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Importance: Influenza vaccine effectiveness (VE) is commonly assessed against prevention of illness that requires medical attention. Few studies have evaluated VE against secondary influenza infections., Objective: To determine the estimated effectiveness of influenza vaccines in preventing secondary infections after influenza was introduced into households., Design, Settings, and Participants: During 3 consecutive influenza seasons (2017-2020), primary cases (the first household members with laboratory-confirmed influenza) and their household contacts in Tennessee and Wisconsin were enrolled into a prospective case-ascertained household transmission cohort study. Participants collected daily symptom diaries and nasal swabs for up to 7 days. Data were analyzed from September 2022 to February 2024., Exposures: Vaccination history, self-reported and verified through review of medical and registry records., Main Outcomes and Measures: Specimens were tested using reverse transcription-polymerase chain reaction to determine influenza infection. Longitudinal chain binomial models were used to estimate secondary infection risk and the effectiveness of influenza vaccines in preventing infection among household contacts overall and by virus type and subtype and/or lineage., Results: The analysis included 699 primary cases and 1581 household contacts. The median (IQR) age of the primary cases was 13 (7-38) years, 381 (54.5%) were female, 60 (8.6%) were Hispanic, 46 (6.6%) were non-Hispanic Black, 553 (79.1%) were Non-Hispanic White, and 343 (49.1%) were vaccinated. Among household contacts, the median age was 31 (10-41) years, 833 (52.7%) were female, 116 (7.3%) were Hispanic, 78 (4.9%) were non-Hispanic Black, 1283 (81.2%) were non-Hispanic White, 792 (50.1%) were vaccinated, and 356 (22.5%) had laboratory-confirmed influenza during follow-up. The overall secondary infection risk of influenza among household contacts was 18.8% (95% CI, 15.9% to 22.0%). The risk was highest among children and was 20.3% (95% CI, 16.4% to 24.9%) for influenza A and 15.9% (95% CI, 11.8% to 21.0%) for influenza B. The overall estimated VE for preventing secondary infections among unvaccinated household contacts was 21.0% (95% CI, 1.4% to 36.7%) and varied by type; estimated VE against influenza A was 5.0% (95% CI, -22.3% to 26.3%) and 56.4% (95% CI, 30.1% to 72.8%) against influenza B., Conclusions and Relevance: After influenza was introduced into households, the risk of secondary influenza among unvaccinated household contacts was approximately 15% to 20%, and highest among children. Estimated VE varied by influenza type, with demonstrated protection against influenza B virus infection.

Importance: Influenza virus infections declined globally during the COVID-19 pandemic. Loss of natural immunity from lower rates of influenza infection and documented antigenic changes in circulating viruses may have resulted in increased susceptibility to influenza virus infection during the 2021-2022 influenza season., Objective: To compare the risk of influenza virus infection among household contacts of patients with influenza during the 2021-2022 influenza season with risk of influenza virus infection among household contacts during influenza seasons before the COVID-19 pandemic in the US., Design, Setting, and Participants: This prospective study of influenza transmission enrolled households in 2 states before the COVID-19 pandemic (2017-2020) and in 4 US states during the 2021-2022 influenza season. Primary cases were individuals with the earliest laboratory-confirmed influenza A(H3N2) virus infection in a household. Household contacts were people living with the primary cases who self-collected nasal swabs daily for influenza molecular testing and completed symptom diaries daily for 5 to 10 days after enrollment., Exposures: Household contacts living with a primary case., Main Outcomes and Measures: Relative risk of laboratory-confirmed influenza A(H3N2) virus infection in household contacts during the 2021-2022 season compared with prepandemic seasons. Risk estimates were adjusted for age, vaccination status, frequency of interaction with the primary case, and household density. Subgroup analyses by age, vaccination status, and frequency of interaction with the primary case were also conducted., Results: During the prepandemic seasons, 152 primary cases (median age, 13 years; 3.9% Black; 52.0% female) and 353 household contacts (median age, 33 years; 2.8% Black; 54.1% female) were included and during the 2021-2022 influenza season, 84 primary cases (median age, 10 years; 13.1% Black; 52.4% female) and 186 household contacts (median age, 28.5 years; 14.0% Black; 63.4% female) were included in the analysis. During the prepandemic influenza seasons, 20.1% (71/353) of household contacts were infected with influenza A(H3N2) viruses compared with 50.0% (93/186) of household contacts in 2021-2022. The adjusted relative risk of A(H3N2) virus infection in 2021-2022 was 2.31 (95% CI, 1.86-2.86) compared with prepandemic seasons., Conclusions and Relevance: Among cohorts in 5 US states, there was a significantly increased risk of household transmission of influenza A(H3N2) in 2021-2022 compared with prepandemic seasons. Additional research is needed to understand reasons for this association.

