Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

PbABCG1 and PbABCG2 transporters are required for the emission of floral monoterpenes in Phalaenopsis bellina.

Terrestrial plants emit volatiles into the atmosphere to attract both pollinators and the enemies of herbivores, for defense. Phalaenopsis bellina is a scented orchid species in which the main scent components are monoterpenes, including linalool and geraniol, and their derivatives. Here, we investigated whether ABC transporters are involved in floral scent emission. We carried out whole-genome identification of ABC transporter-related genes using four floral transcriptomics libraries of P. bellina. We identified 86 ABC subfamily G genes related to terpenoid transport. After comparing the gene expression patterns of P. bellina with that of Phalaenopsis aphrodite subsp. formosana, a scentless species, followed by gene-to-gene correlation analysis, PbABCG1 and PbABCG2 were selected. The temporal expression of both PbABCG1 and PbABCG2 was highly correlated with that of the key enzyme PbGDPS and the major transcription factor PbbHLH4 in monoterpene biosynthesis, with optimal expression on day 5 post-anthesis. Spatial gene expression analysis showed that PbABCG1 was highly expressed in sepals, whereas PbABCG2 was expressed in the lip. Subcellular localization with a GFP fusion protein revealed that both PbABCG1 and PbABCG2 are cytoplasmic membrane proteins. Co-downregulation of PbABCG1 and PbABCG2 using both double-strand RNA interference and tobacco rattle virus-based gene silencing led to a significant decrease in monoterpene emission, accompanied by an increase in the internal monoterpene pools. Furthermore, ectopic expression of PbABCG1 and PbABCG2 in an ABC16- mutant yeast strain rescued its tolerance to geraniol. Altogether, our results indicate that PbABCG1 and PbABCG2 play substantial roles in monoterpene transport/emission in P. bellina floral scent.

Secular trend of Kawasaki disease and its correlation with viral activity in Taiwan: a nationwide population-based study.

BACKGROUND: Kawasaki disease (KD) is the most important acquired heart disease in children. This study investigated annual incidence, seasonality, secular trend and the correlation of KD incidence with viral activity in Taiwan. METHODS: Through the national health insurance database, we identified KD during 2001-2020. The viral activity was obtained from nationwide surveillance database. We analyzed KD age-specific annual incidence, secular trends, seasonality and the correlation between KD incidence and common enteric or respiratory viral activity. RESULTS: The KD incidence of subjects younger than 18 years significantly increased from 2001 to 2020 (11.78 and 22.40 per 100,000 person-years, respectively), and substantially decreased with age. Infants younger than 1 year presented the highest KD annual incidence at 105.82 to 164.34 per 100,000 person-years from 2001 to 2020. For all KD patients, the most frequently occurring season was summer followed by autumn. The KD incidence of infants younger than 1 year had significantly positive correlation with enteric (r = 0.14) and respiratory (r = 0.18) viral activity. CONCLUSIONS: This study demonstrates the increasing trend of KD annual incidence and seasonality (more in summer and autumn) in Taiwan. The activity of common respiratory and enteric viruses was significantly correlated with KD incidence in infants.

Clinical manifestations and risk factors of shock in children with multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a novel disease associated with COVID-19. The COVID-19 epidemic peaked in May 2022 in Taiwan, and we encountered our first case of MIS-C in late May 2022. We aimed to present patients' clinical manifestations and identify risk factors for shock. METHODS: We included patients diagnosed with MIS-C at two medical centers from May 2022 to August 2022. We separated those patients into two groups according to whether they experienced shock. We collected demographic, clinical manifestation, and laboratory data of the patients and performed statistical analysis between the two groups. RESULTS: We enrolled 28 patients, including 13 (46 %) with shock and 15 (54 %) without shock. The median age was 6.4 years (IQR: 1.9-7.5). In single variable analysis, patients with shock tended to be older, had more neurological symptoms, more conjunctivitis and strawberry tongue, lower lymphocyte count, lower platelet counts, and higher C-reactive protein, higher procalcitonin, higher ferritin, and higher D-dimer levels than those without shock. The area under the ROC curve that used procalcitonin to be the risk factor of shock with MIS-C was 0.815 (95 % CI 0.644 to 0.987). The cutoff value obtained by ROC analysis of procalcitonin was 1.68 ng/mL. With this cutoff, the test characteristics of procalcitonin were as follows: sensitivity 77 %, specificity 93 %, positive predictive value 91 %, negative predictive value 82 %. Multivariable analysis revealed that procalcitonin was the only independent risk factor of shock with MIS-C on admission (OR, 26.00, 95 % CI, 1.01-668.89). CONCLUSIONS: MIS-C patients with high initial procalcitonin levels have higher risks of experiencing shock and may need ICU admission.

Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus (RSV) Vaccine in Healthy RSV-Seropositive Children 12-23 Months of Age.

BACKGROUND: Safe and effective respiratory syncytial virus (RSV) vaccines remain elusive. This was a phase I/II trial (NCT02927873) of ChAd155-RSV, an investigational chimpanzee adenovirus-RSV vaccine expressing 3 proteins (fusion, nucleoprotein, and M2-1), administered to 12-23-month-old RSV-seropositive children followed up for 2 years after vaccination. METHODS: Children were randomized to receive 2 doses of ChAd155-RSV or placebo (at a 1:1 ratio) (days 1 and 31). Doses escalated from 0.5 × 1010 (low dose [LD]) to 1.5 × 1010 (medium dose [MD]) to 5 × 1010 (high dose [HD]) viral particles after safety assessment. Study end points included anti-RSV-A neutralizing antibody (Nab) titers through year 1 and safety through year 2. RESULTS: Eighty-two participants were vaccinated, including 11, 14, and 18 in the RSV-LD, RSV-MD, and RSV-HD groups, respectively, and 39 in the placebo groups. Solicited adverse events were similar across groups, except for fever (more frequent with RSV-HD). Most fevers were mild (≤38.5°C). No vaccine-related serious adverse events or RSV-related hospitalizations were reported. There was a dose-dependent increase in RSV-A Nab titers in all groups after dose 1, without further increase after dose 2. RSV-A Nab titers remained higher than prevaccination levels at year 1. CONCLUSIONS: Three ChAd155-RSV dosages were found to be well tolerated. A dose-dependent immune response was observed after dose 1, with no observed booster effect after dose 2. Further investigation of ChAd155-RSV in RSV-seronegative children is warranted. CLINICAL TRIALS REGISTRATION: NCT02927873.

Respiratory syncytial virus (RSV) is among the main causes of bronchiolitis and pneumonia regularly leading to hospitalization in children. A safe and effective vaccine to prevent RSV infection in this age group has not yet been found, despite great efforts over several decades. This study tested a new candidate RSV vaccine, expressing 3 important pieces of the virus, in toddlers who already had a previous RSV infection. The vaccine was generally well tolerated. Vaccination triggered antibodies against RSV that were able to block the virus in laboratory tests and that persisted for 1 year.

Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Children are susceptible to severe or fatal enterovirus 71 (EV71) infections. We aimed to evaluate the efficacy, safety, and immunogenicity of EV71vac, an aluminium phosphate-adjuvanted inactivated EV71 vaccine in children aged 2-71 months. METHODS: We did a randomised, double-blinded, placebo-controlled, phase 3 trial at five hospitals in Taiwan and two in Vietnam. Children aged 2-71 months were stratified by country and age, and randomly assigned (1:1) to receive two doses of EV71vac or placebo via intramuscular injection 56 days apart. Children aged 2-23 months received a third booster dose on day 366. The primary endpoint was the clinical efficacy of the total vaccinated cohort against EV71-associated diseases during the follow-up period, from 14 days after the second dose to when 15 cases of EV71 infections were confirmed in the per-protocol population. Our safety analysis included all participants who received at least one dose of EV71vac. This trial is registered with ClinicalTrials.gov, NCT03865238, and is complete. FINDINGS: Between April 23 and Dec 25, 2019, of 3663 children assessed, 3061 were randomly assigned, of whom 3049 were vaccinated: 1521 children in the EV71vac group and 1528 in the placebo group. By May 20, 2021, our primary efficacy analysis included 2959 children, with 1476 children in the EV71vac group and 1483 children in the placebo group. The vaccine efficacy of EV71vac was 96·8% (95% CI 85·5-100) against EV71 associated diseases (p<0·0001). The percentage of participants who reported solicited adverse events were similar in both groups: 865 (56·9%) in the EV71vac group and 852 (55·8%) in the placebo group. Almost all reported solicited adverse events were mild and self-limited. INTERPRETATION: EV71vac is safe, well-tolerated, and highly effective in preventing EV71 associated diseases in children aged 2-71 months. FUNDING: Medigen Vaccine Biologics and A+ Industrial Innovative R&D Program of the Ministry of Economic Affairs, Taiwan.

