The lack of specificity of tracheal aspirates in the diagnosis of pulmonary infection in intubated children.

OBJECTIVES: Ventilator-associated pneumonia is the first or second most commonly diagnosed nosocomial infection in the PICU. Centers for Disease Control diagnostic criteria include clinical signs or symptoms in conjunction with a "positive" tracheal aspirate, defined as more than 10 colony-forming units/mL of bacteria on quantitative culture and/or more than 25 polymorphonuclear neutrophils per low-power field on Gram stain. We hypothesized that tracheal aspirate cultures and Gram stains would not correlate with clinical signs and symptoms and would therefore not distinguish between colonization and infection. DESIGN: Prospective observational study. SETTING: PICU in an academic tertiary care center. PATIENTS: Children intubated more than 48 hours. INTERVENTIONS: Sequential tracheal aspirate quantitative cultures and Gram stains in conjunction with daily collection of concordant clinical signs and symptoms. MEASUREMENTS AND MAIN RESULTS: Time since intubation correlated strongly (p < 0.001) with the proportion of positive (> 10 colony-forming units/mL) tracheal aspirate quantitative cultures, but Centers for Disease Control-defined clinical signs or symptoms of ventilator-associated pneumonia, either singly or in combination, did not. Use of in-line suction catheters versus new, sterile catheters to obtain tracheal aspirates was associated with significantly greater proportion of positive tracheal aspirate bacterial cultures (p < 0.001). Most subjects had more than 25 polymorphonuclear neutrophils per low-power field on Gram stain; polymorphonuclear neutrophils on Gram stain correlated with positive bacterial culture (p = 0.04). Seventy-seven percent of the bacterial isolates detected in positive quantitative cultures were "pathogens." Antibiotic use at the time tracheal aspirates were obtained was associated with a lower frequency of positive quantitative cultures only with antibiotic regimens that included cefepime. CONCLUSIONS: Positive bacterial cultures of tracheal aspirates increase rapidly after intubation and usually include bacteria considered to be pathogens. Tracheal aspirate cultures and Gram stains do not appear to distinguish between infection and colonization. Antibiotic regimens that include cefepime decrease the frequency of positive cultures, but the significance of this is unclear.

The diagnostic dilemma of ventilator-associated pneumonia in critically ill children.

OBJECTIVE: A review of the existing literature on ventilator-associated pneumonia in children with emphasis on problems in diagnosis. DATA SOURCES: A systematic literature review from 1947 to 2010 using Ovid MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, and ISI Web of Science using key words "ventilator associated pneumonia" and "children." Where pediatric data were lacking, appropriate adult studies were reviewed and similarly referenced. STUDY SELECTION: Two hundred sixty-two pediatric articles were reviewed and data from 48 studies selected. Data from 61 adult articles were also included in this review. DATA EXTRACTION AND SYNTHESIS: Ventilator-associated pneumonia is the second most common nosocomial infection and the most common reason for antibiotic use in the pediatric intensive care unit. Attributable mortality is uncertain but ventilator-associated pneumonia is associated with significant morbidity and cost. Diagnosis is problematic in that clinical, radiologic, and microbiologic criteria lack sensitivity and specificity relative to autopsy histopathology and culture. Qualitative tracheal aspirate cultures are commonly used in diagnosis but lack specificity. Quantitative tracheal aspirate cultures have sensitivity (31-69%) and specificity (55-100%) comparable to bronchoalveolar lavage (11-90% and 43-100%, respectively) but concordance for the same bacterial species when compared with autopsy lung culture was better for bronchoalveolar lavage (52-90% vs. 50-76% for quantitative tracheal aspirate). Staphylococcus aureus and Pseudomonas species are the most common organisms, but microbiologic flora change over time and with antibiotic use. Initial antibiotics should offer broad-spectrum coverage but should be narrowed as clinical response and cultures dictate. CONCLUSIONS: Ventilator-associated pneumonia is an important nosocomial infection in the pediatric intensive care unit. Conclusions regarding epidemiology, treatment, and outcomes are greatly hampered by the inadequacies of current diagnostic methods. We recommend a more rigorous approach to diagnosis by using the Centers for Disease Control and Prevention algorithm. Given that ventilator-associated pneumonia is the most common reason for antibiotic use in the pediatric intensive care unit, more systematic studies are sorely needed.

