Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease.

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD): Epidemiology, diagnosis and multidisciplinary management.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause significant disease in both immunocompromised and immunocompetent individuals. The incidence of NTM pulmonary disease (NTM-PD) is rising globally. Diagnostic challenges persist and treatment efficacy is variable. This article provides an overview of NTM-PD for clinicians. We discuss how common it is, who is at risk, how it is diagnosed and the multidisciplinary approach to its clinical management.

Obesity dysregulates the pulmonary antiviral immune response.

Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.

Silicosis, tuberculosis and silica exposure among artisanal and small-scale miners: A systematic review and modelling paper.

An estimated 44 million artisanal and small-scale miners (ASM), largely based in developing economies, face significant occupational risks for respiratory diseases which have not been reviewed. We therefore aimed to review studies that describe silicosis and tuberculosis prevalence and respirable crystalline silica (RCS) exposures among ASM and use background evidence to better understand the relationship between exposures and disease outcomes. We searched PubMed, Web of Science, Scopus and Embase for studies published before the 24th March 2023. Our primary outcome of interest was silicosis or tuberculosis among ASM. Secondary outcomes included measurements of respirable dust or silica, spirometry and prevalence of respiratory symptoms. A systematic review and narrative synthesis was performed and risk of bias assessed using the Joanna Briggs Prevalence Critical Appraisal Tool. Logistic and Poisson regression models with predefined parameters were used to estimate silicosis prevalence and tuberculosis incidence at different distributions of cumulative silica exposure. We identified 18 eligible studies that included 29,562 miners from 13 distinct populations in 10 countries. Silicosis prevalence ranged from 11 to 37%, despite four of five studies reporting an average median duration of mining of <6 years. Tuberculosis prevalence was high; microbiologically confirmed disease ranged from 1.8 to 6.1% and clinical disease 3.0 to 17%. Average RCS intensity was very high (range 0.19-89.5 mg/m3) and respiratory symptoms were common. Our modelling demonstrated decreases in cumulative RCS are associated with reductions in silicosis and tuberculosis, with greater reductions at higher mean exposures. Despite potential selection and measurement bias, prevalence of silicosis and tuberculosis were high in the studies identified in this review. Our modelling demonstrated the greatest respiratory health benefits of reducing RCS are in those with highest exposures. ASM face a high occupational respiratory disease burden which can be reduced by low-cost and effective reductions in RCS.

Chest CT features and functional correlates of COVID-19 at 3 months and 12 months follow-up.

Long-term pulmonary sequelae of Coronavirus 2019 (COVID-19) remain unclear. Thus, we aimed to establish post-COVID-19 temporal changes in chest computed tomography (CT) features of pulmonary fibrosis and to investigate associations with respiratory symptoms and physiological parameters at 3 and 12 months' follow-up. Adult patients who attended our initial COVID-19 follow-up service and developed chest CT features of interstitial lung disease, in addition to cases identified using British Society of Thoracic Imaging codes, were evaluated retrospectively. Clinical data were gathered on respiratory symptoms and physiological parameters at baseline, 3 months, and 12 months. Corresponding chest CT scans were reviewed by two thoracic radiologists. Associations between CT features and functional correlates were estimated using random effects logistic or linear regression adjusted for age, sex and body mass index. In total, 58 patients were assessed. No changes in reticular pattern, honeycombing, traction bronchiectasis/bronchiolectasis index or pulmonary distortion were observed. Subpleural curvilinear lines were associated with lower odds of breathlessness over time. Parenchymal bands were not associated with breathlessness or impaired lung function overall. Based on our results, we conclude that post-COVID-19 chest CT features of irreversible pulmonary fibrosis remain static over time; other features either resolve or remain unchanged. Subpleural curvilinear lines do not correlate with breathlessness. Parenchymal bands are not functionally significant. An awareness of the different potential functional implications of post-COVID-19 chest CT changes is important in the assessment of patients who present with multi-systemic sequelae of COVID-19 infection.

