Interferon-gamma release assay conversion after Mycobacterium tuberculosis exposure specifically associates with greater risk of progression to tuberculosis: A prospective cohort study in Leicester, UK.

OBJECTIVES: We investigated whether quantifying the serial QuantiFERON-TB Gold (QFT) response improves tuberculosis (TB) risk stratification in pulmonary TB (PTB) contacts. METHODS: A total of 297 untreated adult household PTB contacts, QFT tested at baseline and 3 months after index notification, were prospectively observed (median 1460 days). Normal variance of serial QFT responses was established in 46 extrapulmonary TB contacts. This informed categorisation of the response in QFT-positive PTB contacts as converters, persistently QFT-positive with significant increase (PPincrease), and without significant increase (PPno-increase). RESULTS: In total, eight co-prevalent TB (disease ≤3 months after index notification) and 12 incident TB (>3 months after index notification) cases were diagnosed. Genetic linkage to the index strain was confirmed in all culture-positive progressors. The cumulative 2-year incident TB risk in QFT-positive contacts was 8.4% (95% confidence interval, 3.0-13.6%); stratifying by serial QFT response, significantly higher risk was observed in QFT converters (28%), compared with PPno-increase (4.8%) and PPincrease (3.7%). Converters were characterised by exposure to index cases with a shorter interval from symptom onset to diagnosis (median reduction 50.0 days, P = 0.013). CONCLUSIONS: QFT conversion, rather than quantitative changes of a persistently positive serial QFT response, is associated with greater TB risk and exposure to rapidly progressive TB.

Prognostication of co-morbidity clusters on hospitalisation and mortality in advanced COPD.

RATIONALE: As the prevalence of multimorbidity increases, understanding the impact of isolated comorbidities in people COPD becomes increasingly challenging. A simplified model of common comorbidity patterns may improve outcome prediction and allow targeted therapy. OBJECTIVES: To assess whether comorbidity phenotypes derived from routinely collected clinical data in people with COPD show differences in risk of hospitalisation and mortality. METHODS: Twelve clinical measures related to common comorbidities were collected during annual reviews for people with advanced COPD and k-means cluster analysis performed. Cox proportional hazards with adjustment for covariates was used to determine hospitalisation and mortality risk between clusters. MEASUREMENTS AND MAIN RESULTS: In 203 participants (age 66 ± 9 years, 60 % male, FEV1%predicted 31 ± 10 %) no comorbidity in isolation was predictive of worse admission or mortality risk. Four clusters were described: cluster A (cardiometabolic and anaemia), cluster B (malnourished and low mood), cluster C (obese, metabolic and mood disturbance) and cluster D (less comorbid). FEV1%predicted did not significantly differ between clusters. Mortality risk was higher in cluster A (HR 3.73 [95%CI 1.09-12.82] p = 0.036) and B (HR 3.91 [95%CI 1.17-13.14] p = 0.027) compared to cluster D. Time to admission was highest in cluster A (HR 2.01 [95%CI 1.11-3.63] p = 0.020). Cluster C was not associated with increased risk of mortality or hospitalisation. CONCLUSIONS: Despite presence of advanced COPD, we report striking differences in prognosis for both mortality and hospital admissions for different co-morbidity phenotypes. Objectively assessing the multi-system nature of COPD could lead to improved prognostication and targeted therapy for patients.

PET-CT-guided characterisation of progressive, preclinical tuberculosis infection and its association with low-level circulating Mycobacterium tuberculosis DNA in household contacts in Leicester, UK: a prospective cohort study.

