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.

Neuraminidase inhibitor therapy in a military population.

BACKGROUND: Although neuraminidase inhibitors (NI) are the mainstay of treatment for influenza infection, prescribing practice for these agents is not well described. Additionally, benefit is contested. OBJECTIVES: We examined provider prescriptions of NI during the 2009 pandemic and post-pandemic periods. We also evaluated the effectiveness of NI in reducing severity of influenza infection. STUDY DESIGN: Data on NI prescription and severity of influenza infection were compiled in healthy pediatric and adult beneficiaries enrolled in a prospective study of influenza like illness conducted at five military medical centers over five years. Subjects underwent nasal swabs to determine viral etiology of their infection. Demographic, medication and severity data were collected. Subjects with positive influenza were included. RESULTS: Two hundred sixty three subjects were influenza positive [38% [H1N1] pdm09, 38.4% H3N2, and 20.5% B); 23.9% were treated with NI. NI were initiated within 48h in 63% of treated subjects. Although NI use increased over the five years of the study, early use declined. Most measures for severity of illness were not significantly reduced with NI; adults treated within 48h had only a modest reduction in duration and severity of some of their symptoms. CONCLUSIONS: NI use in our population is increasing, but early use is not. NI use resulted in no reduction in complications of illness. Resolution of symptoms and reduction in severity of some symptoms were slightly better in adults who were treated early. These modest benefits do not support routine treatment with NI in otherwise healthy individuals with influenza.

Epidemiologic, clinical, and virologic characteristics of human rhinovirus infection among otherwise healthy children and adults: rhinovirus among adults and children.

BACKGROUND: human rhinovirus (HRV) is a major cause of influenza-like illness (ILI) in adults and children. Differences in disease severity by HRV species have been described among hospitalized patients with underlying illness. Less is known about the clinical and virologic characteristics of HRV infection among otherwise healthy populations, particularly adults. OBJECTIVES: to characterize molecular epidemiology of HRV and association between HRV species and clinical presentation and viral shedding. STUDY DESIGN: observational, prospective, facility-based study of ILI was conducted from February 2010 to April 2012. Collection of nasopharyngeal specimens, patient symptoms, and clinical information occurred on days 0, 3, 7, and 28. Patients recorded symptom severity daily for the first 7 days of illness in a symptom diary. HRV was identified by RT-PCR and genotyped for species determination. Cases who were co-infected with other viral respiratory pathogens were excluded from the analysis. We evaluated the associations between HRV species, clinical severity, and patterns of viral shedding. RESULTS: eighty-four HRV cases were identified and their isolates genotyped. Of these, 62 (74%) were >18 years. Fifty-four were HRV-A, 11HRV-B, and 19HRV-C. HRV-C infection was more common among children than adults (59% vs. 10%, P<0.001). Among adults, HRV-A was associated with higher severity of upper respiratory symptoms compared to HRV-B (P=0.02), but no such association was found in children. In addition, adults shed HRV-A significantly longer than HRV-C (P trend=0.01). CONCLUSIONS: among otherwise healthy adults with HRV infection, we observed species-specific differences in respiratory symptom severity and duration of viral shedding.

Local changes in rates of group A Streptococcus disease and antibiotic resistance are associated with geographically widespread strain turnover events.

This study addresses the effects of dynamic strain turnover and antibiotic prophylaxis on rates of group A Streptococcus (GAS) antibiotic resistance and disease. The authors analyzed the strain distributions, disease rates, and patterns of antibiotic resistance of 802 GAS isolates collected from 2002 through 2007. These samples were collected from patients with GAS infection symptoms at 10 military facilities. Macrolide resistance peaked at 25% during 2004, due to the geographically widespread dominance of a single resistant strain (M75). The resistant strain was not retained regardless of local patterns of macrolide use, and resistance rates decreased upon replacement of M75 with macrolide-susceptible strains. Disease rates were similarly correlated with dominance of specific M types. Statistical analysis revealed temporal correlations between strain distributions at multiple locations. Only the most common strains yielded enough data at multiple sites for statistically significant comparison of temporal fluctuations in dominance, but these (including M44, M3, M18, M118, and M6) all yielded highly significant temporal correlations of 90% or greater on yearly scales. As expected given the complexity and variability of strain distributions on shorter time scales, analysis on a monthly scale yielded lower degrees of positive correlation (31-62%), but in this case all significant correlations were still positive. Shifts in antibiotic resistance profiles and disease rates at specific sites appear to be associated with strain replacements happening on larger scales, independent of antibiotic use at individual sites.

Inference of antibiotic resistance and virulence among diverse group A Streptococcus strains using emm sequencing and multilocus genotyping methods.

BACKGROUND: Group A Streptococcus pyogenes (GAS) exhibits a high degree of clinically relevant phenotypic diversity. Strains vary widely in terms of antibiotic resistance (AbR), clinical severity, and transmission rate. Currently, strain identification is achieved by emm typing (direct sequencing of the genomic segment coding for the antigenic portion of the M protein) or by multilocus genotyping methods. Phenotype analysis, including critical AbR typing, is generally achieved by much slower and more laborious direct culture-based methods. METHODOLOGY/PRINCIPAL FINDINGS: We compare genotype identification (by emm typing and PCR/ESI-MS) with directly measured phenotypes (AbR and outbreak associations) for 802 clinical isolates of GAS collected from symptomatic patients over a period of 6 years at 10 military facilities in the United States. All independent strain characterization methods are highly correlated. This shows that recombination, horizontal transfer, and other forms of reassortment are rare in GAS insofar as housekeeping genes, primary virulence and antibiotic resistance determinants, and the emm gene are concerned. Therefore, genotyping methods offer an efficient way to predict emm type and the associated AbR and virulence phenotypes. CONCLUSIONS/SIGNIFICANCE: The data presented here, combined with much historical data, suggest that emm typing assays and faster molecular methods that infer emm type from genomic signatures could be used to efficiently infer critical phenotypic characteristics based on robust genotype: phenotype correlations. This, in turn, would enable faster and better-targeted responses during identified outbreaks of constitutively resistant or particularly virulent emm types.

A cluster of Legionella-associated pneumonia cases in a population of military recruits.

A Legionella cluster was identified through retrospective PCR analysis of 240 throat swab samples from X-ray-confirmed pneumonia cases. These were identified among young and otherwise healthy U.S. military recruits during population-based surveillance for pneumonia pathogens. Results were confirmed by sequence analysis. Cases clustered tightly, suggesting a local environmental etiology.

A multiplex PCR for detection of Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, and Bordetella pertussis in clinical specimens.

A multiplex PCR was developed that is capable of detecting four of the most important bacterial agents of atypical pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, and Bordetella pertussis in uncultured patient specimens. These organisms cause similar symptomologies and are often not diagnosed because they are difficult to identify with classical methods such as culture and serology. Given this, the overall impact of these pathogens on public health may be grossly underestimated. The molecular test presented here provides a simple method for identification of four common, yet diagnostically challenging, pathogens.