Abstract
Despite the high rates of COVID-19 vaccination achieved in Spain, work must continue to ensure that vulnerable populations are protected. The aim of this study was to identify comorbidities associated with increased mortality in adult patients hospitalized with COVID-19 in Spain. We obtained all hospital discharge data for COVID-19-related diseases from January 2020 to December, 2021. Specific data were collected on potential poor prognostic risk factors, such as solid tumours, haematological malignancies, immunodeficiencies, diabetes, hypertension, cardiopulmonary disease, chronic lower respiratory tract disease, COPD, or liver disease. There were 751,598 hospitalizations for COVID-19 in adults in Spain between 2020 and 2021, with a hospitalization rate of 958.57 per 100,000, reaching 4439.36 hospitalizations per 100,000 persons in patients ≥ 80 years. The case fatality rate in adults hospitalized with COVID-19 was 13.7%, and it exceeded 24% in those ≥ 80 years. Hospitalized adult patients with COVID-19 with any of the comorbidities studied were 4.70 times more likely to die than those without comorbidities. The risk of death increased by a factor of 6.25 for patients with solid tumours, 7.98 for patients with haematologic malignancies, 4.81 for patients with diabetes or 4.22 for patients with hypertension. When stratified by age, comorbidities conferred the largest relative mortality increases in younger adults (e.g., hypertension in 60–64-year-olds: CFR 7.34%, OR 3.13 [95% CI 2.79–3.51] vs. no comorbidities). In‑hospital mortality associated with COVID‑19 increased markedly with age, but comorbidities conferred substantial additional risk across all age groups, with particularly high relative risks in younger adults. These findings support the continued prioritization of older adults and targeted high‑risk groups, including younger patients with chronic conditions such as hypertension and diabetes, for preventive interventions.
Keywords: Hospitalizations, COVID-19, Comorbidities, Hypertension, Vaccine, Epidemiology, Spain
Subject terms: Diseases, Health care, Medical research, Risk factors
Introduction
A novel coronavirus disease causing a wide range of symptoms, from mild symptoms to severe viral pneumonia with severe acute respiratory syndrome, was first described in 2019 and named SARS-CoV-21,2. The World Health Organization declared a public health emergency in January 2020 and a pandemic in March 20203. Spain reported one of the highest incidence rates in Europe and one of the highest mortality rates, especially in the first wave of the pandemic4. COVID-19 has continued evolving and has now become endemic. This is a new situation, with new long-term challenges, that our healthcare system will face despite being already overloaded.
Despite the high rates of vaccination achieved in Spain, work must continue to ensure that vulnerable populations, which are at increased risk of severe illness, hospitalization, intensive care unit (ICU) stays, mechanical ventilation and death, are protected, as recent data continue to show a disproportionate burden of severe outcomes in older adults and high‑risk groups even in highly vaccinated settings5.
As of November 2022, the U.S. Centers for Disease Control categorized COVID-19 high-risk populations into the following groups: (a) older adults (+ 60); (b) people with medical conditions such as cancer, chronic kidney disease, liver disease, lung disease, dementia, neurological conditions, diabetes (types 1 & 2), heart conditions, HIV, overweight, obesity, physical inactivity, sickle cell disease, thalassemia, smoking (current or former), stroke, substance abuse, tuberculosis, being immunocompromised, having a weakened immune system, or taking medications that lower the immune system response; and (c) pregnant and recently pregnant people, who were considered at higher risk of severe COVID-19 and of complications affecting the pregnancy, developing baby and newborn infant6.
Age has been described as the main risk factor for poor prognosis in patients with COVID-19 since the very first stages of the pandemic. Older patients, regardless of underlying disease status, and patients with underlying disease, regardless of age, were at increased risk of death7–9. Some risk factors for in-hospital death in COVID-19 patients treated in the ICU have been described, such as increasing age, male sex, obesity status, diabetes mellitus status, and cardiovascular disease status. Additionally, chronic obstructive pulmonary disease, chronic renal insufficiency and cancer status have been found to be independent risk factors for in-hospital death in COVID-19 patients treated in ICUs10. In Spain, the prevalence of arterial hypertension (AHT) in the adult population ranges between 33% and 43% and increases with age to such an extent that in those over 65 years of age, it exceeds 60%11–14.
Identifying high-risk populations for COVID-19 infection, especially for poor prognosis and increased risk of death, on the basis of age, sex and underlying comorbid conditions continues to be essential to clearly define public health priorities and target groups for future education, vaccination, medications, and preventative treatments, both in the current context and in a potential future context of seasonal vaccination. The primary objective of this nationwide study was to quantify the excess risk of in‑hospital death associated with specific comorbidities in adults hospitalized with COVID‑19 in Spain during 2020–2021, using a large and representative administrative database. A secondary objective was to characterize how the magnitude of this excess risk varies by age and by calendar year (2020 versus 2021), thereby providing age‑stratified estimates that can inform long‑term, risk‑based prevention strategies in the current endemic context.
Methods
In this retrospective study, we used the national surveillance system for hospital data (Minimum Basic Data Set; MBDS) maintained by the Ministry of Health. This system covers an estimated 98% of public hospitals. Compulsory health insurance covers an estimated 99.5% of the Spanish population, but even persons not covered by health insurance can be treated in hospitals of the health care system15.
