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The validity of test-negative design for assessment of typhoid conjugate vaccine protection: comparison of estimates by different study designs using data from a cluster-randomised controlled trial.
BACKGROUND: Typhoid fever remains a substantial public health challenge in low-income and middle-income countries. By 2023, typhoid conjugate vaccines (TCVs) had been introduced in six countries globally, with more than 50 million doses distributed. Now that TCVs are being deployed, there is a need for observational studies to assess vaccine effectiveness in the field. We aimed to evaluate the validity of different observational study designs in estimating vaccine protection. METHODS: We compared different observational and experimental study designs for assessing vaccine effectiveness by re-analysing data from the TyVAC Bangladesh trial, a participant-blinded and observer-blinded cluster-randomised controlled trial done in Mirpur, Dhaka, Bangladesh. 150 geographical clusters were randomly assigned (1:1) to receive either TCV or Japanese encephalitis vaccine. Eligible children aged 9 months to 15 years were offered a single dose of the vaccine randomly assigned to their cluster of residence, and baseline vaccination was done between April 15 and May 15, 2018. We compared estimates of vaccine effectiveness from the cluster-randomised controlled trial analysis-which assessed the risk of blood-culture-confirmed typhoid fever among recipients of TCV versus recipients of Japanese encephalitis vaccine-with estimates from cohort study and test-negative case-control study design (TND) analyses, which compared recipients of TCV with non-vaccinees in the 75 geographical clusters where TCV was administered. We further conducted negative-control exposure (NCE) and negative-control outcome (NCO) analyses as bias indicators. FINDINGS: 41 344 (67%) of 62 025 age-eligible children in the study area received the TCV or Japanese encephalitis vaccine during the baseline vaccination campaign. Among the 62 025 age-eligible children, 5582 blood-culture specimens were collected by passive surveillance, including 2546 (46%) specimens from the 75 TCV clusters. The estimated vaccine efficacy was 89% (95% CI 81-93) in the cluster-randomised controlled trial analysis, 79% (70-86) by the cohort design, 88% (79-93) by the TND when pan-negatives were used as test-negative controls, and 90% (75-96) by the TND when specimens positive for pathogens other than Salmonella enterica serotype Typhi were used as test-negative controls. Using NCE analysis, Japanese encephalitis vaccination was associated with an increased risk of typhoid fever compared with non-vaccinees in the 75 Japanese encephalitis clusters in the cohort design (incidence rate ratio 1·98 [95% CI 1·56-2·52]), but no significant association between Japanese encephalitis vaccination and typhoid fever was found with the TND. Similarly, an increased risk of non-typhoid infections was observed in the cohort NCO analyses when comparing vaccinees with non-vaccinees in both Japanese encephalitis vaccine clusters and TCV clusters, but not in the TND NCO analyses. INTERPRETATION: Our findings suggests that the TND provides reliable estimates of TCV effectiveness, whereas the cohort design can bias vaccine effectiveness estimates, possibly due to unmeasured confounding effects, such as health-care-seeking behaviours. NCE and NCO approaches are useful tools for identifying such biases. FUNDING: The Bill & Melinda Gates Foundation.
Autoimmunity in inflammatory bowel disease: a holobiont perspective
Adaptive immunity towards self-antigens (autoimmunity) and intestinal commensal microbiota is a key feature of inflammatory bowel disease (IBD). Considering mucosal adaptive immunity from a holobiont perspective, where the host and its microbiome form a single physiological unit, emphasises the challenge of avoiding damaging responses to self-antigen and symbiotic microbial communities in the gut while protecting against potential pathogens. Intestinal tolerance mechanisms prevent maladaptive T and B cell responses to microbial, environmental, and self-antigens, which drive inflammation. We discuss the spectrum of antimicrobial and autoantibody responses and highlight mechanisms by which common IBD-associated adaptive immune responses contribute to disease.
