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.

Paediatric actinomycosis: A 16-year, single-institution retrospective review of cases.

AIM: Actinomycosis is a rare subacute to chronic granulomatous infection which can mimic other infectious or malignant diseases. This study examined the epidemiology and treatment outcome of actinomycosis in children. METHODS: A retrospective study on children admitted for actinomycosis in a tertiary paediatric hospital in Singapore, from January 2004 to December 2020. Clinical profile, therapeutic interventions and outcomes were examined. RESULTS: A total of 10 patients were identified; 7 were female. The median age at first presentation was 9.8 years (range 4.7-15.7). The most common presenting symptom was fever (n = 6, 60%), followed by facial or neck swelling (n = 3, 30%) and ear pain (n = 3, 30%). Actinomycosis occurred predominantly in the orocervicofacial region (n = 6, 60%). Four patients (40%) had preceding dental infections in the form of dental caries or gingivitis. One patient had poorly controlled insulin-dependent diabetes mellitus. Actinomycosis was confirmed via culture in four patients, histopathology in four patients and both methods in two patients. All except one patient (n = 9, 90%) underwent surgical procedures. All patients received ampicillin or amoxicillin/clavulanate or other beta-lactams, for a median duration of 6.5 months (range 1.5-14). Complications included osteomyelitis (n = 4, 40%), mastoiditis (n = 2, 20%), brain abscess (n = 1, 10%) and recurrent neck abscess (n = 1, 10%). There was no mortality and all patients achieved complete resolution. CONCLUSIONS: Paediatric actinomycosis was rare in our 16-year review, but had a high complication rate. It can occur in immunocompetent patients, and dental infection was the predominant risk factor identified. Prognosis was excellent after surgical intervention and appropriate antimicrobial therapy.

Postoperative Rather Than Preoperative Neutropenia Is Associated With Early Catheter-related Bloodstream Infections in Newly Diagnosed Pediatric Cancer Patients.

BACKGROUND: The relationship of early catheter-related bloodstream infections (CRBSIs) with perioperative neutropenia and antibiotic prophylaxis is not well established. We sought to evaluate perioperative factors associated with early CRBSIs in newly diagnosed pediatric cancer patients, particularly hematologic indices and antibiotic use. METHODS: We retrospectively reviewed national registry records of newly diagnosed pediatric cancer patients with port-a-caths inserted using standardized perioperative protocols where only antibiotic use was not regulated. Thirty-day postoperative CRBSI incidence was correlated with preoperative factors using logistic regression and with postoperative blood counts using linear trend analysis. RESULTS: Among 243 patients, 17 CRBSIs (7.0%) occurred at median 14 (range, 8-28) postoperative days. Early CRBSIs were significantly associated with cancer type [acute myeloid leukemia and other leukemias (AML/OLs) vs. solid tumors and lymphomas (STLs): odds ratio (OR), 5.09; P = 0.0036; acute lymphoblastic leukemia vs. STL: OR 0.83; P = 0.0446] but not preoperative antibiotics, absolute neutrophil counts and white blood cell counts. Thirty-day postoperative absolute neutrophil counts and white blood cell trends differed significantly between patients with acute lymphoblastic leukemia and STLs (OR 0.83, P < 0.05) and between AML/OLs and STLs (OR 5.09, P < 0.005), with AML/OL patients having the most protracted neutropenia during this period. CONCLUSIONS: Contrary to common belief, low preoperative absolute neutrophil counts and lack of preoperative antibiotics were not associated with higher early CRBSI rates. Instead, AML/OL patients, particularly those with prolonged neutropenia during the first 30 postoperative days, were at increased risk. Our findings do not support the use of empirical preoperative antibiotics and instead identify prolonged postoperative neutropenia as a major contributing factor for early CRBSI.

Patient, staff empowerment and hand hygiene bundle improved and sustained hand hygiene in hospital wards.

