antibiotics

Article
Burden of Hospitalizations Related to Pneumococcal Infection
in Spain (2016–2020)
Ruth Gil-Prieto 1, * , Nizar Allouch 1 , Isabel Jimeno 2 , Valentín Hernández-Barrera 1 , Raquel Arguedas-Sanz 3
and Ángel Gil-de-Miguel 1,4

1 Preventive Medicine and Public Health, Rey Juan Carlos University, 28922 Madrid, Spain
2 Primary Care Health Center Isla de Oza, Vaccine Responsible of SEMG, 28035 Madrid, Spain
3 Department of Business Economics and Accounting, Universidad Nacional de Educación a Distancia UNED,
28004 Madrid, Spain
4 CIBER of Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
* Correspondence: [email protected]

Abstract: Pneumococcal infection strongly contributes to morbidity and mortality in Spain. A total of
253,899 hospitalizations related to pneumococcal infection occurred from 2016 to 2020. Fifty-eight percent
were men, the mean age was 67 years old, and the average length of hospitalization was 12.72 days.
The annual hospitalization rate was 10.84 hospitalizations per 10,000 population, increasing signifi-
cantly with age, reaching 65.75 per 10,000 population in those aged >85 years. The hospitalization
rates for pneumococcal pneumonia, sepsis, and meningitis were 2.91, 0.12, and 0.08 hospitalizations
per 10,000, respectively, and reached the highest value in those aged >85 for pneumococcal pneumo-
nia and sepsis, with 22.29 and 0.71 hospitalizations per 10,000, respectively, and in children up to
1 year old for pneumococcal meningitis, with 0.33 hospitalizations per 10,000. The total number of
deaths during the study period was 35,716, with a case-fatality rate of 14.07%. For pneumococcal
pneumonia, sepsis, and meningitis, the case-fatality rates were 8.47%, 23.71%, and 9.99%, respectively.
The case-fatality rate increased with age and did not vary by sex. The annual cost of these hospital-
izations was more than EUR 359 million. There is therefore a high burden of disease and mortality
caused by pneumococcal infection in our country, especially in elderly individuals.
Citation: Gil-Prieto, R.; Allouch, N.;
Jimeno, I.; Hernández-Barrera, V.; Keywords: pneumococcal infection; epidemiology; hospitalizations; pneumococcal pneumonia
Arguedas-Sanz, R.; Gil-de-Miguel, Á.
Burden of Hospitalizations Related to
Pneumococcal Infection in Spain
(2016–2020). Antibiotics 2023, 12, 172. 1. Introduction
https://doi.org/10.3390/
Streptococcus pneumoniae (pneumococcus) is a leading cause of acute respiratory and
antibiotics12010172
invasive infections in all ages [1] and leads to a high number of hospitalizations and costs,
Academic Editor: Masafumi Seki especially in groups considered at risk [2]. This includes lifestyle factors (smoking, alcohol
abuse, being underweight, having regular contact with children, and poor dental hygiene),
Received: 25 November 2022
comorbid conditions (chronic respiratory and cardiovascular diseases, cerebrovascular
Revised: 9 January 2023
disease, Parkinson’s disease, epilepsy, dementia, dysphagia, HIV, or chronic renal or liver
Accepted: 11 January 2023
disease) and age. Immunosenescence [3] makes age the most important risk factor, dra-
Published: 14 January 2023
matically increasing the morbimortality of pneumonia. Among the community-acquired
pneumonias with an identified microbiological cause, Streptococcus pneumoniae and respira-
tory viruses are the most frequently detected pathogens [4].
Copyright: © 2023 by the authors. Although the trend in recent years points towards a decrease in the incidence of
Licensee MDPI, Basel, Switzerland. pneumococcal pneumonia due to preventive measures such as vaccination, pneumococcal
This article is an open access article disease continues to be associated with high rates of morbidity and mortality and long
distributed under the terms and periods of hospitalization, which translates into high health costs [5].
conditions of the Creative Commons In a recent retrospective multicenter study on pneumococcal infection in Spanish
Attribution (CC BY) license (https:// hospitals between 2008 and 2017 [6], the mean patient age was 63 years, and pneumococcal
creativecommons.org/licenses/by/
4.0/).

