Acute Cardiac Events in Hospitalized Older Adults With Respiratory Syncytial Virus Infection.

Importance: Respiratory syncytial virus (RSV) infection can cause severe respiratory illness in older adults. Less is known about the cardiac complications of RSV disease compared with those of influenza and SARS-CoV-2 infection. Objective: To describe the prevalence and severity of acute cardiac events during hospitalizations among adults aged 50 years or older with RSV infection. Design, Setting, and Participants: This cross-sectional study analyzed surveillance data from the RSV Hospitalization Surveillance Network, which conducts detailed medical record abstraction among hospitalized patients with RSV infection detected through clinician-directed laboratory testing. Cases of RSV infection in adults aged 50 years or older within 12 states over 5 RSV seasons (annually from 2014-2015 through 2017-2018 and 2022-2023) were examined to estimate the weighted period prevalence and 95% CIs of acute cardiac events. Exposures: Acute cardiac events, identified by International Classification of Diseases, 9th Revision, Clinical Modification or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification discharge codes, and discharge summary review. Main Outcomes and Measures: Severe disease outcomes, including intensive care unit (ICU) admission, receipt of invasive mechanical ventilation, or in-hospital death. Adjusted risk ratios (ARR) were calculated to compare severe outcomes among patients with and without acute cardiac events. Results: The study included 6248 hospitalized adults (median [IQR] age, 72.7 [63.0-82.3] years; 59.6% female; 56.4% with underlying cardiovascular disease) with laboratory-confirmed RSV infection. The weighted estimated prevalence of experiencing a cardiac event was 22.4% (95% CI, 21.0%-23.7%). The weighted estimated prevalence was 15.8% (95% CI, 14.6%-17.0%) for acute heart failure, 7.5% (95% CI, 6.8%-8.3%) for acute ischemic heart disease, 1.3% (95% CI, 1.0%-1.7%) for hypertensive crisis, 1.1% (95% CI, 0.8%-1.4%) for ventricular tachycardia, and 0.6% (95% CI, 0.4%-0.8%) for cardiogenic shock. Adults with underlying cardiovascular disease had a greater risk of experiencing an acute cardiac event relative to those who did not (33.0% vs 8.5%; ARR, 3.51; 95% CI, 2.85-4.32). Among all hospitalized adults with RSV infection, 18.6% required ICU admission and 4.9% died during hospitalization. Compared with patients without an acute cardiac event, those who experienced an acute cardiac event had a greater risk of ICU admission (25.8% vs 16.5%; ARR, 1.54; 95% CI, 1.23-1.93) and in-hospital death (8.1% vs 4.0%; ARR, 1.77; 95% CI, 1.36-2.31). Conclusions and Relevance: In this cross-sectional study over 5 RSV seasons, nearly one-quarter of hospitalized adults aged 50 years or older with RSV infection experienced an acute cardiac event (most frequently acute heart failure), including 1 in 12 adults (8.5%) with no documented underlying cardiovascular disease. The risk of severe outcomes was nearly twice as high in patients with acute cardiac events compared with patients who did not experience an acute cardiac event. These findings clarify the baseline epidemiology of potential cardiac complications of RSV infection prior to RSV vaccine availability.

Characteristics and Outcomes Among Adults Aged ≥60 Years Hospitalized with Laboratory-Confirmed Respiratory Syncytial Virus - RSV-NET, 12 States, July 2022-June 2023.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults. In May 2023, two RSV vaccines were approved for prevention of RSV lower respiratory tract disease in adults aged ≥60 years. In June 2023, CDC recommended RSV vaccination for adults aged ≥60 years, using shared clinical decision-making. Using data from the Respiratory Syncytial Virus-Associated Hospitalization Surveillance Network, a population-based hospitalization surveillance system operating in 12 states, this analysis examined characteristics (including age, underlying medical conditions, and clinical outcomes) of 3,218 adults aged ≥60 years who were hospitalized with laboratory-confirmed RSV infection during July 2022-June 2023. Among a random sample of 1,634 older adult patients with RSV-associated hospitalization, 54.1% were aged ≥75 years, and the most common underlying medical conditions were obesity, chronic obstructive pulmonary disease, congestive heart failure, and diabetes. Severe outcomes occurred in 18.5% (95% CI = 15.9%-21.2%) of hospitalized patients aged ≥60 years. Overall, 17.0% (95% CI = 14.5%-19.7%) of patients with RSV infection were admitted to an intensive care unit, 4.8% (95% CI = 3.5%-6.3%) required mechanical ventilation, and 4.7% (95% CI = 3.6%-6.1%) died; 17.2% (95% CI = 14.9%-19.8%) of all cases occurred in long-term care facility residents. These data highlight the importance of prioritizing those at highest risk for severe RSV disease and suggest that clinicians and patients consider age (particularly age ≥75 years), long-term care facility residence, and underlying medical conditions, including chronic obstructive pulmonary disease and congestive heart failure, in shared clinical decision-making when offering RSV vaccine to adults aged ≥60 years.

Characteristics and Outcomes Among Adults Aged ≥60 Years Hospitalized with Laboratory-Confirmed Respiratory Syncytial Virus - RSV-NET, 12 States, July 2022-June 2023.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults. In May 2023, two RSV vaccines were approved for prevention of RSV lower respiratory tract disease in adults aged ≥60 years. In June 2023, CDC recommended RSV vaccination for adults aged ≥60 years, using shared clinical decision-making. Using data from the Respiratory Syncytial Virus-Associated Hospitalization Surveillance Network, a population-based hospitalization surveillance system operating in 12 states, this analysis examined characteristics (including age, underlying medical conditions, and clinical outcomes) of 3,218 adults aged ≥60 years who were hospitalized with laboratory-confirmed RSV infection during July 2022-June 2023. Among a random sample of 1,634 older adult patients with RSV-associated hospitalization, 54.1% were aged ≥75 years, and the most common underlying medical conditions were obesity, chronic obstructive pulmonary disease, congestive heart failure, and diabetes. Severe outcomes occurred in 18.5% (95% CI = 15.9%-21.2%) of hospitalized patients aged ≥60 years. Overall, 17.0% (95% CI = 14.5%-19.7%) of patients with RSV infection were admitted to an intensive care unit, 4.8% (95% CI = 3.5%-6.3%) required mechanical ventilation, and 4.7% (95% CI = 3.6%-6.1%) died; 17.2% (95% CI = 14.9%-19.8%) of all cases occurred in long-term care facility residents. These data highlight the importance of prioritizing those at highest risk for severe RSV disease and suggest that clinicians and patients consider age (particularly age ≥75 years), long-term care facility residence, and underlying medical conditions, including chronic obstructive pulmonary disease and congestive heart failure, in shared clinical decision-making when offering RSV vaccine to adults aged ≥60 years.

COVID-19-Associated Hospitalizations Among U.S. Adults Aged ≥65 Years - COVID-NET, 13 States, January-August 2023.

Adults aged ≥65 years remain at elevated risk for severe COVID-19 disease and have higher COVID-19-associated hospitalization rates compared with those in younger age groups. Data from the COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to estimate COVID-19-associated hospitalization rates during January-August 2023 and identify demographic and clinical characteristics of hospitalized patients aged ≥65 years during January-June 2023. Among adults aged ≥65 years, hospitalization rates more than doubled, from 6.8 per 100,000 during the week ending July 15 to 16.4 per 100,000 during the week ending August 26, 2023. Across all age groups, adults aged ≥65 years accounted for 62.9% (95% CI = 60.1%-65.7%) of COVID-19-associated hospitalizations, 61.3% (95% CI = 54.7%-67.6%) of intensive care unit admissions, and 87.9% (95% CI = 80.5%-93.2%) of in-hospital deaths associated with COVID-19 hospitalizations. Most hospitalized adults aged ≥65 years (90.3%; 95% CI = 87.2%-92.8%) had multiple underlying conditions, and fewer than one quarter (23.5%; 95% CI = 19.5%-27.7%) had received the recommended COVID-19 bivalent vaccine. Because adults aged ≥65 years remain at increased risk for COVID-19-associated hospitalization and severe outcomes, guidance for this age group should continue to focus on measures to prevent SARS-CoV-2 infection, encourage vaccination, and promote early treatment for persons who receive a positive SARS-CoV-2 test result to reduce their risk for severe COVID-19-associated outcomes.

High Influenza Incidence and Disease Severity Among Children and Adolescents Aged <18 Years - United States, 2022-23 Season.

