Twenty years and counting: epidemiology of an outbreak of isoniazid-resistant tuberculosis in England and Wales, 1995 to 2014

An outbreak of isoniazid-resistant tuberculosis first identified in London has now been ongoing for 20 years, making it the largest drug-resistant outbreak of tuberculosis documented to date worldwide. We identified culture-confirmed cases with indistinguishable molecular strain types and extracted demographic, clinical, microbiological and social risk factor data from surveillance systems. We summarised changes over time and used kernel-density estimation and k-function analysis to assess geographic clustering. From 1995 to 2014, 508 cases were reported, with a declining trend in recent years. Overall, 70% were male (n = 360), 60% born in the United Kingdom (n = 306), 39% white (n = 199), and 26% black Caribbean (n = 134). Median age increased from 25 years in the first 5 years to 42 in the last 5. Approximately two thirds of cases reported social risk factors: 45% drug use (n = 227), 37% prison link (n = 189), 25% homelessness (n = 125) and 13% alcohol dependence (n = 64). Treatment was completed at 12 months by 52% of cases (n = 206), and was significantly lower for those with social risk factors (p < 0.05), but increased over time for all patients (p < 0.05). The outbreak remained focused in north London throughout. Control of this outbreak requires continued efforts to prevent and treat further active cases through targeted screening and enhanced case management

Recent TB transmission, clustering and predictors of large clusters in London, 2010-2012: results from first 3 years of universal MIRU-VNTR strain typing

BACKGROUND: The incidence of TB has doubled in the last 20 years in London. A better understanding of risk groups for recent transmission is required to effectively target interventions. We investigated the molecular epidemiological characteristics of TB cases to estimate the proportion of cases due to recent transmission, and identify predictors for belonging to a cluster. METHODS: The study population included all culture-positive TB cases in London residents, notified between January 2010 and December 2012, strain typed using 24-loci multiple interspersed repetitive units-variable number tandem repeats. Multivariable logistic regression analysis was performed to assess the risk factors for clustering using sociodemographic and clinical characteristics of cases and for cluster size based on the characteristics of the first two cases. RESULTS: There were 10 147 cases of which 5728 (57%) were culture confirmed and 4790 isolates (84%) were typed. 2194 (46%) were clustered in 570 clusters, and the estimated proportion attributable to recent transmission was 34%. Clustered cases were more likely to be UK born, have pulmonary TB, a previous diagnosis, a history of substance abuse or alcohol abuse and imprisonment, be of white, Indian, black-African or Caribbean ethnicity. The time between notification of the first two cases was more likely to be <90 days in large clusters. CONCLUSIONS: Up to a third of TB cases in London may be due to recent transmission. Resources should be directed to the timely investigation of clusters involving cases with risk factors, particularly those with a short period between the first two cases, to interrupt onward transmission of TB

The challenge of estimating tuberculosis mortality accurately in England and Wales

BACKGROUND: Accurate estimates of tuberculosis (TB) mortality are required to monitor progress towards the World Health Organization End TB goal of reducing TB deaths by 95% by 2035. We compared TB death data for England and Wales from the national surveillance system (Enhanced Tuberculosis Surveillance System [ETS]) and the vital registration system from the Office for National Statistics (ONS). METHODS: TB cases notified in ETS were matched to deaths in ONS (dONS) with International Classification of Diseases, Tenth Revision (ICD-10) codes indicating that TB caused/contributed to the death (A15–A19). Deaths captured in one but not both systems were assessed to identify if ONS captured all TB deaths and if there was under-notification of TB in ETS. We stratified deaths into active TB, TB sequelae, incidental deaths and not TB. RESULTS: Between 2005 and 2015, there were fewer deaths in ETS (dETS) than dONS with ICD-10 codes A15–A19 (n = 4207 vs. n = 6560); 57% of dETS were recorded as dONS and 53% of dONS were notified to ETS. A total of 9289 deaths were identified from dETS and dONS: 64% were due to active TB, 23% were TB sequelae, 6% were incidental and 7% were not TB. CONCLUSIONS: TB deaths in ETS and ONS differ substantially. Almost one third of TB deaths recorded by ONS are not due to active TB; this can be amended through coding changes

A model of tuberculosis clustering in low incidence countries reveals more transmission in the United Kingdom than the Netherlands between 2010 and 2015

Tuberculosis (TB) remains a public health threat in low TB incidence countries, through a combination of reactivated disease and onward transmission. Using surveillance data from the United Kingdom (UK) and the Netherlands (NL), we demonstrate a simple and predictable relationship between the probability of observing a cluster and its size (the number of cases with a single genotype). We demonstrate that the full range of observed cluster sizes can be described using a modified branching process model with the individual reproduction number following a Poisson lognormal distribution. We estimate that, on average, between 2010 and 2015, a TB case generated 0.41 (95% CrI 0.30,0.60) secondary cases in the UK, and 0.24 (0.14,0.48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 39% (26%,60%) of UK cases and 23%(13%,37%) of NL cases. We predict that reducing UK transmission rates to those observed in the NL would result in 538(266,818) fewer cases annually in the UK. In conclusion, while TB in low incidence countries is strongly associated with reactivated infections, we demonstrate that recent transmission remains sufficient to warrant policies aimed at limiting local TB spread

The Effects on Milk Yield and Composition, and Animal Nitrogen and Phosphorus Status, of Offering Early-Lactation Dairy Cows Concentrate Feeds of Differing Crude Protein and Phosphorus Concentrations

Milk composition is affected by the dietary concentration of crude protein (CP) (Kung Jr and Huber 1983) and minerals such as phosphorus (P) (Wu and Satter 2000). Milk composition has consequent effects on the processing properties of milk (Dillon et al. 1997). The objective of this study was to determine the effects of offering supplementary concentrate feeds differing in CP and P concentration to lactating dairy cows in the early lactation period (Feb-May) on milk yield and composition, and on animal nitrogen (N) and P status

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations