Human diseases attributed to ehrlichiosis have been described since 198618. Human monocytic ehrlichiosis, the most common form of ehrlichiosis in the United States, is caused by Ehrlichia chaffeensis, with 70% of the cases reported from 7 states (Arkansas, Georgia, Missouri, Maryland, North Carolina, Oklahoma, and Tennessee)23. Other causes of ehrlichiosis include Ehrlichia ewingii and Anaplasma phagocytophilum, which cause Ewingii ehrlichiosis and anaplasmosis (a disease with similar clinical features to ehrlichiosis), respectively. Ehrlichia species are obligate intracellular, coccobacillary Gram-negative bacteria that infect phagocytic bone marrow-derived cells6. Both of these infections are tick-borne illnesses with similar constitutional signs and symptoms including fever, headache, myalgia, and anorexia. A macular or papular rash has also been associated with some forms of ehrlichiosis, although this is less common (approximately 36% of patients in 1 study)7. Laboratory abnormalities include leukopenia, thrombocytopenia, and elevated liver function tests (alanine aminotransferase and aspartate aminotransferase levels)21.
Most forms of ehrlichiosis readily respond to antimicrobial treatment. However reports of severe and fatal ehrlichiosis have been described, particularly in older and immunocompromised patients6. Complications observed include meningoencephalitis, adult respiratory distress syndrome, and sepsis-like syndrome6. The relationship of early appropriate antibiotic therapy to outcome has not been previously well described. We performed a study with 2 main goals. Our first goal was to describe the clinical presentations of patients hospitalized with ehrlichiosis at Barnes-Jewish Hospital. We also wanted to evaluate the relationship between the administration of early appropriate antibiotic treatment and clinical outcome.
Study Location and Patients
The study was conducted at a university-affiliated, urban teaching hospital: Barnes-Jewish Hospital in St. Louis, MO (1200 beds). During a 10-year period (January 1996 to December 2006), all patients with a positive blood polymerase chain reaction (PCR) test for Ehrlichia and a compatible clinical presentation were eligible for the investigation. This study was approved by the Washington University School of Medicine Human Studies Committee, and informed consent was waived.
Study Design and Data Collection
A retrospective cohort study design was employed assessing the administration of early appropriate antibiotic treatment with doxycycline. Additionally, we assessed secondary outcomes including the need for admission to the intensive care unit (ICU), hospital length of stay, complications, and hospital mortality. A computerized list of patients with ehrlichiosis was generated by the Medical Informatics Department through retrospective query of the Microbiology Laboratory database at Barnes-Jewish Hospital, which allowed identification of potential study patients. Patients could not be entered into the study more than once.
All definitions were selected prospectively as part of the original study design. Appropriate antimicrobial treatment was defined as the administration of doxycycline within the first 24 hours of hospital admission to either Barnes-Jewish Hospital or another hospital before transfer to Barnes-Jewish Hospital. Patients were identified as being on chronic steroids if they were on prednisone at a dose of at least 10 mg/d (or an alternative steroid at an equivalent dose). Symptoms and findings on physical exam were determined by the notations made in the medical record from the treating physicians. Specifically, an abnormal neurologic exam was noted when the treating physician found a focal neurologic deficit during the initial physical exam. An abnormal chest radiograph was any chest radiograph with an infiltrate as read by the radiologist. Pulmonary complications that occurred during hospitalization included adult respiratory distress syndrome, pneumonia, and alveolar hemorrhage. Disseminated intravascular coagulation was determined based on laboratory studies, including elevated prothrombin time, elevated international normalized ratio, elevated partial thromboplastin time, and a decreased fibrinogen level. Acute renal failure was defined as renal failure significant enough to require dialysis. Duration of illness was based on the length of time from the onset of initial symptoms as noted in the medical record until hospital discharge. The term sepsis was defined based on the guidelines from the American College of Chest Physicians-Society of Critical Care Medicine (ACCP-SCCM) Consensus Conference on Sepsis and Organ Failure.
The 16S ribosomal RNA gene (rrs) assay used has been previously described6,7. Patient samples were tested initially with a broad-range assay designed to amplify all known Ehrlichia species plus Anaplasma phagocytophilum. This assay employs primers ECA and HE3. Samples that were positive by the screening assay were subsequently tested using primer pairs HE1 and HE3, which are specific for Ehrlichia chaffeensis, and EWi and HE3, which are specific for Ehrlichia ewingii; Anaplasma phagocytophilum DNA was amplified using primers Ehr 521 and 747. For each patient, PCR assays were performed on lysates containing DNA from 105 leukocytes (1996-2002) or 10 μL of MagNA Pure (Roche, Indianapolis, IN)-extracted whole blood eluate (2002-2006). Reactions were performed in 100 μL samples with a DNA thermal cycler (model 480, Perkin-Elmer Cetus, Norwalk, CT). Final concentrations of reaction mixtures and cycling protocols for the broad-range assay, the Ehrlichia chaffeensis-specific assay, and the Ehrlichia ewingii-specific assay were performed according to previously reported procedures2,3.
