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Rationale: Research suggests that respiratory and cardiovascular drugs can ameliorate the rate of lung function decline. Objectives: To investigate the impact of respiratory and cardiovascular pharmacotherapy on lung function trajectories in the general population. Methods: Repeated spirometry was performed in the Rotterdam Study, a population-based cohort of adults aged ≥45 years. Exposure to long-acting beta2-agonists (LABA), long-acting muscarinic antagonists (LAMA), inhaled corticosteroids (ICS), cardioselective beta-blockers, calcium channel blockers, ACE-inhibitors, angiotensin-II receptor blockers, and statins was quantified from pharmacy records to account for therapy adherence. Propensity-score matching and multinomial logistic regression were performed to model medication effects on lung function trajectories, which were previously identified based on FEV 1 and FVC patterns. Models were additionally stratified by genetic variation in each drug target. Measurement and Main Results: Among 3,783 individuals, 2,974 (78.6%) were classified as normal lung function decliners, 432 (11.4%) as rapid decliners, and 377 (10.0%) as improvers. Exposure to LABA (odds ratio (OR) =1.09 [95%-CI: 1.03-1.16] per 10% increase in exposure), ICS (OR=1.08 [95%-CI: 1.02-1.14]), and statins (OR=1.04 [95%-CI: 1.02-1.06]) significantly increased the odds of being an improver compared to a normal decliner. Beta 1 -blocker use was associated with higher odds of being a rapid decliner (OR=1.04 [95%-CI: 1.00-1.09]), which was driven by incident users. Pharmacogenetic analysis suggests that the effects of LABA, ICS, and beta 1 -blockers are dependent on genetic variation in their drug targets. Conclusions: Our study suggests that LABA, ICS, and statins may favorably modulate lung function trajectories in adults, while initiation of beta 1 -blockers was associated with rapid lung function decline.

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 (FEV 1 , FVC, and FEV 1 /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 FEV 1 /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 FEV 1 (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., Competing Interests: NH-P was supported with a Medium-Term Research Fellowship by the European Academy of Allergy and Clinical Immunology (EAACI) and a Long-Term Research Fellowship by the European Respiratory Society (ERS) (LTRF202101-00861), and lecture honoraria from OMNIPREX, S.L (outside of the submitted work). LLa was supported by the Fund for Scientific Research Flanders (Grant 3G037618), lecture honoraria from IPSA vzw, a non-profit organization facilitating lifelong learning for health care providers, and Chiesi; and consulting fees from AstraZeneca, all paid to the institution. LLa also declares unpaid membership of faculty board and faculty committees of the European Respiratory Society and Belgian Respiratory Society. LB received support from the K.G. Jebsen Center for Genetic Epidemiology funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU; The Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. YS was supported by a grant from the China Scholarship Council. AL declares consulting fees regarding presentation of spirometry from Diagnostica Ltb and lecture honoraria from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline. AC reports research grants funded by MRC, EPSRC, and Wellcome Trust; consulting fees from Worg Pharmaceuticals; lecture honoraria from GlaxoSmithKline, AstraZeneca, Stallergens-Greer, and Sanofi; and unpaid membership of a board of officers of the World Allergy Organization. GK was supported by grants from ZON-MW, Lung Foundation of the Netherlands, UBBO EMMIUS Foundation, GSK, Vertex, European Union (H2020 program), TEVA the Netherlands; consulting fees from AstraZeneca and PURE IMS; lecture fees from AstraZeneca, Boehringer Ingelheim and Sanofi; and participation as a chair at the exquAIro foundation (AI education for medicine and pharma). RF received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 101044387), Instituto de Salud Carlos III (PI18/00018, PI21/00735), SEPAR and Serra Hunter Program. AA reports research grants, consulting fees, and lecture honoraria by GlaxoSmithKline, AstraZeneca, Menarini, Chiesi, and Sanofi; and unpaid roles as Chair Board of Directors of GOLD and Co-chair of CADSET. MS received funding from ERC under the European Union's Horizon 2020 research and innovation program (grant agreement No. 949906). EM is supported by grants from the EU (ERC, TRIBAL No 757919). EM also declares advisory board and lecture fees from ALK, AstraZeneca, and Chiesi outside the submitted work. The rest of the authors declare no conflicts of interest that might be perceived to influence the interpretation of this article., (© 2024 The Author(s).)