Antibiotics 2023, 12, 172. https://doi.org/10.3390/antibiotics12010172 https://www.mdpi.com/journal/antibiotics

Antibiotics 2023, 12, 172 2 of 13

pneumonia was the cause of 64% of pneumococcal disease, with a mortality of 7%. S. pneu-
moniae is also responsible for invasive pneumococcal diseases (IPDs), such as meningitis
and sepsis, and more common noninvasive illnesses, such as sinusitis and otitis media.
Four vaccines have been commercialized for protection against pneumococcal disease
in Spain: a 23-valent polysaccharide vaccine (PPV-23), three pneumococcal conjugated
vaccines (PCV) (a 10-valent conjugated vaccine (PCV10) and a 13-valent conjugated vaccine
(PCV13) and the recently approved 20-valent conjugated vaccine). The Spanish vaccination
policy recommends the administration of PCV13 for children (two doses of primary vacci-
nation and one booster), for high-risk adults (PCV13 followed by PPV23), for those older
than 2 years who are at risk due to underlying conditions (a dose of PPV23 after having
completed the usual immunization with PCV13), and for all adults aged 65 years and older
(one dose of PPV23) [7,8].
Due to the expected indirect effects of PCV13 vaccination of the pediatric population
on the reduction of the pneumococcal disease burden in adults, policy has moved away
from routinely recommending PCV13 for elderly individuals. In the last months of 2022,
after the approval of the 20-valent conjugated vaccine, some regions in Spain began shifting
their vaccination policies and recommending vaccination in the elderly with PCV20.
The objective of this study was to provide population-based estimates of the burden
of hospitalization for pneumococcal infection (PI) and specifically for pneumococcal pneu-
monia (PP), pneumococcal sepsis (PS), and pneumococcal meningitis (PM) in the general
population in Spain during a five-year period (2016–2020).

2. Results
In total, 253,899 patients were hospitalized in Spain due to pneumococcal infection
from 2016 to 2020. Of those, 58% (146,081 cases) were men and 42% (107,818) were women.
The mean age was 67.00 (CI 95%: 66.92–67.08) years old, and the average length of stay was
12.72 days (CI 95%: 12.67–12.80).
The overall annual hospitalization rate was 10.84 hospitalizations per 10,000 pop-
ulation (CI 95%: 10.8–10.88), with significant differences by age group (p < 0.001 in all
diagnoses and in both females and males) (Table 1, Figure 2A). The hospitalization rate in
children up to 1 year of age was 18.6 cases per 10,000 population (CI 95%: 17.99–19.21),
decreasing with age until adolescence (1.5 cases per 100,000, CI 95%: 1.45–1.55 in the
5–14 year old group) and then increasing again with age, reaching 65.75 cases per 10,000
population (CI 95%: 65.17–66.33) in those aged 85 or over (Table 1).

Table 1. Hospitalization rate and case-fatality rate by sex and age group due to pneumococcal
infection in Spain (2016–2020).

Hospitalization Case-Fatality
Sex Age Group Rate/per 10,000 p-Value Rate/% p
(CI 95%) (CI 95%)
Male <1 years 20.22 (19.33–21.11) 0.000 2.03 (1.47–2.72) 0.014
1–4 years 5.29 (5.07–5.51) 0.000 1.43 (1–1.98) 0.736
5–14 years 1.49 (1.42–1.56) 0.000 1.4 (0.94–2.01) 0.170
15–44 years 2.47 (2.42–2.52) 0.000 4.52 (4.15–4.93) 0.804
45–64 years 11.03 (10.92–11.14) 0.000 12.86 (12.53–13.21) 0.360
65–74 years 31.51 (31.17–31.85) 0.453 15.87 (15.49–16.27) 0.007
75–84 years 56.26 (55.68–56.84) 0.000 16.65 (16.26–17.04) 0.000
85 or over 90.93 (89.75–92.11) 0.000 18.98 (18.48–19.49) 0.001
Total 12.72 (12.65–12.79) 0.046 14.34 (14.17–14.52) 0.000
Antibiotics 2023, 12, 172 3 of 13

Antibiotics 2023, 12, x FOR PEER REVIEW 3 of 14

Table 1. Cont.

