Influenza Antiviral Treatment and Length of Stay.

BACKGROUND: Antiviral treatment is recommended for hospitalized patients with suspected and confirmed influenza, but evidence is limited among children. We evaluated the effect of antiviral treatment on hospital length of stay (LOS) among children hospitalized with influenza. METHODS: We included children <18 years hospitalized with laboratory-confirmed influenza in the US Influenza Hospitalization Surveillance Network. We collected data for 2 cohorts: 1 with underlying medical conditions not admitted to the ICU (n = 309, 2012-2013) and an ICU cohort (including children with and without underlying conditions; n = 299, 2010-2011 to 2012-2013). We used a Cox model with antiviral receipt as a time-dependent variable to estimate hazard of discharge and a Kaplan-Meier survival analysis to determine LOS. RESULTS: Compared with those not receiving antiviral agents, LOS was shorter for those treated ≤2 days after illness onset in both the medical conditions (adjusted hazard ratio: 1.37, P = .02) and ICU (adjusted hazard ratio: 1.46, P = .007) cohorts, corresponding to 37% and 46% increases in daily discharge probability, respectively. Treatment ≥3 days after illness onset had no significant effect in either cohort. In the medical conditions cohort, median LOS was 3 days for those not treated versus 2 days for those treated ≤2 days after symptom onset (P = .005). CONCLUSIONS: Early antiviral treatment was associated with significantly shorter hospitalizations in children with laboratory-confirmed influenza and high-risk medical conditions or children treated in the ICU. These results support Centers for Disease Control and Prevention recommendations for prompt empiric antiviral treatment in hospitalized patients with suspected or confirmed influenza.

Waning of Measured Influenza Vaccine Effectiveness Over Time: The Potential Contribution of Leaky Vaccine Effect.

BACKGROUND: Several observational studies have shown decreases in measured influenza vaccine effectiveness (mVE) during influenza seasons. One study found decreases of 6-11%/month during the 2011-2012 to 2014-2015 seasons. These findings could indicate waning immunity but could also occur if vaccine effectiveness is stable and vaccine provides partial protection in all vaccinees ("leaky") rather than complete protection in a subset of vaccinees. Since it is unknown whether influenza vaccine is leaky, we simulated the 2011-2012 to 2014-2015 influenza seasons to estimate the potential contribution of leaky vaccine effect to the observed decline in mVE. METHODS: We used available data to estimate daily numbers of vaccinations and infections with A/H1N1, A/H3N2, and B viruses. We assumed that vaccine effect was leaky, calculated mVE as 1 minus the Mantel-Haenszel relative risk of vaccine on incident cases, and determined the mean mVE change per 30 days since vaccination. Because change in mVE was highly dependent on infection rates, we performed simulations using low (15%) and high (31%) total (including symptomatic and asymptomatic) seasonal infection rates. RESULTS: For the low infection rate, decreases (absolute) in mVE per 30 days after vaccination were 2% for A/H1N1 and 1% for A/H3N2and B viruses. For the high infection rate, decreases were 5% for A/H1N1, 4% for A/H3, and 3% for B viruses. CONCLUSIONS: The leaky vaccine bias could account for some, but probably not all, of the observed intraseasonal decreases in mVE. These results underscore the need for strategies to deal with intraseasonal vaccine effectiveness decline.

An evaluation and update of methods for estimating the number of influenza cases averted by vaccination in the United States.