Importance: The burden of influenza among young children is high, and influenza vaccination is the primary strategy to prevent the virus and its complications. Less is known about differences in clinical protection following 1 vs 2 doses of initial influenza vaccination., Objectives: To describe patterns of influenza vaccination among young children who receive outpatient care for acute respiratory tract illness in the US and compare vaccine effectiveness (VE) against medically attended laboratory-confirmed influenza by number of influenza vaccine doses received., Design: This test-negative case-control study was conducted in outpatient clinics, including emergency departments, at 5 sites of the US Influenza Vaccine Effectiveness Network during the 2014-2015 through 2017-2018 influenza seasons. The present study was performed from November 5, 2014, to April 12, 2018, during periods of local influenza circulation. Children aged 6 months to 8 years with an acute respiratory tract illness with cough who presented for outpatient care within 7 days of illness onset were included. All children were tested using real-time, reverse-transcriptase polymerase chain reaction for influenza for research purposes., Exposures: Vaccination in the enrollment season with either 1 or 2 doses of inactivated influenza vaccine as documented from electronic medical records, including state immunization information systems., Main Outcomes and Measures: Medically attended acute respiratory tract infection with real-time, reverse-transcriptase polymerase chain reaction testing for influenza., Results: Of 7533 children, 3480 children (46%) were girls, 4687 children (62%) were non-Hispanic white, and 4871 children (65%) were younger than 5 years. A total of 3912 children (52%) were unvaccinated in the enrollment season, 2924 children (39%) were fully vaccinated, and 697 children (9%) were partially vaccinated. Adjusted VE against any influenza was 51% (95% CI, 44%-57%) among fully vaccinated children and 41% (95% CI, 25%-54%) among partially vaccinated children. Among 1519 vaccine-naive children aged 6 months to 2 years, the VE of 2 doses in the enrollment season was 53% (95% CI, 28%-70%), and the VE of 1 dose was 23% (95% CI, -11% to 47%); those who received 2 doses were less likely to test positive for influenza compared with children who received only 1 dose (adjusted odds ratio, 0.57; 95% CI, 0.35-0.93)., Conclusions and Relevance: Consistent with US influenza vaccine policy, receipt of the recommended number of doses resulted in higher VE than partial vaccination in 4 influenza seasons. Efforts to improve 2-dose coverage for previously unvaccinated children may reduce the burden of influenza in this population.

