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EHRLICHIOSIS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tick-borne bacterial diseases characterized by acute febrile illness and pancytopenia.
    1) There are two distinct forms in the US with different microbial etiologies: Human monocytic ehrlichiosis (HME), caused by Ehrlichia chaffeensis, which infects mononuclear phagocytes in blood and tissues and Human granulocytic ehrlichiosis (HGE), caused by an agent closely related to E equi, which infects granulocytes.
    B) Sennetsu fever, a rare mononucleosis-like illness, is caused by Ehrlichia sennetsu.

Specific Substances

    A) CONSTITUENTS OF THE GROUP
    1) Human granulocytic ehrlichiosis
    2) HGE
    3) Human monocytic ehrlichiosis
    4) HME
    5) Ehrlichia chaffeensis
    6) Sennetsu fever
    7) Ehrlichia sennetsu

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) HUMAN MONOCYTE EHRLICHIOSIS (HME): Vary from asymptomatic or mildly symptomatic infection to severe multisystem failure and death. Characterized by nonspecific flu-like illness with high, persistent fever and severe headache (most prominent features), and generalized malaise; myalgias, nausea, and vomiting are common. CNS manifestations, usually in form of meningitis, occur in about 20% of patients with HME. Vomiting, cough, abdominal pain, diarrhea, rash, and lymphadenopathy tend to develop later in course, if at all.
    B) HUMAN GRANULOCYTIC EHRLICHIOSIS (HGE): Similar to those of HME. Undifferentiated flu-like illness with fever, shaking chills, malaise, nausea, vomiting, headache, myalgia, arthralgia. Later in course, cough or confusion may occur, but rash and seizures are rare. Brachial plexopathy in a patient with HGE has been reported.
    C) SENNETSU FEVER: Mononucleosis-like illness, characterized by remittent fever, postauricular and posterior cervical lymphadenopathy, mild hepatosplenomegaly. Fatigue, anorexia, chills, headache, myalgias, arthralgias common; rash is unusual.
    D) Reported complications include acute renal failure, acute respiratory failure/ARDS, encephalopathy, myocarditis, meningitis, DIC, shock, GI bleeding, opportunistic infections. Complications tend to develop at end of first or beginning of second week of illness.
    E) COURSE: In HME, prolonged interval between illness onset and institution of therapy is associated with more severe course or death. In HGE, increased age, anemia, and detection of morulae in peripheral blood smears are associated with more severe illness.
    F) Consider diagnosis in patients with a history of tick exposure, acute febrile illness with evidence of multisystem involvement and lack of specific localizing symptoms/signs, decreasing WBC and platelet counts, and elevated liver enzymes.
    0.2.20) REPRODUCTIVE
    A) HGE has been transmitted perinatally to the infant. It has been treated successfully with doxyclycline.

Laboratory Monitoring

    A) Monitor CBC, renal and hepatic function.
    B) Laboratory values often are normal or near normal during first few days of illness. Abnormalities are transient and most pronounced at 5 to 7 days after onset.
    C) Diagnostic and confirmatory tests include careful examination of peripheral blood smears, immunocytology, immunohistology, PCR, isolation of Ehrlichia, serology; not available in most laboratories.

Treatment Overview

    0.4.7) BITES/STINGS
    A) Treatment is symptomatic and supportive. Initiate antibiotic treatment without delay based on epidemiologic and clinical information. Prompt treatment of seriously ill patients in whom ehrlichiosis is suspected is essential and cannot await the preparation and transport of specimens to the few research facilities where rapid diagnostic tests are available. Make presumptive diagnosis in patients presenting with nonspecific flu-like febrile illness after possible recent tick exposure, particularly if cytopenias or abnormal liver profiles, or both, are present.
    B) TICK REMOVAL: Early removal of the tick, if present, is important; risk of infection is increased with tick attachment longer than 48 to 72 hours. Grasp tick by head or mouth parts as close to skin as possible, using a fine forceps; pull with steady upward pressure until tick releases. Disinfect area with soap and water.
    C) ANTIBIOTICS: Doxycycline is the drug of choice for adults and children (8 years of age and older and severely ill children less than 8 years of age) with symptomatic human granulocytic anaplasmosis (HGA; formerly known as human granulocytic ehrlichiosis) or for patients who have coinfection with Lyme disease. Rifampin may be used in all children with mild HGA illness without concomitant Lyme disease and intolerant of doxycycline.
    D) DOXYCYCLINE
    1) ADULTS: 100 mg twice daily ORALLY or IV for 10 days for HGA alone or concomitant Lyme disease
    2) CHILDREN 8 YEARS AND OLDER: 4 mg/kg per day ORALLY or IV in 2 divided doses for 10 days for HGA alone or concomitant Lyme disease; maximum 100 mg/dose
    3) SEVERELY ILL CHILDREN LESS THAN 8 YEARS OF AGE WITHOUT CONCOMITANT LYME DISEASE: 4 mg/kg per day ORALLY or IV in 2 divided doses for 4 to 5 days (eg; for approximately 3 days after resolution of fever); maximum 100 mg/dose
    4) SEVERELY ILL CHILDREN LESS THAN 8 YEARS OF AGE WITH CONCOMITANT LYME DISEASE: 4 mg/kg per day ORALLY or IV in 2 divided doses for 4 to 5 days (eg; for approximately 3 days after resolution of fever); maximum 100 mg/dose; amoxicillin 50 mg/kg/day orally in 3 divided doses (maximum of 500 mg per dose) or cefuroxime axetil 30 mg/kg/day orally in 2 divided doses should be used after the conclusion of the course of doxycycline to complete a 14-day total course
    E) RIFAMPIN
    1) ADULTS (IN PATIENTS WITH MILD HGA ILLNESS WITHOUT CONCOMITANT LYME DISEASE AND INTOLERANT OF DOXYCYCLINE, OR DURING PREGNANCY): 300 mg ORALLY twice daily for 7 to 10 days. Patients COINFECTED WITH LYME DISEASE should also be treated concomitantly amoxicillin 500 mg orally three times daily or cefuroxime axetil 500 mg orally twice a day for 14 days (range, 14 to 21 days).
    2) CHILDREN WITH MILD HGA ILLNESS WITHOUT CONCOMITANT LYME DISEASE AND INTOLERANT OF DOXYCYCLINE): 10 mg/kg ORALLY twice daily for 7 to 10 days; maximum of 300 mg per dose. Patients COINFECTED WITH LYME DISEASE should also be treated concomitantly with amoxicillin 50 mg/kg/day orally in 3 divided doses or cefuroxime axetil 30 mg/kg/day orally in 2 divided doses for 14 days (range, 14 to 21 days).
    F) ANTIPYRETICS/ANALGESICS
    1) ACETAMINOPHEN: ADULTS: 650 to 1000 mg PO Q4H PRN; maximum 4 g/day (CHILDREN: 10 to 15 mg/kg PO Q4-6H PRN; maximum 650 mg/dose).
    2) IBUPROFEN: ADULTS: 400 to 600 mg PO Q6H PRN; maximum 3.2 g/day (CHILDREN: 10 mg/kg PO Q6H PRN; maximum 40 mg/kg/day).
    G) Intravenous fluids - Cardiac monitoring and pacing for patients with cardiac complications.
    H) Steroids for specific cardiac, neurologic, or arthritic complications.
    I) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    J) ITCHING/INFLAMMATION - A topical corticosteroid, antihistamine, local anesthetic combination may be of value.
    K) Subcutaneous injection of local anesthetics (lidocaine with or without epinephrine, chloroprocaine) have NOT been found to assist with tick removal in animal models.
    L) ALLERGIC REACTION: MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

