Assessment of Risk Factors and Outcomes of Severe Ehrlichiosis Infection

Key Points Question What risk factors are associated with severe ehrlichiosis? Findings This cross-sectional study including 155 patients identified a delay in doxycycline therapy as a significant factor associated with severe ehrlichiosis. Documentation of tick exposure was independently associated with a decreased need for intensive care unit admission, and a change toward a decreased need for intensive care unit admission among immunosuppressed persons was identified. Meaning In this study, delay in initiation of empirical doxycycline therapy appears to be a risk factor for severe ehrlichiosis; education focused on early recognition and treatment may decrease morbidity associated with this infection.


Introduction
Ehrlichiosis, a tick-borne infection caused by 3 closely related species (Ehrlichia chaffeensis, E ewingii, and E muris eauclairensis), is an increasingly recognized cause of human infection. The number of cases reported to the US Centers for Disease Control and Prevention (CDC) has increased more than 8-fold since reporting began in 2000. 1 In 2017, 1642 cases of E chaffeensis were identified in the US, representing a 19% increase compared with the previous year. 1 The 2 other species are less commonly diagnosed, with a total of 218 cases of E ewingii and 115 cases of E muris eauclairensis reported since dedicated surveillance began. 1 However, reported cases of tick-borne infections almost certainly underestimate the actual burden of disease owing to limitations in laboratory confirmation and passive surveillance. 2 For instance, it is estimated that the number of cases of Lyme disease reported to the CDC annually represents a 10-fold underrepresentation of the true incidence. 3 Clinical manifestations of ehrlichiosis are nonspecific. 4 Definitive diagnosis requires laboratory confirmation, defined as a 4-fold increase in IgG antibody titer between paired serum samples or detection of E chaffeensis or E ewingii DNA by polymerase chain reaction (PCR) in a clinical specimen. 5 Serologic diagnosis is limited by delayed seroconversion 6 and paired testing is inconsistently performed. 7 Polymerase chain reaction has been shown to be highly sensitive during acute illness. 8 Despite the availability of effective antibiotic therapy, life-threatening Ehrlichia infections are common. Among probable and confirmed E chaffeensis cases reported to the CDC between 2008 and 2012, 57% required hospitalization and 11% had life-threatening complications. 7 The cumulative case fatality rate was 1% overall. Among the subset of cases with confirmed laboratory infection, 5 the overall case fatality rate was 2%, but increased to 14% in children younger than 5 years and 53% in those older than 70 years. 7 Previous reports have identified immunocompromised state, including HIV infection and solid organ transplant, as well as recent treatment with trimethoprim plus sulfamethoxazole, as risk factors for serious infections. 7,[9][10][11][12][13][14][15][16][17][18][19][20][21][22] More recent studies using PCR for diagnosis of ehrlichiosis have not substantiated this association. 23,24 Identification of populations at increased risk for serious ehrlichiosis is crucial to improving prevention and treatment strategies. To examine risk factors for severe ehrlichiosis, we identified patients at a tertiary care center with a positive Ehrlichia PCR over an 11-year period and elucidated characteristics associated with need for intensive care unit (ICU) admission.

Study Population
We conducted an analytic cross-sectional study to capture unique patients with ehrlichiosis Patients with a positive PCR result underwent review of their electronic medical records and those who did not have a clinically compatible illness were excluded. In cases with multiple positive PCR results, the initial test was used for the date of diagnosis. Patients hospitalized or cared for by a clinician at an external institution or who had insufficient information to ascertain severity of illness were excluded.

Data Collection and Study Definitions
An electronic medical records review was performed to collect demographic, clinical, laboratory, treatment, and outcomes data. Demographic characteristics included age at presentation, birth sex, and self-reported race/ethnicity. Tick exposure was ascertained through documentation of selfreport by patients or family members. Clinical characteristics included Charlson Comorbidity Index level, 26  Clinical variables included presence of rash, fatigue, diarrhea, abdominal pain, nausea/vomiting, cough, dyspnea, myalgias, arthralgias, headache, meningismus, seizures, and altered mental status.
Laboratory data included white blood cell count, platelet count, sodium level, aspartate aminotransferase level, alanine aminotransferase level, alkaline phosphatase level, total bilirubin level, and cerebrospinal fluid white blood cell count. When sequential results were available, the most abnormal value (nadir or apex) was included. Treatment data included day of symptom onset, day of initial health care contact, day of positive PCR result, and day of doxycycline initiation.
The primary exposure of interest was immunosuppression as defined above, and the primary outcome of interest was admission to an ICU at any time during the illness. This outcome was ascertained via electronic medical record review and a recorded ICU stay of any duration. Those not requiring ICU admission included patients whose treatment was managed in the outpatient setting or in non-ICU hospital wards.