BACKGROUND: Incipient tuberculosis, a progressive state of Mycobacterium tuberculosis infection with an increased risk of developing into tuberculosis disease, remains poorly characterised. Animal models suggest an association of progressive infection with bacteraemia. Circulating M tuberculosis DNA has previously been detected in pulmonary tuberculosis by use of Actiphage, a bacteriophage-based real-time PCR assay. We aimed to investigate whether serial [18F]fluorodeoxyglucose ([18F]FDG)-PET-CT could be used to characterise the state and progressive trajectory of incipient tuberculosis, and examine whether these PET-CT findings are associated with Actiphage-based detection of circulating M tuberculosis DNA. METHODS: We did a prospective 12-month cohort study in healthy, asymptomatic adults (aged ≥16 years) who were household contacts of patients with pulmonary tuberculosis, and who had a clinical phenotype of latent tuberculosis infection, in Leicester, UK. Actiphage testing of participants' blood samples was done at baseline, and [18F]FDG PET-CT at baseline and after 3 months. Baseline PET-CT features were classified as positive, indeterminate, or negative, on the basis of the quantitation (maximum standardised uptake value [SUVmax]) and distribution of [18F]FDG uptake. Microbiological sampling was done at amenable sites of [18F]FDG uptake. Changes in [18F]FDG uptake after 3 months were quantitatively categorised as progressive, stable, or resolving. Participants received treatment if features of incipient tuberculosis, defined as microbiological detection of M tuberculosis or progressive PET-CT change, were identified. FINDINGS: 20 contacts were recruited between Aug 5 and Nov 5, 2020; 16 of these participants had a positive result on IFNγ release assay (QuantiFERON-TB Gold Plus [QFT]) indicating tuberculosis infection. Baseline PET-CT scans were positive in ten contacts (all QFT positive), indeterminate in six contacts (three QFT positive), and negative in four contacts (three QFT positive). Four of eight PET-CT-positive contacts sampled had M tuberculosis identified (three through culture, one through Xpert MTB/RIF Ultra test) from intrathoracic lymph nodes or bronchial wash and received full antituberculosis treatment. Two further unsampled PET-CT-positive contacts were also treated: one with [18F]FDG uptake in the lung (SUVmax 9·4) received empirical antituberculosis treatment and one who showed progressive [18F]FDG uptake received preventive treatment. The ten untreated contacts with [18F]FDG uptake at baseline (seven QFT positive) had stable or resolving changes at follow-up and remained free of tuberculosis disease after 12 months. A positive baseline Actiphage test was associated with the presence of features of incipient tuberculosis requiring treatment (p=0·018). INTERPRETATION: Microbiological and inflammatory features of incipient tuberculosis can be visualised on PET-CT and are associated with M tuberculosis detection in the blood, supporting the development of pathogen-directed blood biomarkers of tuberculosis risk. FUNDING: MRC Confidence in Concept.

A data-driven framework for clinical decision support applied to pneumonia management.

Despite their long history, it can still be difficult to embed clinical decision support into existing health information systems, particularly if they utilise machine learning and artificial intelligence models. Moreover, when such tools are made available to healthcare workers, it is important that the users can understand and visualise the reasons for the decision support predictions. Plausibility can be hard to achieve for complex pathways and models and perceived "black-box" functionality often leads to a lack of trust. Here, we describe and evaluate a data-driven framework which moderates some of these issues and demonstrate its applicability to the in-hospital management of community acquired pneumonia, an acute respiratory disease which is a leading cause of in-hospital mortality world-wide. We use the framework to develop and test a clinical decision support tool based on local guideline aligned management of the disease and show how it could be used to effectively prioritise patients using retrospective analysis. Furthermore, we show how this tool can be embedded into a prototype clinical system for disease management by integrating metrics and visualisations. This will assist decision makers to examine complex patient journeys, risk scores and predictions from embedded machine learning and artificial intelligence models. Our results show the potential of this approach for developing, testing and evaluating workflow based clinical decision support tools which include complex models and embedding them into clinical systems.

A Persistent Tuberculosis Outbreak in the UK Is Characterized by Hydrophobic fadB4-Deficient Mycobacterium tuberculosis That Replicates Rapidly in Macrophages.

