Clinical Course and Management of Dengue in Children Admitted to Hospital: A 5 Years Prospective Cohort Study in Jakarta, Indonesia Background: Dengue incidence is rising globally which was estimated 100 million per year, whereas in Indonesia was estimated 7.5 million per year. Dengue clinical course varies from mild dengue fever (DF) to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Patients, clinicians and care facilities would benefit if reliable predictors can determine at admission which cases with clinically suspected dengue will progress to DHF or DSS. Methods: From 2009 through 2013, a cohort of 494 children admitted with clinically suspected dengue at a tertiary care hospital in Jakarta, Indonesia, was followed until discharge. We evaluated the clinical course and disease outcome of admitted patients and estimated the burden of dengue cases hospitalized over time. Results: Of all 494 children, 185 (37%) were classified at admission as DF, 158 (32%) as DHF and 151 (31%) as DSS. Of DF patients, 52 (28%) progressed to DHF or DSS, 10 (5%) had other viral diseases. Of DHF patients, 9(6%) progressed to DSS. Of 33 routinely collected parameters at admission, duration of fever ≤4 days was the only significant predictor of disease progression (P = 0.01). Five cases (3%) admitted with DSS died. Between 2009 and 2013, annual dengue admissions declined, while distribution of disease severity remained stable. Conclusions: Almost a third of children admitted to tertiary care with clinically suspected DF progress to DHF or DSS. Among routinely collected parameters at admission, only fever duration was significantly associated with clinical progression, emphasizing unpredictability of dengue disease course from parameters currently routinely collected.

Prevalence of Bacterial Infection in Febrile Infant 61–90 Days Old Compared With Younger Infants Background: The objective is to compare the prevalence of serious bacterial infection (SBI) and invasive bacterial infection (IBI) in febrile infants <60 days of age and in those between 61 and 90 days. Methods: Prospective registry-based cohort study including all the infants ≤90 days with fever without a source evaluated in a pediatric emergency department between 2003 and 2017. We compared the prevalence of SBI and IBI in febrile infants <60 days of age and those between 61 and 90 days. Results: We included 3,301 infants. Overall, 605 (18.3%) had a SBI (mainly urinary tract infection), of these 81 (2.5%) had an IBI (bacteremia 60, meningitis 12, sepsis 9). The prevalence of SBI in infants >60 days old was 18.5% (95% CI: 16.4–20.7) versus 16.6% (95% CI: 14.7–18.7; n.s.) in those between 29 and 60 days and versus 21.5% (95% CI: 18.6–24.7; n.s.) in those <28 days of age. The prevalence of IBI among infants >60 days old was 1.1% (95% CI: 0.6–2.2) versus 2.3% (95% CI: 1.6–3.3; P < 0.05) in those between 29 and 60 days and 5.1% (95% CI: 3.7–7.0; P < 0.05) in those <28 days of age. The prevalence of IBI in well appearing >60 days was 1.0% (versus 4.5% in those <28 days old, P < 0.01; and 2.0% in those between 29 and 60 days, P = 0.06). All bacterial meningitis, except one, were diagnosed in infants <28 days. Conclusions: The prevalence of IBI in febrile infants between 61 and 90 days of age is high enough to support the recommendation for obtaining urine and blood tests in this population.

Molecular Characterization of Streptococcus pyogenes Causing Invasive Disease in Pediatric Population in Spain A 12-year Study Objectives: To perform a comprehensive description of the epidemiology of Streptococcus pyogenes invasive disease in the pediatric population in 2 regions of Spain (Catalonia and Gipuzkoa) through 12 years. Methods: All S. pyogenes isolates causing invasive disease in pediatric patients between 2005 and 2016 were included. The emm-type and the presence of 13 exotoxin genes (speA, speB, speC, speF, speG, speH, speI, speJ, speK, speL, speM, smeZ, ssa and slo) were determined in all 93 available isolates and the Multi Locus Sequece Typing in 10% of isolates of each different emm-type. Results: Overall, 103 cases of S. pyogenes invasive infections were detected: 77 in Catalonia and 26 in Gipuzkoa, being 50.5% females. The incidence rate per 100,000 children was 2.5 for Gipuzkoa and 2.6 for Catalonia, with no significant temporal trends. The median age was 30 months. The most frequent clinical presentations were: pneumonia (26.2%), bacteremia/sepsis (23.3%), septic arthritis/osteomyelitis (22.3%), cellulitis/mastoiditis (12.6%) and meningitis (6.8%). Eight children developed streptococcal toxic shock syndrome. Nine cases were preceded by varicella infection. The associated mortality rate was 3.9%. Three isolates were resistant to erythromycin, being one of them also resistant to clindamycin and 4 isolates were resistant to levofloxacine. Forteen different emm-types were detected being emm1/ST28 (40.9%) the most frequent clone in both regions followed by emm12/ST36-ST242, emm6/ST382, emm3/ST15, emm75/ST150 and emm4/ST38-39. speA gene was only detected in emm1 and emm3 isolates. Eight exotoxins were enough to assign an emm-type with a very high degree of accuracy (95%). The 30-valent vaccine would include 96.8% of isolates.