During the 2022-23 influenza season, early increases in influenza activity, co-circulation of influenza with other respiratory viruses, and high influenza-associated hospitalization rates, particularly among children and adolescents, were observed. This report describes the 2022-23 influenza season among children and adolescents aged <18 years, including the seasonal severity assessment; estimates of U.S. influenza-associated medical visits, hospitalizations, and deaths; and characteristics of influenza-associated hospitalizations. The 2022-23 influenza season had high severity among children and adolescents compared with thresholds based on previous seasons' influenza-associated outpatient visits, hospitalization rates, and deaths. Nationally, the incidences of influenza-associated outpatient visits and hospitalization for the 2022-23 season were similar for children aged <5 years and higher for children and adolescents aged 5-17 years compared with previous seasons. Peak influenza-associated outpatient and hospitalization activity occurred in late November and early December. Among children and adolescents hospitalized with influenza during the 2022-23 season in hospitals participating in the Influenza Hospitalization Surveillance Network, a lower proportion were vaccinated (18.3%) compared with previous seasons (35.8%-41.8%). Early influenza circulation, before many children and adolescents had been vaccinated, might have contributed to the high hospitalization rates during the 2022-23 season. Among symptomatic hospitalized patients, receipt of influenza antiviral treatment (64.9%) was lower than during pre-COVID-19 pandemic seasons (80.8%-87.1%). CDC recommends that all persons aged ≥6 months without contraindications should receive the annual influenza vaccine, ideally by the end of October.

Impact of antimicrobial stewardship interventions on peripartum antibiotic prescribing in patients with penicillin allergy.

BACKGROUND: Beta-lactam antibiotics (eg, penicillins, cephalosporins, and carbapenems) are preferred for group B streptococcus prophylaxis, intra-amniotic infection, and cesarean surgical site infection prophylaxis. Non-beta-lactam alternatives are associated with inferior efficacy and contribute to higher rates of surgical site infection and longer lengths of stay. Most patients who report a penicillin allergy can tolerate penicillins without any adverse reaction. There are low rates of cross-reactivity between penicillins and other beta-lactams, including cephalosporins and carbapenems. Efforts to evaluate penicillin allergy and promote the use of beta-lactams are needed. OBJECTIVE: This study aimed to evaluate whether an antimicrobial stewardship intervention improved the use of first-line antibiotics for peripartum indications in patients with a reported penicillin allergy, following updates to institutional guidelines. STUDY DESIGN: This was a retrospective study of adult patients presenting for vaginal or cesarean delivery at 2 hospitals within a healthcare system. Patients received at least 1 dose of antibiotics for a peripartum indication between May 1, 2018, and October 31, 2018 (preintervention group) and May 1, 2020, to October 31, 2020 (postintervention group). The stewardship intervention bundle, which was implemented between March 2019 and April 2020, included updates to institutional antibiotic guidelines, reclassification of severe penicillin allergy, development of obstetrical prophylaxis and treatment order sets, promotion of allergy referral services, and establishment of a physician champion. The primary outcome was the composite rates of patients with reported penicillin allergy who received a preferred antibiotic for a peripartum indication. The secondary measures included maternal and neonatal outcomes. RESULTS: A total of 192 patients with a history of documented penicillin allergy were evaluated (96 patients in the preintervention group and 96 patients in the postintervention group). Hives were the most commonly reported index symptom in both groups (40/96 [41.7%] vs 39/96 [40.6%]; P=.883). After stewardship interventions, there was a significant increase in the rate of preferred antibiotic use (33/96 [34.3%] vs 81/96 [84.3%]; P<.001). The effect was the greatest in patients with nonsevere allergy (14/76 [18.4%] vs 68/82 [82.9%]; P<.001). There was no difference in the rates of postpartum endometritis, 30-day readmission, 90-day surgical site infection, or neonatal early-onset sepsis between the pre- and postintervention groups. Of note, 1 patient in the postintervention group experienced itching, and another patient developed a rash, both of which resolved with medical management. CONCLUSION: A comprehensive antibiotic stewardship intervention was associated with a 50% increase in the use of preferred antibiotics for peripartum indications in patients with penicillin allergy. Allergic reactions with first-line beta-lactams were minimal and manageable.

Health Care-Associated Infections in Older Adults: Epidemiology and Prevention.