Range Of Toxicity

    A) One tick may be enough to cause an infection. Risk of infection is increased with tick attachment longer than 48 to 72 hours.

Clinical Effects

Summary Of Exposure

    A) HUMAN MONOCYTE EHRLICHIOSIS (HME): Vary from asymptomatic or mildly symptomatic infection to severe multisystem failure and death. Characterized by nonspecific flu-like illness with high, persistent fever and severe headache (most prominent features), and generalized malaise; myalgias, nausea, and vomiting are common. CNS manifestations, usually in form of meningitis, occur in about 20% of patients with HME. Vomiting, cough, abdominal pain, diarrhea, rash, and lymphadenopathy tend to develop later in course, if at all.
    B) HUMAN GRANULOCYTIC EHRLICHIOSIS (HGE): Similar to those of HME. Undifferentiated flu-like illness with fever, shaking chills, malaise, nausea, vomiting, headache, myalgia, arthralgia. Later in course, cough or confusion may occur, but rash and seizures are rare. Brachial plexopathy in a patient with HGE has been reported.
    C) SENNETSU FEVER: Mononucleosis-like illness, characterized by remittent fever, postauricular and posterior cervical lymphadenopathy, mild hepatosplenomegaly. Fatigue, anorexia, chills, headache, myalgias, arthralgias common; rash is unusual.
    D) Reported complications include acute renal failure, acute respiratory failure/ARDS, encephalopathy, myocarditis, meningitis, DIC, shock, GI bleeding, opportunistic infections. Complications tend to develop at end of first or beginning of second week of illness.
    E) COURSE: In HME, prolonged interval between illness onset and institution of therapy is associated with more severe course or death. In HGE, increased age, anemia, and detection of morulae in peripheral blood smears are associated with more severe illness.
    F) Consider diagnosis in patients with a history of tick exposure, acute febrile illness with evidence of multisystem involvement and lack of specific localizing symptoms/signs, decreasing WBC and platelet counts, and elevated liver enzymes.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER: Infection manifests as an acute febrile illness; high persistent (>2 to 3 days) fever accompanied by severe headaches is prominent clinical feature (Standaert, 1995; (Fishbein et al, 1994) Bakken, 1996; Everett, 1994; (Dumler & Bakken, 1995) Rohrbach, 1990; Knapp, 1995; (Walker, 1996a) Aguero-Rosenfeld, 1996; (CDC, 1998) 1996).
    1) Fever is present during first week in almost all cases; temperature often exceeds 39 degrees C; unaltered by antipyretics (CDC, 1998) Standaert, 1995; (Fishbein et al, 1994) Bakken, 1996; Everett, 1994; (Dumler & Bakken, 1995) Rohrbach, 1990; Knapp, 1995).
    2) May be associated with prolonged fever (more than 2 wk) when there is delay in seeking care or when infection is unrecognized and untreated (Roland, 1995; (Dumler et al, 1993; Golden, 1989). Children tend to have a higher maximum temperature than adults (Eng, 1990). Saddleback fever (acute febrile illness that lasts several days, remits without treatment, then recurs) due to HGE has been reported (Horowitz, 1998a).
    B) CHILLS
    1) Shaking chills (rigors) typically present early in course, particularly in HGE (Fishbein et al, 1994) Everett, 1994; Bakken, 1996).