Hospitalization Case-Fatality
Sex Age Group Rate/per 10,000 p-Value Rate/% p
1–4 years 5.42 (5.2–5.64)
(CI 95%)
0.000 1.16(CI
(0.78–1.68)
95%)
0.722
5–14 years 1.52 (1.45–1.59) 0.000 1.68 (1.16–2.36) 0.513
Female <1 years 16.89 (16.05–17.73) 0.000 1.86 (1.28–2.63) 0.026
15–44 1–4
years
years
1.74 (1.7–1.78)
5.42 (5.2–5.64)
0.000
0.000
6.54 (6–7.12)
1.16 (0.78–1.68)
0.165
0.722
45–645–14
yearsyears 7.16 (7.07–7.25)
1.52 (1.45–1.59) 0.000
0.000 12.53
1.68 (12.12–12.95)
(1.16–2.36) 0.382
0.513
65–74 years
15–44 years 16.15 (15.92–16.38)
1.74 (1.7–1.78) 0.000
0.000 13.06
6.54(12.59–13.54)
(6–7.12) 0.135
0.165
75–8445–64
yearsyears 29.17 7.16(28.81–29.53)
(7.07–7.25) 0.000
0.000 12.53 (12.12–12.95)
14.51 (14.08–14.95) 0.382
0.092
65–74 years 16.15 (15.92–16.38) 0.000 13.06 (12.59–13.54) 0.135
85 or over 52.88 (52.24–53.52) 0.169 19.15 (18.67–19.63) 0.105
75–84 years 29.17 (28.81–29.53) 0.000 14.51 (14.08–14.95) 0.092
Total
85 or over 9.04 (52.24–53.52)
52.88 (8.99–9.09) 0.000
0.169 13.69(18.67–19.63)
19.15 (13.49–13.9) 0.009
0.105
BOTH <1 years Total 18.6
9.04(17.99–19.21)
(8.99–9.09) 0.000
0.000 1.96 (13.49–13.9)
13.69 (1.54–2.45) 0.001
0.009
BOTH 1–4 years <1 years 18.6
5.35(17.99–19.21)
(5.19–5.51) 0.000
0.000 1.96
1.3(1.54–2.45)
(1–1.66) 0.001
0.994
1–4 years 5.35 (5.19–5.51) 0.000 1.3 (1–1.66) 0.994
5–14 years 1.5 (1.45–1.55) 0.000 1.54 (1.17–1.97) 0.164
5–14 years 1.5 (1.45–1.55) 0.000 1.54 (1.17–1.97) 0.164
15–4415–44
yearsyears 2.11 (2.08–2.14)
2.11 (2.08–2.14) 0.000
0.000 5.35 (5.03–5.68)
5.35 (5.03–5.68) 0.264
0.264
45–6445–64
yearsyears 9.08
9.08 (9.01–9.15)
(9.01–9.15) 0.000
0.000 12.73 (12.47–13)
12.73 (12.47–13) 0.880
0.880
65–7465–74
yearsyears 23.37 23.37 (23.17–23.57)
(23.17–23.57) 0.022
0.022 14.84 (14.54–15.15)
14.84 (14.54–15.15) 0.004
0.004
75–8475–84
yearsyears 40.68 (40.36–41)
40.68 (40.36–41) 0.000
0.000 15.77 (15.48–16.06)
15.77 (15.48–16.06) 0.001
0.001
85 or over 65.75 (65.17–66.33) 0.001 19.07 (18.72–19.42) 0.000
85 or over
Total 65.75
10.84(65.17–66.33)
(10.8–10.88) 0.001
0.000 19.07
14.07 (18.72–19.42)
(13.93–14.2) 0.000
0.000
Total 10.84 (10.8–10.88) 0.000
The p-value represents significant differences during the period 2016–2020. 14.07 (13.93–14.2) 0.000
The p-value represents significant differences during the period 2016–2020.

(A)

Figure 1. Cont.
Antibiotics 2023, 12,
Antibiotics 2023, 12, 172
x FOR PEER REVIEW 44 of
of 13
14

(B)

(C)