Cytokine polymorphisms predict the frequency of otitis media as a complication of rhinovirus and RSV infections in children.

Previous studies suggested that the otitis media (OM) complication rate of viral upper respiratory infection (vURI) is conditioned by genes affecting cytokine production. Two hundred and thirty children (114 male; 187 White, 25 Black; aged 1-9.3 years, average=3.6+/-1.6 years) were prospectively followed over the typical cold season for cold-like illness and OM. Nasopharyngeal secretion samples collected during cold-like illness and OM were assayed for upper respiratory viruses and buccal samples were assayed for TNFalpha (-308), IL-10(-1082, -819, -592), IL-6 (-174) and IFN-gamma (+874) polymorphisms. Logistic regression was used to identify genotypes that predict OM coincident with RSV and rhinovirus (RV) infection. Of the 157 children with RV detection (79 male; 132 White, 13 Black, 12 Other; aged 3.6+/-1.5 years), simple logistic regression identified age (B= -0.34, Z= -2.8, P<0.01, OR=0.71), IL-6 (B= -0.76, Z= -3.3, P<0.01, OR=0.47) and IL-10 (B=0.49, Z=2.0, P=0.05, OR=1.6) as significant predictors of OM coincidence. A more complex logistic regression model for RV detection that included selected OM risk factors identified these factors as well as the TNFalpha genotype, OM history, breastfeeding history and daily environment as significant predictors of OM coincidence. Of the 43 children with RSV detection (21 male; 35 White, 5 Black, 3 Other, aged 3.9+/-1.7 years), logistic regression identified IL-10 (B=1.05, Z=2.0, P=0.05, OR=2.9) as a significant predictor of OM coincidence. New OM episodes coincident with evidence of RSV and RV infection were significantly more frequent in children with high production IL-10 phenotypes. The low production IL-6 and high production TNFalpha phenotypes also contributed to OM risk during RV detection. Cytokine polymorphisms may be one of an expectedly large number of genetic factors contributing to the known heritability of OM.

Symptom profile of common colds in school-aged children.

BACKGROUND: Signs and symptoms of a common cold reported in young children are those perceived by caretakers. Objective signs include cough, fever, and sneezing. Subjective symptoms include nasal congestion, feverishness, headache, and sore throat. School-aged children may provide a more accurate picture of the symptom profile during colds because they can self-report. METHODS: Using preprinted diary sheets listing common signs and symptoms, diaries were kept for school-aged children for 10 days after onset of a cold. Nasopharyngeal aspirates were analyzed for respiratory viruses and potential bacterial pathogens. RESULTS: Out of 81 colds studied, the most common signs were cough and sneezing, although the most common symptoms were nasal congestion and runny nose. Other symptoms, including feverishness and headache, were each reported in 15% of children at onset. The majority of children (73%) continued to be symptomatic 10 days after onset. Rhinovirus was detected in 46% and 1 or more potential bacterial pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) in 29% of episodes. Symptom profiles for rhinovirus illnesses and those in which potential pathogenic bacteria were detected were not different from the rest. CONCLUSION: The common cold in school-aged children is characterized by nasal congestion, cough, and runny nose. Signs and symptoms usually continue for at least 10 days.

Upper respiratory virus detection without parent-reported illness in children is virus-specific.

