VirA+EmiC project: Evaluating real-world effectiveness and sustainability of integrated routine opportunistic hepatitis B and C testing in a large urban emergency department.

Innovative testing approaches and care pathways are required to meet global hepatitis B virus (HBV) and hepatitis C virus (HCV) elimination goals. Routine blood-borne virus (BBV) testing in emergency departments (EDs) in high-prevalence areas is suggested by the European Centre for Disease Prevention and Control (ECDC) but there is limited evidence for this. Universal HIV testing in our ED according to UK guidance has been operational since 2015. We conducted a real-world service evaluation of a modified electronic patient record (EPR) system to include opportunistic opt-out HBV/reflex-HCV tests for any routine blood test orders for ED attendees aged ≥16 years. Reactive laboratory results were communicated directly to specialist clinical teams. Our model for contacting patients requiring linkage to care (new diagnoses/known but disengaged) evolved from initially primarily hospital-led to collaborating with regional health and community service networks. Over 11 months, 81,088 patients attended the ED; 36,865 (45.5%) had a blood test. Overall uptake for both HBV and HCV testing was 75%. Seroprevalence was 0.9% for hepatitis B surface antigen (HBsAg) and 0.9% for HCV antigen (HCV-Ag). 79% of 140 successfully contacted HBsAg+patients required linkage to care, of which 87% engaged. 76% of 130 contactable HCV-Ag+patients required linkage, 52% engaged. Our results demonstrate effectiveness and sustainability of universal ED EPR opt-out HBV/HCV testing combined with comprehensive linkage to care pathways, allowing care provision particularly for marginalized at-risk groups with limited healthcare access. The findings support the ECDC BBV testing guidance and may inform future UK hepatitis testing guidance.

Clinical management and impact of scarlet fever in the modern era: findings from a cross-sectional study of cases in London, 2018-2019.

OBJECTIVES: In response to increasing incidence of scarlet fever and wider outbreaks of group A streptococcal infections in London, we aimed to characterise the epidemiology, symptoms, management and consequences of scarlet fever, and to identify factors associated with delayed diagnosis. DESIGN AND SETTING: Cross-sectional community-based study of children with scarlet fever notified to London's three Health Protection Teams, 2018-2019. PARTICIPANTS: From 2575 directly invited notified cases plus invitations via parental networks at 410 schools/nurseries with notified outbreaks of confirmed/probable scarlet fever, we received 477 responses (19% of those directly invited), of which 412 met the case definition. Median age was 4 years (range <1 to 16), 48% were female, and 70% were of white ethnicity. OUTCOME MEASURES: Preplanned measures included quantitative description of case demographics, symptoms, care-seeking, and clinical, social, and economic impact on cases and households. After survey completion, secondary analyses of factors associated with delayed diagnosis (by logistic regression) and consequences of delayed diagnosis (by Cox's regression), and qualitative analysis of free text comments were added. RESULTS: Rash was reported for 89% of cases, but followed onset of other symptoms for 71%, with a median 1-day delay. Pattern of onset varied with age: sore throat was more common at onset among children 5 years and older (OR3.1, 95% CI 1.9 to 5.0). At first consultation, for 28%, scarlet fever was not considered: in these cases, symptoms were frequently attributed to viral infection (60%, 64/106). Delay in diagnosis beyond first consultation occurred more frequently among children aged 5+ who presented with sore throat (OR 2.8 vs 5+without sore throat; 95% CI 1.3 to 5.8). Cases with delayed diagnosis took, on average, 1 day longer to return to baseline activities. CONCLUSIONS: Scarlet fever may be initially overlooked, especially among older children presenting with sore throat. Raising awareness among carers and practitioners may aid identification and timely treatment.

Increasingly limited options for the treatment of enteric fever in travellers returning to England, 2014-2019: a cross-sectional analytical study.

