Severity-dependent test-seeking behaviors and test-negative designs: impact on estimated vaccine effectiveness and utility of analytic and design choices.

Test-negative designs are increasingly used to evaluate vaccine effectiveness because of desirable properties like reduced confounding due to healthcare-seeking behaviors and lower cost compared to other study designs. An individual's decision to seek care often depends on their disease severity, with severe disease more likely to be captured than mild disease. As many vaccines likely attenuate disease severity, this phenomenon generally results in an upward-biased estimate of vaccine effectiveness against symptomatic disease. To address the resulting bias, analytic solutions like adjusting for or matching on severity have been suggested. In this paper, we examine the performance of the test-negative design under different vaccine effects on disease severity and the utility of adjusting or matching on severity. We further consider the implications of studies that focus only on milder disease by restricting recruitment to outpatient settings. Through an analytic framework and simulations accompanied by a real-world example, we demonstrate that, when vaccination attenuates disease severity, the magnitude of bias is influenced by the degree of under-ascertainment of mild disease relative to severe disease. When vaccination does not attenuate disease severity, bias is not present. We further show that analytic fixes negligibly impact bias and that outpatient-only studies frequently produce downward-biased estimates.

Prevalence, risk factors, and impact of long COVID in a socially vulnerable community in Brazil: a prospective cohort study.

Background: Long COVID is an emerging global public health issue. Socially vulnerable communities in low- and-middle-income countries were severely impacted by the pandemic and are underrepresented in research. This prospective study aimed to determine the prevalence of long COVID, its impact on health, and associated risk factors in one such community in Rio de Janeiro, Brazil. Methods: A total of 710 individuals aged 18 and older, with confirmed SARS-CoV-2 infection at least three months prior, were enrolled between November 25, 2021, and May 5, 2022. Participants were assessed via telephone or in person using a standardized questionnaire to evaluate their perception of recovery, symptoms, quality of life, and functional status. Findings: Twenty percent of participants did not feel fully recovered, 22% experienced new or persistent symptoms, 26% had worsened functional status, 18% had increased dyspnoea, and 32% reported a worse quality of life. Persistent symptoms included headache, cough, fatigue, muscle pain, and shortness of breath. Dyspnoea during the acute phase was the strongest independent predictor of worsening outcomes. Females and individuals with comorbidities were more likely to report worse recovery, functioning, dyspnoea, and quality of life. Interpretation: Our findings reveal a high burden of severe and persistent physical and mental health sequelae in a socially vulnerable community following COVID-19. Funding: UK Foreign, Commonwealth and Development Office and Wellcome Trust Grant (222048/Z/20/Z), Fundação Oswaldo Cruz (FIOCRUZ), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), and the Centers for Disease Control and Prevention (CDC).

Effectiveness of COVID-19 vaccines against severe COVID-19 among patients with cancer in Catalonia, Spain.

Patients with cancer were excluded from pivotal randomized clinical trials of COVID-19 vaccine products, and available observational evidence on vaccine effectiveness (VE) focused mostly on mild, and not severe COVID-19, which is the ultimate goal of vaccination for high-risk groups. Here, using primary care electronic health records from Catalonia, Spain (SIDIAP), we built two large cohorts of vaccinated and matched control cancer patients with a primary vaccination scheme (n = 184,744) and a booster (n = 108,534). Most patients received a mRNA-based product in primary (76.2%) and booster vaccination (99.9%). Patients had 51.8% (95% CI 40.3%-61.1%) and 58.4% (95% CI 29.3%-75.5%) protection against COVID-19 hospitalization and COVID-19 death respectively after full vaccination (two-doses) and 77.9% (95% CI 69.2%-84.2%) and 80.2% (95% CI 63.0%-89.4%) after booster. Compared to primary vaccination, the booster dose provided higher peak protection during follow-up. Calibration of VE estimates with negative outcomes, and sensitivity analyses with slight different population and COVID-19 outcomes definitions provided similar results. Our results confirm the role of primary and booster COVID-19 vaccination in preventing COVID-19 severe events in patients with cancer and highlight the need for the additional dose in this population.

Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study.

Background: The emergence of COVID-19 variants with immune scape and the waning of primary vaccine schemes effectiveness have prompted many countries to indicate first and second booster COVID-19 vaccine doses to prevent severe COVID-19. However, current available evidence on second booster dose effectiveness are mostly limited to high-income countries, older adults, and mRNA-based vaccination schemes scenarios. We aimed to investigate the relative vaccine effectiveness (rVE) of the fourth dose compared to three doses for severe COVID-19 outcomes in Brazil; and compare the rVE of a fourth dose with an mRNA vaccine compared to adenovirus-based product in the same settings. Methods: We performed a target emulated trial using a population-based cohort of individuals aged 40 years or older who have received a homologous primary scheme of CoronaVac, ChAdOx1, or BNT162b2, and any third dose product and were eligible for the fourth dose in Brazil. The primary outcome was COVID-19 associated hospitalization or death. We built Cohort A matching individuals vaccinated with a fourth dose to individuals who received three doses to estimate the rVE of the fourth dose. We built Cohort B, a subset of Cohort A, matching mRNA-based (mRNA) to adenovirus-based fourth dose vaccinated individuals to compare their relative hazards for severe COVID-19. Findings: 46,693,484 individuals were included in Cohort A and 6,763,016 in Cohort B. 45% of them were aged between 40 and 60 years old, and 48% between 60 and 79 years old. In Cohort A, the most common previous series was a ChAdOx1 two-dose followed by BNT162b2 (44%), and a CoronaVac two-dose followed by a BNT162b2 (36%). Among those fourth dose vaccinated, 36.9% received ChAdOx1, 32.7% Ad26.COV2.S, 25.8% BNT162b2, and 4.7% CoronaVac. In Cohort B, among those who received an adenovirus fourth dose, 53.7% received ChAdOx1 and 46.3% received Ad26.COV2.S. The estimated rVE for the primary outcome of four doses compared to three doses was 44.1% (95% CI 42.3-46.0), with some waning during follow-up (rVE 7-60 days 46.8% [95% CI 44.4-49.1], rVE after 120 days 33.8% [95% CI 18.0-46.6]). Among fourth dose vaccinated individuals, mRNA-based vaccinated individuals had lower hazards for hospitalization or death compared to adenovirus-vaccinated individuals (HR 0.81, 95% CI 0.75-0.87). After 120 days, no difference in hazards between groups was observed (HR 1.35, 95% CI 0.93-1.97). Similar findings were observed for hospitalization and death separately, except no evidence for differences between fourth dose brands for death in Cohort B. Interpretation: In a heterogeneous scenario of primary and first booster vaccination combinations, a fourth dose provided meaningful and durable protection against severe COVID-19 outcomes. Compared to adenovirus-based booster, a fourth dose wild-type mRNA vaccine was associated with immediate lower hazards of hospitalization or death unsustained after 120 days. Funding: None.

The Association Between Prepandemic ICU Performance and Mortality Variation in COVID-19: A Multicenter Cohort Study of 35,619 Critically Ill Patients.

