Viral Co-infection In Children Research Articles

Clinical and Virologic Impacts of Respiratory Viral Co-infections in Children With Influenza.

Advances in multiplex polymerase chain reaction (PCR) methods have enabled the simultaneous detection of multiple respiratory viruses. We aimed to estimate the clinical and virologic impacts of influenza and other respiratory virus co-infection in children. We enrolled 38 and 35 children diagnosed with influenza and treated with baloxavir marboxil (baloxavir) and oseltamivir, respectively. We performed quantitative reverse transcription-PCR to detect and measure the levels of noninfluenza viruses from 3 nasopharyngeal swab samples collected before and on days 3 and 5 after the initial antiviral dose. We assessed patients' clinical information using questionnaires. One or more respiratory viruses other than influenza virus were detected in 26 (35.6%) of 73 children before antiviral treatment. The influenza virus load and clinical characteristics on the day of influenza onset were similar between children with and without virus co-infections. Of the 26 and 32 children without the emergence of the reduced baloxavir and oseltamivir susceptible variants after treatment, 8 (30.8%) and 7 (21.9%) children were dually co-infected with human rhinovirus only, respectively. The level of human rhinovirus RNA on day 0 in these children was less than -3 log 10 that of influenza virus RNA, and the human rhinovirus co-infection had no impact on the disease course either clinically or virologically. When multiple respiratory viruses are detected in the same patient, it is necessary to assess clinical symptoms as well as the levels of detected viruses to determine which virus contributes to the development of illness.

Comparison of Clinical, Demographic Features, and Costs in Respiratory Syncytial Virus, Rhinovirus, and Viral Co-infections in Children Hospitalized with Viral Infections of the Lower Respiratory Tract.

Viruses are the most common cause of lower respiratory tract infections (LRTIs) in children. Our study aimed to shed light on co-infection by comparing it with the most common single agents, such as respiratory syncytial virus (RSV) and rhinovirus (RV), in terms of epidemiological, clinical, laboratory findings, and cost. This retrospective study analyzed medical records pertaining to infants aged below 5 years, hospitalized with a diagnosis of LRTI with RSV, RV, or co-infection. The study group consisted of 199 children, RSV was detected in 116 patients (58.3%), RV in 46 (23.1%), and co-infections in 37 (18.6%). The average age of patients infected with RV was higher (P = 0.006), and the length of hospital stay of patients infected with RSV was longer (P = 0.03) than that with other agents. There was no significant difference between the groups in terms of oxygen requirement, intensive care unit admission, intubation, and development of complications. The cost was significantly higher in the RSV group (P = 0.02) compared to the other groups. Viral co-infections, RSV, and RV constitute an important part of the etiology in patients aged below 5 years; co-infections do not cause more severe clinical findings compared to single viral agents.

Prevalence of and risk factors for hepatitis B and C viral co-infections in HIV infected children in Lagos, Nigeria.

The study was carried out to determine the prevalence of and risk factors for hepatitis B and C viral co-infections in HIV infected children in Lagos. A cross-sectional study conducted to determine the prevalence and risk factors for hepatitis B and C viral co-infection in children aged 2 months to 13 years. There were 187 HIV infected and 187 HIV naïve age, sex-matched controls. Blood samples of participants were assayed for the serologic markers [HBsAg, anti-HBc, and anti-HCV)] of HBV and HCV viral infections using the Enzyme-Linked Immunosorbent assay (ELISA) method. The prevalence of HBV infection using HBsAg was 5.3% and 4.8% (p = 0.814), among HIV-infected and HIV naïve children respectively, while using anti-HBc the prevalence was 7.0% and 7.5% (p = 0.842) among HIV- infected and HIV naïve children respectively. The prevalence of HCV infection among HIV- infected and HIV naive children were equal to 0.5% (p = 1.000). There was also no significant association with the identifiable risk factors (sharing of a toothbrush, sharing of needles, incision marks/tattoo, hepatitis B immunization status, history of blood transfusion, previous surgical operation, sexual exposure/abuse, history of jaundice, and genital circumcision) and the HBV and or HCV status among both groups of children. History of sexual exposure/abuse and history of jaundice were however found to be predictors of the presence of HBsAg among HIV infected children only, using a binary logistic regression model. The prevalence of HBV and or HCV infection among HIV-infected children is similar to the prevalence among HIV naïve children, suggesting that HIV-infected children are not more predisposed to viral hepatitis than healthy children. Also, there was no significant difference in the prevalence of HBV infection irrespective of the use of HBsAg or anti-HBc.