Background: The determinants and health outcomes of lung function trajectories in adults among the general population are poorly understood. We aimed to identify and characterise clusters of lung function trajectories in adults aged ≥45 years., Methods: Gaussian finite-mixture modelling was applied to baseline and annualised change of forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC ratio z-scores in participants of the Rotterdam Study, a prospective population-based cohort study, with repeated spirometry (n=3884; mean±sd age 64.7±8.9 years). Longitudinal outcomes were all-cause mortality, respiratory outcomes (symptoms, COPD (FEV 1 /FVC <0.7 in absence of asthma), preserved ratio impaired spirometry (PRISm; FEV 1 /FVC ≥0.7 and FEV 1 or FVC <80%)), smoking cessation and weight changes. Independent risk factors, including genetics, were identified by multiple logistic regression., Results: We identified eight trajectory clusters, with the reference group having persistently normal spirometry (prevalence 42.8%). Three clusters showed higher mortality, adjusted for confounders: 1) the persistently low FEV 1 cluster (prevalence 6.8%, hazard ratio (HR) 1.71, 95% CI 1.37-2.13); 2) rapid FEV 1 decliners (prevalence 4.6%, HR 1.48, 95% CI 1.10-1.99); and 3) FVC decliners (prevalence 3.7%, HR 1.49, 95% CI 1.09-2.03). In contrast, FVC improvers (prevalence 6.7%, HR 0.61, 95% CI 0.41-0.90) and persistently high FEV 1 (prevalence 29.2%, HR 0.82, 95% CI 0.69-0.98) were protective trajectory clusters. Clusters were characterised by differences in genetic predisposition (polygenic scores of FEV 1 and FEV 1 /FVC), demographics, cigarette smoking, respiratory symptoms (chronic cough, wheezing and dyspnoea), cardiovascular factors (body mass index, hypertension and heart failure) and serum C-reactive protein levels. Frailty, weight changes and the development of respiratory symptoms, COPD and PRISm were significantly associated with trajectory clusters., Conclusions: This study reveals clinically relevant lung function trajectory clusters in older adults of the general population., Competing Interests: Conflict of interest: X. Bertels reports BOF.SIP.2020 funding for international mobility in relation to the submitted work. Conflict of interest: R. Faner reports grants from the Serra Húnter Program, Instituto de Salud Carlos III (PI21/00735) and European Research Council under the Horizon Europe research and innovation programme (101044387) outside the submitted work. Conflict of interest: M.H. Cho reports NHLBI funding (R01HL153248, R01HL149861 and R01HL147148), grants from Bayer and GSK, consulting fees from Genentech, AstraZeneca and Illumina, and honoraria for lectures from Genentech, AstraZeneca and Illumina outside the submitted work. Conflict of interest: G.G. Brusselle reports fees for advisory boards and/or lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Merck Sharp & Dohme, Novartis and Sanofi Regeneron outside the submitted work. Conflict of interest: L. Lahousse reports BOF.SIP.2020 funding for international mobility in relation to the submitted work, consulting fees from AstraZeneca, and speaking/lecture fees from Chiesi and IPSA (non-profit) outside the submitted work. Conflict of interest: J.C. Ross and M.A. Irfan declare no conflicts of interest., (Copyright ©The authors 2024.)