Health care-associated infections (HAIs) are a global public health threat, which disproportionately impact older adults. Host factors including aging-related changes, comorbidities, and geriatric syndromes, such as dementia and frailty, predispose older individuals to infection. The HAI risks from medical interventions such as device use, antibiotic use, and lapses in infection control follow older adults as they transfer among a network of interrelated acute and long-term care facilities. Long-term care facilities are caring for patients with increasingly complex needs, and the home-like communal environment of long-term care facilities creates distinct infection prevention challenges.

Value Added from Same-day Discharge after Appendectomy for Children with Simple Appendicitis.

Same-day discharge of children after appendectomy for simple appendicitis is safe and associated with enhanced parent satisfaction. Our general pediatric surgeons aimed to improve the rate of same-day discharge after appendectomy for simple appendicitis. Methods: We implemented a clinical practice guideline in September 2019. A surgeon-of-the-week service model and the urgent operating room started in November 2019 and January 2020, respectively. Data for children with simple appendicitis from our academic medical center were gathered prospectively using National Surgical Quality Improvement Program-Pediatric. Patient outcomes before intervention implementation (n = 278) were compared with patients following implementation (n = 264). Results: The average monthly percentage of patients discharged on the day of surgery increased in the postimplementation group (32% versus 75%). Median postoperative length of stay decreased [16.5 hours (interquartile range, 15.9) versus 4.4 hours (interquartile range, 11.7), P < 0.001], and the proportion of patients discharged directly from the postoperative anesthesia care unit increased (22.8% versus 43.6%; P < 0.001). There were no differences in balancing measures, including the return to the emergency department and readmission. Fewer children were discharged home on oral antibiotics after implementation (6.8% versus 1.5%, P = 0.002), and opioid prescribing at discharge remained low (2.5% versus 1.1%, P = 0.385). Conclusions: Using quality improvement methodology and care standardization, we significantly improved the rate of same-day discharge after appendectomy for simple appendicitis without impacting emergency department visits or readmissions. As a result, our health care system saved 140 hospital days over the first 21 months.

Low Sensitivity of International Classification of Diseases, Tenth Revision Coding for Culture-Confirmed Candidemia Cases in an Active Surveillance System: United States, 2019-2020.

We evaluated healthcare facility use of International Classification of Diseases, Tenth Revision (ICD-10) codes for culture-confirmed candidemia cases detected by active public health surveillance during 2019-2020. Most cases (56%) did not receive a candidiasis code, suggesting that studies relying on ICD-10 codes likely underestimate disease burden.

Reduction of surgical site infections in pediatric patients with complicated appendicitis: Utilization of antibiotic stewardship principles and quality improvement methodology.

BACKGROUND: The rate of surgical site infection (SSI) after appendectomy for complicated appendicitis (CA) was high at our children's hospital. We hypothesized that practice standardization, including obtaining intra-operative cultures of abdominal fluid in patients with CA, would improve outcomes and reduce healthcare utilization after appendectomy. METHODS: A quality improvement team designed and implemented a clinical practice guideline for CA that included obtaining intra-operative culture of purulent fluid, administering piperacillin/tazobactam for at least 72 h post-operatively, and transitioning to oral antibiotics based on intraoperative culture data. We compared outcomes before and after guideline implementation. RESULTS: From July 2018-October 2019, 63 children underwent appendectomy for CA compared to 41 children from January-December 2020. Compliance with our process measures are as follows: Intra-operative culture was obtained in 98% of patients post-implementation; 95% received at least 72 h of piperacillin-tazobactam; and culture results were checked on all patients. Culture results altered the choice of discharge antibiotics in 12 (29%) of patients. All-cause morbidity (SSI, emergency department visit, readmission to hospital, percutaneous drain, unplanned return to operating room) decreased significantly from 35% to 15% (p=0.02). Surgical site infections became less frequent, occurring on average every 27 days pre-implementation and every 60 days after care pathway implementation (p=0.03). CONCLUSIONS: Utilization of a clinical practice guideline was associated with reduced morbidity after appendectomy for CA. Intra-operative fluid culture during appendectomy for CA appears to facilitate the selection of appropriate post-operative antibiotics and, thus, minimize SSIs and overall morbidity.