Vulnerability and tuberculosis treatment outcomes in urban settings in England: A mixed-methods study.

BACKGROUND: Evidence on factors contributing to poor treatment outcome and healthcare priorities in vulnerable populations affected by tuberculosis (TB) in urban areas of England other than London is needed to inform setting-specific prevention and care policies. We addressed this knowledge gap in a cohort of TB patients and healthcare providers in Birmingham and Leicester, UK. METHODS: A mixed-methods study was performed. Logistic regression was used to identify TB patients more likely to have poor treatment outcomes according to clinical and demographic characteristics and social risk factors (SRFs) in a 2013-18 cohort. 25 semi-structured interviews were undertaken in purposely selected individuals (9 patients and 16 healthcare professionals) to glean insights on their healthcare priorities and the factors that contribute to poor treatment outcome. RESULTS: The quantitative cohort comprised 2252 patients. Those who were ≥ 55 years of age, foreign-born from Central Europe, East Asia and Sub Saharan Africa and with MDR-TB were more likely to have poor treatment outcomes. According to patients and healthcare professionals, the factors that contribute to vulnerability to develop TB and poor treatment outcomes include poor working and living conditions, inadequate or absent welfare protection, poor primary healthcare responsiveness, treatment duration and side effects. These factors could be addressed by increased networking, partnership and integration between healthcare and social services and better integration between primary and secondary healthcare. CONCLUSIONS: In both cities, being ≥ 55 years of age, having MDR-TB and being of foreign-birth are predictors of unfavourable treatment outcome. Risk of poor treatment outcome and vulnerability seem to be multidimensional. A better understanding of specific vulnerabilities and how they affect patient care pathway is needed to design adequate support programmes.

Anti-tubercular therapy in the treatment of tubercular uveitis: A systematic review and meta-analysis.

We quantitatively evaluated the efficacy of antitubercular therapy (ATT) in tubercular uveitis (TBU) patients. Main outcome measures include inflammation recurrence, inflammation reduction, complete resolution of inflammation, improved visual acuity (VA), ability to taper corticosteroids to < 10 mg/day without inflammatory progression, and use of adjunctive immunosuppressants while on ATT. This review is prospectively registered in PROSPERO (CRD42020206845). Forty-nine studies reporting data for 4,017 TBU patients were included. In comparative studies, the odds ratio (OR) of inflammatory recurrence was 0.33 (95%CI:0.19-0.60) for TBU patients treated with ATT±corticosteroid versus no ATT. For TBU patients treated with ATT±corticosteroid, the pooled absolute incidences of inflammatory recurrence, inflammatory reduction, complete resolution of inflammation, and visual acuity improvement were 13% (n=310/2,216; 95%CI:9-18), 81% (n=217/276; 95%CI: 62-95), 83% (n=1,167/1,812; 95%CI: 77-89), and 65% (n=347/542; 95%CI:51-78), respectively. Corticosteroids were tapered to <10 mg/day without inflammatory progression in 91% (n=326/395; 95%CI:78-99) of patients, 9% (n=121/1,376; 95%CI:6-13) of whom were administered concomitant immunosuppressive agents alongside ATT. We conclude that treatment of TBU with ATT±corticosteroid is associated with a high level of control or improvement of inflammation. More prospective studies with detailed reporting of ATT regimens, patient subgroups, and outcomes are required to better evaluate ATT effectiveness.

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination.

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript.

Interferon-γ release assay screening in biologics: safe and reliable, but not perfect.