Introduction. Enteric fever (caused by Salmonella enterica serovars Typhi and Paratyphi) frequently presents as an acute, undifferentiated febrile illness in returning travellers, requiring timely empirical antibiotics.Gap Statement. Determining which empirical antibiotics to prescribe for enteric fever requires up-to-date knowledge of susceptibility patterns.Aim. By characterising factors associated with antimicrobial resistance in cases of S. Typhi and S. Paratyphi imported to England, we aim to guide effective empirical treatment.Methodology. All English isolates of S. Typhi and S. Paratyphi 2014-2019 underwent antimicrobial susceptibility testing; results were compared to a previous survey in London 2005-2012. Risk factors for antimicrobial resistance were analysed with logistic regression models to predict adjusted odds ratios (aOR) for resistance to individual antibiotics and multi-drug resistance.Results. We identified 1088 cases of S. Typhi, 729 S. Paratyphi A, 93 S. Paratyphi B, and one S. Paratyphi C. In total, 93 % were imported. Overall, 90 % of S. Typhi and 97 % of S. Paratyphi A isolates were resistant to ciprofloxacin; 26 % of S. Typhi were multidrug resistant to ciprofloxacin, amoxicillin, co-trimoxazole, and chloramphenicol (MDR+FQ). Of the isolates, 4 % of S. Typhi showed an extended drug resistance (XDR) phenotype of MDR+FQ plus resistance to third-generation cephalosporins, with cases of XDR rising sharply in recent years (none before 2017, one in 2017, six in 2018, 32 in 2019). For S. Typhi isolates, resistance to ciprofloxacin was associated with travel to Pakistan (aOR=32.0, 95 % CI: 15.4-66.4), India (aOR=21.8, 95 % CI: 11.6-41.2), and Bangladesh (aOR=6.2, 95 % CI: 2.8-13.6) compared to travel elsewhere, after adjusting for rising prevalence of resistance over time. MDR+FQ resistance in S. Typhi isolates was associated with travel to Pakistan (aOR=3.5, 95 % CI: 2.4-5.2) and less likely with travel to India (aOR=0.07, 95 % CI 0.04-0.15) compared to travel elsewhere. All XDR cases were imported from Pakistan. No isolate was resistant to azithromycin. Comparison with the 2005-2012 London survey indicates substantial increases in the prevalence of resistance of S. Typhi isolates to ciprofloxacin associated with travel to Pakistan (from 79-98 %) and Africa (from 12-60 %).Conclusion. Third-generation cephalosporins and azithromycin remain appropriate choices for empirical treatment of enteric fever in most returning travellers to the UK from endemic countries, except from Pakistan, where XDR represents a significant risk.

Epidemiological, clinical, and public health response characteristics of a large outbreak of diphtheria among the Rohingya population in Cox's Bazar, Bangladesh, 2017 to 2019: A retrospective study.

