Paul Cleary

The Effectiveness of Convalescent Plasma and Hyperimmune Immunoglobulin for the Treatment of Severe Acute Respiratory Infections of Viral Etiology: A Systematic Review and Exploratory Meta-analysis

Abstract Background. Administration of convalescent plasma, serum, or hyperimmune immunoglobulin may be of clinical benefit for treatment of severe acute respiratory infections (SARIs) of viral etiology. We conducted a systematic review and exploratory meta-analysis to assess the overall evidence. Methods. Healthcare databases and sources of grey literature were searched in July 2013. All records were screened against the protocol eligibility criteria, using a 3-stage process. Data extraction and risk of bias assessments were undertaken. Results. We identified 32 studies of SARS coronavirus infection and severe influenza. Narrative analyses revealed consistent evidence for a reduction in mortality, especially when convalescent plasma is administered early after symptom onset. Exploratory post hoc meta-analysis showed a statistically significant reduction in the pooled odds of mortality following treatment, compared with placebo or no therapy (odds ratio, 0.25; 95% confidence interval, .14–.45; I2 = 0%). Studies were commonly of low or very low quality, lacked control groups, and at moderate or high risk of bias. Sources of clinical and methodological heterogeneity were identified. Conclusions. Convalescent plasma may reduce mortality and appears safe. This therapy should be studied within the context of a well-designed clinical trial or other formal evaluation, including for treatment of Middle East respiratory syndrome coronavirus CoV infection.

Phylogenetic structure of European Salmonella Enteritidis outbreak correlates with national and international egg distribution network

Outbreaks of Salmonella Enteritidis have long been associated with contaminated poultry and eggs. In the summer of 2014 a large multi-national outbreak of Salmonella Enteritidis phage type 14b occurred with over 350 cases reported in the United Kingdom, Germany, Austria, France and Luxembourg. Egg supply network investigation and microbiological sampling identified the source to be a Bavarian egg producer. As part of the international investigation into the outbreak, over 400 isolates were sequenced including isolates from cases, implicated UK premises and eggs from the suspected source producer. We were able to show a clear statistical correlation between the topology of the UK egg distribution network and the phylogenetic network of outbreak isolates. This correlation can most plausibly be explained by different parts of the egg distribution network being supplied by eggs solely from independent premises of the Bavarian egg producer (Company X). Microbiological sampling from the source premises, traceback information and information on the interventions carried out at the egg production premises all supported this conclusion. The level of insight into the outbreak epidemiology provided by whole-genome sequencing (WGS) would not have been possible using traditional microbial typing methods.

Identifying areas and risk groups with localised Mycobacterium tuberculosis transmission in northern England from 2010 to 2012: spatiotemporal analysis incorporating highly discriminatory genotyping data

Background Information on geographical variation in localised transmission of TB can inform targeting of disease control activities. The aim of this study was to estimate the proportion of TB attributable to localised transmission for the period 2010–2012 in northern England and to identify case characteristics associated with spatiotemporal-genotypical clusters. Methods We combined genotyping data with spatiotemporal scan statistics to define an indicator of localised TB transmission and identified factors associated with localised TB transmission thus defined in a multivariable logistics regression model. Results The estimated proportion of TB cases in northern England attributable to localised transmission was 10% (95% CI 9% to 12%). Clustered cases (cases which were spatiotemporally clustered with others of identical genotype) were on average younger than non-clustered cases (mean age 34 years vs 43 years; p value <0.05). Being UK born (adjusted OR (aOR) 3.6, 95% CI 2.9 to 6.0), presenting with pulmonary disease (aOR 2.2, 95% CI 1.3 to 3.6) and history of homelessness (aOR 2.8, 95% CI 1.2 to 6.8) or incarceration (aOR 2.6, 95% CI 1.2 to 5.9) were independently associated with being part of a spatiotemporal-genotypical cluster in a multivariable model. Belonging to an ethnic group other than white or mixed/other was also significantly associated with localised transmission. We identified localised transmission in 103/1958 middle super output areas mostly in urban areas. Conclusions Incorporating highly discriminatory genotyping data into spatiotemporal analysis of TB incidence is feasible as part of routine surveillance and can provide valuable information on groups at greater risk and areas with localised transmission of TB, which could be used to inform control measures, such as intensified contact tracing.