Heent

    3.4.3) EYES
    A) Photophobia has been reported in a few patients (Everett, 1994).
    3.4.6) THROAT
    A) Pharyngeal erythema is an uncommon finding. It may be present in children, usually without a sore throat (Knapp, 1995; (Barton et al, 1992; Harkess, 1991).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) Febrile illness may be associated with a relative bradycardia (Conrad, 1989).
    B) HYPOTENSIVE EPISODE
    1) Occasionally, ehrlichiosis can present as a severe, life-threatening illness with multisystem organ failure resembling toxic shock syndrome (TSS) (Tal & Shannahan, 1995) Fichtenbaum, 1995). Timing of hypotension may be useful in distinguishing TSS from ehrlichiosis.
    2) Onset of hypotension is usually abrupt in TSS but is a later manifestation in ehrlichiosis (mean time of onset is about 7 days after beginning of illness) (Fichtenbaum, 1995). Diffuse erythematous rash is more common with TSS.
    C) CARDIOVASCULAR FINDING
    1) Multiorgan system failure with clinically prominent myocardial dysfunction (heart failure, left ventricular dilatation) due to ehrlichiosis has been reported (Williams et al, 1995) Vanek, 1996).
    D) MYOCARDITIS
    1) Fatal pancarditis associated with HGE in a man previously treated for presumptive acute Lyme disease is reported (Jahangir, 1998).
    2) ECG and chemical evidence of myocarditis may be absent, suggesting that acute Ehrlichia infection can produce cardiac dysfunction with little myocardial inflammation (Vanek, 1996).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) Cough is present in 10% to 30% of patients (Fishbein et al, 1994) Bakken, 1996; Everett, 1994; (Dumler & Bakken, 1995).
    B) ACUTE LUNG INJURY
    1) Pulmonary complications are common and may be severe. In one series, acute respiratory failure requiring intubation and mechanical ventilation occurred in 7/40 patients (Eng, 1990).
    2) Ehrlichiosis as a cause of ARDS has been reported and should be considered in patients presenting with rapidly progressive respiratory distress, particularly in geographic regions where the tick vectors are found (Weaver et al, 1999; (Patel & Byrd, 1999; Wong & Grady, 1996) Vugia, 1996).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) CNS manifestations occur in about 20% of patients with ehrlichiosis. Include mental status changes, severe headache, confusion, lethargy, broad-based gait, hyperreflexia, clonus, photophobia, cranial nerve palsy, seizures, blurred vision, nuchal rigidity, ataxia (Everett, 1995; (Fishbein et al, 1994) Ratnasamy, 1996; (Grant et al, 1997).
    B) HEADACHE
    1) Severe headache accompanied by high persistent fever is prominent clinical feature, noted in a vast majority of patients (Dawson, 1996; Standaert, 1995; Everett, 1995; (Fishbein et al, 1994) Rohrbach, 1990; Bakken, 1996; Aguero-Rosenfeld, 1996).
    2) More common in HGE than in HME (Bakken, 1994, 1996).
    C) ALTERED MENTAL STATUS
    1) Confusion may occur toward end of first week of illness; noted in about 20% of patients with HME and 40% of those with HGE (Fishbein et al, 1994) Bakken, 1994, 1996; Everett, 1994; (Dumler & Bakken, 1995; Harkess et al, 1990).
    2) In patients with HME, change in mental status is most common clinical finding predictive of cerebrospinal fluid (CSF) abnormalities, most commonly due to meningitis (Standaert, 1998; Ratnasamy, 1996).
    D) MALAISE
    1) Common presenting symptom, noted in >85% of patients. More common in HGE than in HME (Fishbein et al, 1994) Bakken, 1996).
    E) MENINGITIS
    1) Neurologic involvement, usually in form of meningitis, is a frequent complication of HME but rarely, if ever, occurs in HGE. HME should be considered in differential diagnosis of all cases of aseptic meningitis in endemic areas, particularly when accompanied by fever, nonspecific abdominal pain, thrombocytopenia, and hepatic dysfunction (Berry, 1999; Standaert, 1998).
    2) Most patients with HME meningitis do not have signs of meningismus, and mental status changes may be only suggestion of CNS involvement (Berry, 1999; Standaert, 1998; Ratnasamy, 1996; Everett, 1994; Eng, 1990; (Harkess et al, 1990; Golden, 1989; Dimmitt et al, 1989).
    3) Less common neurologic findings that may be associated with HME meningitis include seizures, coma, ataxia, hyperreflexia, clonus, nuchal rigidity, photophobia, and cranial nerve palsies (Standaert, 1998; Ratnasamy, 1996; Everett, 1994; Eng, 1990; (Harkess et al, 1990; Golden, 1989; Dimmitt et al, 1989).
    4) CSF examination may be indicative of meningeal inflammation, e.g., a lymphocytic pleocytosis or elevated protein level; higher CSF cell counts are seen in children than adults. However, CSF findings are nonspecific and may mimic those found in encephalitis and infectious mononucleosis (Standaert, 1998; Everett, 1994; Eng, 1990; (Harkess et al, 1990; Golden, 1989; Dimmitt et al, 1989) Ratnasamy, 1996).