INTRODUCTION: To evaluate the public health benefit of yearly influenza vaccinations, CDC estimates the number of influenza cases and hospitalizations averted by vaccine. Available input data on cases and vaccinations is aggregated by month and the estimation model is intentionally simple, raising concerns about the accuracy of estimates. METHODS: We created a synthetic dataset with daily counts of influenza cases and vaccinations, calculated "true" averted cases using a reference model applied to the daily data, aggregated the data by month to simulate data that would actually be available, and evaluated the month-level data with seven test methods (including the current method). Methods with averted case estimates closest to the reference model were considered most accurate. To examine their performance under varying conditions, we re-evaluated the test methods when synthetic data parameters (timing of vaccination relative to cases, vaccination coverage, infection rate, and vaccine effectiveness) were varied over wide ranges. Finally, we analyzed real (i.e., collected by surveillance) data from 2010 to 2017 comparing the current method used by CDC with the best-performing test methods. RESULTS: In the synthetic dataset (population 1 million persons, vaccination uptake 55%, seasonal infection risk without vaccination 12%, vaccine effectiveness 48%) the reference model estimated 28,768 averted cases. The current method underestimated averted cases by 9%. The two best test methods estimated averted cases with <1% error. These two methods also worked well when synthetic data parameters were varied over wide ranges (≤6.2% error). With the real data, these two methods estimated numbers of averted cases that are a median 8% higher than the currently-used method. CONCLUSIONS: We identified two methods for estimating numbers of influenza cases averted by vaccine that are more accurate than the currently-used algorithm. These methods will help us to better assess the benefits of influenza vaccination.

Seasonal Incidence of Symptomatic Influenza in the United States.

Background: The seasonal incidence of influenza is often approximated as 5%-20%. Methods: We used 2 methods to estimate the seasonal incidence of symptomatic influenza in the United States. First, we made a statistical estimate extrapolated from influenza-associated hospitalization rates for 2010-2011 to 2015-2016, collected as part of national surveillance, covering approximately 9% of the United States, and including the existing mix of vaccinated and unvaccinated persons. Second, we performed a literature search and meta-analysis of published manuscripts that followed cohorts of subjects during 1996-2016 to detect laboratory-confirmed symptomatic influenza among unvaccinated persons; we adjusted this result to the US median vaccination coverage and effectiveness during 2010-2016. Results: The statistical estimate of influenza incidence among all ages ranged from 3.0%-11.3% among seasons, with median values of 8.3% (95% confidence interval [CI], 7.3%-9.7%) for all ages, 9.3% (95% CI, 8.2%-11.1%) for children <18 years, and 8.9% (95% CI, 8.2%-9.9%) for adults 18-64 years. Corresponding values for the meta-analysis were 7.1% (95% CI, 6.1%-8.1%) for all ages, 8.7% (95% CI, 6.6%-10.5%) for children, and 5.1% (95% CI, 3.6%-6.6%) for adults. Conclusions: The 2 approaches produced comparable results for children and persons of all ages. The statistical estimates are more versatile and permit estimation of season-to-season variation. During 2010-2016, the incidence of symptomatic influenza among vaccinated and unvaccinated US residents, including both medically attended and nonattended infections, was approximately 8% and varied from 3% to 11% among seasons.

Outbreak of Middle East Respiratory Syndrome at Tertiary Care Hospital, Jeddah, Saudi Arabia, 2014.

During March-May 2014, a Middle East respiratory syndrome (MERS) outbreak occurred in Jeddah, Saudi Arabia, that included many persons who worked or received medical treatment at King Fahd General Hospital. We investigated 78 persons who had laboratory-confirmed MERS during March 2-May 10 and documented contact at this hospital. The 78 persons with MERS comprised 53 patients, 16 healthcare workers, and 9 visitors. Among the 53 patients, the most probable sites of acquisition were the emergency department (22 patients), inpatient areas (17), dialysis unit (11), and outpatient areas (3). Infection control deficiencies included limited separation of suspected MERS patients, patient crowding, and inconsistent use of infection control precautions; aggressive improvements in these deficiencies preceded a decline in cases. MERS coronavirus transmission probably was multifocal, occurring in multiple hospital settings. Continued vigilance and strict application of infection control precautions are necessary to prevent future MERS outbreaks.

Health care worker contact with MERS patient, Saudi Arabia.

