Human Ehrlichiosis -- Maryland, 1994

Ehrlichiosis is an emerging tickborne infectious disease caused by obligate intracellular, gram-negative rickettsia that infect leukocytes. Human monocytic ehrlichiosis (HME) is caused by Ehrlichia chaffeensis and is believed to be transmitted by Amblyomma americanum (the Lone Star tick). Most HME cases have been reported in southeastern and south-central states. During May-July 1994, five cases of serologically confirmed HME were identified among residents of Maryland. All five persons lived near the Chesapeake Bay and had antecedent histories of tick exposure. This report summarizes the clinical and epidemiologic features of these cases and the results of serologic testing at CDC of specimens from Maryland residents with suspected tickborne infection.

Case 1. On May 17, 1994, a 35-year-old man had onset of fever, headache, malaise, fatigue, myalgia, and back pain. His illness progressed to include anorexia, nausea, vomiting, diarrhea, and a nonproductive cough. On May 22, he was admitted to a hospital for evaluation with a white blood cell count (WBC) of 7.2 X 106/L (with 63% neutrophils and 20% band forms) and a temperature of 100.3 F (37.9 C), and rales were noted in the right lung base. Other laboratory abnormalities included thrombocytopenia (platelet count: 118 X 106/L {normal: 150-400 X 106/L}) and elevated aspartate aminotransferase (AST) (87 IU/L {normal: 8-20 IU/L}) and lactate dehydrogenase (LDH) (303 IU/L {normal: 45-90 IU/L}). The patient's hospital course included persistent fever despite intravenous (IV) treatment with a third-generation cephalosporin, hypotension, and progressive confusion and somnolence. Bacterial cultures of blood, cerebrospinal fluid (CSF), and stool and serologic tests, including an antibody titer for E. chaffeensis, were negative. He was placed in intensive care for pharmacologic support of his blood pressure. Analysis of CSF indicated lymphocytic pleocytosis. Because he did not improve within 48 hours, the antibiotic regimen was empirically changed to IV ciprofloxacin and doxycycline, and symptoms began to resolve within 24 hours. He was discharged on May 30. A serum specimen obtained at discharge was positive for E. chaffeensis antibody by immunofluorescent assay (IFA) (titer of 1:4096). The patient reported a history of extensive tick exposure associated with his job as a surveyor and at his residence on a farm in Kent County.

Case 2. On June 3, 1994, a 41-year-old man had onset of fever, chills, severe headache, malaise, fatigue, myalgia, and back pain. His illness progressed during the next week, and he was evaluated as an outpatient. On June 10, he was admitted to a hospital because of continuing fever and progression of symptoms. Physical examination was normal except for a temperature of 101 F (38.3 C). Laboratory tests included a WBC of 3.4 X 106/L (with 12% atypical lymphocytes); AST, 268 IU/L; LDH, 517 IU/L; alkaline phosphatase (AP), 150 IU/L (normal: 20-70 IU/L); 1+ protein, ketones, and bilirubin in the urine; and CSF lymphocytic pleocytosis. An initial serologic test for E. chaffeensis antibodies and other infectious agents and bacterial cultures of blood were negative. Because the patient's physician was aware of case 1 and recognized clinical similarities to that case, E. chaffeensis infection was suspected, and he was treated with IV ciprofloxacin and doxycycline. Although the patient's fever resolved in 3 days, headache, myalgia, and lethargy persisted. He was discharged on June 16. Analysis of a serologic specimen obtained at discharge detected a titer to E. chaffeensis of greater than 1:1024; a follow-up titer to E. chaffeensis obtained 2 months after the onset of his illness was less than 1:16. Diplopia attributed to a palsy of the sixth cranial nerve developed late in the course of illness but subsequently resolved. The patient reported frequent exposure to ticks in the vicinity of his residence in a small town and while hiking and biking in the neighboring woods of Kent County.

Case 3. In July 1994, a 45-year-old construction worker who lived near Annapolis and worked in Aberdeen had gradual onset of fatigue, fever, headache, myalgia, and malaise. He sought care from his physician on July 20 and received trimethoprim-sulfamethoxazole for suspected sinusitis. However, he developed nausea, vomiting, diarrhea, and jaundice, and on July 27 his physician prescribed doxycycline and obtained a serum sample for Lyme disease (LD) serology (antibody to Borrellia burgdorferi). On about August 1, the physician notified the patient to discontinue the doxycycline because his LD test was negative (titer less than 1:75). On August 8, the patient was hospitalized because of continuation and progression of his symptoms. Clinical and laboratory findings included an elevated temperature, petechial rash, leukopenia, thrombocytopenia, and modestly elevated levels of serum alanine aminotransferase (ALT) and AST. IV doxycycline and cefotaxime were initiated for treatment of the unexplained fever and severe headache. When analysis of CSF, an abdominal ultrasound, and a computerized axial tomography of the brain were normal, the cefotaxime was discontinued. Analysis of a blood specimen obtained August 10 included an indeterminate IFA for Rocky Mountain spotted fever (RMSF) and an E. chaffeensis titer of 1:1024. Symptoms began to resolve within 3-4 days after initiation of IV doxycycline, and monocytic inclusion bodies were detected in a peripheral blood smear obtained August 15. The patient reported that on some days he removed 25-30 ticks from his clothes and that 2 weeks before onset of symptoms, he removed a partially engorged tick from his hip approximately 36 hours after attachment.

