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Children exposed to antibiotics develop community-associated Clostridioides difficile infections in the 12 weeks following exposure. This secondary analysis was a retrospective review of children with filled prescriptions for commonly prescribed antibiotics between January 1, 2012, and December 31, 2016. Compared with amoxicillin, incident rates of community-associated Clostridioides difficile infections were highest following clindamycin, cephalosporins, and amoxicillin-clavulanate.

Human metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract illness in children and adults. Repeated infections are common and can be severe in young, elderly, and immunocompromised persons due to short-lived protective humoral immunity. In turn, few protective T cell epitopes have been identified in humans. Thus, we infected transgenic mice expressing the common human HLA MHC-I allele B*07:02 (HLA-B7) with HMPV and screened a robust library of overlapping and computationally predicted HLA-B7 binding peptides. Six HLA-B7-restricted CD8+ T cell epitopes were identified using ELISPOT screening in the F, M, and N proteins, with M195–203 (M195) eliciting the strongest responses. MHC-tetramer flow cytometric staining confirmed HLA-B7 epitope-specific CD8+ T cells migrated to lungs and spleen of HMPV-immune mice. Immunization with pooled HLA-B7-restricted peptides reduced viral titer and protected mice from virulent infection. Finally, we confirmed that CD8+ T cells from HLA-B7 positive humans also recognize the identified epitopes. These results enable identification of HMPV-specific CD8+ T cells in humans and help to inform future HMPV vaccine design.

The host tropism of viral infection is determined by a variety of factors, from cell surface receptors to innate immune signaling. Many viruses encode proteins that interfere with host innate immune recognition in order to promote infection. STAT2 is divergent between species and therefore has a role in species restriction of some viruses. To understand the role of STAT2 in human metapneumovirus (HMPV) infection of human and murine tissues, we first infected STAT2&minus, /&minus, mice and found that HMPV could be serially passaged in STAT2&minus, but not WT, mice. We then used in vitro methods to show that HMPV inhibits expression of both STAT1 and STAT2 in human and primate cells, but not in mouse cells. Transfection of the murine form of STAT2 into STAT2-deficient human cells conferred resistance to STAT2 inhibition. Finally, we sought to understand the in vivo role of STAT2 by infecting hSTAT2 knock-in mice with HMPV, and found that mice had increased weight loss, inhibition of type I interferon signaling, and a Th2-polarized cytokine profile compared to WT mice. These results indicate that STAT2 is a target of HMPV in human infection, while the murine version of STAT2 restricts tropism of HMPV for murine cells and tissue.

Public health agencies have recommended that the public wear face coverings as a major non-pharmaceutical intervention to mitigate COVID-19 transmission. However, there is concern whether or not the public has adopted this recommendation. An observational study of 3,271 members of the public was conducted during the COVID-19 pandemic and examined the use of face coverings at grocery stores across 20 Wisconsin counties between May 16th and June 1st, 2020. Of the total individuals observed, we found that only 41.2% used face coverings. Individuals who appeared to be adults (aOR = 1.65; 95% CI = 1.20-2.27) or older adults (aOR = 3.67; 95% CI = 2.59-5.19) were more likely to be wearing face coverings than younger individuals. Additionally, individuals with female gender expression (aOR = 1.43; 95% CI = 1.24-1.66) and individuals shopping at a more expensive grocery store (aOR = 1.95; 95% CI = 1.69-2.25) were more likely to be wearing face coverings. We did not find an association between county level prevalence of COVID-19 cases and face covering use. To our knowledge, this is the first study using direct observations to examine face covering behavior by the public and our findings have implications for public health agencies.