Risk analysis for outpatient experimental infection as a pathway for affordable RSV vaccine development
Controlled human infection models (CHIMs) are an important tool for accelerating clinical development of vaccines. CHIM costs are driven by quarantine facilities but may be reduced by performing CHIM in the outpatient setting. Furthermore, outpatient CHIMs offer benefits beyond costs, such as a participant-friendly approach and increased real-world aspect. We analyze safety, logistic and ethical risks of respiratory syncytial virus (RSV) CHIM in the outpatient setting. A review of the literature identified outpatient CHIMs involving respiratory pathogens. RSV transmission risk was assessed using data from our inpatient and outpatient RSV CHIMs (EudraCT 020-004137-21). Fifty-nine outpatient CHIMs using RSV, Streptococcus pneumoniae, rhinovirus, and an ongoing Bordetella Pertussis outpatient CHIM were included. One transmission event was recorded. In an inpatient RSV CHIM, standard droplet and isolation measures were sufficient to limit RSV transmission and no symptomatic third-party transmission was measured in the first outpatient RSV CHIM. Logistic and ethical advantages support outpatient CHIM adoption. We propose a framework for outpatient RSV CHIM with risk mitigation strategies to enhance affordable vaccine development.
Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study.
SARS-CoV-2 is associated with new-onset neurological and psychiatric conditions. Detailed clinical data, including factors associated with recovery, are lacking, hampering prediction modelling and targeted therapeutic interventions. In a UK-wide cross-sectional surveillance study of adult hospitalized patients during the first COVID-19 wave, with multi-professional input from general and sub-specialty neurologists, psychiatrists, stroke physicians, and intensivists, we captured detailed data on demographics, risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions were used, with cross-specialty independent adjudication for discrepant cases. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome. A total of 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by other central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy (n = 13) not meeting delirium criteria; and peripheral nerve disorders (41, 15%). Those with the severe encephalopathy, in comparison to delirium, were younger, had higher rates of admission to intensive care and a longer duration of ventilation. Compared to normative data during the equivalent time period prior to the pandemic, cases of stroke in association with COVID-19 were younger and had a greater number of conventional, modifiable cerebrovascular risk factors. Twenty-seven per cent of strokes occurred in patients <60 years. Relative to those >60 years old, the younger stroke patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and systemic thrombotic events. Clinical outcomes varied between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of older age and a higher pre-COVID-19 frailty score, and a high admission white cell count, which were independently associated with a poor outcome. In summary, this study describes the spectrum of neurological and psychiatric conditions associated with COVID-19. In addition, we identify a severe COVID-19 encephalopathy atypical for delirium, and a phenotype of COVID-19 associated stroke in younger adults with a tendency for multiple infarcts and systemic thromboses. These clinical data will be useful to inform mechanistic studies and stratification of patients in clinical trials.
Aetiology and outcome of non-traumatic coma in African children: protocol for a systematic review and meta-analysis.
BACKGROUND: Non-traumatic coma is a common acute childhood presentation to healthcare facilities in Africa and is associated with high morbidity and mortality. Historically, the majority of cases were attributed to cerebral malaria (CM). With the recent drastic reduction in malaria incidence, non-malarial coma is becoming a larger proportion of cases and determining the aetiology is diagnostically challenging, particularly in resource-limited settings. The purpose of this study will be to evaluate the aetiology and prognosis of non-traumatic coma in African children. METHODS: With no date restrictions, systematic searches of MEDLINE, Embase, and Scopus will identify prospective and retrospective studies (including randomised controlled trials, cluster randomised trials, cohort studies, cross-sectional, and case-control studies) recruiting children (1 month-16 years) with non-traumatic coma (defined by Blantyre Coma Score ≤ 2 or comparable alternative) from any African country. Disease-specific studies will be included if coma is associated and reported. The primary outcome is to determine the aetiology (infectious and non-infectious) of non-traumatic coma in African children, with pooled prevalence estimates of causes (e.g., malaria). Secondary outcomes are to determine overall estimates of morbidity and mortality of all-cause non-traumatic coma and disease-specific states of non-traumatic coma, where available. Random effects meta-analysis will summarise aetiology data and in-hospital and post-discharge mortality. Heterogeneity will be quantified with τ2, I2, and Cochran's Q test. DISCUSSION: This systematic review will provide a summary of the best available evidence on the aetiology and outcome of non-traumatic coma in African children. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020141937.
Subdural Empyema Caused by Neisseria meningitidis: A Case Report and Review of the Literature.