Application of nested multiplex polymerase chain reaction respiratory and pneumonia panels in children with severe community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a serious clinical concern. A lack of accurate diagnosis could hinder pathogen-directed therapeutic strategies. To solve this problem, we evaluated clinical application of nested multiplex polymerase chain reaction (PCR) in children with severe CAP. We prospectively enrolled 60 children with severe CAP requiring intensive care between December 2019 and November 2021 at a tertiary medical center. Nested multiplex PCR respiratory panel (RP) and pneumonia panel (PP) were performed on upper and lower respiratory tract specimens. We integrated standard-of-care tests and quantitative PCR for validation. The combination of RP, PP, and standard-of-care tests could detect at least one pathogen in 98% of cases and the mixed viral-bacterial detection rate was 65%. The positive percent agreement (PPA), and negative percent agreement (NPA) for RP were 94% and 99%; the PPA and NPA for PP were 89% and 98%. The distribution of pathogens was similar in the upper and lower respiratory tracts, and the DNA or RNA copies of pathogens in the lower respiratory tract were equal to or higher than those in the upper respiratory tract. PP detected bacterial pathogens in 40 (67%) cases, and clinicians tended to increase bacterial diagnosis and escalate antimicrobial therapy for them. RP and PP had satisfactory performance to help pediatricians make pathogenic diagnoses and establish therapy earlier. The pathogens in the upper respiratory tract had predictive diagnostic values for lower respiratory tract infections in children with severe CAP.

Viral dynamics of SARS-CoV-2 Omicron infections in a previously low COVID-19 prevalence region: Effects of vaccination status, antiviral agents, and age.

BACKGROUND: In Taiwan, the prevalence of COVID-19 was low before April 2022. The low SARS-CoV-2 seroprevalence in the population of Taiwan provides an opportunity for comparison with fewer confounding factors than other populations globally. Cycle threshold (Ct) value is an easily accessible method for modeling SARS-CoV-2 dynamics. In this study, we used clinical samples collected from hospitalized patients to explore the Ct value dynamics of the Omicron variant infection. METHODS: From Jan 2022 to May 2022, we retrospectively included hospitalized patients tested positive by nasopharyngeal SARS-CoV-2 PCR. We categorized the test-positive subjects into different groups according to age, vaccination status, and use of antiviral agents. To investigate the nonlinear relationship between symptom onset days and Ct value, a fractional polynomial model was applied to draw a regression line. RESULTS: We collected 1718 SARS-CoV-2 viral samples from 812 individuals. The Ct values of unvaccinated individuals were lower than those of vaccinated persons from Day 4 to Day 10 after symptom onset. The Ct value increased more rapidly in those individuals with antiviral drug treatment from Day 2 to Day 7. In elderly individuals, the Ct values increased slowly from Day 5 to Day 10, and the increasing trend was unique compared with that in children and adults. CONCLUSION: Our study demonstrated the primary viral infection dynamics of the Omicron variant in hospitalized patients. Vaccination significantly affected viral dynamics, and antiviral agents modified viral dynamics irrespective of vaccination status. In elderly individuals, viral clearance is slower than that in adults and children.

Noninvasive prediction of axillary lymph node status in breast cancer using promoter profiling of circulating cell-free DNA.

BACKGROUND: Lymph node metastasis (LNM) is one of the most important factors affecting the prognosis of breast cancer. The accurate evaluation of lymph node status is useful to predict the outcomes of patients and guide the choice of cancer treatment. However, there is still lack of a low-cost non-invasive method to assess the status of axillary lymph node (ALN). Gene expression signature has been used to assess lymph node metastasis status of breast cancer. In addition, nucleosome footprint of cell-free DNA (cfDNA) carries gene expression information of its original tissues, so it may be used to evaluate the axillary lymph node status in breast cancer. METHODS: In this study, we found that the cfDNA nucleosome footprints between the ALN-positive patients and ALN-negative patients showed different patterns by implementing whole-genome sequencing (WGS) to detect 15 ALN-positive and 15 ALN-negative patients. In order to further evaluate its potential for assessing ALN status, we developed a classifier with multiple machine learning models by using 330 WGS data of cfDNA from 162 ALN-positive and 168 ALN-negative samples to distinguish these two types of patients. RESULTS: We found that the promoter profiling between the ALN-positive patients and ALN-negative patients showed distinct patterns. In addition, we observed 1071 genes with differential promoter coverage and their functions were closely related to tumorigenesis. We found that the predictive classifier based on promoter profiling with a support vector machine model, named PPCNM, produced the largest area under the curve of 0.897 (95% confidence interval 0.86-0.93). CONCLUSIONS: These results indicate that promoter profiling can be used to distinguish ALN-positive patients from ALN-negative patients, which may be helpful to guide the choice of cancer treatment.