BACKGROUND: Viral upper respiratory tract infection (vURI) may or may not present with a cold/flu-like illness (CFLI). OBJECTIVES: For common upper respiratory viruses that cause vURIs, to determine the relative frequencies of virus detection by PCR in subjects with and without CFLIs. STUDY DESIGN: Prospective follow-up of 170 children aged 1-8.6 years through the CFLI season by daily parental diary for CFLI episodes and nasal secretion sampling using PCR assays for adenovirus, coronavirus (types 229E and OC43), influenza virus (types A and B), parainfluenza (types 1-3) virus, rhinovirus, and respiratory syncytial virus (RSV). RESULTS: Virus was detected in 415 of 956 independent assays: 425 CFLI episodes and 531 non-CFLI periods were sampled; samples from 270 (64%) CFLI episodes and 145 (27%) non-CFLI periods contained virus detected by PCR. Rhinovirus was most frequently detected at 64%, followed by mixed viruses at 12%, RSV at 7%, and the other viruses at 3-5% of all detections. About 85% of RSV, influenza A and adenovirus detections were associated with a CFLI, whereas less than 62% of other virus detections were associated with CFLI. CONCLUSIONS: The frequency of PCR virus detection without CFLI was different among viruses. This introduces virus-specific biases to estimating the frequencies of specific complications attributable to a vURI when ascertained by CFLI identification.

Middle ear pressure in preschool age children: influence of respiratory illness, season, and picornavirus or bacteria in the nasopharynx.

CONCLUSION: Middle ear pressure was affected by respiratory illness and season; picornavirus (without illness) or pathogenic bacteria in the nasopharynx had no or minor effect. OBJECTIVE: To examine the effect of respiratory illness, season, and nasopharyngeal microbial flora on middle ear pressure. SUBJECTS AND METHODS: Thirteen children were followed longitudinally with daily recording of respiratory symptoms, weekly tympanometry, and weekly testing of nasal aspirate/washes for Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis by culture and for picornavirus by RT-PCR. RESULTS: Abnormal middle ear pressure was present at 47% of 473 weekly visits by 11 preschool age (

Weekly point prevalence of Streptococcus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis in the upper airways of normal young children: effect of respiratory illness and season.

The aim was to determine the effect of respiratory illness and season on carriage rates in the upper airways of Streptococcus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis in normal children. Sixteen healthy children, 1-10 years old, amenable to weekly sampling were followed longitudinally for at least three seasons of the year. Respiratory symptoms were recorded daily; weekly nasal aspirate/wash samples were cultured on selective agars. Urea concentration in samples was used to define dilution of secretion. 68% of 950 samples were culture positive; 44% of positives had two or all three species. Each species was detected in about one third of samples. Bacteria were detected in 76% of samples during illness vs. 65% during wellness (p=0.004). Seasonal carriage rates varied from 56% in summer and fall to 85% in winter. There was a strong inverse correlation between dilution of secretion and bacterial detection rate in illness and wellness aspirate samples during the four seasons (r=-0.82, p=0.01). Detection of bacteria varied with the amount of secretion in the sample. This variation accounts for the apparent differences in bacterial carriage during illness vs. wellness and during different seasons.

Symptom severity patterns in experimental common colds and their usefulness in timing onset of illness in natural colds.

Mean total symptom severity scores for subjects with experimental rhinovirus colds peak 48 h after viral inoculation. Also, total symptom scores for natural rhinovirus and nonrhinovirus colds peaked on day 2 of illness in a long-term, noncompensated epidemiology study. In contrast, the mean total symptom scores for compensated patients receiving placebo in natural cold treatment trials peaked on day 1. Comparisons by day indicated that scores for symptoms reported as occurring on day 1 in the natural cold treatment trials corresponded with experimental cold scores for symptoms reported 48 h after viral inoculation. Comparisons of frequency and cumulative distribution scores for the 2 groups indicated that natural colds in the treatment trials were of longer duration than reported. A mean total symptom severity score of

Cross-linked fibrin in the nasal fluid of patients with the common cold.