BACKGROUND: Unrest in Myanmar in August 2017 resulted in the movement of over 700,000 Rohingya refugees to overcrowded camps in Cox's Bazar, Bangladesh. A large outbreak of diphtheria subsequently began in this population. METHODS AND FINDINGS: Data were collected during mass vaccination campaigns (MVCs), contact tracing activities, and from 9 Diphtheria Treatment Centers (DTCs) operated by national and international organizations. These data were used to describe the epidemiological and clinical features and the control measures to prevent transmission, during the first 2 years of the outbreak. Between November 10, 2017 and November 9, 2019, 7,064 cases were reported: 285 (4.0%) laboratory-confirmed, 3,610 (51.1%) probable, and 3,169 (44.9%) suspected cases. The crude attack rate was 51.5 cases per 10,000 person-years, and epidemic doubling time was 4.4 days (95% confidence interval [CI] 4.2-4.7) during the exponential growth phase. The median age was 10 years (range 0-85), and 3,126 (44.3%) were male. The typical symptoms were sore throat (93.5%), fever (86.0%), pseudomembrane (34.7%), and gross cervical lymphadenopathy (GCL; 30.6%). Diphtheria antitoxin (DAT) was administered to 1,062 (89.0%) out of 1,193 eligible patients, with adverse reactions following among 229 (21.6%). There were 45 deaths (case fatality ratio [CFR] 0.6%). Household contacts for 5,702 (80.7%) of 7,064 cases were successfully traced. A total of 41,452 contacts were identified, of whom 40,364 (97.4%) consented to begin chemoprophylaxis; adherence was 55.0% (N = 22,218) at 3-day follow-up. Unvaccinated household contacts were vaccinated with 3 doses (with 4-week interval), while a booster dose was administered if the primary vaccination schedule had been completed. The proportion of contacts vaccinated was 64.7% overall. Three MVC rounds were conducted, with administrative coverage varying between 88.5% and 110.4%. Pentavalent vaccine was administered to those aged 6 weeks to 6 years, while tetanus and diphtheria (Td) vaccine was administered to those aged 7 years and older. Lack of adequate diagnostic capacity to confirm cases was the main limitation, with a majority of cases unconfirmed and the proportion of true diphtheria cases unknown. CONCLUSIONS: To our knowledge, this is the largest reported diphtheria outbreak in refugee settings. We observed that high population density, poor living conditions, and fast growth rate were associated with explosive expansion of the outbreak during the initial exponential growth phase. Three rounds of mass vaccinations targeting those aged 6 weeks to 14 years were associated with only modestly reduced transmission, and additional public health measures were necessary to end the outbreak. This outbreak has a long-lasting tail, with Rt oscillating at around 1 for an extended period. An adequate global DAT stockpile needs to be maintained. All populations must have access to health services and routine vaccination, and this access must be maintained during humanitarian crises.

Seasonality in extra-pulmonary tuberculosis notifications in Germany 2004-2014- a time series analysis.

BACKGROUND: Seasonality in tuberculosis (TB) has been found in different parts of the world, showing a peak in spring/summer and a trough in autumn/winter. The evidence is less clear which factors drive seasonality. It was our aim to identify and evaluate seasonality in the notifications of TB in Germany, additionally investigating the possible variance of seasonality by disease site, sex and age group. METHODS: We conducted an integer-valued time series analysis using national surveillance data. We analysed the reported monthly numbers of started treatments between 2004 and 2014 for all notified TB cases and stratified by disease site, sex and age group. RESULTS: We detected seasonality in the extra-pulmonary TB cases (N = 11,219), with peaks in late spring/summer and troughs in fall/winter. For all TB notifications together (N = 51,090) and for pulmonary TB only (N = 39,714) we did not find a distinct seasonality. Additional stratified analyses did not reveal any clear differences between age groups, the sexes, or between active and passive case finding. CONCLUSION: We found seasonality in extra-pulmonary TB only, indicating that seasonality of disease onset might be specific to the disease site. This could point towards differences in disease progression between the different clinical disease manifestations. Sex appears not to be an important driver of seasonality, whereas the role of age remains unclear as this could not be sufficiently investigated.

Completeness of tuberculosis case notifications in Germany in 2013-2017: first results of an inventory study.

BACKGROUND: Evaluating the completeness of tuberculosis (TB) notification data is important for monitoring of TB surveillance systems. We conducted an inventory study to calculate TB underreporting in Germany in 2013-2017. METHODS: Acquisition of two pseudonymized case-based data sources (national TB notification data and antibiotic resistance surveillance data) was followed by two-source Capture-recapture (CRC) analysis, as case-based data from a third source was unavailable. Aggregated data on consumption of a key anti-TB drug (pyrazinamide [PZA]) was compared to an estimated need for PZA based on TB notification data to obtain an independent underreporting estimation. Additionally, notified TB incidence was compared to TB rate in an aggregated health insurance fund dataset. RESULTS: CRC and PZA-based approaches indicated that between 93 and 97% (CRC) and between 91 and 95% (PZA) of estimated cases were captured in the national TB notification data in the years 2013-2017. Insurance fund dataset did not indicate TB underreporting on the national level in 2017. CONCLUSIONS: Our results suggest that more than 90% of estimated TB cases are captured within the German TB surveillance system, and accordingly the TB notification rate is likely a good proxy of the diagnosed TB incidence rate. An increase in underreporting and discrepancies however should be further investigated.