All hospital discharge data for COVID-19 among adults over 18 years of age reported in any diagnostic position from January 1 st, 2020, through December 31 st, 2021, were obtained. The Spanish version of the 10th International Classification of Diseases (Modificación Clínica Clasificación Internacional de Enfermedades) ICD-10-CM (CIE-10-MC) codes for COVID-19 (U07.1 y B97.29) were selected.
Specific data were collected on potential risk factors for poor prognosis: HIV, solid tumours, haematological malignancies, immunodeficiencies, diabetes, essential hypertension, cardiopulmonary disease, chronic lower respiratory tract disease, cerebrovascular disease, COPD, asthma, acute renal failure and liver disease.
Statistical methods
The incidence of hospital admissions (per 100,000 people), rate of death (per 100,000 people) and case–fatality rate (CFR, %) were calculated. As the denominator, we used data on the population covered by hospitals included in the MBDS adjusted for population figures obtained from municipal registers. The distribution by age of the population covered by these public hospitals was assumed to be equal to that of the general population. The estimated incidence rates of death during hospitalization due to COVID-19 and ORs by risk factor were calculated among those exposed to a given risk factor. In a sensitivity analysis, the ORs by risk factor were calculated for 2020 and 2021 separately to avoid differences due to the potential effect of the vaccination status in risk groups.
Differences in proportions were assessed via the chi-square test, and confidence intervals (95% CIs) were calculated. ANOVA was used for multiple comparisons. Post hoc Bonferroni correction was used to adjust statistical significance for multiple comparisons. Poisson regression was used to assess differences in hospitalization, mortality and CFRs.
For all tests, p < 0.05 was considered to indicate statistical significance. Statistical analyses were performed via SPSS 27 and Stata 16.1 software.
This study was performed in accordance with the principles of the Declaration of Helsinki of 1964 and its later amendments and comparable ethical standards. The Rey Juan Carlos University Ethics Committee ruled that no formal ethics approval was required due to the retrospective nature of the data that were delivered to the researchers anonymously and deidentifed before the analysis, in strict compliance with the current Spanish and European legislation.
Results
There were 751,598 hospitalizations related to COVID-19 infections in adults in Spain between 2020 and 2021, with a hospitalization rate (HR) of 958.57 (95% CI: 956.41–960.73) per 100,000 persons ≥ 18 years old. There were significantly more hospitalized men than hospitalized women (n = 419976 vs. n = 331622, and HR = 1104.29 (95% CI: 1100.97–1107.61.97.61) and 821.32 (95% CI: 818.54–824.1), respectively, p > 0.001) (Table 1).
Table 1.
Hospitalization rates related to COVID-19 by sex in Spain from 2020–2021.
| Age (Years) | Total (hospitalizations/100,000 (95%CI)) | Male (hospitalizations/100,000 (95%CI)) | Female (hospitalizations/100,000 (95%CI)) |
|---|---|---|---|
| 20–24 | 141.93 (138.54–145.32.54.32) | 127.56 (123.07–132.05.07.05) | 157.03 (151.93–162.13.93.13) |
| 25–29 | 205.35 (201.43–209.27.43.27) | 187.27 (182.02–192.52.02.52) | 223.93 (218.11–229.75.11.75) |
| 30–34 | 266.13 (261.87–270.39.87.39) | 247.98 (242.17–253.79.17.79) | 284.37 (278.14–290.6) |
| 35–39 | 302.02 (297.85–306.19.85.19) | 320.71 (314.64–326.78.64.78) | 283.24 (277.52–288.96.52.96) |
| 40–44 | 358.79 (354.63–362.95.63.95) | 422.4 (416.05–428.75.05.75) | 293.64 (288.28–299) |
| 45–49 | 453.19 (448.49–457.89.49.89) | 562.79 (555.43–570.15.43.15) | 341.14 (335.34–346.94.34.94) |
| 50–54 | 610.3 (604.68–615.92.68.92) | 760.04 (751.16–768.92.16.92) | 461.27 (454.36–468.18.36.18) |
| 55–59 | 797.05 (790.36–803.74.36.74) | 993.88 (983.23–1004.53.23.53) | 606.89 (598.7–615.08.7.08) |
| 60–64 | 1068.12 (1059.84–1076.4.84.4) | 1360.4 (1346.99–1373.81.99.81) | 793.66 (783.71–803.61.71.61) |
| 65–69 | 1317.85 (1307.76–1327.94.76.94) | 1732.86 (1716.12–1749.6.12.6) | 941.02 (929.22–952.82.22.82) |
| 70–74 | 1665.12 (1653.18–1677.06.18.06) | 2245.5 (2225.15–2265.85.15.85) | 1167.69 (1154.03–1181.35.03.35) |
| 75–79 | 2284.46 (2268.84–2300.08.84.08) | 3098.31 (3071.09–3125.53.09.53) | 1637.79 (1620.01–1655.57.01.57) |