Figure 2. Cont.
Antibiotics 2023, 12, 172
x FOR PEER REVIEW 55of
of 14
13

(D)
Figure
Figure 1.
2. (A):
(A): Hospitalization
Hospitalization rate
rate related
related to
to pneumococcal
pneumococcal infection
infection by
by age
age group
group and
and year
year of
of study
study
in Spain (2016-2020). (B) Hospitalization rate related to pneumococcal pneumonia by age group
in Spain (2016–2020). (B) Hospitalization rate related to pneumococcal pneumonia by age group and
year of study in Spain (2016-2020). (C) Hospitalization rate related to pneumococcal sepsis by age
and year of study in Spain (2016–2020). (C) Hospitalization rate related to pneumococcal sepsis by
group and year of study in Spain (2016-2020). (D) Hospitalization rate related to pneumococcal
age group and year of study in Spain (2016–2020). (D) Hospitalization rate related to pneumococcal
meningitis by age group and year of study in Spain (2016-2020).
meningitis by age group and year of study in Spain (2016–2020).
Pneumococcal pneumonia accounted for 68,189 hospitalizations, pneumococcal
Pneumococcal pneumonia accounted for 68,189 hospitalizations, pneumococcal menin-
meningitis accounted for 2763, and sepsis accounted for 1761, with 57%, 60%, and 53% of
gitis accounted for 2763, and sepsis accounted for 1761, with 57%, 60%, and 53% of the
the hospitalizations occurring in males, respectively. The differences by year were statis-
hospitalizations occurring in males, respectively. The differences by year were statistically
tically significant in most of the age groups (p < 0.001), mainly because of the decrease in
significant in most of the age groups (p < 0.001), mainly because of the decrease in the
the hospitalization rate in 2020 (Figure 1). The hospitalization rates for pneumococcal
hospitalization rate in 2020 (Figure 2). The hospitalization rates for pneumococcal pneu-
pneumonia,
monia, sepsis, sepsis, and meningitis
and meningitis were were 2.91 hospitalizations
2.91 hospitalizations per 10,000
per 10,000 (CI 95%:
(CI 95%: 2.89–
2.89–2.93),
2.93), 0.12 hospitalizations per 10,000 (CI 95%: 0.12–0.12), and 0.08 hospitalizations
0.12 hospitalizations per 10,000 (CI 95%: 0.12–0.12), and 0.08 hospitalizations per 10,000 per
10,000 (CI 95%: 0.08–0.08), respectively. The highest values were reached
(CI 95%: 0.08–0.08), respectively. The highest values were reached in those aged >85 for in those aged
>85 for pneumococcal
pneumococcal pneumonia,pneumonia,
with 22.29 with 22.29 hospitalizations
hospitalizations per 10,000per
(CI 10,000 (CI 95%: 21.95–
95%: 21.95–22.63), and
22.63),
sepsis, with 0.71 hospitalizations per 10,000 (CI 95%: 0.65–0.77), and in thoseand
and sepsis, with 0.71 hospitalizations per 10,000 (CI 95%: 0.65–0.77), up toin1those
year
up
old to
for1pneumococcal
year old for pneumococcal
meningitis, with meningitis, with 0.33 hospitalizations
0.33 hospitalizations per 10,000 (CI 95%:per 10,000 (CI
0.25–0.41).
95%: The
0.25–0.41).
hospitalization rates were generally higher in males than in females (Tables 1
Thereaching
and 2), hospitalization ratessignificant
statistically were generally higher
differences inin males
those than
aged <1in females
year (Tables
and all groups 1
and 2), reaching statistically significant differences in those aged <1 year
aged older than 15 years for all hospitalizations and pneumococcal pneumonia. In sepsis, and all groups
aged older than were
the differences 15 years for all hospitalizations
significant in those older andthanpneumococcal
15 years of age.pneumonia. In sepsis,
In pneumococcal
the differences
meningitis, were significant
statistical significance inwas
those older
only than 15
reached in years of age. In pneumococcal
the <1-year-old, 15–44-year-old,men-and
ingitis, statistical
65–74-year-old significance was only reached in the <1-year-old, 15–44-year-old, and 65–
groups.
74-year-old
The total groups.
number of deaths among patients hospitalized with pneumococcal infection
The total number
during the 5-year study of period
deaths was
among patients
35,716. hospitalized
Of those, withrelated
5,774 were pneumococcal infection
to pneumococcal
during the 5-year
pneumonia, 655 tostudy period
sepsis, and was
176 35,716. Of those, 5,774
to pneumococcal were related
meningitis. This to pneumococcal
corresponded to
pneumonia,
a case-fatality 655rate
to sepsis,
of 14.07%and(CI17695%:
to pneumococcal meningitis.
13.93–14.2) for This corresponded
pneumococcal to a
infection-related
case-fatality
hospitalizationsrate (Table
of 14.07% (CI of
1) and 95%: 13.93–14.2)
8.47% (CI 95%:for pneumococcal
8,26–8,68), 23.71%infection-related hospi-
(CI 95%: 22.15–25.32),
talizations
and 9.99% (Table
(CI 95%:1) and of 8.47%for
8.66–11.46) (CIpneumococcal
95%: 8,26–8,68), 23.71% (CIsepsis,
pneumonia, 95%: 22.15–25.32),
and meningitis,and
respectively (Table 2).
Antibiotics 2023, 12, 172 6 of 13

Table 2. Hospitalization rate and case-fatality rate by sex and age group due to pneumococcal pneumonia, sepsis, and meningitis in Spain (2016–2020).

