Highlights
- •In Spain, nearly 30% of SARS-CoV-2 infections in the first wave were asymptomatic.
- •Asymptomatic infections were more frequent in areas with lower viral circulation.
- •Men, young and old people, and smokers had more asymptomatic infections.
- •We developed a symptom-based score applicable in primary care or community settings.
- •A score ≥3 detects over 70% of cases among symptomatic people with specificity >70%.
Abstract
Objectives
Study design and setting
Results
Conclusion
Graphical abstract

Keywords
- •Little is known about the factors associated with asymptomatic SARS-CoV-2 infection, as most studies are based on clinical COVID-19 cases.
- •Reviews highlight the need to explore the predictive ability of symptoms to identify individuals with COVID-19 in the general population, but available prediction models lack enough quality or are not suitable for this purpose.
- •This nationwide seroepidemiological study found that nearly 30% of SARS-CoV-2 infections in Spain were asymptomatic, with higher prevalence of asymptomatic infections in regions with lower viral circulation and among men, children and adolescents, old people, and smokers.
- •A symptomatic risk score was constructed and validated, providing an easy tool to predict COVID-19 based on three situations: a) presence of anosmia or ageusia, b) fever with severe tiredness, or c) fever without sore throat. It detects over 70% of cases in the general population, with a specificity greater than 70%.
- •The proposed symptomatic risk score outperforms other combinations of symptoms frequently used to suspect COVID-19 and can be applied in primary care or community settings.
1. Introduction
- Wiersinga WJ
- Rhodes A
- Cheng AC
- Peacock SJ
- Prescott HC.
- Pollán M
- Pérez-Gómez B
- Pastor-Barriuso R
- et al.
- Oran DP
- Topol EJ.
- Qiu X
- Nergiz AI
- Maraolo AE
- et al.
- Wiersinga WJ
- Rhodes A
- Cheng AC
- Peacock SJ
- Prescott HC.
- Struyf T
- Deeks JJ
- Dinnes J
- et al.
- Pollán M
- Pérez-Gómez B
- Pastor-Barriuso R
- et al.
2. Methods
2.1 Study design and population
- Pollán M
- Pérez-Gómez B
- Pastor-Barriuso R
- et al.
2.2 Data collection
- Pollán M
- Pérez-Gómez B
- Pastor-Barriuso R
- et al.
Instituto de Salud Carlos III. National Study of SARS-CoV-2 Sero-Epidemiology in Spain (ENE-COVID) [Internet]. 2020 [cited 2020 Jul 24]. Available from: https://portalcne.isciii.es/enecovid19/
2.3 Detection of SARS-CoV-2 antibodies
2.4 Statistical analysis
- Pollán M
- Pérez-Gómez B
- Pastor-Barriuso R
- et al.
3. Results
Characteristic | No. of participants (%) | No. of positive cases | SARS-CoV-2 seroprevalence (%; 95% CI) |
Overall | 61,092 | 2,669 | 4.6 (4.2–4.9) |
Sex | |||
Men | 29,122 (48.9) | 1,246 | 4.4 (4.1–4.8) |