| 80–84 | 3306.28 (3284.41–3328.15.41.15) | 4433.39 (4393.81–4472.97.81.97) | 2539.9 (2514.95–2564.85.95.85) |
| 85–89 | 4833.47 (4803.65–4863.29.65.29) | 6341.6 (6285.39–6397.81.39.81) | 3972.54 (3938.51–4006.57.51.57) |
| Total ≥ 18 | 958.57 (956.41–960.73.41.73) | 1104.29 (1100.97–1107.61.97.61) | 821.32 (818.54–824.1) |
| Total ≥ 50 | 1641.29 (1637.28–1645.3.28.3) | 1979.53 (1973.08–1985.98.08.98) | 1348.93 (1343.96–1353.9.96.9) |
| Total ≥ 60 | 2186.36 (2180.56–2192.16.56.16) | 2693.11 (2683.49–2702.73.49.73) | 1779.53 (1772.49–1786.57.49.57) |
| Total ≥ 65 | 2543.62 (2536.45–2550.79.45.79) | 3169.49 (3157.37–3181.61.37.61) | 2065.94 (2057.34–2074.54.34.54) |
| Total ≥ 70 | 2984.95 (2975.91–2993.99.91.99) | 3759.26 (3743.63–3774.89.63.89) | 2430.27 (2419.56–2440.98.56.98) |
| Total ≥ 75 | 3617.1 (3605.04–3629.16.04.16) | 4603.79 (4582.29–4625.29.29.29) | 2969.6 (2955.49–2983.71.49.71) |
| Total ≥ 80 | 4439.36 (4422.45–4456.27.45.27) | 5722.92 (5691.46–5754.38.46.38) | 3693.56 (3674.09–3713.03.09.03) |
| Total ≥ 90 | 6300.69 (6256.13–6345.25.13.25) | 8411.37 (8316.98–8505.76.98.76) | 5434.82 (5385.44–5484.2.44.2) |
*p < 0.001 for the sex comparisons in all the age groups.
The hospitalization rate dramatically increased with age; 71% of the hospitalized patients were 60 years or older, with an HR of 2186.36 (95% CI: 2180.56–2192.16.56.16) per 100,000, 34% of the hospitalized patients were 80 years old or older, reaching an HR of 4439.36 (95% CI: 4422.45–4456.27.45.27) hospitalizations per 100,000, and 10% of the hospitalized patients were 90 years old or older, reaching an HR of 6300.69 (95% CI: 6256.13–6345.25.13.25) hospitalizations per 100,000 (Table 1). Among all the age groups, the HR was significantly greater for men (p < 0.001).
There were 105,807 deaths among adult patients hospitalized for COVID-19 (59% men vs. 41% women), with CFRs of 13.7% (95% CI: 13.62–13.78), 14.42% (95% CI: 14.32–14.52) in men and 12.79% (95% CI: 12.68–12.9) in women.
The CFR increased significantly with age (p < 0.001); 93% of the deaths occurred in those aged 60 years or older, reaching a CFR of 18.46% (95% CI: 18.36–18.56) (Table 2). When focusing on elderly individuals, a CFR of 24.43% (95% CI: 24.26–24.6) was found in those aged 80 years or older, and a CFR of 28.9% (95% CI: 28.57–29.23) was found in those aged 90 years or older. Among all the age groups, the CFR was significantly greater in men (p < 0.05) (Table 2).
Table 2.
Case–fatality rates related to COVID-19 by sex in Spain from 2020–2021.
| Age (Years) | Total (hospitalizations/100,000 (95%CI)) | Male (hospitalizations/100,000 (95%CI)) | Female (hospitalizations/100,000 (95%CI)) |
|---|---|---|---|
| 20–24 | 1.04 (0.8–1.28) | 1.45 (1.03–1.87) | 0.69 (0.42–0.96) |
| 25–29 | 1.04 (0.85–1.23) | 1.27 (0.96–1.58) | 0.85 (0.61–1.09) |
| 30–34 | 1.15 (0.98–1.32) | 1.4 (1.12–1.68) | 0.93 (0.72–1.14) |
| 35–39 | 1.33 (1.17–1.49) | 1.55 (1.32–1.78) | 1.08 (0.87–1.29) |
| 40–44 | 1.77 (1.62–1.92) | 1.92 (1.71–2.13) | 1.55 (1.32–1.78) |
| 45–49 | 2.66 (2.49–2.83) | 2.84 (2.62–3.06) | 2.37 (2.11–2.63) |
| 50–54 | 4.07 (3.89–4.25) | 4.54 (4.3–4.78) | 3.31 (3.04–3.58) |
| 55–59 | 5.91 (5.71–6.11) | 6.63 (6.36–6.9) | 4.77 (4.48–5.06) |
| 60–64 | 8.18 (7.97–8.39) | 9.42 (9.13–9.71) | 6.18 (5.88–6.48) |
| 65–69 | 11.14 (10.9–11.38.9.38) | 12.9 (12.57–13.23) | 8.19 (7.84–8.54) |
| 70–74 | 14.17 (13.92–14.42) | 16.03 (15.69–16.37) | 11.11 (10.74–11.48) |
| 75–79 | 17.59 (17.33–17.85) | 19.54 (19.19–19.89) | 14.66 (14.27–15.05) |
| 80–84 | 21.04 (20.77–21.31) | 23.27 (22.88–23.66) | 18.39 (18–18.78.78) |
| 85–89 | 24.08 (23.81–24.35) | 26.57 (26.17–26.97) | 21.8 (21.44–22.16) |
| Total ≥ 18 | 13.7 (13.62–13.78) | 14.42 (14.32–14.52) | 12.79 (12.68–12.9) |
| Total ≥ 50 | 16.37 (16.28–16.46) | 17.18 (17.06–17.3) | 15.34 (15.21–15.47) |
| Total ≥ 60 | 18.46 (18.36–18.56) | 19.58 (19.44–19.72) | 17.11 (16.96–17.26) |
| Total ≥ 65 | 19.84 (15.82–23.86) | 21.14 (15.49–26.79) | 18.33 (12.64–24.02) |
| Total ≥ 70 | 21.23 (21.1–21.36.1.36) | 22.7 (22.52–22.88) | 19.6 (19.42–19.78) |
| Total ≥ 75 | 22.78 (17.66–27.9) | 24.51 (17.03–31.99) | 21.02 (14.03–28.01) |
| Total ≥ 80 | 24.43 (24.26–24.6) | 26.52 (26.27–26.77) | 22.56 (22.34–22.78) |
| Total ≥ 90 | 28.9 (28.57–29.23) | 31.76 (31.21–32.31) | 27.09 (26.67–27.51) |
*p < 0.05 for the sex comparisons in all the age groups.