Background: Systemic biologic agents can increase the risk of re-activation of latent tuberculosis (TB). Prior to initiation, screening for latent TB using an interferon-γ release assay (IGRA) is recommended. There is concern that false-negative IGRAs may be more likely in this context. Methods: This retrospective analysis of IGRAs, specifically T-SPOT.TB, results and outcomes of patients already on or due to start biologics identifies the rate of TB re-activation in a low TB incidence setting. Additionally, we estimate the negative predictive value (NPV) of IGRAs in this population. Results: Patients on biologics were more likely to have a negative IGRA result than patients not on biologics. There was no statistically significant change in conversion or reversion rates between groups. Of 9263 patients on biologics, 19 developed active TB after starting biologics at an incidence rate of 55.1 per 100 000 patient-years. This occurred despite screening in half of the 16 patients for whom we were able to review medical records. Most drugs implicated were known to be high risk, although rituximab and natalizumab were being taken by five patients and one patient, respectively. The T-SPOT.TB NPV was 99.20% and dropped only slightly to 99.17% when we simulated an approach where all borderline IGRA results were regarded as being negative. Conclusions: Negative IGRA results confer a low risk of subsequent active TB in patients on biologics in a low TB incidence setting. However, continued awareness is needed given that a number of active TB cases will have had a prior negative result.

Recovering from COVID-19: lessons learnt from an intensive secondary care follow-up service.

In response to the first COVID-19 surge in 2020, secondary care outpatient services were rapidly reconfigured to provide specialist review for disease sequelae. At our institution, comprising hospitals across three sites in London, we initially implemented a COVID-19 follow-up pathway that was in line with expert opinion at the time but more intensive than initial clinical guidelines suggested. We retrospectively evaluated the resource requirements for this service, which supported 526 patients from April 2020 to October 2020. At the 6-week review, 193/403 (47.9%) patients reported persistent breathlessness, 46/336 (13.7%) desaturated on exercise testing, 167/403 (41.4%) were discharged from COVID-19-related secondary care services and 190/403 (47.1%) needed 12-week follow-up. At the 12-week review, 113/309 (36.6%) patients reported persistent breathlessness, 30/266 (11.3%) desaturated on exercise testing and 150/309 (48.5%) were discharged from COVID-19-related secondary care services. Referrals were generated to multiple medical specialties, particularly respiratory subspecialties. Our analysis allowed us to justify rationalising and streamlining provisions for subsequent COVID-19 waves while reassured that opportunities for early intervention were not being missed.

Intestinal perforation due to miliary tuberculosis in a patient with myasthenia gravis.

A man in his early 70s presented to the emergency department with a fall, following a history of fatigue and malodorous urine. On presentation, he was feverish, tachycardic and confused and was treated for presumed urinary sepsis. A chest radiograph showed increased opacification in the left upper lobe with calcification. CT imaging and bronchoalveolar lavage demonstrated miliary tuberculosis infection. His background included myasthenia gravis, which led to challenges in selecting appropriate antituberculosis treatment. During his stay, he developed sudden-onset abdominal pain due to intestinal perforation. He subsequently deteriorated and underwent multiple interventions, including a Hartmann's procedure and ileocaecal resection. Histological examination of his sigmoid colon revealed abundant acid-fast bacilli. Unfortunately, the patient died due to multiorgan failure in the context of several complications. This case highlights intestinal perforation as a rare complication of miliary tuberculosis and emphasises the importance of being vigilant for this potential complication.

Diagnosis of tuberculosis in dialysis and kidney transplant patients.