BACKGROUND: During the COVID-19 pandemic, ICUs remained under stress and observed elevated mortality rates and high variations of outcomes. A knowledge gap exists regarding whether an ICU performing best during nonpandemic times would still perform better when under high pressure compared with the least performing ICUs. RESEARCH QUESTION: Does prepandemic ICU performance explain the risk-adjusted mortality variability for critically ill patients with COVID-19? STUDY DESIGN AND METHODS: This study examined a cohort of adults with real-time polymerase chain reaction-confirmed COVID-19 admitted to 156 ICUs in 35 hospitals from February 16, 2020, through December 31, 2021, in Brazil. We evaluated crude and adjusted in-hospital mortality variability of patients with COVID-19 in the ICU during the pandemic. Association of baseline (prepandemic) ICU performance and in-hospital mortality was examined using a variable life-adjusted display (VLAD) during the pandemic and a multivariable mixed regression model adjusted by clinical characteristics, interaction of performance with the year of admission, and mechanical ventilation at admission. RESULTS: Thirty-five thousand six hundred nineteen patients with confirmed COVID-19 were evaluated. The median age was 52 years, median Simplified Acute Physiology Score 3 was 42, and 18% underwent invasive mechanical ventilation. In-hospital mortality was 13% and 54% for those receiving invasive mechanical ventilation. Adjusted in-hospital mortality ranged from 3.6% to 63.2%. VLAD in the most efficient ICUs was higher than the overall median in 18% of weeks, whereas VLAD was 62% and 84% in the underachieving and least efficient groups, respectively. The least efficient baseline ICU performance group was associated independently with increased mortality (OR, 2.30; 95% CI, 1.45-3.62) after adjusting for patient characteristics, disease severity, and pandemic surge. INTERPRETATION: ICUs caring for patients with COVID-19 presented substantial variation in risk-adjusted mortality. ICUs with better baseline (prepandemic) performance showed reduced mortality and less variability. Our findings suggest that achieving ICU efficiency by targeting improvement in organizational aspects of ICUs may impact outcomes, and therefore should be a part of the preparedness for future pandemics.

Vaccine coverage and effectiveness against laboratory-confirmed symptomatic and severe Covid-19 in indigenous people in Brazil: a cohort study.

BACKGROUND: Indigenous people have historically suffered devastating impacts from epidemics and continue to have lower access to healthcare and be especially vulnerable to respiratory infections. We estimated the coverage and effectiveness of Covid-19 vaccines against laboratory-confirmed Covid-19 cases among indigenous people in Brazil. METHODS: We linked nationwide Covid-19 vaccination data with flu-like surveillance records and studied a cohort of vaccinated indigenous people aged ≥ 5 years between 18th January 2021 and 1st March 2022. We considered individuals unexposed from the date they received the first dose of vaccine until the 13th day of vaccination, partially vaccinated from the 14th day after the first dose until the 13th day after receiving the second dose, and fully vaccinated onwards. We estimated the Covid-19 vaccination coverage and used Poisson regression to calculate the relative risks (RR) and vaccine effectiveness (VE) of CoronaVac, ChAdOx1, and BNT162b2 against Covid-19 laboratory-confirmed cases incidence, mortality, hospitalisation, and hospital-progression to Intensive Care Unit (ICU) or death. VE was estimated as (1-RR)*100, comparing unexposed to partially or fully vaccinated. RESULTS: By 1st March 2022, 48.7% (35.0-62.3) of eligible indigenous people vs. 74.8% (57.9-91.8) overall Brazilians had been fully vaccinated for Covid-19. Among fully vaccinated indigenous people, we found a lower risk of symptomatic cases (RR: 0.47, 95%CI: 0.40-0.56) and mortality (RR: 0.47, 95%CI: 0.14-1.56) after the 14th day of the second dose. VE for the three Covid-19 vaccines combined was 53% (95%CI:44-60%) for symptomatic cases, 53% (95%CI:-56-86%) for mortality and 41% (95%CI:-35-75%) for hospitalisation. In our sample, we found that vaccination did not reduce Covid-19 related hospitalisation. However, among hospitalised patients, we found a lower risk of progression to ICU (RR: 0.14, 95%CI: 0.02-0.81; VE: 87%, 95%CI:27-98%) and Covid-19 death (RR: 0.04, 95%CI:0.01-0.10; VE: 96%, 95%CI: 90-99%) after the 14th day of the second dose. CONCLUSIONS: Lower coverage but similar Covid-19 VE among indigenous people than overall Brazilians suggest the need to expand access, timely vaccination, and urgently offer booster doses to achieve a great level of protection among this group.

Effectiveness of a multicomponent intervention to face the COVID-19 pandemic in Rio de Janeiro's favelas: difference-in-differences analysis.