AIM: We piloted a hand hygiene (HH) project in a ward, focusing on World Health Organization moments 1 and 4. Our aim was to design highly reliable interventions to achieve >90% compliance. METHODS: Baseline HH compliance was 57 and 67% for moments 1, 4, respectively, in 2015. After the pilot ward showed sustained improvement, we launched the 'HH bundle' throughout the hospital. This included: (i) appointment of HH champions; (ii) verbal/visual bedside reminders; (iii) patient empowerment; (iv) hand moisturisers; (v) tagging near-empty handrub (HR) bottles. Other hospital-wide initiatives included: (vi) Smartphone application for auditing; (vii) 'Speak up for Patient Safety' Campaign in 2017 for staff empowerment; (viii) making HH a key performance indicator. RESULTS: Overall HH compliance increased from a baseline median of 79.6-92.6% in end-2019. Moments 1 and 4 improved from 71 to 92.7% and from 77.6 to 93.2%, respectively. Combined HR and hand wash consumption increased from a baseline median of 82.6 ml/patient day (PD) to 109.2 mL/PD. Health-care-associated rotavirus infections decreased from a baseline median of 4.5 per 10 000 PDs to 1.5 per 10 000 PDs over time. CONCLUSIONS: The 'HH Bundle' of appointing HH champions, active reminders and feedback, patient education and empowerment, availability of hand moisturisers, tagging near-empty hand rub bottles together with hospital-wide initiatives including financial incentives and the 'Speak Up for Patient Safety' campaign successfully improved the overall HH compliance to >90%. These interventions were highly reliable, sustained over 4 years and also reduced health-care-associated rotavirus infection rates.

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.

Respiratory viral infections in hospitalised paediatric patients in the tropics.

AIM: Respiratory viruses are a huge disease burden globally. An understanding of the seasonal trends and the ability to predict peak periods of respiratory virus disease incidence is useful for clinical care. METHODS: This is a retrospective analysis of paediatric hospitalizations of laboratory-confirmed viral respiratory tract infections in KK Women's and Children's Hospital, Singapore, from 1 January 2011 to 31 December 2016. Standard direct immunofluorescence was used to detect respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza 1, 2 and 3 viruses, metapneumovirus and adenovirus. RESULTS: A total of 97 840 specimens were analysed with a positive detection rate of 23.8%. RSV made up the largest proportion (42% of the total positive results), predominating between May to September. Influenza A had two peaks, June to July and December to January. Type 3 was the most common parainfluenza virus and showed annually recurring peaks. In contrast, parainfluenza 1 and 2, metapneumovirus and adenovirus had a biennial pattern. The test of seasonality detected identifiable seasonality for RSV and parainfluenza 3 virus. CONCLUSIONS: In conclusion, respiratory viruses have different and overlapping seasonality in tropical Singapore. Respiratory virus testing for patients admitted for acute respiratory infection is useful to target antiviral therapies and appropriate infection control practices.

DISSEMINATED BACILLUS-CALMETTE-GUÉRIN INFECTIONS AND PRIMARY IMMUNODEFICIENCY DISORDERS IN SINGAPORE: A SINGLE CENTER 15-YEAR RETROSPECTIVE REVIEW.

BACKGROUND: Disseminated Bacillus Calmette-Guérin (BCG) disease (BCGosis) is a classical feature of children with primary immunodeficiency disorders (PIDs). METHODS: A 15-year retrospective review was conducted in KK Women's and Children's Hospital in Singapore, from January 2003 to October 2017. RESULTS: Ten patients were identified, the majority male (60.0%). The median age at presentation of symptoms of BCG infections was 3.8 (0.8 - 7.4) months. All the patients had likely underlying PIDS - four with Severe Combined Immunodeficiency (SCID), three with Mendelian Susceptibility to Mycobacterial Diseases (MSMD), one with Anhidrotic Ectodermal Dysplasia with Primary Immunodeficiency (EDA-ID), one with combined immunodeficiency (CID), and one with STAT-1 gain-of-function mutation. Definitive BCGosis was confirmed in all patients by the identification of Mycobacterium bovis subsp BCG from microbiological cultures. The susceptibility profiles of Mycobacterium bovis subsp BCG are as follows: Rifampicin (88.9%), Isoniazid (44.47%), Ethambutol (100.0%), Streptomycin (100.0%), Kanamycin (100.0%), Ethionamide (25.0%), and Ofloxacin (100.0%). Four patients (40.0%) received a three-drug regimen. Five patients (50.0%) underwent hematopoietic stem cell transplant (HSCT), of which three (60%) have recovered. Overall mortality was 50.0%. CONCLUSION: Disseminated BCG disease (BCGosis) should prompt immunology evaluation to determine the diagnosis of the immune defect. A three-drug regimen is adequate for treatment if the patient undergoes early HSCT.

Epidemiology of Adenovirus Infections and Outcomes of Cidofovir Treatment in Severely Ill Children.