The genetic diversity of Mycobacterium tuberculosis can influence disease severity and transmissibility. To better understand how this diversity influences individuals and communities, we phenotyped M. tuberculosis that was causing a persistent outbreak in the East Midlands, United Kingdom. Compared to nonoutbreak isolates, bacilli had higher lipid contents and more hydrophobic cell surfaces. In macrophage infection models, the bacteria increased more rapidly, provoked the enhanced accumulation of macrophage lipid droplets and enhanced the secretion of IL-1ß. Natural deletions in fadB4, nrdB, and plcC distinguished the outbreak isolates from other lineage 3 isolates in the region. fadB4 is annotated with a putative role in cell envelope biosynthesis, so the loss of this gene has the potential to alter the interactions of bacteria with immune cells. Reintroduction of fadB4 to the outbreak strain led to a phenotype that more closely resembled those of nonoutbreak strains. The improved understanding of the microbiological characteristics and the corresponding genetic polymorphisms that associate with outbreaks have the potential to inform tuberculosis control. IMPORTANCE Tuberculosis (TB) killed 1.5 million people in 2020 and affects every country. The extent to which the natural genetic diversity of Mycobacterium tuberculosis influences disease manifestation at both the individual and epidemiological levels remains poorly understood. Insights into how pathogen polymorphisms affect patterns of TB have the potential to translate into clinical and public health practice. Two distinct lineage 3 strains isolated from local TB outbreaks, one of which (CH) was rapidly terminated and the other of which (Lro) persistently transmitted for over a decade, provided us with an opportunity to study these issues. We compared genome sequences, microbiological characteristics, and early immune responses that were evoked upon infection. Our results indicate that the natural lack of fadB4 in the Lro strain contributes to its unique features.

Neurogenic Pulmonary Edema Presenting as a Pulmonary Entity.

Acute dyspnea is one of the most common presentations in acute/emergency settings, and acute pulmonary edema remains a leading cause in adults resulting from either cardiogenic or non-cardiogenic etiologies. Neurogenic pulmonary edema (NPE) is one of the less common forms of non-cardiogenic pulmonary edema seen in emergency departments, neurology units, or intensive care units. It usually develops rapidly following significant neurological insult seen in patients with intracranial hemorrhage, traumatic brain injuries, and epileptic seizures. It is less commonly seen after a multitude of other sudden catastrophic neurologic insults. Here, we report a case study of a 32-year-old female with a history of epilepsy since childhood who was admitted to our respiratory admission unit on two separate occasions with acute NPE and type I respiratory failure after a witnessed tonic-clonic seizure episode. Although the clinical features of NPE and the results of investigations can mimic more common cardiorespiratory conditions, an accurate and timely diagnosis is vital for the appropriate emergency management and to improve the patient's outcome.

Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis.

Blood transcriptomics have revealed major characteristics of the immune response in active TB, but the signature early after infection is unknown. In a unique clinically and temporally well-defined cohort of household contacts of active TB patients that progressed to TB, we define minimal changes in gene expression in incipient TB increasing in subclinical and clinical TB. While increasing with time, changes in gene expression were highest at 30 d before diagnosis, with heterogeneity in the response in household TB contacts and in a published cohort of TB progressors as they progressed to TB, at a bulk cohort level and in individual progressors. Blood signatures from patients before and during anti-TB treatment robustly monitored the treatment response distinguishing early and late responders. Blood transcriptomics thus reveal the evolution and resolution of the immune response in TB, which may help in clinical management of the disease.

Clinical utility of a rapid 'on-demand' laboratory-based SARS-CoV-2 diagnostic testing service in an acute hospital setting admitting COVID-19 patients.