Importance: Some studies have reported negative effects of prior-season influenza vaccination. Prior-season influenza vaccination effects on vaccine effectiveness (VE) in children are not well understood., Objective: To assess the association of prior-season influenza vaccination with subsequent VE in children aged 2 to 17 years., Design, Setting, and Participants: This multiseason, test-negative case-control study was conducted in outpatient clinics at 4 US sites among children aged 2 to 17 years with a medically attended febrile acute respiratory illness. Participants were recruited during the 2013-2014, 2014-2015, and 2015-2016 seasons when influenza circulated locally. Cases were children with influenza confirmed by reverse-transcription polymerase chain reaction. Test-negative control individuals were children with negative test results for influenza., Exposures: Vaccination history, including influenza vaccine type received in the enrollment season (live attenuated influenza vaccine [LAIV], inactivated influenza vaccine [IIV], or no vaccine) and season before enrollment (LAIV, IIV, or no vaccine), determined from medical records and immunization registries., Main Outcomes and Measures: LAIV and IIV effectiveness by influenza type and subtype (influenza A[H1N1]pdm09, influenza A[H3N2], or influenza B), estimated as 100 × (1 - odds ratio) in a logistic regression model with adjustment for potential confounders. Prior season vaccination associations were assessed with an interaction term., Results: Of 3369 children (1749 [52%] male; median age, 6.6 years [range, 2-17 years]) included in the analysis, 772 (23%) had a positive test result for influenza and 1674 (50%) were vaccinated in the enrollment season. Among LAIV recipients, VE against influenza A(H3N2) was higher among children vaccinated in both the enrollment and 1 prior season (50.3% [95% CI, 17.0% to 70.2%]) than among those without 1 prior season vaccination (-82.4% [95% CI, -267.5% to 9.5%], interaction P < .001). The effectiveness of LAIV against influenza A(H1N1)pdm09 was not associated with prior season vaccination among those with prior season vaccination (47.5% [95% CI, 11.4% to 68.9%]) and among those without prior season vaccination (7.8% [95% CI, -101.9% to 57.9%]) (interaction P = .37). Prior season vaccination was not associated with effectiveness of IIV against influenza A(H3N2) (38.7% [95% CI, 6.8% to 59.6%] among those with prior-season vaccination and 23.2% [95% CI, -38.3% to 57.4%] among those without prior-season vaccination, interaction P = .16) or with effectiveness of IIV against influenza A[H1N1]pdm09 (72.4% [95% CI, 56.0% to 82.7%] among those with prior season vaccination and 67.5% [95% CI, 32.1% to 84.4%] among those without prior season vaccination, interaction P = .93). Residual protection from prior season vaccination only (no vaccination in the enrollment season) was observed for influenza B (LAIV: 60.0% [95% CI, 36.8% to 74.7%]; IIV: 60.0% [36.9% to 74.6%]). Similar results were observed in analyses that included repeated vaccination in 2 and 3 prior seasons., Conclusions and Relevance: Influenza VE varied by influenza type and subtype and vaccine type, but prior-season vaccination was not associated with reduced VE. These findings support current recommendations for annual influenza vaccination of children.

Importance: Acute respiratory infections (ARIs) are the syndrome for which antibiotics are most commonly prescribed; viruses for which antibiotics are ineffective cause most ARIs., Objectives: To characterize antibiotic prescribing among outpatients with ARI during influenza season and to identify targets for reducing inappropriate antibiotic prescribing for common ARI diagnoses, including among outpatients with laboratory-confirmed influenza., Design, Setting, and Participants: Cohort study enrolling outpatients aged 6 months or older with ARI evaluated at outpatient clinics associated with 5 US Influenza Vaccine Effectiveness Network sites during the 2013-2014 and 2014-2015 influenza seasons. All patients received influenza testing by real-time reverse transcriptase-polymerase chain reaction for research purposes only. Antibiotic prescriptions, medical history, and International Classification of Diseases, Ninth Revision diagnosis codes were collected from medical and pharmacy records, as were group A streptococcal (GAS) testing results in a patient subset., Exposure: Visit for ARI, defined by a new cough of 7 days' duration or less., Main Outcomes and Measures: Antibiotic prescription within 7 days of enrollment. Appropriateness of antibiotic prescribing was based on diagnosis codes, clinical information, and influenza and GAS testing results., Results: Of 14 987 patients with ARI (mean [SD] age, 32 [24] years; 8638 [58%] women; 11 892 [80%] white), 6136 (41%) were prescribed an antibiotic. Among these 6136 patients, 2522 (41%) had diagnoses for which antibiotics are not indicated; 2106 (84%) of these patients were diagnosed as having a viral upper respiratory tract infection or bronchitis (acute or not otherwise specified). Among the 3306 patients (22%) not diagnosed as having pneumonia and who had laboratory-confirmed influenza, 945 (29%) were prescribed an antibiotic, accounting for 17% of all antibiotic prescriptions among patients with nonpneumonia ARI. Among 1248 patients with pharyngitis, 1137 (91%) had GAS testing; 440 of the 1248 patients (35%) were prescribed antibiotics, among whom 168 (38%) had negative results on GAS testing. Of 1200 patients with sinusitis and no other indication for antibiotic treatment who received an antibiotic, 454 (38%) had symptoms for 3 days or less prior to the outpatient visit, suggesting acute viral sinusitis not requiring antibiotics., Conclusions and Relevance: Antibiotic overuse remains widespread in the treatment of outpatient ARIs, including among patients with laboratory-confirmed influenza, although study sites may not be representative of other outpatient settings. Identified targets for improved outpatient antibiotic stewardship include eliminating antibiotic treatment of viral upper respiratory tract infections and bronchitis and improving adherence to prescribing guidelines for pharyngitis and sinusitis. Increased access to sensitive and timely virus diagnostic tests, particularly for influenza, may reduce unnecessary antibiotic use for these syndromes.