78% of the adults hospitalized for COVID-19 during the study period had at least one of the comorbidities considered a potential risk factor for poor prognosis.
The CFR was significantly greater in patients with comorbidities than in patients without specific risk factors (16.80% vs. 4.11%, p < 0.001). Hospitalized adult patients with COVID-19 with any of the comorbidities studied were 4.70 (4.58–4.82) times more likely to die than those without associated comorbidities. The risk of death increased 6.25-fold in patients with solid tumours, 7.98-fold in patients with haematologic malignancies, 4.81-fold in patients with diabetes, 4.22-fold in patients with hypertension, 7.58-fold in patients with cerebrovascular disease, 4.06-fold in patients with COPD, 5.81-fold in patients with liver disease and 8.8-fold in patients with renal disease. When stratified by age, this increased risk due to comorbidities was much greater in younger adults (Table 3). For example, in the case of adult patients of any age with hypertension, the risk of death in hospitalized patients with COVID-19 reached 15.33%, indicating that the impact of hypertension was much greater in younger patients. Among hospitalized patients between 60 and 64 years of age with hypertension, the CFR was 7.34%, increasing the rate of death by 3.13 (95% CI: 2.79–3.51) times compared with those without comorbidities (Table 3).
Table 3.
Estimated mortality rates and odds ratios according to risk factors among hospitalized adult patients with COVID-19 from 2020–2021 in Spain.
| ≥ 65 years | ≥ 18 years | ≥ 60 years | 60–64 years | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | |
| No risk group | 5434 | 1 | 14.42% | 6633 | 1 | 4.11% | 5812 | 1 | 10.97% | 378 | 1 | 2.47% |
| Any risk group | 88,084 | 1.51 (1.46–1.56) | 20.31% | 99,174 | 4.70 (4.58–4.82) | 16.80% | 92,878 | 1.94 (1.88–1.99) | 19.29% | 4794 | 4.39 (3.95–4.88) | 10.00% |
| HIV | 58 | 1.41 (1.47–1.55) | 19.27% | 247 | 2.31 (2.02–2.64) | 9.01% | 95 | 1.40 (1.12–1.75) | 14.73% | 37 | 4.763 (3.33–6.80) | 10.76% |
| Solid tumours | 27,414 | 1.90 (1.85–1.97) | 24.31% | 32,611 | 6.25 (6.08–6.43) | 21.16% | 29,604 | 2.52 (2.44–2.60) | 23.69% | 2190 | 3.55 (3.35–3.77) | 17.91% |
| Haematological malignancies | 13,042 | 2.22 (2.13–2.29) | 27.18% | 16,463 | 7.98 (7.74–8.27) | 25.52% | 14,498 | 2.95 (2.86–3.05) | 26.68% | 1456 | 11.74 (10.44–13.21) | 22.92% |
| Immunodeficiencies | 1167 | 1.79 (1.67–1.93) | 23.23% | 1474 | 4.32 (4.06–4.59) | 15.65% | 1263 | 2.13 (1.99–2.28) | 20.76% | 96 | 3.94 (3.12–4.97)) | 9.07% |
| Diabetes | 29,535 | 1.45 (1.41–1.50) | 19.67% | 32,209 | 4.81 (4.68–4.94) | 17.10% | 30,917 | 1.87 (1.81–1.93) | 18.73% | 1382 | 4.03 (3.58–4.52) | 9.26% |
| Essential hypertension | 34,878 | 1.34 (1.30–1.38) | 18.43% | 38,108 | 4.22 (4.11–4.33) | 15.33% | 36,539 | 1.69 (1.64–1.74) | 17.24% | 1661 | 3.13 (2.79–3.51) | 7.34% |
| Cardiopulmonary disease | 73,134 | 1.58 (1.53–1.63) | 21.05% | 80,190 | 5.53 (5.39–5.67) | 19.18% | 76,369 | 2.08 (2.02–2.14) | 20.38% | 3235 | 5.34 (4.79–5.95) | 11.90% |
| Chronic lower respiratory tract disease | 18,810 | 1.08 (1.05–1.12) | 15.48% | 20,701 | 3.44 (3.34–3.54) | 12.87% | 19,786 | 1.40 (1.36–1.15) | 14.75% | 976 | 3.30 (2.93–3.73) | 7.72% |
| Cerebrovascular disease | 8988 | 2.02 (1.95–2.10) | 25.43% | 9914 | 7.58 (7.33–7.83) | 24.54% | 9396 | 2.72 (2.62–2.81) | 25.08% | 408 | 9.47 (8.16–10.98) | 19.33% |
| COPD | 11,125 | 1.15 (1.11–1.19) | 16.30% | 11,970 | 4.06 (3.94–4.19) | 14.86% | 11,640 | 1.51 (1.45–1.56) | 15.68% | 515 | 3.72 (3.24–4.25) | 8.60% |