INTRODUCTION: Few community-based interventions addressing the transmission control and clinical management of COVID-19 cases have been reported, especially in poor urban communities from low-income and middle-income countries. Here, we analyse the impact of a multicomponent intervention that combines community engagement, mobile surveillance, massive testing and telehealth on COVID-19 cases detection and mortality rates in a large vulnerable community (Complexo da Maré) in Rio de Janeiro, Brazil. METHODS: We performed a difference-in-differences (DID) analysis to estimate the impact of the multicomponent intervention in Maré, before (March-August 2020) and after the intervention (September 2020 to April 2021), compared with equivalent local vulnerable communities. We applied a negative binomial regression model to estimate the intervention effect in weekly cases and mortality rates in Maré. RESULTS: Before the intervention, Maré presented lower rates of reported COVID-19 cases compared with the control group (1373 vs 1579 cases/100 000 population), comparable mortality rates (309 vs 287 deaths/100 000 population) and higher case fatality rates (13.7% vs 12.2%). After the intervention, Maré displayed a 154% (95% CI 138.6% to 170.4%) relative increase in reported case rates. Relative changes in reported death rates were -60% (95% CI -69.0% to -47.9%) in Maré and -28% (95% CI -42.0% to -9.8%) in the control group. The case fatality rate was reduced by 77% (95% CI -93.1% to -21.1%) in Maré and 52% (95% CI -81.8% to -29.4%) in the control group. The DID showed a reduction of 46% (95% CI 17% to 65%) of weekly reported deaths and an increased 23% (95% CI 5% to 44%) of reported cases in Maré after intervention onset. CONCLUSION: An integrated intervention combining communication, surveillance and telehealth, with a strong community engagement component, could reduce COVID-19 mortality and increase case detection in a large vulnerable community in Rio de Janeiro. These findings show that investment in community-based interventions may reduce mortality and improve pandemic control in poor communities from low-income and middle-income countries.

What we talk about when we talk about COVID-19 vaccination campaign impact: a narrative review.

Background: The lack of precise definitions and terminological consensus about the impact studies of COVID-19 vaccination leads to confusing statements from the scientific community about what a vaccination impact study is. Objective: The present work presents a narrative review, describing and discussing COVID-19 vaccination impact studies, mapping their relevant characteristics, such as study design, approaches and outcome variables, while analyzing their similarities, distinctions, and main insights. Methods: The articles screening, regarding title, abstract, and full-text reading, included papers addressing perspectives about the impact of vaccines on population outcomes. The screening process included articles published before June 10, 2022, based on the initial papers' relevance to this study's research topics. The main inclusion criteria were data analyses and study designs based on statistical modelling or comparison of pre- and post-vaccination population. Results: The review included 18 studies evaluating the vaccine impact in a total of 48 countries, including 32 high-income countries (United States, Israel, and 30 Western European countries) and 16 low- and middle-income countries (Brazil, Colombia, and 14 Eastern European countries). We summarize the main characteristics of the vaccination impact studies analyzed in this narrative review. Conclusion: Although all studies claim to address the impact of a vaccination program, they differ significantly in their objectives since they adopt different definitions of impact, methodologies, and outcome variables. These and other differences are related to distinct data sources, designs, analysis methods, models, and approaches.

Effect of walnut consumption on neuropsychological development in healthy adolescents: a multi-school randomised controlled trial.