Subdural empyema complicating meningococcal meningitis is rare. We describe a case and 14 previously reported cases; all had persistent fever and 12 had seizures. Initial cerebrospinal fluid showed raised protein with low glucose values. Neuroimaging confirmed the diagnosis in all cases where undertaken. Ten children had neurosurgical intervention. Clinical outcome was available in 14 cases; a full recovery was reported in 10 and 1 child died.
Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study.
BACKGROUND: The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents. METHODS: We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group. Paediatric neurologists were invited to notify any children and adolescents (age <18 years) admitted to hospital with neurological or psychiatric disorders in whom they considered SARS-CoV-2 infection to be relevant to the presentation. Patients were excluded if they did not have a neurological consultation or neurological investigations or both, or did not meet the definition for confirmed SARS-CoV-2 infection (a positive PCR of respiratory or spinal fluid samples, serology for anti-SARS-CoV-2 IgG, or both), or the Royal College of Paediatrics and Child Health criteria for paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Individuals were classified as having either a primary neurological disorder associated with COVID-19 (COVID-19 neurology group) or PIMS-TS with neurological features (PIMS-TS neurology group). The denominator of all hospitalised children and adolescents with COVID-19 was collated from National Health Service England data. FINDINGS: Between April 2, 2020, and Feb 1, 2021, 52 cases were identified; in England, there were 51 cases among 1334 children and adolescents hospitalised with COVID-19, giving an estimated prevalence of 3·8 (95% CI 2·9-5·0) cases per 100 paediatric patients. 22 (42%) patients were female and 30 (58%) were male; the median age was 9 years (range 1-17). 36 (69%) patients were Black or Asian, 16 (31%) were White. 27 (52%) of 52 patients were classified into the COVID-19 neurology group and 25 (48%) were classified into the PIMS-TS neurology group. In the COVID-19 neurology group, diagnoses included status epilepticus (n=7), encephalitis (n=5), Guillain-Barré syndrome (n=5), acute demyelinating syndrome (n=3), chorea (n=2), psychosis (n=2), isolated encephalopathy (n=2), and transient ischaemic attack (n=1). The PIMS-TS neurology group more often had multiple features, which included encephalopathy (n=22 [88%]), peripheral nervous system involvement (n=10 [40%]), behavioural change (n=9 [36%]), and hallucinations at presentation (n=6 [24%]). Recognised neuroimmune disorders were more common in the COVID-19 neurology group than in the PIMS-TS neurology group (13 [48%] of 27 patients vs 1 [<1%] of 25 patients, p=0·0003). Compared with the COVID-19 neurology group, more patients in the PIMS-TS neurology group were admitted to intensive care (20 [80%] of 25 patients vs six [22%] of 27 patients, p=0·0001) and received immunomodulatory treatment (22 [88%] patients vs 12 [44%] patients, p=0·045). 17 (33%) patients (10 [37%] in the COVID-19 neurology group and 7 [28%] in the PIMS-TS neurology group) were discharged with disability; one (2%) died (who had stroke, in the PIMS-TS neurology group). INTERPRETATION: This study identified key differences between those with a primary neurological disorder versus those with PIMS-TS. Compared with patients with a primary neurological disorder, more patients with PIMS-TS needed intensive care, but outcomes were similar overall. Further studies should investigate underlying mechanisms for neurological involvement in COVID-19 and the longer-term outcomes. FUNDING: UK Research and Innovation, Medical Research Council, Wellcome Trust, National Institute for Health Research.
A Pilot Study of Obesogenic Eating Behaviors in Children With Migraine.
We studied associations between migraine severity and obesogenic eating behaviors in children with a prospective cross-sectional, clinic-based study. Migraine severity was quantified using the PedMIDAS tool and attack frequency. Eating behaviors were assessed using the Dutch Eating Behaviour Questionnaire and the Child Eating Behaviour Questionnaire. Food intake was assessed using a Food Intake Questionnaire. Statistical tests of association between eating behavior, food intake, and adiposity with migraine severity were performed. Sixty children (mean age = 10.9 years, standard deviation = 3.1; 26 males) were recruited. There was a positive correlation between the Child Eating Behaviour Questionnaire desire to drink subscale and PedMIDAS scores (r = 0.41, P = .01). Attack frequency was associated with higher intake of high fat or sugar content food and drink (r = 0.27, P = .04). No association between migraine severity and adiposity was found. Suggestion that migraine severity in children is associated with certain obesogenic eating behaviors requires further large study investigation.
