TY  - JOUR
AB  - Background: Sequelae post-SARS-CoV-2 infection, including lung and functional impairment, pose a significant challenge post-recovery. We explored the burden and risk factors for post-COVID-19 sequelae in an African population with prevalent comorbidities including tuberculosis (TB) and HIV. Methods: We conducted an observational cohort study on hospitalised adults with confirmed SARS-CoV-2 infection from 20 March to 06 October 2021 at Chris Hani Baragwanath Academic Hospital, South Africa. We collected data on comorbidities, and COVID-19 severity using the World Health Organization (WHO) clinical progression scale. Prospectively, we followed up all participants within 40-days post-discharge to assess body mass index (BMI), COVID-19 symptoms and quality of life using St George's Respiratory Questionnaire (SGRQ), 6-min walking-test (6MWT), and spirometry. A subsequent in-depth visit assessed plethysmography, diffusing capacity for the lung for carbon monoxide (DLCO), and high-resolution chest-CT. Findings: We followed up 111 participants, where 65.8% were female, median age 50.5 years, and predominantly black-African (92.8%). Relevant comorbidities included TB disease (18.9%) and HIV infection (36%). SGRQ total scores were elevated in 78.9%, median 6MWT distance was reduced at 300 m (IQR 210–400), and nearly half (49.5%) exhibited spirometry findings below the lower limit of normal (LLN). In-depth pulmonary assessment for 61 participants revealed abnormalities in total lung capacity (31.6% <80% predicted), DLCO (53.4% <80% predicted), and chest-CT (86.7% abnormal). Significant risk factors for individual abnormal outcomes, adjusted for age and sex, were TB disease, HIV with CD4 <200 cells/mm3, BMI <18.5 kg/m2 and >35 kg/m2, and initial COVID-19 severity. Interpretation: This study demonstrates substantial lung and functional morbidity within the first weeks post-COVID-19, particularly in individuals with pre-existing comorbidities including TB, HIV, and low or high BMI. Chest-CT and DLCO show best early potential at reflecting COVID-19-related pathologies. Funding: The Bavarian State Ministry of Science and Arts.
AU  - Glover, N.A.*
AU  - Ivanova, O.*
AU  - Sathar, F.*
AU  - Riess, F.*
AU  - Shambhu, R.R.*
AU  - Mekota, A.M.*
AU  - Zurba, L.*
AU  - Menezes, C.*
AU  - Alexandra van Blydenstein, S.*
AU  - Kalla, I.*
AU  - Hoelscher, M.
AU  - Saathoff, E.*
AU  - Charalambous, S.*
AU  - Rachow, A.
C1  - 70526
C2  - 55582
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Lung outcomes and related risk factors in patients after SARS-CoV-2 infection: A hospitalised single-centre cohort from Johannesburg, South Africa.
JO  - EClinicalMedicine
VL  - 71
PB  - Elsevier
PY  - 2024
SN  - 2589-5370
ER  - 

TY  - JOUR
AB  - Background: Chronic obstructive pulmonary disease (COPD) is caused by interactions between many factors across the life course, including genetics. A proportion of COPD may be due to reduced lung growth in childhood. We hypothesized that a polygenic risk score (PRS) for COPD is associated with lower lung function already in childhood and up to adulthood. Methods: A weighted PRS was calculated based on the 82 association signals (p ≤ 5 × 10−8) revealed by the largest GWAS of airflow limitation (defined as COPD) to date. This PRS was tested in association with lung function measures (FEV1, FVC, and FEV1/FVC) in subjects aged 4–50 years from 16 independent cohorts participating in the Chronic Airway Diseases Early Stratification (CADSET) Clinical Research Collaboration. Age-stratified meta-analyses were conducted combining the results from each cohort (n = 45,406). These findings were validated in subjects >50 years old. Findings: We found significant associations between the PRS for airflow limitation and: (1) lower pre-bronchodilator FEV1/FVC from school age (7–10 years; β: −0.13 z-scores per one PRS z-score increase [–0.15, −0.11], q-value = 7.04 × 10−53) to adulthood (41–50 years; β: −0.16 [–0.19, −0.13], q-value = 1.31 × 10−24); and (2) lower FEV1 (from school age: 7–10 years; β: −0.07 [–0.09, −0.05], q-value = 1.65 × 10−9, to adulthood: 41–50 years; β: −0.17 [–0.20, −0.13], q-value = 4.48 x 10−20). No effect modification by smoking, sex, or a diagnosis of asthma was observed. Interpretation: We provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards. Funding: This study was supported by CADSET, a Clinical Research Collaboration of the European Respiratory Society.
