Heterotypic Infection and Spread of Rhinovirus A, B, and C among Childcare Attendees.

Background: Despite the frequency of human rhinovirus (HRV), data describing the molecular epidemiology of HRV in the community are limited. Childcare centers are optimal settings to characterize heterotypic HRV cocirculation. Methods: HRV specimens were prospectively obtained from a cohort of childcare attendees at enrollment and weekly during respiratory illness. The 5' noncoding region sequences were used to determine HRV species (A, B, C) and genotypes. Results: Among 225 children followed, sequence data were available for 92 HRV infections: HRV-A (n = 80; 59%) was most common, followed by HRV-C (n = 52, 39%), and HRV-B (n = 3, 2%). Forty-one genotypes were identified and cocirculation was common. Frequent spread between classrooms occurred with 2 HRV-A genotypes. Repeated detections within single illnesses were a combination of persistent (n = 7) and distinct (n = 7) genotypes. Prevalence of HRV among asymptomatic children was 41%. HRV-C was clinically similar to HRV-A and HRV-B. Conclusions: HRV epidemiology in childcare consists of heterotypic cocirculation of genotypes with periodic spread within and among classrooms. Based on our finding of multiple genotypes evident during the course of single illnesses, the use of sequence-based HRV type determination is critical in longitudinal studies of HRV epidemiology and transmission.

Reliability, Validity, and Responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO©) Scores in Influenza-Positive Patients.

OBJECTIVES: To assess the reliability, validity, and responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO©) scores for quantifying the presence and severity of influenza symptoms. METHODS: An observational prospective cohort study of adults (≥18 years) with influenza-like illness in the United States, the United Kingdom, Mexico, and South America was conducted. Participants completed the 37-item draft FLU-PRO daily for up to 14 days. Item-level and factor analyses were used to remove items and determine factor structure. Reliability of the final tool was estimated using Cronbach α and intraclass correlation coefficients (2-day reliability). Convergent and known-groups validity and responsiveness were assessed using global assessments of influenza severity and return to usual health. RESULTS: Of the 536 patients enrolled, 221 influenza-positive subjects comprised the analytical sample. The mean age of the patients was 40.7 years, 60.2% were women, and 59.7% were white. The final 32-item measure has six factors/domains (nose, throat, eyes, chest/respiratory, gastrointestinal, and body/systemic), with a higher order factor representing symptom severity overall (comparative fit index = 0.92; root mean square error of approximation = 0.06). Cronbach α was high (total = 0.92; domain range = 0.71-0.87); test-retest reliability (intraclass correlation coefficient, day 1-day 2) was 0.83 for total scores and 0.57 to 0.79 for domains. Day 1 FLU-PRO domain and total scores were moderately to highly correlated (≥0.30) with Patient Global Rating of Flu Severity (except nose and throat). Consistent with known-groups validity, scores differentiated severity groups on the basis of global rating (total: F = 57.2, P < 0.001; domains: F = 8.9-67.5, P < 0.001). Subjects reporting return to usual health showed significantly greater (P < 0.05) FLU-PRO score improvement by day 7 than did those who did not, suggesting score responsiveness. CONCLUSIONS: Results suggest that FLU-PRO scores are reliable, valid, and responsive to change in influenza-positive adults.

Development of the Flu-PRO: a patient-reported outcome (PRO) instrument to evaluate symptoms of influenza.