    5) Rarely, ehrlichial meningitis with morulae evident on Gram-smear of initial CSF sample may be seen (Berry, 1999).
    F) TOXIC ENCEPHALOPATHY
    1) Patients may have clinical findings suggestive of encephalopathy, e.g., change in mental status (confusion, coma). Reported in 6/40 patients in one series (Eng, 1990).
    G) NEUROPATHY
    1) Brachial plexopathy (Horowitz, 1996) and demyelinating polyneuropathy (Bakken, 1998a) have been reported in patients with HGE.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) TASTE SENSE ALTERED
    1) Dysgeusia or altered sense of taste has been reported in a few patients (Everett, 1994).
    B) LOSS OF APPETITE
    1) Typically presenting symptom; usually profound and may result in weight loss (Harkess, 1991).
    C) NAUSEA
    1) Reported by >50% of patients; tends to occur early in illness; usually transient and rarely predominant feature (Standaert, 1995; Bakken, 1996; (Fishbein et al, 1994) Everett, 1994; (Dumler & Bakken, 1995) Rohrbach, 1990).
    D) VOMITING
    1) Occurs in 30% to 50% of cases; tends to develop later in course; usually transient and rarely predominant feature (Standaert, 1995; (Fishbein et al, 1994) Bakken, 1996; (Dumler & Bakken, 1995).
    E) DIARRHEA
    1) Uncommon in adults; more likely in children. Occurs toward end of first week of illness onset; usually transient and rarely predominant feature (Fishbein et al, 1994) Eng, 1990; Bakken, 1996).
    2) A case of HME presenting as febrile diarrhea has been reported (Devereaux, 1997).
    F) ABDOMINAL PAIN
    1) Occasionally, patients may have symptoms suggesting predominant involvement of a single organ system, including acute abdominal pain. Reported by 25% to 50% of patients; tends to develop later in course (Standaert, 1995; (Fishbein et al, 1994) Bakken, 1994; (Dumler & Bakken, 1995).
    2) Abdominal tenderness may be noted on physical examination (Everett, 1994).
    G) SPLENOMEGALY
    1) May be noted occasionally on physical examination; occurs a week or more after illness onset (Eng, 1990; Everett, 1994). HME presenting as progressive hepatosplenomegaly has been reported (Friedman et al, 1997).
    H) GASTROINTESTINAL HEMORRHAGE
    1) In severe and fatal infections, thrombocytopenia and coagulopathy may predispose to hemorrhagic complications (Bakken, 1994, 1996; (Dumler & Bakken, 1995). Disseminated intravascular coagulation (DIC) is rare complication that may be associated with upper GI bleeding (Taylor, 1988; Bakken, 1996).
    2) Severe infectious esophagitis with GI hemorrhage has been reported in patients with complicating opportunistic infections (Bakken, 1996).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) Occasionally may be a late finding (>10 d after illness onset) (Eng, 1990).
    B) LARGE LIVER
    1) Nontender hepatomegaly may be noted occasionally on physical examination; occurs a week or more after illness onset (Eng, 1990; Everett, 1994).
    2) HME presenting as progressive hepatosplenomegaly has been reported (Friedman et al, 1997).
    3) Infrequent occurrence may help differentiate ehrlichiosis from viral hepatitis and hematologic malignancies (Conrad, 1989). More common in children than in adults (Eng, 1990).
    C) LIVER ENZYMES ABNORMAL
    1) Common finding during first week of illness, noted in >75% of patients (Standaert, 1995; (Fishbein et al, 1994) Everett, 1994; (Dumler & Bakken, 1995) Eng, 1990). Due to focal hepatocellular necrosis (Walker, 1996a).
    2) Characterized by mild-to-moderate elevations in aspartate and alanine aminotransferases, alkaline phosphatase, and lactate dehydrogenase; occasionally may be in range of viral hepatitis. Total bilirubin (mainly direct bilirubin) levels less frequently increased (Standaert, 1995; (Fishbein et al, 1994) Everett, 1994; (Dumler & Bakken, 1995) Eng, 1990).
    3) LFTs generally increase rapidly during first days of illness, then slowly return to normal (Fishbein et al, 1994).
    4) ALANINE AMINOTRANSFERASE, INCREASED: Mild-to-moderate elevations in serum transferase levels are a typical finding during first week of illness, noted in 75% to 80% of patients (Fishbein et al, 1994) Everett, 1994).
    5) ASPARTATE AMINOTRANSFERASE, INCREASED: Mild-to-moderate elevations in serum transferase levels are a typical finding during first week of illness, noted in about 85% of patients (Fishbein et al, 1994) Everett, 1994).
    D) HYPERBILIRUBINEMIA
    1) Total bilirubin (mainly direct bilirubin) levels are less frequently increased (about 25% of cases) (Everett, 1994).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) A rare complication. Cause is unknown. May require dialysis (Eng, 1990; Maeda, 1987; (Fishbein et al, 1994) Bakken, 1994, 1996; Everett, 1994).
    B) SERUM CREATININE RAISED