Background: Wastewater-based epidemiology (WBE) has been implemented to monitor surges of COVID-19. Yet, multiple factors impede the usefulness of WBE and quantitative adjustment may be required., Aim: We aimed to model the relationship between WBE data and incident COVID-19 cases, while adjusting for confounders and autocorrelation., Methods: This nationwide WBE study includes data from 40 wastewater treatment plants (WWTPs) in Belgium (02/2021-06/2022). We applied ARIMA-based modelling to assess the effect of daily flow rate, pepper mild mottle virus (PMMoV) concentration, a measure of human faeces in wastewater, and variants (alpha, delta, and omicron strains) on SARS-CoV-2 RNA levels in wastewater. Secondly, adjusted WBE metrics at different lag times were used to predict incident COVID-19 cases. Model selection was based on AICc minimization., Results: In 33/40 WWTPs, RNA levels were best explained by incident cases, flow rate, and PMMoV. Flow rate and PMMoV were associated with -13.0 % (95 % prediction interval: -26.1 to +0.2 %) and +13.0 % (95 % prediction interval: +5.1 to +21.0 %) change in RNA levels per SD increase, respectively. In 38/40 WWTPs, variants did not explain variability in RNA levels independent of cases. Furthermore, our study shows that RNA levels can lead incident cases by at least one week in 15/40 WWTPs. The median population size of leading WWTPs was 85.1 % larger than that of non‑leading WWTPs. In 17/40 WWTPs, however, RNA levels did not lead or explain incident cases in addition to autocorrelation., Conclusion: This study provides quantitative insights into key determinants of WBE, including the effects of wastewater flow rate, PMMoV, and variants. Substantial inter-WWTP variability was observed in terms of explaining incident cases. These findings are of practical importance to WBE practitioners and show that the early-warning potential of WBE is WWTP-specific and needs validation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Delphine Brogna reports financial support was provided by E-BIOM. Catherine Linard reports financial support was provided by E-BIOM. Christian Didy reports financial support was provided by SPGE. Rosalie Pype reports financial support was provided by SPGE. Jonathan Marescaux reports financial support was provided by E-BIOM. Sven Hanoteaux reports a relationship with Sciensano that includes: employment. Raphael Janssens reports a relationship with Sciensano that includes: employment. Hadrien Maloux reports a relationship with Sciensano that includes: employment. Bavo Verhaegen reports a relationship with Sciensano that includes: employment. Jonathan Marescaux reports a relationship with E-BIOM that includes: employment. Koenraad Van Hoorde reports a relationship with Sciensano that includes: employment. Marie Lesenfants reports a relationship with Sciensano that includes: employment. Rosalie Pype reports a relationship with SPGE that includes: employment. Christian Didy reports a relationship with SPGE that includes: employment., (Copyright © 2023. Published by Elsevier B.V.)

Background: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts., Methods: This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV 1 /FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model., Results: The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI., Conclusions: AO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only., Competing Interests: Competing interests: LL reports consulting fees from AstraZeneca and speaking/lecture fees from Chiesi and IPSA (non-profit) outside the submitted work. CHV reports presentations at symposia and/or served on scientific advisory boards sponsored by Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Novartis, Nuvaira, MedUpdate, Sanofi and Roche outside the submitted work. AA reports grants from GSK, AstraZeneca and Menarini and speaking/lecture fees from GSK, AstraZeneca, Chiesi, Menarini, CIPLA, Zambon, and Sanofi Regeneron outside the submitted work, and is chair of the GOLD board of directors. JAW reports grants from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Novartis, Genentech, and 37Clinical, advisory board fees from AstraZeneca, Epiendo, GSK, Gilead, Novartis, Pieris and Pulmatrix, speaker fees from AstraZeneca, GSK, Boehringer, Recipharm and Novartis, and DSMB chair for Virtus outside the submitted work, and is Editor in Chief of AJRCCM. GGB reports fees for advisory boards and/or lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Merck Sharp & Dohme, Novartis, and Sanofi Regeneron outside the submitted work. HB reports personal fees from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline for presentations at scientific meetings outside the submitted work. AL reports speaking/lecture fees from Boehringer-Ingelheim and Novartis, and participation on a advisory board for AstraZeneca, GSK, Novartis, and Boehringer-Ingelheim outside the submitted work. KFC reports advisory board fees from GSK, AstraZeneca, Roche, Novartis, Merck, Nocion, Shionogi