To investigate potential transmission of Middle East respiratory syndrome coronavirus (MERS-CoV) to health care workers in a hospital, we serologically tested hospital contacts of the index case-patient in Saudi Arabia, 4 months after his death. None of the 48 contacts showed evidence of MERS-CoV infection.

Health-related quality of life in the CDC Anthrax Vaccine Adsorbed Human Clinical Trial.

BACKGROUND: After the Department of Defense implemented a mandatory anthrax vaccination program in 1998 concerns were raised about potential long-term safety effects of the current anthrax vaccine. The CDC multicenter, randomized, double-blind, placebo-controlled Anthrax Vaccine Adsorbed (AVA) Human Clinical Trial to evaluate route change and dose reduction collected data on participants' quality of life. Our objective is to assess the association between receipt of AVA and changes in health-related quality of life, as measured by the SF-36 health survey (Medical Outcomes Trust, Boston, MA), over 42 months after vaccination. METHODS: 1562 trial participants completed SF-36v2 health surveys at 0, 12, 18, 30 and 42 months. Physical and mental summary scores were obtained from the survey results. We used Generalized Estimating Equations (GEE) analyses to assess the association between physical and mental score difference from baseline and seven study groups receiving either AVA at each dose, saline placebo at each dose, or a reduced AVA schedule substituting saline placebo for some doses. RESULTS: Overall, mean physical and mental scores tended to decrease after baseline. However, we found no evidence that the score difference from baseline changed significantly differently between the seven study groups. CONCLUSIONS: These results do not favor an association between receipt of AVA and an altered health-related quality of life over a 42-month period.

Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines in pregnant women.

OBJECTIVE: We sought to characterize reports to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women who received tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap). STUDY DESIGN: We searched VAERS for reports of pregnant women who received Tdap from Jan. 1, 2005, through June 30, 2010. We conducted a clinical review of reports and available medical records. RESULTS: We identified 132 reports of Tdap administered to pregnant women; 55 (42%) described no adverse event (AE). No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 22 (16.7%) reports. Injection site reactions were the most frequent non-pregnancy-specific AE found in 6 (4.5%) reports. One report with a major congenital anomaly (gastroschisis) was identified. CONCLUSION: During a time when Tdap was not routinely recommended in pregnancy, review of reports to VAERS in pregnant women after Tdap did not identify any concerning patterns in maternal, infant, or fetal outcomes.

The risk of Guillain-Barré syndrome associated with influenza A (H1N1) 2009 monovalent vaccine and 2009-2010 seasonal influenza vaccines: results from self-controlled analyses.

PURPOSE: The Centers for Disease Control and Prevention Emerging Infections Program implemented active, population-based surveillance for Guillain-Barré syndrome (GBS) following H1N1 vaccines in 10 states/metropolitan areas. We report additional analyses of these data using self-controlled methods, which avoid potential confounding from person-level factors and co-morbidities. METHODS: Surveillance officers identified GBS cases with symptom onset during October 2009-April 2010 and ascertained receipt of H1N1 vaccines. We calculated self-controlled relative risks by comparing the number of cases with onset during a risk interval 1-42 days after vaccination with cases with onset during fixed (days 43-84) or variable (days 43-end of study period) control intervals. We calculated attributable risks by applying statistically significant relative risks to an independent estimate of GBS incidence. RESULTS: Fifty-nine GBS cases received H1N1 vaccine with or without seasonal vaccine. The relative risk was 2.1 (95%CI 1.2, 3.5) by the variable-window and 3.0 (95%CI 1.4, 6.4) by the fixed-window analyses. The corresponding attributable risks per million doses administered were 1.5 (95%CI 0.3, 3.4) and 2.8 (95%CI 0.6, 7.4). CONCLUSIONS: These attributable risks are similar to those of some previous formulations of seasonal influenza vaccine (about one to two cases per million doses administered), suggesting a low risk of GBS following the H1N1 vaccine that is not clearly higher than that of seasonal influenza vaccines.