BACKGROUND: An increase in human adenovirus (HAdV) infections among hospitalized children in Singapore was observed since 2013. Young age (<2 years) and significant comorbidities have been associated with severe HAdV infections which can result in significant morbidity and mortality. Cidofovir (CDV) has been used to treat severe HAdV infections despite limited data and efficacy. METHODS: This is a retrospective, observational review of infants and children 1 month to 17 years of age with laboratory-confirmed severe HAdV infection, admitted to a pediatric tertiary care hospital in Singapore between January 2013 and September 2017. Severe infection was defined as requiring intensive care unit or high dependency care at any point during hospital admission. Clinical characteristics, potential risk factors for mortality, as well as the outcome of cases treated with CDV were examined. RESULTS: A total of 1167 children were admitted for HAdV infection, of which 85 (7.3%) were severe. For severe infections, the median age was 1.5 years (interquartile range: 0.72-3.2 years). The majority had comorbidities (69.4%) and presented with pneumonia (32.9%). Genotypes HAdV-7 (29.4%) and HAdV-3 (27.0%) were the most common HAdV genotypes identified. Thirteen (15.3%) patients died. Patients who died had a higher proportion of existing neurologic comorbidity (46.2% vs. 13.9%; P = 0.014) and presentation with pneumonia (69.2% vs. 26.4%; P = 0.008) compared with survivors. Patients who presented with pneumonia had a higher risk of 30-day mortality (odds ratio 4.3, 95% confidence interval: 1.0-28.6; P < 0.05). CDV was administered to 17 (20%) children for mainly viremia (47.1%) and/or pneumonia (41.2%). Mortality rate was 41.2% for severe HAdV cases treated with CDV. A significant proportion of patients who died when compared with recovered patients presented with pneumonia (6 of 7, 85.7% vs 1 of 10, 10%; P = 0.004). All 8 patients who had viremia received CDV and survived. CONCLUSIONS: Mortality can be high in pediatric patients with severe HAdV infections. HAdV-7 and HAdV-3 were the most common genotypes identified in our cohort with severe HAdV infection. Pneumonia is a potential risk factor for mortality in severe HAdV infections in our cohort. Early CDV administration may be considered in patients with severe HAdV infection and existing comorbidities but more studies are required.

Pediatric Abdominal Tuberculosis in Singapore: A 10-Year Retrospective Series.

Background. Tuberculosis (TB) remains a major cause of mortality and morbidity globally. Pediatric patients are more likely to develop severe disease. Abdominal TB is a rare manifestation of pediatric TB and can present with chronic and nonspecific abdominal symptoms. This study examines the clinical profile of pediatric patients with abdominal TB and treatment outcomes. Method. A retrospective study of patients admitted to a tertiary pediatric hospital in Singapore over 10 years. Clinical characteristics and outcomes were examined. Results. There were 3 male and 3 female patients with mean age of 11.3 years. Household contacts were traced in 3 cases. The most common presenting symptoms were fever, weight loss, and abdominal symptoms such as diarrhea, vomiting, and loss of appetite. Inflammatory markers were raised with mean C-reactive protein (CRP) and erythrocyte sedimentation (ESR) rate at 70.9 mg/L and 90 mm/h respectively. Abdominal imaging showed abnormalities such as splenic foci and thickened bowel wall with significant intraabdominal lymphadenopathy. Mycobacterium tuberculosis was isolated from stool, rectal swabs and intra-adominal specimens. Two patients underwent excisional biopsy of lymph node to obtain diagnosis. Two patients required emergency laparotomy and 1 patient received esophagogastroduodenoscopy and colonoscopy. Four out of the 6 patients had pulmonary involvement. Conclusion. Abdominal TB should be a differential diagnosis in children with chronic abdominal symptoms for at least 8 weeks with anemia, raised ESR and CRP. The gold standard for diagnosis still remains as positive microbiological culture. However, abdominal imaging studies are also vital in obtaining further supportive evidence for chronic infection.

Taurolidine-citrate lock solution for the prevention of central line-associated bloodstream infection in paediatric haematology-oncology and gastrointestinal failure patients with high baseline central-line associated bloodstream infection rates.

