Potential relevance of salivary legumain for the clinical diagnostic of hand, foot, and mouth disease.

The fight against hand, foot, and mouth disease (HFMD) remains an arduous challenge without existing point-of-care (POC) diagnostic platforms for accurate diagnosis and prompt case quarantine. Hence, the purpose of this salivary biomarker discovery study is to set the fundamentals for the realization of POC diagnostics for HFMD. Whole salivary proteome profiling was performed on the saliva obtained from children with HFMD and healthy children, using a reductive dimethylation chemical labeling method coupled with high-resolution mass spectrometry-based quantitative proteomics technology. We identified 19 upregulated (fold change = 1.5-5.8) and 51 downregulated proteins (fold change = 0.1-0.6) in the saliva samples of HFMD patients in comparison to that of healthy volunteers. Four upregulated protein candidates were selected for dot blot-based validation assay, based on novelty as biomarkers and exclusions in oral diseases and cancers. Salivary legumain was validated in the Singapore (n = 43 healthy, 28 HFMD cases) and Taiwan (n = 60 healthy, 47 HFMD cases) cohorts with an area under the receiver operating characteristic curve of 0.7583 and 0.8028, respectively. This study demonstrates the feasibility of a broad-spectrum HFMD POC diagnostic test based on legumain, a virus-specific host systemic signature, in saliva.

Clinical profile of children with parechovirus meningitis in Singapore.

Human parechovirus (HPeV) is one of the most common causes of aseptic meningitis in children worldwide. This study aims to review the epidemiology, clinical presentation, and cerebrospinal fluid (CSF) findings in HPeV meningitis and compare these with Enterovirus (EV) meningitis. This is a retrospective study of children aged ≤ 1 year admitted for HPeV meningitis between November 2015 and July 2017, with positive CSF HPeV PCR and negative blood and CSF bacterial cultures. The clinical findings were compared with a historical cohort of children with EV meningitis admitted between July 2008 and July 2011. There were 71 children with HPeV meningitis, aged between 2 and 127 days, with the majority (96%) being ≤ 90 days old. The most common symptoms reported were poor feeding (42%), tachycardia out of proportion to fever (27%), and lethargy (20%). Only 2 patients (3%) had CSF pleocytosis. Cerebral spinal fluid white blood cell counts ranged from 0 to 28 cells/mm3, with a median of 3 cells/mm3 [interquartile range (IQR) 1-6 cells/mm3]. When compared to our historical cohort of EV meningitis ≤ 90 days old, children with HPeV meningitis ≤ 90 days old were less likely to have CSF pleocytosis (OR 0.008, 95% CI 0.001-0.057). HPeV and EV meningitis are known to cause sepsis-like illness in infants < 90 days old. This study further supports this, with the requirement for fluid bolus therapy for tachycardia or poor perfusion noted to be higher in children with HPeV meningitis ≤ 90 days old (OR 6.3, 95% CI 2.7-14.2).

Novel Coronavirus 2019 Transmission Risk in Educational Settings.

Transmission risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in schools is unknown. Our investigations, especially in preschools, could not detect SARS-CoV-2 transmission despite screening of symptomatic and asymptomatic children. The data suggest that children are not the primary drivers of SARS-CoV-2 transmission in schools and could help inform exit strategies for lifting of lockdowns.

Serotype distribution and incidence of invasive early onset and late onset group B streptococcal disease amongst infants in Singapore.

BACKGROUND: The current group B streptococcal (GBS) preventive measures had reduced invasive GBS early onset disease (EOD) incidences worldwide, but the late onset disease (LOD) incidences had remained unchanged. Administration of a safe and effective GBS vaccine in addition to the current strategies were thought to be the next steps in reducing the incidences of invasive GBS infection especially LOD. In this study, we aimed to examine the causative GBS serotypes in invasive GBS disease, determine the incidences of EOD and LOD, and compare the risk factors between EOD and LOD. METHODS: A retrospective study of infants ≤ 90-day-old over an 8-year period (2010-2017). The incidences of EOD and LOD were obtained by using patients with EOD and LOD who were born in our institution as the numerator and the live births in our institution per year of the study period as the denominator. Available GBS isolates were serotyped by the National Public Health Laboratory using capsular serotyping methods. The risk factors of EOD and LOD were compared. RESULTS: A total of 71 infants were identified; 16 (22.5%) and 55 (77.5%) of them had EOD and LOD, respectively. Serotype III (n = 42, 71.2%) was the most common serotype amongst the 59 isolates available for serotyping. Serotypes Ia, Ib, II, III, and V accounted for 98.3% (n = 58) of the invasive GBS diseases. The overall incidence was 0.42 per 1000 live births. The mean incidences of EOD and LOD were 0.13 per 1000 live births and 0.29 per 1000 live births, respectively. On multivariate analysis, risk factors for LOD as compared to EOD were: Chinese ethnicity (OR 27.1, 95% CI 3.0-243.1, p = 0.003) and negative/unknown maternal GBS status (OR 20.0, 95% CI 2.0-250.0, p = 0.012). Prematurity and intrapartum risk factors (peripartum maternal pyrexia, prolonged rupture of membrane) of EOD were not associated with LOD. CONCLUSIONS: The LOD incidence had remained higher than EOD incidence in our cohort. A GBS vaccine that covers the major causative serotypes found in our cohort can potentially reduce the overall GBS disease burden in the country.

Osteomyelitis in Immunocompromised children and neonates, a case series.

BACKGROUND: Osteomyelitis in immunocompromised children can present differently from immunocompetent children and can cause devastating sequelae if treated inadequately. We aim to review the aetiology, clinical profile, treatment and outcomes of immunocompromised children with osteomyelitis. METHODS: Retrospective review of all immunocompromised children aged < 16 years and neonates admitted with osteomyelitis in our hospital between January 2000 and January 2017, and referred to the Paediatric Infectious Disease Service. RESULTS: Fourteen patients were identified. There were 10 boys (71%), and the median age at admission was 70.5 months (inter-quartile range: 12.3-135.0 months). Causal organisms included, two were Staphylococcus aureus, two were Mycobacterium bovis (BCG), and one each was Mycobacterium tuberculosis, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia pseudomallei and Rhizopus sp. One patient had both Clostridium tertium and Clostridium difficile isolated. Treatment involved appropriate antimicrobials for a duration ranging from 6 weeks to 1 year, and surgery in 11 patients (79%). Wherever possible, the patients received treatment for their underlying immunodeficiency. For outcomes, only three patients (21%) recovered completely. Five patients (36%) had poor bone growth, one patient had recurrent discharge from the bone and one patient had palliative care for underlying osteosarcoma. CONCLUSIONS: Although uncommon, osteomyelitis in immunocompromised children and neonates can be caused by unusual pathogens, and can occur with devastating effects. Treatment involves prolonged administration of antibiotics and surgery. Immune recovery also seems to be an important factor in bone healing.

A Well Infant With Coronavirus Disease 2019 With High Viral Load.

A well 6-month-old infant with coronavirus disease 2019 (COVID-19) had persistently positive nasopharyngeal swabs up to day 16 of admission. This case highlights the difficulties in establishing the true incidence of COVID-19, as asymptomatic individuals can excrete the virus. These patients may play important roles in human-to-human transmission in the community.

Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 from Adults to Children.

Knowledge of transmission dynamics of severe acute respiratory syndrome coronavirus 2 from adults to children in household settings is limited. We found an attack rate among 213 children in 137 households to be 6.1% in households with confirmed adult 2019 novel coronavirus disease index case(s). Transmission from adult to child occurred in only 5.2% of households. Young children <5 years old were at lowest risk of infection (1.3%). Children were most likely to be infected if the household index case was the mother.

Kikuchi-Fujimoto disease in children.

