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  • Journal article
    Philip K, Owles H, McVey S, Pagnuco T, Bruce K, Harry B, Banya W, Mollica J, Lound A, Zumpe S, Abrahams A, Padmanaban V, Hardy T, Lewis A, Lalvani A, Elkin S, Hopkinson Net al., 2022,

    Impact of an online breathing and wellbeing programme (ENO Breathe) in people with persistent symptoms following COVID-19: a randomised controlled trial

    , The Lancet Respiratory Medicine, Vol: 60, ISSN: 2213-2600

    Aims: ENO Breathe is an online breathing and wellbeing programme for people with Long COVID focusing on breathing re-training using singing techniques.Aim: to assess whether ENO Breathe improves health related quality-of-life (HRQoL) in people with persistent breathlessness following COVID-19.Method:A parallel-group, single-blind, RCT, comparing ENO Breathe(6 weeks) with usual care in adults, with persisting breathlessness +/− anxiety, following assessment at an NHS Long COVID clinic.Primary outcome: change in HRQoL using the RAND SF-36 Mental(MHC) and Physical(PHC) Health Composite Scores.Secondary outcomes: CAT, VAS for breathlessness (rest, walking, stairs, and running), Dysp-12, GAD-7. Participant experience was assessed using focus groups and free-text responses.Results: 150 participants (mean(SD) 49(12)years, 81% female, 320(127) days symptomatic; ENO Breathe(n=74), Control(n=76). ENO Breathe was associated with improvement in MHC of 2.42 points (95%CI 0.03 to 4.80, p=0.045), but not PHC 0.6 (-1.33 to 2.52, p=0.541). VAS breathlessness (running) favoured ENO Breathe -10.48(-17.23 to -3.73, p=0.003). Three participant experience themes were identified 1) improvements in symptoms; 2) feeling that the programme was complementary to standard care; 3) the particular suitability of singing and music to address their needs.Conclusion: An online breathing and wellbeing programme can improve the mental component of HRQoL and elements of breathlessness in people with persisting symptoms after COVID-19. Mind-body and music-based approaches, including practical, enjoyable symptom-management techniques may have a role supporting recovery.

  • Journal article
    Houston H, Hakki S, Pillay TD, Madon K, Derqui-Fernandez N, Koycheva A, Singanayagam A, Fenn J, Kundu R, Conibear E, Varro R, Cutajar J, Quinn V, Wang L, Narean JS, Tolosa-Wright MR, Barnett J, Kon OM, Tedder R, Taylor G, Zambon M, Ferguson N, Dunning J, Deeks JJ, Lalvani Aet al., 2022,

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

    , European Respiratory Journal, Vol: 60, Pages: 1-13, ISSN: 0903-1936

    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.Tweetable abstract @ERSpublications

  • Journal article
    Elliott P, Eales O, Steyn N, Tang D, Bodinier B, Wang H, Elliott J, Whitaker M, Atchison C, Diggle PJ, Page AJ, Trotter AJ, Ashby D, Barclay W, Taylor G, Ward H, Darzi A, Cooke GS, Donnelly CA, Chadeau-Hyam Met al., 2022,

    Twin peaks: The Omicron SARS-CoV-2 BA.1 and BA.2 epidemics in England.

    , Science, Vol: 376

    Rapid transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has led to record-breaking incidence rates around the world. The Real-time Assessment of Community Transmission-1 (REACT-1) study has tracked SARS-CoV-2 infection in England using reverse transcription polymerase chain reaction (RT-PCR) results from self-administered throat and nose swabs from randomly selected participants aged 5 years and older approximately monthly from May 2020 to March 2022. Weighted prevalence in March 2022 was the highest recorded in REACT-1 at 6.37% (N = 109,181), with the Omicron BA.2 variant largely replacing the BA.1 variant. Prevalence was increasing overall, with the greatest increase in those aged 65 to 74 years and 75 years and older. This was associated with increased hospitalizations and deaths, but at much lower levels than in previous waves against a backdrop of high levels of vaccination.

  • Journal article
    Halliday A, Masonou T, Tolosa-Wright MR, Guo Y, Hoang L, Parker R, Boakye A, Takwoingi Y, Badhan A, Jain P, Marwah I, Berrocal-Almanza LC, Deeks J, Beverley P, Kon OM, Lalvani Aet al., 2022,

    Defining the role of cellular immune signatures in diagnostic evaluation of suspected tuberculosis

    , Journal of Infectious Diseases, Vol: 225, Pages: 1632-1641, ISSN: 0022-1899

    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.