AIM: Central line-associated bloodstream infection associated bloodstream infection (CLABSI) is a serious complication of patients on central venous catheters (CVC). Taurolidine-citrate solution (TCS) is a catheter-lock solution with broad-spectrum antimicrobial action. This study's aim was to evaluate the efficacy of TCS in reducing CLABSI rates in paediatric haematology-oncology (H/O) and gastrointestinal (GI) patients with long-term CVC. METHODS: This was an open-label trial of H/O and GI inpatients with the following inclusion criteria: <17 years old, more than or equal to one previous CLABSI and a minimum TCS dwell time of ≥8 h. CLABSI per 1000 catheter-days was calculated from each patient's first CVC insertion till 14 December 2017 or until TCS discontinuation. RESULTS: Thirty-three patients were recruited with a median age of 3.5 years; H/O and GI constituted 60.6 and 39.4% respectively. CVC types were Hickman line (45.5%), implantable port (24.2%) and peripherally inserted central catheter (30.3%). Mean pre- and post-TCS CLABSI rates per 1000 catheter-days were 14.44 and 2.45 (P < 0.001) for all patients; 16.55 and 2.81 for H/O patients; and 11.21 and 1.90 for GI patients, respectively. Pre- and post-TCS rate ratio was 0.20, 0.10 and 0.30 for all, H/O and GI patients, respectively (P < 0.001). TCS also led to a reduction in CVC removal from 66.7 to 9.09% (P < 0.001). CONCLUSIONS: TCS usage was highly successful in CLABSI reduction by 80% in all patients, 90% in H/O and 70% in GI patients. In patients with high baseline CLABSI rates, TCS is an effective catheter-lock therapy to reduce CLABSI rates in paediatric patients.

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.

A rare case of purpuric rash caused by Saprochaete clavata in a pediatric patient with acute leukemia.

We present a 13-year-old boy who developed invasive infection with Saprochaete clavata after induction chemotherapy for B-cell acute lymphoblastic leukemia, complicated by fungemia, septic shock and acute renal, and liver failure. He developed purpuric papulonodules over bilateral upper and lower limbs, which also grew S clavata on fungal culture.

Long-term immunogenicity and safety of tetravalent dengue vaccine (CYD-TDV) in healthy populations in Singapore and Vietnam: 4-year follow-up of randomized, controlled, phase II trials.

Dengue is prevalent in the Asia-Pacific region. Participants of two immunogenicity and safety phase II studies conducted in Singapore and Vietnam (NCT0088089 and NCT00875524, respectively) were followed for up to four years after third vaccine dose of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV). Participants (2-45 years) received three doses of CYD-TDV or control at 0, 6, and 12 months. Dengue plaque reduction neutralization test (PRNT50) antibody titers were measured in both studies. Cytokine-producing antigen-specific CD4+ and CD8+ T-cells were quantified to assess cell-mediated immunity (CMI) in Singapore. Post-hoc analyses were carried out for participants aged <9 and ≥9 years old. Related and fatal serious adverse events (SAEs) were collected during long-term follow-up. Of participants who received ≥1 CYD-TDV injection in Singapore (n = 1198) and Vietnam (n = 180), 87% and 92% participants completed long-term follow-up, respectively. At four years, geometric mean titers (GMTs) in participants who received CYD-TDV ranged from 30.2 1/dil (95% CI 23.9-38.3) to 73.7 (49.3-110) 1/dil in Vietnam and 9.73 1/dil (95% CI 8.28-11.4) to 21.8 (18.9-25.1) 1/dil in Singapore. Interferon and interleukin-13 levels were lower at four years than one year post-vaccination but were still present. Tumor necrosis factor-α levels at four years were similar to those after the third vaccine dose. Seropositivity rates were higher at year four in participants who were seropositive vs. seronegative at baseline in both studies. No safety concerns were identified. CYD-TDV demonstrated long-term immunogenicity and was well-tolerated for four years after the third vaccine dose.

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.

Risk Factors for Severe Adenovirus Infection in Children during an Outbreak in Singapore.