Dynamics and predisposition of respiratory viral co-infections in children and adults

ObjectivesThe epidemiology of respiratory co-infection pairings is poorly understood. Here we assess the dynamics of respiratory viral co-infections in children and adults and determine predisposition for or against specific viral pairings. MethodsOver five respiratory seasons from 30 November 2013 through 6 June 2018, the mono-infection and co-infection prevalence of 13 viral pathogens was tabulated at The Cleveland Clinic. Employing a model to proportionally distribute viral pairs using individual virus co-infection rate with prevalence patterns of concurrent co-circulating viruses, we compared predicted occurrence with observed occurrence of 132 viral pairing permutations using binomial analysis. ResultsOf 30 535 respiratory samples, 9843 (32.2%) were positive for at least one virus and 1018 (10.8%) of these were co-infected. Co-infected samples predominantly originated from children. Co-infection rate in paediatric population was 35.0% (2068/5906), compared with only 5.8% (270/4591) in adults. Adenovirus C (ADVC) had the highest co-infection rate (426/623, 68.3%) while influenza virus B had the lowest (55/546, 10.0%). ADVC–rhinovirus (HRV), respiratory syncytial virus A (RSVA)–HRV and RSVB–HRV pairings occurred at significantly higher frequencies than predicted by the proportional distribution model (p < 0.05). Additionally, several viral pairings had fewer co-infections than predicted by our model: notably metapneumovirus (hMPV)–parainfluenza virus 3, hMPV–RSVA and RSVA–RSVB. ConclusionsThis is one of the largest studies on respiratory viral co-infections in children and adults. Co-infections are substantially more common in children, especially under 5 years of age, and the most frequent pairings occurred at a higher frequency than would be expected by random. Specific pairings occur at altered rates compared with those predicted by proportional distribution, suggesting either direct or indirect interactions result between specific viral pathogens.

Management of COVID-19-positive asymptomatic and mildly symptomatic children

Coronavirus disease (COVID) in children is milder in comparison to adults with a better prognosis and minimal mortality. The most common clinical presentation of COVID-19 in children includes fever and cough, but a significant number of infected children may be asymptomatic contributing to transmission of the disease. Several hypotheses have been put forth to explain the less severe disease in children including lower expression of angiotensin converting enzyme 2 (ACE2) receptors in the lungs of pediatric patients which is the main receptor through which the virus enters the cells in the lung and mediates its effects, lower exposure to virions, higher likelihood of viral co-infection in children which may be responsible for limited replication of the severe acute respiratory syndrome coronavirus 2 by direct virus-to-virus interaction and competition and the protective role of Bacillus Calmette-Guerin vaccine. Reverse transcriptase-polymerase chain reaction testing of upper or lower respiratory tract secretions is the recommended confirmatory test and management is guided by the severity of illness in the child. In this review, we will discuss the management of asymptomatic and mildly symptomatic children.

High prevalence of norovirus and rotavirus co-infection in children with acute gastroenteritis hospitalised in Brazzaville, Republic of Congo.

To evaluate the clinical severity of diarrhoea associated to viral co-infection in children with acute gastroenteritis. About 461 children under five years hospitalised with acute diarrhoea (266 males and 187 females) were enrolled in the study. Using stool samples, rotavirus and adenovirus infections were investigated by ELISA, and norovirus infections by nested duplex RT-PCR. We assessed social, demographic, clinical and behavioural conditions that might influence the occurrence of rotavirus, adenovirus and norovirus infections. Mono-viral infection was detected in 49% and mixed viral infection in 12% of patients. The prevalence of mixed infection was neither dependent on age nor sex. Three samples were infected with all three viruses. A significant association was found between fever (axillary temperature>37.5°C) and rotavirus-norovirus dual infection (aOR (CI 95%) = 2.1 (1.14-3.84), P=0.016; aOR (CI 95%) = 0.37 (0.19-0.73), P=0.004). Mixed infection was the most common during the dry season from June to October (71.4% versus 54.7%, P=0.023). Co-infection with both rotavirus and norovirus is common in under-five hospitalised children but does not contribute to the severity of the disease.