    1) Elevated in 25% of patients with HME and 70% of those with HGE. Usually detected during second week of illness but may be present earlier (Dumler & Bakken, 1995) Eng, 1990).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) In severe infection, thrombocytopenia and coagulopathy may predispose to hemorrhagic complications (Bakken, 1994). DIC may be associated with bleeding from GI tract or multiple sites (Taylor, 1988; (Fishbein et al, 1994).
    2) Fatal cases have been associated with pulmonary or gastrointestinal hemorrhage that presumably was secondary to thrombocytopenia and possible concurrent DIC (Dumler & Bakken, 1995).
    B) PANCYTOPENIA
    1) Characterized by development of pancytopenia, although mechanism is not clear. Sequestration or destruction of various blood elements (hemophagocytic syndrome) is probable mechanism (Abbott, 1991; (Walker, 1996a).
    C) LEUKOPENIA
    1) Progressive leukopenia (less than 4.3/mm(3)), often with left shift is hallmark of disease. Noted in about 60% to 75% of patients with HME and about 50% of those with HGE (CDC, 1998; Dumler & Bakken, 1995; Fishbein et al, 1994) Bakken, 1996; Naqvi, 1996; (Walker, 1996a; Fishbein et al, 1987).
    2) Occurs during first week of illness; often present on initial evaluation and is most severe 5 to 7 days after illness onset. Typically reaches nadir of 1.3 to 4.0 X 10(9)/L (Fishbein et al, 1994) Standaert, 1995; Everett, 1994; (Dumler & Bakken, 1995).
    3) Most leukocyte elements tend to decrease simultaneously, with largest decrease occurring in total lymphocyte count (almost 60% decrease from day 1 to 3) (Fishbein et al, 1994). Count typically rebounds to normal or supranormal values by days 10 to 14 (Fishbein et al, 1994).
    D) LYMPHOCYTOPENIA
    1) Absolute lymphopenia common during first week of illness, with nadir at 5 to 7 days after symptom onset (Dumler et al, 1993a) 1995; Everett, 1994; Fichtenbaum, 1995; Bakken, 1996; (Fishbein et al, 1994). Most leukocyte elements tend to decrease simultaneously, with largest decrease occurring in total lymphocyte count (almost 60% decrease from day 1 to 3) (Fishbein et al, 1994).
    E) LYMPHOCYTOSIS
    1) Occurs on 7th to 14th day of illness in about 2/3 of patients; count may be as high as 80% of total WBC count. Cause is unknown (Everett, 1994; (Fishbein et al, 1994).
    2) A mononucleosis-like illness has been reported in Japan and Malaysia, and has been associated with Ehrlichiosis sennetsu infection (Fishbein et al, 1987).
    F) THROMBOCYTOPENIC DISORDER
    1) Characteristic feature during first week of illness, noted in about 70% of patients with HME and 90% of those with HGE (Dumler & Bakken, 1995; Fishbein et al, 1994) Bakken, 1996).
    2) Often present on initial evaluation and is most severe 6 to 7 d after illness onset (Standaert, 1995; (Fishbein et al, 1994) Everett, 1994; (Dumler & Bakken, 1995).
    3) In severe infection, thrombocytopenia and coagulopathy may predispose to hemorrhagic complications (Bakken, 1994).
    G) ANEMIA
    1) Minimal anemia (usually normocytic normochromic) is common finding, noted in about 50% of cases (Dumler et al, 1993a) 1995; Everett, 1994; Fichtenbaum, 1995; Bakken, 1996).
    2) Develops later in course (after 1st week of illness) and usually is transient (Eng, 1990). May indicate more severe illness, particularly in elderly patients (Bakken, 1996).
    H) BLOOD COAGULATION PATHWAY FINDING
    1) Findings may include prolongation of aPTT, increased FSPs, normal fibrinogen levels, particularly in more seriously ill patients; prolonged PT/INR rare (Everett, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) Uncommon in adults; more likely to occur in children (60% to 100%) (Eng, 1990; (Harkess, 1991) Knapp, 1995); noted in 20% to 30% of patients with HME and in <10% of those with HGE. If it occurs, it develops later in course (Fishbein et al, 1994) Bakken, 1996; (McDade, 1990) Everett, 1994).
    2) Appears in various forms and is not reliable or specific sign of the disease; location and extent usually related to area of tick bite. Typically maculopapular or petechial. Most commonly involves trunk, legs, arms; rarely involves palms or soles (McDade, 1990; Fishbein et al, 1994) Bakken, 1994, 1996; Everett, 1994; Eng, 1990; (Harkess, 1991) Fichtenbaum, 1995).
    3) Often not present until several days after illness onset or initial presentation; often faint and short-lived (Harkess, 1991).
    B) EXCESSIVE SWEATING
    1) Occurs in about 50% of patients with HME and 90% of those the HGE (Fishbein et al, 1994) Bakken, 1994).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) Muscle pain, a classic presenting symptom; noted in >70% of patients. More common in HGE than in HME (Standaert, 1995; Bakken, 1996; (Fishbein et al, 1994; Dumler & Bakken, 1995) Aguero-Rosenfeld, 1996). Pain typically severe and usually diffuse, but can be localized to one area, e.g., lower back (Harkess, 1991) Everett, 1994).
    B) JOINT PAIN
    1) Joint pain occurs in about 40% of patients with HME and 25% of those with HGE (Bakken, 1996; (Fishbein et al, 1994) Petersen, 1989; (Dumler & Bakken, 1995).