Women | 31,970 (51.1) | 1,423 | 4.7 (4.3–5.1) |
Age (years) | |||
0–19 | 7,682 (19.0) | 280 | 3.6 (3.1–4.3) |
20–39 | 13,427 (23.1) | 585 | 5.0 (4.5–5.6) |
40–59 | 22,561 (32.2) | 1,071 | 4.8 (4.4–5.3) |
60–79 | 14,375 (21.2) | 621 | 4.5 (3.9–5.1) |
≥80 | 3,047 (4.5) | 112 | 4.2 (3.2–5.5) |
Nationality | |||
Spain | 58,441 (95.2) | 2,555 | 4.5 (4.2–4.8) |
Other | 2,642 (4.8) | 114 | 5.5 (4.2–7.1) |
Occupation IV Online work, non-healthcare on-site work (retail, transport, police/firefighter/public safety, cleaning, or other on-site work), healthcare (hospital, primary care, nursing home, or other health/social work), unemployed, or not economically active (student, retired, permanent/temporal disability, house person, or other unpaid work). | |||
Online work | 12,676 (21.2) | 651 | 5.8 (5.2–6.4) |
Non-healthcare on-site work | 12,840 (18.3) | 555 | 4.3 (3.8–4.9) |
Healthcare | 2,397 (3.4) | 211 | 9.1 (7.7–10.7) |
Unemployed | 4,764 (7.3) | 143 | 3.3 (2.7–4.2) |
Not economically active | 28,386 (49.7) | 1,107 | 4.0 (3.6–4.4) |
Smoking | |||
No | 45,604 (76.1) | 2,229 | 5.0 (4.7–5.4) |
Yes | 15,346 (23.9) | 433 | 3.0 (2.6–3.4) |
Body mass index (kg/m2) | |||
<25 | 22,064 (42.8) | 1,019 | 5.0 (4.5–5.5) |
25–30 | 20,673 (38.0) | 912 | 4.6 (4.2–5.0) |
≥30 | 10,667 (19.2) | 458 | 4.5 (3.9–5.2) |
No. of chronic conditions | |||
0 | 21,182 (52.9) | 999 | 4.8 (4.3–5.2) |
1 | 9,849 (24.6) | 412 | 4.4 (3.9–5.1) |
2 | 5,545 (13.7) | 255 | 4.8 (4.1–5.7) |
≥3 | 3,407 (8.8) | 138 | 4.3 (3.5–5.4) |
Chronic condition | |||
Diabetes | 4,660 (11.5) | 190 | 4.1 (3.3–5.1) |
Hypertension | 11,742 (29.5) | 506 | 4.7 (4.1–5.3) |
Cardiovascular disease | 5,828 (14.4) | 248 | 4.5 (3.8–5.4) |
Cancer | 1,720 (4.5) | 81 | 5.0 (3.8–6.5) |
Chronic pulmonary disease | 3,264 (8.4) | 134 | 4.3 (3.4–5.3) |
Asthma | 2,170 (5.5) | 102 | 4.9 (3.9–6.2) |
Sleep apnea | 1,632 (4.3) | 84 | 5.4 (4.1–7.1) |
Chronic kidney disease | 859 (2.3) | 25 | 3.7 (2.2–6.0) |
Immunosuppressive disease | 772 (1.9) | 35 | 5.3 (3.5–7.9) |
Self-reported symptoms | |||
Asymptomatic | 40,090 (64.8) | 781 | 2.0 (1.8–2.3) |
Symptomatic <21 days before blood draw | 4,565 (7.5) | 155 | 3.2 (2.6–4.0) |
Symptomatic ≥21 days before blood draw | 16,437 (27.7) | 1,733 | 10.8 (10.0–11.7) |
Pneumonia | |||
No | 60,937 (99.7) | 2,570 | 4.4 (4.1–4.7) |
Yes | 155 (0.3) | 99 | 60.0 (48.9–70.1) |
Contact with COVID-19 case VIII Contact with non-cohabitating (relative, friend, co-worker, housemaid, caregiver, or client/patient) or cohabitating (household member) suspected case (non-confirmed symptomatic person) or confirmed COVID-19 case. If multiple contacts were reported, we first considered cohabitating cases and then confirmed cases. | |||
No known contact | 48,882 (79.0) | 1,189 | 2.4 (2.2–2.7) |