2626. Rhinovirus in Children Presenting to the Emergency Department: Role of Viral Load in Disease Severity and Co-Infections

BackgroundRhinovirus (RV) quantitation by reverse transcription-quantitative PCR is limited by variable amplification efficiency across genotypes. We used a precise viral quantitation method, reverse transcription-digital PCR (RT-dPCR), to characterize the role of viral load in clinical outcomes and in viral co-infections in children presenting to a tertiary hospital emergency department (ED).MethodsChildren < 18 years with respiratory symptoms for ≤ 14 days were enrolled from December 1, 2016 to December 31, 2018. Participants had nasal and throat specimens obtained and multiplex PCR testing with a commercial assay (FilmArray; bioMerieux). RV positive samples were quantified using RT-dPCR. Samples with sufficient viral load were sequenced at a 543 bp fragment of the RV VP4/VP2 region. RV species were assigned by comparison to RV sequences in GenBank using BLAST. Clinical data were collected into REDCap. T-tests were used to compare mean viral loads between groups.ResultsOf 1703 children enrolled in the ED, 697 were RV/enterovirus positive by FilmArray [median age 18 months (interquartile range 9–39 months)]. Of 590 subjects with viral load available, 276 (47%) were admitted to the hospital. Among RV mono-infections (N = 434), mean viral load did not differ between subjects admitted vs. discharged from the ED (7.03 log copies/mL for both, P = 0.97). Among admitted subjects with RV mono-infection, viral load also did not differ between subjects requiring supplemental oxygen vs. not (7.01 vs. 7.10 log copies/mL, P = 0.6). Subjects with viral co-infections had lower mean RV viral loads (6.31 log copies/mL) compared with those with RV only (7.03 log copies/mL; P < 0.001) (figure). Significantly different RV viral loads were seen with co-infections with respiratory syncytial virus (RSV), metapneumovirus (MPV) and parainfluenza (PIV), but not with influenza, adenovirus or coronavirus. In 525 sequenced samples (46% RV-A, 4% RV-B, 50% RV-C), viral load did not vary between RV viral species (P = 0.09).ConclusionPrecise viral quantitation demonstrates children co-infected with RV and RSV, MPV or PIV have lower nasal viral loads than those with RV alone. Among RV mono-infections, RV viral load was not associated with admission or need for supplemental oxygen. Disclosures All authors: No reported disclosures.

Short-term relevance of lower respiratory viral coinfection in inpatients under 2 years of age.

IntroductionAdvances in molecular diagnosis have made it possible to detect previously unknown viral agents as causative agents of lower respiratory tract infections (LRTI). The frequency and relevance of viral coinfections is still debatable.ObjectiveCompare clinical presentation and severity between single virus infection and viral coinfection in children admitted for LRTI.MethodsA 3-year period observational study (2012–2015) included children younger than two years admitted for LRTI. Viral identification was performed using PCR technique for 16 viruses. Clinical data and use of health resources was gathered during hospital stay using a standard collection form and we compared single virus infection and viral coinfections.ResultsThe study included 524 samples (451 patients); 448 (85.5%) had at least one virus identified. Viral coinfections were found in 159 (35.5%). RSV and HRV were the most commonly identified virus; bronchiolitis and pneumonia the most frequent diagnosis. Patients with viral coinfections were older, attended day-care centers, had previous recurrent wheezing more frequently and were more symptomatic at admission. These patients did not have more complementary exams performed but were prescribed medications more often. Viral coinfection group did not show longer length of hospital stay and oxygen need, more need for ICU nor ventilatory support.DiscussionOur study showed a significant proportion of viral coinfections in young infants admitted with LRTI and confirmed previous data showing that prescription was more frequent in inpatients with viral coinfections, without an association with worst clinical outcome.

Systematic review and meta-analysis of respiratory viral coinfections in children.