and Rickett-Beckinson and has been renumerated for speaking engagements for GSK, AstraZeneca and Merck outside the submitted work. IMA reports investigator-led awards from GSK and Sanofi in addition to travel awards, speakers' fees and advisory board fees from AZ, Chiesi, GSK, Eurodrug, Kineset, Sanofi and Sunovion outside the submitted work. None declared (XB, AE, JG-A, RF, HM, TS, PA, NO, NZK, GCD, ER, JMV and MvdB)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Wastewater-based epidemiology (WBE) includes the analysis of human metabolic biomarkers of xenobiotics in influent wastewater. WBE complements existing drug utilization approaches and provides objective, spatio-temporal information on the consumption of pharmaceuticals in the general population. This approach was applied to 24-h composite influent wastewater samples from Leuven, Belgium. Daily samples were analysed from September 2019 to December 2019 (n = 76), and on three days of the week (Monday, Wednesday, Saturday) from January 2020 to April 2022 (n = 367). Sample analysis consisted of 96-well solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry. Measured concentrations of 21 biomarkers for antidepressant and opioid use were converted to population-normalized mass loads (PNML) by considering the flow rate and catchment population. To capture population movements, mobile phone data was used. Amitriptyline, hydroxy-bupropion, norcitalopram, citalopram, normirtazapine, trazodone, O-desmethylvenlafaxine, codeine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), methadone, morphine, O-desmethyltramadol, and tramadol were included in the temporal assessment since concentrations were above the lower limit of quantification. The PNML of most biomarkers increased (with 3-119 %) throughout the sampling period. The population disruption during the COVID-19 pandemic led to a major change in the socio-demographics of the catchment area, resulting in temporal differences in the PNML of the different biomarkers. As such, higher PNML were observed during the different lockdown phases, which were characterized by the outflow of university students and a decreasing commuting in and out the catchment area. The effects of the fluctuating socio-demographics of the catchment population were further evidenced by the different week-weekend pattern of PNMLs over the course of the sampling campaign. Mean parent/metabolite ratios (i.e., citalopram/norcitalopram, tramadol/O-desmethyltramadol, venlafaxine/O-desmethylvenlafaxine, and methadone/EDDP) remained relatively stable throughout the entire sampling campaign (RSD% below 25 % for all ratios, except for methadone/EDDP) and therefore were not affected by this population change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Although non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management, direct long-term head-to-head comparisons are lacking. Therefore, their risk-benefit profiles were investigated compared to VKAs and between NOACs. Methods: AF patients initiating anticoagulation between 2013-2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate effectiveness and safety outcomes and were additionally stratified by NOAC dose. Results: Among 254,478 AF patients (328,796 person-years of follow-up), NOACs were associated with significantly lower risks of stroke or systemic embolism (stroke/SE) (hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.64-0.72)), all-cause mortality (HR 0.76, 95%CI (0.74-0.79)), major or clinically relevant non-major bleeding (MB/CRNMB) (HR 0.94, 95%CI (0.91-0.98)) and intracranial hemorrhage (HR 0.73, 95%CI (0.66-0.79)), but non-significantly different risks of myocardial infarction, gastrointestinal and urogenital bleeding compared to VKAs. Despite similar stroke/SE risks, dabigatran and apixaban were associated with significantly lower MB/CRNMB risks compared to rivaroxaban (HR 0.86, 95%CI (0.83-0.90); HR 0.86, 95%CI (0.83-0.89), respectively) and edoxaban (HR 0.91, 95%CI (0.83-0.99); HR 0.86, 95%CI (0.81-0.91), respectively), and apixaban with significantly lower major bleeding risks compared to dabigatran (HR 0.86, 95%CI (0.80-0.92)) and edoxaban (HR 0.79, 95%CI (0.72-0.86)). However, higher mortality risks were observed in some risk groups including with apixaban in patients with diabetes or concomitantly using digoxin compared to dabigatran and edoxaban, respectively. Conclusion: NOACs had better long-term risk-benefit profiles than VKAs. While effectiveness was comparable, apixaban was overall associated with a more favorable safety profile followed by dabigatran., Competing Interests: Outside this manuscript, TDB has served as a chairperson during a lecture for Bayer and Daiichi Sankyo, and participated in an expert meeting for Pfizer. Outside this manuscript, SS has given a lecture sponsored by BMS. Neither author has received any fees personally. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Grymonprez, De Backer, Bertels, Steurbaut and Lahousse.)