BACKGROUND: With the onset of the COVID-19 pandemic in 2020, hospital clinical teams have realised that there is a need for a rapid, accurate testing facility that will allow them to move patients quickly into isolation rooms or specific COVID-19 cohort wards as soon as possible after admission. METHODS: Starting from July 2020, PCR-based test platforms, which could test 4-8 samples in parallel with turnaround (sample-to-result) times of 50-80 min, were placed in a satellite laboratory. This laboratory was on the same floor and within walking distance to the acute respiratory admissions ward. It was staffed by a team of three mid-Band 4 staff that split a 0700-2200 h-work day, 7 days a week, with 2 senior supervisors. Urgent sample testing was decided upon by the clinical teams and requested by phone. The test results were entered manually in real-time as they became available, and sent electronically to the requesting ward teams. RESULTS: The daily/monthly PCR positive test numbers approximately followed the local and national UK trend in COVID-19 case numbers, with the daily case numbers being reflective of the November and December 2020 surges. Test results were used to rapidly segregate positive patients into dedicated COVID-19 ward areas to minimise risk of potential nosocomial transmission in crowded waiting areas. Testing capacity was sufficient to include cases with uncertain diagnosis likely to require hospital admission. Following completion of other admission processes, based on these rapid test results, patients were allocated to dedicated COVID-19 positive or negative cohort wards. CONCLUSIONS: This rapid testing facility reduced unnecessary 'length-of-stay' in a busy acute respiratory ward. In the current absence of a treatment for mild-to-moderate COVID-19, on which patients could be discharged home to complete, the rapid test facility has become a successful aid to patient flow and reduced exposure and nosocomial transmission.

Specialist pneumonia intervention nurse service improves pneumonia care and outcome.

BACKGROUND: A specialist pneumonia intervention nursing (SPIN) service was set up across a single National Health Service Trust in an effort to improve clinical outcomes. A quality improvement evaluation was performed to assess the outcomes associated with implementing the service before (2011-2013) and after (2014-2016) service implementation. RESULTS: The SPIN service reviewed 38% of community-acquired pneumonia (CAP) admissions in 2014-2016. 82% of these admissions received antibiotic treatment in <4 hours (68.5% in the national audit). Compared with the pre-SPIN period, there was a significant reduction in both 30-day (OR=0.77 (0.70-0.85), p<0.0001) and in-hospital (OR=0.66 (0.60-0.73), p<0.0001) mortality after service implementation, with a review by the service showing the largest independent 30-day mortality benefit (HR=0.60 (0.53-0.67), p<0.0001). There was no change in length of stay (median 6 days). CONCLUSION: Implementation of a SPIN service improved adherence to BTS guidelines and achieved significant reductions in CAP-associated mortality. This enhanced model of care is low cost, highly effective and readily adoptable in secondary care.

Discovery and validation of a personalized risk predictor for incident tuberculosis in low transmission settings.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.

A Novel, High-sensitivity, Bacteriophage-based Assay Identifies Low-level Mycobacterium tuberculosis Bacteremia in Immunocompetent Patients With Active and Incipient Tuberculosis.

The haematogenous dissemination of Mycobacterium tuberculosis (Mtb) is critical to the pathogenesis of progressive tuberculous infections in animal models. Using a novel, phage-based blood assay, we report the first concordant evidence in well-characterized, immunocompetent human cohorts, demonstrating associations of Mtb bacteremia with progressive phenotypes of latent infection and active pulmonary tuberculosis.

Clinical utility of existing and second-generation interferon-γ release assays for diagnostic evaluation of tuberculosis: an observational cohort study.

BACKGROUND: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting. METHODS: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined. FINDINGS: Of the 1060 adults enrolled in the study, 845 were included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs. INTERPRETATION: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis. FUNDING: National Institute for Health Research.

A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection.

Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise the information from the entire transcriptome, which includes overabundance of type I interferon-inducible genes and underabundance of IFNG and TBX21, to develop a signature that discriminates active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. We suggest that methods targeting gene selection across multiple discriminant modules can improve the development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach, we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts.

A nested case-control study of predictors for tuberculosis recurrence in a large UK Centre.