Presentation and healthcare delays among people with tuberculosis in London, and the impact on treatment outcome.

Background: A quarter of London's pulmonary tuberculosis (TB) patients have over 4 months of delay. Late diagnosis increases disease severity and the risk of transmission. We aim to classify delays, identify associated risk factors and assess treatment outcome. Methods: We conducted a retrospective cohort study using London surveillance data, 2012-2018 on adults aged ≥18 years with pulmonary TB. We defined presentation delay (days from symptom onset to first healthcare visit) and healthcare delay (first healthcare visit to treatment commencement) as dichotomous variables; positive delay being days equal or greater than the third quartile. We applied logistic regression models to identify risk factors associated with delays and treatment outcome at 12 months. Results: Of 7216 people, 4539 reported presentation and 5193 healthcare delays. The third quartiles for presentation and healthcare delay were 84 and 61 days, respectively. Presentation delay was associated with female sex (adjusted OR (aOR)=1.21; 95% CI 1.04 to 1.39), increasing age (aOR=1.004; 95% CI 1.001 to 1.008), white compared to Asian ethnicity (aOR=1.35; 95% CI 1.12 to 1.62), previous imprisonment (aOR=1.66; 95% CI 1.22 to 2.26) and alcohol misuse (aOR=1.44; 95% CI 1.04 to 1.89). Healthcare delay was associated with female sex (aOR=1.39; 95% CI 1.21 to 1.59), increasing age (aOR=1.014; 95% CI 1.009 to 1.018) and white ethnicity (aOR=1.41; 95% CI 1.19 to 1.68). 16% of 5678 people with known outcome did not complete treatment. Neither delay was associated with non-completion (p value <0.05). Conclusions: Female, white and older people with TB were more likely to experience both presentation and healthcare delays. Social risk factors were also associated with delay in presentation. Early diagnosis and treatment remain critical to reduce transmission, regardless of whether delay affected completion.

Isoniazid (INH) mono-resistance and tuberculosis (TB) treatment success: analysis of European surveillance data, 2002 to 2014.

INTRODUCTION: Isoniazid (INH) is an essential drug for tuberculosis (TB) treatment. Resistance to INH may increase the likelihood of negative treatment outcome. AIM: We aimed to determine the impact of INH mono-resistance on TB treatment outcome in the European Union/European Economic Area and to identify risk factors for unsuccessful outcome in cases with INH mono-resistant TB. METHODS: In this observational study, we retrospectively analysed TB cases that were diagnosed in 2002-14 and included in the European Surveillance System (TESSy). Multilevel logistic regression models were applied to identify risk factors and correct for clustering of cases within countries. RESULTS: A total of 187,370 susceptible and 7,578 INH mono-resistant TB cases from 24 countries were included in the outcome analysis. Treatment was successful in 74.0% of INH mono-resistant and 77.4% of susceptible TB cases. In the final model, treatment success was lower among INH mono-resistant cases (Odds ratio (OR): 0.7; 95% confidence interval (CI): 0.6-0.9; adjusted absolute difference in treatment success: 5.3%). Among INH mono-resistant TB cases, unsuccessful treatment outcome was associated with age above median (OR: 1.3; 95% CI: 1.2-1.5), male sex (OR: 1.3; 95% CI: 1.1-1.4), positive smear microscopy (OR: 1.3; 95% CI: 1.1-1.4), positive HIV status (OR: 3.3; 95% CI: 1.6-6.5) and a prior TB history (OR: 1.8; 95% CI: 1.5-2.2). CONCLUSIONS: This study provides evidence for an association between INH mono-resistance and a lower likelihood of TB treatment success. Increased attention should be paid to timely detection and management of INH mono-resistant TB.

World Health Organization Early Warning, Alert and Response System in the Rohingya Crisis, Bangladesh, 2017-2018.

The Early Warning, Alert and Response System (EWARS) is a web-based system and mobile application for outbreak detection and response in emergency settings. EWARS provided timely information on epidemic-potential diseases among >700,000 Rohingya refugees across settlements. EWARS helped in targeting new measles vaccination campaigns and investigating suspected outbreaks of acute jaundice syndrome.