IMPORTANCE The first dose of live attenuated measles-containing vaccines is associated with an increased risk of febrile seizures 7 to 10 days following immunization among 12- to 23-month-old children. The combination measles, mumps, rubella, and varicella vaccine is associated with a 2-fold increased risk of febrile seizures 7 to 10 days following immunization compared with the separately administered measles, mumps, and rubella and varicella vaccines. It is unknown whether the magnitude of these increased risks depends on age at immunization. OBJECTIVE To examine the potential modifying effect of age on the risk of fever and seizures following immunization with measles-containing vaccines. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 8 Vaccine Safety Datalink sites of a total of 840,348 children 12 to 23 months of age who had received a measles-containing vaccine from 2001 through 2011. EXPOSURES Any measles-containing vaccines and measles-containing vaccines by type. MAIN OUTCOMES AND MEASURES Fever and seizure events occurring during a 42-day postimmunization observation period. RESULTS In the analysis of any measles-containing vaccines, the increased risk of seizures during the 7- to 10-day risk interval, using the remainder of the observation period as the control interval, was significantly greater among older children (relative risk, 6.5; 95% CI, 5.3-8.1; attributable risk, 9.5 excess cases per 10,000 doses; 95% CI, 7.6-11.5) than among younger children (relative risk, 3.4; 95% CI, 3.0-3.9; attributable risk = 4.0 excess cases per 10,000 doses; 95% CI, 3.4-4.6). The relative risk of postimmunization fever was significantly greater among older children than among younger children; however, its attributable risk was not. In the analysis of vaccine type, measles, mumps, rubella, and varicella vaccine was associated with a 1.4-fold increase in the risk of fever and 2-fold increase in the risk of seizures compared with measles, mumps, and rubella vaccine administered with or without varicella vaccine in both younger and older children. CONCLUSIONS AND RELEVANCE Measles-containing vaccines are associated with a lower increased risk of seizures when administered at 12 to 15 months of age. Findings of this study that focused on safety outcomes highlight the importance of timely immunization of children with the first dose of measles-containing vaccines.

Context: Current rotavirus vaccines were not associated with intussusception in large prelicensure trials. However, recent postlicensure data from international settings suggest the possibility of a low-level elevated risk, primarily in the first week after the first vaccine dose., Objective: To examine the risk of intussusception following pentavalent rotavirus vaccine (RV5) in US infants., Design, Setting, and Patients: This cohort study included infants 4 to 34 weeks of age, enrolled in the Vaccine Safety Datalink (VSD) who received RV5 from May 2006-February 2010. We calculated standardized incidence ratios (SIRs), relative risks (RRs), and 95% confidence intervals for the association between intussusception and RV5 by comparing the rates of intussusception in infants who had received RV5 with the rates of intussusception in infants who received other recommended vaccines without concomitant RV5 during the concurrent period and with the expected number of intussusception visits based on background rates assessed prior to US licensure of the RV5 (2001-2005)., Main Outcome Measure: Intussusception occurring in the 1- to 7-day and 1- to 30-day risk windows following RV5 vaccination., Results: During the study period, 786,725 total RV5 doses, which included 309,844 first doses, were administered. We did not observe a statistically significant increased risk of intussusception with RV5 for either comparison group following any dose in either the 1- to 7-day or 1- to 30-day risk window. For the 1- to 30-day window following all RV5 doses, we observed 21 cases of intussusception compared with 20.9 expected cases (SIR, 1.01; 95% CI, 0.62-1.54); following dose 1, we observed 7 cases compared with 5.7 expected cases (SIR, 1.23; 95% CI, 0.5-2.54). For the 1- to 7-day window following all RV5 doses, we observed 4 cases compared with 4.3 expected cases (SIR, 0.92; 95% CI, 0.25-2.36); for dose 1, we observed 1 case compared with 0.8 expected case (SIR, 1.21; 95% CI, 0.03-6.75). The upper 95% CI limit of the SIR (6.75) from the historical comparison translates to an upper limit for the attributable risk of 1 intussusception case per 65,287 RV5 dose-1 recipients., Conclusion: Among US infants aged 4 to 34 weeks who received RV5, the risk of intussusception was not increased compared with infants who did not receive the rotavirus vaccine.