The Landscape of Candidemia During the Coronavirus Disease 2019 (COVID-19) Pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in unprecedented healthcare challenges, and COVID-19 has been linked to secondary infections. Candidemia, a fungal healthcare-associated infection, has been described in patients hospitalized with severe COVID-19. However, studies of candidemia and COVID-19 coinfection have been limited in sample size and geographic scope. We assessed differences in patients with candidemia with and without a COVID-19 diagnosis. METHODS: We conducted a case-level analysis using population-based candidemia surveillance data collected through the Centers for Disease Control and Prevention's Emerging Infections Program during April-August 2020 to compare characteristics of candidemia patients with and without a positive test for COVID-19 in the 30 days before their Candida culture using chi-square or Fisher's exact tests. RESULTS: Of the 251 candidemia patients included, 64 (25.5%) were positive for SARS-CoV-2. Liver disease, solid-organ malignancies, and prior surgeries were each >3 times more common in patients without COVID-19 coinfection, whereas intensive care unit-level care, mechanical ventilation, having a central venous catheter, and receipt of corticosteroids and immunosuppressants were each >1.3 times more common in patients with COVID-19. All-cause in-hospital fatality was 2 times higher among those with COVID-19 (62.5%) than without (32.1%). CONCLUSIONS: One-quarter of candidemia patients had COVID-19. These patients were less likely to have certain underlying conditions and recent surgery commonly associated with candidemia and more likely to have acute risk factors linked to COVID-19 care, including immunosuppressive medications. Given the high mortality, it is important for clinicians to remain vigilant and take proactive measures to prevent candidemia in patients with COVID-19.

Treatment Practices for Adults With Candidemia at 9 Active Surveillance Sites-United States, 2017-2018.

BACKGROUND: Candidemia is a common opportunistic infection causing substantial morbidity and mortality. Because of an increasing proportion of non-albicans Candida species and rising antifungal drug resistance, the Infectious Diseases Society of America (IDSA) changed treatment guidelines in 2016 to recommend echinocandins over fluconazole as first-line treatment for adults with candidemia. We describe candidemia treatment practices and adherence to the updated guidelines. METHODS: During 2017-2018, the Emerging Infections Program conducted active population-based candidemia surveillance at 9 US sites using a standardized case definition. We assessed factors associated with initial antifungal treatment for the first candidemia case among adults using multivariable logistic regression models. To identify instances of potentially inappropriate treatment, we compared the first antifungal drug received with species and antifungal susceptibility testing (AFST) results from initial blood cultures. RESULTS: Among 1835 patients who received antifungal treatment, 1258 (68.6%) received an echinocandin and 543 (29.6%) received fluconazole as initial treatment. Cirrhosis (adjusted odds ratio = 2.06; 95% confidence interval, 1.29-3.29) was the only underlying medical condition significantly associated with initial receipt of an echinocandin (versus fluconazole). More than one-half (n = 304, 56.0%) of patients initially treated with fluconazole grew a non-albicans species. Among 265 patients initially treated with fluconazole and with fluconazole AFST results, 28 (10.6%) had a fluconazole-resistant isolate. CONCLUSIONS: A substantial proportion of patients with candidemia were initially treated with fluconazole, resulting in potentially inappropriate treatment for those involving non-albicans or fluconazole-resistant species. Reasons for nonadherence to IDSA guidelines should be evaluated, and clinician education is needed.

Burden of Candidemia in the United States, 2017.

BACKGROUND: Candidemia is a common healthcare-associated bloodstream infection with high morbidity and mortality. There are no current estimates of candidemia burden in the United States (US). METHODS: In 2017, the Centers for Disease Control and Prevention conducted active population-based surveillance for candidemia through the Emerging Infections Program in 45 counties in 9 states encompassing approximately 17 million persons (5% of the national population). Laboratories serving the catchment area population reported all blood cultures with Candida, and a standard case definition was applied to identify cases that occurred in surveillance area residents. Burden of cases and mortality were estimated by extrapolating surveillance area cases to national numbers using 2017 national census data. RESULTS: We identified 1226 candidemia cases across 9 surveillance sites in 2017. Based on this, we estimated that 22 660 (95% confidence interval [CI], 20 210-25 110) cases of candidemia occurred in the US in 2017. Overall estimated incidence was 7.0 cases per 100 000 persons, with highest rates in adults aged ≥ 65 years (20.1/100 000), males (7.9/100 000), and those of black race (12.3/100 000). An estimated 3380 (95% CI, 1318-5442) deaths occurred within 7 days of a positive Candida blood culture, and 5628 (95% CI, 2465-8791) deaths occurred during the hospitalization with candidemia. CONCLUSIONS: Our analysis highlights the substantial burden of candidemia in the US. Because candidemia is only one form of invasive candidiasis, the true burden of invasive infections due to Candida is higher. Ongoing surveillance can support future burden estimates and help assess the impact of prevention interventions.