To determine whether adherent material found on the walls of the paranasal sinuses during common colds might be fibrin clot, we examined the nasal fluid (a surrogate for sinus secretion) of 11 young adults with experimentally induced rhinovirus colds and that of 4 control subjects for the presence of fibrin. The mean concentration (+/- the standard error) of insoluble fibrin (measured as D-dimer) in subjects with rhinovirus colds increased from a baseline level of 0.8+/-0.4 microgram/mL to a peak of 2.4+/-0.7 microgram/mL (P=.0008) on day 4 after inoculation of the virus, but the fibrin concentration remained at baseline levels in the 4 uninfected control subjects.

Viral titers in nasal lining fluid compared to viral titers in nasal washes during experimental rhinovirus infection.

BACKGROUND: The concentration of rhinovirus in nasal wash specimens from infected volunteers peaks at 48-72 h after inoculation. The volume of expelled nasal fluid peaks at the same time, raising the question of whether the viral concentration in nasal wash reflects viral replication in nasal cells or merely the production of an increased volume of nasal fluid during a cold. OBJECTIVES: To determine the amount of rhinovirus in nasal lining fluid during colds before the nasal fluid has been diluted in a nasal wash. STUDY DESIGN: Rhinovirus titers were determined in nasal wash specimens collected daily for five days from 14 subjects with type16 rhinovirus infection. The urea concentration in nasal lining fluid equals that in blood. By determining the urea concentration in a nasal wash and comparing it to the urea concentration in blood from the same subject, it was possible to determine the amount of dilution of the nasal lining fluid. The dilution factor (reciprocal of the dilution) was then used to calculate the viral concentration in undiluted nasal lining fluid. RESULTS: The dilution factor in 70 nasal washes varied from 5 to 64. The viral GMTs (+S.E.) in nasal washes were 1.79 (+0.3) TCID(50)/ml at 24 h, 3.11 (+0.15) at 48 h, and 2.61 (+0.3) at 72 h. The viral GMTs in nasal lining fluid, based on urea adjusted values, paralleled those in nasal washes but were approximately one log higher. Virus concentrations returned to near baseline values by day 5. CONCLUSIONS: The temporal pattern of rhinovirus shedding observed in nasal wash specimens, with a peak in virus concentration at 48-72 h after infection, is a true indication of virus production in nasal cells and not an artifact of the increased amount of nasal fluid produced during the early phase of a cold.

Epidemiology, pathogenesis, and treatment of the common cold.

The common cold is an acute illness of the upper respiratory tract caused by a virus acquired from another person. Some viruses that produce colds are capable of infecting an individual repeatedly (eg, respiratory syncytial virus); others, with many serotypes (eg, rhinovirus), infect only once. The sustained epidemic of colds that occurs annually during September through April is explained by successive waves of different viruses moving through a community. The peak incidence of colds occurs in preschool children, who typically sustain at least one illness per month during the epidemic period. Clinical manifestations of colds are largely subjective in adults. Colds in preschoolers differ from those in adults as follows: (1) fever is common in children during the first 3 days; (2) colored nasal secretions may be the only indication of nasal involvement in children; and (3) colds in children last 10 to 14 days, as compared with a duration of less than a week in adults. The paranasal sinuses and the middle ear cavities are commonly involved during viral colds in adults (and presumably in children) in the absence of bacterial superinfection. Cold symptoms are due to the host's response to the virus rather than to destruction of the nasal mucosa. Viral infection of a very limited portion of the nasal epithelium results in an influx of polymorphonuclear leukocytes, cytokine release, and a vascular leak. Colds are self-limited illnesses. Therefore, in the absence of adequate blinding of controls, ineffective treatments erroneously may be considered efficacious. None of the medicines used for symptom relief in colds is curative.

Characterization of the nasopharyngeal microbiota in health and during rhinovirus challenge.