BACKGROUND: To develop content validity of a comprehensive patient-reported outcome (PRO) measure following current best scientific methodology to standardize assessment of influenza (flu) symptoms in clinical research. METHODS: Stage I (Concept Elicitation): 1:1 telephone interviews with influenza-positive adults (≥18 years) in the US and Mexico within 7 days of diagnosis. Participants described symptom type, character, severity, and duration. Content analysis identified themes and developed the draft Flu-PRO instrument. Stage II (Cognitive Interviewing): The Flu-PRO was administered to a unique set of influenza-positive adults within 14 days of diagnosis; telephone interviews addressed completeness, respondent interpretation of items and ease of use. RESULTS: Samples: Stage I: N = 46 adults (16 US, 30 Mexico); mean (SD) age: 38 (19), 39 (14) years; % female: 56%, 73%; race: 69% White, 97% Mestizo. Stage II: N = 34 adults (12 US, 22 Mexico); age: 37 (14), 39 (11) years; % female: 50%, 50%; race: 58% White, 100% Mestizo. SYMPTOMS: Symptoms identified by >50%: coughing, weak or tired, throat symptoms, congestion, headache, weakness, sweating, chills, general discomfort, runny nose, chest (trouble breathing), difficulty sleeping, and body aches or pains. No new content was uncovered during Stage II; participants easily understood the instrument. CONCLUSIONS: Results show the 37-item Flu-PRO is a content valid measure of influenza symptoms in adults with a confirmed diagnosis of influenza. Research is underway to evaluate the suitability of the instrument for children and adolescents. This work can form the basis for future quantitative tests of reliability, validity, and responsiveness to evaluate the measurement properties of Flu-PRO for use in clinical trials and epidemiology studies.

Epidemiology of multiple respiratory viruses in childcare attendees.

BACKGROUND: The identification of multiple viruses during respiratory illness is increasing with advances in rapid molecular testing; however, the epidemiology of respiratory viral coinfections is not well known. METHODS: In total, 225 childcare attendees were prospectively followed for up to 2 years. Nasal swabs were collected at respiratory illness onset and every 7-10 days until illness resolution. Swabs were tested by polymerase chain reaction for 15 respiratory viruses and subtypes. RESULTS: At least 1 virus was detected in 382 (84%) of 455 new-onset illnesses with multiple viruses identified in 212 (46%). The proportion of subject swabs with multiple viruses detected changed as respiratory illnesses progressed from week to week, as did the prevalence of individual viruses. Children with multiple viruses detected at the time of illness onset had less frequent fever (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35, 0.90), however, these children more often had illness symptoms lasting over 7 days (OR, 1.94; 95% CI, 1.20, 3.14). CONCLUSIONS: A high proportion of daycare attendees had multiple viruses detected during respiratory illnesses. Delay between onset of illness and viral detection varied by virus, indicating that some viruses may be underrepresented in studies of virus epidemiology that rely on only a single test at symptom onset.

Influenza Vaccine Effectiveness: Analysis of the Impact of Repeated Vaccinations in Military Health System Beneficiaries.

Background: Influenza has long burdened the Military Health System (MHS). This study assesses the impact of repeated annual vaccination on influenza vaccine effectiveness (VE). Methods: This retrospective, case control study using the test-negative design utilized data extracted from the MHS Data Repository (MDR). Cases had a positive influenza test and controls sought care for an influenza-like illness within 2 weeks of a case, had no positive influenza tests, and were matched by sex, race, age, and location. Vaccine effectiveness was assessed using conditional logistic regression separately for those who received inactivated and live attenuated influenza vaccines (LAIV). Results: A total of 6860 cases and controls were identified in the MDR, among whom 53% were vaccinated in all 3 seasons. Among those who received inactivated influenza vaccine during the current season, VE ranged from 26% to 37% (2012/13 [A(H3N2)]: VE 26%, 95% confidence interval [CI] = 1%-45%; 2013/14 [A(H1N1)pdm09]: VE 37%, 95% CI = 18%-52%; 2014/15 [A(H3N2)]: VE 31%, 95% CI = 17%-42%). The VE ranged from 25% to 49% for those only vaccinated this season (2012/13 [A(H3N2)]: VE 38%, 95% CI = -3% to 63%; 2013/14 [A(H1N1)pdm09]: VE 49%, 95% CI = 11%-71%; 2014/15 [A(H3N2)]: VE 25%, 95% CI = -7% to 48%). The VE was more variable in those who received LAIV in the current season. No statistically significant differences in VE were observed between those frequently vaccinated and those vaccinated only during the current season. Conclusions: These results underscore the value of annual influenza vaccinations for preventing infection while highlighting the need for continued improvements in influenza vaccine effectiveness.

