Remdesivir and Mortality in Patients With Coronavirus Disease 2019.

BACKGROUND: The impact of remdesivir (RDV) on mortality rates in coronavirus disease 2019 (COVID-19) is controversial, and the mortality effect in subgroups of baseline disease severity has been incompletely explored. The purpose of this study was to assess the association of RDV with mortality rates in patients with COVID-19. METHODS: In this retrospective cohort study we compared persons receiving RDV with those receiving best supportive care (BSC). Patients hospitalized between 28 February and 28 May 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection were included with the development of COVID-19 pneumonia on chest radiography and hypoxia requiring supplemental oxygen or oxygen saturation ≤94% with room air. The primary outcome was overall survival, assessed with time-dependent Cox proportional hazards regression and multivariable adjustment, including calendar time, baseline patient characteristics, corticosteroid use, and random effects for hospital. RESULTS: A total of 1138 patients were enrolled, including 286 who received RDV and 852 treated with BSC, 400 of whom received hydroxychloroquine. Corticosteroids were used in 20.4% of the cohort (12.6% in RDV and 23% in BSC). Comparing persons receiving RDV with those receiving BSC, the hazard ratio (95% confidence interval) for death was 0.46 (.31-.69) in the univariate model (P < .001) and 0.60 (.40-.90) in the risk-adjusted model (P = .01). In the subgroup of persons with baseline use of low-flow oxygen, the hazard ratio (95% confidence interval) for death in RDV compared with BSC was 0.63 (.39-1.00; P = .049). CONCLUSION: Treatment with RDV was associated with lower mortality rates than BSC. These findings remain the same in the subgroup with baseline use of low-flow oxygen.

Antibodies reactive to Rickettsia rickettsii among children living in the southeast and south central regions of the United States.

BACKGROUND: The reported annual incidence of Rocky Mountain spotted fever in the United States is 2.2 per million, but studies have suggested that human infection with Rickettsia rickettsii may be more common. This study estimated the prevalence of antibodies reactive to R rickettsii among children living in the southeastern and south central United States. STUDY DESIGN: Approximately 300 specimens were obtained from children at each of 7 pediatric referral centers (N = 1999). Serum was tested for R rickettsii antibodies by means of indirect immunofluorescence antibody assay. Three different cutoff titers (>or=64, >or=128, and >or=256) represented increasing levels of stringency to define positive specimens. RESULTS: Overall, 12.0% of children had R rickettsii antibody titers of at least 64; 7.3%, at least 128; and 4.3%, at least 256. Strong relationships were seen between increasing age and seroprevalence at each cutoff titer. Remarkably, 6.4% of children aged 13 to 17 years had titers of at least 256. Age-adjusted seroprevalence rates at titers of at least 64 varied from 21.9% in Little Rock, Ark, to 3.5% in Louisville, Ky. At titers of at least 256, seroprevalence ranged from 7.7% in Nashville, Tenn, to 1.8% in Winston-Salem, NC. Only site and age group were strong predictors of seropositivity; a weak association was seen with nonurban residence. CONCLUSIONS: To our knowledge, this is the largest serosurvey of rickettsial infection in children in the United States. Within the limitations of the immunofluorescence antibody assay, these data suggest that infections with R rickettsii or antigenically related spotted-fever group rickettsiae may be common and subclinical. The results also have implications for the interpretation of single immunofluorescence antibody assay titers in children with suspected Rocky Mountain spotted fever.

Ehrlichia chaffeensis seroprevalence among children in the southeast and south-central regions of the United States.

