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The Perils of Country Life: Human Monocytic Ehrlichiosis

      Presentation

      An ordinary day began with a patient transfer from a rural hospital in Eastern Kentucky. The 26-year-old woman presented to the outside hospital with a 2-day history of shortness of breath and productive cough, which had been preceded by several days of generalized fatigue, subjective fever, and chills. She denied recent travel, exposure to animals, or sick contacts but reported exposure to tick bites. She had a 6 pack-year smoking history and did not use alcohol or illicit drugs. The time of year was not typical for the flu, and the patient had been in perfect health prior to the current presentation.
      She arrived at our institution several hours after the morning phone call. Her vital signs were as follows: temperature, 99.7°F (37.6°C); heart rate, 116 beats/minute; blood pressure, 99/43 mmHg; and respiratory rate, 28 breaths/minute. Oxygen saturation was 93% on 3L/min via nasal cannula. Physical examination revealed periorbital ecchymosis and subconjunctival hemorrhages. The patient was alert and oriented to person, place, and time and exhibited no focal neurological deficits. Auscultation of her chest disclosed reduced breath sounds and crackles bilaterally, especially in the bases. Examinations of the heart and abdomen were normal.

      Assessment

      A chest x-ray and computed tomography (CT) demonstrated bilateral pulmonary infiltrates in an airspace pattern (Figure 1). Laboratory data identified a leukocyte count of 2.2 × 103 cells/μL, hemoglobin count of 10.8 g/dL, and platelet count of 37,000 platelets/uL. Blood chemistry measured sodium at 130 mmol/L, potassium at 3.8 mmol/L, chloride at 98 mmol/L, bicarbonate at 18 mmol/L, blood urea nitrogen at 26 mg/dL, and creatinine at 1.63 mg/dL. Liver enzymes were markedly elevated with an aspartate aminotransferase level of 1312 U/L, and alanine aminotransferase level of 581 U/L. Total bilirubin was 2.7 mg/dL, with 2.2 mg/dL constituting the conjugated fraction, and alkaline phosphatase was 320 U/L. The international normalized ratio was 1.8; prothrombin time, 18 sec. Tylenol, salicylate, alcohol, methanol, and ethylene glycol levels were all negative, and a urine drug screen was unremarkable.
      Figure thumbnail gr1
      Figure 1A, The chest x-ray revealed bilateral pulmonary infiltrates. B, Computed tomography (CT) of the chest showed bilateral airspace disease.
      The patient had pancytopenia, acute kidney injury with a high anion gap, metabolic acidosis, acute liver injury with impaired liver synthetic function, and coagulopathy. Shortly after admission, her temperature and heart rate increased to 102.6°F (39.2°C) and 145 beats/min, respectively, and her blood pressure dropped to a systolic reading of less than 80 mmHg without a significant response to fluid resuscitation. She became disoriented and had evidence of bleeding from oral mucous membranes. The overall clinical and biochemical picture was consistent with septic shock, disseminated intravascular coagulation, and multiorgan failure from a presumed infectious source.
      Blood cultures were obtained, and the patient was started on empiric broad-spectrum antibiotics. Doxycycline was added, based on her history of tick exposure and the geographic location in which she lived. She was transferred to the intensive care unit, where she required mechanical ventilation, transfusion of blood products, and initiation of vasopressor support. The differential diagnosis included 2 broad categories: infection and autoimmune disease with superimposed infection. Legionnaires' disease, acute viral hepatitis, infectious mononucleosis, bacterial meningitis, autoimmune hepatitis, acute Wilson's disease, and anti-neutrophil cytoplasmic antibody-associated vasculitides were under consideration.
      Active bleeding and disseminated intravascular coagulation prevented us from doing a lumbar puncture. A bronchoscopy was performed, and bronchoalveolar lavage samples were sent for Gram stain, bacterial culture, influenza and respiratory syncytial virus polymerase chain reaction, and fungal evaluation, all of which were negative. Furthermore, blood and urine studies were negative, including testing for viral hepatitis, human immunodeficiency virus, Legionella and Histoplasma urinary antigens, and leptospirosis antibodies. Viral polymerase chain reaction and serology for parvovirus B19, cytomegalovirus, Epstein-Barr virus, herpes simplex viruses types 1 and 2, and human herpes virus-6 were also negative.
      Laboratory studies for antinuclear antibodies, anti-double-stranded DNA, anti-smooth muscle antibody, ceruloplasmin, antineutrophil cytoplasmic antibodies, anti-glomerular body antibodies, and anti-Jo-1 antibody, were negative as well. The tick-borne disease work-up included indirect fluorescent antibody (IFA) testing for Rickettsia ricketsii IgG and IgM titers, polymerase chain reaction for Babesia microti, and IFA testing for IgG and IgM and polymerase chain reaction for detection of Anaplasma phagocytophilum and Ehrlichia chafeensis. An elevated (1:512) initial IgG antibody titer to E. chaffeensis was identified, but all other tests were negative. These results, combined with the clinical presentation, made the diagnosis of human monocytic ehrlichiosis the most likely one.