  • Journal article
    Norris T, Razieh C, Yates T, Zaccardi F, Gillies CL, Chudasama YV, Rowlands A, Davies MJ, McCann GP, Banerjee A, Docherty AB, Openshaw PJM, Baillie JK, Semple MG, Lawson CA, Khunti Ket al., 2022,

    Admission blood glucose level and its association with cardiovascular and renal complications in patients hospitalized with COVID-19

    , Diabetes Care, Vol: 45, Pages: 1132-1140, ISSN: 0149-5992

    OBJECTIVE: To investigate the association between admission blood glucose levels and risk of in-hospital cardiovascular and renal complications. RESEARCH DESIGN AND METHODS: In this multicenter prospective study of 36,269 adults hospitalized with COVID-19 between 6 February 2020 and 16 March 2021 (N = 143,266), logistic regression models were used to explore associations between admission glucose level (mmol/L and mg/dL) and odds of in-hospital complications, including heart failure, arrhythmia, cardiac ischemia, cardiac arrest, coagulation complications, stroke, and renal injury. Nonlinearity was investigated using restricted cubic splines. Interaction models explored whether associations between glucose levels and complications were modified by clinically relevant factors. RESULTS: Cardiovascular and renal complications occurred in 10,421 (28.7%) patients; median admission glucose level was 6.7 mmol/L (interquartile range 5.8-8.7) (120.6 mg/dL [104.4-156.6]). While accounting for confounders, for all complications except cardiac ischemia and stroke, there was a nonlinear association between glucose and cardiovascular and renal complications. For example, odds of heart failure, arrhythmia, coagulation complications, and renal injury decreased to a nadir at 6.4 mmol/L (115 mg/dL), 4.9 mmol/L (88.2 mg/dL), 4.7 mmol/L (84.6 mg/dL), and 5.8 mmol/L (104.4 mg/dL), respectively, and increased thereafter until 26.0 mmol/L (468 mg/dL), 50.0 mmol/L (900 mg/dL), 8.5 mmol/L (153 mg/dL), and 32.4 mmol/L (583.2 mg/dL). Compared with 5 mmol/L (90 mg/dL), odds ratios at these glucose levels were 1.28 (95% CI 0.96, 1.69) for heart failure, 2.23 (1.03, 4.81) for arrhythmia, 1.59 (1.36, 1.86) for coagulation complications, and 2.42 (2.01, 2.92) for renal injury. For most complications, a modifying effect of age was observed, with higher odds of complications at higher glucose levels for patients age <69 years. Preexisting diabetes status had a similar modifying effect on odds of c

  • Journal article
    Swets MC, Russell CD, Harrison EM, Docherty AB, Lone N, Girvan M, Hardwick HE, Investigators I, Visser LG, Openshaw PJM, Groeneveld GH, Semple MG, Baillie JKet al., 2022,

    SARS-CoV-2 co-infection with influenza viruses, respiratory syncytial virus, or adenoviruses

    , LANCET, Vol: 399, Pages: 1463-1464, ISSN: 0140-6736
  • Journal article
    Park M, Lalvani A, Satta G, Kon OMet al., 2022,

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

    , BMC Infectious Diseases, Vol: 22, Pages: 1-10, ISSN: 1471-2334

    BackgroundThe 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.MethodsThis 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.Results189 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.ConclusionWGS 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

  • Journal article
    Walker TM, Miotto P, Köser CU, Fowler PW, Knaggs J, Iqbal Z, Hunt M, Chindelevitch L, Farhat M, Cirillo DM, Comas I, Posey J, Omar SV, Peto TE, Suresh A, Uplekar S, Laurent S, Colman RE, Nathanson C-M, Zignol M, Walker AS, CRyPTIC Consortium, Seq&Treat Consortium, Crook DW, Ismail N, Rodwell TCet al., 2022,

    The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

    , The Lancet Microbe, Vol: 3, Pages: e265-e273, ISSN: 2666-5247

    Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: This first WHO endorsed catalogue of mol