Frequent and prolonged shedding of bocavirus in young children attending daycare.

BACKGROUND: Little is known about human bocavirus (HBoV) persistence and shedding and the association between HBoV detection and the onset and resolution of respiratory symptoms. METHODS: We performed HBoV testing on nasal swab samples from a prospective, longitudinal study of respiratory illness in 119 children who attended daycare. RESULTS: HBoV was detected in 70 children (59%) and in 106 (33%) of the 318 cases of illness. Another virus was detected in 76 (72%) of 106 HBoV-positive cases. Extended and intermittent shedding was observed, with consistent HBoV detection documented for up to 75 days. HBoV was detected in 20 (44%) of 45 asymptomatic enrollment samples, and HBoV prevalence and viral load did not differ significantly between children with and children without symptoms at enrollment. HBoV-positive illnesses were longer than HBoV-negative illnesses (odds ratio for duration of symptoms >7 days, 2.44; 95% confidence interval, 1.41-4.22), and illnesses with HBoV load 4 log(10) copies/mL required a visit to a health care provider more often than did HBoV-negative illnesses (odds ratio, 1.64; 95% confidence interval, 1.02-2.64). CONCLUSION: HBoV was more common in illnesses with greater severity. However, detection of HBoV was not associated with the presence of respiratory illness or with specific respiratory symptoms in this prospective study of infants and toddlers attending daycare centers.

Effects of human immunodeficiency virus status on symptom severity in influenza-like illness in an otherwise healthy adult outpatient cohort.

The impact of HIV on influenza-like illness (ILI) has been incompletely described in the era of combination antiretroviral therapy, particularly in the post-H1N1 pandemic period. This analysis informs on ILI in an otherwise healthy, predominantly outpatient cohort of adults with HIV in the USA. From September 2010 to March 2015, this multisite observational cohort study enrolled otherwise healthy adults presenting to a participating US military medical center with ILI, a subset of whom were HIV positive. Demographics, clinical data, and self-reported symptom severity were ascertained, and enrollees completed a daily symptom diary for up to 10 days. 510 men were included in the analysis; 50 (9.8%) were HIV positive. Subjects with HIV were older and less likely to be on active duty. Rhinovirus and influenza A were the most commonly identified pathogens. Moderate-severe diarrhea (p<0.001) and fatigue (p=0.01) were more frequently reported by HIV-positive men. HIV positivity was associated with higher gastrointestinal scores, but not other measures of ILI symptom severity, after controlling for age, race, military status, and influenza season. Few were hospitalized. HIV-positive subjects had more influenza B (p=0.04) and were more likely to receive antivirals (32% vs 6%, p<0.01). Antiviral use was not significantly associated with symptom scores when accounting for potential confounders. In this predominantly outpatient cohort of adult men, HIV had minimal impact on ILI symptom severity. Despite similar illness severity, a higher percentage of subjects with HIV reported undergoing antiviral treatment for ILI, likely reflecting differences in prescribing practices.Trial registration number: NCT01021098.

Mupirocin resistance related to increasing mupirocin use in clinical isolates of methicillin-resistant Staphylococcus aureus in a pediatric population.

We investigated the proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolates from pediatric patients demonstrating mupirocin resistance related to mupirocin use at our institution. No mupirocin resistance was found in 98% of isolates, whereas mupirocin prescriptions increased by 110%. Resistance rates remained low despite the increasing use of mupirocin.

Comparable Disease Severity by Influenza Virus Subtype in the Acute Respiratory Infection Consortium Natural History Study.