A cluster of nonspecific adverse events in a military reserve unit following pandemic influenza A (H1N1) 2009 vaccination-possible stimulated reporting?

BACKGROUND: On February 20, 2010, a 23 year old male Army Reservist (index case) with symptom onset 4 h after receiving inactivated monovalent pandemic 2009 (H1N1) vaccine (MIV) was hospitalized with possible Guillain-Barré syndrome (GBS). Within 1-2 days, 13 reservists from the same unit presented to the emergency department and 14 filed Vaccine Adverse Event Reporting System (VAERS) reports of nonspecific symptoms following MIV. OBJECTIVES: To describe the spectrum of adverse events (AE) among reservists in the unit after MIV and to identify factors contributing to this cluster of reports. METHODS: We reviewed the reservists' VAERS reports and hospital records for demographics, influenza vaccination status, diagnostic results and outcome. All VAERS reports after vaccination from the same MIV lot were also screened. We conducted a survey of unit reservists to identify contributing factors for this cluster. RESULTS: The presumptive diagnosis of GBS in the index case was not confirmed. All other reservists demonstrated normal exam findings and laboratory investigations. VAERS reports following vaccination from the same MIV lot revealed no consistent pattern. Our survey of factors contributing to the cluster was returned by 55 reservists (response rate 28%). AEs following MIV were significantly more often reported by female and black reservists. There was a tendency for concern about the safety of the 2010-2011 seasonal influenza vaccine to be higher for reservists that reported an AE to MIV (p=0.13) or that sought medical attention for their symptoms (p=0.08). CONCLUSIONS: This cluster represents possible stimulated reporting following receipt of inactivated pandemic 2009 (H1N1) vaccine among service personnel.

Health-related quality of life in the Anthrax Vaccination Program for workers in the Laboratory Response Network.

BACKGROUND: In 2002 CDC initiated the Anthrax Vaccination Program (AVP) to provide voluntary pre-exposure vaccination with Anthrax Vaccine Adsorbed (AVA) for persons at high risk of exposure to Bacillus anthracis spores. There has been concern that AVA could be associated with long term impairment of physical and/or mental health. OBJECTIVES: To ascertain whether physical and mental functional status, as measured by the SF-36v2 health survey (Medical Outcomes Trust, Boston, MA), of AVA recipients and controls changed differently over time. METHODS: We enrolled 437 exposed (received AVA) and 139 control subjects. The exposed group received AVA under then-current Advisory Committee on Immunization Practices (ACIP) recommendations. SF-36v2 surveys were completed at 0, 12, and 30 months. SF-36v2 physical and mental scores both range from 0 to 100 with an estimated national average of 50 points. RESULTS: For physical scores, the average change from baseline was -0.53 for exposed vs. -0.67 for controls at 12 months (p=0.80) and -1.09 for exposed vs. -1.97 for controls at 30 months (p=0.23). For mental scores, the average change from baseline was -1.50 for exposed vs. -1.64 for controls at 12 months (p=0.86) and -2.11 for exposed vs. -0.24 for controls at 30 months (p=0.06). In multivariable analysis, the difference in mental score change between exposed vs. controls at 30 months was less pronounced (p=0.37) but other findings were similar to univariate analyses. CONCLUSIONS: These results do not favor an association between receipt of AVA and an altered health related quality of life over a 30-month period.

Vaccination and risk of type 1 diabetes mellitus in active component U.S. Military, 2002-2008.