Pneumococcal Pneumonia Pneumococcal Sepsis Pneumococcal Meningitis

Hospitalization Case-Fatality Hospitalization Case-Fatality Hospitalization Case-Fatality
Sex Age Group Rate/per 10,000 p-Value Rate/% p-Value Rate/per 10,000 p-Value Rate/% p-Value Rate/per 10,000 p-Value Rate/% p-Value
(CI 95%) (CI 95%) (CI 95%) (CI 95%) (CI 95%) (CI 95%)
Male <1 years 1.06 (0.86–1.26) 0.248 0.97 (0.1–4.45) 0.532 0.38 (0.26–0.5) 0.352 0 (0–0) - 0.42 (0.29–0.55) 0.200 2.44 (0.26–10.84) -
1–4 years 1.21 (1.11–1.31) 0.000 0.19 (0.02–0.88) 0.592 0.11 (0.08–0.14) 0.083 6.25 (1.79–15.75) 0.142 0.11 (0.08–0.14) 0.003 2.04 (0.22–9.14) -
5–14 years 0.25 (0.22–0.28) 0.037 1.3 (0.44–3.07) 0.181 0.01 (0–0.02) 0.066 0 (0–0) - 0.03 (0.02–0.04) 0.628 0 (0–0) -
15–44 years 0.7 (0.68–0.72) 0.000 1.97 (1.53–2.51) 0.964 0.03 (0.02–0.04) 0.319 9.32 (5.05–15.55) 0.705 0.03 (0.02–0.04) 0.035 4.64 (2.1–8.89) 0.818
45–64 years 2.71 (2.65–2.77) 0.000 6.5 (6.01–7.03) 0.034 0.14 (0.13–0.15) 0.445 20.84 (17.29–24.77) 0.181 0.09 (0.08–0.1) 0.088 6.98 (4.56–10.2) 0.344
65–74 years 7.76 (7.59–7.93) 0.000 8.34 (7.76–8.95) 0.093 0.35 (0.31–0.39) 0.024 24.19 (20.05–28.73) 0.917 0.19 (0.16–0.22) 0.002 15.46 (11.03–20.85) 0.498
75–84 years 15.65 (15.34–15.96) 0.000 10.11 (9.53–10.71) 0.004 0.6 (0.54–0.66) 0.269 26.05 (21.83–30.64) 0.322 0.17 (0.14–0.2) 0.076 19.63 (12.97–27.9) 0.514
85 or over 31.02 (30.33–31.71) 0.000 14.17 (13.41–14.96) 0 0.98 (0.86–1.1) 0.025 30.49 (24.99–36.44) 0.39 0.08 (0.04–0.12) 0.938 50 (29.34–70.66) 0.111
Total 3.41 (3.38–3.44) 0.000 8.84 (8.56–9.12) 0 0.15 (0.14–0.16) 0.012 22.29 (20.34–24.33) 0.84 0.08 (0.07–0.09) 0.000 10.18 (8.36–12.26) 0.906
Female <1 years 0.78 (0.6–0.96) 0.176 1.39 (0.15–6.31) 0.532 0.3 (0.19–0.41) 0.710 10.71 (3.11–25.91) 0.275 0.23 (0.13–0.33) 0.240 4.76 (0.52–20.18) -
1–4 years 1.2 (1.09–1.31) 0.000 0.4 (0.08–1.29) 0.68 0.09 (0.06–0.12) 0.319 10.81 (3.76–23.69) 0.977 0.09 (0.06–0.12) 0.336 2.56 (0.28–11.36) -
5–14 years 0.25 (0.22–0.28) 0.000 0.34 (0.04–1.57) 0.371 0.01 (0–0.02) 0.833 0 (0–0) - 0.02 (0.01–0.03) 0.280 3.7 (0.4–16.04) -
15–44 years 0.54 (0.52–0.56) 0.000 1.71 (1.24–2.3) 0.942 0.02 (0.02–0.02) 0.754 10.45 (4.8–19.42) 0.494 0.02 (0.02–0.02) 0.758 4.71 (1.61–10.8) 0.927
45–64 years 1.73 (1.69–1.77) 0.000 4.2 (3.7–4.73) 0.23 0.07 (0.06–0.08) 0.193 17.47 (12.97–22.78) 0.047 0.09 (0.08–0.1) 0.692 5.9 (3.66–8.97) 0.468
65–74 years 3.83 (3.72–3.94) 0.000 5.23 (4.61–5.9) 0.016 0.18 (0.16–0.2) 0.878 26.27 (20.75–32.41) 0.64 0.15 (0.13–0.17) 0.158 7.07 (4.02–11.45) 0.746