Background Recurrence of community-associated (CA) Clostridiodes difficile infection (CDI) approaches 30%. Studies on risk factors and treatment of choice for pediatric CA-CDI are scarce with variable recommendations. Methods This was a retrospective cohort study of the electronic health records of children 1-17 years with stool specimens sent for C. difficile at Kaiser Permanente Northern California from January 01, 2012 to December 31, 2016. Children with (1) CA disease, (2) confirmatory C. difficile laboratory testing with no other identified causes of diarrhea and (3) clinical symptoms consistent with CDI were defined as cases. Recurrent CA-CDI was defined using the above-described case criteria and onset of diarrhea within 8 weeks of primary CA-CDI. Results Of the 7350 children with stool samples sent for C. difficile testing, 408 had primary CA-CDI. Forty-five (11%) experienced a recurrence. Using multivariable logistic regression, inflammatory bowel disease [odds ratio (OR) 7.5; 95% confidence interval (CI): 2.6-21.1] and cancer (OR 6.3; 95% CI: 1.6-24.1) diagnoses were risk factors for recurrent disease. Compared with children of Caucasian race, those with multi/other/unknown race had an OR of 3.03 (95% CI: 1.04-8.82) of recurrence. There was no statistically significant difference in the type or duration of therapy as a predictor for recurrent CA CDI. Six percent of children who received metronidazole were switched to vancomycin due to subjective metronidazole allergy or intolerance or metronidazole treatment failure. Conclusions Recurrent CA-CDI in children in our population is less common than previously reported. This study supports first-line treatment with the standard, short course metronidazole in most cases of primary CA-CDI.

Objective To assess which risk factors are associated with community-associated Clostridioides difficile infection (CDI) in children. Study design This case control study was a retrospective review of all children 1-17 years of age with stool specimens sent for C difficile testing from January 1, 2012, to December 31, 2016. Cases and controls were children who had C difficile testing performed in the community or first 48 hours of hospital admission and >12 weeks after hospital discharge, with no prior positive C difficile testing in last 8 weeks, without other identified causes of diarrhea, and with clinical symptoms. Cases had positive confirmatory testing for C difficile. Controls had negative testing for C difficile and were matched to cases 1:1 by age and year of specimen collection. Results The overall incidence rate of community-acquired CDI in this cohort was 13.7 per 100 000 children per year. There was a substantial increase in community-acquired CDI from 9.6 per 100 000 children per year in 2012 to a peak of 16.9 per 100 000 children per year in 2015 (Cochran-Armitage test for trend P = .002). The risk factors for community-acquired CDI included non-Hispanic ethnicity; amoxicillin-clavulanate, cephalosporin, and clindamycin use within the previous 12 weeks; a previous positive C difficile test within 6 months; and increased health care visits in the last year. Conclusions As rates of community-acquired CDI are increasing, enhanced antibiotic stewardship and recognition of health care disparities may ease the burden of community-acquired CDI.

Background Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in children and adults. However, mechanisms of pathogenesis are not fully understood. Methods We tested HMPV clinical and laboratory isolates in an established C57BL/6 mouse model and measured weight loss, airway function, and viral titers. Immune responses were determined using cytokine quantitation and flow cytometry. Results HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Laboratory strain TN/94-49 did not cause weight loss, but mice infected with clinical isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection (Figure 1). These findings were confirmed in other inbred mouse strains. C2-202-infected mice also suffered from impaired pulmonary function post-recovery. Lung viral titer did not correlate with disease severity, suggesting immune-mediated pathogenesis. C2-202-infected mice exhibited increased production of type I and III interferons (IFN) and pro-inflammatory cytokines, and lung neutrophil infiltration. However, neutrophil depletion or inflammasome inactivation did not reduce disease. Stat1/Stat2 double knockout (KO) mice lacking type I and III IFN signaling exhibited reduced weight loss but increased lung viral titer after C2-202 infection (Figure 2). Type I IFN receptor (IFNAR) KO mice infected with C2-202 had reduced weight loss but unchanged lung viral titer (Figure 3), while the addition of type III IFN blockade to C2-202-infected IFNAR mice had no effect on disease but increased lung viral titer (Figure 4). Conclusion These results suggest that severe disease caused by virulent HMPV was due to exuberant IFN response. Moreover, type I IFN was primarily associated with disease, while type III IFN was associated with viral clearance. These data suggest that IFN signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target. Disclosures All Authors: No reported Disclosures.

Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in infants and children. The disease outcome of HMPV infection ranges from mild infection to severe bronchiolitis and fatal pneumonia. HMPV was discovered in 2001 and its disease mechanisms are not fully understood. To study HMPV pathogenesis, we tested nine HMPV clinical isolates in an established C57BL/6 mouse model. HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Mice infected by non-virulent strain TN/94-49 did not show significant weight loss, but mice infected with virulent isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection. These findings were confirmed in other inbred mouse strains. C2-202 infected mice also suffered from impaired pulmonary function post-recovery. Lung virus replication did not correlate with disease severity, suggesting immune-mediated pathogenesis. Further investigation revealed increased type I and III interferons, pro-inflammatory cytokine production, and neutrophil infiltration in C2-202 infected mice. HMPV C2-202 infection also inhibited dendritic cell recruitment and down-regulated MHC-II surface expression on macrophages. Stat1/Stat2 double knockout mice lacking interferon signaling exhibited reduced weight loss, lessened disease severity, and increased dendritic cell recruitment after C2-202 infection. Our results indicate that severe disease caused by HMPV clinical isolates was due to exuberant interferon response leading to immuno-pathological tissue damage. These data suggest interferon signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target.

Background As rates of pediatric community-associated (CA) Clostridium difficile infection (CDI) increase, additional research is needed to address the paucity of data in this cohort. Studies in pediatrics suggest concurrent antibiotics, CA CDI, malignancy, recent surgery, the number of antibiotic exposures by class and tracheostomy as independent risk factors for recurrent CDI (rCDI). Methods This study was a retrospective review of the electronic health records of all children 1- 17 years with stool specimens sent for C difficile from January 1st 2012 – December 31st2016 at Kaiser Permanente Northern California. Children with clinical symptoms consistent with CDI, confirmatory laboratory testing, no other identified causes of diarrhea, and community associated disease were defined as cases. Results Of the 961 positive C. difficile cases from 2012 to 2016, 744 were community-associated. There were 558 total cases of CA CDI fitting case definition. Of these 507 were primary, 43 recurrence and 8 recurrence following recurrence. The incident rate of CDI was 17 per 100,000 children. The overall rate of recurrence in our cohort was 8.5%. Race and having a diagnosis of inflammatory bowel disease (IBD) were statistically significant risk factors for rCDI. Compared with other races, we observed increased rates of rCDI in multi-racial and “other/unknown” children. Though not statistically significant, there appeared to be a correlation between the age subset of 2–5 years of age and developing rCDI. (Table) Table: Demographics and comorbidities in rCDI Total Primary Recurrence

Background As rates of pediatric community-associated (CA) Clostridium difficile infection (CDI) increase, additional research is needed to address rates of infection following common antibiotics. Methods This study was a retrospective review of the electronic health records of all children with stool specimens sent for C difficile from January first 2012 – December 31st2016 at Kaiser Permanente Northern California. Children with clinical symptoms consistent with CDI, confirmatory laboratory testing, no other identified causes of diarrhea, and community associated disease were defined as cases. Using outpatient and ED antibiotic prescription records for children, incidence rates were calculated for subsequent CA CDI for the most commonly prescribed antibiotics. Results Of 507 primary CDI cases in our cohort, 327 had any antibiotic use 2012–2015. There were 205 primary CDI cases that were preceded by an antibiotic in the previous 1–365 days. Many of these patients had more than 1 antibiotic in the preceding year. Of those, rates of CA CDI were uncommon following common antibiotics. (Table) The highest rate of CA CDI followed ceftriaxone, cefdinir, ciprofloxacin and augmentin. The lowest rates were seen following penicillin, doxycycline and azithromycin. Ninety-three percent of the antibiotic prescriptions were in outpatients, 7% in inpatients. Conclusion As rates of CA CDI increase, clinicians should be aware of rates of infection following administration of common antibiotics. The most common antibiotics to cause CA CDI were third-generation cephalosporins (ceftriaxone and cefdinir) and ciprofloxacin. Disclosures All authors: No reported disclosures.