key: cord-0798921-enoexk6n
authors: Vila-corcoles, A.; Satue-Gracia, E.; Vila-Rovira, A.; de Diego-Cabanes, C.; Forcadell-Peris, M. J.; Ochoa-Gondar, O.
title: COVID19-related and all-cause mortality among middle-aged and older adults across the first epidemic wave of SARS-COV-2 infection in the region of Tarragona, Spain: results from the COVID19 TARRACO Cohort Study, March-June 2020.
date: 2021-02-05
journal: nan
DOI: 10.1101/2021.02.02.21251028
sha: e52ea6086ee37e594bb1a3d5f9cb46b40c37743a
doc_id: 798921
cord_uid: enoexk6n

Background: Direct and indirect COVID19-related mortality is uncertain. This study investigated COVID19-related and all-cause deaths among middle-aged and older adults during the first wave of COVID19 epidemic period, assessing mortality risks by pre-existing socio-demographic and medical underlying conditions. Methods: Population-based cohort study involving 79,083 individuals [≥]50 years-old in Tarragona (Southern Catalonia, Spain). Baseline cohort characteristics (age/sex, comorbidities and medications/vaccinations history) were established at study start (01/03/2020) and main outcomes were COVID19-related deaths (occurred in patients diagnosed with the disease) and all-cause deaths occurred among cohort members between 01/03/2020-30/06/2020. Mortality risks were assessed by Cox regression analyses. Results: Cohort members were followed for 1,356,358 persons-weeks, occurring 576 all-cause deaths (124 COVID19-related). All-cause mortality rate was 42.5 deaths per 100,000 persons-week, being 22.8 in healthy/unrelated-COVID19 subjects, 236.4 in COVID19-excluded/PCR-negative subjects, 493.7 in COVID19-compatible/PCR-unperformed subjects and 4009.1 in COVID19-confirmed patients. In multivariable analyses, increasing age, sex male, nursing-home residence, cancer, neurologic, cardiac or liver disease, receiving diuretics, systemic corticosteroids, proton-pump inhibitors and benzodiazepines were associated with increased risk of all-cause mortality; conversely, receiving renin-angiotensin inhibitors and statins were associated with reduced risk. Age/years, sex male and nursing-home residence were strong predictors for COVID19-related mortality, but none comorbidity appeared significantly associated with an increased risk. Conclusion: Apart from direct COVID19-related deaths (which represented almost 22% of all-cause mortality), theoretically COVID19-excluded patients (PCR-negative) suffered considerable greater all-cause mortality than healthy/unrelated-COVID19 subjects, which could explain, in part, the large excess deaths observed across the COVID19 pandemic.

A year ago, following an outbreak of pneumonia in Wuhan (China), a new coronavirus was detected. Said virus, later named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- , is the cause of the disease designated by the World Health Organization (WHO) as COVID19 in February 2020. [1] Currently, the pandemic caused by this virus continues to be a threat to public health worldwide. [2] Available publications have reported different percentages of asymptomatic or mild cases of COVID19 but, even if they account for around 80%, [2, 3] due to the high infectivity of the virus, the number of disease's related deaths is very high. [2] The mortality rates reported are very heterogeneous, depending on the countries (with important differences between regions, even within the same country), and also on the availability / policy of conducting diagnostic tests. [2] .

For example, in Lombardy (Italy) the case fatality rate ranged between 1.6% and 18.3%, [4] while the Chinese Centre for Disease Control and Prevention, in a cohort of 72,314 cases, estimated a 2.3% case-fatality rate (14.8% for patients ≥ 80 years) [5] . Most articles report inhospital mortality or case fatality rates (mortality rate among confirmed cases); it must be taken into account that infection fatality rate (which consider all infected individuals) would be lower.

On the other hand, many deaths from COVID19 occur in undiagnosed patients. Lastly, we have to keep in mind the "excess mortality" (deaths caused by other conditions, linked to a delay in care, overburden of the health system and socioeconomic determinants of health). [6, 7] In the case of Spain, the latest scientific-technical report of the Ministry of Health (dated November 12) informed a fatality rate of 11% in patients 

Primary outcome was death from any cause (COVID19-related or not) occurred among cohort members during the 4-month of study period (01/03/2020-30/06/2020). Laboratory-confirmed COVID-19 case was defined when a cohort member tested positive in SARS-COV-2 using Reverse Transcription-Polymerase Chain Reaction (RT-PCR) or serological tests, according institutional guidelines.