Respiratory infections are a common cause of paediatric morbidity. Clinical outcomes in children hospitalized with single respiratory virus infection are compared with those with two or more viral-viral coinfection. Studies were restricted to those reporting on children aged less than 5 years (PROSPERO CRD#42014009133). Published data to calculate risk ratios (RR) comparing children with single viral infections to coinfection using a random effects model were used. Similar analyses by pathogen pairs and by excluding children with comorbidities were performed. Of 4443 articles reviewed, 19 were included. Overall, no differences in the risk of fever, admission to an intensive care unit (ICU), oxygen use, mechanical ventilation and abnormal radiographs between children with single infection and those with coinfection were found. When analysing only children without comorbidities, the risk of fever (RR = 1.16 to RR = 1.24, 95% confidence intervals (CI) = 1.00-1.55) and ICU admission (RR = 1.08 to RR = 1.31, 95% CI = 0.93-1.83) increased but remained non-significant. Point estimates suggested an increased risk of ICU admission in those coinfected with either respiratory syncytial virus or human metapneumovirus compared with those with single infection but was non-significant. Our findings suggest that coinfection is not associated with increased clinical severity, but further investigations by pathogen pairs are warranted.

Clinical Impact of Mixed Respiratory Viral Infection in Children with Adenoviral Infection.

BackgroundAlthough adenovirus (ADV) infection occurs steadily all year round in Korea and the identification of respiratory viral coinfections has been increasing following the introduction of multiplex real-time polymerase chain reaction tests, the clinical impact of viral coinfection in children with ADV infection has rarely been reported.Materials and MethodsMedical records of children diagnosed with ADV infection were retrospectively reviewed. The enrolled children were divided into two groups based on the identified respiratory viruses: ADV group and coinfection group. Clinical and laboratory parameters were compared between the two groups.ResultsIn total, 105 children (60 males and 45 females) with a median age of 29 months (range: 0-131 months) diagnosed with an ADV infection were enrolled. Fever (99.0%) was by far the most frequent symptom, followed by respiratory (82.9%), and gastrointestinal (22.9%) symptoms. Upper and lower respiratory tract infections were diagnosed in 56 (53.3%), and 32 (30.5%) children, respectively. Five (4.8%) children received oxygen therapy, and no child died due to ADV infection. Coinfection was diagnosed in 32 (30.5%) children, with rhinovirus (46.9%), and respiratory syncytial virus (21.9%) being the most frequent. The proportions of children younger than 24 months (P <0.001), with underlying medical conditions (P = 0.020), and diagnosed with lower respiratory tract infection (P = 0.011) were significantly higher in the coinfection group than in the ADV group. In a multivariate analysis, only the younger age was significantly associated with coinfection (P <0.001). Although more children in the coinfection group received oxygen therapy (P = 0.029), the duration of fever and hospitalization was not significantly different between the two groups.ConclusionRespiratory viral coinfection with ADV occurred more frequently in children younger than 24 months of age compared with children aged 24 months or older. Respiratory viral coinfection may increase the severity of ADV infection, however, appropriate therapy prevented prolonged hospitalization and poor prognosis due to coinfection.

Viral Co-Infections in Pediatric Patients Hospitalized with Lower Tract Acute Respiratory Infections.

BackgroundMolecular techniques can often reveal a broader range of pathogens in respiratory infections. We aim to investigate the prevalence and age pattern of viral co-infection in children hospitalized with lower tract acute respiratory infection (LT-ARI), using molecular techniques.MethodsA nested polymerase chain reaction approach was used to detect Influenza (A, B), metapneumovirus, respiratory syncytial virus (RSV), parainfluenza (1–4), rhinovirus, adenovirus (A—F), bocavirus and coronaviruses (NL63, 229E, OC43) in respiratory samples of children with acute respiratory infection prospectively admitted to any of the GENDRES network hospitals between 2011–2013. The results were corroborated in an independent cohort collected in the UK.ResultsA total of 204 and 97 nasopharyngeal samples were collected in the GENDRES and UK cohorts, respectively. In both cohorts, RSV was the most frequent pathogen (52.9% and 36.1% of the cohorts, respectively). Co-infection with multiple viruses was found in 92 samples (45.1%) and 29 samples (29.9%), respectively; this was most frequent in the 12–24 months age group. The most frequently observed co-infection patterns were RSV—Rhinovirus (23 patients, 11.3%, GENDRES cohort) and RSV—bocavirus / bocavirus—influenza (5 patients, 5.2%, UK cohort).ConclusionThe presence of more than one virus in pediatric patients admitted to hospital with LT-ARI is very frequent and seems to peak at 12–24 months of age. The clinical significance of these findings is unclear but should warrant further analysis.