Statistical Analysis
Data analysis was conducted from February 27, 2018, to September 9, 2020. Categorical variables were determined with frequencies and proportions and compared using the Fisher exact test.
Continuous variables were measured using medians and interquartile ranges (IQRs) and compared using the Wilcoxon rank sum test. Modified Poisson regression with robust variance was used to estimate the adjusted prevalence ratio (aPR) and 95% CI of ICU care. 27 Variables were chosen for the multivariable analysis a priori; all demographic characteristics (age, birth sex, race/ethnicity), factors associated with severity of disease in previous studies (immunosuppression and trimethoprim plus sulfamethoxazole use), clinical characteristic variables that would not independently favor transfer to the ICU with P values Յ.05 in the unadjusted analyses (tick exposure and rash), and time from initial health care contact to treatment initiation were included. Age was modeled with restricted cubic splines to relax linear distribution assumptions and to allow for model flexibility. All P values were 2-sided and considered statistically significant at <.05. Analyses were conducted using Stata, version 14.2 (StataCorp). Case fatality ratio was calculated as the proportion of patients who died over the total number of patients. A violin plot was generated to visualize distribution of days from first health care contact to treatment initiation. 28

Demographic Characteristics
A total of 155 unique patients met study criteria, with a median age of 50 years (interquartile range, 23-64 years); 99 patients (63.9%) were men, 56 patients (36.1%) were women, and 145 patients (93.5%) identified as non-Hispanic White ( Table 1). These study cases represented 40.5% of the 383 unique patients with positive PCR test results (Figure 1). Excluded cases included 222 samples submitted as reference testing from an outside institution with no clinical information, 3 cases with insufficient clinical data to evaluate severity of illness, and 3 tests deemed to be false-positive results based on the absence of a clinically compatible illness consistent with the CDC case definition. 7 Among study cases, the index positive test included whole blood (94.8%), cerebrospinal fluid were no statistically significant demographic differences between those requiring and those not requiring ICU care (Table 1).