AIM: Kikuchi-Fujimoto disease (KFD) is an important cause of lymphadenitis in children. The primary aim of this study was to investigate the clinical characteristics of children with KFD and to assess the recurrence of this disease. METHODS: This is a retrospective study of patients younger than 18 years old, who were diagnosed with KFD from January 2000 to September 2017 at KK Women's and Children's Hospital. Records of children with a histological diagnosis of KFD from a lymph node biopsy were obtained from the Department of Pathology. Case notes and electronic medical records of the patients were reviewed. Data collected included patient characteristics, symptoms, clinical and laboratory findings, treatment and follow-up. RESULTS: A total of 98 patients were identified. There were 52 boys and 46 girls with a median age of 11.2 years old. Recurrence occurred in 12 (12.2%) patients. One patient developed systemic lupus erythematosus 10 years after diagnosis of KFD. Recurrent cases were more likely to be managed as an inpatient and have fever at presentation of their first episode of KFD. CONCLUSION: In our study, KFD in children had a higher prevalence among boys, and had a recurrence rate of 12.2%, with 1% of patients developing systemic lupus erythematosus. We recommend that patients be followed up for recurrence and advised to monitor for symptoms of recurrence.

Impact of a Carbapenem Antimicrobial Stewardship Program on Patient Outcomes.

Antimicrobial stewardship programs (ASPs) aim to improve appropriate antimicrobial use. However, concerns of the negative consequences from accepting ASP interventions exist, particularly when deescalation or discontinuation of broad-spectrum antibiotics is recommended. Hence, we sought to evaluate the impact on clinical outcomes when ASP interventions for inappropriate carbapenem use were accepted or rejected by primary providers. We retrospectively reviewed all carbapenem prescriptions deemed inappropriate according to institutional guidelines with ASP interventions between July 2011 and December 2014. Intervention acceptance and outcomes, including carbapenem utilization, length of stay, hospitalization charges, 30-day readmission, and mortality rates were reviewed. Data were analyzed in two groups, one in which physicians accepted all interventions ("accepted") and one in which interventions were rejected ("rejected"). A total of 158 ASP interventions were made. These included carbapenem discontinuation (35%), change to narrower-spectrum antibiotic (32%), dose optimization (17%), further investigations (including imaging and procalcitonin) (11%), infectious diseases referral (3%), antibiotic discontinuation (other than carbapenem) (1%), and source control (1%). Of 220 unique patients, carbapenem use was inappropriate in 101 (45.9%) patients. A significant reduction in carbapenem utilization was observed in the accepted group versus rejected group (median defined daily doses, 0.224 versus 0.668 per 1,000 patient-days, respectively; P < 0.001). There was a significant reduction in 30-day mortality in the accepted (none) versus rejected group (10 deaths, P = 0.015), but there were no differences in length of stay, hospitalization charge, or 30-day readmission rates. Hypotension was independently associated with mortality in multivariate analysis (odds ratio, 5.25; 95% confidence interval, 1.34 to 20.6). In our institution, acceptance of carbapenem ASP interventions did not compromise patient safety in terms of clinical outcomes while reducing consumption.

Cerebrospinal fluid white cell count: discriminatory or otherwise for enteroviral meningitis in infants and young children?

Non-polio enteroviruses (EV) are the most common viruses causing aseptic meningitis in children. We aim to evaluate the cerebrospinal fluid (CSF) characteristics of neonates and children with EV meningitis with a view to determine whether it could be discriminatory or otherwise in making a positive diagnosis. We performed a 3-year (July 2008-July 2011) retrospective study of children ≤16 years, treated at a tertiary children's hospital, with positive CSF EV polymerase chain reaction (PCR) and negative blood and CSF bacterial cultures. A total of 206 children were studied. The median CSF white cell count was 79 cells/mm(3) (range 0-4608 cells/mm(3)). CSF pleocytosis was observed in 99/150 (66%) aged ≤90 days, 3/4 (75%) aged 90 days-1 year, and 49/52 (94%) children ≥3 years. There was a huge variability in CSF pleocytosis in infants ≤90 days, where 34% of them had no pleocytosis, while in 66%, a wide range of pleocytosis that might even suggest bacterial meningitis was noted. CSF red cells were low, and protein or sugar values were not discriminatory. CSF pleocytosis in relation to increasing age was found to be statistically significant (p < 0.001). Early lumbar puncture within 48 h of symptoms and absence of CSF pleocytosis was also statistically significant (p = 0.039). CSF pleocytosis in EV meningitis is commoner in older children. As there was a huge variability in CSF pleocytosis in infants ≤90 days particularly, CSF analysis including EV PCR could avoid unnecessary antibiotic therapy.