BACKGROUND AND OBJECTIVES: In patients with chronic kidney disease the risk of developing Tuberculosis is increased, while the presentation is often atypical making the diagnosis more difficult. The aim of this study is to describe the presentation of Tuberculosis in dialysis and kidney transplant patients, including the range of diagnostic approaches and the utility of different sample types. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: In this retrospective study, case records of dialysis and kidney transplant patients were reviewed, including all those treated for Tuberculosis between January 2009 and December 2020. RESULTS: Over 12 years, there were 143 cases of Tuberculosis in 141 patients (aged 17-86, 50.4% male). Tuberculosis was most common in Asian patients (64%) and those receiving hemodialysis (82%), particularly during the first year after dialysis initiation (54% of dialysis cases). Non-pleural/pulmonary disease accounted 40% of cases, and non-organ-specific presenting features were prominent including fever, lymphadenopathy, and weight loss. The diagnosis was confirmed microbiologically or histologically in 87 cases (61%), with low sensitivity observed for many types of samples including sputum (18%) and pleural fluid (12%). Higher sensitivity was observed with tissue samples including bronchoscopic lymph node aspiration (75%) and other lymph node sampling (92%). In the 52 cases where drug sensitivities were available, resistance to a first line treatment, most commonly isoniazid, was seen in 12 cases (23%). Furthermore, 1- and 5-year survival from diagnosis were 78% and 61%, respectively. Baseline variables independently associated with poorer survival were age (OR 1.8 per decade, 95% CI 1.4-2.3), weight loss over 10% (OR 1.9, 95% CI 1.0-3.5), and a non-confirmed diagnosis (OR 1.6, 95% CI 1.2-2.1). CONCLUSIONS: Tuberculosis is common in dialysis and kidney transplant patients, particularly during the first year of dialysis. Short-term mortality is high, but the diagnostic sensitivity of many types of samples is low, so that diagnosis is difficult, with treatment often initiated without confirmation. These data highlight the importance of judgment and clinical experience with this complex patient group.

Evaluating the clinical impact of routine whole genome sequencing in tuberculosis treatment decisions and the issue of isoniazid mono-resistance.

BACKGROUND: The UK has implemented routine use of whole genome sequencing (WGS) in TB diagnostics. The WHO recommends addition of a fluoroquinolone for isoniazid mono-resistance, so early detection may be of use. The aim of this study was to describe the clinical utility and impact of WGS on treatment decisions for TB in a low incidence high resource clinical setting. The clinical turnaround time (TAT) for WGS was analysed in comparison to TB PCR using Xpert MTB/RIF (Cepheid, Sunnyvale, CA) results where available and subsequent phenotypic drug susceptibility testing (DST) when required. METHODS: This was a retrospective analysis of TB cases from January 2018 to March 2019 in London. Susceptibility and TAT by WGS, phenotypic DST, TB PCR using Xpert MTB/RIF were correlated to drug changes in order to describe the utility of WGS on treatment decisions on isoniazid mono-resistance in a low incidence high resource setting. RESULTS: 189 TB cases were identified; median age 44 years (IQR 28-60), m:f ratio 112:77, 7 with HIV and 6 with previous TB. 80/189 cases had a positive culture and WGS result. 50/80 were fully sensitive to 1st line treatment on WGS, and the rest required additional DST. 20/80 cases required drug changes; 12 were defined by WGS: 8 cases had isoniazid mono-resistance, 2 had MDR-TB, 1 had isoniazid and pyrazinamide resistance and 1 had ethambutol resistance. The median TAT for positive culture was 16 days (IQR 12.5-20.5); for WGS was 35 days (IQR 29.5-38.75) and for subsequent DST was 86 days (IQR 69.5-96.75), resulting in non-WHO regimens for a median of 50.5 days (IQR 28.0-65.0). 9/12 has TB PCRs (Xpert MTB/RIF), with a median TAT of 1 day. CONCLUSION: WGS clearly has a substantial role in our routine UK clinical settings with faster turnaround times in comparison to phenotypic DST. However, the majority of treatment changes defined by WGS were related to isoniazid resistance and given the 1 month TAT for WGS, it would be preferable to identify isoniazid resistance more quickly. Therefore if resources allow, diagnostic pathways should be optimised by parallel use of WGS and new molecular tests to rapidly identify isoniazid resistance in addition to rifampicin resistance and to minimise delays in starting WHO isoniazid resistance treatment.

BTS clinical statement for the diagnosis and management of ocular tuberculosis.