  • Journal article
    Chadeau-Hyam M, Wang H, Eales O, Haw D, Bodinier B, Whitaker M, Walters CE, Ainslie KEC, Atchison C, Fronterre C, Diggle PJ, Page AJ, Trotter AJ, Ashby D, Barclay W, Taylor G, Cooke G, Ward H, Darzi A, Riley S, Donnelly CA, Elliott P, Chadeau M, Wang H, Eales O, Haw D, Bodinier B, Whitaker M, Walters C, Ainslie K, Atchison C, Fronterre C, Diggle P, Page A, Trotter A, Ashby D, Barclay W, Taylor G, Cooke G, Ward H, Darzi A, Riley S, Donnelly C, Elliott Pet al., 2022,

    SARS-CoV-2 infection and vaccine effectiveness in England (REACT-1): a series of cross-sectional random community surveys

    , The Lancet Respiratory Medicine, Vol: 10, Pages: 355-366, ISSN: 2213-2600

    SummaryBackground England has experienced a third wave of the COVID-19 epidemic since the end of May, 2021, coincidingwith the rapid spread of the delta (B.1.617.2) variant, despite high levels of vaccination among adults. Vaccinationrates (single dose) in England are lower among children aged 16–17 years and 12–15 years, whose vaccination inEngland commenced in August and September, 2021, respectively. We aimed to analyse the underlying dynamicsdriving patterns in SARS-CoV-2 prevalence during September, 2021, in England.Methods The REal-time Assessment of Community Transmission-1 (REACT-1) study, which commenced datacollection in May, 2020, involves a series of random cross-sectional surveys in the general population of Englandaged 5 years and older. Using RT-PCR swab positivity data from 100 527 participants with valid throat and noseswabs in round 14 of REACT-1 (Sept 9–27, 2021), we estimated community-based prevalence of SARS-CoV-2 andvaccine effectiveness against infection by combining round 14 data with data from round 13 (June 24 to July 12, 2021;n=172 862).Findings During September, 2021, we estimated a mean RT-PCR positivity rate of 0·83% (95% CrI 0·76–0·89), with areproduction number (R) overall of 1·03 (95% CrI 0·94–1·14). Among the 475 (62·2%) of 764 sequenced positiveswabs, all were of the delta variant; 22 (4·63%; 95% CI 3·07–6·91) included the Tyr145His mutation in the spikeprotein associated with the AY.4 sublineage, and there was one Glu484Lys mutation. Age, region, key worker status,and household size jointly contributed to the risk of swab positivity. The highest weighted prevalence was observedamong children aged 5–12 years, at 2·32% (95% CrI 1·96–2·73) and those aged 13–17 years, at 2·55% (2·11–3·08).The SARS-CoV-2 epidemic grew in those aged 5–11 years, with an R of 1&m

  • Journal article
    Killingley B, Mann AJ, Kalinova M, Boyers A, Goonawardane N, Zhou J, Lindsell K, Hare SS, Brown J, Frise R, Smith E, Hopkins C, Noulin N, Londt B, Wilkinson T, Harden S, McShane H, Baillet M, Gilbert A, Jacobs M, Charman C, Mande P, Nguyen-Van-Tam JS, Semple MG, Read RC, Ferguson NM, Openshaw PJ, Rapeport G, Barclay WS, Catchpole AP, Chiu Cet al., 2022,

    Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults

    , Nature Medicine, Vol: 28, Pages: 1031-1041, ISSN: 1078-8956

    Since its emergence in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused hundreds of millions of cases and continues to circulate globally. To establish a novel SARS-CoV-2 human challenge model that enables controlled investigation of pathogenesis, correlates of protection and efficacy testing of forthcoming interventions, 36 volunteers aged 18–29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally in an open-label, non-randomized study ( identifier NCT04865237; funder, UK Vaccine Taskforce). After inoculation, participants were housed in a high-containment quarantine unit, with 24-hour close medical monitoring and full access to higher-level clinical care. The study’s primary objective was to identify an inoculum dose that induced well-tolerated infection in more than 50% of participants, with secondary objectives to assess virus and symptom kinetics during infection. All pre-specified primary and secondary objectives were met. Two participants were excluded from the per-protocol analysis owing to seroconversion between screening and inoculation, identified post hoc. Eighteen (~53%) participants became infected, with viral load (VL) rising steeply and peaking at ~5 days after inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies per milliliter (median, 95% confidence interval (8.41, 9.53)). Viable virus was recoverable from the nose up to ~10 days after inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected participants, beginning 2–4 days after inoculation, whereas two (11%) participants remained asymptomatic (no reportable symptoms). Anosmia or dysosmia developed more slowly in 15 (83%) participants. No quantitative cor

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