A phase I/II study of adoptive SARS-CoV-2-specific T cells in immunocompromised hosts with or at risk of severe COVID-19 infection.

BACKGROUND: Post-transplant or hematological cancer patients have a higher risk of mortality after infection with ancestral and early variants of severe acute respiratory syndrome (SARS)-CoV-2. Adoptive cell therapy (ACT) with virus-specific T cells (VSTs) could augment endogenous T cell immunity to avoid disease deterioration before viral clearance. METHODS: We established a third-party SARS-CoV-2-specific T cell (COVID-T) bank in 2020 (NCT04351659) using convalescent and/or vaccinated donors. In a phase I/II study (NCT04457726), 13 adult and pediatric patients, acutely positive for SARS-CoV-2 and predicted to have a high chance of mortality, were recruited from September 2021 to February 2022. Twelve patients received a single dose of COVID-T cells, matched on at least 1 HLA. RESULTS: A dose of either 75,000 or 150,000 IFN-γ+CD3+ cells/m2 SARS-COV-2-specific T cells did not cause cytokine release syndrome, acute respiratory distress syndrome, or graft-versus-host disease. In the 8 patients who had detectable donor SARS-COV-2-specific T cells after ACT, none progressed to severe disease or died with COVID-19. In contrast, among the other four patients without evidence of donor micro-chimerism, two died of COVID-19. CONCLUSIONS: Long-acting third-party VSTs from convalescent or vaccinated donors could be expediently produced and might be clinically useful in future pandemics, particularly before global vaccination is implemented.

The influence of air quality and meteorological variations on influenza A and B virus infections in a paediatric population in Singapore.

INTRODUCTION: Influenza is an important cause of paediatric illness across the globe. However, information about the relationships between air pollution, meteorological variability and paediatric influenza A and B infections in tropical settings is limited. METHODS: We analysed all daily reports of influenza A and B infections in children <5 years old obtained from the largest specialist women and children's hospital in Singapore. In separate negative binomial regression models, we assessed the dependence of paediatric influenza A and B infections on air quality and meteorological variability, using multivariable fractional polynomial modelling and adjusting for time-varying confounders. RESULTS: Approximately 80% of 7329 laboratory-confirmed reports were caused by influenza A. We observed positive associations between sulphur dioxide (SO2) exposure and the subsequent risk of infection with both influenza types. We observed evidence of a harvesting effect of SO2 on Influenza A but not Influenza B. Ambient temperature was associated with a decline in influenza A reports (Relative Risk at lag 5 [RRlag5]: 0.949, 95% CI: 0.916-0.983). Rainfall was positively associated with a subsequent increase in influenza A reports (RRlag3: 1.044, 95% CI: 1.017-1.071). Nitrogen dioxide (NO2) concentration was positively associated with influenza B reports (RRlag5: 1.015, 95% CI: 1.005-1.025). There was a non-linear association between CO and influenza B reports. Absolute humidity increased the ensuing risk of influenza B (RRlag5: 4.799, 95% CI: 2.277-10.118). Influenza A and B infections displayed dissimilar but predictable within-year seasonal patterns. CONCLUSIONS: We observed different independent associations between air quality and meteorological variability with paediatric influenza A and B infections. Anticipated seasonal infection peaks and variations in air quality and meteorological parameters can inform the timing of community measures aimed at reducing influenza infection risk.

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.

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).

Tropheryma whipplei in Feces of Patients with Diarrhea in 3 Locations on Different Continents.

We examined fecal specimens of patients with diarrhea from 3 continents for Tropheryma whipplei and enteropathogens. T. whipplei was most common in South Africa, followed by Singapore and Germany. Its presence was associated with the presence of other pathogens. An independent causative role in diarrhea appears unlikely.

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.

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.

Elizabethkingia anophelis and Association with Tap Water and Handwashing, Singapore.

We report an Elizabethkingia anophelis case cluster associated with contaminated aerators and tap water in a children's intensive care unit in Singapore in 2017. We demonstrate a likely transmission route for E. anophelis to patients through acquisition of the bacteria on hands of healthcare workers via handwashing.

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.

Pitfalls in evidence assessment: the case of chlorhexidine and alcohol in skin antisepsis.

Chlorhexidine has attracted increasing attention for its role in skin antisepsis in recent years. It was tested in several prominent clinical trials and subsequently recommended in important guidelines for blood culture collection, vascular catheter insertion and surgical skin preparation. We noticed and subsequently reported a widespread misinterpretation of evidence surrounding chlorhexidine and its role in skin antisepsis. Multiple clinical trial reports and systematic reviews that had assessed the clinical efficacy of chlorhexidine/alcohol combinations for skin antisepsis had attributed efficacy solely to the chlorhexidine component. This misinterpretation was carried over into the tertiary literature, including evidence-based guidelines. Here we discuss some of the scientific, ethical, patient safety and infection control implications of this misinterpretation, as well as broader implications for evidence-based medicine.

Frontline Worker Safety in the Age of COVID-19: A Global Perspective.