The BTS clinical statement for the diagnosis and management of ocular tuberculosis (TB) draws on the expertise of both TB and and ophthalmic specialists to outline the current understanding of disease pathogenesis, diagnosis and management in adults. Published literature lacks high-quality evidence to inform clinical practice and there is also a paucity of data from animal models to elucidate mechanisms of disease. However, in order to improve and standardise patient care, this statement provides consensus points with the currently available data and agreed best practice.

Effectiveness of nationwide programmatic testing and treatment for latent tuberculosis infection in migrants in England: a retrospective, population-based cohort study.

BACKGROUND: In low-incidence countries, tuberculosis mainly affects migrants, mostly resulting from reactivation of latent tuberculosis infection (LTBI) acquired in high-incidence countries before migration. A nationwide primary care-based LTBI testing and treatment programme for migrants from high-incidence countries was therefore established in high tuberculosis incidence areas in England. We aimed to assess the effectiveness of this programme. METHODS: We did a retrospective, population-based cohort study of migrants who registered in primary care between Jan 1, 2011, and Dec 31, 2018, in 55 high-burden areas with programmatic LTBI testing and treatment. Eligible individuals were aged 16-35 years, born in a high-incidence country, and had entered England in the past 5 years. Individuals who tested interferon-γ release assay (IGRA)-negative were advised about symptoms of tuberculosis, whereas those who tested IGRA-positive were clinically assessed to rule out active tuberculosis and offered preventive therapy. The primary outcome was incident tuberculosis notified to the national Enhanced Tuberculosis Surveillance system. FINDINGS: Our cohort comprised 368 097 eligible individuals who had registered in primary care, of whom 37 268 (10·1%) were tested by the programme. 1446 incident cases of tuberculosis were identified: 166 cases in individuals who had IGRA testing (incidence 204 cases [95% CI 176-238] per 100 000 person-years) and 1280 in individuals without IGRA testing (82 cases [77-86] per 100 000 person-years). Overall, in our primary analysis including all diagnosed tuberculosis cases, a time-varying association was identified between LTBI testing and treatment and lower risk of incident tuberculosis (hazard ratio [HR] 0·76 [95% CI 0·63-0·91]) when compared with no testing. In stratified analysis by follow-up period, the intervention was associated with higher risk of tuberculosis diagnosis during the first 6 months of follow-up (9·93 [7·63-12·9) and a lower risk after 6 months (0·57 [0·41-0·79]). IGRA-positive individuals had higher risk of tuberculosis diagnosis than IGRA-negative individuals (31·9 [20·4-49·8]). Of 37 268 migrants who were tested, 6640 (17·8%) were IGRA-positive, of whom 1740 (26·2%) started preventive treatment. LTBI treatment lowered the risk of tuberculosis: of 135 incident cases in the IGRA-positive cohort, seven cases were diagnosed in the treated group (1·87 cases [95% CI 0·89-3·93] per 1000 person-years) and 128 cases were diagnosed in the untreated group (10·9 cases [9·16-12·9] per 1000 person-years; HR 0·14 [95% CI 0·06-0·32]). INTERPRETATION: A low proportion of eligible migrants were tested by the programme and a small proportion of those testing positive started treatment. Despite this, programmatic LTBI testing and treatment of individuals migrating to a low-incidence region is effective at diagnosing active tuberculosis earlier and lowers the long-term risk of progression to tuberculosis. Increasing programme participation and treatment rates for those testing positive could substantially impact national tuberculosis incidence. FUNDING: National Institute for Health Research Health Protection Research Unit in Respiratory Infections.

Utility of Esophageal Ultrasound-guided Biopsy of Mediastinal Lymph Nodes in Diagnosis of Childhood Tuberculosis.