High rate of respiratory viral co-infection in children with lower and upper respiratory tract infections in rural Gambia

High rate of respiratory viral co-infection in children with lower and upper respiratory tract infections in rural Gambia

Incidence and Clinical Course of Respiratory Viral Coinfections in Children Aged 0-59 Months.

Clinical data available on coinfections are contradictory concerning both the number of viruses involved and the severity of the condition. A total of 114 patients aged 0–59 months with symptoms of respiratory tract infection were enrolled into the study. Nasal and pharyngeal swabs were tested using the PCR method for the following 12 viruses: influenza A, influenza B, respiratory syncytial virus A (RSV A), respiratory syncytial virus B (RSV B), adenovirus, metapneumovirus, coronavirus 229E/NL63 (hCoV229), coronavirus OC43 (hCoVOC43), parainfluenza virus 1 (PIV-1), parainfluenza virus 2 (PIV-2), parainfluenza virus 3 (PIV-3), and rhinovirus A/B. Coinfections were detected in nine (8 %) patients. Five of the coinfections were related to influenza A (H3N2) virus associated with the following other, single or combined, respiratory viruses: influenza B in one case, hCoV229 in two cases, hCoV229, RSV A, and PIV-2 in one case, and PIV-1, PIV-2, RSV A, RSV B, and adenovirus in one case. The other four coinfections were caused by: adenovirus and hCoVOC43, adenovirus, and rhinovirus, RSV A and PIV-1, influenza B, and RSV B. We did not observe any significant differences in the clinical course of infections caused either by a single or multiple viral factors.

Co-infección viral respiratoria en niños hospitalizados por infección respiratoria aguda y su impacto en la gravedad clínica

Respiratory viruses are the leading cause of acute respiratory tract infection (ARI) in children. It has been reported that viral respiratory co-infection could be associated with severe clinical course. To describe the frequency of viral co-infection in children admitted for AlRI and evaluate whether this co-infection was associated with more severe clinical course. Prospective, descriptive study in pediatric patients who were hospitalized for ARI, with molecular detection of at least 1 respiratory virus in nasopharyngeal sample studied by PCR-Microarray for 17 respiratory viruses. 110 out of 147 patients with detection of > 1 respiratory virus were included. Viral co-infection was detected in 41/110 (37%). 22/110 children (20%) were classified as moderate to severe clinical course and 88/110 (80%) were classified as mild clinical course. In the group of moderate to severe clinical course, viral respiratory co-infection was detected in 6/22 (27.3%), compared to 35/88 (39.8 %) in the mild clinical course group. No statistically significant difference was found regarding the presence of co-infection between groups (p = 0.33). We detected high rates of viral co-infection in children with ARI. It was not possible to demonstrate that viral co-infections were related with severe clinical course in hospitalized children.

Viral Coinfections in Children With Invasive Pneumococcal Disease

Respiratory viruses contribute to the seasonal pattern of invasive pneumococcal disease (IPD), but the impact of viral coinfections on the clinical characteristics and outcomes of patients with IPD have not been well defined. This study was designed to describe and compare the clinical presentations and outcomes of patients with IPD with or without viral coinfections. Retrospective analyses of records of all children treated at Children's Medical Center Dallas (CMCD) for IPD from July 2005 to June 2008. Viral studies included viral direct fluorescent antibody staining and culture. For comparisons, patients were classified in 3 groups: with positive, negative, and no viral studies performed. A total of 129 patients were admitted to CMCD with IPD during the 3 year study; 57% were male. Ages ranged from 2 months to 18 years (median 25 months) and 48% were <2 years. Viral studies were performed in 82 (63%) patients, and 28 (34%) had positive results. The most common viruses isolated were influenza (7, 25%), rhinoviruses (6, 21%), adenoviruses (6, 21%), and RSV (5, 18%). Peaks of positive viral studies occurred in February and November which coincided with the peak numbers of patients admitted with IPD. Of 6 with adenovirus coinfection, 5 were admitted to Pediatric Intensive Care Unit (PICU). The most common pneumococcal serotypes were 19A (41, 32.5%), 7F (14, 11%), and 23A (13, 10.3%). Pneumonia (42%), bacteremia (22%), and meningitis (17%) were the most common clinical syndromes. There were no differences in duration of fever before admission, maximum temperatures during hospitalization and white blood cell counts, duration of fever and hospitalization between patients with positive and negative viral studies, but there was a trend for patient with positive viral studies to be admitted to PICU more frequently and to have longer PICU stay. Three of the 6 patients who died had documented viral coinfections (2 adenovirus, 1 parainfluenza 3), and all 3 had no underlying conditions. The other 3 patients who died had no viral studies performed. Duration of treatment ranged from 1 to -210 days (median 14), with no differences among the groups. Viral coinfections were common in children with IPD. Future prospective studies should include new PCR assays to characterize better the impact of viral coinfections in the occurrence and outcome of IPD.