INTRODUCTION: Since the influenza A/H1N1 pandemic of 2009 to 2010, numerous studies have described the clinical course and outcome of the different subtypes of influenza (A/H1N1, A/H3N2, and B). A recent systematic literature review concluded that there were no appreciable differences in either clinical presentation or disease severity among these subtypes, but study parameters limit the applicability of these results to military populations. We sought to evaluate differences in disease severity among influenza subtypes in a cohort of healthy, primarily outpatient adult U.S. Department of Defense beneficiaries. MATERIALS AND METHODS: From 2009 to 2014, we enrolled otherwise healthy adults age 18 to 65 years with influenza-like illness in an observational cohort study based in 5 U.S. military medical centers. Serial nasopharyngeal swabs were collected for determination of etiology and viral shedding by polymerase chain reaction. The presence and severity of symptoms was assessed by interview and patient diary. RESULTS: Over a 5-year period, a total of 157 adults with laboratory-confirmed influenza and influenza subtype were enrolled. Of these, 69 (44%) were positive for influenza A(H1N1), 69 (44%) for influenza A(H3N2), and 19 (12%) for influenza B. About 61% were male, 64% were active duty military personnel, and 72% had received influenza vaccine in the past 8 months. Almost 10% were hospitalized with influenza. Seasonal influenza virus distribution among enrollees mirrored that of nationwide trends each year of study. Individuals with A/H1N1 had upper respiratory composite scores that were lower than those with A/H3N2. Multivariate models indicated that individuals with A(H1N1) and B had increased lower respiratory symptom scores when compared to influenza A(H3N2) (A[H1N1]: 1.51 [95% CI 0.47, 2.55]; B: 1.46 [95% CI 0.09, 2.83]), whereas no other differences in symptom severity scores among influenza A(H1N1), influenza A(H3N2), and influenza B infection were observed. Overall, influenza season (maximum in 2012-2013 season) and female sex of the participant were found to be associated with increased influenza symptom severity. CONCLUSIONS: Our study of influenza in a cohort of otherwise healthy, outpatient adult Department of Defense beneficiaries over 5 influenza seasons revealed few differences between influenza A(H1N1), influenza A(H3N2), and influenza B infection with respect to self-reported disease severity or clinical outcomes. This study highlights the importance of routine, active, and laboratory-based surveillance to monitor ongoing trends and severity of influenza in various populations to inform prevention measures.

A Comparison of Pretravel Health Care, Travel-Related Exposures, and Illnesses among Pediatric and Adult U.S. Military Beneficiaries.

We evaluated differences in pretravel care, exposures, and illnesses among pediatric and adult travelers, using a prospective, observational cohort. Eighty-one pediatric travelers were matched 1:1 with adult military dependents by travel region, destination's malaria risk, and travel duration. Pediatric travelers were more likely to have coverage for hepatitis A and B (90% versus 67% of adults; 85% versus 44%), visit friends and relatives (36% versus 16%), report mosquito bites (69% versus 44%), and have close contact with wild or domesticated animals (40% versus 20%) than adults (P < 0.05). Subjects < 10 years of age were less likely to be prescribed antibiotics (28% versus 95%; RR = 0.63; 95% CI: 0.46-0.85) and antidiarrheals (9% versus 100%; RR = 0.10; 95% CI: 0.03-0.29) for travelers' diarrhea (TD) self-treatment than adults. Travel medicine providers should emphasize strategies for vector avoidance, prevention of animal bites and scratches, and TD self-treatment in pediatric pretravel consultations.

Alternating antipyretics: antipyretic efficacy of acetaminophen versus acetaminophen alternated with ibuprofen in children.