Case 4. On July 27, 1994, a 63-year-old woman began a camping trip to Virginia, North Carolina, South Carolina, and Tennessee. On August 6, she removed an engorged tick attached to her back, which she believed had become attached 24-48 hours earlier during a hike in the mountains of eastern Tennessee. On August 8, she had onset of a backache followed by fever, headache, myalgia, abdominal pain, fatigue, and confusion. She was admitted to a hospital in Maryland on August 15 because of progression of her symptoms. Laboratory abnormalities on admission included pancytopenia -- which progressed over a 24-hour period to a WBC of 2.6 X 106/L, a red blood cell count of 3.5 X 106/L, and a platelet count of 88 X 106/L -- and increased levels of AP (245 IU/L) and AST (201 IU/L). Atypical pneumonia and hepatitis were suspected, and IV erythromycin was initiated. IV doxycycline subsequently was added to the regimen when a consulting physician suspected RMSF or ehrlichiosis. Because of persistent abdominal pain and tenderness with mildly elevated bilirubin, ALT, and AST, an ultrasonogram of the gall bladder was performed. The wall appeared thickened, and on August 16 she underwent a cholecystectomy; complications included extensive bleeding. Analysis of a blood sample obtained August 15 was negative for ehrlichiosis and RMSF; however, an IFA titer to E. chaffeensis was 1:1024 in a sample obtained August 23. Administration of doxycycline was continued, and she was discharged on September 11.

Case 5. On June 20, 1994, a 38-year-old man who worked at a golf course had onset of fatigue, "a feverish feeling," myalgia, arthralgia, mild headache, and generalized weakness. On June 23, he was examined by a physician who diagnosed atrial fibrillation; neutropenia (1.2 X 106/L) with a lymphocytosis (59%) was detected. Digoxin was initiated for treatment of atrial fibrillation. On June 27, he was hospitalized to evaluate his persistent fever. Findings included a temperature of 104 F (40 C), headache, facial flushing, generalized mild lymphadenopathy, and enlarged erythematous tonsils. Although his WBC had increased to 4.2 X 106/L, his platelet count had decreased (from 153 X 106/L to 100 X 106/L), and liver enzymes were slightly elevated (AST: 70 IU/L and ALT: 72 IU/L). Treatment with gentamicin and piperacillin was initiated for fever of uncertain origin. However, because rickettsial disease infection was suspected, on June 30 treatment was changed to include ampicillin and doxycycline. His clinical condition improved markedly within 48 hours. An IFA of a serum specimen obtained June 30 indicated a titer to E. chaffeensis of greater than or equal to 1:512, and an enzyme immunoassay for LD indicated a titer of 1:435. The patient reported removing nonengorged ticks from his body approximately 2-3 weeks before the onset of his illness.

Serologic testing. The Shore Health Laboratory in eastern Maryland saved frozen aliquots of serum specimens from 91 patients submitted for RMSF serology by physicians practicing on the eastern shore of Maryland during 1993 and 1994. CDC performed IFAs for Rickettsia rickettsii and E. chaffeensis antibodies on these specimens. Of the 12 persons who provided both acute- and convalescent-phase specimens, one was positive for R. rickettsii and two for E. chaffeensis; of the latter two, one had at least an eightfold increase in IFA titer, and the other had titers of 1:256 and 1:512 on serum samples drawn 6 weeks apart. Of the 79 patients with one blood specimen, no samples were positive for R. rickettsii; however, 11 (14%) had titers to E. chaffeensis of greater than or equal to 1:128, which is considered to be consistent with recent infection.