Epstein-Barr Virus Seroprevalence and Force of Infection in a Multiethnic Pediatric Cohort, Singapore Background: Epstein-Barr virus (EBV) spreads through bodily fluids, especially saliva, and can cause infectious mononucleosis. EBV immunity and infection status can be assessed by testing EBV viral capsid antigen and nuclear antigen (EBNA) antibodies in blood. In this study, we investigated the seroprevalence and force of infection (FOI) of EBV antibodies among children and young people in 3 ethnic groups in Singapore. Methods: Eight hundred ninety-six residual serum samples at a tertiary hospital were tested for viral capsid antigen (IgG and IgM) and EBNA IgG antibodies using Abbott Architect assays. We calculated the EBV seroprevalence using catalytic models to estimate the EBV force of infection from age-stratified seroprevalence data, both overall and by ethnic group. Results: Overall seropositivity was 68.3% (n = 612). Seropositivity was higher in Malays (81.8%) compared with both Chinese (64.2%) and Indians (58.4%). EBV FOI was consistently higher in Malays, with an estimated annual rate of seroconversion of 25% in children 1 year, of age compared with 14% among Chinese and Indians at the same age. Conclusions: The seroprevalence patterns of EBV antibodies in the Chinese and Indian, but not Malay children in Singapore by 19 years of age resemble those previously reported in developed countries. Ideally, any future EBV vaccination strategy would need to target infants <1 year of age for maximum population benefit.

Assessment and Validation of Syndromic Case Definitions for Respiratory Syncytial Virus Infections in Young Infants: A Latent Class Analysis Background: Respiratory syncytial virus (RSV) is a major cause of pediatric morbidity and mortality worldwide. Standardized case definitions that are applicable to variety of populations are critical for robust surveillance systems to guide decision-making regarding RSV control strategies including vaccine evaluation. Limited data exist on performance of RSV syndromic case definitions among young infants or in high-resource settings. Objective: The purpose of this study was to evaluate existing and potential syndromic case definitions for RSV among young infants in an urban, high-income setting using latent class analyses (LCA). Methods: We used data collected on infants <6 months of age tested for RSV as part of routine clinical care at Children’s Healthcare of Atlanta between January 2010 and December 2015. We computed the sensitivity, specificity, positive and negative predictive values of clinical features, existing syndromic case definitions used by the World Health Organization (WHO) and alternative definitions we constructed using LCA to detect RSV infection. Results: Among 565 infants tested for RSV, 161 (28.5%) had laboratory-confirmed RSV infection. Among all case definitions evaluated, the definition developed through LCA (cough plus shortness of breath plus coryza plus wheeze plus poor feeding plus chest in-drawing) was the most specific (95.8%, 95% CI 93.8–97.8) and had the highest positive predictive value (51.4%, 95% CI, 34.9–68.0). WHO-acute respiratory infection (cough or sore throat or shortness of breath or coryza, plus a clinician’s judgment that illness is due to infection) was the most sensitive (98.1%, 95% CI, 96.1–100.0; negative predictive value 96.3%, 95% CI 92.2–100.0). Conclusions: The WHO acute respiratory infection definition could be useful for initial screening for RSV among infants <6 months, whereas our alternative syndromic case definition may serve as the strongest confirmatory case definition in the same population. Appropriate case definitions will vary depending on the content and setting in which they are utilized.