Reproductive

    3.20.1) SUMMARY
    A) HGE has been transmitted perinatally to the infant. It has been treated successfully with doxyclycline.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Two cases occurred during pregnancy (at 25 and 35 weeks' gestation); the infants did well (Buitrago, 1998). In another case, HGE was transmitted perinatally to the infant. Route of infection (intrauterine, intrapartum, or through breast-feeding) could not be determined, although transplacental transmission is suspected (Horowitz, 1998). Both the mother who developed HGE near-term and her infant were treated successfully with doxycycline.
    2) HGE during pregnancy treated successfully with rifampin has been reported (Buitrago, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC, renal and hepatic function.
    B) Laboratory values often are normal or near normal during first few days of illness. Abnormalities are transient and most pronounced at 5 to 7 days after onset.
    C) Diagnostic and confirmatory tests include careful examination of peripheral blood smears, immunocytology, immunohistology, PCR, isolation of Ehrlichia, serology; not available in most laboratories.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Laboratory values often are normal or near normal during first few days of illness. Abnormalities are transient and most pronounced at 5 to 7 days after onset (Fishbein et al, 1994; Dumler & Bakken, 1995). Because HME and HGE are separate diseases caused by different etiologic agents, serologic diagnosis requires different tests for each; assays that confirm one do not confirm the other (Dumler & Bakken, 1995).
    2) Monitor CBC, renal and hepatic function. Thrombocytopenia, depressed lymphocyte counts, anemia, elevated aminotransferase and serum creatinine levels have been reported (Bakken et al, 1994; Standaert et al, 1995).
    3) Diagnostic and confirmatory tests include careful examination of peripheral blood smears, immunocytology, immunohistology, PCR, isolation of Ehrlichia, serology; not available in most laboratories. Of these, careful exam of peripheral blood smears (especially by examiner familiar with ehrlichial morulae), PCR (acute infection), and serology (convalescence) are used primarily (Dumler & Bakken, 1995).
    4) Diagnostic and confirmatory tests are not available in most laboratories (Dumler & Bakken, 1995). Serologic testing for HME is available at the CDC and selected state health department laboratories. Testing for HGE is available only at a few research laboratories (Dawson, 1996).
    4.1.4) OTHER
    A) OTHER
    1) OTHER
    a) CEREBROSPINAL FLUID: In patients with HME, change in mental status is most common clinical finding predictive of CSF abnormalities (Ratnasamy, 1996).
    1) May be indicative of meningeal inflammation, e.g., increased protein and lymphocyte counts and slight decrease in glucose level. However, CSF findings are nonspecific and may mimic those found in encephalitis and infectious mononucleosis (Standaer, 1998; Everett, 1994; Fichtenbaum, 1995; (Harkess et al, 1990; Golden, 1989; Dimmitt et al, 1989).
    2) The most common CSF abnormalities are lymphocytic pleocytosis and increased protein levels, each noted in about 75% of patients with CNS manifestations, with borderline low glucose in about 25% (Ratnasamy, 1996). PCR has identified E chaffeensis morulae in CSF mononuclear cells (Dunn, 1992).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Patients may have symptoms suggesting predominant involvement of a single organ system, including the lungs. Infiltrates may be seen on chest radiographs (Patel & Byrd, 1999) Weaver et al, 1999; (Fishbein et al, 1994) Bakken, 1996; Everett, 1994; (Dumler & Bakken, 1995) Eng, 1990).
    2) Ehrlichiosis should be included in the differential diagnosis for pulmonary edema-type patterns with alveolar opacities and pleural effusion seen on chest radiographs (Patel & Byrd, 1999) Weaver et al, 1999; Fordham, 1998).
    B) CT/MRI
    1) Although radiologic studies performed in patients presenting with CNS findings may not show lesions that aid in any specific diagnosis, these studies may be of value in ruling out other diagnoses such as subdural empyema, brain abscess, and focal viral encephalitis (Ratnasamy, 1996).

Methods

    A) BIOASSAY
    1) POLYMERASE CHAIN REACTION ASSAY
    a) PCR assay appears to be the most sensitive technique for timely laboratory diagnosis, but the test is not widely available (Bakken, 1996).
    b) A rapid and sensitive PCR-based procedure using unfractionated whole blood is described that can detect and differentiate HGE and HME with speed (less than 1 h), simplicity, specificity, and sensitivity (Chu, 1998).
    c) In absence of whole blood specimens, PCR assay of acute-phase serum may be useful method for early detection of ehrlichiosis and determination of etiology when serologic testing is inconclusive; results available within 24 to 48 hours. Has sensitivity of 80% to 87% during acute phase (Comer, 1999; Dumler, 1995a; Everett, 1994; Anderson, 1992).
    B) GENERAL
    1) PERIPHERAL BLOOD SMEAR: Ehrlichial infections may be recognized by presence of morulae (coccobacilli) in circulating peripheral blood leukocytes (HME) or neutrophils (HGE). Morulae contain up to several dozen organisms and take on characteristic mulberry-like configuration that can be seen on light microscopy.
    a) May provide useful information at institutions with appropriately trained personnel (Dumler & Bakken, 1995).
    b) HGE: Quickest and most practical screening method for diagnosing HGE in endemic areas (e.g., upper Midwest), where 80% of acutely infected patients are smear-positive. However, a negative blood smear should not rule out the diagnosis nor the need for antibiotic therapy (Bakken, 1994, 1996; (Dumler & Bakken, 1995) Aguero-Rosenfeld, 1996).
    c) HME: This method of diagnosis is extremely insensitive (Dumler & Bakken, 1995) Everett, 1994).
    2) ANTIBODY TITER, EHRLICHIA: Used to confirm clinical diagnosis during convalescence; provides little information that might assist in management of acute phase of illness since seroconversion may take 4 or more weeks to occur (Everett, 1994; Bakken, 1996). Serologic testing for HME is available at the CDC and selected state health department laboratories; for HGE, is available only at a few research laboratories (Dawson, 1996).
    a) HME: Serologic response indicated by 4-fold increase in E chaffeensis antibody titer (minimum titer, 64) or single high serum antibody titer (>/=128) for patients with clinical compatible history (Fishbein et al, 1994). Response may be absent in persons coinfected with HIV (Paddock, 1993).
    b) HGE: Serologic response indicated by 4-fold increase in titer to E equi antigen (minimum titer, 80) (Bakken, 1994).
    3) PROTEIN, C-REACTIVE: Moderate elevation may be seen in HGE, but this is nonspecific test (Bakken, 1996).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.6) DISPOSITION/BITE-STING EXPOSURE
    6.3.6.1) ADMISSION CRITERIA/BITE-STING
    A) At least 50% to 60% of patients require hospitalization, and some may require ICU care. About 15% develop severe disease, related to delay in diagnosis and treatment (Bakken, 1996; (Fishbein et al, 1994).
    B) Elderly patients and those not receiving appropriate antibiotics within first week after illness onset are at particular risk for severe disease or death (Fishbein et al, 1994) Bakken, 1996).
    6.3.6.2) HOME CRITERIA/BITE-STING
    A) Reliable patients with mild illness may be discharged home with close follow up.
    6.3.6.3) CONSULT CRITERIA/BITE-STING
    A) Consultation with an infectious disease or critical care specialist may be required in patients with severe disease or who develop complications. Diagnostic and confirmatory tests are not available in most laboratories (Dumler & Bakken, 1995). Serologic testing for HME is available at the CDC, selected state health department laboratories, and one commercial laboratory in California. Testing for HGE is available only at a few research laboratories (Dawson, 1996).