Control selection methods in recent case–control studies conducted as part of infectious disease outbreaks

Successful investigation of national outbreaks of communicable disease relies on rapid identification of the source. Case–control methodologies are commonly used to achieve this. We assessed control selection methods used in recently published case–control studies for methodological and resource issues to determine if a standard approach could be identified. Neighbourhood controls were the most frequently used method in 53 studies of a range of different sizes, infections and settings. The most commonly used method of data collection was face to face interview. Control selection issues were identified in four areas: method of identification of controls, appropriateness of controls, ease of recruitment of controls, and resource requirements. Potential biases arising from the method of control selection were identified in half of the studies assessed. There is a need to develop new ways of selecting controls in a rapid, random and representative manner to improve the accuracy and timeliness of epidemiological investigations and maximise the effectiveness of public health interventions. Innovative methods such as prior recruitment of controls could improve timeliness and representativeness of control selection.

Social and Economic Impacts of School Influenza Outbreaks in England: Survey of Caregivers

BACKGROUND Influenza is a cause of considerable morbidity in England, particularly among children. A total of 39% of all influenza-attributable general practitioner consultations and 37% of all influenza-attributable hospital admissions occur in those aged under 15 years. Few studies have quantified the impact of influenza outbreaks on families. We assessed this impact during 2 influenza seasons. METHODS We used questionnaires to obtain data in primary schools that reported an outbreak of an influenza-like-illness (ILI). We sought data on the loss of productivity, costs borne by families and loss in health-related quality of life (HRQoL). ILIs were identified using the symptoms criteria from the European Centre for Disease Prevention and Control and the UK Flusurvey. RESULTS For each child reporting ILI, mean school absence was 3.8 days (95% confidence interval [CI]): 3.0-4.8) with mean work absence for caregivers reported as 3.7 days (95% CI: 2.7-4.8). The mean loss in HRQoL was 2.1 quality-adjusted life days (95% CI: 1.5-2.7). The estimated total pediatric burden of disease for reported school-based outbreaks during the 2 influenza seasons was 105.3 QALYs (95% CI: 77.7-139.0). CONCLUSIONS This study shows the potential social and economic benefit of vaccination of children during mild influenza seasons.

High prevalence of TB disease in contacts of adults with extrapulmonary TB

UK guidelines no longer recommend routine screening of household contacts of adult patients with extrapulmonary TB (EPTB). From 27 March 2012 to 28 June 2016, we investigated the prevalence of active TB disease in household contacts of 1023 EPTB index cases in North West England, and compared estimates with: published new entrant migrant screening programme prevalence (~147/100 000 person-years); London-based contact screening data (700/100 000 contacts screened); and National Institute for Health and Care Excellence (NICE) new entrant TB screening thresholds (TB prevalence >40/100 000 people). Active TB disease prevalence in EPTB contacts was 440/100 000 contacts screened, similar to UK new entrant screening programmes, London EPTB contact prevalence and >10 times NICE’s threshold for new entrant screening. The decision to no longer recommend routine screening of EPTB contacts should be re-evaluated and cost-effectiveness analyses of screening strategies for EPTB contacts should be performed.

Screening for carbapenemase-producing Enterobacteriaceae-issues for consideration

We read with interest the letter by Venanzio et al. on CPE screening and the required isolation capacity if the PHE CPE toolkit is implemented, compared to an alternative strategy. We welcome the start of a discussion on CPE control including identification of carriers but we wish to challenge some of the assumptions made, and the alternative strategy outlined. We also outline an alternative “alternative strategy” currently in use in a number of trusts across North West England. Venanzio et al. consider an alternative strategy focusing on admissions to intensive care, nephrology, cardiothoracic surgery, neurosurgery and oncology. The choice of these specialties was based on invasive devices being a known risk factor for CPE infection. This is well described however it is not clear that invasive devices are a risk factor for CPE colonization. Several factors have been identified as independent risk factors for CPE colonization including advancing age, comorbidity, prior antimicrobial exposure, length of hospital stay and hospital stay overseas. Current UK strategy is to control the spread of CPE rather than reduce harm from infection. In contrast, the strategy suggested by Venanzio et al. primarily aims to prevent morbidity rather than transmission. Preventing transmission and preventing morbidity require different strategies. The prevalence of CPE among patients being admitted is likely to vary across the UK. This will alter positive and negative predictive values of any screening test and thus different approaches may be required in different areas rather than a universal approach. The proportion of patients in one West London hospital that meet the criteria for being “high risk” was applied to the whole NHS. One of those criteria was previous admission to a London Hospital. Based on current hospital use patterns, patients being admitted to a London hospital are more likely to have previously been admitted to a London