All comparisons were unpaired and all tests of significance were 2-tailed. SPSS version 11.0 for Windows (SPSS, Inc., Chicago, IL) was used for statistical analysis. Continuous variables were compared using the Student t-test for normally distributed variables and the Mann-Whitney U test for non-normally distributed variables. The chi-square or Fisher exact test was used to compare categorical variables. The primary data analysis compared patients with a delay in the administration of doxycycline for more than 24 hours from hospital admission with patients without a treatment delay.
Over the time period 1996-2006, 46 patients with a clinical presentation consistent with Ehrlichia infection and a positive Ehrlichia PCR were admitted to Barnes-Jewish Hospital. Demographic characteristics of these patients are shown in Table 1. The mean age of the patients was 52 ± 16 years (range, 20-86 yr); 35 (76.1%) patients were men and 11 (23.9%) were woman. Twenty-eight (60.9%) patients had a delay in the institution of doxycycline therapy of greater than 24 hours from hospital admission. Twenty-three patients initially presented to a different hospital before being transferred to Barnes-Jewish Hospital. Of the patients with delayed administration of doxycycline therapy, 18 (64.3%) were initially admitted to a different hospital before being transferred to Barnes-Jewish Hospital, compared with 5 (27.8%) patients with no delay in administration of doxycycline (p = 0.016). There was no significant difference between the 2 groups in the average days from tick exposure to initial hospital admission, nor in the interval from onset of symptoms to hospital admission (at a different hospital or Barnes-Jewish Hospital) (see Table 1). The number of days ill to treatment with doxycycline was statistically different in the group of patients with a delay in doxycycline therapy compared with those patients with appropriate empiric treatment (see Table 1).
Presenting Signs, Symptoms, and Physical Examination Findings
No significant differences in symptoms at hospital presentation were identified between patients with and without a delay in the administration of doxycycline (Table 2). Patients with delayed administration of doxycycline were significantly more likely to have an abnormal lung examination and to have altered mental status at hospital presentation compared to patients without a delay in doxycycline therapy (Table 3).
Laboratory and Radiographic Findings
Patients with delayed administration of doxycycline had significantly greater total bilirubin values at hospital admission compared with patients without doxycycline treatment delays (Table 4). No patient had a diagnosis of ehrlichiosis suggested by initial evaluation of the blood smear. All abnormal findings on peripheral smear were nonspecific to ehrlichiosis. The presence of an abnormal chest radiograph was more common among patients with doxycycline treatment delays (see Table 4). Patients with a delay in doxycycline therapy were also significantly more likely to have more abnormal laboratory values for hemoglobin, total bilirubin, and aspartate aminotransferase during their hospitalization (Table 5).
Empiric Diagnosis of Ehrlichiosis and Treatment
None of the patients with delayed administration of doxycycline had the diagnosis of ehrlichiosis suspected and documented in the medical record at the time of hospital admission, compared with 13 (72.2%) of the patients with no delay in doxycycline therapy (p < 0.001). The mean number of days between hospital admission and the administration of the first dose of any antibiotic was similar between patients with delayed administration of doxycycline treatment and those with no delay (1.9 ± 8.1 d vs. 0.3 ± 0.7 d; p = 0.422). Patients with delayed administration of doxycycline had an average time to the first dose of doxycycline of 4.6 ± 5.3 days.
Consequences of a Delay in Appropriate Therapy
Patients with a delay in the administration of doxycycline had significantly more complications during their hospitalization compared with patients with no delay in doxycycline therapy (Table 6). Pulmonary complications, admission to the ICU, mechanical ventilation, and the need for vasopressors were significantly more common among patients with a delay in the administration of doxycycline (see Table 6). None of the patients who received appropriate empiric therapy with doxycycline at admission required admission to an ICU, while 11 (39.3%) of the patients with a delay in therapy required care in an ICU (p = 0.002). Of note, all patients who required ICU care were initially admitted to a regular medicine floor as opposed to being directly admitted to the ICU.
The average length of illness was longer for patients with delayed administration of doxycycline than for patients who received doxycycline at admission (20.9 ± 14.1 d vs. 8.9 ± 2.7 d; p = 0.001) (Figure 1). Patients with a delay in doxycycline administration were also in the hospital longer than patients who received doxycycline at admission (12.3 ± 11 d vs. 3.9 ± 1.9 d; p < 0.001) (Figure 2).
The findings of the current study demonstrate that delayed administration of doxycycline in patients admitted to the hospital with ehrlichiosis is associated with a statistically greater need for ICU admission and mechanical ventilation, and a prolonged length of hospitalization and illness. It is noteworthy that patients with more abnormalities at presentation, including an abnormal lung exam, abnormal neurologic exam, abnormal chest radiograph, and elevated bilirubin, were more likely to have a delay in appropriate antibiotic therapy. This finding suggests that clinicians may not recognize that ehrlichiosis is associated with severe illness at presentation, as these patients demonstrate. Thus, the patients who would most benefit from early antibiotic therapy with doxycycline are not receiving treatment, resulting in worse outcomes for these patients.