AU  - Hernandez-Pacheco, N.*
AU  - Kilanowski, A.
AU  - Kumar, A.*
AU  - Curtin, J.A.*
AU  - Olvera, N.*
AU  - Kress, S.*
AU  - Bertels, X.*
AU  - Lahousse, L.*
AU  - Bhatta, L.*
AU  - Granell, R.*
AU  - Marí, S.*
AU  - Bilbao, J.R.*
AU  - Sun, Y.*
AU  - Tingskov Pedersen, C.E.*
AU  - Karramass, T.*
AU  - Thiering, E.
AU  - Dardani, C.*
AU  - Kebede Merid, S.*
AU  - Wang, G.*
AU  - Hallberg, J.*
AU  - Koch, S.*
AU  - Garcia-Aymerich, J.*
AU  - Esplugues, A.*
AU  - Torrent, M.*
AU  - Ibarluzea, J.*
AU  - Lowe, L.*
AU  - Simpson, A.*
AU  - Gehring, U.*
AU  - Vermeulen, R.C.H.*
AU  - Roberts, G.*
AU  - Bergström, A.*
AU  - Vonk, J.M.*
AU  - Felix, J.F.*
AU  - Duijts, L.*
AU  - Bønnelykke, K.*
AU  - Timpson, N.*
AU  - Brusselle, G.*
AU  - Brumpton, B.M.*
AU  - Langhammer, A.*
AU  - Turner, S.*
AU  - Holloway, J.W.*
AU  - Arshad, S.H.*
AU  - Ullah, A.*
AU  - Custovic, A.*
AU  - Cullinan, P.*
AU  - Murray, C.S.*
AU  - van den Berge, M.*
AU  - Kull, I.*
AU  - Schikowski, T.*
AU  - Wedzicha, J.A.*
AU  - Koppelman, G.*
AU  - Faner, R.*
AU  - Agustí, À.*
AU  - Standl, M.
AU  - Melén, E.*
C1  - 71654
C2  - 56122
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study.
JO  - EClinicalMedicine
VL  - 75
PB  - Elsevier
PY  - 2024
SN  - 2589-5370
ER  - 

TY  - JOUR
AB  - Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes. Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype. Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14–1.86] and 0.96 [95% CI 0.70–1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18–2.22] and 0.66 [95% CI 0.44–1.00] per hour of MSFsc, respectively; interaction p < 0.001). No interaction between chronotype and antihypertensive dosing time was observed for stroke events. Interpretation: Alignment of dosing time of usual antihypertensives with personal chronotype could lower the incidence of non-fatal MI compared to a ‘misaligned’ dosing time regimen. Future studies are warranted to establish whether synchronizing administration time of antihypertensive therapy with individual chronotype reduces risk of MI. Funding: The TIME study was funded by the British Heart Foundation (CS/14/1/30659) with support from the British and Irish Hypertension Society.
AU  - Pigazzani, F.*
AU  - Dyar, K.A.
AU  - Morant, S.V.*
AU  - Vetter, C.*
AU  - Rogers, A.*
AU  - Flynn, R.W.V.*
AU  - Rorie, D.A.*
AU  - Mackenzie, I.S.*
AU  - Cappuccio, F.P.*
AU  - Manfredini, R.*
AU  - MacDonald, T.M.*
C1  - 70711
C2  - 55562
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes: The Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study.
JO  - EClinicalMedicine
VL  - 72
PB  - Elsevier
PY  - 2024
SN  - 2589-5370
ER  - 

TY  - JOUR
AB  - Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively). Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials. Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.
AU  - Gentilotti, E.*
AU  - Gorska, A.*
AU  - Tami, A.*
AU  - Gusinow, R.
AU  - Mirandola, M.*
AU  - Rodríguez Baño, J.*
AU  - Palacios Baena, Z.R.*
AU  - Rossi, E.*
AU  - Hasenauer, J.