Impact of pneumococcal conjugate vaccination on hospitalized childhood pneumonia in Taiwan.

BACKGROUND: A national 13-valent pneumococcal conjugate vaccine (PCV13) catch-up program among children aged 2-5 years in 2013, before routine infant immunization in 2015, successfully reduced serotype 19A-related invasive pneumococcal diseases in Taiwan. We aimed to investigate its impact on hospitalized childhood pneumonia. METHODS: We analyzed the National Health Insurance Research Database, 2001-2017, for hospitalized children aged <18 years with the diagnoses of all-cause pneumonia, lobar/pneumococcal pneumonia, and pneumococcal parapneumonic diseases. The study period was divided into 2001-2005 (pre-PCV), 2006-2012 (private sectors), and 2013-2017 (universal PCV13 vaccination). RESULTS: On pneumococcal parapneumonic diseases, the national PCV13 vaccination program was associated with an immediate decline in 2-4-year-old children and significant decreasing trends in all ages. The incidence rate ratios of 2016-2017/2011-2012 were 0.16 (95% confidence interval [CI], 0.06-0.40) and 0.18 (95% CI, 0.13-0.23) in children aged < 2 and 2-4 years, respectively. We observed an increase of lobar/pneumococcal pneumonia cases after an early decline. The intensive/invasive medical needs and the fatality of all-cause pneumonia decreased significantly in children of all ages. CONCLUSIONS: Pneumococcal parapneumonic diseases and the disease burden of lobar/pneumococcal pneumonia and lower respiratory tract infections declined after the national PCV13 vaccination program. IMPACT: The impact study of the PCV13 immunization program on childhood pneumonia in Asian countries remained limited. The unique PCV13 immunization program in Taiwan, catch-up before primary infantile series, reduced severe childhood pneumococcal pneumonia at 5 years post PCV13. The intensive and invasive medical needs and fatality of all-cause pneumonia decreased significantly in children of all ages. We observed an increase in lobar/pneumococcal pneumonia after an early decline.

Children with Mycoplasma pneumoniae infection in Taiwan: Changes in molecular characteristics and clinical outcomes.

BACKGROUND: Mycoplasma pneumoniae is a pathogen that causes respiratory diseases in children. Infections caused by M. pneumoniae are usually self-limited but occasionally can be severe. We observed emerging cases of severe mycoplasma infection requiring extracorporeal membrane oxygenation (ECMO). Thus, we investigated chronological changes in the molecular features of the M. pneumoniae and its clinical impacts among the pediatric population. METHODS: From 2011 to 2019, respiratory samples were collected from patients younger than 18 years old with pneumonia in a tertiary children's hospital. Focused multiple-locus variable number of tandem repeats analysis (MLVA) typing was performed on samples positive for M. pneumoniae in 2016 and 2019. Clinical data from the patients' electronic medical records were collected. We described the annual trend of macrolide resistance and MLVA type and analyzed the associations between clinical manifestations and MLVA types. RESULTS: The percentage of macrolide-resistant (MLR) M. pneumoniae gradually increased from 22% (27/122) in 2015 to 70% (82/117) in 2019. Among the MLRM. pneumoniae, the predominant strain shifted from type P (31% [13/42]) to type A (40% [19/46]). The demographics, initial presentations, and clinical courses of the subjects with MLRM. pneumoniae did not differ significantly between 2011 and 2019. However, in 2019, two fulminant cases requiring venovenous ECMO were observed, which indicates that more attention to the clinical severity of MLRM. pneumoniae infections is warranted. CONCLUSION: Obtaining accurate information on macrolide susceptibility is crucial for physicians to initiate appropriate antibiotic treatment in a timely fashion. Although we could not identify significant differences among mycoplasma pneumonias caused by different MLVAs over a span of 9 years, the emergence of severe mycoplasma infections requiring ECMO was clinically significant, and further monitoring was required.