Rapid Identification of Microorganisms by FilmArray Blood Culture Identification Panel Improves Clinical Management in Children.
BACKGROUND: Blood cultures are a common investigation for children admitted to hospital. In routine practice, it takes at least 24 hours to identify an organism as a contaminant or clinically significant. FilmArray Blood Culture Identification Panel (FA-BCIP) is a multiplex polymerase chain reaction that can detect 24 pathogens within 1 hour. We assessed whether results from FA-BCIP lead to changes in clinical management in a tertiary referral paediatric hospital. METHODS: We prospectively studied children having blood cultures taken at our tertiary children's hospital. Blood cultures were monitored and organisms identified using standard methods. FA-BCIP was performed when growth was initially detected in first positive blood cultures per episode, between January 1 and June 30, 2014. Assessment of whether the FA-BCIP result altered clinical management was made, specifically focused on antimicrobial stewardship and length of stay. RESULTS: FA-BCIP was done on 117 positive blood cultures; 74 (63%) grew clinically significant organisms, 43 (37%) grew contaminants. FA-BCIP results were judged to alter clinical management in 63 of the 117 episodes (54%). Antimicrobials were started/altered in 23 (19%) episodes and de-escalated/withheld/stopped in 29 (25%) episodes. Ten children were discharged from hospital earlier, which saved a cumulative total of 14 bed days. CONCLUSIONS: Rapid identification of microorganisms in pediatric blood cultures by FA-BCIP, led to changes in clinical management for half of the episodes. This improved antimicrobial stewardship and allowed early discharge from hospital for 10% of children. Future studies should focus on how best to use this technology in a cost-effective manner.
Plasma cell-free DNA predicts pediatric cerebral malaria severity.
BACKGROUNDPrediction of adverse outcomes in cerebral malaria (CM) is difficult. We hypothesized that cell-free DNA (cfDNA) levels would facilitate identification of severe and potentially fatal CM cases.METHODSIn this retrospective study, plasma from Malawian children with CM (n = 134), uncomplicated malaria (UM, n = 77), and healthy controls (HC, n = 60) was assayed for cfDNA using a fluorescence assay. Host and parasite cfDNA was measured by quantitative PCR. Immune markers were determined by ELISA, Luminex, or cytometric bead array.RESULTSTotal cfDNA increased with malaria severity (HC versus UM, P < 0.001; HC versus CM, P < 0.0001; UM versus CM, P < 0.0001), was elevated in retinopathy-positive (Ret+) CM relative to Ret- CM (7.66 versus 5.47 ng/μL, P = 0.027), and differentiated Ret+ fatal cases from survivors (AUC 0.779; P < 0.001). cfDNA levels in patients with non-malarial febrile illness (NMF, P = 0.25) and non-malarial coma (NMC, P = 0.99) were comparable with UM. Host DNA, rather than parasite DNA, was the major cfDNA contributor (UM, 268 versus 67 pg/μL; CM, 2824 versus 463 pg/μL). Host and parasite cfDNA distinguished CM by retinopathy (host, AUC 0.715, P = 0.0001; parasite, AUC 0.745, P = 0.0001), but only host cfDNA distinguished fatal cases (AUC 0.715, P = 0.0001). Total cfDNA correlated with neutrophil markers IL-8 (rs = 0.433, P < 0.0001) and myeloperoxidase (rs = 0.683, P < 0.0001).CONCLUSIONQuantifying plasma cfDNA is a simple assay useful in identifying children at risk for fatal outcome and has promise as a point-of-care assay. Elevated cfDNA suggests a link with host inflammatory pathways in fatal CM.FUNDINGNIH NCATS (AK), Burroughs-Wellcome (AK), and National Health and Medical Research Council of Australia (SJR).
Acquired torticollis due to primary pyomyositis of the paraspinal muscles in an 11-year-old boy.