A 15-year retrospective analysis of prognostic factors in childhood bacterial meningitis.

AIM: This retrospective chart review aimed to identify factors in childhood bacterial meningitis that predicted disease severity and long-term outcome. METHODS: The study included 112 episodes of microbiologically confirmed bacterial meningitis in children aged three days to 15 years who were admitted to a Singapore hospital from 1998 to 2013. RESULTS: The mortality rate was 6%, and 44% required intensive care unit (ICU) admission. Predictive factors associated with ICU admission included pneumococcal meningitis, with an odds ratio (OR) of 5.2 and 95% confidence interval (CI) of 1.5-18.2, leukopenia (OR 5.6, 95% CI 1.7-17.9) and a cerebrospinal fluid (CSF):serum glucose ratio <0.25 (OR 4.5, 95% CI 1.4-14.4). An initial CSF white blood cell count >1000/mm(3) (OR 0.26, 95% CI 0.086-0.76) was negatively associated with ICU admission. Five years after meningitis, 32% had residual sequelae, and the associated prognostic factors were Haemophilus influenzae type b (Hib) meningitis (OR 29.5, 95% CI 2-429), seizures during their inpatient stay (OR 10.6, 95% CI 1.9-60.2) and septic shock (OR 8.4, 95% CI 1.1-62.1). CONCLUSION: As mortality was low in this bacterial meningitis study, ICU admission was used as a marker of disease severity. These findings underscore the importance of the pneumococcal and Hib meningitis vaccines.

Severe Pediatric Adenovirus 7 Disease in Singapore Linked to Recent Outbreaks across Asia.

During November 2012-July 2013, a marked increase of adenovirus type 7 (Ad7) infections associated with severe disease was documented among pediatric patients in Singapore. Phylogenetic analysis revealed close genetic links with severe Ad7 outbreaks in China, Taiwan, and other parts of Asia.

SARS-CoV-2 antigen rapid tests and universal screening for COVID-19 Omicron variant among hospitalized children.

BACKGROUND: Clinical utility of universal antigen rapid test (ART) in the pediatric setting is unknown. We aimed to assess the performance and utility of universal ART in hospitalized children (≥5-year-old) to prevent nosocomial COVID-19 transmission. METHODS: Cross-sectional study involving all hospitalized pediatric patients aged ≥5-year-old from 2 periods during Omicron wave. Clinical data, ART and polymerase chain reaction test results were collected. RESULTS: A total of 444 patients were included from the 2 study periods, and 416 patients (93.7%) had concordant results between ART and polymerase chain reaction. The overall sensitivity and specificity of ART were 83.3% (95% CI: 75.2-89.3) and 97.5% (95% CI: 95.0-98.8), respectively. Negative predictive values of ART between the Omicron emergence and Omicron peak periods for a probable case group were 71.4% and 66.7%, respectively, and for a suspect case group 91.4% and 75.0%, respectively. Negative predictive values for an unlikely case group was >95% in both periods. Positive predictive value of ART was >85% for probable and suspect case groups in both periods. Seventy-five percent of patients (n = 15) who were incorrectly classified as SARS-CoV-2 negative by ART had potentially viable virus. No large nosocomial transmission clusters were detected. CONCLUSIONS: Universal ART screening may limit nosocomial outbreaks in hospitalized children. The performance can be optimized by considering clinical symptoms, exposure and periods within COVID waves.

Remdesivir therapy for severe pediatric COVID-19 in Singapore: A single-center retrospective observational cohort study.