BACKGROUND: The bacterial communities of the nasopharynx play an important role in upper respiratory tract infections (URTIs). Our study represents the first survey of the nasopharynx during a known, controlled viral challenge. We aimed to gain a better understanding of the composition and dynamics of the nasopharyngeal microbiome during viral infection. METHODS: Rhinovirus illnesses were induced by self-inoculation using the finger to nose or eye natural transmission route in ten otherwise healthy young adults. Nasal lavage fluid samples (NLF) samples were collected at specific time points before, during, and following experimental rhinovirus inoculation. Bacterial DNA from each sample (N = 97 from 10 subjects) was subjected to 16S rRNA sequencing by amplifying the V1-V2 hypervariable region followed by sequencing using the 454-FLX platform. RESULTS: This survey of the nasopharyngeal microbiota revealed a highly complex microbial ecosystem. Taxonomic composition varied widely between subjects and between time points of the same subject. We also observed significantly higher diversity in not infected individuals compared to infected individuals. Two genera - Neisseria and Propionibacterium - differed significantly between infected and not infected individuals. Certain phyla, including Firmicutes, Actinobacteria, and Proteobacteria, were detected in all samples. CONCLUSIONS: Our results reveal the complex and diverse nature of the nasopharyngeal microbiota in both healthy and viral-challenged adults. Although some phyla were common to all samples, differences in levels of diversity and selected phyla were detected between infected and uninfected participants. Deeper, species-level metagenomic sequencing in a larger sample is warranted.

Bacteria in the nose of young adults during wellness and rhinovirus colds: detection by culture and microarray methods in 100 nasal lavage specimens.

BACKGROUND: Patients  with  viral respiratory infections/viral rhinitis/common colds are often treated with antibiotic; however, there is little information on whether or how bacterial microbiota in the nose and nasopharynx might influence the course of viral illnesses. METHODS: To initiate investigation of possible interaction between viral respiratory illness and microbiota of the nose/nasopharynx, we used microarray technology to examine 100 nasal lavage fluid (NLF) samples for bacterial species and recorded the bacterial titer of culturable bacteria. Rhinovirus illnesses were induced by self-inoculation using the "finger to nose or eye natural transmission route" in 10 otherwise healthy young adults. NLF samples were collected during wellness and at specific time points following experimental rhinovirus inoculation. RESULTS: The rhinovirus infection rate was 70%. There were no consistent changes in the prevalence of different bacterial species determined by microarray and bacterial titer by culture methods during rhinovirus infection. The bacterial profile in NLF samples showed high variability between volunteers but low variability in multiple NLFs obtained before and following infection from the same volunteer. Streptococcus epidermidis/coagulase-negative staphylococcus (CNS) were identified in all 10 subjects. One or more bacterial sinus/otitis pathogens were identified by microarray in 6 of the 10 volunteers. The microarray identified a few bacteria not included in traditional bacterial cultures. CONCLUSION: Our pilot study showed that each of the 10 volunteers had a unique bacterial profile in the nose by microarray analysis and that bacterial load did not change during experimental rhinovirus colds. Larger scale studies are warranted.

Occurrence of group A ß-hemolytic streptococcal pharyngitis in the four months after treatment of an index episode with amoxicillin once-daily or twice-daily or with cephalexin.