Background: Omega-3 fatty acids are critical for neuropsychological functioning. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. The potential benefit on adolescent neurodevelopment of consuming walnuts, a source of omega-3 alpha-linolenic acid (ALA), remains unclear. Methods: We conducted a 6-month multi-school-based randomised controlled nutrition intervention trial to assess whether walnut consumption has beneficial effects on the neuropsychological and behavioural development of adolescents. The study took place between 04/01/2016 and 06/30/2017 in twelve different high schools in Barcelona, Spain (ClinicalTrials.gov Identifier: NCT02590848). A total of 771 healthy teenagers aged 11-16 years were randomised into two equal groups (intervention or control). The intervention group received 30 g/day of raw walnut kernels to be incorporated into their diet for 6 months. Multiple primary endpoints concerning neuropsychological (working memory, attention, fluid intelligence, and executive function) and behavioural (socio-emotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were assessed at baseline and after intervention. Red blood cell (RBC) ALA status was determined at baseline and 6 months as a measure of compliance. Main analyses were based on intention-to-treat using a linear mixed-effects model. A per-protocol effect of the intervention was analysed using inverse-probability weighting to account for post-randomisation prognostic factors (including adherence) using generalised estimating equations. Findings: In intention-to-treat analyses, at 6 months there were no statistically significant changes between the intervention and control groups for all primary endpoints. RBC ALA (%) significantly increased only in the intervention group, coefficient = 0.04 (95% Confidence Interval (CI) = 0.03, 0.06; p < 0.0001). The per-protocol (adherence-adjusted) effect on improvement in attention score (hit reaction time variability) was -11.26 ms (95% CI = -19.92, -2.60; p = 0.011) for the intervention group as compared to the control group, improvement in fluid intelligence score was 1.78 (95% CI = 0.90, 2.67; p < 0.0001), and reduction of ADHD symptom score was -2.18 (95% CI = -3.70, -0.67; p = 0.0050). Interpretation: Our study suggested that being prescribed eating walnuts for 6 months did not improve the neuropsychological function of healthy adolescents. However, improved sustained attention, fluid intelligence, and ADHD symptoms were observed in participants who better complied with the walnut intervention. This study provides a foundation for further clinical and epidemiological research on the effect of walnuts and ALA on neurodevelopment in adolescents. Funding: This study was supported by Instituto de Salud Carlos III through the projects 'CP14/00108, PI16/00261, PI21/00266' (co-funded by European Union Regional Development Fund 'A way to make Europe'). The California Walnut Commission (CWC) has given support by supplying the walnuts for free for the Walnuts Smart Snack Dietary Intervention Trial.

Association between primary or booster COVID-19 mRNA vaccination and Omicron lineage BA.1 SARS-CoV-2 infection in people with a prior SARS-CoV-2 infection: A test-negative case-control analysis.

BACKGROUND: The benefit of primary and booster vaccination in people who experienced a prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains unclear. The objective of this study was to estimate the effectiveness of primary (two-dose series) and booster (third dose) mRNA vaccination against Omicron (lineage BA.1) infection among people with a prior documented infection. METHODS AND FINDINGS: We conducted a test-negative case-control study of reverse transcription PCRs (RT-PCRs) analyzed with the TaqPath (Thermo Fisher Scientific) assay and recorded in the Yale New Haven Health system from November 1, 2021, to April 30, 2022. Overall, 11,307 cases (positive TaqPath analyzed RT-PCRs with S-gene target failure [SGTF]) and 130,041 controls (negative TaqPath analyzed RT-PCRs) were included (median age: cases: 35 years, controls: 39 years). Among cases and controls, 5.9% and 8.1% had a documented prior infection (positive SARS-CoV-2 test record ≥90 days prior to the included test), respectively. We estimated the effectiveness of primary and booster vaccination relative to SGTF-defined Omicron (lineage BA.1) variant infection using a logistic regression adjusted for date of test, age, sex, race/ethnicity, insurance, comorbidities, social venerability index, municipality, and healthcare utilization. The effectiveness of primary vaccination 14 to 149 days after the second dose was 41.0% (95% confidence interval (CI): 14.1% to 59.4%, p 0.006) and 27.1% (95% CI: 18.7% to 34.6%, p < 0.001) for people with and without a documented prior infection, respectively. The effectiveness of booster vaccination (≥14 days after booster dose) was 47.1% (95% CI: 22.4% to 63.9%, p 0.001) and 54.1% (95% CI: 49.2% to 58.4%, p < 0.001) in people with and without a documented prior infection, respectively. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds of infection among boosted (≥14 days after booster dose) and booster-eligible people (≥150 days after second dose). The odds ratio (OR) comparing boosted and booster-eligible people with a documented prior infection was 0.79 (95% CI: 0.54 to 1.16, p 0.222), whereas the OR comparing boosted and booster-eligible people without a documented prior infection was 0.54 (95% CI: 0.49 to 0.59, p < 0.001). This study's limitations include the risk of residual confounding, the use of data from a single system, and the reliance on TaqPath analyzed RT-PCR results. CONCLUSIONS: In this study, we observed that primary vaccination provided significant but limited protection against Omicron (lineage BA.1) infection among people with and without a documented prior infection. While booster vaccination was associated with additional protection against Omicron BA.1 infection in people without a documented prior infection, it was not found to be associated with additional protection among people with a documented prior infection. These findings support primary vaccination in people regardless of documented prior infection status but suggest that infection history may impact the relative benefit of booster doses.