Comparisons of the clinical and mycological characteristics of pediatric candidemia.

BACKGROUND/PURPOSE: Invasive candidiasis is a severe infectious disease that could lead to mortality in critically ill children. METHODS: We collected data regarding demographics, underlying diseases, predisposing factors, outcomes for pediatric patients with candidemia at a medical centre in Taiwan from 2011 to 2017. RESULTS: Fifty-eight patients with 60 candidemia episodes were diagnosed. The 3 most common species were Candida albicans (42%), Candida parapsilosis (25%) and Candida tropicalis (23%). C. parapsilosis predominantly infected infants and neonates (median age: 0.8 years, range: 0.1-14.5). Cases with C. tropicalis had significantly higher rates of multidrug resistance (p = 0.011) and disseminated candidiasis (p = 0.025) compared with other cases. The all-cause mortality rate was 43%, and the candidemia-related mortality rate was 29%. Pediatric sequential organ failure assessment score >8 [adjusted odds ratio (aOR) 66.2, 95% CI 4.03-1088.5] and posaconazole resistance (aOR 33.57, 95% CI 1.61-700.3) were the most significant risk factors associated with candidemia-related mortality, whereas treatment with effective antifungal agents within 48 h (aOR 0.07, 95% CI 0.01-0.9) was the only significant protective factor. CONCLUSION: Candidemia-related mortality was related to azole resistance; therefore, empirical therapy with echinocandin or amphotericin B is recommended pending species and susceptibility results.

Clinical and epidemiological features in hospitalized young children with acute gastroenteritis in Taiwan: A multicentered surveillance through 2014-2017.

BACKGROUND/PURPOSE: Acute gastroenteritis (AGE) remains a significant health issue in children. The worldwide evolution of pediatric AGE pathogens had been recorded since the introduction of rotavirus vaccine. Ten years after the rotavirus vaccine was introduced to the private sectors in Taiwan, a nationwide study was conducted to elucidate the epidemiological changes among major AGE pathogens. METHODS: From January 2014 to December 2017, children younger than 5 years old, hospitalized with AGE at 10 hospitals across Taiwan were enrolled. Stool specimens were tested for Salmonella spp., Campylobacter spp., Clostridiodes difficile, norovirus, and rotavirus by polymerase chain reaction (PCR). The epidemiological and clinical information was collected. RESULTS: Enteric pathogen were detected in 1983 (42.2%) of 4700 subjects, with Salmonella spp. (12.5%) being the leading cause of AGE, followed by norovirus (11.2%), rotavirus (8.7%), C. difficile (4.2%), Campylobacter spp. (1.0%), and a mixture of at least 2 of 5 above-mentioned pathogens (4.6%). The case distributions varied across different regions. In eastern Taiwan, rotavirus (21/131, 16.0%) remained the most common pathogen detected. The rotavirus vaccine uptake rate is significantly lower in patients with rotavirus AGE. Besides, rotavirus AGE frequently occurred in children with foreign parent(s), Taiwanese indigenous people, and those with the household monthly income < NT$ 60,000. CONCLUSION: Salmonella spp. and norovirus were two major pathogens of pediatric AGE in Taiwan during 2014-17. Providing low-to middle-income households with free rotavirus vaccine nationwide and an industry-led act to reduce salmonellosis should be considered by the authorities.

Clinical characteristics of influenza with or without Streptococcus pneumoniae co-infection in children.

BACKGROUND/PURPOSE: Influenza is frequently complicated with bacterial co-infection. This study aimed to disclose the significance of Streptococcus pneumoniae co-infection in children with influenza. METHODS: We retrospectively reviewed medical records of pediatric patients hospitalized for influenza with or without pneumococcal co-infection at the National Taiwan University Hospital from 2007 to 2019. Clinical characteristics and outcomes were compared between patients with and without S. pneumoniae co-infection. RESULTS: There were 558 children hospitalized for influenza: 494 had influenza alone whereas 64 had S. pneumoniae co-infection. Patients with S. pneumoniae co-infection had older ages, lower SpO2, higher C-Reactive Protein (CRP), lower serum sodium, lower platelet counts, more chest radiograph findings of patch and consolidation on admission, longer hospitalization, more intensive care, longer intensive care unit (ICU) stay, more mechanical ventilation, more inotropes/vasopressors use, more surgical interventions including video-assisted thoracoscopic surgery (VATS) and extracorporeal membrane oxygenation (ECMO), and higher case-fatality rate. CONCLUSION: Compared to influenza alone, patients with S. pneumoniae co-infection had more morbidities and mortalities. Pneumococcal co-infection is considered when influenza patients have lower SpO2, lower platelet counts, higher CRP, lower serum sodium, and more radiographic patches and consolidations on admission.