BACKGROUND: Prospective studies using bacterial eradication as the endpoint have demonstrated that once-daily amoxicillin is as effective as twice-daily amoxicillin for treatment of group A ß-hemolytic streptococcal (GABHS) pharyngitis. OBJECTIVE: The aim of this study was to determine, in a retrospective study, whether treatment of symptomatic GABHS pharyngitis with once-daily amoxicillin was as effective in preventing clinical recurrences as twice-daily amoxicillin or cephalexin in pediatric office practice, using patient-initiated return visits for streptococcal pharyngitis as a pragmatic, clinical endpoint. METHODS: The charts of consecutive patients 2 years of age and older with laboratory-proven GABHS pharyngitis for a period of 2 years were reviewed to identify index cases of streptococcal pharyngitis and subsequent episodes. Age, weight, antibiotic treatment and time from index to subsequent episodes of GABHS pharyngitis were recorded. RESULTS: In 1402 index episodes, patients received amoxicillin once-daily (231), amoxicillin twice-daily (846) or cephalexin (325). The risk of symptomatic streptococcal pharyngitis in the 4 months after treatment of the index episode was not statistically different among the 3 treatment groups: amoxicillin once-daily (15.1%), amoxicillin twice-daily (19.6%) and cephalexin (19.1%). There was a trend toward reduction in the risk of recurrences in the 6 weeks after completion of antibiotics in the cephalexin (9%) group compared with the combined amoxicillin (13%) groups. CONCLUSIONS: Amoxicillin once-daily or twice-daily was equally effective in terms of frequency of recurrence of symptomatic GABHS pharyngitis.

Presence of viral nucleic acids in the middle ear: acute otitis media pathogen or bystander?

Viruses play an important role in acute otitis media (AOM) pathogenesis, and live viruses may cause AOM in the absence of pathogenic bacteria. Detection of AOM pathogens generally relies on bacterial culture of middle ear fluid. When viral culture is used and live viruses are detected in the middle ear fluid of children with AOM, the viruses are generally accepted as AOM pathogens. Because viral culture is not sensitive and does not detect the comprehensive spectrum of respiratory viruses, polymerase chain reaction assays are commonly used to detect viral nucleic acids in the middle ear fluid. Although polymerase chain reaction assays have greatly increased the viral detection rate, new questions arise on the significance of viral nucleic acids detected in the middle ear because nucleic acids of multiple viruses are detected simultaneously, and nucleic acids of specific viruses are detected repeatedly and in a high proportion of asymptomatic children. This article first reviews the role of live viruses in AOM and presents the point-counterpoint arguments on whether viral nucleic acids in the middle ear represent an AOM pathogen or a bystander status. Although there is evidence to support both directions, helpful information for interpretation of the data and future research direction is outlined.

Bacterial pathogens of acute sinusitis in the osteomeatal complex during common colds and wellness.

BACKGROUND: Pathogenic bacteria have been cultured from the osteomeatal complex (OMC) in one-third of adults with apparent acute bacterial sinusitis; however, it is not known whether bacteria are present in the OMC during uncomplicated viral colds in adults. METHODS: Adult volunteers were recruited for a study during wellness and at the time of acute common cold. Swab cultures were obtained from the OMC and from the nasopharynx by 2 routes (through the nose and through the mouth). Swab eluates were inoculated on selective agars to detect S. pneumoniae, H. influenzae, and M. catarrhalis. RESULTS: Bacterial pathogens were detected in the OMC more frequently during common colds than during wellness (31% vs 8%, p < 0.008). Pathogens detected in the OMC were always present in the nasopharynx of the subject. CONCLUSION: Bacterial pathogens are present in the OMC in a subgroup of adult patients with uncomplicated upper respiratory illness/common cold. The nasopharynx appears to be the reservoir for bacterial pathogens in the OMC.

Occurrence of acute otitis media during colds in children younger than four years.

To determine how frequently acute otitis media (AOM) occurs, we enrolled children between 6 months and 3 years of age who returned several weeks before and 6 to 10 times during a cold for tympanometry and photography of the tympanic membrane. American Academy of Pediatrics (AAP) criteria were used to diagnose AOM. Children visited their physicians at their discretion. AOM occurred in 17 (55%) of 31 colds; in 12 (100%) colds with pre-existing middle ear effusion (MEE); and in 5 (26%) of 19 colds with no pre-existing MEE (P < 0.0001). Four patients received antibiotics from their physicians. Of 17 children with AOM, 12 did not seek care. AOM is common during colds, particularly with pre-existing MEE.