[19] COVID19-related death was considered when the patient died from any cause within the first 30-days after the onset of the disease or at any time during hospitalstay. Death by COVID-19 (likely due to or death with COVID-19 (likely due to other concomitant causes) were differentiated according to family physician's criteria after checking hospital and primary care clinical records in each of deceased COVID19 cases.

Baseline covariates were age, sex, type of residence (community-dwelling or nursing-home), vaccinations' history, previous comorbidities and chronic medications' use; they were considered according to data registered in the e-CAP system. Criteria used to define comorbidities and chronic medication use are extensively described in an appendix elsewhere.

[15] Unrecorded comorbidities, medications or vaccinations were considered as absent.

In addition, at the end of the study period, according to their COVID-19 relation, cohort members were classified as: COVID19-unrelated/healthy, COVID19-excluded (PCR/serological test performed with negative result), COVID19-compatible (clinical suspicion alone, without any test performed) and COVID19-confirmed (positive PCR or serological test).

Descriptive statistics of socio-demographic and clinical variables include frequencies/ percentages for categorical variables; and means/ standard deviations (SD) for continuous variables. Chi-squared or Fisher test (categorical variables) and Student's t test (continuous variables) were used for comparison of differences between groups.

Mortality Rates (MRs) for COVID19-related and all-cause deaths were calculated per 100,000 persons-week, considering in the denominator the sum of the persons-time contributed for each cohort member during the study period (17.4 weeks). The confidence intervals (CIs) for the MRs were calculated assuming a Poisson distribution for uncommon events.

Cox regression analyses were used to calculate unadjusted, age&sex-adjusted and multivariable-adjusted hazards ratios (HRs) and estimate the association between baseline conditions and the time to the first outcome (COVID19-related or all-cause death) occurred among cohort members throughout the study period (from 1st March to 30th June 2020). All exposure above mentioned covariates (i.e., age, sex, residence, comorbidities/underlying conditions, chronic medications' use and vaccinations' history) were considered for multivariable Cox models; the method to select a subset of covariates to include in final models was the purposeful selection.

[20] Final models include both significant or confounder variables and all covariates judged clinically or epidemiologically relevant. We performed a main analysis including the total study cohort (N=79,083) and two subgroup analyses restricted to community- Table 3 shows univariate analyses reporting all-cause deaths (n=576) by age, sex and preexisting conditions (comorbidities, chronic medications' use and vaccinations' history) in the total study cohort. Table 4 reports it for COVID19-related deaths (n=124). Tables 5 and 6 show Cox regression analyses assessing unadjusted, age&sex-adjusted and multivariable-adjusted risks of suffer all-cause death and COVID19-related death, respectively, in the total study cohort.

Supplementary tables S1-S4 show subgroup analyses restricted to community-dwelling individuals and supplementary tables S5-S8 show subgroup analyses restricted to nursinghome residents.

After multivariable-adjustments assessing risks of all-cause mortality in the total study cohort (see Table 5 If we consider COVID19-related mortality (see Table 6 ), many comorbidities (cancer, neurological, renal, respiratory, cardiac disease, diabetes and hypertension) appeared associated with an increased risk in the crude analyses. However, after age&sex-adjustment only neurological, respiratory and cardiac disease were associated with increased risk, and none of them appeared significantly associated with an increased risk after multivariable- (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; https://doi.org/10.1101/2021.02.02.21251028 doi: medRxiv preprint altered the risk of COVID19-related death after multivariable-adjustments in these communitydwelling individuals (see supplementary Table S4 ).

In subgroup analyses restricted to nursing-home residents, apart from increasing age and male sex, only receiving antineoplastic agents (HR: 3.81; 95% CI: 1.00-14.44; p=0.049) and, surprisingly, influenza vaccination in prior autumn (HR: 2.34; 95% CI: 1.08-5.07; p=0.031) significantly altered the risk of COVID19-related death after multivariable adjustment (see supplementary Table S8 ).

Direct and indirect mortality due to COVID19 is controversial. [4, 5, 8, 11, 13, 21, 22] This study investigated all-cause and COVID19-related deaths among middle-aged and older adults in the region of Tarragona (Southern Catalonia, Spain) across the first wave of COVID19 epidemic period (March-June 2020), assessing mortality risks by demographic characteristics and underlying medical conditions. Of note, the study was conducted in a region with relatively low incidence of COVID19 as compared with other European and Spanish regions. [2, 3, 8] As main findings, all-cause mortality rate across study period was 42.5 deaths per 100,000 persons-week, and COVID19-related deaths represented 21.5% of overall deaths. Considering specifically COVID19-related deaths (those occurred among patients with laboratory-confirmed COVID19), 90.3% died by COVID-19 and 9.7% died with COVID19 (i.e., the death may be attributed to other baseline or concomitant cause.