Prevalence, Clinical Features and Antibiotic Susceptibility of Group A Streptococcal Skin Infections in School Children in Urban Western and Northern Uganda Background: Group A Streptococcus (GAS) skin infections can lead to invasive sepsis, poststreptococcal glomerulonephritis, and potentially rheumatic heart disease (RHD). Within a study to identify predisposing factors of RHD in Ugandan schoolchildren, we determined the prevalence of skin infections and assessed the clinical features and antibiotic susceptibility of GAS skin infection. Methods: Cross-sectional study conducted at 3 urban primary schools in Western and Northern Uganda in March 2017. A dermatologist rendered clinical diagnoses and obtained a skin swab specimen from lesions with signs of bacterial infection. Beta-hemolytic colonies underwent Lancefield grouping, species identification by polymerase chain reaction and antimicrobial susceptibility testing. Results: From 3265 schoolchildren, we observed 32% with ≥1 fungal, 1.8% with ≥1 bacterial, 0.9% with ≥1 viral, and 0.2% with ≥1 ectoparasitic infection. Of 79, 25 (32%) specimens were GAS-positive, of which one-third demonstrated tetracycline resistance. Of 17 impetigo cases, 13 (76%) were located on the leg/foot and 3 (18%) on the head/neck. Prevalence of GAS skin infection was 0.8% (25 of 3265). In Northern Uganda, where subclinical definite RHD prevalence is 1.1%, GAS skin infection prevalence was 1.2% (4 of 343) and 0.9% (3 of 352). Conclusion: This study identifies tetracycline-resistant GAS in Ugandan communities, suggests modified skin examination of exposed anatomic locations may be appropriate for population-based GAS skin infection studies, and underscores need for clear case definitions of GAS skin infection. Future studies are needed to evaluate the role of GAS skin infection in development of RHD in Ugandan communities.

Extrapulmonary Coccidioidomycosis Among Children in Central California: A Retrospective Review Background: The literature on pediatric extrapulmonary coccidioidomycosis is limited. We reviewed the clinical course, diagnostic studies, treatment and outcomes of children with extrapulmonary coccidioidomycosis followed at a tertiary care center in central California. Methods: Retrospective study of 78 patients ≤21 years old with extrapulmonary coccidioidomycosis diagnosed over 10 years (1/1/07–12/31/16). Results: The median age was 9.7 years (interquartile range, 4.5–14.8). The majority of patients were males (55%), Hispanic (65%) and without comorbid conditions (85%). Over two-thirds (68%) had concurrent pulmonary disease. Organ involvements included bones and joints (33%), mediastinum (19%), central nervous system (19%), cervical lymph nodes (15%), larynx (6%) and skin (5%). Most cases (84%) resolved and/or became stable on maintenance therapy, 14% experienced relapse and/or progressive disease, and 2% were fatal. Children ≥10 years of age tended to have >1 site of involvement (47% vs. 25%, P = 0.06), and more relapsed/progressive/fatal disease (21% vs. 5%, P = 0.06) compared with those <10 years. They also required longer durations of treatment (median, 611 vs. 349 days, P = 0.02). Non-Hispanics were more likely to require >1 drug therapy (85% vs. 70%, P = 0.04) and tended to have Coccidioides complement fixation titers ≥1:32 (89% vs. 72%, P = 0.04) compared with Hispanics. Conclusions: Extrapulmonary coccidioidomycosis in children can be severe and spread to multiple sites and requires prolonged treatment. Non-Hispanics and those ≥10 years of age are more likely to experience severe disease, suggesting a need for early recognition and intervention in these populations.

Increasing Rates of Pediatric Empyema and Disease Severity With Predominance of Serotype 3 S. pneumonia: An Australian Single-center, Retrospective Cohort 2011 to 2018 Background: The impact of universal 13-valent pneumococcal conjugate vaccine immunization on pediatric empyema rates and pathogens in Australia is not known. We aimed to describe empyema epidemiology, clinical characteristics and treatment during an 8-year period. Methods: A retrospective study between 2011 and 2018 of empyema cases admitted to a large pediatric referral hospital, for management with either pleural drainage and fibrinolytics or surgical intervention. Results: There were 195 cases in 8 years. Empyema incidence and ICU admission rates significantly increased during the study with a peak incidence of 7.1/1000 medical admissions in 2016 (χ2 for trend of incidence 37.8, P < 0.001 and for ICU admissions 15.3, P < 0.001). S. pneumoniae was the most common pathogen (75/195, 39%) with serotype 3 the most detected (27/75: 27%). S. pyogenes compared with S. pneumoniae had significantly fewer days of fever before admission (3.9 vs. 6.4, mean difference 2.4, 95% CI: 0.84–4.08, P = 0.003) and higher proportion requiring direct ICU admission (6/75; 8% vs. 7/15; 47%, P < 0.001). Compared with S. pneumoniae, cases with no pathogen detected by culture or PCR had fewer days of fever post intervention (4.4 vs. 7.4 days, mean difference 2.7 days, P = 0.002). S. aureus occurred more commonly in infants (10/25; 40% vs. 1/75; 1%, P < 0.001) and children of indigenous background (5/25; 20% vs. 1/75; 1%, P < 0.001) compared with S. pneumoniae. Conclusions: We report increasing rates of pediatric empyema with higher proportions requiring ICU treatment. The most common pathogens detected were S. pneumoniae, S. aureus and S. pyogenes. Despite high 13-valent pneumococcal conjugate vaccine coverage, serotype 3 was the most common S. pneumoniae serotype identified.