Immunological recovery in tuberculosis/HIV co-infected patients on antiretroviral therapy: implication for tuberculosis preventive therapy.

BACKGROUND: Understanding the immune response to combination antiretroviral therapy (cART) is essential for a clear approach to tuberculosis (TB) preventive therapy. We investigated the immunological recovery in cART-treated HIV-infected patients developing TB compared to those who remained free of TB. METHODS: We extracted data of HIV-infected patients from a multicenter cohort for the HIV clinical surveillance in Germany. No patients included in our study had TB at the beginning of the observation. Using a longitudinal mixed model, we assessed the differences in the mean change of biomarkers (CD4+ cell count, CD8+ cell count, CD4:CD8 ratio and viral load) since cART initiation in patients who remained free of TB vs. those developing TB. To detect the best-fit trajectories of the immunological biomarkers, we applied a multivariable fractional polynomials model. RESULTS: We analyzed a total of 10,671 HIV-infected patients including 139 patients who developed TB during follow-up. The highest TB incidences were observed during the first two years since cART initiation (0.32 and 0.50 per 100 person-years). In an adjusted multivariable mixed model, we found that the average change in CD4+ cell count recovery was significantly greater by 33 cells/µl in patients who remained free of TB compared with those developing TB. After the initial three months of cART, 65.6% of patients who remaining free of TB achieved CD4+ count of ≥400 cells/µl, while only 11.3% of patients developing TB reached this immunological status after the three months of cART. We found no differences in the average change of CD8+ cell count, CD4:CD8 ratio or viral load between the two-patient groups. CONCLUSION: All HIV-infected patients responded to cART. However, patients developing TB showed reduced recovery in CD4+ cell count and this might partly explain the incident TB in HIV-infected patients receiving cART. These findings reinforce the importance of adjunctive TB preventive therapy for patients with reduced recovery in CD4+ cell count.

Drivers of airborne human-to-human pathogen transmission.

Airborne pathogens - either transmitted via aerosol or droplets - include a wide variety of highly infectious and dangerous microbes such as variola virus, measles virus, influenza A viruses, Mycobacterium tuberculosis, Streptococcus pneumoniae, and Bordetella pertussis. Emerging zoonotic pathogens, for example, MERS coronavirus, avian influenza viruses, Coxiella, and Francisella, would have pandemic potential were they to acquire efficient human-to-human transmissibility. Here, we synthesize insights from microbiological, medical, social, and economic sciences to provide known mechanisms of aerosolized transmissibility and identify knowledge gaps that limit emergency preparedness plans. In particular, we propose a framework of drivers facilitating human-to-human transmission with the airspace between individuals as an intermediate stage. The model is expected to enhance identification and risk assessment of novel pathogens.

Impact of HIV infection on treatment outcome of tuberculosis in Europe.

BACKGROUND: The effect of HIV on tuberculosis (TB) treatment outcomes has not been well established. We aimed to assess the impact of HIV infection on TB treatment outcomes by using data from notifiable disease surveillance in Europe. METHODS: We analyzed the treatment outcomes of TB cases reported from nine European countries during 2010-2012. We investigate the effect of HIV on TB treatment outcomes using a multilevel and a multinomial logistic model, and considering the interaction between HIV and multidrug-resistant (MDR) TB. RESULTS: A total of 61,138 TB cases including 5.5% HIV-positive were eligible for our analysis. In the multilevel model adjusted for age and an interaction with MDR TB, HIV was significantly associated with lower treatment success in all MDR strata [non-MDR TB: odds ratio (OR) 0.24 CI (confidence interval) 0.20-0.29; unknown MDR TB status: OR 0.26 CI 0.23-0.30; MDR TB: OR 0.57 CI 0.35-0.91]. In the multinomial regression model, HIV-positive cases had significantly higher relative risk ratio (RRR) for death (non-MDR TB: RRR 4.30 CI 2.31-7.99; unknown MDR TB status: 5.55 CI 3.10-9.92; MDR TB: 3.59 CI 1.56-8.28) and being 'still on treatment' (non-MDR TB: RRR 7.27 CI 3.00-17.6; unknown MDR TB status: 5.36 CI 2.44-11.8; MDR TB: 3.76 CI 2.48-5.71). We did not find any significant association between HIV and TB treatment failure (non-MDR TB: RRR 0.50 CI 0.15-1.67; unknown MDR TB status: 1.51 CI 0.86-2.64; MDR TB: 0.51 CI 0.13-1.87). CONCLUSION: This large study confirms that HIV is a strong risk factor for an adverse TB treatment outcome, which is mainly manifested by an increased risk of death and still being on TB treatment.