Effectiveness of an inactivated Covid-19 vaccine with homologous and heterologous boosters against Omicron in Brazil.

The effectiveness of inactivated vaccines (VE) against symptomatic and severe COVID-19 caused by omicron is unknown. We conducted a nationwide, test-negative, case-control study to estimate VE for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac in Brazil in the Omicron context. Analyzing 1,386,544 matched-pairs, VE against symptomatic disease was 8.6% (95% CI, 5.6-11.5) and 56.8% (95% CI, 56.3-57.3) in the period 8-59 days after receiving a homologous and heterologous booster, respectively. During the same interval, VE against severe Covid-19 was 73.6% (95% CI, 63.9-80.7) and 86.0% (95% CI, 84.5-87.4) after receiving a homologous and heterologous booster, respectively. Waning against severe Covid-19 after 120 days was only observed after a homologous booster. Heterologous booster might be preferable to individuals with completed primary series inactivated vaccine.

Primary healthcare protects vulnerable populations from inequity in COVID-19 vaccination: An ecological analysis of nationwide data from Brazil.

Background: There is limited information on the inequity of access to vaccination in low-and-middle-income countries during the COVID-19 pandemic. Here, we described the progression of the Brazilian immunisation program for COVID-19, and the association of socioeconomic development with vaccination rates, considering the potential protective effect of primary health care coverage. Methods: We performed an ecological analysis of COVID-19 immunisation data from the Brazilian National Immunization Program from January 17 to August 31, 2021. We analysed the dynamics of vaccine coverage in the adult population of 5,570 Brazilian municipalities. We estimated the association of human development index (HDI) levels (low, medium, and high) with age-sex standardised first dose coverage using a multivariable negative binomial regression model. We evaluated the interaction between the HDI and primary health care coverage. Finally, we compared the adjusted monthly progression of vaccination rates, hospital admission and in-hospital death rates among HDI levels. Findings: From January 17 to August 31, 2021, 202,427,355 COVID-19 vaccine doses were administered in Brazil. By the end of the period, 64·2% of adults had first and 31·4% second doses, with more than 90% of those aged ≥60 years with primary scheme completed. Four distinct vaccine platforms were used in the country, ChAdOx1-S/nCoV-19, Sinovac-CoronaVac, BNT162b2, Ad26.COV2.S, composing 44·8%, 33·2%, 19·6%, and 2·4% of total doses, respectively. First dose coverage differed between municipalities with high, medium, and low HDI (Median [interquartile range] 72 [66, 79], 68 [61, 75] and 63 [55, 70] doses per 100 people, respectively). Municipalities with low (Rate Ratio [RR, 95% confidence interval]: 0·87 [0·85-0·88]) and medium (RR [95% CI]: 0·94 [0·93-0·95]) development were independently associated with lower vaccination rates compared to those with high HDI. Primary health care coverage modified the association of HDI and vaccination rate, improving vaccination rates in those municipalities of low HDI and high primary health care coverage. Low HDI municipalities presented a delayed decrease in adjusted in-hospital death rates by first dose coverage compared to high HDI locations. Interpretation: In Brazil, socioeconomic disparities negatively impacted the first dose vaccination rate. However, the primary health care mitigated these disparities, suggesting that the primary health care coverage guarantees more equitable access to vaccines in vulnerable locations. Funding: This work is part of the Grand Challenges ICODA pilot initiative, delivered by Health Data Research UK and funded by the Bill & Melinda Gates Foundation and the Minderoo Foundation. This study was supported by the National Council for Scientific and Technological Development (CNPq), the Coordination for the Improvement of Higher Education Personnel (CAPES) - Finance Code 001, Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) and the Pontifical Catholic University of Rio de Janeiro.