Non-cohabitating suspected case | 3,332 (5.9) | 225 | 8.4 (7.0–10.0) |
Non-cohabitating confirmed case | 4,228 (6.8) | 492 | 11.4 (10.0–12.9) |
Cohabitating suspected case | 3,504 (6.4) | 397 | 10.4 (8.8–12.3) |
Cohabitating confirmed case | 1,011 (1.9) | 360 | 36.7 (31.8–41.9) |
Household size (residents) | |||
1 | 5,306 (7.9) | 225 | 4.4 (3.7–5.3) |
2 | 15,170 (23.5) | 667 | 5.0 (4.4–5.7) |
3 | 15,858 (25.5) | 644 | 4.1 (3.6–4.7) |
4 | 16,458 (29.0) | 806 | 5.0 (4.4–5.7) |
≥5 | 8,300 (14.1) | 327 | 3.7 (3.0–4.5) |
Census tract average income | |||
<25th percentile | 16,143 (24.8) | 737 | 4.5 (3.8–5.3) |
25–50th percentile | 15,462 (25.7) | 561 | 4.6 (3.8–5.5) |
50–75th percentile | 13,920 (25.0) | 559 | 4.2 (3.5–5.0) |
≥75th percentile | 15,567 (24.5) | 812 | 5.0 (4.3–5.8) |
Municipality size (inhabitants) | |||
<5,000 | 11,159 (11.4) | 511 | 3.8 (3.0–4.7) |
5,000–20,000 | 12,939 (18.2) | 507 | 3.3 (2.8–3.9) |
20,000–100,000 | 18,066 (29.5) | 720 | 3.6 (3.2–4.1) |
≥100,000 | 18,928 (40.9) | 931 | 6.0 (5.4–6.6) |
Province seroprevalence X (%)Provinces with population seroprevalence <3% (Alicante, Almería, Badajoz, Baleares, Cádiz, Castellón, Córdoba, A Coruña, Girona, Gipuzkoa, Huelva, Jaén, Lleida, Lugo, Murcia, Ourense, Asturias, Las Palmas, Pontevedra, Tenerife, Sevilla, Tarragona, Teruel, Valencia, Ceuta, and Melilla), 3–5% (Álava, Burgos, Cáceres, Granada, Huesca, La Rioja, Málaga, Navarra, Palencia, Cantabria, Valladolid, Bizkaia, Zamora, and Zaragoza), 5–10% (Ávila, Barcelona, León, and Salamanca), or ≥10% (Albacete, Ciudad Real, Cuenca, Guadalajara, Madrid, Segovia, Soria, and Toledo) with IgG antibody chemiluminescent microparticle immunoassay. | |||
<3 | 29,991 (48.6) | 505 | 1.6 (1.4–1.9) |
3–5 | 15,426 (18.2) | 586 | 3.6 (3.1–4.1) |
5–10 | 6,111 (14.1) | 432 | 6.7 (5.6–7.9) |
≥10 | 9,564 (19.2) | 1,146 | 11.3 (10.2–12.6) |
Entry round | |||
First (April 27–May 11) | 52,318 (84.2) | 2,291 | 4.5 (4.2–4.9) |
Second (May 18–June 1) | 7,122 (12.8) | 305 | 4.6 (3.9–5.5) |
Third (June 8–June 22) | 1,652 (3.0) | 73 | 4.7 (3.3–6.6) |
3.1 Asymptomatic SARS-CoV-2 infection
Characteristic | No. of positive cases (%) | No. of asymptomatic cases | Asymptomatic prevalence (%; 95% CI) | Crude prevalence ratio (95% CI) | Standardized prevalence ratio (95% CI) |
Overall | 2,669 | 781 | 28.7 (26.1–31.4) | ||
Sex | |||||
Men | 1,246 (47.5) | 406 | 31.8 (28.4–35.5) | 1.00 (reference) | 1.00 (reference) |
Women | 1,423 (52.5) | 375 | 25.8 (22.5–29.5) | 0.81 (0.69–0.96) | 0.84 (0.71–0.98) |
Age (years) | |||||
0–19 | 280 (15.2) | 118 | 44.9 (36.4–53.7) | 2.06 (1.61–2.64) | 1.82 (1.33–2.50) |
20–39 | 585 (25.6) | 143 | 25.0 (20.6–30.0) | 1.15 (0.91–1.44) | 1.18 (0.94–1.47) |