Objectives: To evaluate the safety of trivalent inactivated influenza vaccine (TIV) in children aged 24 to 59 months and to evaluate the risk of medically attended events (MAEs) in a subcohort of children who had multiple annual doses of TIV over their lifetimes., Design: Self-controlled screening study., Setting: Seven US managed care organizations from October 1, 2002, to March 31, 2006., Participants: Children aged 24 to 59 months who received at least 1 TIV dose (66 283 children and 91 692 TIV doses)., Exposure: Vaccination with TIV., Main Outcome Measures: Medically attended events in inpatient and emergency department settings in one of the following risk windows: 0 to 2, 1 to 14, or 1 to 42 days after vaccination. All MAEs that met the screening criteria of incidence rate ratios (IRRs) exceeding 1.0 and P ≤ .05 or IRRs exceeding 2.0 and P < .20 underwent medical record review. A secondary analysis examined the risk of MAEs in children who had multiple annual lifetime TIV doses., Results: Nine diagnoses met the screening criteria. After medical record review, gastrointestinal tract symptoms (IRR, 1.18; 95% confidence interval [CI], 1.10-1.25), gastrointestinal tract disorders (7.70; 1.11-53.52), and fever (1.71; 1.64-1.80) remained significantly associated with vaccination. None of the events seemed to be serious, and none had complications. In the secondary analysis, there was an apparent dose response for vaccine and allergic reactions in the 1- to 3-day risk window., Conclusions: There was no evidence of serious MAEs following vaccination with TIV among children aged 24 to 59 months. Further studies are warranted to evaluate the risk of MAEs in children with multiple lifetime TIV doses.

Context: The clinical characteristics of pandemic 2009 influenza A(H1N1) infections have not been compared directly with illnesses caused by other influenza A strains., Objective: To compare clinical features and outcomes for 2009 H1N1, seasonal H1N1, and H3N2 influenza in a population-based cohort., Design, Setting, and Participants: Active surveillance with 30-day follow-up for influenza cases among children and adults living in a 14-zip code area in Wisconsin. Patients with subjective fever, chills, or cough of fewer than 8 days' duration were screened for eligibility during an outpatient or inpatient encounter. Consenting patients were interviewed and tested for influenza A during the 2007-2008 and 2008-2009 influenza seasons and from May to November 2009; 6874 patients (70%-86% of eligible patients) agreed to participate. Medical records were reviewed to assess outcomes., Main Outcome Measures: Hospital admission, radiographically confirmed pneumonia, and clinical characteristics of influenza A by strain., Results: We identified 545 2009 H1N1, 221 seasonal H1N1, and 632 H3N2 infections. The median ages of infected participants were 10, 11, and 25 years, respectively (P < .001). Hospital admission occurred within 30 days for 6 of 395 children with 2009 H1N1 (1.5%; 95% confidence interval [CI], 0.6%-3.1%), 5 of 135 with seasonal H1N1 (3.7%; 95% CI, 1.4%-8.0%), and 8 of 255 with H3N2 (3.1%; 95% CI, 1.5%-5.9%). Among adults, hospital admission occurred in 6 of 150 with 2009 H1N1 (4.0%; 95% CI, 1.6%-8.1%), 2 of 86 with seasonal H1N1 (2.3%; 95% CI, 0.3%-8.1%), and 17 of 377 with H3N2 (4.5%; 95% CI, 2.7%-7.0%). Pneumonia occurred in 10 children with 2009 H1N1 (2.5%; 95% CI, 1.3%-4.5%), 2 with seasonal H1N1 (1.5%; 95% CI, 0.2%-5.2%), and 5 with H3N2 (2.0%; 95% CI, 0.7%-4.3%). Among adults, pneumonia occurred in 6 with 2009 H1N1 (4.0%; 95% CI, 1.6%-8.1%), 2 with seasonal H1N1 (2.3%; 95% CI, 0.3%-8.1%), and 4 with H3N2 (1.1%; 95% CI, 0.3%-2.7%)., Conclusions: In this population, individuals with 2009 H1N1 infection were younger than those with H3N2. The risk of most serious complications was not elevated in adults or children with 2009 H1N1 compared with recent seasonal strains.