      Diagnosis

      Human monocytic ehrlichiosis is a tick-born illness caused by Ehrlichia species, including Ehrlichia chaffeensis. It commonly presents as a self-limited sickness with symptoms that most often include fever (>95%), headache (60-75%), myalgias (40-60%), nausea (40-50%), arthralgias (30-35%), and malaise (30-80%).
      • Ganguly S.
      • Mukhopadhayay S.K.
      Tick-borne ehrlichiosis infection in human beings.
      In rare cases, it manifests as a life-threatening illness with features of toxic shock-like syndrome and end-organ damage; this mostly occurs in the immunocompromised, geriatric, or pediatric populations.
      • Fichtenbaum C.J.
      • Peterson L.R.
      • Weil G.J.
      Ehrlichiosis presenting as a life-threatening illness with features of the toxic shock syndrome.
      The most important determinant in the diagnosis of human monocytic ehrlichiosis is clinical suspicion. In addition to symptoms, pancytopenia is an important hematologic abnormality that is frequently associated with human monocytic ehrlichiosis.
      • Ismael N.
      • Bloch K.C.
      • McBride J.W.
      Human ehrlichiosis and anaplasmosis.
      Thrombocytopenia is detected in 70-90% of patients over the course of the illness, leukopenia is observed within the first week in 60-70%, and anemia is noted within the first 2 weeks of presentation in 50% of patients. Elevated hepatic transaminases are present in almost 90% of patients.
      • Olano J.P.
      • Hogrefe W.
      • Seaton B.
      • Walker D.H.
      Clinical manifestations, epidemiology, and laboratory diagnosis of human monocytotropic ehrlichiosis in a commercial laboratory setting.
      Rapid diagnostic tests, such as polymerase chain reaction, are not readily available in all hospitals, and the delay in the appearance of detectable antibodies until 7-14 days after clinical presentation makes it essential to treat empirically based on clinical presentation and laboratory abnormalities. Confirmatory testing is still necessary when the clinical suspicion is high and includes antibody serology, polymerase chain reaction, and the visualization of morulae in leukocytes on a peripheral blood smear (Table).
      TableDiagnostic Tests for Human Monocytic Ehrlichiosis with the Corresponding Sensitivities and Specificities in Relation to Disease Course
      Diagnostic TestTime CourseSensitivitySpecificity
      Peripheral smear showing morulaeEarly (first wk)3-20%>90%
      Polymerase chain reaction (PCR)Early (first wk)55-87%99%
      Serology with immunofluorescence assay (IFA)Late (after 7-14 d) and requires documented 4-fold rise in 2-3 wk94-100%99%
      Serologic detection of IgM and IgG antibodies specific to E. chaffeensis with IFA is considered the gold standard for diagnosis. Human monocytic ehrlichiosis is confirmed with a single IgG titer of at least 1:256, the detection of IgG or IgM antibodies 2-3 weeks after an initial negative result on IFA, or a 4-fold increase in antibody titer on a repeat test performed 2 weeks after the first.
      • Childs J.E.
      • Sumner J.W.
      • Nicholson W.L.
      • Massung R.F.
      • Standaert S.M.
      • Paddock C.D.
      Outcome of diagnostic tests using samples from patients with culture-proven human monocytic ehrlichiosis: implications for surveillance.
      Our patient's repeat serology 2 weeks later revealed an IgG antibody titer >1:1024 and an IgM titer of 1:32, verifying the diagnosis.
      Polymerase chain reaction testing for detection of DNA is a popular adjunct to serology, and results are often positive during the first week of infection when antibody titers are still undetectable. Our patient's polymerase chain reaction result was negative, but the sample was taken almost a week after the initiation of doxycycline, which significantly diminishes the sensitivity of the test. Finally, the visualization of morulae in leukocytes from a peripheral smear provides a rapid answer that is highly suggestive of infection, but the test has low sensitivity (Table).
      • Chapman A.S.
      • Bakken J.S.
      • Folk S.M.
      • et al.
      Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis—United States: a practical guide for physicians and other health-care and public health professionals.
      Our patient's peripheral smear was negative for morulae.

      Management

      The current recommended regimen for the treatment of human monocytic ehrlichiosis is doxycycline, 100 mg, twice daily for 5-14 days.
      • Thomas R.J.
      • Dumler J.S.
      • Carlyon J.A.
      Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis.
      Our patient was given doxycycline immediately upon admission because of suspicion for a tick-borne illness, and she went on to complete a 14-day course of intravenous doxycycline, 100 mg, twice daily. Unfortunately, because of the patient's late presentation—she was symptomatic for several days before presenting to the outside hospital and was still symptomatic when transferred to our facility after a few more days—and the severity of her illness, her hospital stay was prolonged by complications. These were septic shock, disseminated intravascular coagulation, acute renal failure, fulminant liver failure causing diffuse cerebral edema with uncal herniation (Figure 2), and acute pancreatitis. Her illness was managed supportively, and she was discharged to a long-term acute care facility where she remained for about 2 months. Ultimately, she made a full recovery.
      Figure thumbnail gr2
      Figure 2Head CT demonstrated diffuse brain swelling with uncal herniation.
      Patients with a delay in treatment have a significantly increased rate of transfer to the intensive care unit, increased risk for mechanical ventilation, longer hospital stay, and longer duration of illness.
      • Fishbein D.B.
      • Dawson J.E.
      • Robinson L.E.
      Human ehrlichiosis in the United States, 1985 to 1990.
      • Hamburg B.J.
      • Storch G.A.
      • Micek S.T.
      • Kollef M.H.
      The importance of early treatment with doxycycline in human ehrlichiosis.
      Encephalopathy, acute renal failure, pulmonary infiltrates, and death have been reported in patients with severe human monocytic ehrlichiosis.
      • Olano J.P.
      • Hogrefe W.
      • Seaton B.
      • Walker D.H.
      Clinical manifestations, epidemiology, and laboratory diagnosis of human monocytotropic ehrlichiosis in a commercial laboratory setting.
      • Eng T.R.
      • Harkess J.R.
      • Fishbein D.B.
      • et al.
      Epidemiologic, clinical, and laboratory findings of human ehrlichiosis in the United States, 1988.
      Physicians should be aware of the broad spectrum of potential disease manifestations. Careful questioning about tick exposures, knowledge of endemic areas, and recognition of common laboratory abnormalities can aid in the early initiation of empiric therapy and the prevention of morbidity and mortality.

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