40–59 | 1,071 (34.2) | 259 | 21.8 (18.8–25.1) | 1.00 (reference) | 1.00 (reference) |
60–79 | 621 (20.9) | 215 | 31.1 (26.3–36.4) | 1.43 (1.15–1.77) | 1.24 (0.94–1.64) |
≥80 | 112 (4.2) | 46 | 36.1 (25.4–48.5) | 1.66 (1.16–2.37) | 1.45 (0.96–2.18) |
Nationality | |||||
Spain | 2,555 (94.2) | 754 | 29.3 (26.7–32.2) | 1.00 (reference) | 1.00 (reference) |
Other | 114 (5.8) | 27 | 17.7 (10.6–28.2) | 0.60 (0.37–0.99) | 0.69 (0.44–1.10) |
Occupation | |||||
Online work | 651 (26.9) | 126 | 19.6 (15.9–23.9) | 1.00 (reference) | 1.00 (reference) |
Non-healthcare on-site work | 555 (17.2) | 163 | 27.7 (22.9–33.0) | 1.41 (1.09–1.84) | 1.22 (0.96–1.55) |
Healthcare | 211 (6.8) | 43 | 16.9 (11.9–23.6) | 0.87 (0.59–1.27) | 0.98 (0.71–1.36) |
Unemployed | 143 (5.3) | 44 | 31.8 (22.3–43.1) | 1.62 (1.09–2.42) | 1.31 (0.92–1.87) |
Not economically active | 1,107 (43.8) | 405 | 36.1 (31.6–40.9) | 1.84 (1.46–2.33) | 1.25 (0.95–1.66) |
Smoking | |||||
No | 2,229 (84.2) | 634 | 27.8 (25.0–30.8) | 1.00 (reference) | 1.00 (reference) |
Yes | 433 (15.8) | 143 | 33.0 (27.2–39.4) | 1.19 (0.96–1.46) | 1.27 (1.03–1.55) |
Body mass index (kg/m2) | |||||
<25 | 1,019 (45.0) | 260 | 25.6 (22.0–29.6) | 1.00 (reference) | 1.00 (reference) |
25–30 | 912 (36.9) | 275 | 26.9 (23.0–31.2) | 1.05 (0.85–1.30) | 0.93 (0.76–1.14) |
≥30 | 458 (18.1) | 128 | 23.9 (18.9–29.8) | 0.94 (0.72–1.21) | 0.86 (0.67–1.10) |
No. of chronic conditions | |||||
0 | 999 (54.1) | 269 | 23.5 (20.3–27.1) | 1.00 (reference) | 1.00 (reference) |
1 | 412 (23.4) | 134 | 27.8 (22.6–33.6) | 1.18 (0.94–1.49) | 1.01 (0.80–1.28) |
2 | 255 (14.2) | 79 | 32.3 (25.8–39.7) | 1.37 (1.06–1.78) | 1.06 (0.81–1.37) |
≥3 | 138 (8.2) | 38 | 27.4 (18.5–38.6) | 1.16 (0.78–1.74) | 0.93 (0.62–1.41) |
Contact with COVID-19 case | |||||
No known contact | 1,189 (42.4) | 497 | 41.4 (37.3–45.8) | 1.00 (reference) | 1.00 (reference) |
Non-cohab. suspected case | 225 (10.9) | 35 | 15.5 (10.0–23.4) | 0.37 (0.24–0.58) | 0.43 (0.28–0.66) |
Non-cohab. confirmed case | 492 (17.1) | 93 | 18.8 (14.3–24.3) | 0.45 (0.34–0.59) | 0.58 (0.43–0.76) |
Cohab. suspected case | 397 (14.5) | 72 | 18.8 (13.8–25.3) | 0.45 (0.33–0.63) | 0.48 (0.36–0.65) |
Cohab. confirmed case | 360 (15.0) | 81 | 22.9 (17.1–30.0) | 0.55 (0.41–0.74) | 0.58 (0.43–0.77) |
Household size (residents) | |||||
1 | 225 (7.7) | 65 | 27.0 (20.7–34.3) | 0.87 (0.66–1.17) | 0.94 (0.71–1.26) |
2 | 667 (25.9) | 204 | 28.7 (24.2–33.7) | 0.93 (0.75–1.16) | 0.93 (0.75–1.16) |
3 | 644 (23.1) | 191 | 28.4 (23.7–33.7) | 0.92 (0.75–1.13) | 0.95 (0.76–1.18) |
4 | 806 (31.9) | 231 | 30.8 (26.4–35.6) | 1.00 (reference) | 1.00 (reference) |
≥5 | 327 (11.3) | 90 | 24.3 (17.6–32.5) | 0.79 (0.56–1.12) | 0.85 (0.63–1.14) |
Census tract average income | |||||