Increasing age, male sex, and nursing-home residence appear as the strongest predictors for both COVID19-related death and all-cause death. Other pre-existing conditions may also alter mortality risk, especially some comorbidities and chronic medications' use, which emerged significantly related with all-cause mortality risk. Importantly, apart from COVID19-related deaths (occurring among patients with laboratoryconfirmed COVID19), theoretically COVID19-excluded patients (i.e., those persons with a negative PCR) suffered ten times greater all-cause mortality than unrelated-COVID19/healthy subjects. This fact suggests that, apart from baseline excess risk in PCR-negative subjects (who were older and had more comorbidities than healthy/COVID19-unrelated subjects), some of the observed excess mortality in PCR-negative subjects could be due to undiagnosed/undetected COVID19 despite PCR performed. In this sense, we note that the reliability of PCR testing depends on the quality of the nasopharyngeal samples collected, timing of collection and sensitivity of tests used, [19] which could explain, in part, the excess all-cause mortality observed in PCR-negative subjects in this study.

Regarding excess mortality, the Statistics National Institute (INE) reported an increase in deceases in 2020 (compared to 2019) of 18.95%; which corresponds in absolute numbers to 70,715 deaths, of which only 43,131 were attributed to COVID19.

[10] The considerably larger all-cause mortality in PCR-negative subjects observed in the present study may reflect All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; https://doi.org/10.1101/2021.02.02.21251028 doi: medRxiv preprint COVID19 underdiagnosis and could explain, in part, some excess all-cause deaths observed across the current COVID19 pandemic.

We note the importance of providing adjusted data instead of crude data. Thus, while crude allcause mortality rate was almost 25-times greater in nursing-home (766 deaths per 100,000 persons-week) than in community-dwelling individuals (31 deaths per 100,000 persons-week), we found that after multivariable adjustments (by age/sex and pre-existing conditions) nursinghome residence only increased approximately 1.6 times the adjusted risk of all-cause mortality (HR: 1.63; 95% CI: 1.28-2.09) as compared with community-dwelling. In this same way, apart from increasing age and sex male, many pre-existing conditions appeared significantly associated with an increased risk of COVID19-related mortality in the crude analysis (and several in the age&sex-adjusted analysis), but none comorbidity emerged significantly associated with an increased risk after multivariable adjustment.

This highlights the importance of maximizing adjusted data assessing event's risk in observational studies. In fact, this could explain distinct/opposite data reported in different studies evaluating relationships between some pre-existing comorbidities/conditions and susceptibility/risk of suffering COVID19 infection or death. [4, 5, 11, 13, [21] [22] [23] [24] [25] [26] To illustrate it, besides subgroup analyses, we reported all unadjusted, age&sex-adjusted and multivariableadjusted results here, which is a major strength in this study.

Considering chronic medication, there is scarce data reporting the possible influence of previous use of these drugs on the risk of COVID19-related mortality. We did not observe any significant association in this sense but, interestingly, receiving statins and renin-angiotensin inhibitors were significantly associated with a lower risk of all-cause mortality in our study cohort.

Major strengths in this study were the large size and representativity of the cohort (that included more than 79,000 people, which represents approximately 75% of overall population over 50 years of age in the study area, and the use of survival analysis methods to accurately estimate both risks of all-cause and COVID19-related mortality by distinct important population subgroups (based in its relation with COVID19): COVID19-confirmed subjects, COVID19suspected subjects (without PCR performed), COVID19-excluded subjects (negative PCR testing) and COVID19-unrelated/healthy subjects). The large size of the study cohort together with the adjustment of major possible confounding variables (e.g., age, type of residence, preexisting underlying conditions/comorbidities and chronic medications' use) in the multivariable analyses may provide an acceptable basis to assess mortality risk among the general population ≥ 50 years across the first wave of COVID19 epidemic period in our setting.