A 6-year-old boy with autistic spectrum disorder was diagnosed with tuberculosis infection following contact tracing of his mother who had isoniazid-resistant pulmonary tuberculosis. He progressed to develop mediastinal lymphadenopathy causing a persistent cough. He was too small to undergo endobronchial ultrasound-guided biopsy. As an alternative, he underwent esophageal endoscopic ultrasound-guided biopsy, leading to confirmation of the diagnosis. We believe this approach to diagnostic biopsy is underrecognized in pediatric practice, and highlight its utility with this case and a brief literature review.

Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial.

BACKGROUND AND AIMS: The chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesised that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses. METHODS: Atopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomised to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 3 weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection. RESULTS: Six subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant-treated and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0-14 (difference 3.0 (95% CI -29.0 to 17.0), p=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo-treated but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events or drug-related withdrawals. CONCLUSION: Timapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.

Broadening symptom criteria improves early case identification in SARS-CoV-2 contacts.

BACKGROUND: The success of case isolation and contact tracing for the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission depends on the accuracy and speed of case identification. We assessed whether inclusion of additional symptoms alongside three canonical symptoms (CS), i.e. fever, cough and loss or change in smell or taste, could improve case definitions and accelerate case identification in SARS-CoV-2 contacts. METHODS: Two prospective longitudinal London (UK)-based cohorts of community SARS-CoV-2 contacts, recruited within 5 days of exposure, provided independent training and test datasets. Infected and uninfected contacts completed daily symptom diaries from the earliest possible time-points. Diagnostic information gained by adding symptoms to the CS was quantified using likelihood ratios and area under the receiver operating characteristic curve. Improvements in sensitivity and time to detection were compared with penalties in terms of specificity and number needed to test. RESULTS: Of 529 contacts within two cohorts, 164 (31%) developed PCR-confirmed infection and 365 (69%) remained uninfected. In the training dataset (n=168), 29% of infected contacts did not report the CS. Four symptoms (sore throat, muscle aches, headache and appetite loss) were identified as early-predictors (EP) which added diagnostic value to the CS. The broadened symptom criterion "≥1 of the CS, or ≥2 of the EP" identified PCR-positive contacts in the test dataset on average 2 days earlier after exposure (p=0.07) than "≥1 of the CS", with only modest reduction in specificity (5.7%). CONCLUSIONS: Broadening symptom criteria to include individuals with at least two of muscle aches, headache, appetite loss and sore throat identifies more infections and reduces time to detection, providing greater opportunities to prevent SARS-CoV-2 transmission.

Defining the Role of Cellular Immune Signatures in Diagnostic Evaluation of Suspected Tuberculosis.

BACKGROUND: Diagnosis of paucibacillary tuberculosis (TB) including extrapulmonary TB is a significant challenge, particularly in high-income, low-incidence settings. Measurement of Mycobacterium tuberculosis (Mtb)-specific cellular immune signatures by flow cytometry discriminates active TB from latent TB infection (LTBI) in case-control studies; however, their diagnostic accuracy and clinical utility in routine clinical practice is unknown. METHODS: Using a nested case-control study design within a prospective multicenter cohort of patients presenting with suspected TB in England, we assessed diagnostic accuracy of signatures in 134 patients who tested interferon-gamma release assay (IGRA)-positive and had final diagnoses of TB or non-TB diseases with coincident LTBI. Cellular signatures were measured using flow cytometry. RESULTS: All signatures performed less well than previously reported. Only signatures incorporating measurement of phenotypic markers on functional Mtb-specific CD4 T cells discriminated active TB from non-TB diseases with LTBI. The signatures measuring HLA-DR+IFNγ + CD4 T cells and CD45RA-CCR7-CD127- IFNγ -IL-2-TNFα + CD4 T cells performed best with 95% positive predictive value (95% confidence interval, 90-97) in the clinically challenging subpopulation of IGRA-positive but acid-fast bacillus (AFB) smear-negative TB suspects. CONCLUSIONS: Two cellular immune signatures could improve and accelerate diagnosis in the challenging group of patients who are IGRA-positive, AFB smear-negative, and have paucibacillary TB.