BACKGROUND: Human adenoviruses (HAdVs) can cause a variety of human illnesses, with associated temporal and geographic changes in disease incidence. We report the emergence of an outbreak of HAdV infections in Singapore, presumably caused by a change of the predominating type to HAdV-7. We examined the clinical features of children admitted with HAdV infection to 1 institution and the risk factors for severe infection. MATERIALS AND METHODS: This is a retrospective case-control study of all HAdV-infected children admitted during weeks 1 to 19 in 2013, as identified from laboratory records. A descriptive retrospective analysis of epidemiology, clinical data and the outcome of these children was also performed. Patients with severe infections were defined as cases, those with non-severe infections as controls, and the 2 groups were compared to find possible independent risk factors. RESULTS: Eighty-five patients with HAdV infection were studied, including 11 (12.9%) cases and 74 (87.1%) controls. Binary logistic regression showed that cases were more likely to be <2 years old (adjusted OR 10.6, 95% CI, 1.8 to 63.2) and to have significant comorbidities (adjusted OR 19.9, 95% CI, 3.4 to 116.1) compared to controls. The predominant type in 2013 was HAdV-7, which differed from 2011 and 2012, when HAdV-3 was more common. There was a trend towards pneumonia being more common in patients infected with HAdV-7 than in patients infected with other types, although this did not reach statistical significance (OR 2.8, 95% CI, 0.9 to 8.7). CONCLUSION: The emergence of HAdV-7 in a population where other HAdV types had circulated previously may have caused the outbreak in Singapore, and this was associated with more serious infections in children. Young age (<2 years) and significant comorbidities were associated with more severe HAdV infection.

Granulomatous cervicofacial lymphadenitis in children: a nine-year study in Singapore.

INTRODUCTION: Granulomatous cervicofacial lymphadenitis (GCL) is not uncommon in children. Nontuberculous mycobacteria (NTM) seem to be the predominant cause. We sought to study the clinical and microbiological profile of patients with GCL, and identify features that may impact outcome. METHODS: Children aged < 16 years who presented to KK Women's and Children's Hospital, Singapore, between January 1998 and December 2006, and who had GCL were identified from laboratory records. Clinical and laboratory data was collected and analysed for risk factors for patients with positive lymph node cultures, and for patients with and without recurrence after treatment. RESULTS: In all, 60 children were identified, with a median age of 56 (interquartile range [IQR] 34-101) months. Median duration of symptoms before presentation was 5 (IQR 4-8) weeks. The majority presented with single (73.3%) or unilateral (96.7%) lymphadenopathy, located in the submandibular, preauricular/parotid or infra-/post-auricular region (76.7%). Out of 51 patients, 26 (51.0%) had a tuberculin skin test reading of ≥ 10 mm. Out of 52 patients, 10 (19.2%) had positive mycobacterial cultures, which included seven isolates of NTM. Out of 34 cases, tuberculous polymerase chain reaction was positive in 11 (32.4%). With regard to recurrence after initial treatment, age < 5 years at presentation was found to be a predictor for recurrence (p = 0.008), while initial complete excision of affected nodes predicted no recurrence (p = 0.003). CONCLUSION: In our study, younger age was noted to be associated with a higher chance of recurrence, while complete excision of the involved node at initial presentation predicted non-recurrence.

Skin manifestation of Stenotrophomonas maltophilia infection--a case report and review article.

INTRODUCTION: Stenotrophomonas maltophilia is an aerobic gram-negative bacillus that is a frequent coloniser of fluids used in the hospital setting. It causes infection in immunosuppressed hosts, especially those who are neutropaenic, on chemotherapy and broad spectrum antibiotics. Skin and soft tissue manifestations of Stenotrophomonas maltophilia infection are becoming an increasingly recognised entity; the clinical spectrum ranges from mucocutaneous, skin to soft tissue infections. MATERIALS AND METHODS: We present a case of an 8-year-old girl with acute myeloid leukaemia who developed metastatic skin lesions secondary to Stenotrophomonas maltophilia bacteraemia. The authors reviewed a total of 24 reported cases of mucocutaneous, skin and soft tissue infections by Stenotrophomonas maltophilia. The presentations include metastatic cellulitis, primary cellulitis and infected mucocutaneous ulcers. RESULTS: This is the first locally reported case of metastatic nodular skin lesions caused by Stenotrophomonas maltophilia bacteraemia. This is also the first reported paediatric case of embolic skin lesions caused by Stenotrophomonas maltophilia. Of the 6 cases of Stenotrophomonas maltophilia bacteraemia seen in the paediatric oncology patients from year 2000 to 2004 at our hospital, only 1 case developed metastatic skin lesions. CONCLUSION: Stenotrophomonas maltophilia skin infection should be included into the list of differential diagnoses for metastatic skin lesions in neutropaenic patients, especially with an underlying haematologic malignancy who has received recent chemotherapy and broad spectrum antibiotics. Haematologic malignancy, transplantation, neutropaenic, immunosuppressive therapy and a high severity of illness score were important prognostic factors.