Background and Aims: There is a paucity of information on remdesivir (RDV) use in severe pediatric coronavirus disease 2019 (COVID-19). We aimed to explore the effectiveness of RDV as the cumulative proportion of pediatric COVID-19 patients deescalated from Day 5 of high dependency or intensive care unit (HD/ICU). Methods: All children ≤18 years admitted to Singapore's largest pediatric hospital from January 1, 2020 to March 18, 2022 were reviewed retrospectively. Patients were included if they were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on reverse transcriptase polymerase chain reaction, required oxygen, and HD/ICU care. The characteristics and outcomes of those who received RDV or not (no-RDV) were compared. Results: We reviewed 15 children with a median age of 2.5 years (interquartile range [IQR]: 0.8-11.0), of which 7 (46.7%) received RDV. There was no difference in cumulative proportion of children deescalated from Day 5 of HD/ICU care in the RDV versus the no-RDV group (5/7, 70% vs. 7/8, 87.5%, p = 0.57). The RDV versus no-RDV group had higher disease severity, that is, WHO Ordinal Scale scores (median 6, IQR: 5-7 vs. 5, IQR: 4-5, p = 0.03), higher procalcitonin levels (ug/L) (median 4.31, IQR: 0.8-24.2 vs. 0.12, IQR: 0.09-0.26, p = 0.02), and longer HD/ICU care days (median 5, IQR: 4-9, vs. 1, IQR: 1-4, p = 0.01). There was no significant difference in hospitalization days. There were no adverse events directly attributable to RDV. None died from COVID-19 infection. Conclusion: Our observational analysis was unable to detect any clear benefit of RDV in terms of reducing duration in HD/ICU. RDV was well-tolerated in children with severe COVID-19.

Pediatric COVID-19 Risk Factors in Southeast Asia-Singapore and Malaysia: A Test-Negative Case-Control Study.

There is a scarcity of population-level data of pediatric COVID-19 infection from Southeast Asia. This study aims to describe and compare epidemiological, clinical, laboratory and outcome data among pediatric COVID-19 cases versus controls in two neighboring countries, Singapore and Malaysia. We used a test-negative case-control study design recruiting all suspected COVID-19 cases (defined by either clinical or epidemiological criteria) from January 2020 to March 2021 admitted to two main pediatric centers in Singapore and Malaysia. Data were collected using a standardized registry (Pediatric Acute and Critical Care COVID-19 Registry of Asia). The primary outcome was laboratory-confirmed COVID-19. Univariate and multivariable logistic regression analysis was used to determine factors associated with COVID-19. This study included 923 children with median age of 4 (interquartile range 2-9) years. Of these, 35.3% were COVID-19 cases. Children with COVID-19 were more likely to be asymptomatic compared with controls (49.4 versus 18.6%; P < 0.0001). They were also less likely to develop respiratory complications, such as bronchitis or pneumonia, or organ dysfunction. Four (1.2%) of our COVID-19 patients required respiratory support compared with 14.2% of controls needing respiratory support. COVID-19 cases tended to have lower neutrophil count but higher hemoglobin compared with controls. There were no reported deaths of COVID-19 infection; in contrast, 0.7% of the control group died. In the multivariable analysis, older age, travel history, and close contact with an infected household member were associated with COVID-19 infection. This study shows that the majority of pediatric COVID-19 cases were of lesser severity compared with other community acquired respiratory infections.

Effectiveness of maternal pertussis vaccination in Singapore: A test-negative case-control study.

Pertussis vaccination (Tdap -Tetanus-diphtheria-acellular pertussis) for pregnant women has been recommended since November 2017 in Singapore. In this prospective test-negative case-control study from 2018 to 2019, we aimed to evaluate vaccine effectiveness (VE) against pertussis infection and pertussis-related intensive care unit (ICU) admission according to Tdap (Tetanus-diphtheria-acellular pertussis) during pregnancy and/or infant pertussis vaccination. A total of 58 children (26 cases, 32 controls) were recruited with 4 ICU admissions. The median age was 3 months (interquartile range [IQR] 1.50-4.56 months). Overall, 25.9 % of mothers had received antenatal Tdap vaccination and 43.1 % of infants received pertussis vaccination, majority only 1 dose. Tdap in pregnancy alone without infant vaccine or with 0-1 infant dose had a VE of 97.62 % (95 % confidence interval [CI] 53.25-99.88 %), 98.17 % (95 %CI 66.61-99.9 %) respectively, against pertussis infection and 71.9 % (95 %CI 0.0-98.64), 75.86 % (95 % CI 0.0-98.78) respectively, against ICU admissions. Conclusion: Maternal Tdap vaccination was highly protective against infant pertussis and should be routinely recommended for all pregnant women.