The Changing Epidemiology of Candidemia in the United States: Injection Drug Use as an Increasingly Common Risk Factor-Active Surveillance in Selected Sites, United States, 2014-2017.

BACKGROUND: Injection drug use (IDU) is a known, but infrequent risk factor on candidemia; however, the opioid epidemic and increases in IDU may be changing the epidemiology of candidemia. METHODS: Active population-based surveillance for candidemia was conducted in selected US counties. Cases of candidemia were categorized as IDU cases if IDU was indicated in the medical records in the 12 months prior to the date of initial culture. RESULTS: During 2017, 1191 candidemia cases were identified in patients aged >12 years (incidence: 6.9 per 100 000 population); 128 (10.7%) had IDU history, and this proportion was especially high (34.6%) in patients with candidemia aged 19-44. Patients with candidemia and IDU history were younger than those without (median age, 35 vs 63 years; P < .001). Candidemia cases involving recent IDU were less likely to have typical risk factors including malignancy (7.0% vs 29.4%; relative risk [RR], 0.2 [95% confidence interval {CI}, .1-.5]), abdominal surgery (3.9% vs 17.5%; RR, 0.2 [95% CI, .09-.5]), and total parenteral nutrition (3.9% vs 22.5%; RR, 0.2 [95% CI, .07-.4]). Candidemia cases with IDU occurred more commonly in smokers (68.8% vs 18.5%; RR, 3.7 [95% CI, 3.1-4.4]), those with hepatitis C (54.7% vs 6.4%; RR, 8.5 [95% CI, 6.5-11.3]), and in people who were homeless (13.3% vs 0.8%; RR, 15.7 [95% CI, 7.1-34.5]). CONCLUSIONS: Clinicians should consider injection drug use as a risk factor in patients with candidemia who lack typical candidemia risk factors, especially in those with who are 19-44 years of age and have community-associated candidemia.

Next-Generation-Sequencing-Based Hospital Outbreak Investigation Yields Insight into Klebsiella aerogenes Population Structure and Determinants of Carbapenem Resistance and Pathogenicity.

Klebsiella aerogenes is a nosocomial pathogen associated with drug resistance and outbreaks in intensive care units. In a 5-month period in 2017, we experienced an increased incidence of cultures for carbapenem-resistant K. aerogenes (CR-KA) from an adult cardiothoracic intensive care unit (CICU) involving 15 patients. Phylogenomic analysis following whole-genome sequencing (WGS) identified the outbreak CR-KA isolates to group together as a tight monoclonal cluster (with no more than six single nucleotide polymorphisms [SNPs]), suggestive of a protracted intraward transmission event. No clonal relationships were identified between the CICU CR-KA strains and additional hospital CR-KA patient isolates from different wards and/or previous years. Carbapenemase-encoding genes and drug-resistant plasmids were absent in the outbreak strains, and carbapenem resistance was attributed to mutations impacting AmpD activity and membrane permeability. The CICU outbreak strains harbored an integrative conjugative element (ICE) which has been associated with pathogenic Klebsiella pneumoniae lineages (ICEKp10). Comparative genomics with global K. aerogenes genomes showed our outbreak strains to group closely with global sequence type 4 (ST4) strains, which, along with ST93, likely represent dominant K. aerogenes lineages associated with human infections. For poorly characterized pathogens, scaling analyses to include sequenced genomes from public databases offer the opportunity to identify emerging trends and dominant clones associated with specific attributes, syndromes, and geographical locations.

Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus.

Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection "imprints" for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus.IMPORTANCE Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.

Immunization with Pneumocystis Cross-Reactive Antigen 1 (Pca1) Protects Mice against Pneumocystis Pneumonia and Generates Antibody to Pneumocystis jirovecii.