Treatment and Outcomes
All patients with ehrlichiosis were treated with doxycycline. Patients requiring ICU care had a significantly longer delay from onset of symptoms to diagnostic testing (median, 7 vs 6 days; P = .002) and doxycycline initiation (median, 7 vs 5 days; P = .008). Patients admitted to the ICU also had a longer delay from initial interaction with the health care system to diagnostic testing (median,   In adjusted analysis, only the median time from initial health care interaction to initiation of doxycycline therapy was independently associated with an increased risk for ICU care (aPR, 1.09; 95% CI, 1.04-1.14; P < .001) ( Surveillance were classified as probable infections. The finding of less severe disease in the surveillance population may reflect a bias introduced by including probable cases, classified as patients with a single elevated titer, which may reflect false-positive diagnoses due to prior exposure or cross-reactive antibodies. Alternatively, despite the high analytic sensitivity of PCR to detect ehrlichial DNA, estimated between 52% and 87%, [29][30][31] there is the potential for mild cases with low bacteremic burden to provide negative test results. 32 Taking these considerations into account, the hospitalization (88.4%) and case fatality (3.9%) rates in our study were higher than the 77% hospitalization and 2% case fatality rates among the more analogous subset of confirmed cases reported to the CDC. 7 A commonly cited risk factor for severe disease is immunosuppression. 25   patients with ehrlichiosis who had undergone transplantation found a significantly higher rate of ICU care among lung transplant recipients compared with other solid organ transplants. 11 In our population there was an unexpected change (P = .05) for immunocompromising conditions to be protective against ICU admission. This possible association held true even when controlling for potential confounders, such as use of trimethoprim plus sulfamethoxazole and time to initiation of doxycycline therapy. This finding may reflect a higher proportion of less virulent E ewingii infections in immunocompromised patients. 22,23,33 As the assay used in the present study was unable to differentiate between Ehrlichia species, we were unable to confirm this hypothesis.
Alternatively, the decreased severity of infection in the immunocompromised patients in our study may have been due to a higher linkage to care and prompt medical evaluation. Because the case definition for immunocompromise in our study excluded diabetes, our findings cannot be directly compared with the national surveillance data, which included diabetes as an immunocompromising state.
Other factors previously associated with increased severity of ehrlichiosis were not identified in our study. In national surveillance data, the case fatality rate for ehrlichiosis was significantly increased in children younger than 5 years (4%) and older individuals (>70 years) (3%) compared with the overall case fatality rate of 1%. 7 However, age did not appear to be associated with increased risk of ICU care in our study, although the numbers of children aged 5 years or younger (n = 6) and patients aged 65 years or older (n = 35) were low. Prior treatment with trimethoprim plus sulfamethoxazole has been associated with severe or fatal disease in a number of anecdotal case reports/series. [15][16][17][18][19][20][21][22] Controlling for potential confounders, such as comorbid disease and delay in doxycycline therapy initiation, we did not find antecedent use of trimethoprim plus sulfamethoxazole to be correlated with disease severity.
In the present study, only 2 factors were statistically significantly associated with the need for ICU care in adjusted analysis: recent tick exposure and delay in doxycycline therapy initiation. A documented history of tick exposure was present in 73.5% of patients overall but was significantly less common in the group requiring ICU care (aPR, 0.54; 95% CI, 0.34-0.86). Absence of tick bite has been associated with delayed diagnosis and increased mortality among other tickborne infections, 34 presumably due to failure to consider the diagnosis and initiate empirical therapy with doxycycline.
However, the inverse association between documented tick exposure and need for ICU care held true in the present study even after controlling for the timeliness of doxycycline therapy. We hypothesize that this association may reflect that sicker patients had cognitive impairment leading to limitations in recall or communication of tick exposure. Therefore, lack of documented tick exposure should not dissuade clinicians from a diagnosis of ehrlichiosis.
The second variable independently associated with severe ehrlichiosis appears to be a delay in time from initial health care encounter to doxycycline therapy initiation. The importance of early antibiotic treatment has been well established for spotted fever rickettsioses with delay in therapy associated with severe disease, morbidity, and death. [34][35][36][37] This association has been less clearly proven for ehrlichiosis. An early study reported that initiation of doxycycline within 5 days of symptom onset was associated with better outcomes. 38 A more recent case series noted that patients who had more than a 24-hour delay in initiation of doxycycline therapy after hospital admission were more likely to need ICU care (39% vs 0%) and had longer hospitalization (12 vs 4 days) and duration of illness (21 vs 9 days). 39 Historically, there has been concern among pediatricians regarding prescription of doxycycline in children owing to the perceived risk of dental discoloration. In a survey of more than 1500 health care clinicians, only 35% chose doxycycline to treat Rocky Mountain spotted fever in children younger than 8 years. 40 More recent studies have refuted the association between short-course doxycycline therapy and tooth discoloration 41 and empirical use of doxycycline is now strongly recommended by the CDC and American Academy of Pediatrics for all age groups with suspected rickettsial infection. 42 Our study noted that patients with more severe ehrlichiosis had a statistically significant delay from initial health care interaction to initiation of doxycycline therapy, supporting the importance of early initiation of doxycycline treatment irrespective of age.

Strengths and Limitations
To our knowledge, this study is the first to include a large number of patients, both hospitalized and nonhospitalized patients, and definitive laboratory confirmation of acute infection through PCR testing. The use of rigorous molecular diagnostic testing sets this study apart from older studies that relied on serologic diagnosis.
Several limitations should be considered in interpreting the findings of this observational study.
It is likely that this study was biased toward inclusion of more severely ill patients, as mild illness may be treated empirically without laboratory confirmation or may be missed by PCR if the bacterial burden is low. Similarly, the study population was accrued from a single tertiary care facility, and it is likely that the population was biased toward more severe cases who were transferred for a higher level of care. In addition, the Ehrlichia PCR test used by the clinical laboratory does not distinguish between the 3 species of Ehrlichia and between Ehrlichia and Anaplasma, a closely related tick-borne pathogen. In the study catchment area, only 2 species-E chaffeensis and E ewingii-are endemic. 43 Ehrlichia ewingii has been shown both to be more common in immunocompromised hosts and to cause milder disease. 22,23,33

Conclusions
Reported cases of ehrlichiosis have increased by more than 70% since implementation of the current surveillance case definition adopted in 2008. 7 The elucidation of modifiable risk factors for severe disease is critical to improving outcomes. Coronavirus disease 2019, which may present in a similar fashion, adds further relevance to the early diagnosis and management of ehrlichiosis. Delay in initiation of doxycycline therapy despite interaction with a health care clinician remains a significant factor associated with severe disease and underscores that knowledge gaps in the treatment of tickborne infections persist. 40,44 Clinician education may be a key factor in improving outcomes of this increasingly common infection.