Etiology of Acute Febrile Illness in the Peruvian Amazon as determined by modular formatted quantitative PCR: A Protocol for RIVERA, a Health Facility-Based Case-Control Study.

Background : The study of the etiology of acute febrile illness (AFI) has historically been designed as a prevalence of pathogens detected from a case series. This strategy has an inherent unrealistic assumption that all pathogen detection allows for causal attribution, despite known asymptomatic carriage of the principal causes of acute febrile illness in most low- and middle-income countries (LMICs). We designed a semi-quantitative PCR in a modular format to detect bloodborne agents of acute febrile illness that encompassed common etiologies of AFI in the region, etiologies of recent epidemics, etiologies that require an immediate public health response and additional pathogens of unknown endemicity. We then designed a study that would delineate background levels of transmission in the community in the absence of symptoms to provide corrected estimates of attribution for the principal determinants of AFI. Methods : A case-control study of acute febrile illness in patients ten years or older seeking health care in Iquitos, Loreto, Peru, was planned. Upon enrollment, we will obtain blood, saliva, and mid-turbinate nasal swabs at enrollment with a follow-up visit on day 21-28 following enrollment to attain vital status and convalescent saliva and blood samples, as well as a questionnaire including clinical, socio-demographic, occupational, travel, and animal contact information for each participant. Whole blood samples are to be simultaneously tested for 32 pathogens using TaqMan array cards. Mid-turbinate samples will be tested for SARS-CoV-2, Influenza A and Influenza B. Conditional logistic regression models will be fitted treating case/control status as the outcome and with pathogen-specific sample positivity as predictors to attain estimates of attributable pathogen fractions for AFI. Discussion : The modular PCR platforms will allow for reporting of all primary results of respiratory samples within 72 hours and blood samples within one week, allowing for results to influence local medical practice and enable timely public health responses. The inclusion of controls will allow for a more accurate estimate of the importance of specific, prevalent pathogens as a cause of acute illness. Study Registration: Project 1791, Registro de Proyectos de Investigación en Salud Pública (PRISA), Instituto Nacional de Salud, Perú.

Etiology of acute febrile illness in the peruvian amazon as determined by modular formatted quantitative PCR: a protocol for RIVERA, a health facility-based case-control study.

BACKGROUND: The study of the etiology of acute febrile illness (AFI) has historically been designed as a prevalence of pathogens detected from a case series. This strategy has an inherent unrealistic assumption that all pathogen detection allows for causal attribution, despite known asymptomatic carriage of the principal causes of acute febrile illness in most low- and middle-income countries (LMICs). We designed a semi-quantitative PCR in a modular format to detect bloodborne agents of acute febrile illness that encompassed common etiologies of AFI in the region, etiologies of recent epidemics, etiologies that require an immediate public health response and additional pathogens of unknown endemicity. We then designed a study that would delineate background levels of transmission in the community in the absence of symptoms to provide corrected estimates of attribution for the principal determinants of AFI. METHODS: A case-control study of acute febrile illness in patients ten years or older seeking health care in Iquitos, Loreto, Peru, was planned. Upon enrollment, we will obtain blood, saliva, and mid-turbinate nasal swabs at enrollment with a follow-up visit on day 21-28 following enrollment to attain vital status and convalescent saliva and blood samples, as well as a questionnaire including clinical, socio-demographic, occupational, travel, and animal contact information for each participant. Whole blood samples are to be simultaneously tested for 32 pathogens using TaqMan array cards. Mid-turbinate samples will be tested for SARS-CoV-2, Influenza A and Influenza B. Conditional logistic regression models will be fitted treating case/control status as the outcome and with pathogen-specific sample positivity as predictors to attain estimates of attributable pathogen fractions for AFI. DISCUSSION: The modular PCR platforms will allow for reporting of all primary results of respiratory samples within 72 h and blood samples within one week, allowing for results to influence local medical practice and enable timely public health responses. The inclusion of controls will allow for a more accurate estimate of the importance of specific prevalent pathogens as a cause of acute illness. STUDY REGISTRATION: Project 1791, Registro de Proyectos de Investigación en Salud Pública (PRISA), Instituto Nacional de Salud, Perú.

Secondary Infections following Tocilizumab for Treatment of COVID-19 Pneumonia

Background Guidelines recommend use of tocilizumab (TCZ), an inhibitor of pro-inflammatory IL-6 signaling, for hospitalized patients with progressive severe or critical Coronavirus disease 2019 (COVID-19). The incidence of infectious complications following the use of TCZ for COVID-19 has not been well-described. Methods We conducted a retrospective, observational matched cohort study of severely ill, hospitalized adult patients with confirmed COVID-19 who were treated with TCZ between 2/24/2021 and 6/1/2021. The intervention group, comprised of patients who received a single dose of TCZ, was matched based on c-reactive protein (CRP) and fraction of inspired oxygen (FiO2) with a control group who did not receive TCZ, and were hospitalized between 10/12/2020 and 3/6/2021. The primary outcome of the study was diagnosis of a bacterial or fungal infection after day 3 of the index hospitalization. Secondary outcomes included all-cause mortality during the study period and length of stay. Results 75 patients who received TCZ were identified during the study period, and matched 1:1 with 75 control patients. Baseline CRP and FiO2 were similar between groups, while the median age in the TCZ group was younger (61 versus 71 years), reflecting the epidemiology of the outbreak during the TCZ and control study periods. 15 bacterial and fungal infections were identified in the TCZ group (20.0%) and 4 (5.3%) infections in the control group (p = 0.012). The majority of infections in both groups were bacterial, with a disproportionate number of bloodstream infections in the TCZ group [7 (9.3%) vs 2(2.6%);p = 0.166]. 28 patients (37.3%) died in the TCZ group compared to 39 (52.0%) in the matched control (p = 0.068). Median time to discharge was similar between TCZ and control patients (11 versus 12 days;95% CI -2,2). Conclusion Secondary infections in adult patients with severe and critical COVID-19 were more common in patients who had received TCZ. Prospective studies are needed to confirm and further describe this association. Disclosures All Authors: No reported disclosures