Cerebrospinal Fluid Pleocytosis and Elevated C-X-C Motif Chemokine Ligand 13 Value Predict Lyme Borreliosis in Children With Facial Palsy Background: Lyme borreliosis (LB) is a common cause of acute facial palsy in children living in endemic areas for Borrelia burgdorferi. The need for lumbar puncture in diagnostics of LB in children with facial palsy has been questioned. Our aim was to evaluate the prevalence of LB and the diagnostic value of a cerebrospinal fluid (CSF) sample among children with an acute facial palsy. Methods: We collected medical records and laboratory data of children and adolescents 0–16 years of age (n = 94) diagnosed with facial palsy between 2002 and 2016 in the Turku University Hospital. A positive B. burgdorferi serology in serum or CSF or a positive B. burgdorferi polymerase chain reaction in CSF were considered as signs of definite LB. C-X-C motif chemokine ligand 13 (CXCL13) values were measured in CSF samples from 28 children during 2014–2016. Results: Lumbar puncture was performed on 84 of 94 children with facial palsy. LB was confirmed in 29 of 42 children with, and in 4 of 42 without, pleocytosis. The sensitivity and specificity of pleocytosis to predict LB were 88% (95% confidence interval, 78%–98%) and 75% (62%–88%), respectively, and the positive and negative predictive values were 69% (55%–83%) and 90% (81%–99%), respectively. An increased CSF CXCL13 value had 67% (51%–83%) sensitivity and 100% specificity for LB. Conclusions: Because serum serology can be negative at presentation, lumbar puncture is a valuable tool when diagnosing LB among children with facial palsy. Pleocytosis and increased protein and CXCL13 values in the CSF suggest LB as the cause of facial palsy.

Comprehensive Detection of Respiratory Bacterial and Viral Pathogens in the Middle Ear Fluid and Nasopharynx of Pediatric Patients With Acute Otitis Media Background: Acute otitis media (AOM) is a common ear infection caused by respiratory viruses and bacteria of the nasopharynx. The present study aimed to detect various respiratory viruses and bacteria in middle ear fluid (MEF) and nasopharyngeal aspirates (NPA) using polymerase chain reaction (PCR). Methods: We collected MEF and NPA samples from 122 pediatric patients with AOM. Real-time PCR detected 11 types of respiratory viruses (respiratory syncytial virus A/B, parainfluenza virus 1/2/3, human metapneumovirus, influenza virus A/B, adenovirus, human bocavirus and rhino virus) and 7 types of bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Streptococcus pyogenes, Legionella pneumophila and Moraxella catarrhalis). MEF specimens were also examined using bacterial culture. Results: At least 1 respiratory viral or bacterial pathogen was detected in MEF of 120 cases (98%) by viral and bacterial PCR and of 93 cases (76%) by viral PCR and bacterial culture. Respiratory viruses were detected in NPA of 84 cases (69%) and MEF of 67 cases (55%). The most common virus detected in MEF was respiratory syncytial virus (21%), followed by parainfluenza virus (15%). All the viruses present in MEF were also detected in NPA specimens. Bacteria were detected by PCR in MEF of 109 cases (89%); H. influenzae was the most frequently detected (65%). Conclusions: In many cases, pediatric AOM was found to constitute a respiratory polymicrobial infection. Multiplex PCR was useful to detect multiple respiratory viruses and bacteria in AOM. To understand intractable AOM, further studies regarding the clinical features of each viral and bacterial coinfection are required.