Monitoring

    A) Monitor CBC, renal and hepatic function.
    B) Laboratory values often are normal or near normal during first few days of illness. Abnormalities are transient and most pronounced at 5 to 7 days after onset.
    C) Diagnostic and confirmatory tests include careful examination of peripheral blood smears, immunocytology, immunohistology, PCR, isolation of Ehrlichia, serology; not available in most laboratories.

Range Of Toxicity

Summary

    A) One tick may be enough to cause an infection. Risk of infection is increased with tick attachment longer than 48 to 72 hours.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) One tick may be enough to cause an infection. Risk of infection is increased with tick attachment longer than 48 to 72 hours. Duration of symptomatic illness usually is 2 to 3 weeks but may be as long as 6 weeks (Dumler & Bakken, 1995) Fowler, 1993; Eng, 1990).
    2) Mortality is estimated to be as high as 2% to 5%; related to delayed or inappropriate treatment (Fishbein et al, 1994; Dumler & Bakken, 1995).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Pathophysiology is poorly understood, although similar clinical and laboratory manifestations of HME and HGE despite different microbial etiologies suggest similar pathogenesis (Dumler & Bakken, 1995) Bakken, 1996).
    1) Target cells in both infections are professional phagocytes (ie, macrophages in HME and granulocytes in HGE). Therefore, liver, spleen, bone marrow, and lymph nodes are predominant organs affected, although involvement of lungs, kidneys, and CSF has been reported. Both infections may alter normal host defenses (Dumler & Bakken, 1995) Bakken, 1996).
    2) Spectrum of agents involved implies defects in both nonspecific neutrophil phagocytic host defenses and specific T and B cell-mediated immunity. Host immunocompetence may be major determinant of outcome (Dumler & Bakken, 1995) Bakken, 1996).
    3) Both agents can infect many organs and tissues; however, heaviest burden of infection is seen in liver, spleen, bone marrow, and lymph nodes. Also may infect pulmonary interstitium, adrenal glands, kidneys, and CSF (E chaffeensis) (Dumler & Bakken, 1995) Bakken, 1996).
    4) Despite clinical presentation that may suggest a defect in systemic microvascular integrity, vasculitis is NOT underlying pathologic feature (Dumler & Bakken, 1995) Bakken, 1996).
    B) HME
    1) Infection occurs primarily in fixed tissue mononuclear phagocytes; granulomas often identified in liver and bone marrow (Dumler et al, 1993a) Yu, 1993).
    2) Leukopenia and thrombocytopenia most often result from peripheral sequestration or destruction of various blood elements (hemophagocytic syndrome), although hypoplasia of marrow elements is present occasionally (Dumler et al, 1993a).
    3) Disease progression (Dumler & Bakken, 1995):
    a) Tick inoculation of E chaffeensis into dermis, followed by spread via microvasculature or lymphatics.
    b) Organisms enter or spread to other mononuclear phagocytes in spleen, liver, bone marrow, lymph nodes, and occasionally lung. Subsequently, organisms proliferate, heavily infected cells are injured, tissue is injured indirectly by cytokines or other mediators, and ehrlichiae are released.
    c) This initiates immunologic and nonspecific inflammatory mechanisms, leading to sequestration, destruction of infected circulating cells, or granuloma formation.
    d) Disease severity may be determined by balance between induced protective immunity, inflammatory host-cell injury, and mediation of cytolysis by the organisms. However, other evidence suggests that direct ehrlichia- mediated injury, rather than immune mechanisms initiated after infection, determine severity of infection (Marty, 1995).
    C) HGE: Still being studied. May be microbial synergy with Lyme disease in pathogenesis of clinical features (Walker, 1996).

