported since its discovery in 2009.[27]


Morula inside a monocyte
Morula inside a monocyte [15]

Ehrlichia are small, gram-negative bacteria, round or ellipsoidal in shape. They preferentially invade monocytes, macrophages, and neutrophils. In all of these cell types they occupy cytoplasmic vacuoles, usually in bacterial microcolonies known as morulae.[28]


Early Signs and Symptoms of Ehrlichiosis[29]

Signs and symptoms of ehrlichiosis typically begin within 5 to 14 days after the bite of an infected tick.


Early signs and symptoms are usually mild or moderate and may include:

  • Fever, chills

  • Severe headache

  • Muscle aches

  • Nausea, vomiting, diarrhea, loss of appetite

    • Gastrointestinal symptoms are less common in patients with E. ewingii ehrlichiosis than with the other two species.

  • Confusion

  • Rash

    • A rash develops in up to 60% of children, and less than 30% of adults, and typically begins about 5 days after symptom onset.

    • The rash usually spares the face, but in some cases may spread to the palms of hands and soles of feet.

    • The rash associated with E. chaffeensis infection may range from maculopapular to petechial in nature and is usually non-pruritic.

    • Rash is infrequent in cases of E. muris eauclairensis.

Late Symptoms of Ehrlichiosis[29]

If treatment is delayed and the ehrlichiosis infection is allowed to continue, the disease may become severe. Severe illness may involve:

  • Meningitis, meningoencephalitis, and other central nervous system involvement (20% of patients)

  • Acute respiratory distress syndrome

  • Toxic shock-like or septic shock-like syndromes

  • Renal failure

  • Hepatic failure

  • Coagulopathies

E.chaffeensis generally is the more serious illness, as neither E. ewingii nor E. muris eauclairensis infections have been associated with fatalities. The case fatality rate of E. chaffeensis is about 1%.


Laboratory Findings in Ehrlichiosis[28]

  • General laboratory findings in ehrlichiosis can include absolute leukopenia, thrombocytopenia, and moderately elevated hepatic transaminases.

  • Anemia is reported in about half of patients, but generally occurs later in the course of the illness.

Testing for Ehrlichiosis[29]

Microscopic examination of a blood smear may reveal morulae, which are microcolonies of Ehrlichiae in the cytoplasm of white blood cells. E. chaffeensis most commonly infects monocytes while E. ewingii more commonly infects granulocytes. No specific target cell has been identified for E. muris eauclairensis. A concentrated buffy-coat smear can improve the yield of morulae evaluation compared with a standard blood smear. When positive, the diagnosis can be made relatively easily, but unfortunately blood smear examination is relatively insensitive for detecting the disease. If a bone marrow biopsy is performed as part of the investigation of cytopenias, immunostaining the bone marrow biopsy specimen to look for morulae, may help diagnose ehrlichiosis. Organ biopsies, if done for other purposes may also show evidence of morulae.


Immunohistochemical stain demonstrating Ehrlichia chaffeensis morulae (red) within monocytes in the kidney
Immunohistochemical stain demonstrating Ehrlichia chaffeensis morulae (red) within monocytes in the kidney [15]

The indirect immunofluorescence antibody (IFA) assay for IgG, is the test most widely performed to diagnose ehrlichiosis. IgG IFA assays should be performed on paired acute and convalescent serum samples collected 2–4 weeks apart with a fourfold increase or decrease in the titers needed to be interpreted as positive. Antibody titers are frequently negative in the first week of illness. Ehrlichiosis cannot be confirmed using a single acute set of antibody results. IgM IFA assays are also offered by reference laboratories but are not necessarily indicators of acute infection, and appear to be less specific than IgG antibodies. It is therefore not recommended to use IgM antibody titers alone for diagnosis.


Polymerase chain reaction (PCR) amplification can be performed from whole blood specimens. PCR is most sensitive in the first week of illness and decreases in sensitivity following the administration of appropriate antibiotics (within 48 hours). Although a positive PCR result is helpful, a negative result does not rule out the diagnosis, and treatment should not be withheld due to a negative result if ehrlichiosis is clinically suspected. PCR may also be used to amplify DNA in solid tissue and bone marrow specimens.