Urban-rural differences in hypertension prevalence in low-income and middle-income countries, 1990-2020: A systematic review and meta-analysis.

BACKGROUND: The influence of urbanicity on hypertension prevalence remains poorly understood. We conducted a systematic review and meta-analysis to assess the difference in hypertension prevalence between urban and rural areas in low-income and middle-income countries (LMICs), where the most pronounced urbanisation is underway. METHODS AND FINDINGS: We searched PubMed, Web of Science, Scopus, and Embase, from 01/01/1990 to 10/03/2022. We included population-based studies with ≥400 participants 15 years and older, selected by using a valid sampling technique, from LMICs that reported the urban-rural difference in hypertension prevalence using similar blood pressure measurements. We excluded abstracts, reviews, non-English studies, and those with exclusively self-reported hypertension prevalence. Study selection, quality assessment, and data extraction were performed by 2 independent reviewers following a standardised protocol. Our primary outcome was the urban minus rural prevalence of hypertension. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure as ≥90 mm Hg and could include use of antihypertensive medication, self-reported diagnosis, or both. We investigated heterogeneity using study-level and socioeconomic country-level indicators. We conducted meta-analysis and meta-regression using random-effects models. This systematic review and meta-analysis has been registered with PROSPERO (CRD42018091671). We included 299 surveys from 66 LMICs, including 19,770,946 participants (mean age 45.4 ± SD = 9 years, 53.0% females and 63.1% from rural areas). The pooled prevalence of hypertension was 30.5% (95% CI, 28.9, 32.0) in urban areas and 27.9% (95% CI, 26.3, 29.6) in rural areas, resulting in a pooled urban-rural difference of 2.45% (95% CI, 1.57, 3.33, I-square: 99.71%, tau-square: 0.00524, Pheterogeneity < 0.001). Hypertension prevalence increased over time and the rate of change was greater in rural compared to urban areas, resulting in a pooled urban-rural difference of 5.75% (95% CI, 4.02, 7.48) in the period 1990 to 2004 and 1.38% (95% CI, 0.40, 2.37) in the period 2005 to 2020, p < 0.001 for time period. We observed substantial heterogeneity in the urban-rural difference of hypertension, which was partially explained by urban-rural definition, probably high risk of bias in sampling, country income status, region, and socioeconomic indicators. The urban-rural difference was 5.67% (95% CI, 4.22, 7.13) in low, 2.74% (95% CI, 1.41, 4.07) in lower-middle and -1.22% (95% CI, -2.73, 0.28) in upper-middle-income countries in the period 1990 to 2020, p < 0.001 for country income. The urban-rural difference was highest for South Asia (7.50%, 95% CI, 5.73, 9.26), followed by sub-Saharan Africa (4.24%, 95% CI, 2.62, 5.86) and reversed for Europe and Central Asia (-6.04%, 95% CI, -9.06, -3.01), in the period 1990 to 2020, p < 0.001 for region. Finally, the urban-rural difference in hypertension prevalence decreased nonlinearly with improvements in Human Development Index and infant mortality rate. Limitations included lack of data available from all LMICs and variability in urban and rural definitions in the literature. CONCLUSIONS: The prevalence of hypertension in LMICs increased between 1990 and 2020 in both urban and rural areas, but with a stronger trend in rural areas. The urban minus rural hypertension difference decreased with time, and with country-level socioeconomic development. Focused action, particularly in rural areas, is needed to tackle the burden of hypertension in LMICs.