AIMS/HYPOTHESIS: To evaluate whether vaccination increases the risk of type 1 diabetes mellitus in active component U.S. military personnel. METHODS: We conducted a retrospective cohort study among active component U.S. military personnel age 17-35 years. Individuals with first time diagnoses of type 1 diabetes between January 1, 2002 and December 31, 2008 were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. We used Poisson regression to estimate risk ratios between individual vaccine exposures and type 1 diabetes. Secondary analyses were performed controlling for receipt of multiple vaccines and available demographic variables. RESULTS: Our study population consisted of 2,385,102 individuals followed for approximately 7,644,098 person-years of service. This included 1074 incident type 1 diabetes cases. We observed no significant increased risk of type 1 diabetes after vaccination with anthrax vaccine adsorbed (AVA) [RR=1.00; 95% CI (0.85, 1.17)], smallpox vaccine [RR=0.84; 95% (CI 0.70, 1.01)], typhoid vaccine [RR=1.03; 95% CI (0.87, 1.22)], hepatitis B vaccine [RR=0.83; 95% CI (0.72, 0.95)], measles mumps rubella vaccine (MMR) [RR=0.71, 95% CI (0.61, 0.83)], or yellow fever vaccine [RR=0.70; 95% CI (0.59, 0.82)]. CONCLUSIONS: We did not find an increased risk of diagnosed type 1 diabetes and any of the study vaccines. We recommend that follow-up studies using medical record review to confirm case status should be considered to corroborate these findings.

Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination.

BACKGROUND: Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009-2010 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) network sought to characterize these SAEs and to assess their possible causal relationship to vaccination. METHODS: Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR§314.80) after receipt of H1N1 vaccine reported to VAERS between October 1, 2009 and March 31, 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined. RESULTS: 212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barré Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as "possibly" related (33%), 108 as "unlikely" related (51%), and 20 as "unrelated" (9%) to H1N1 vaccination; none were classified as "probable" or "definite" and 12 were unclassifiable (6%). CONCLUSION: The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols for providers to use in evaluation of adverse events following immunization, and rapid identification and follow-up of VAERS reports could improve causality assessment.

Overview of the Clinical Consult Case Review of adverse events following immunization: Clinical Immunization Safety Assessment (CISA) network 2004-2009.

BACKGROUND: In 2004 the Clinical Consult Case Review (CCCR) working group was formed within the CDC-funded Clinical Immunization Safety Assessment (CISA) Network to review individual cases of adverse events following immunizations (AEFI). METHODS: Cases were referred by practitioners, health departments, or CDC employees. Vaccine Adverse Event Reporting System (VAERS) searches and literature reviews for similar cases were performed prior to review. After CCCR discussion, AEFI were assessed for a causal relationship with vaccination and recommendations regarding future immunizations were relayed back to the referring physicians. In 2010, surveys were sent to referring physicians to determine the utility and effectiveness of the CCCR service. RESULTS: CISA investigators reviewed 76 cases during 68 conference calls between April 2004 and December 2009. Almost half of the cases (35/76) were neurological in nature. Similar AEFI for the specific vaccines received were discovered for 63 cases through VAERS searches and for 38 cases through PubMed searches. Causality assessment using the modified WHO criteria resulted in classifying 3 cases as definitely related to vaccine administration, 12 as probably related, 16 as possibly related, 18 as unlikely related, 10 as unrelated, and 17 had insufficient information to assign causality. The physician satisfaction survey was returned by 30 (57.7%) of those surveyed and a majority of respondents (93.3%) felt that the CCCR service was useful. CONCLUSIONS: The CCCR provides advice about AEFI to practitioners, assigns potential causality, and contributes to an improved understanding of adverse health events following immunizations.

Automated surveillance of Clostridium difficile infections using BioSense.