Objective: To determine the influence of certain potential risk factors on the occurrence of nonarteritic anterior ischemic optic neuropathy., Design: Case-control using 2 independent control groups, one involving a geographically defined population and the other involving patients who underwent a routine comprehensive medical evaluation., Setting: Multispecialty clinic in a rural setting providing primary, secondary, and tertiary care for residents of central and northern Wisconsin and the Upper Peninsula of Michigan., Patients: Fifty-one patients older than 45 years with first ever acute nonarteritic anterior ischemic optic neuropathy., Main Outcome Measures: Potential risk factors defined using standardized definitions abstracted from the medical records, including diabetes, hypertension, hypercholesterolemia, coronary artery disease, tobacco use, chronic obstructive pulmonary disease, body mass index, hematocrit, and white blood cell count., Methods: Conditional logistic regression analyses, first using a univariate analysis and then employing a multivariate analysis using a forward selection process., Results: The geographically defined case-control multivariate analysis revealed that diabetes (odds ratio = 2.7, 95% confidence interval = 1.2-6.3, P = .02) and body mass index (odds ratio = 1.07, 95% confidence interval = 1.00-1.14, P = .08) were associated with case status. The comprehensive case-control multivariate analysis revealed that only diabetes (odds ratio = 5.0, 95% confidence interval = 1.4-17.3, P = .01) was a significant risk factor. The attributable risk estimation for diabetes was 0.21 and 0.27 for the geographically defined and comprehensive controls, respectively., Conclusions: Diabetes seems to be a major risk factor for the development of nonarteritic anterior ischemic optic neuropathy. The low attributable risk estimation suggests that factors other than diabetes are important in the development of nonarteritic anterior ischemic optic neuropathy or in predisposing individuals to it.

Objective: Escherichia coli O157:H7 infection can cause hemorrhagic colitis and hemolytic uremic syndrome. Since 1988 the Minnesota Department of Health has carried out surveillance for this infection. To assess the occurrence of person-to-person transmission within day-care facilities, we investigated facilities where an infected child attended after onset of symptoms., Design: Parents of children less than 5 years old with E coli O157:H7 infection were interviewed from July 1988 through December 1989. If the child attended day care after onset, stool cultures were obtained from other children in attendance and their parents were interviewed. If there was presumptive evidence of ongoing E coli O157:H7 transmission in a facility, all preschool children were excluded from attending day-care facilities until two consecutive stool cultures were negative., Results: Sixty-eight cases of E coli O157:H7 infection were identified in Minnesota during the 18-month period, including 29 cases identified through investigations at nine day-care facilities. There was evidence of person-to-person transmission in all nine facilities. The median number of infected children per facility was two (range, two to 18), and the median attack rate was 22% (range, 3% to 38%). The median age of the primary case at each facility was 26 months (range, 12 to 59 months). There was no evidence of further transmission at facilities where children were temporarily excluded until two consecutive stool cultures were negative., Conclusion: Person-to-person transmission of E coli O157:H7 is common when infected preschool children attend day care while symptomatic. The number of unrecognized day-care outbreaks in the United States may be substantial due to the lack of routine testing for this pathogen in stool cultures, the absence of public health surveillance in many regions, and incomplete follow-up of infected children. Temporary exclusion of all children was an effective control strategy in this population, but additional investigations are needed to determine the optimal intervention.