<25th percentile | 737 (24.3) | 232 | 29.0 (24.2–34.4) | 1.00 (reference) | 1.00 (reference) |
25–50th percentile | 561 (25.9) | 183 | 30.7 (25.1–36.9) | 1.06 (0.82–1.37) | 1.11 (0.88–1.41) |
50–75th percentile | 559 (23.0) | 168 | 27.4 (22.4–33.0) | 0.94 (0.73–1.23) | 1.02 (0.82–1.29) |
≥75th percentile | 812 (26.8) | 198 | 27.5 (22.6–33.0) | 0.95 (0.73–1.23) | 1.02 (0.79–1.31) |
Municipality size (inhabitants) | |||||
<5,000 | 511 (9.4) | 203 | 36.6 (30.8–42.9) | 1.00 (reference) | 1.00 (reference) |
5,000–20,000 | 507 (13.3) | 170 | 36.2 (31.2–41.5) | 0.99 (0.79–1.23) | 0.94 (0.75–1.17) |
20,000–100,000 | 720 (23.7) | 183 | 27.5 (22.3–33.3) | 0.75 (0.58–0.97) | 0.77 (0.61–0.98) |
≥100,000 | 931 (53.7) | 225 | 26.0 (22.1–30.2) | 0.71 (0.56–0.89) | 0.80 (0.64–1.00) |
Province seroprevalence (%) | |||||
<3 | 505 (17.5) | 205 | 40.3 (35.0–45.9) | 1.00 (reference) | 1.00 (reference) |
3–5 | 586 (14.2) | 177 | 30.0 (25.2–35.4) | 0.74 (0.60–0.93) | 0.76 (0.61–0.94) |
5–10 | 432 (20.6) | 126 | 26.9 (21.9–32.7) | 0.67 (0.52–0.85) | 0.77 (0.61–0.97) |
≥10 | 1,146 (47.7) | 273 | 24.7 (20.6–29.4) | 0.61 (0.49–0.77) | 0.73 (0.59–0.90) |
Entry round | |||||
First (April 27–May 11) | 2,291 (83.8) | 674 | 28.5 (25.7–31.4) | 1.00 (reference) | 1.00 (reference) |
Second (May 18–June 1) | 305 (13.0) | 83 | 28.0 (21.5–35.7) | 0.98 (0.75–1.30) | 1.02 (0.79–1.33) |
Third (June 8–June 22) | 73 (3.2) | 24 | 37.3 (22.1–55.5) | 1.31 (0.82–2.09) | 1.05 (0.66–1.67) |
3.2 Seroprevalence-based combination of symptoms

3.3 Predictive accuracy of symptoms for SARS-CoV-2 infection
Symptom | No. of symptomatic participants (%) | No. of positive cases | SARS-CoV-2 seroprevalence (%; 95% CI) | Crude seroprevalence ratio (95% CI) | Standardized seroprevalence ratio IV (95% CI)Ratio of SARS-CoV-2 seroprevalence and 95% confidence interval (CI) standardized to the overall distribution of sex, age group, nationality, occupation, smoking, body mass index, number of chronic conditions, contact with COVID-19 case, household size, census tract average income, municipality size, province seroprevalence, and entry round in the entire symptomatic population in Spain. Seroprevalence ratios for individual symptoms were further standardized to the overall distribution of all other symptoms. |
Overall | 16,437 | 1,733 | 10.8 (10.0–11.7) | ||
Fever | |||||
No | 11,890 (69.6) | 797 | 6.8 (6.1–7.5) | 1.00 (reference) | 1.00 (reference) |
Yes | 4,547 (30.4) | 936 | 20.1 (18.2–22.2) | 2.97 (2.61–3.37) | 1.66 (1.46–1.89) |
Chills | |||||
No | 12,232 (74.2) | 1,006 | 8.5 (7.8–9.4) | 1.00 (reference) | 1.00 (reference) |
Yes | 4,205 (25.8) | 727 | 17.5 (15.6–19.5) | 2.04 (1.81–2.31) | 1.02 (0.89–1.16) |
Severe tiredness | |||||
No | 11,127 (67.8) | 774 | 6.9 (6.2–7.7) | 1.00 (reference) | 1.00 (reference) |