Reported by: LE Silvers, DVM, S Watkins, GT Strickland, MD, School of Medicine, Univ of Maryland, Baltimore; M Clothier, J Grant, MD, Kent County Health Dept, Chestertown; E Hall, DVM, L Joe, MD, Anne Arundel County Health Dept, Annapolis; MA Thompson, Queen Anne's County Health Dept, Centreville; S Sullivan, MS, Talbot County Health Dept, Easton; J Ryan, MD, Queen Anne's and Talbot county health depts; P Shanahan, MD, CG Baumann, MD, Chestertown; M Shochet, MD, Glen Burnie; G Sprouse, MD, Chester; JT Nevins, MS, H McQuay, Shore Health Laboratories, Easton; E Israel, MD, DM Dwyer, MD, State Epidemiologist, Maryland Dept of Health and Mental Hygiene. Viral and Rickettsial Zoonoses Br, Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: The findings of this investigation and results of IFAs for E. chaffeensis conducted by CDC on serum specimens from Maryland residents indicate that cases of HME occurred in Maryland at least as early as 1988 and that the incidence of HME may be increasing (Table_1). In addition, these findings are consistent with other reports indicating that the incidence of HME is equal to or greater than that of RMSF (1-3). Although no cases of human granulocytic ehrlichiosis (HGE) have been confirmed in Maryland, the clinical features of HGE are identical to those of HME (4), and its suspected vector, Ixodes scapularis, is present throughout the eastern and central part of the state. The IFAs for HME and HGE usually do not crossreact, and each test must be performed independently if ehrlichiosis is suspected in patients potentially exposed in areas where both vectors are present (4,5).

The cases described in this report underscore that serologic testing for ehrlichiosis often is negative during the acute phase of infection. Therefore, therapy with a tetracycline antibiotic or with chloramphenicol should be initiated based on clinical suspicion before the diagnosis is serologically confirmed (1-3). The responses of the cases in Maryland are consistent with previous reports (1,2), which indicate that IV therapy with large doses of third-generation cephalosporins -- a practice often used for treating fevers of unknown origin -- is not effective for treating ehrlichiosis, and treatment with doxycycline generally is associated with clinical improvement within 24-48 hours.

The cases in Maryland also reflect the spectrum of illness caused by HME. HME, HGE, and RMSF should be considered in the differential diagnosis of febrile patients with generalized illness who reside, work, or vacation in tick-endemic areas and who have histories of tick exposure (1-3). These tickborne infections may be associated with thrombocytopenia, elevated hepatic enzymes, and CSF pleocytosis, and should be included in the differential diagnosis of patients with suspected influenza, viral hepatitis, aseptic meningitis, and cholecystitis.

Because HME is transmitted by ticks, persons who work outdoors, participate in outdoor activities, or reside in tick-endemic areas should take precautions to reduce tick exposures. These include wearing long pants and pulling socks over the pants cuffs when walking in woods or grassy areas, using insect repellent, and carefully checking for and removing ticks found on clothing and skin.

The CDC surveillance case definition for ehrlichiosis requires a clinically compatible history with a minimum antibody titer of greater than or equal to 1:64 or a fourfold or greater change in antibody titers to E. chaffeensis using the IFA. Serum samples from persons with clinically suspected cases should be sent to CDC through the state health department or, in Maryland, to the Shore Health Laboratory at the Easton Memorial Hospital or to the Clinical Microbiology Laboratory at the Johns Hopkins Medical Systems in Baltimore.

References

1. Fishbein DB, Kemp A, Dawson JE, Greene NR, Redus MA, Fields DH. Human ehrlichiosis: prospective active surveillance in febrile hospitalized patients. J Infect Dis 1989;160:803-9.

2. Harkess JR, Ewing SA, Crutcher JM, Kudlac J, McKee G, Istre GR. Human ehrlichiosis in Oklahoma. J Infect Dis 1989;159:576-9.

3. Eng TR, Harkess JR, Fishbein DB, et al. Epidemiologic, clinical, and laboratory findings of human ehrlichiosis in the United States, 1988. JAMA 1990;264:2251-8.

4. Walker DH, Dumler JS. Emergence of ehrlichioses as human health problems. Emerging Infectious Diseases 1996;2:18-29.

5. Dawson JE, Fishbein DB, Eng TR, Redus MA, Greene NR. Diagnosis of human ehrlichiosis with the indirect fluorescent antibody test: kinetics and specificity. J Infect Dis 1990;162:91-5.

TABLE 1. Results of immunofluorescent assays for Ehrlichia chaffeensis antibody
conducted by CDC on serum specimens, by year -- Maryland, 1985-1994
=================================================================================
Year   Negative   Positive *   Total
------------------------------------
1985       2           0          2
1986       1           0          1
1987       0           0          0
1988      10           2         12
1989      11           1         12
1990      10           0         10
1991      10           0         10
1992      14           1         15
1993       8           1          9
1994      27           8+        35
------------------------------------
* Titers >=1:128.
+ Includes all five cases described in this report.
=================================================================================

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