Methods A prospective, randomized double-blind placebo control study comparing the efficacy of acetaminophen to acetaminophen alternated with ibuprofen in 38 healthy outpatient children 6 months to 6 years presenting to the outpatient clinic with fever >38 degrees C was conducted. Temperatures were recorded at 0, 3, 4, 5, and 6 hours. Side effect diaries and parental perception of efficacy were filled out hourly by parents.Results There were no significant differences in temperature between the 2 groups at times 0, 3, and 6 hours. The alternating group had significantly lower mean temperatures at both 4 hours (38.0 degrees C vs 37.4 degrees C; P = .05) and 5 hours (37.1 degrees C vs 37.9 degrees C; P = .0032). Parents did not perceive any difference in fever control between the groups.Conclusions An alternating regimen of acetaminophen with ibuprofen significantly decreased fever at 4 and 5 hours compared with acetaminophen alone. However, parents did not perceive a difference in efficacy.

Mupirocin resistance screening of methicillin-resistant Staphylococcus aureus isolates at Madigan Army Medical Center.

Mupirocin is an antibiotic used for eradication and infection control of methicillin-resistant Staphylococcus aureus (MRSA). Mupirocin binds to the bacterial isoleucyl tRNA synthetase, thus disrupting bacterial protein synthesis. Four hundred nine MRSA clinical isolates collected in 2006 and 2007 at Madigan Army Medical Center were screened for mupirocin resistance by E test and polymerase chain reaction; 7 MRSA isolates (1.7%) were found to be fully resistant to mupirocin (minimum inhibitory concentration [MIC] by E test: > 1,024 microg/mL), 10 isolates (2.4%) had MIC values of 1 to 32 microg/mL, while 392 MRSA isolates (95.9%) had MIC values of < 1 microg/mL. No trend of increased mupirocin resistance was found when compared with subsequent years. These results show that mupirocin remains a valid infection control measure due to its unique mechanism of action and the high susceptibility rate of MRSA isolates. In addition, rapid screening by polymerase chain reaction of MRSA shows promise in assessing the fully resistant mupirocin phenotype.

Influenza-Like Illness in Travelers to the Developing World.

Travelers to developing regions are at risk for development of influenza-like illness (ILI). Little is known of traveler and trip characteristics associated with the development of ILI. TravMil is a prospective observational study, enrolling subjects presenting to six military travel clinics or predeployment-screening sites. We analyzed pre- and post-travel surveys from travelers visiting regions outside of the continental United States, Western or Northern Europe, Canada, Australia, or New Zealand between January 2010 and March 2016. Influenza-like illness was defined as a self-reported fever associated with either sore throat or cough. Trip and traveler characteristics were analyzed to determine risk factors for the development of ILI. Two thousand nine hundred and thirty-two trips were recorded (55% male, median age 45 years, 69% white, 51% on vacation, median travel duration 17 days). The 2,337 trips included the number of self-reported influenza vaccinations in the preceding 5 years (median 5). Eleven percent of the trips were complicated by an ILI lasting a median of 5 days; 70% and 17% of these reported upper and lower respiratory tract infection, respectively, and 12% reported both. On multivariate analysis, increased risk of ILI was associated with female gender (odds ratio [OR]: 1.60 [confidence interval (CI): 1.25-2.05], P < 0.01), age (years) (OR: 1.01 [CI: 1.01-1.02], P < 0.01); and duration of travel (days) (OR: 1.01 [CI: 1.00-1.01], P < 0.01). Influenza-like illness is common in travelers, regardless of traveler characteristics, purpose of travel, destination, or season of year. Female gender, older age, and longer duration of travel were associated with an increased risk of ILI. Additional tools and strategies are needed to prevent ILI in international travelers.

Species-specific clinical characteristics of human coronavirus infection among otherwise healthy adolescents and adults.

Human coronavirus (HCoV) is a known cause of influenza-like illness (ILI). In a multisite, observational, longitudinal study of ILI among otherwise healthy adolescents and adults, 12% of subjects were PCR-positive for HCoV. The distribution of species was as follows: HCoV-OC43 (34%), HCoV-229E (28%), HCoV-NL63 (22%), and HCoV-HKU1 (16%). We did not observe species-specific differences in the clinical characteristics of HCoV infection, with the exception of HCoV-HKU1, for which the severity of gastrointestinal symptoms trended higher on the fourth day of illness.

Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI).

BACKGROUND: The inFLUenza Patient Reported Outcome (FLU-PRO) measure is a daily diary assessing signs/symptoms of influenza across six body systems: Nose, Throat, Eyes, Chest/Respiratory, Gastrointestinal, Body/Systemic, developed and tested in adults with influenza. OBJECTIVES: This study tested the reliability, validity, and responsiveness of FLU-PRO scores in adults with influenza-like illness (ILI). METHODS: Data from the prospective, observational study used to develop and test the FLU-PRO in influenza virus positive patients were analyzed. Adults (≥18 years) presenting with influenza symptoms in outpatient settings in the US, UK, Mexico, and South America were enrolled, tested for influenza virus, and asked to complete the 37-item draft FLU-PRO daily for up to 14-days. Analyses were performed on data from patients testing negative. Reliability of the final, 32-item FLU-PRO was estimated using Cronbach's alpha (α; Day 1) and intraclass correlation coefficients (ICC; 2-day reproducibility). Convergent and known-groups validity were assessed using patient global assessments of influenza severity (PGA). Patient report of return to usual health was used to assess responsiveness (Day 1-7). RESULTS: The analytical sample included 220 ILI patients (mean age = 39.3, 64.1% female, 88.6% white). Sixty-one (28%) were hospitalized at some point in their illness. Internal consistency reliability (α) of FLU-PRO Total score was 0.90 and ranged from 0.72-0.86 for domain scores. Reproducibility (Day 1-2) was 0.64 for Total, ranging from 0.46-0.78 for domain scores. Day 1 FLU-PRO scores correlated (≥0.30) with the PGA (except Gastrointestinal) and were significantly different across PGA severity groups (Total: F = 81.7, p<0.001; subscales: F = 6.9-62.2; p<0.01). Mean score improvements Day 1-7 were significantly greater in patients reporting return to usual health compared with those who did not (p<0.05, Total and subscales, except Gastrointestinal and Eyes). CONCLUSIONS: Results suggest FLU-PRO scores are reliable, valid, and responsive in adults with influenza-like illness.

Mosquito Exposure and Chikungunya and Dengue Infection Among Travelers During the Chikungunya Outbreak in the Americas.

AbstractTravelers are at risk for arbovirus infection. We prospectively enrolled 267 Department of Defense beneficiaries traveling to chikungunya-outbreak regions in the Americas between December 2013 and May 2015 and assessed travel characteristics and serologic exposure to chikungunya virus (CHIKV) and dengue virus (DENV). Ten ill-returning travelers were also assessed retrospectively. Self-reported mosquito exposure was common (64% of 198 evaluable travelers saw mosquitoes; 53% of 201 reported ≥ 1 bite). Increased exposure was associated with active-duty travelers (odds ratio [OR] = 2.6 [1.3-5.4] for seeing mosquitoes) or travelers visiting friends and relatives (VFR) (OR = 3.5 [1.0-10.0] for high-intensity bite exposure). Arbovirus infection was defined as seroconversion on plaque reduction neutralization testing (PRNT) of pre- and posttravel sera. For ill subjects enrolled posttravel, infection was defined by a positive convalescent PRNT and/or a positive reverse transcription polymerase chain reaction for CHIKV or DENV. We identified seven cases of arbovirus infection: four with CHIKV, five with DENV, and two with both. The composite attack rate for CHIKV and DENV infection was 3.7% of 108 evaluable, immunologically naïve, prospectively assessed travelers; there was serologic and/or polymerase chain reaction evidence of arbovirus infection in three of four evaluable (three of 10 total) ill-returning travelers. We identified both symptomatic and asymptomatic cases. Military purpose of travel and VFR travel accounted for five of seven cases. Pretravel counseling is important and should target higher risk groups. Given a shared vector between CHIKV, DENV, and Zika virus (ZIKV), this study can also help guide counseling for travelers to ZIKV-outbreak regions.