| Asthma | 3551 | 0.91 (0.87–0.95) | 13.30% | 4020 | 2.22 (2.13–2.32) | 8.72% | 3729 | 1.15 (1.10–1.19) | 12.37% | 178 | 2.16 (1.80–2.59) | 5.18% |
| Acute renal failure | 39,538 | 2.33 (2.26–2.41) | 28.26% | 43,958 | 8.81 (8.57–9.05) | 27.44% | 41,490 | 3.17 (3.08–3.27) | 28.10% | 1952 | 13.38 (11.94–15.00.94.00) | 25.30% |
| Liver disease | 1490 | 1.72 (1.62–1.84) | 22.52% | 2244 | 5.81 (5.51–6.12) | 19.96% | 1799 | 2.26 (2.13–2.39) | 21.76% | 309 | 9.08 (7.75–10.68) | 18.72% |
All the comorbidities or health conditions studied were significantly associated with an increased risk of death among hospitalized adults in Spain; only asthma lost this effect in those aged 65 years or older.
In the sensitivity analysis, the ORs for increased risk of death in risk groups were gathered by year and studied separately in 2020 and 2021. The results are consistent in both years, irrespective of the COVID-19 vaccination status of the population (Tables 4 and 5). To facilitate visual comparison of the effect sizes over time, we summarized the odds ratios for the main comorbidities in 2020 and 2021 in a forest plot (Fig. 1). The pattern of increased mortality risk associated with each risk group was consistent across both years, with largely overlapping confidence intervals, despite differences in vaccination coverage and circulating variants.
Table 4.
Comparison of mortality rates and odds ratios according to risk factors among hospitalized adult patients with COVID-19 in 2020 in Spain.
| ≥ 65 | ≥ 18 | ≥ 60 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | Deaths (n) | Odds ratio- (95%CI) | Case fatality rate (%) | Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | |
| No risk group | 3520 | 1 | 16.12% | 4191 | 1 | 4.65% | 3722 | 1 | 12.38% |
| Any risk group | 50,480 | 1.39 (1.33–1.44) | 21.01% | 56,290 | 4.34 (4.20–4.48) | 17.48% | 52,977 | 1.76 (1.70–1.83) | 19.99% |
| HIV | 36 | 1.61 (1.09–2.33) | 23.53% | 135 | 2.03 (1.69–2.42) | 9.00% | 55 | 1.51 (1.13–2.03) | 17.63% |
| Solid tumours | 14,236 | 1.71 (1.64–1.78) | 24.74% | 16,822 | 5.74 (5.54–5.95) | 21.89% | 15,318 | 2.25 (2.16–2.34) | 24.16% |
| Haematological malignancies | 7079 | 1.96 (1.87–2.06) | 27.42% | 8900 | 7.00 (6.73–7.28) | 25.46% | 7839 | 2.60 (2.49–2.71) | 26.87% |
| Immunodeficiencies | 593 | 1.70 (1.54–1.88) | 24.68% | 738 | 4.33 (3.97–4.71) | 17.43% | 633 | 2.01 (1.83–2.21) | 22.14% |
| Diabetes | 16,900 | 1.35 (1.29–1.40) | 20.58% | 18,286 | 4.50 (4.34–4.66) | 18.01% | 17,616 | 1.73 (1.66–1.80) | 19.64% |
| Essential hypertension | 20,422 | 1.24 (1.19–1.20) | 19.30% | 22,106 | 3.98 (3.85–4.12) | 16.27% | 21,308 | 1.57 (1.51–1.63) | 18.16% |
| Cardiopulmonary disease | 41,471 | 1.44 (1.38–1.50) | 21.64% | 45,058 | 5.05 (4.89–5.22) | 19.78% | 43,118 | 1.88 (1.81–1.95) | 20.99% |
| Chronic lower respiratory tract disease | 10,467 | 0.98 (0.94–1.02) | 15.87% | 11,437 | 3.11 (2.99–3.22) | 13.14% | 10,964 | 1.26 (1.21–1.31) | 15.11% |
| Cerebrovascular disease | 5079 | 1.82 (1.73–1.91) | 25.90% | 5565 | 6.82 (6.53–7.12) | 24.97% | 5298 | 2.43 (2.32–2.55) | 25.58% |
| COPD | 6309 | 1.06 (1.01–1.11) | 16.94% | 6774 | 3.74 (3.59–3.90) | 15.44% | 6586 | 1.37 (1.32–1.44) | 16.29% |
| Asthma | 1991 | 0.82 (0.77–0.87) | 13.59% | 2230 | 2.02 (1.91–2.13) | 8.96% | 2088 | 1.03 (0.97–1.09) | 12.72% |
| Acute renal failure | 22,413 | 2.13 (2.04–2.21) | 29.01% | 24,707 | 7.99 (7.72–8.27) | 28.06% | 23,412 | 2.86 (2.75–2.97) | 28.79% |
| Liver disease | 821 | 1.56 (1.43–1.70) | 23.05% | 1198 | 5.12 (4.76–5.49) | 19.98% | 986 | 2.03 (1.87–2.19) | 22.27% |
Table 5.