BACKGROUND: The reported annual incidence of human monocytic ehrlichiosis, which is due to infection with Ehrlichia chaffeensis, is as high as 5.5 per million in some states, but serosurveys suggest much higher infection rates in some populations. OBJECTIVE: To estimate the prevalence of E chaffeensis infection among children aged 1 to 17 years living in the southeast and south-central United States. DESIGN: Cross-sectional serosurvey. SETTING: Seven academic pediatric medical centers in the southeastern and south-central United States. PATIENTS: Nineteen hundred ninety-nine children (approximately 300 at each center) having their blood drawn for any reason. MAIN OUTCOME MEASURE: The presence of antibody at 2 different cutoff titers to E chaffeensis, as detected by indirect immunofluorescence assay. RESULTS: Overall, 250 children (13%) had E chaffeensis antibody titers of 1:80 or higher and 61 (3%) had titers of 1:160 or higher. Age-adjusted seroprevalence rates varied widely between sites. At 1:80 or higher, the highest rate was in Winston-Salem, NC (22%), and the lowest was in Louisville, Ky (2%). At 1:160 or higher, the highest rate was in Kansas City, Mo (9%), and the lowest was in Oklahoma City, Okla (<1%). In univariate analyses, no associations were found between seroprevalence at either cutoff value and sex, race, source of specimen, or residence demographics. However, age was a significant predictor of seroprevalence at both cutoff values. In multiple logistic regression analysis, study site and age remained strong predictors of seroprevalence, but living in a nonurban ZIP code was not significantly related. CONCLUSION: Infection with E chaffeensis, or related ehrlichiae, may be more common in children than previously recognized.

Characteristic peripheral blood findings in human ehrlichiosis.

Human ehrlichiosis is a potentially fatal tick-borne illness if not treated promptly. Ehrlichia infection is difficult to diagnose as the organism does not grow in standard blood culture medium and serological confirmation of infection takes several days to weeks. The most timely way of confirming Ehrlichia infection is identification of characteristic cytoplasmic morulae in peripheral blood leukocytes. A total of 23 patients with clinical and laboratory findings suggesting a rickettsial infection were tested for Ehrlichia using polymerase chain reaction and culture: 16 cases contained Ehrlichia DNA by polymerase chain reaction (15 E. chaffeensis, one E. ewingii), including 14 cases in which the blood culture grew Ehrlichia. The cases that contained Ehrlichia DNA by polymerase chain reaction had lower mean white blood cell and platelet counts and more numerous atypical lymphocytes and pronounced toxic change than cases in which Ehrlichia DNA was not detected. Cytoplasmic morulae were identified on peripheral blood smears in six (five E. chaffeensis, one E. ewingii) of 16 (38%) of the cases that contained Ehrlichia DNA, including 4/4 (100%) immunocompromised and 2/12 (17%) immunocompetent patients. Morulae were present in monocytes in E. chaffeensis-infected cases and granulocytes in the E. ewingii-infected case. In two immunocompromised patients, the number of infected cells was 1-10%, but in four patients it was <0.2%. In conclusion, peripheral blood film examination is diagnostic in a substantial number of Ehrlichia infections, particularly in immunocompromised patients. The number of infected white blood cells may be less than 0.2%, requiring examination of more than 500 white blood cells. Associated changes prompting careful film review include prominent toxic granulation and atypical large granular lymphocytes.

Antigenic variation of Ehrlichia chaffeensis resulting from differential expression of the 28-kilodalton protein gene family.

The transcriptional activity and allele variation of the 28-kDa outer membrane protein gene (p28) of Ehrlichia chaffeensis were analyzed to determine the mechanism of the antigenic variation of the 28-kDa outer membrane proteins. Reverse transcriptase PCR amplification of mRNA indicated that 16 of the 22 members of the p28 multigene family were transcribed. Amino acid sequence analysis indicated that the p28-19 protein was produced in vitro in the Arkansas strain. The p28-19 gene and its promoter region were sequenced and compared in 12 clinical isolates of E. chaffeensis to determine allele variation. The variation of the p28-19 gene among the isolates is limited to three types represented by strains Arkansas, 91HE17, and Sapulpa, respectively. These results indicate that the majority of the p28 genes are active genes and that antigenic variation of the E. chaffeensis 28-kDa proteins may result from differential expression of the p28 gene family members rather than gene conversion.