Culture of Ehrlichia species is only available at specialized laboratories, and routine hospital blood cultures cannot detect the organism.


Treatment of Ehrlichiosis [30]

As opposed to Lyme disease, post-tick bite antibiotic prophylaxis is currently not recommended to prevent ehrlichiosis.


Doxycycline is the treatment of choice for ehrlichiosis if the diagnosis is suspected, for patients of all ages, including children <8 years. Doxycycline is most effective at preventing severe complications from developing if started within the first week of illness.


The recommended dosage for is doxycycline for adults is 100 mg every 12 hours, and for children under 45 kg (100 lbs.) the dose is 2.2 mg/kg body weight given twice a day. Dental staining in children has been a concern with doxycycline, but a study of 58 children under eight years of age with Rocky Mountain spotted fever, found no evidence of dental staining from doxycycline treatment.[31] Patients with suspected ehrlichiosis should be treated with doxycycline for at least 3 days after the fever subsides, and there is evidence of clinical improvement, typically in 5-7 days.


In cases of life-threatening allergies to doxycycline, severe doxycycline intolerance, and in some pregnant patients for whom the clinical course of ehrlichiosis appears mild, physicians might consider alternate antibiotics. Rifampin appears effective against E. chaffeensis in a laboratory setting, but has not been evaluated as an alternative therapy in a clinical setting. Caution is advised when exploring treatments other than doxycycline, as other tickborne co-infections like Lyme disease or Rocky Mountain spotted fever may go intreated. An infectious disease consult is recommended when treating the pregnant patient.


Anaplasmosis

Anaplasmosis, also known as human granulocytic anaplasmosis, is a tickborne disease caused by the bacterium Anaplasma phagocytophilum.


Blacklegged ticks, Ixodes scapularis, in the eastern United States, and western blacklegged ticks, Ixodes pacificus, on the West Coast are the main causes of infection. Coinfections with other tickborne illness such as Lyme disease have been reported. Infections have occasionally been reported through blood transfusion and organ donation.[32]


Peak transmission is during June to November. Two peaks of increased case reporting usually occur, with the first peak during June–July and a smaller peak during October-November. There are about 4,000 to 5,700 cases reported per year to the CDC.[33]


Signs and Symptoms of Early Illness of Anaplasmosis[34]


Signs and symptoms typically begin within 5-14 days after the bite of an infected tick, and are non-specific. They may include:

  • Fever, chills, rigors

  • Severe headache

  • Malaise

  • Myalgia

  • Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia) in about 20% of cases

  • A non-specific rash occurs in less than 10% of patients with anaplasmosis. As rash is a rare finding in anaplasmosis, if a rash is present, consider a coinfection with Lyme disease, or another tickborne disease.

  • Rarely: Nervous system involvement (e.g., meningoencephalitis, focal paralysis)

Late Illness Symptoms of Anaplasmosis[34]

If treatment is delayed severe illness can occur but is rare. Symptoms may include:

  • Renal or respiratory failure

  • Peripheral neuropathies

  • Disseminated intravascular coagulation (DIC)-like coagulopathies

  • Rhabdomyolysis

  • Hemorrhage

The clinical course of anaplasmosis varies from person to person, and may depend on patient age, co-morbid conditions, immune status and time of treatment.


Laboratory Findings in Anaplasmosis[34]

Laboratory findings can include mild anemia, thrombocytopenia, leukopenia and mild to moderate elevations in hepatic transaminases. However, normal laboratory findings do not rule out possible infection.


Testing for Anaplasmosis[35]

Laboratory testing for anaplasmosis is similar to ehrlichiosis.