Clinical characteristics of recurrent pneumonia in children with or without underlying diseases.

BACKGROUND: Recurrent pneumonia is uncommon in children and few studies investigate the clinical impact of underlying diseases on this issue. This study aimed to explore the difference in clinical manifestations, pathogens, and prognosis of recurrent pneumonia in children with or without underlying diseases. METHODS: We conducted a retrospective study of pediatric recurrent pneumonia from 2007 to 2019 in National Taiwan University Hospital. Patients under the age of 18 who had two or more episodes of pneumonia in a year were included, and the minimum interval of two pneumonia episodes was more than one month. Aspiration pneumonia was excluded. Demographic and clinical characteristics of patients were collected and compared. RESULTS: Among 8508 children with pneumonia, 802 (9.4%) of them had recurrent pneumonia. Among these 802 patients, 655 (81.7%) had underlying diseases including neurological disorders (N = 252, 38.5%), allergy (N = 211, 32.2%), and cardiovascular diseases (N = 193, 29.5%). Children without underlying diseases had more viral bronchopneumonia (p < 0.001). Children with underlying diseases were more likely to acquire Staphylococcus aureus (p = 0.001), and gram-negative bacteriae, more pneumonia episodes (3 vs 2, p < 0.001), a longer hospital stay (median: 7 vs. 4 days, p < 0.001), a higher ICU rate (28.8% vs 3.59%, p < 0.001), and a higher case-fatality rate (5.19% vs 0%, p < 0.001) than those without underlying diseases. CONCLUSION: Children with underlying diseases, prone to have recurrent pneumonia and more susceptible to resistant microorganisms, had more severe diseases and poorer clinical outcomes. Therefore, more attention may be paid on clinical severity and the therapeutic plan.

RSV pneumonia with or without bacterial co-infection among healthy children.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of childhood pneumonia, but there is limited understanding of whether bacterial co-infections affect clinical severity. METHODS: We conducted a retrospective cohort study at National Taiwan University Hospital from 2010 to 2019 to compare clinical characteristics and outcomes between RSV with and without bacterial co-infection in children without underlying diseases, including length of hospital stay, intensive care unit (ICU) admission, ventilator use, and death. RESULTS: Among 620 inpatients with RSV pneumonia, the median age was 1.33 months (interquartile range, 0.67-2 years); 239 (38.6%) under 1 year old; 366 (59.0%) males; 201 (32.4%) co-infected with bacteria. The three most common bacteria are Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae. The annually seasonal analysis showed that spring and autumn were peak seasons, and September was the peak month. Compared with single RSV infection, children with bacterial co-infection were younger (p = 0.021), had longer hospital stay (p < 0.001), needed more ICU care (p = 0.02), had higher levels of C-reactive protein (p = 0.009) and more frequent hyponatremia (p = 0.013). Overall, younger age, bacterial co-infection (especially S. aureus), thrombocytosis, and lower hemoglobin level were associated with the risk of requiring ICU care. CONCLUSION: RSV related bacterial co-infections were not uncommon and assoicated with ICU admission, especially for young children, and more attention should be given. For empirical antibacterial treatment, high-dose amoxicillin-clavulanic acid or ampicillin-sulbactam was recommended for non-severe cases; vancomycin and third-generation cephalosporins were suggested for critically ill patients requiring ICU care.

Continental transmission of emerging COVID-19 on the 38° north latitude.