Yes | 5,310 (32.2) | 959 | 19.1 (17.3–20.9) | 2.75 (2.43–3.12) | 1.34 (1.19–1.52) |
Sore throat | |||||
No | 9,726 (57.9) | 1,079 | 11.2 (10.2–12.3) | 1.00 (reference) | 1.00 (reference) |
Yes | 6,711 (42.1) | 654 | 10.3 (9.2–11.6) | 0.92 (0.81–1.05) | 0.75 (0.67–0.84) |
Cough | |||||
No | 8,320 (49.8) | 799 | 9.6 (8.6–10.6) | 1.00 (reference) | 1.00 (reference) |
Yes | 8,117 (50.2) | 934 | 12.1 (11.0–13.4) | 1.27 (1.12–1.44) | 1.01 (0.91–1.13) |
Shortness of breath | |||||
No | 13,213 (80.3) | 1,266 | 9.7 (8.9–10.6) | 1.00 (reference) | 1.00 (reference) |
Yes | 3,224 (19.7) | 467 | 15.5 (13.7–17.6) | 1.60 (1.40–1.83) | 0.99 (0.87–1.12) |
Headache | |||||
No | 8,008 (48.3) | 768 | 9.6 (8.7–10.6) | 1.00 (reference) | 1.00 (reference) |
Yes | 8,429 (51.7) | 965 | 12.0 (10.8–13.2) | 1.25 (1.10–1.41) | 0.92 (0.83–1.02) |
Nausea/vomiting/diarrhea | |||||
No | 12,533 (75.6) | 1,136 | 9.4 (8.6–10.3) | 1.00 (reference) | 1.00 (reference) |
Yes | 3,904 (24.4) | 597 | 15.3 (13.6–17.1) | 1.63 (1.44–1.84) | 1.06 (0.95–1.17) |
Anosmia/ageusia | |||||
No | 14,589 (88.7) | 884 | 6.3 (5.7–7.0) | 1.00 (reference) | 1.00 (reference) |
Yes | 1,848 (11.3) | 849 | 46.2 (42.8–49.7) | 7.29 (6.49–8.19) | 4.10 (3.57–4.72) |
No. of symptoms | |||||
1–2 | 9,157 (54.2) | 547 | 5.8 (5.2–6.5) | 1.00 (reference) | 1.00 (reference) |
3–4 | 4,115 (25.5) | 446 | 11.7 (10.2–13.3) | 2.00 (1.71–2.35) | 1.72 (1.48–1.99) |
5–6 | 2,124 (13.5) | 432 | 19.4 (17.0–21.9) | 3.32 (2.83–3.89) | 2.53 (2.18–2.95) |
7–9 | 1,041 (6.7) | 308 | 31.0 (26.9–35.4) | 5.30 (4.49–6.27) | 3.58 (3.05–4.21) |
Symptomatic risk score | |||||
0–1 | 9,574 (56.7) | 352 | 3.9 (3.4–4.5) | 1.00 (reference) | 1.00 (reference) |
2–3 | 4,211 (26.7) | 380 | 9.2 (8.0–10.7) | 2.38 (1.95–2.90) | 2.04 (1.69–2.45) |
4–5 | 964 (6.2) | 195 | 19.4 (16.2–23.2) | 5.00 (3.95–6.33) | 3.76 (3.02–4.68) |
6–7 | 845 (4.9) | 344 | 40.8 (36.2–45.5) | 10.5 (8.75–12.6) | 6.61 (5.46–8.00) |
8–9 | 843 (5.5) | 462 | 54.4 (49.5–59.2) | 14.0 (11.9–16.5) | 8.71 (7.37–10.3) |

4. Discussion
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- Struyf T
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- Wiersinga WJ
- Rhodes A
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- Peacock SJ
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WHO. COVID-19 Case definition [Internet]. 2020 [cited 2021 Feb 1]. Available from: https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-Surveillance_Case_Definition-2020.2
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5. Conclusion
Author contributions
Ethical approval
Funding
Data availability
Acknowledgements
Appendix. Supplementary materials
References
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