Vol. 17, No. 24
THE JOHNS HOPKINS MICROBIOLOGY NEWSLETTER
Monday, June 15, 1998
A. Provided by Carmela Groves, R.N., M.S., Chief, Division of Outbreak Investigation, Maryland Department of Health and Mental Hygiene.
From May 28, 1998 to June 5, 1998, 6 outbreaks have been reported to the Maryland Department of Health and Mental Hygiene. They are as follows: 5 foodborne gastroenteritis and 1 scombroid poisoning associated with fresh tuna fish.
B. The Johns Hopkins Hospital. Information provided by Dr.Cybele Dey, Pediatric Elective Resident, Department of Pediatric Infectious Diseases.
Patient History: The patient is a six year old Caucasian female who presented with a ten-day history of fever (to 40oC), increasing lethargy, headache, hyperosmia, and photophobia. She had had a tender 3 by 5cm posterior cervical lymph node at the beginning of the illness and had vomited on two occasions. Physical examination was remarkable for hypotension (80/40), moderate tender hepatosplenomegaly (5-6 and 4-5cm) below the costal margins respectively) and non-tender mild cervical lymphadenopathy. Initial laboratory evaluation revealed a pancytopenia, with increased band forms, hyponatremia, elevated aspartate transaminase and lactate dehydrogenase. C-Xray was notable for bilateral pleural effusions and left basal atelectasis. Bone marrow aspiration performed to investigate the pancytopenia, and revealed evidence of resolving myelosuppression but no malignancy nor infective cause. Serology and polymerase chain reaction of serum was performed for diagnosis.
The patient had been previously well apart from having a bladder diverticulum and vesico-ureteric reflux found on investigation for a urinary tract infection, for which she was receiving Trimethoprim-Sulphamethoxazole prophylaxis. Travel history was significant for having been on a camping trip in Northern Maryland seven days before the illness began. There was no history of tick bite.
Organism: The clinical and laboratory features of the above case were consistent with a diagnosis of human monocytic ehrlichiosis (HME). Ehrlichia chaffeensis is the etiologic agent for human monocytic ehrlichiosis and is a member of the Ehrlichia genus. Ehrlichia are small, obligate intracellular gram negative organisms 0.2-0.8 (m in diameter, which infect circulating leukocytes. Ehrlichia form intracytoplasmic inclusions called morulae (2-5 um diameter) which are composed of membrane bound vacuoles containing up to 40 bacteria. Phagolysosomal fusion does not occur in infected cells, suggesting that ehrlichia inhibit fusion. Ehrlichia are divided into three subgroups on the basis of host cell tropism and serologic responses elicited. E.chaffeensis is part of genogroup I, which includes E. ewingii and E.canis. E.canis has 98.2% sequence homology to E.chaffeensis and was the antigen used for serologic testing prior to the characterization of E.chaffeensis in 1991. Ehrlichia causing disease in humans infect monocytes and granulocytes. The cause of human granulocytic ehrlichiosis is HGE agent, which is a member of genogroup II, and induces antibodies, which are protective against E.equi the cause of equine ehrlichiosis. However HGE agent has antigenic differences from E.chaffeensis and antibodies to HGE agent are not usually protective against infection with E.chaffeensis.
Ehrlichia are transmitted to humans by ticks, and E.chaffeensis has been found in both Amblyomma americanum (Lone Star Tick) and Dermatcentor variabilis (Dog Tick). A.americanum appears to be the major vector for E.chaffeensis. HGE agent has been found in Ixodes scapularis (Deer Tick) and in Dermatcentor variabilis. Most patients with HME report a tick attachment or tick exposure within three weeks of the onset of illness, however a definite history of tick attachment is not always elicited. This is particularly true of pediatric cases.