Comparison of mortality rates and odds ratios according to risk factors among hospitalized adult patients with COVID-19 in 2021 in Spain.
| ≥ 65 | ≥ 18 | ≥ 60 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Deaths (n) | Odds ratio (95%CI) | Case fatality rate | Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | Deaths (n) | Odds ratio (95%CI) | Case fatality rate (%) | |
| No risk group | 1914 | 1 | 12.08% | 2476 | 1 | 2.82% | 2090 | 1 | 9.11% |
| Any risk group | 37,604 | 1.75 (1.67–1.84) | 19.45% | 43,006 | 6.44 (6.17–6.71) | 15.73% | 39,901 | 2.25 (2.15–2.35) | 18.42% |
| HIV | 22 | 1.27 (0.81–2.00.81.00) | 14.86% | 112 | 3.42 (2.80–4.17) | 9.02% | 40 | 1.36 (0.97–1.90) | 12.01% |
| Solid tumours | 13,178 | 2.28 (2.1–2.40) | 23.87% | 15,854 | 8.67 (8.30–9.05) | 20.10% | 14,286 | 3.01 (2.86–3.16) | 23.20% |
| Haematological malignancies | 5963 | 2.68 (2.53–2.83) | 26.90% | 7598 | 11.61 (11.07–12.17) | 25.19% | 6659 | 3.59 (3.40–3.78) | 26.46% |
| Immunodeficiencies | 574 | 2.04 (1.84–2.26) | 21.90% | 754 | 5.58 (5.11–6.08) | 13.93% | 630 | 2.42 (2.19–2.67) | 19.54% |
| Diabetes | 12,635 | 1.66 (1.58–1.75) | 18.57% | 13,924 | 6.57 (6.29–6.87) | 16.02% | 13,301 | 2.13 (2.03–2.24) | 17.63% |
| Essential hypertension | 14,456 | 1.52 (1.45–1.60) | 17.32% | 16,013 | 5.70 (5.45–5.95) | 14.19% | 15,231 | 1.91 (1.82–2.00.82.00) | 16.11% |
| Cardiopulmonary disease | 31,663 | 1.85 (1.76–1.95) | 20.32% | 35,210 | 7.77 (7.45–8.10) | 18.40% | 33,251 | 2.44 (2.32–2.55) | 19.65% |
| Chronic lower respiratory tract disease | 8343 | 1.28 (1.22–1.36) | 15.01% | 9268 | 4.81 (4.60–5.03) | 12.25% | 8822 | 1.66 (1.58–1.75) | 14.31% |
| Cerebrovascular disease | 3909 | 2.40 (2.26–2.55) | 24.83% | 4364 | 10.85 (10.30–11.44.30.44) | 23.95% | 4098 | 3.23 (3.05–3.42) | 24.46% |
| COPD | 4816 | 1.34 (1.26–1.42) | 15.53% | 5196 | 5.68 (5.40–5.97) | 14.15% | 5054 | 1.75 (1.66–1.85) | 14.95% |
| Asthma | 1560 | 1.08 (1.01–1.16) | 12.95% | 1793 | 2.98 (2.80–3.17) | 7.96% | 1641 | 1.35 (1.26–1.45) | 11.96% |
| Acute renal failure | 17,125 | 2.73 (2.60–2.88) | 27.32% | 19,301 | 12.51 (11.98–13.07) | 26.63% | 18,078 | 3.74 (3.56–3.92) | 27.26% |
| Liver disease | 669 | 2.04 (1.85–2.25) | 21.90% | 1047 | 8.57 (7.93–9.28) | 19.92% | 813 | 2.68 (2.45–2.93) | 21.17% |
Fig. 1.