Pneumocystis pneumonia (PcP) is a life-threatening infection that affects immunocompromised individuals. Nearly half of all PcP cases occur in those prescribed effective chemoprophylaxis, suggesting that additional preventive methods are needed. To this end, we have identified a unique mouse Pneumocystis surface protein, designated Pneumocystis cross-reactive antigen 1 (Pca1), as a potential vaccine candidate. Mice were immunized with a recombinant fusion protein containing Pca1. Subsequently, CD4+ T cells were depleted, and the mice were exposed to Pneumocystis murina Pca1 immunization completely protected nearly all mice, similar to immunization with whole Pneumocystis organisms. In contrast, all immunized negative-control mice developed PcP. Unexpectedly, Pca1 immunization generated cross-reactive antibody that recognized Pneumocystis jirovecii and Pneumocystis carinii Potential orthologs of Pca1 have been identified in P. jirovecii Such cross-reactivity is rare, and our findings suggest that Pca1 is a conserved antigen and potential vaccine target. The evaluation of Pca1-elicited antibodies in the prevention of PcP in humans deserves further investigation.

Development of a Global Respiratory Severity Score for Respiratory Syncytial Virus Infection in Infants.

Background: Respiratory syncytial virus (RSV) infection in infants has recognizable clinical signs and symptoms. However, quantification of disease severity is difficult, and published scores remain problematic. Thus, as part of a RSV pathogenesis study, we developed a global respiratory severity score (GRSS) as a research tool for evaluating infants with primary RSV infection. Methods: Previously healthy infants <10 months of age with RSV infections representing the spectrum of disease severity were prospectively evaluated. Clinical signs and symptoms were collected at 3 time points from hospitalized infants and those seen in ambulatory settings. Data were also extracted from office, emergency department, and hospital records. An unbiased data-driven approach using factor analysis was used to develop a GRSS. Results: A total of 139 infants (84 hospitalized and 55 nonhospitalized) were enrolled. Using hospitalization status as the output variable, 9 clinical variables were identified and weighted to produce a composite GRSS. The GRSS had an area under the receiver operator curve of 0.961. Construct validity was demonstrated via a significant correlation with length of stay (r = 0.586, P < .0001). Conclusions: Using routine clinical variables, we developed a severity score for infants with RSV infection that should be useful as an end point for investigation of disease pathogenesis and as an outcome measure for therapeutic interventions.

The Healthy Infant Nasal Transcriptome: A Benchmark Study.

Responses by resident cells are likely to play a key role in determining the severity of respiratory disease. However, sampling of the airways poses a significant challenge, particularly in infants and children. Here, we report a reliable method for obtaining nasal epithelial cell RNA from infants for genome-wide transcriptomic analysis, and describe baseline expression characteristics in an asymptomatic cohort. Nasal epithelial cells were collected by brushing of the inferior turbinates, and gene expression was interrogated by RNA-seq analysis. Reliable recovery of RNA occurred in the absence of adverse events. We observed high expression of epithelial cell markers and similarity to the transcriptome for intrapulmonary airway epithelial cells. We identified genes displaying low and high expression variability, both inherently, and in response to environmental exposures. The greatest gene expression differences in this asymptomatic cohort were associated with the presence of known pathogenic viruses and/or bacteria. Robust bacteria-associated gene expression patterns were significantly associated with the presence of Moraxella. In summary, we have developed a reliable method for interrogating the infant airway transcriptome by sampling the nasal epithelium. Our data demonstrates both the fidelity and feasibility of our methodology, and describes normal gene expression and variation within a healthy infant cohort.

Clinical impact of primary infection with roseoloviruses.

The roseoloviruses, human herpesvirus-6A -6B and -7 (HHV-6A, HHV-6B and HHV-7) cause acute infection, establish latency, and in the case of HHV-6A and HHV-6B, whole virus can integrate into the host chromosome. Primary infection with HHV-6B occurs in nearly all children and was first linked to the clinical syndrome roseola infantum. However, roseolovirus infection results in a spectrum of clinical disease, ranging from asymptomatic infection to acute febrile illnesses with severe neurologic complications and accounts for a significant portion of healthcare utilization by young children. Recent advances have underscored the association of HHV-6B and HHV-7 primary infection with febrile status epilepticus as well as the role of reactivation of latent infection in encephalitis following cord blood stem cell transplantation.