Tuberculosis treatment outcome in the European Union and European Economic Area: an analysis of surveillance data from 2002-2011.

Monitoring the treatment outcome (TO) of tuberculosis (TB) is essential to evaluate the effectiveness of the intervention and to identify potential barriers for TB control. The global target is to reach a treatment success rate (TSR) of at least 85%. We aimed to assess the TB TO in the European Union and European Economic Area (EU/EEA) between 2002 and 2011, and to identify factors associated with unsuccessful treatment. Only 18 countries reported information on TO for the whole observation period accounting for 250,854 new culture-confirmed pulmonary TB cases. The 85% target of TSR was not reached in any year between 2002 and 2011 and was on average 78%. The TSR for multidrug-resistant (MDR)-TB cases at 24-month follow-up was 49%. In the multivariable regression model, unsuccessful treatment was significantly associated with increasing age (odds ratio (OR) = 1.02 per a one-year increase, 95% confidence interval (CI): 1.02-1.02), MDR-TB (OR = 8.7, 95% CI: 5.09-14.97), male sex (OR = 1.40, 95% CI: 1.28-1.52), and foreign origin (OR = 1.32, 95% CI: 1.03-1.70). The data highlight that special efforts are required for patients with MDR-TB and the elderly aged ≥65 years, who have particularly low TSR. To allow for valid monitoring at EU level all countries should aim to report TO for all TB cases.

Tuberculosis among people living with HIV/AIDS in the German ClinSurv HIV Cohort: long-term incidence and risk factors.

BACKGROUND: Tuberculosis (TB) still presents a leading cause of morbidity and mortality among people living with HIV/AIDS (PLWHA), including those on antiretroviral therapy. In this study, we aimed to determine the long-term incidence density rate (IDR) of TB and risk factors among PLWHA in relation to combination antiretroviral therapy (cART)-status. METHODS: Data of PLWHA enrolled from 2001 through 2011 in the German ClinSurv HIV Cohort were investigated using survival analysis and Cox regression. RESULTS: TB was diagnosed in 233/11,693 PLWHA either at enrollment (N = 62) or during follow-up (N = 171). The TB IDR during follow-up was 0.37 cases per 100 person-years (PY) overall [95% CI, 0.32-0.43], and was higher among patients who never started cART and among patients originating from Sub-Saharan Africa (1.23 and 1.20 per 100PY, respectively). In two multivariable analyses, both patients (I) who never started cART and (II) those on cART shared the same risk factors for TB, namely: originating from Sub-Saharan Africa compared to Germany (I, hazard ratio (HR); [95% CI]) 4.05; [1.87-8.78] and II, HR 5.15 [2.76-9.60], CD4+ cell count <200 cells/µl (I, HR 8.22 [4.36-15.51] and II, HR 1.90 [1.14-3.15]) and viral load >5 log10 copies/ml (I, HR 2.51 [1.33-4.75] and II, HR 1.77 [1.11-2.82]). Gender, age or HIV-transmission risk group were not independently associated with TB. CONCLUSION: In the German ClinSurv HIV cohort, patients originating from Sub-Saharan Africa, with low CD4+ cell count or high viral load at enrollment were at increased risk of TB even after cART initiation. As patients might be latently infected with Mycobacterium tuberculosis complex, early screening for latent TB infection and implementing isoniazid preventive therapy in line with available recommendations is crucial.