Evidence of ehrlichiosis has been found in Western Europe, Africa, Scandinavia and Japan, however the majority of cases of HME and HGE are recognized in the United States. HME is reported more frequently than HGE, especially in children. The majority of cases of ehrlichiosis occur in residents of rural areas, and from May to July, when ticks are most active. The median age of infection is 44 years and three-quarters of infections occur in men. Male children are also infected slightly more frequently than female children are. Most infections are probably not diagnosed, based on seroprevalence data for endemic areas and a high rate of seroconversion (1.3%) in mainly asymptomatic military personnel (67%) exposed in a tick-infested area. This may reflect lack of physician awareness of the diagnosis as well as reflecting minimally symptomatic or asymptomatic infections, which do not lead affected persons to seek medical attention. A prospective study of febrile hospitalized patients in Georgia found that ehrlichiosis was eight times more prevalent than Rocky Mountain spotted fever (RMSF). Although children make up only 10% of reported cases of ehrlichiosis, seroprevalence data suggest that they may be at higher risk of infection when living in endemic areas.
Clinical Disease: Ehrlichiosis can vary from asymptomatic to fatal disease. Fever, headache, hepatosplenomegaly, anorexia, nausea and a systolic murmur characterize the illness, a pleomorphic rash may be associated, but its absence does not assist in excluding the diagnosis. HGE is less often associated with a rash than HME, and an acute non-specific febrile illness with myalgias is typical of HGE. Features of more severe disease are: ARDS (adult respiratory distress syndrome), a toxic or septic shock-like picture, meningo-encephalitis, renal failure, DIC (disseminated intravascular coagulation), gastrointestinal hemorrhage and immunosupression leading to secondary infection. Patients may also have pharyngitis, lymphadenitis, photophobia, conjunctivitis, strawberry tongue, edema of the hands and feet, pleural effusions and genital or oral ulcers. Central nervous system dysfunction is probably more frequent with HME than HGE. There have been reports of long-term neurologic sequelae. Ehrlichiosis should therefore be included in the differential diagnosis of an influenza-like illness, pharyngitis with lymphadenitis, endocarditis, septic or toxic shock, Kawasaki syndrome, Rocky Mountain spotted fever (RMSF) and meningitis in a patient who has been in an endemic area for ticks in the preceding three weeks. The usual duration of illness is 4 to 12 days.
Laboratory Findings and Diagnosis: Hyponatremia, elevated aspartate transaminase, elevated lactate dehydrogenase and pancytopenia are typical features of human ehrlichiosis. Peripheral blood smear may reveal morulae in circulating leukocytes, which if present are helpful in making the diagnosis. However, they are seen in only 1-8% of neutrophils in HGE and in 0-2% of monocytes in HME, and are not a sensitive method of diagnosis. CSF analysis in patients with CNS features of ehrlichiosis shows a leukocytosis with a lymphocyte predominance, and in adults there has also been elevated protein and low CSF glucose. Bone marrow may demonstrate granulomas evidence of myelosuppression or myeloproliferation. Pleural effusion or pulmonary infiltrate may be seen on CX-ray, and are suggestive of more severe disease. Serology or polymerase chain reaction to look for ehrlichia DNA are the most sensitive methods of diagnosis. Culture of Ehrlichia requires 30 days of incubation and is thus not helpful for determining management. A fourfold increase in titer for serology, with a minimum titer of 1:80, or identification of ehrlichial DNA by PCR in the appropriate clinical setting is diagnostic.
Treatment: Tetracycline, or one of its analogs, is the treatment of choice in both adults and children, and leads to rapid defervescence (24 to 48 hours) and hematologic recovery. Doxycycline should be given at a dose of 3mg/kg in two divided doses for a minimum of 5-7 days, and at least 3 days after defervescence, and the total dose should be minimized to decreased the risk of teeth staining. Chloramphenicol has been suggested as an alternative treatment, particularly for children, due to concerns of teeth staining with doxycycline. However, in vitro evidence suggests that chloramphenicol may not be as effective as doxycycline, and the risk of teeth staining with a single course of doxycycline even in children under the age of eight is thought to be low. Chloramphenicol may not be effective therapy for HGE. Limited clinical data are available to compare therapy with tetracycline and chloramphenicol in children, however because doxycycline is effective for HME, HGE and RMSF it is recommended as the drug of choice in areas in which both ehrlichiosis and RMSF are endemic.
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