The third annual Health Watch USA sm webinar conference assembled 16 speakers from 4 continents who shared information regarding frontline worker safety in the age of COVID-19. The U.S. Bureau of Labor Statistics reported a nearly 4000% increase in workplace illness in 2020 compared with 2019. It is estimated that 2% of the U.S. workforce is not working because of long COVID. In addition, the impact is growing with each surge. After the acute illness, patients are often described as recovered, when in fact many have only survived and are coping with the multisystem impacts of long COVID. Long COVID, including its late cognitive, cardiovascular, embolic, and diabetic complications, disproportionately impacts frontline workers, many of whom are of lower socioeconomic status and represented by ethnic minorities. Natural infection and current vaccines do not provide durable protection for reinfection. Herd immunity is not possible at this time. Although SARS-CoV-2 is unlikely to be eliminated, decreasing spread is imperative to slow the rate of mutations, decrease the number of reinfections, and lower the chances of developing long COVID. The primary mode of spread is through aerosolization. Both routine breathing and talking aerosolizes the virus. With the extremely high infectivity of SARS-CoV-2, it is unlikely that central building ventilation alone will be enough to satisfactorily mitigate spread. Additional safe active air cleaning technology, such as upper-room germicidal UV-C lighting, needs to be deployed. Misinformation and disinformation have inhibited response effectiveness. Examples include downplaying the benefit of well-fitted masks and the risks that COVID-19 and long COVID pose to children, along with believing children cannot spread the disease. The engagement of local community leaders is essential to educate the community and drive social change to accept vaccinations and other public health interventions. Vaccinations and natural immunity alone are unlikely to adequately prevent community spread and do not provide durable protection against the risk of long COVID. Frontline workers must keep their immunity as high as possible and work in settings with clean air, along with wearing N95 masks when they are in contact with the public. Finally, there needs to be a financial safety net for frontline workers and their families in the event of incapacitation or death from COVID-19.

Air quality, meteorological variability and pediatric respiratory syncytial virus infections in Singapore.

Respiratory syncytial virus (RSV) is an important cause of respiratory illness among children. While studies have focused on the air-quality and climate dependence of RSV infections, few have been undertaken in South-East Asia where the burden of respiratory illness is among the highest across the globe. This study aimed to determine the relationships between climatic factors and air quality with RSV infections among children in Singapore. We obtained all laboratory-confirmed reports of RSV infections in children below 5 years old from the largest public hospital specializing in pediatric healthcare in Singapore. We assessed the independent cumulative effects of air quality and meteorological factors on RSV infection risk using the Distributed Lag Non-Linear Model (DLNM) framework in negative binomial models adjusted for long-term trend, seasonality and changes in the diagnostic systems. We included 15,715 laboratory-confirmed RSV reports from 2009 to 2019. Daily maximum temperature exhibited a complex, non-linear association with RSV infections. Absolute humidity (Relative Risk, 90th percentile [RR90th percentile]: 1.170, 95% CI: [1.102, 1.242]) was positively associated with RSV risk. Higher levels of particulate matter of aerodynamic diameter of less than (i) 2.5 µm (PM2.5), (ii) 10 µm (PM10), carbon monoxide (CO) and sulfur dioxide (SO2) were associated with lower RSV infection risk. RSV infections exhibited both annual and within-year seasonality. Our findings suggest that falls in ambient temperature and rises in absolute humidity exacerbated pediatric RSV infection risk while increases in air pollutant concentrations were associated with lowered infection risk. These meteorological factors, together with the predictable seasonality of RSV infections, can inform the timing of mitigation measures aimed at reducing transmission.

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.

Climate variability and seasonal patterns of paediatric parainfluenza infections in the tropics: An ecological study in Singapore.

OBJECTIVES: Evidence of the relationship between climate variability, air pollution and human parainfluenza virus (HPIV) infections has been inconsistent. We assessed this in a paediatric population from a highly urbanized tropical city-state. METHODS: We analysed all reports of HPIV infections in children <5 years old obtained from a major specialist women and children's hospital in Singapore. Assuming a negative binomial distribution and using multivariable fractional polynomial modelling, we examined the relations between climate variability, air quality and the risk of HPIV infections, adjusting for time-varying confounders. RESULTS: We identified 6393 laboratory-confirmed HPIV infections from 2009 to 2019. Every 1 °C decline in temperature was associated with a 5.8% increase (RR: 0.943, 95% Confidence Interval [95% CI]: 0.903-0.984) in HPIV infection risk 6 days later. Every 10% decrease in relative humidity was associated with a 15.8% cumulative increase in HPIV risk over the next 6 days (cumulative RR: 0.842, 95% CI: 0.771-0.919). Rainfall was positively associated with HPIV risk 2 days later (RR: 1.021, 95% CI: 1.000-1.043). A within-year seasonal rise of HPIV was driven by HPIV-3 and HPIV-1 and preceded by a seasonal decline in temperature. Gender was an effect modifier of the climate-HPIV relationship. Air quality was not associated with HPIV risk. CONCLUSIONS: This study demonstrates a close association between HPIV infection risk and tropical climate variability. The climate dependence and seasonal predictability of HPIV can inform the timing of community campaigns aimed at reducing infection risk and the development of hospital resources and climate adaption plans.

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.