Major limitations in this study are related with its retrospective design and scarce availability of PCR tests during the first weeks of study period. Indeed, considering that PCR testing was not routinely performed for all clinically compatible/suspected COVID19 patients across the study period, the laboratory-confirmed COVID19 cases (and, consequently, the number of COVID19related deaths) were likely underestimated. Then, all-cause mortality (which is not influenced by the frequency of PCR testing) may be a better measure of COVID19 pandemic impact. As another limitation, the study was conducted in a single geographical area and, logically, specific All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; https://doi.org/10.1101/2021.02.02.21251028 doi: medRxiv preprint mortality data may not be directly extrapolated to other geographical regions with distinct epidemic conditions. The authors recognise these inherent limitations but note that, opposite to many papers reporting only crude COVID19 data, the present study provides age&sex-adjusted and multivariable-adjusted data evaluating both all-cause and COVID19-related mortality risks.

Importantly, the estimations may considerably vary depending on type of analyses/adjustments performed; therefore, we underline again the importance of maximizing adjustments. We did subgroup analysis (nursing-home/community-dwelling) and multivariable-adjustments, but, as in all observational studies, a residual confounding due to unmeasured factors (e.g., socioeconomical, lifestyle, job-or healthcare-related factors) cannot be excluded.

In summary, in this large cohort study including 79,083 middle-aged and older adults followed across the first wave of COVID19 epidemic period in the region of Tarragona, we found that deaths from COVID19 represented 21.5% of all-cause mortality occurred across study period (March-June 2020). Increasing age, sex male, nursing-home residence, cancer, neurologic, cardiac or liver disease, receiving diuretics, systemic corticosteroids, proton-pump inhibitors and benzodiazepines were associated with an increased risk of all-cause mortality; conversely, receiving renin-angiotensin inhibitors and statins were associated with a reduced risk.

Age/years, sex male and nursing-home residence were strong predictors for COVID19-related mortality, but no comorbidity was independently associated with increased risk.

Interestingly, apart from COVID19-related deaths (approximately 10% of them could be attributed to another baseline or concomitant cause), theoretically COVID19-excluded patients (PCR-negative) suffered considerable greater all-cause mortality than healthy/unrelated-COVID19 subjects. This data suggests COVID19 underdiagnosis and it could explain, in part, the unexpected excess deaths observed during the COVID19 pandemic.

CONTRIBUTORS: AVC designed the study; AVC and ESG assessed outcomes and wrote the manuscript; ESG, CDC and MFP obtained data; ESG and AVR did statistical analyses and edited the manuscript; OOG revised the final version; AVC coordinated the study.

FUNDING: This study is supported by a grant from the Instituto de Salud Carlos III of the Spanish Health Ministry (file COV20/00852; call for the SARS-COV-2/COVID-19 disease, RDL 8/2020, March 17, 2020). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

All authors, none declared. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; potential of asymptomatic and presymptomatic SARS-CoV-2 infections: A living systematic review and meta-analysis. PLoS Med. 2020;17 (9) (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; Table 2 . Distribution of all-cause deaths according to COVID19-related status in cohort members. Tarragona, 01/03/2020-30/06/2020. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; Table 3 . Incidence of all-cause mortality according to baseline demographical and clinical characteristics (comorbidities/medications) in the total study cohort (N=79,083). Tarragona region (Southern Catalonia, Spain), 01/03/2020-30/06/2020. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ; https://doi.org/10.1101/2021.02.02.21251028 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 5, 2021. ;

Director-General's remarks at the media briefing on 2019-nCoV on 11

European Centre for Disease Prevention and Control. Novel coronavirus disease 2019 (COVID-19) pandemic: increased transmission in the EU/EEA and the UK-sixth update-12

Beta blockers 2.32 (1.85-2.91)

Calcium channel blockers 1.77 (1.34-2.35)

Oral antidiabetic drugs 1.81 (1.43-2.29)

Systemic corticosteroids 9

NOTE: P-values in univariate analysis were calculated by chi-squared, or Fisher's test as appropriate, comparing percentages in the study population vs all-cause deaths cases

CIs denotes confidence intervals for mortality rates and were calculated assuming a Poisson distribution for uncommon events

NOTE: P-values in univariate analysis were calculated by chi-squared, or Fisher's test as appropriate, comparing percentages in the study population vs Covid19-related cases

CIs denotes confidence intervals for mortality rates and were calculated assuming a Poisson distribution for uncommon events

Cox regression analyses assessing unadjusted, age & sex-adjusted and multivariable-adjusted risk of all-cause mortality in nursing-home residents (N=1,414)

Tarragona region

) 0.141 1.30 (0.86-1.95) 0.216

Cox regression analyses assessing unadjusted, age & sex-adjusted and multivariable-adjusted risk of Covid19-related mortality in nursing-home residents (N=1,414). Tarragona region