Odds ratios for in-hospital death associated with comorbidities in adults hospitalized with COVID-19 in Spain, 2020 and 2021 (≥ 18 years). Legend: Forest plot showing odds ratios (ORs) and 95% confidence intervals for in‑hospital death among adults (≥ 18 years) hospitalized with COVID‑19 in Spain during 2020 and 2021, according to the presence of each comorbidity. ORs are calculated with patients without any of the specified risk conditions as the reference group (OR = 1.0, not shown). Estimates are presented on a logarithmic scale. While absolute case‑fatality rates declined between 2020 and 2021, the relative increase in mortality associated with each comorbidity remained consistently elevated across both years.
Discussion
Beyond confirming, on a nationwide scale, that age and common chronic conditions are major risk factors for death in hospitalized COVID‑19 patients, our study adds two elements of novelty. First, the large sample size enables precise estimation of mortality risks for a broad range of comorbidities and detailed age strata. Second, by examining the age pattern of excess risk and comparing 2020 with 2021, we show that comorbidities confer particularly high relative risks in younger adults, which is directly relevant to defining life‑course and risk‑based vaccination policies as COVID‑19 transitions to an endemic phase. This retrospective epidemiologic study highlights the hospital burden related to COVID-19 in Spain during the first two years of the pandemic and focuses on the high burden of the disease, especially among elderly individuals, for whom COVID-19 vaccination is recommended, and among patients with associated comorbidities. The epidemiology was discussed in detail in a previous publication16. The main result of our study was the increased risk of death among hospitalized patients with COVID-19 with comorbidities, such as HIV infection, solid tumours, haematological malignancies, immunodeficiencies, diabetes, essential hypertension, cardiopulmonary disease, chronic lower respiratory tract disease, cerebrovascular disease, COPD, asthma, acute renal failure and liver disease.
The main finding of this study is that all the chronic conditions studied, known to be risk factors for respiratory diseases, increased the risk of death among hospitalized patients with COVID-19. Interestingly, the presence of underlying conditions increased the risk of hospitalization to a greater degree in patients aged 18–64 years than in older patients. These results suggest that COVID-19 vaccination should be recommended not only to older adults but also to targeted risk groups among immunocompetent young adults, such as those with diabetes or hypertension.
Since the onset of the COVID-19 pandemic, older adults have accounted for the largest proportion of severe COVID-19 cases17–20. Between January and June 2023, adults aged ≥ 65 years accounted for 63% of COVID-19-associated hospitalizations and 88% of in-hospital mortalities in the United States (US)20, which is in line with the 93% of deaths occurring in those aged 60 years or older in our study. Regardless of age, the presence of comorbidities, such as chronic lung, cardiovascular, metabolic (including diabetes mellitus), neurological, or liver diseases, is associated with an increased risk of ICU admission and death17,21–23.
All the comorbidities or health conditions studied were significantly associated with an increased risk of death among hospitalized adults in Spain; only asthma lost this effect in those aged 65 or older. Our results are also in line with those published for Germany10 or the UK24.
Patients with immunocompromising conditions, such as various cancers, solid organ or haematopoietic stem cell transplants, or advanced human immunodeficiency virus infections, are known to be among the most vulnerable25–27. In our study, the most important risk factors for increased death were haematologic malignancies, solid tumours, cerebrovascular disease, liver or renal disease, diabetes, hypertension, and COPD.
More than three years after the first introduction of COVID-19 vaccines, the optimal vaccination strategy in the endemic period has remained unclear, and policy makers worldwide have adopted different approaches. COVID-19 vaccination should be integrated into routine vaccination programs throughout life, and cocirculation with other respiratory viruses should be monitored to avoid combined incidence peaks, which stresses healthcare systems. Effective, combined vaccines and improved education may help overcome vaccine hesitancy/booster fatigue and increase vaccination uptake28. A COVID-19 vaccination strategy should prioritize high-risk groups, emphasize seasonal administration aligned with influenza vaccination campaigns, and advocate coadministration with influenza vaccines to increase coverage29.
The analysis of hospitalization rates demonstrated a steady decline as vaccination coverage increased in various countries; however, a slight increase in COVID-19-related hospitalizations has been reported beyond approximately 6 months after vaccination, consistent with waning protection and underscoring the need for continued vigilance and booster strategies30.
COVID-19 vaccination has proven to be effective in reducing the incidence of cases, hospitalizations, and ICU admissions. However, ongoing surveillance, variant monitoring, and adaptive vaccination strategies are crucial for maximizing the benefits of vaccination and effectively controlling the spread of the virus31. COVID-19 vaccination is critical for reducing serious illness and hospitalizations, yet many remain hesitant32. Policymakers should continue to prioritize vulnerable groups for subsequent COVID-19 booster doses to minimize the risk of COVID-19 death. The effect of age dilutes that of comorbidity, so the focus should be on age as the main risk factor but also on the presence of comorbidities in young adults. It is essential to assess the increased risk of death associated with the presences of different comorbidities, including those that are very common, such as diabetes or hypertension, to help policy makers clearly define public health priorities and address these challenges to avoid situations such as ambiguity in the recommendation or even the exclusion of hypertensive patients from influenza vaccination recommendations for years33,34. Hypertension is known to be an important risk factor for the most severe form of COVID-19, to an appreciable extent because of its cardiovascular impact. The relatively stronger impact of hypertension in younger adults may reflect several, non‑mutually exclusive mechanisms. First, hypertension tends to cluster with other high‑risk conditions, such as obesity, diabetes, and chronic kidney disease, which are not fully captured or cannot be jointly modeled in our analysis. Second, in older age groups, the very high baseline risk of death may dilute the relative contribution of hypertension compared with other factors such as frailty or multimorbidity. Third, suboptimal control of blood pressure and associated cardiovascular damage might be more pronounced in some younger patients. Taken together, our data suggest that hypertension in this setting should be interpreted as a marker of underlying cardiovascular and metabolic vulnerability.