Indirect immunofluorescence antibody (IFA) assay for IgG using Anaplasma phagocytophilum antigen, is the standard diagnostic test for anaplasmosis. IgG IFA assays should be performed on paired acute and convalescent serum samples collected 2–4 weeks apart to demonstrate evidence of a fourfold rise. Antibody titers are frequently negative in the first week of illness. Anaplasmosis cannot be confirmed using a single acute antibody test. Between 5–10% of healthy people in some areas might have elevated antibody titers due to past exposure to A. phagocytophilum or similar organisms, which is why comparison of paired, serologic assays provides the best evidence of recent infection. Some reference laboratories offer IgM IFA assays which are not necessarily indicators of acute infection, and might be less specific than IgG antibodies. Therefore, IgM antibody titers alone should not be used for laboratory diagnosis.


Polymerase chain reaction (PCR) amplification can be performed on DNA extracted from whole blood specimens. PCR is most sensitive in the first week of illness, and decreases in sensitivity following the administration of appropriate antibiotics. Unfortunately, a negative result does not rule out the diagnosis. PCR can also be used to amplify DNA in solid tissue and bone marrow specimens for testing.


During the first week of illness a peripheral blood smear might reveal morulae (microcolonies of anaplasmae) in the cytoplasm of granulocytes and is highly suggestive of a diagnosis. However, blood smear examination is relatively insensitive, and should not be relied upon solely to diagnose anaplasmosis. The observance of morulae in a particular cell type cannot reliably differentiate between Anaplasma and Ehrlichia species. If a bone marrow biopsy is performed as part of the investigation of cytopenias, immunostaining of the bone marrow biopsy specimen looking for morulae can diagnose anaplasmosis. They may also be seen in organ biopsies taken for other purposes.


Anaplasma phagocytophilum morela in granulocyte on blood smear
Anaplasma phagocytophilum morela in granulocyte on blood smear [15]

Immunohistochemical stain demonstrating A. phagocytophilum morulae (red) in the spleen
Immunohistochemical stain demonstrating A. phagocytophilum morulae (red) in the spleen [35]

Culture of A. phagocytophilum is only available at specialized laboratories, and routine hospital blood cultures cannot detect the organism


Treatment of Anaplasmosis[36]

Post-tick bite antibiotic prophylaxis is not currently recommended to prevent anaplasmosis.


Doxycycline is recommended as the first-line treatment for anaplasmosis in adults and children of all ages. The dosage in adults is 100 mg every 12 hours, in children under 45 kg (100 lbs.)the dose is 2.2 mg/kg body weight given twice a day.


Patients with suspected anaplasmosis should be treated with doxycycline for 10–14 days to provide appropriate length of therapy for possible concurrent Lyme disease infection. Lack of a clinical response to doxycycline suggests that the patient’s condition might not be due to anaplasmosis, or might be a due to a coinfection. Resistance to doxycycline or relapses in anaplasmosis symptoms after the completion of the recommended course have not been documented.


In cases of life-threatening allergies to doxycycline, severe doxycycline intolerance, and in some pregnant patients for whom the clinical course of anaplasmosis appears mild, rifampin might be considered. Rifampin has been used successfully in several pregnant women with anaplasmosis, and small numbers of children <8 years for a 7–10-day course. However, rifampin is not effective in treating Rocky mountain spotted fever, a disease that might be confused with anaplasmosis, nor is it an effective treatment for a potential Lyme disease coinfection. An infectious disease consult is recommended when treating the pregnant patient.



Babesiosis

Babesiosis is typically caused by a microscopic parasite Babesia microti that infects red blood cells. There are other species of Babesia that can cause infection, but B. microti is the most common. It is transmitted by bites from infected Ixodes scapularis ticks (also called blacklegged ticks or deer ticks), but occasionally can be transmitted by blood transfusion, or congenitally from mother to infant.[37] It is typically seen in the Northeast and upper Midwest. In 2018, 2,161 cases of babesiosis were reported to the CDC.[38]


Babesia Life Cycle


Babesia Life and Feeding Cycle
Babesia Life and Feeding Cycle [39]

The Babesia microti life cycle involves two hosts, most commonly the white-footed mouse, Peromyscus leucopus, and a tick in the genus Ixodes. During a blood meal, a Babesia-infected tick introduces sporozoites into the mouse host. Sporozoites enter erythrocytes and undergo asexual reproduction (budding). In the mouse’s blood, some of the spores differentiate into male and female gametes. These gametes can be ingested by another tick, unite and form more sporozoites. The Babesia-infected tick then can introduce the sporozoites into a human host during a blood meal. The sporozoites enter erythrocytes and undergo asexual replication, (budding) which then is responsible for the clinical manifestations of the disease.[39]