Equitable tuberculosis care in the North West of England: analysis of tuberculosis cohort review data

SUMMARY BACKGROUND: In the United Kingdom, tuberculosis (TB) predominantly affects the most deprived populations, yet the extent to which deprivation affects TB care outcomes is unknown. METHODS: Since 2011, the North West TB Cohort Audit collaboration has undertaken quarterly reviews of outcomes against consensus-defined care standard indicators for all individuals notified with TB. We investigated associations between adverse TB care outcomes and Index of Multiple Deprivation (IMD) 2010 scores measured at lower super output area of residence using logistic regression models. RESULTS: Of 1831 individuals notified with TB between 2011 and 2014, 62% (1131/1831) came from the most deprived national quintile areas. In single variable analysis, greater deprivation was significantly associated with increased likelihood of the completion of a standardised risk assessment (OR 2.99, 95%CI 5.27–19.65) and offer of a human immunodeficiency virus test (OR 1.72, 95%CI 1.10–2.62). In multivariable analysis, there were no significant associations. CONCLUSIONS: TB patients in the most deprived areas had similar care indicators across a range of standards to those of individuals living in the more affluent areas, suggesting that the delivery of TB care in the North West of England is equitable. The extent to which the cohort review process contributes to, and sustains, this standard of care deserves further study.

Enhanced surveillance of carbapenemase-producing Gram-negative bacteria to support national and international prevention and control efforts

Please cite this article as: Freeman R, Ironmonger D, Puleston R, Hopkins KL, Welfare W, Hope R, Staves P, Shemko M, Hopkins S, Cleary P, Patel B, Muller-Pebody B, Li X, Alvarez-Buylla A, Hawkey PM, Johnson AP, Woodford N, Oliver I, Enhanced surveillance of carbapenemase-producing Gram-negative bacteria to support national and international prevention and control efforts, Clinical Microbiology and Infection (2016), doi: 10.1016/j.cmi.2016.07.020.

Health professionals’ experiences of tuberculosis cohort audit in the North West of England: a qualitative study

Objectives Tuberculosis cohort audit (TBCA) was introduced across the North West (NW) of England in 2012 as an ongoing, multidisciplinary, systematic case review process, designed to improve clinical and public health practice. TBCA has not previously been introduced across such a large and socioeconomically diverse area in England, nor has it undergone formal, qualitative evaluation. This study explored health professionals’ experiences of the process after 1515 cases had been reviewed. Design Qualitative study using semistructured interviews. Respondents were purposively sampled from 3 groups involved in the NW TBCA: (1) TB nurse specialists, (2) consultant physicians and (3) public health practitioners. Data from the 26 respondents were triangulated with further interviews with key informants from the TBCA Steering Group and through observation of TBCA meetings. Analysis Interview transcripts were analysed thematically using the framework approach. Results Participants described the evolution of a valuable ‘community of practice’ where interprofessional exchange of experience and ideas has led to enhanced mutual respect between different roles and a shared sense of purpose. This multidisciplinary, regional approach to TB cohort audit has promoted local and regional team working, exchange of good practices and local initiatives to improve care. There is strong ownership of the process from public health professionals, nurses and clinicians; all groups want it to continue. TBCA is regarded as a tool for quality improvement that improves patient safety. Conclusions TBCA provides peer support and learning for management of a relatively rare, but important infectious disease through discussion in a no-blame atmosphere. It is seen as an effective quality improvement strategy which enhances TB care, control and patient safety. Continuing success will require increased engagement of consultant physicians and public health practitioners, a secure and ongoing funding stream and establishment of clear reporting mechanisms within the public health system.