Previous investigations have shown that antimicrobial regimens lacking activity against identified microorganisms causing serious infections (for example, hospital-acquired pneumonia, bloodstream infections) are associated with greater hospital mortality11,13,16,17,19. More recently, the same finding has been demonstrated for patients with severe sepsis5,9,10. Inappropriate antimicrobial treatment has been shown to be an important independent risk factor for mortality among hospitalized patients15. Additionally, the impact of inappropriate initial antimicrobial therapy on outcomes appears to be greater among patients with a lower predicted risk of mortality before the occurrence of the inappropriately treated infection4. Furthermore, the initial antibiotic regimen chosen must be broad enough to cover all possible offending pathogens. Waiting to change antimicrobial therapy to an appropriate regimen after susceptibility data become available has not been demonstrated to improve clinical outcomes1,14,17.
Earlier studies have shown that early appropriate antibiotic treatment of ehrlichiosis is associated with better outcomes. Fishbein et al7 demonstrated that delay in treatment with tetracycline or chloramphenicol of greater than or equal to 8 or more days after the onset of illness was associated with increased risk for complications. The current study is unique in focusing on the clinical impact of early appropriate antimicrobial therapy in patients with ehrlichiosis. It further emphasizes the importance of early appropriate antimicrobial therapy, for an increased risk of complications was associated with a delay in treatment of just 24 hours after hospital admission.
A delay in therapy in patients with ehrlichiosis might occur for many reasons. The signs and symptoms of ehrlichiosis are nonspecific, making the diagnosis difficult if the treating physician does not have ehrlichiosis in his or her differential diagnosis at all times during the appropriate season for infection. Furthermore, based on the current study it appears that physicians are overlooking the severity of illness that Ehrlichia can cause, and that it can affect multiple organ systems. This appears to lead clinicians to look for other causes of the patient's illness, and as a result the opportunity for early antibiotic therapy is missed.
Studies evaluating other types of infections have suggested that the timing of appropriate antibiotic treatment is an important determinant of outcome. Iregui and coworkers12 showed that patients treated more than 12 hours after clinical suspicion of ventilator-associated pneumonia had a statistically greater risk of hospital mortality. Morrell et al20 and Garey et al8 have demonstrated that delayed appropriate treatment for Candida bloodstream infection is associated with increased hospital mortality. More recently, Schramm et al22 found that patients with delayed treatment for sterile site infections due to methicillin-resistant Staphylococcus aureus infections had significantly greater risk of hospital mortality. These investigations suggest that early accurate microbiologic diagnosis to guide specific treatment, or appropriate empiric treatment before culture results are available, may be necessary to improve the outcomes of serious infections.
The current study has several important limitations. First, in this retrospective study we evaluated only patients with a positive PCR to establish the diagnosis of ehrlichiosis. It is possible that we may have excluded patients with PCR-negative cases due to other species of Ehrlichia not identified with our PCR assay. Second, we did not employ a severity of illness score in evaluating these patients. However, the assessment of vasopressor administration, mechanical ventilation, and the need for ICU admission provides similar stratification. Third, we examined only patients in a large, tertiary care teaching hospital in Missouri, where Ehrlichia infection is relatively common, which may lead to referral bias. Also, it is possible that the occurrence of delayed administration of doxycycline therapy would vary if hospitals from other regions were examined. Fourth, due to the observational nature of this investigation, we could not determine the specific rationale for the lack of Ehrlichia coverage in the antibiotic regimens selected by the treating physicians. Fifth, it was difficult to know whether the patients saw a primary care doctor before hospitalization. Thus, we cannot be certain whether the patients were treated with any antibiotics, including doxycycline, as outpatients before admission to the hospital. Another important cofounder could be that the longer length of illness and hospitalization in the delayed treatment group, as well as the increased rate of complications in this group, could be due to the fact that the patient presented to the hospital later in the course of their disease, and not to a delay in therapy. However, when reviewing the data it appears that the statistically significant difference in the number of days ill until treatment with doxycycline was not because of the length of illness before hospitalization (which was not statistically significant) but due to the delay in giving doxycycline (mean of 4.6 d, which essentially accounts for the difference seen between the delayed treatment group and the appropriately treated group). In addition, the syndrome ehrlichiosis is known to be caused by at least 3 distinct species of Ehrlichia or Anaplasma organisms. It is being assumed that the disease course and severity does not differ between organisms, as the PCR used to identify infection did not speciate the organism. Lastly, we had a relatively small number of patients in our analysis. Therefore, we may not have been able to identify all of the clinically important discriminators and outcomes between patients receiving early appropriate doxycycline therapy and those with delayed administration of doxycycline.
In summary, we report that delayed administration of doxycycline is common among patients hospitalized with ehrlichiosis. These treatment delays were likely due to the lack of recognition of the diagnosis of Ehrlichia infection, as suggested by the administration of other antibiotics in these patients to cover more typical bacterial pathogens. Delayed treatment occurred despite all these patients residing in areas where Ehrlichia infection is endemic. This finding underscores the importance of providing early empiric treatment for Ehrlichia to patients presenting with serious organ dysfunction compatible with ehrlichiosis in appropriate clinical situations.
The authors thank Richard Buller, PhD, for his help with the methodology section of this paper.
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