Symptoms of Babesiosis[40]

Many people who are infected with Babesia microti feel fine, and do not have any symptoms. Others develop nonspecific flu-like symptoms, such as fever, chills, sweats, headache, body aches, loss of appetite, nausea, or fatigue. As Babesia parasites infect and destroy red blood cells, hemolytic anemia leading to jaundice may occur. Some patients may have splenomegaly, or hepatomegaly.

Coinfection should be investigated in patients who have a persistent fever while on antibiotic treatment for Lyme disease. If fever persists despite treatment with doxycycline, B. microti infection is an important consideration.


Laboratory Findings in Babesiosis[41]

For acutely ill patients, the findings on routine laboratory testing frequently include hemolytic anemia and thrombocytopenia. Additional findings may include proteinuria, hemoglobinuria, elevated levels of liver enzymes, blood urea nitrogen, and creatinine.


Testing for Babesiosis[42]

Diagnosis can be made by microscopic examination of thick and thin blood smears which are Giemsa stained. Repeated smears may be needed sometimes to detect parasites.


Babesia microti in Giemsa-stained blood smears
Babesia microti in Giemsa-stained blood smears [42]

Antibody testing may be useful in asymptomatic patients who are donating blood, or if the diagnosis is uncertain after a blood smear is checked. The indirect fluorescent antibody test (IFA) using B. microti parasites as antigen detects antibodies in 88-96% of patients with B. microti infection. The extent of cross-reactivity between Babesia species is variable. A negative result with B. microti antigen for a patient exposed on the West Coast of the US may be a false-negative, and the patient should be specifically be tested for antibodies to Babesia duncani.


PCR testing can be used to confirm the diagnosis after a positive blood smear to identify the species and also differentiate it from malarial species, such as Plasmodium falciparum, which can look similar microscopically.


Treatment of Babesiosis [43]

Most asymptomatic persons do not require treatment. Treatment decisions should be individualized, especially for patients who are at risk for severe disease such as asplenic or immunosuppressed individuals.

For ill patients, babesiosis usually is treated for at least 7-10 days with a combination of two medications — typically either:

  • Atovaquone PLUS azithromycin; OR

  • Clindamycin PLUS quinine (this combination is the standard of care for severely ill patients).

Recommended CDC adult dosages are listed in the table below.


chart

Atovaquone is pregnancy category C and the risk to the fetus is unknown. Because there is data about the safe administration of quinine plus clindamycin during pregnancy, this drug combination is generally recommended for treatment of symptomatic babesiosis during pregnancy. An infectious disease consult is recommended when treating a pregnant patient.


Conclusion

Given that diagnostic testing for these tickborne diseases is not 100% sensitive, and symptoms initially may be non-specific, a clinician in an endemic area should keep tickborne infections in mind when considering diagnoses in an ill patient without a clear cause. Unexplained fever, anemia, thrombocytopenia, leukopenia, new onset heart block, myocarditis, pericarditis, cranial nerve palsies, or arthritis can be seen as potential clues to a tickborne infection. A specific history of tick bites may be helpful, although the patient might not even know they have been bitten. Antibiotic prophylaxis for Lyme disease, when appropriate, will help reduce the incidence of symptomatic disease. While this article is just about four tickborne infections, keep in mind that ticks can transmit many different infections including: Borrelia miyamotoi disease, Colorado tick fever, Heartland and Bourbon virus diseases, Pacific Coast tick fever, Powassan virus disease, Rocky Mountain spotted fever, Rickettsia parkeri rickettsiosis, Rickettsialpox, Tickborne relapsing fever, and Tularemia.[44,45]


Author’s Note: Dosages and recommended medications are based on current recommendations, and are correct to the best of my knowledge. However, treatment recommendations may change, and clinicians are advised to review the most current dosages, medications and contraindications prior to treating any patient.


 

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Originally published 4/29/2021

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