Frequent Detection of Viral Coinfection in Children Hospitalized With Acute Respiratory Tract Infection Using a Real-Time Polymerase Chain Reaction

Respiratory viruses are the main cause of acute respiratory tract infection (ARI) in children. Real-time polymerase chain reaction (PCR) technology is highly practicable for the rapid detection of viral pathogens. The simultaneous detection of a broad spectrum of viruses enables the diagnosis and evaluation of viral coinfection in ARI. A 1-step real-time PCR was developed for the detection of 12 respiratory viruses (10 RNA and 2 DNA viruses) in clinical samples. Clinical samples from 254 children admitted to the Departments of Pediatrics with ARI during a 10-month period were tested. Respiratory syncytial virus (RSV) was the most frequently detected pathogen in 112 samples (44.1%), followed by human bocavirus (hBoV) in 49 (19.3%), and rhinovirus in 17 samples (6.7%). Viral coinfection was detected in 41 (16.1%) samples with RSV and hBoV being the most dominating combination (27 cases, 10.6%). Viral coinfection was found in 10 cases (17%) of children with bronchitis (n = 58) and in 7 cases (23%) of bronchiolitis (n = 30). In patients with pneumonia (n = 51), 17 cases (33%) were positive for 2 or more viral pathogens. Simultaneous testing of respiratory viruses by real-time PCR is a suitable tool for the detection of viral coinfections. In children hospitalized because of respiratory infection viral coinfection is frequently detected with RSV and hBoV being a common combination.

Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children.

The precise epidemiology of childhood pneumonia remains poorly defined. Accurate and prompt etiologic diagnosis is limited by inadequate clinical, radiologic, and laboratory diagnostic methods. The objective of this study was to determine as precisely as possible the epidemiology and morbidity of community-acquired pneumonia in hospitalized children. Consecutive immunocompetent children hospitalized with radiographically confirmed lower respiratory infections (LRIs) were evaluated prospectively from January 1999 through March 2000. Positive blood or pleural fluid cultures or pneumolysin-based polymerase chain reaction assays, viral direct fluorescent antibody tests, or viral, mycoplasmal, or chlamydial serologic tests were considered indicative of infection by those organisms. Methods for diagnosis of pneumococcal pneumonia among study subjects were published by us previously. Selected clinical characteristics, indices of inflammation (white blood cell and differential counts and procalcitonin values), and clinical outcome measures (time to defervescence and duration of oxygen supplementation and hospitalization) were compared among groups of children. One hundred fifty-four hospitalized children with LRIs were enrolled. Median age was 33 months (range: 2 months to 17 years). A pathogen was identified in 79% of children. Typical respiratory bacteria were identified in 60% (of which 73% were Streptococcus pneumoniae), viruses in 45%, Mycoplasma pneumoniae in 14%, Chlamydia pneumoniae in 9%, and mixed bacterial/viral infections in 23%. Preschool-aged children had as many episodes of atypical bacterial LRIs as older children. Children with typical bacterial or mixed bacterial/viral infections had the greatest inflammation and disease severity. Multivariate logistic-regression analyses revealed that high temperature (> or = 38.4 degrees C) within 72 hours after admission (odds ratio: 2.2; 95% confidence interval: 1.4-3.5) and the presence of pleural effusion (odds ratio: 6.6; 95% confidence interval: 2.1-21.2) were significantly associated with bacterial pneumonia. This study used an expanded diagnostic armamentarium to define the broad spectrum of pathogens that cause pneumonia in hospitalized children. The data confirm the importance of S pneumoniae and the frequent occurrence of bacterial and viral coinfections in children with pneumonia. These findings will facilitate age-appropriate antibiotic selection and future evaluation of the clinical effectiveness of the pneumococcal conjugate vaccine as well as other candidate vaccines.