Animal Toxicology

Clinical Effects

    11.1.2) BOVINE/CATTLE
    A) TICK-BORNE FEVER -
    1) Clinical Manifestations: A form of Ehrlichiosis seen in European ruminants, which causes fever, abortion, and decreased milk production in lactating dairy cows (Cranwell & Gibbons, 1986).
    11.1.3) CANINE/DOG
    A) EHRLICHIOSIS -
    1) Vector: E. canis or E. platys. Infects dogs and other canids.
    2) Clinical Manifestations: It parasitizes leukocytes and causes fever and hematological disorders. Clinical signs include: thrombocytopenia (that becomes cyclical); inflammatory vasculitis; anorexia; dyspnea; weight loss; epistaxis; late, profound, pancytopenia; fever; myalgia; rigors; headache; nausea; bradycardia; and leukopenia (Fishbein et al, 1987).
    a) Signs occur in three phases, which last 2 to 4 weeks, 6 to 9 weeks, and 12 to 16 weeks, respectively. Signs may worsen during stress periods.
    3) Laboratory: About 10 to 15% of these dogs are Coombs' positive.
    4) Diagnosis: Serological testing is usually diagnostic, especially at 20 days or more following infection. Positive serology to E. risticii, and not to E. canis, has been reported in dogs with clinical signs of ehrlichiosis (Kokoma et al, 1991).
    a) Another good diagnostic method is examination of peripheral blood neutrophils for ehrlichial norulae (Stockham et al, 1992).
    11.1.5) EQUINE/HORSE
    A) EHRLICHIOSIS -
    1) Vector: Ehrlichiosis equi
    2) Clinical manifestations include inflammatory vasculitis, ventral edema, moderate fever, anorexia, depression, mucosal petechiae, and ataxia. The signs usually resolve in 2 weeks, and death is rare. Abnormalities include anemia, leukemia, and thrombocytopenia (Robinson, 1987).
    3) Diagnosis is made by observation of characteristic granular inclusion bodies in neutrophil cytoplasm.
    4) Laboratory: A serological cross-reaction has been reported between Ehrlichia and Cowdria ruminatium, the causative agent of Heartwater disease in ruminants of Africa and the Caribbean (Jongejan et al, 1989).
    11.1.9) OVINE/SHEEP
    A) TICK-BORNE FEVER -
    1) Clinical manifestations include a form of Ehrlichiosis seen in European ruminants, which causes significant losses of lambs after signs of anorexia and depression (Brodie et al, 1986).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Remove the patient and other animals from the tick infested area.
    2) Treatment should always be done on the advice and with the consultation of a veterinarian.
    3) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    4) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) Remove the offending tick if it is still on the animal. If none can be found, consider an insecticidal dip, especially with large animals, to remove ticks.
    11.2.5) TREATMENT
    A) DOGS/CATS
    1) ANAPHYLAXIS -
    a) AIRWAY - Maintain a patent airway via endotracheal tube or tracheostomy.
    b) EPINEPHRINE - For severe reactions.
    1) DOGS - 0.5 to 1 milliliter of 1:10,000 (DILUTE) solution intravenously or subcutaneously.
    2) CATS - 0.5 milliliter of 1:10,000 (DILUTE) solution intravenously or intramuscularly.
    3) DILUTION - Be sure to dilute epinephrine from the bottle (1:1000) one part to 9 parts saline to obtain the correct concentration (1:10,000).
    4) REPEAT DOSES - If indicated, doses may be repeated in 20 minutes.
    c) FLUID THERAPY -
    1) If necessary, begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day) intravenously or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour.
    2) Monitor for urine production and pulmonary edema.
    d) ANTIHISTAMINES - Administer doxylamine succinate (1 to 2.2 milligram/kilogram subcutaneously or intramuscularly every 8 to 12 hours).
    e) STEROIDS - Administer dexamethasone sodium phosphate (1 to 5 milligrams/kilogram intravenously every 12 to 24 hours), or prednisone (1 to 5 milligram/kilogram intravenously every 1 to 6 hours).
    2) EHRLICHIOSIS - Tetracycline (33 milligrams/kilogram twice daily for 12 to 14 days) is recommended. If this fails, use doxycycline (5 to 10 milligrams/kilogram once daily for 7 to 14 days). Animals in the chronic terminal phase of the disease rarely respond to treatment.
    B) RUMINANTS/HORSES/SWINE
    1) ANAPHYLAXIS -
    a) AIRWAY - Maintain a patent airway via endotracheal tube or tracheostomy.
    b) FLUIDS -
    1) HORSES - Administer electrolyte and fluid therapy as needed. Maintenance dose of intravenous isotonic fluids: 10 to 20 milliliters/kilogram per day. High dose for shock: 20 to 45 milliliters/kilogram/hour.
    a) Monitor for packed cell volume, adequate urine output and pulmonary edema. Goal is to maintain a urinary flow of 0.1 milliliters/kilogram/minute (2.4 liters/hour) for an 880 pound horse.
    2) CATTLE - Administer electrolyte and fluid therapy, orally or parenterally as needed. Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day. Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.
    c) EPINEPHRINE -
    1) HORSES - 3 to 5 milliliters/450 kilograms of 1:1000 epinephrine intramuscularly or subcutaneously.
    2) CATTLE & SWINE - 0.02 TO 0.03 milligrams/kilogram of 1:1000 epinephrine subcutaneously, intramuscularly, or intravenously.
    2) EHRLICHIOSIS - Oxytetracycline (2.4 milligram/kilogram intravenously twice daily) will hasten recovery. Recovery is usually complete in two weeks (Robinson, 1987).

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Remove the patient and other animals from the tick infested area.
    2) Treatment should always be done on the advice and with the consultation of a veterinarian.
    3) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    4) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) Remove the offending tick if it is still on the animal. If none can be found, consider an insecticidal dip, especially with large animals, to remove ticks.

References

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