AU  - Lopes-Rafegas, I.*
AU  - Righi, E.*
AU  - Caroccia, N.*
AU  - Cataudella, S.*
AU  - Pasquini, Z.*
AU  - Osmo, T.*
AU  - Del Piccolo, L.*
AU  - Savoldi, A.*
AU  - Kumar-Singh, S.*
AU  - Mazzaferri, F.*
AU  - Caponcello, M.G.*
AU  - de Boer, G.*
AU  - Hara, G.L.*
AU  - Pinho Guedes, M.N.*
AU  - Maccarrone, G.*
AU  - Pezzani, M.D.*
AU  - Sibani, M.*
AU  - Davies, R.J.*
AU  - Vitali, S.*
AU  - Franchina, G.*
AU  - Tomassini, G.*
AU  - Sciammarella, C.*
AU  - Cecchetto, R.*
AU  - Gibellini, D.*
AU  - De Toffoli, C.K.*
AU  - Rosini, G.*
AU  - Perlini, C.*
AU  - Meroi, M.*
AU  - Puviani, F.C.*
AU  - Fasan, D.*
AU  - Micheletto, C.*
AU  - Montemezzi, S.*
AU  - Cardobi, N.*
AU  - Vantini, G.*
AU  - Mazzali, G.*
AU  - Stabile, G.*
AU  - Marcanti, M.*
AU  - Zonta, M.P.*
AU  - Calì, D.*
AU  - Mason, A.*
AU  - Gisondi, P.*
AU  - Mongardi, M.*
AU  - Sorbello, S.*
AU  - Wold, K.I.*
AU  - Vincenti-González, M.F.*
AU  - Veloo, A.C.M.*
AU  - Harmsma, V.P.R.*
AU  - Pantano, D.*
AU  - van der Meer, M.*
AU  - Gard, L.*
AU  - Lizarazo, E.F.*
AU  - Knoester, M.*
AU  - Friedrich, A.W.*
AU  - Niesters, H.G.M.*
AU  - Viale, P.*
AU  - Marzolla, D.*
AU  - Cosentino, F.*
AU  - Di Chiara, M.*
AU  - Fornaro, G.*
AU  - Bonazzetti, C.*
AU  - Tazza, B.*
AU  - Toschi, A.*
AU  - Vetamanu, O.*
AU  - Giacomini, M.E.*
AU  - Trapani, F.*
AU  - Marconi, L.*
AU  - Attard, L.*
AU  - Tedeschi, S.*
AU  - Gabrielli, L.*
AU  - Lazzarotto, T.*
AU  - Olivares, P.*
AU  - Castilla, J.*
AU  - Vélez, J.*
AU  - Almadana, V.*
AU  - Martín-Barrera, L.*
AU  - Martín-Gutiérrez, A.B.*
AU  - Gutiérrez-Campos, D.*
AU  - Fernández-Regaña, M.*
AU  - Silva-Campos, A.*
AU  - Fernández-Riejos, P.*
AU  - García-Sánchez, M.I.*
AU  - Giuliano, C.V.*
AU  - López, C.*
AU  - Neumann, G.*
AU  - Camporro, J.*
AU  - de Vedia, L.*
AU  - Agugliaro, H.*
AU  - Scipione, G.*
AU  - Dellacasa, C.*
AU  - Chandramouli, B.*
C1  - 68346
C2  - 54756
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Clinical phenotypes and quality of life to define post-COVID-19 syndrome: A cluster analysis of the multinational, prospective ORCHESTRA cohort.
JO  - EClinicalMedicine
VL  - 62
PB  - Elsevier
PY  - 2023
SN  - 2589-5370
ER  - 

TY  - JOUR
AB  - Background: Personalised therapy has emerged as a possibly more efficient approach taking disease heterogeneity into account. The aim of this study was to determine whether recently described subgroups of childhood diabetes have prognostic association with diabetes-specific complications and, therefore, might be a basis for personalised therapies. Methods: We applied a previously developed subgroup classification to pediatric patients (diabetes onset <18 years) from the prospective Diabetes Patient Follow-up (DPV) registry with documented data between January 1, 2000 and March 31, 2022, from diabetes centers in Germany, Austria, Switzerland, and Luxembourg. The classification required information on islet autoantibody status, age, haemoglobin A1c (HbA1c), and body-mass index (BMI-SDS) at disease manifestation, as well as follow up data after 2 and after 4 years, which was available in 22,719 patients. Patients without documented data on these parameters were excluded from the analysis. The cumulative risk of severe hypoglycemia, diabetic ketoacidosis (DKA), retinopathy, and nephropathy were analysed by Kaplan–Meier analyses over a median follow-up of 6.8 years (IQR 4.8–9.6). Findings: Patients were classified into 10 subgroups (P1–P7 islet autoantibody-positive, n = 19,811; N1–N3 islet autoantibody-negative, n = 2908). The groups varied markedly with respect to specific acute and chronic complications. Severe hypoglycemia was a characteristic feature in young islet autoantibody-positive subgroups P1, P3, P4 (10-year risk 46, 46 and 47%) and the islet autoantibody-negative groups N1, N2 (43 and 46%). Nephropathy was identified in patient groups P2 and P5 (10-year risk 16%), which had features of moderate disease such as preserved C-peptide, low HbA1c, and very low frequency of DKA at diabetes onset. Group P7, which was defined by a high BMI, was associated with poor metabolic control, DKA, and retinopathy. In contrast, islet autoantibody-negative patients with high BMI (N3) had a low risk for all four complications. Interpretation: Subgrouping of childhood diabetes at diabetes onset provided prognostic value for the development of acute and chronic diabetes-specific complications. Funding: The DPV initiative is supported by The German Ministry of Education and Research (BMBF) within the German Center for Diabetes Research, the diabetes surveillance of the Robert Koch Institute, the German Diabetes Association (DDG) and INNODIA.