Although there are data on differences in total mortality in the first and second waves of the pandemic, the long-term consequences are still unknown35.
This study has several limitations inherent to the use of a nationwide hospital database, as the reliability of the data depends on the quality of the codification process reflected in the discharge report36. The unit of analysis is the hospitalization and not the person, meaning that one patient can be counted more than once if hospitalized for a second or third new COVID-19-related episode. The MBDS database does not provide information on microbiological confirmation or vaccination status. Hence, it is not possible to evaluate the potential effect of COVID-19 vaccination on related hospitalization rates or CFRs. In the present study, we assumed that a differential diagnosis of COVID-19 was confirmed. The clinical and epidemiological context has changed markedly since 2020–2021, with widespread prior infection and vaccination leading to substantially lower case‑fatality rates in recent years. Consequently, the absolute CFRs reported here should be interpreted as estimates of disease severity during the early phase of the pandemic and not directly extrapolated to the current endemic period. The odds ratios were estimated mainly without adjustment for the simultaneous presence of multiple chronic conditions. Because multimorbidity is very common in older adults, our estimates are likely to overstate the independent contribution of individual comorbidities and should be viewed primarily as markers of vulnerability rather than causal effects of single conditions. Finally, we did not study the increased risk associated with more than one comorbidity, which is a very common situation, especially in elderly individuals. The odds ratios shown for individual risk conditions may therefore be elevated by the existence of associated comorbidities. Because the MBDS does not allow us to robustly characterize complex patterns of multimorbidity or disease severity, we did not construct a fully adjusted multivariable model including all comorbidities simultaneously. As a result, the odds ratios we report represent the association between each condition and mortality in the presence of other, potentially correlated comorbidities, rather than independent causal effects. In older adults with multiple chronic diseases, this approach may inflate the apparent effect size for some conditions. Our estimates should therefore be interpreted as quantifying the overall vulnerability of patients with specific chronic conditions, rather than disentangling the precise relative contribution of each disease. The strong associations observed for individual comorbidities, particularly in older adults, likely reflect the combined burden of multimorbidity and frailty in addition to the direct effects of any single disease. The present study was not specifically designed to assess the potential impact of the current preventive measures for the elderly and at-risk populations, as MBDS does not provide information on the vaccination status of hospitalized patients. For that reason, we conducted sensitivity analyses in 2020 and 2021 to check the consistency of the results before and after vaccination. However, the MBDS is currently one of the most valuable tools available for clinical and epidemiological research, with a large sample size, which provides high representativeness and statistical power when analysing clinical variables such as the CFR. Furthermore, the MBDS is subject to a high-quality data audit at the state level37.
Conclusion
In-hospital mortality associated with COVID-19 increased significantly with age and with the presence of comorbidities, both in 2020 (prior to vaccination) and in 2021, when older adults and at-risk groups were already being vaccinated. These results indicate that not only should age-based preventive strategies continue but also that patients with underlying disease, regardless of age, should continue to be priority groups for preventive actions.
Abbreviations
- ICU
intensive care unit
- AHT
arterial hypertension
- MBDS
Minimum Basic Data Set
- ICD-10-CM (CIE-10-MC)
10th International Classification of Diseases (Modificación Clínica Clasificación Internacional de Enfermedades)
- 95% Cis
confidence intervals
- CFR
case–fatality rate
- HR
hospitalization rate
Author contributions
RGP: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editingVHB: Data curation, Formal Analysis, Methodology, Writing – review & editingPMG: Conceptualization, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editingAGE: Conceptualization, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editingAGM: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.
Funding
The study is part of the research activity of the Chair Moderna-URJC.
Data availability
The anonymized datasets used in the current publication are available from the corresponding author upon reasonable request.
Declarations
Competing interests
RGP and AGM have received travel and research grants and have participated in advisory boards from Sanofi, Merck, Pfizer, Seqirus and Moderna. VHB, PMG and AGE have no conflicts of interest.
Ethics approval and consent to participate
This retrospective study was approved by the Research and Ethics Committee of Rey Juan Carlos University, which ruled that no formal ethics approval was required. The personal information of each subject was delivered to the researchers anonymously and was and deidentifed before the analysis, in strict compliance with the current Spanish and European legislation. All procedures involving human participants were conducted in accordance with the ethical standards of the responsible institutional and/or National Research Committee and with the tenets of the 1964 Helsinki Declaration and its later amendments and comparable ethical standards. The informed consent was waived by the Research and Ethics Committee of our institution because of the retrospective nature of the study and the analysis used anonymous clinical data.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The anonymized datasets used in the current publication are available from the corresponding author upon reasonable request.