Wastewater-based epidemiology (WBE) is a complementary approach to monitor alcohol consumption in the general population. This method measures concentrations of xenobiotic biomarkers (e.g., ethyl sulphate) in influent wastewater (IWW) and converts these to population-normalized mass loads (PNML, in g/day/1000 inhabitants) by multiplying with the flow rate and dividing by the catchment population. The aims of this case study were to: (i) investigate temporal trends in alcohol use during the COVID-19 pandemic; and (ii) measure the effect of policy measures on alcohol consumption. Daily 24-h composite IWW samples (n = 735) were collected in the wastewater treatment plant of the university city of Leuven (Belgium) starting from September 2019 to September 2021. This is the first study that investigates alcohol use through WBE for a continuous period of two years on a daily basis. Mobile phone data was used to accurately capture population fluxes in the catchment area. Data was evaluated using a time series based statistical framework to graphically and quantitatively assess temporal differences in the measured PNML. Different WBE studies observed temporal changes in alcohol use during the COVID-19 pandemic. In this study, the PNML of ethyl sulphate decreased during the first lockdown phase, potentially indicating that less alcohol was consumed at the Leuven area during home confinement. Contrastingly, alcohol use increased after the re-opening of the catering industry. Additionally, a decrease in alcohol use was observed during the exam periods at the University of Leuven and an increase during the holiday periods. The present study shows the potential of WBE to rapidly assess the impact of some policy measures on alcohol consumption in Belgium. This study also indicates that WBE could be employed as a complementary data source to fill in some of the current knowledge gaps linked to lifestyle behavior., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Both oral retinoid and valproate containing medicines are highly teratogenic. Their use by women of childbearing age is controlled by risk minimization measures (RMMs) introduced by the European Medicine Agency, including the pregnancy prevention programme (PPP). In 2018, the RMMs were revised as previous measures were insufficient to prevent the use of these medicines during pregnancies., Aim & Methods: A cross-sectional survey was conducted among patients, physicians and pharmacists to evaluate the implementation of the revised RMMs in Belgium. The primary outcome was compliance with key aspects of the PPP. Differences in compliance between oral retinoid and valproate stakeholders were investigated. The relationship between potential determinants (population characteristics and RMM usage) and compliance was studied via multiple logistic regression., Results: A total of 317 eligible patients, physicians and pharmacists participated. The majority of the studied patients fail to comply with the PPP, mainly driven by poor implementation of pregnancy testing. A large number of healthcare providers is unaware of the available educational materials., Conclusion: It is likely that a substantial part of Belgian women of childbearing age using oral retinoids or valproate insufficiently meet the PPP requirements. We propose to better inform healthcare providers about the mandatory PPPs and available educational materials as well as to support them with the implementation of such programmes to improve the safe use of these teratogenic medicines.

Wastewater-based surveillance (WBS) for SARS-CoV-2 RNA is a promising complementary approach to monitor community viral circulation. A myriad of factors, however, can influence RNA concentrations in wastewater, impeding its epidemiological value. This article aims to provide an overview and discussion of factors up to the sampling stage that impact SARS-CoV-2 RNA concentration estimates in wastewater. To this end, a systematic review was performed in three databases (MEDLINE, Web of Science and Embase) and two preprint servers (MedRxiv and BioRxiv). Two authors independently screened and selected articles published between January 1, 2019 and May 4, 2021. A total of 22 eligible articles were included in this systematic review. The following factors up to sampling were identified to have an influence on SARS-CoV-2 RNA concentrations in wastewater and its interpretation: (i) shedding-related factors, including faecal shedding parameters (i.e. shedding pattern, recovery, rate, and load distribution), (ii) population size, (iii) in-sewer factors, including solid particles, organic load, travel time, flow rate, wastewater pH and temperature, and (iv) sampling strategy. In conclusion, factors influencing SARS-CoV-2 RNA concentration estimates in wastewater were identified and research gaps were discussed. The identification of these factors supports the need for further research on WBS for COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)