BACKGROUND: Tuberculosis (TB) recurrence represents a challenge to control programs. In low incidence countries, the prevailing risk factors leading to recurrence are poorly characterised. METHODS: We conducted a nested case-control study using the Leicester TB service TBIT database. Cases were identified from database notifications between 1994 and 2014. Controls had one episode and were matched to cases on a ratio of two to one by the date of notification. Multiple imputation was used to account for missing data. Multivariate conditional logistic regression analysis was employed to identify clinical, sociodemographic and TB specific risk factors for recurrence. RESULTS: From a cohort of 4628 patients, 82 TB recurrences occurred (1.8%). Nineteen of 82 patients had paired isolates with MIRU-VNTR strain type profiles available, of which 84% were relapses and 16% reinfections. On multivariate analysis, smoking (OR 3.8; p = 0.04), grade 3/4 adverse drug reactions (OR 5.6; p = 0.02), ethnicity 'Indian subcontinent' (OR 8.5; p = <0.01), ethnicity 'other' (OR 31.2; p = 0.01) and receipt of immunosuppressants (OR 6.8; p = <0.01) were independent predictors of TB recurrence. CONCLUSIONS: Within this UK setting, the rate of TB recurrence was low, predominantly due to relapse. The identification of an elevated recurrence risk amongst the ethnic group contributing most cases to the national TB burden presents an opportunity to improve individual and population health.

Pulmonary Diseases in Refugees and Migrants in Europe.

More than 2 million people fleeing conflict, persecution, and poverty applied for asylum between 2015 and 2016 in the European Union. Due to this, medical practitioners in recipient countries may be facing a broader spectrum of conditions and unusual presentations not previously encountered, including a wide range of infections with pulmonary involvement. Tuberculosis is known to be more common in migrants and has been covered broadly in other publications. The scope of this review was to provide an overview of exotic infections with pulmonary involvement that could be encountered in refugees and migrants and to briefly describe their epidemiology, diagnosis, and management. As refugees and migrants travel from numerous countries and continents, it is important to be aware of the various organisms that might cause disease according to the country of origin. Some of these diseases are very rare and geographically restricted to certain regions, while others have a more cosmopolitan distribution. Also, the spectrum of severity of these infections can vary from very benign to severe and even life-threatening. We will also describe infectious and noninfectious complications that can be associated with HIV infection as some migrants might originate from high HIV prevalence countries in sub-Saharan Africa. As the diagnosis and treatment of these diseases can be challenging in certain situations, patients with suspected infection might require referral to specialized centers with experience in their management. Additionally, a brief description of noncommunicable pulmonary diseases will be provided.

Survival following pulmonary rehabilitation in patients with COPD: the effect of program completion and change in incremental shuttle walking test distance.

Rationale: Pulmonary rehabilitation (PR) in patients with COPD has consistently been shown to produce benefits in exercise capacity, symptoms, and health status. The data surrounding survival following PR are less clear. Our aims were to compare the long-term survival in two cohorts of patients referred for PR; those who successfully completed PR, and a comparator group constructed from patients who either did not complete PR or did not start the program. Additionally, we compared survival between those people who were able to achieve a clinically meaningful improvement in exercise capacity (incremental shuttle walking test) following PR with those who were not. Methods: A retrospective longitudinal analysis of clinical service outcomes was conducted to compare the long-term survival in "completers" and "non-completers" of rehabilitation at two hospitals within the University Hospitals of Leicester NHS Trust from January 1, 2000 to February 23, 2012. For "completers", we also analyzed survival in those meeting (and not meeting) the desired level of change in the incremental shuttle walking test (≥50 m vs <50 m). Results: We present to you the largest dataset on this topic (n=1,515). Survival data were ascertained for 823 (54.3%) patients with COPD who had completed a course of PR and for 692 (45.7%) patients who dropped out. Survival time was significantly greater in "completers" compared to "non-completers" of PR (p<0.001). In addition, PR success (≥50 m change in walking distance) was also associated with improved survival (p<0.05). Conclusion: The data show an association between completion of PR and survival. In addition, PR success (>50 m change in walking distance) was also associated with improved survival.