Torticollis is characterised by tilting and rotation of the cervical spine in opposite directions. Causes can be congenital or acquired. Primary pyomyositis is a rare subacute deep bacterial infection of skeletal muscles that typically affects individuals under 20 years of age from tropical countries. Infrequently, pyomyositis occurs in individuals from temperate regions, usually in immunocompromised adults, and this is defined as secondary pyomyositis. We report a case of acquired torticollis due to primary pyomyositis of the paraspinal muscles in a previously healthy boy from the UK. A prolonged course of antibiotics and physiotherapy led to a complete resolution of his illness. We review how to differentiate pyomyositis from focal myositis, a more common inflammatory muscular cause of acquired torticollis.
Severe stridor and profound weakness after cerebral malaria.
Cerebral malaria (CM) is defined by WHO as coma (Blantyre Coma Score 2 or less) in a patient with Plasmodium falciparum parasitaemia and no alternative cause of coma identified. Mortality is approximately 15%-30% in African children and up to one-third of survivors have neurological sequelae. We present a patient with severe stridor and prolonged profound weakness during an intensive care admission with CM. These complications initially presented a diagnostic dilemma in our limited resourced setting. The stridor failed to improve with empiric steroids and a subsequent opportunistic ENT consult diagnosed vocal cord paresis. The weakness was so profound that the patient was unable to lift his head during the acute illness. The child received intensive physiotherapy, and at 1-month follow-up, the stridor and weakness had resolved.
Transcranial Doppler Ultrasonographic Evaluation of Cerebrovascular Abnormalities in Children With Acute Bacterial Meningitis.
Introduction: Bacterial meningitis (BM) is a global public health concern that results in significant morbidity and mortality. Cerebral arterial narrowing contributes to stroke in BM and may be amenable to intervention. However, it is difficult to diagnose in resource-limited settings where the disease is common. Methods: This was a prospective observational study from September 2015 to December 2019 in sub-Saharan Africa. Children 1 month-18 years of age with neutrophilic pleocytosis or a bacterial pathogen identified in the cerebrospinal fluid were enrolled. Transcranial Doppler ultrasound (TCD) of the middle cerebral arteries was performed daily with the aim to identify flow abnormalities consistent with vascular narrowing. Results: Forty-seven patients were analyzed. The majority had Streptococcus pneumoniae (36%) or Neisseria meningitides (36%) meningitis. Admission TCD was normal in 10 (21%). High flow with a normal pulsatility index (PI) was seen in 20 (43%) and high flow with a low PI was identified in 7 (15%). Ten (21%) had low flow. All children with a normal TCD had a good outcome. Patients with a high-risk TCD flow pattern (high flow/low PI or low flow) were more likely to have a poor outcome (82 vs. 38%, p = 0.001). Conclusions: Abnormal TCD flow patterns were common in children with BM and identified those at high risk of poor neurological outcome.
Cerebral Metabolic Crisis in Pediatric Cerebral Malaria.
Cerebral metabolic energy crisis (CMEC), often defined as a cerebrospinal fluid (CSF) lactate: pyruvate ratio (LPR) >40, occurs in various diseases and is associated with poor neurologic outcomes. Cerebral malaria (CM) causes significant mortality and neurodisability in children worldwide. Multiple factors that could lead to CMEC are plausible in these patients, but its frequency has not been explored. Fifty-three children with CM were enrolled and underwent analysis of CSF lactate and pyruvate levels. All 53 patients met criteria for a CMEC (median CSF LPR of 72.9 [interquartile range [IQR]: 58.5-93.3]). Half of children met criteria for an ischemic CMEC (median LPR of 85 [IQR: 73-184]) and half met criteria for a nonischemic CMEC (median LPR of 60 [IQR: 54-79]. Children also underwent transcranial doppler ultrasound investigation. Cerebral blood flow velocities were more likely to meet diagnostic criteria for low flow (<2 standard deviation from normal) or vasospasm in children with an ischemic CMEC (73%) than in children with a nonischemic CMEC (20%, p = 0.04). Children with an ischemic CMEC had poorer outcomes (pediatric cerebral performance category of 3-6) than those with a nonischemic CMEC (46 vs. 22%, p = 0.03). CMEC was ubiquitous in this patient population and the processes underlying the two subtypes (ischemic and nonischemic) may represent targets for future adjunctive therapies.