OBJECTIVE: To determine the feasibility of using electronic laboratory and admission-discharge-transfer data from BioSense, a national automated surveillance system, to apply new modified Clostridium difficile infection (CDI) surveillance definitions and calculate overall and facility-specific rates of disease. DESIGN: Retrospective, multicenter cohort study. SETTING: Thirty-four hospitals sending inpatient, emergency department, and/or outpatient data to BioSense. METHODS: Laboratory codes and text-parsing methods were used to extract C. difficile-positive toxin assay results from laboratory data sent to BioSense during the period from January 1, 2007, through June 30, 2008; these were merged with administrative records to determine whether cases were community associated or healthcare onset, as well as patient-day data for rate calculations. A patient was classified as having hospital-onset CDI if he or she had a C. difficile toxin-positive result on a stool sample collected 3 or more days after admission and community-onset CDI if the specimen was collected less than 3 days after admission or the patient was not hospitalized. RESULTS: A total of 4,585 patients from 34 hospitals in 12 states had C. difficile-positive assay results. More than half (53.0%) of the cases were community-onset, and 30.8% of these occurred in patients who were recently hospitalized. The overall rate of healthcare-onset CDI was 7.8 cases per 10,000 patient-days, with a range among facilities of 1.5-27.8 cases per 10,000 patient-days. CONCLUSIONS: Electronic laboratory data sent to the BioSense surveillance system were successfully used to produce disease rates of CDI comparable to those of other studies, which shows the feasibility of using electronic laboratory data to track a disease of public health importance.

Automated monitoring of clusters of falls associated with severe winter weather using the BioSense system.

OBJECTIVES: To identify and characterise clusters of emergency department (ED) visits for fall injuries during the 2007-2008 winter season. METHODS: Hospital ED chief complaints and diagnoses from hospitals reporting to the Centers for Disease Control and Prevention BioSense system were analysed. The authors performed descriptive analyses, used time series charts on data aggregated by metropolitan statistical areas (MSAs), and used SaTScan to find spatial-temporal clusters of visits from falls. RESULTS: In 2007-2008, 17 clusters of falls in 13 MSAs were found; the median number of excess ED visits for falls was 71 per day. SaTScan identified 11 clusters of falls, of which seven corresponded to MSA clusters found by time series and five included more than one state/district. Most clusters coincided with known periods of snowfall or freezing rain. CONCLUSION: The results show the role that a national automated system can play in tracking widespread injuries. Such a system could be harnessed to assist with prevention strategies.

Summary of data reported to CDC's national automated biosurveillance system, 2008.

BACKGROUND: BioSense is the US national automated biosurveillance system. Data regarding chief complaints and diagnoses are automatically pre-processed into 11 broader syndromes (e.g., respiratory) and 78 narrower sub-syndromes (e.g., asthma). The objectives of this report are to present the types of illness and injury that can be studied using these data and the frequency of visits for the syndromes and sub-syndromes in the various data types; this information will facilitate use of the system and comparison with other systems. METHODS: For each major data source, we summarized information on the facilities, timeliness, patient demographics, and rates of visits for each syndrome and sub-syndrome. RESULTS: In 2008, the primary data sources were the 333 US Department of Defense, 770 US Veterans Affairs, and 532 civilian hospital emergency department facilities. Median times from patient visit to record receipt at CDC were 2.2 days, 2.0 days, and 4 hours for these sources respectively. Among sub-syndromes, we summarize mean 2008 visit rates in 45 infectious disease categories, 11 injury categories, 7 chronic disease categories, and 15 other categories. CONCLUSIONS: We present a systematic summary of data that is automatically available to public health departments for monitoring and responding to emergencies.

Enhancing time-series detection algorithms for automated biosurveillance.

BioSense is a US national system that uses data from health information systems for automated disease surveillance. We studied 4 time-series algorithm modifications designed to improve sensitivity for detecting artificially added data. To test these modified algorithms, we used reports of daily syndrome visits from 308 Department of Defense (DoD) facilities and 340 hospital emergency departments (EDs). At a constant alert rate of 1%, sensitivity was improved for both datasets by using a minimum standard deviation (SD) of 1.0, a 14-28 day baseline duration for calculating mean and SD, and an adjustment for total clinic visits as a surrogate denominator. Stratifying baseline days into weekdays versus weekends to account for day-of-week effects increased sensitivity for the DoD data but not for the ED data. These enhanced methods may increase sensitivity without increasing the alert rate and may improve the ability to detect outbreaks by using automated surveillance system data.