AU  - Warncke, K.
AU  - Eckert, A.*
AU  - Bonifacio, E.
AU  - Achenbach, P.
AU  - Kordonouri, O.*
AU  - Meissner, T.*
AU  - Ohlenschläger, U.*
AU  - Bonfig, W.*
AU  - Ziegler, A.-G.
AU  - Holl, R.W.*
C1  - 68292
C2  - 54779
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Characterisation and clinical outcomes in children and adolescents with diabetes according to newly defined subgroups: A cohort study from the DPV registry.
JO  - EClinicalMedicine
VL  - 64
PB  - Elsevier
PY  - 2023
SN  - 2589-5370
ER  - 

TY  - JOUR
AB  - Background: Emerging evidence suggests that androgens and estrogens have a role in respiratory health, but it is largely unknown whether levels of these hormones can affect lung function in adults from the general population. This study investigated whether serum dehydroepiandrosterone sulfate (DHEA-S), a key precursor of both androgens and estrogens in peripheral tissues, was related to lung function in adult women participating in the European Community Respiratory Health Survey (ECRHS). Methods: Lung function and serum DHEA-S concentrations were measured in n = 2,045 and n = 1,725 women in 1999-2002 and in 2010-2013, respectively. Cross-sectional associations of DHEA-S levels (expressed as age-adjusted z-score) with spirometric outcomes were investigated, adjusting for smoking habits, body mass index, menopausal status, and use of corticosteroids. Longitudinal associations of DHEA-S levels in 1999-2002 with incidence of restrictive pattern and airflow limitation in 2010-2013 were also assessed. Findings: Women with low DHEA-S (z-score<-1) had lower FEV1 (% of predicted, adjusted difference: -2.2; 95%CI: -3.5 to -0.9) and FVC (-1.7; 95%CI: -2.9 to -0.5) and were at a greater risk of having airflow limitation and restrictive pattern on spirometry than women with higher DHEA-S levels. In longitudinal analyses, low DHEA-S at baseline was associated with a greater incidence of airflow limitation after an 11-years follow-up (incidence rate ratio, 3.43; 95%CI: 1.91 to 6.14). Interpretation: Low DHEA-S levels in women were associated with impaired lung function and a greater risk of developing airflow limitation later in adult life. Our findings provide new evidence supporting a role of DHEA-S in respiratory health. Funding: EU H2020, grant agreement no.633212.
AU  - Pesce, G.*
AU  - Triebner, K.*
AU  - van der Plaat, D.A.*
AU  - Courbon, D.*
AU  - Hustad, S.*
AU  - Sigsgaard, T.*
AU  - Nowak, D.*
AU  - Heinrich, J.
AU  - Antò, J.M.*
AU  - Dorado-Arenas, S.*
AU  - Martinez-Moratalla, J.*
AU  - Gullon-Blanco, J.A.*
AU  - Sánchez-Ramos, J.L.*
AU  - Raherison, C.*
AU  - Pin, I.*
AU  - Demoly, P.*
AU  - Gislason, T.*
AU  - Torén, K.*
AU  - Forsberg, B.*
AU  - Lindberg, E.*
AU  - Zemp, E.*
AU  - Jogi, R.*
AU  - Probst-Hensch, N.*
AU  - Dharmage, S.C.*
AU  - Jarvis, D.*
AU  - Garcia-Aymerich, J.*
AU  - Marcon, A.*
AU  - Gómez-Real, F.*
AU  - Leynaert, B.*
C1  - 59305
C2  - 48744
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Low serum DHEA-S is associated with impaired lung function in women.
JO  - EClinicalMedicine
VL  - 23
PB  - Elsevier
PY  - 2020
SN  - 2589-5370
ER  -