BACKGROUND: As COVID-19 has become a pandemic emerging infectious disease it is important to examine whether there was a spatiotemporal clustering phenomenon in the globe during the rapid spread after the first outbreak reported from southern China. MATERIALS AND METHODS: The open data on the number of COVID-19 cases reported at daily basis form the globe were used to assess the evolution of outbreaks with international air link on the same latitude and also including Taiwan. The dynamic Susceptible-Infected-Recovered model was used to evaluate continental transmission from December 2019 to March 2020 before the declaration of COVID-19 pandemic with basic reproductive number and effective reproductive number before and after containment measurements. RESULTS: For the initial COVID-19 outbreak in China, the estimated reproductive number was reduced from 2.84 during the overwhelming outbreaks in early January to 0.43 after the strict lockdown policy. It is very surprising to find there were three countries (including South Korea, Iran, and Italy) and the Washington state of the USA on the 38° North Latitude involved with large-scale community-acquired outbreaks since the first imported COVID-19 cases from China. The propagation of continental transmission was augmented from hotspot to hotspot with higher reproductive number immediately before the declaration of pandemic. By contrast, there was not any large community-acquired outbreak in Taiwan. CONCLUSION: The propagated spatiotemporal transmission from China to other hotspots may explain the emerging pandemic that can only be exempted by timely border control and preparedness of containment measurements according to Taiwan experience.

Clinical features of tuberculosis and Bacillus Calmette-Guérin (BCG) -associated adverse effects in children: A 12-year study.

PURPOSE: To investigate the clinical feature of tuberculosis and BCG adverse effects in children and to examine whether delayed BCG vaccination changes the incidence of BCG osteomyelitis. METHODS: We analyzed patients younger than 18 years with tuberculosis or BCG-associated adverse effects from 2008 to 2019. We compared their clinical features, laboratory tests and outcomes. RESULTS: Totally 137 patients were collected, with 27% of pulmonary tuberculosis (PTB), 31% of extrapulmonary tuberculosis (EPTB) and 42% of BCG-associated adverse effects. The median age was older in PTB than EPTB group (17.1 vs 15.4 years; p = 0.015). More patients in EPTB group had fever than PTB group (55% vs 25%; p = 0.008). Compared with exclusively EPTB, more patients in EPTB plus PTB group had fever (78% vs 38%; p = 0.009), and had more systemic symptoms (67% vs 25%; p = 0.007), lower absolute lymphocyte count (1230 vs 1850/µL; p = 0.033), higher CRP level (5.62 vs 2.21 mg/dL; p = 0.024) and longer hospital stay (20 vs 11 days; p = 0.031). In BCG osteomyelitis group, the median time interval from vaccination to diagnosis was 16.4 months (IQR 15.0-20.2). Age at vaccination, either at birth or 5-8 month-old, did not affect the proportion of BCG osteomyelitis among children with BCG-associated adverse effects. CONCLUSION: Children with EPTB plus PTB had more fever, lower lymphocyte count and higher CRP. The median time interval from vaccination to diagnosis of BCG osteomyelitis was 16.4 months and the proportion of BCG osteomyelitis among children with BCG-associated adverse effects was not affected by delayed vaccination in this study.

Severe Mycoplasma pneumoniae pneumonia requiring intensive care in children, 2010-2019.

BACKGROUND/PURPOSE: Despite the high prevalence of Mycoplasma pneumoniae infections, reports on severe life-threatening M. pneumoniae pneumonia (MPP) in children are limited. METHODS: We retrospectively enrolled pediatric patients with PCR-positive MPP requiring ICU admission in a children's hospital in Taipei, Taiwan from Jun 2010 to October 2019. Clinical manifestations and laboratory data of severe MPP were analyzed. Macrolide susceptibility was determined by genotyping, and its relationship with clinical manifestations was also analyzed. RESULTS: Approximately 5% (34/658) children hospitalized for MPP required ICU admission. Compared with non-ICU cases (n = 291), ICU cases (n = 34) were associated with more underlying conditions, more pleural effusion, longer fever duration, longer hospital stay, the requirement of second-line antibiotic treatment, and delayed effective and second-line antibiotic treatment. Macrolide resistance was similar in ICU and non-ICU groups (53% vs 53%; p = 0.986). In severe MPP, patients requiring endotracheal intubation were associated with more septic shock, empyema, ARDS, prolonged fever after effective antibiotic treatment, delayed second-line and effective antibiotic treatment. In 18 of the 22 patients with pleural fluid analysis, the pleural effusion was alkaline (pH > 7.7) and lymphocyte-predominant. CONCLUSION: M. pneumoniae infection can cause severe life-threatening pneumonia in children. Delayed effective and second-line antibiotic treatments are associated with severe life-threatening MPP.