75–84 years 7.73 (7.54–7.92) 0.000 8.29 (7.65–8.97) 0.001 0.26 (0.23–0.29) 0.033 27.93 (22.34–34.09) 0.515 0.14 (0.12–0.16) 0.168 15.45 (9.89–22.6) 0.815
85 or over 17.83 (17.46–18.2) 0.000 14.13 (13.41–14.87) 0 0.58 (0.51–0.65) 0.648 38.87 (33.33–44.64) 0.633 0.11 (0.08–0.14) 0.337 46.3 (33.48–59.5) 0.644
Total 2.44 (2.41–2.47) 0.079 7.97 (7.66–8.29) 0 0.09 (0.08–0.1) 0.100 25.87 (23.34–28.52) 0.25 0.07 (0.07–0.07) 0.621 9.79 (7.91–11.94) 0.936
BOTH <1 years 0.92 (0.78–1.06) 0.000 1.14 (0.24–3.62) 0.435 0.34 (0.26–0.42) 0.646 4.62 (1.32–11.81) 34 0.33 (0.25–0.41) 0.719 3.23 (0.68–9.95) 0.695
1–4 years 1.21 (1.14–1.28) 0.000 0.29 (0.08–0.78) 0.993 0.1 (0.08–0.12) 0.060 8.24 (3.76–15.49) 0.317 0.1 (0.08–0.12) 0.105 2.27 (0.48–7.09) 0.452
5–14 years 0.25 (0.23–0.27) 0.000 0.83 (0.32–1.81) 0.098 0.01 (0.01–0.01) 0.113 0 (0–0) - 0.02 (0.01–0.03) 0.277 1.67 (0.18–7.53) -
15–44 years 0.62 (0.6–0.64) 0.000 1.86 (1.53–2.24) 0.916 0.02 (0.02–0.02) 0.546 9.73 (6.08–14.62) 0.906 0.03 (0.03–0.03) 0.060 4.66 (2.5–7.92) 0.81
45–64 years 2.22 (2.18–2.26) 0.000 5.6 (5.24–5.97) 0.022 0.1 (0.09–0.11) 0.167 19.71 (16.85–22.82) 0.028 0.09 (0.08–0.1) 0.135 6.45 (4.72–8.59) 0.227
65–74 years 5.68 (5.58–5.78) 0.000 7.23 (6.79–7.68) 0.015 0.26 (0.24–0.28) 0.060 24.96 (21.59–28.57) 0.734 0.17 (0.15–0.19) 0.001 11.51 (8.63–14.95) 0.825
75–84 years 11.09 (10.92–11.26) 0.000 9.38 (8.95–9.83) 0 0.4 (0.37–0.43) 0.033 26.74 (23.33–30.39) 0.693 0.15 (0.13–0.17) 0.027 17.39 (12.92–22.68) 0.768
85 or over 22.29 (21.95–22.63) 0.000 14.15 (13.62–14.69) 0 0.71 (0.65–0.77) 0.069 34.97 (31–39.11) 0.299 0.1 (0.08–0.12) 0.393 47.3 (36.21–58.59) 0.191
Total 2.91 (2.89–2.93) 0.000 8.47 (8.26–8.68) 0 0.12 (0.12–0.12) 0.003 23.71 (22.15–25.32) 0.596 0.08 (0.08–0.08) 0.000 9.99 (8.66–11.46) 0.991
The p-value represents significant differences during the period 2016–2020.
Antibiotics 2023, 12, 172 7 of 13

The case-fatality rate increased with age (p < 0.001), reaching a higher value in the
>85-year-old group, with 19.07% (CI95%: 18.72–19.42) for PI. For pneumococcal pneumonia,
sepsis, and meningitis, the highest case fatality rate was also found in those aged >85, with
14.15% (CI 95%: 13.62–14.69), 34.97% (CI 95%: 31–39.11), and 47.3% (CI 95%: 36.21–58.59),
respectively (Table 2).
There were no statistically significant differences in the case fatality rates by year
during the study period, except for those patients aged 65 or over with a diagnosis of
pneumococcal pneumonia; in this age group, the case-fatality rate was significantly higher
in 2020.
The mean cost per hospitalization was EUR 7081 (CI 95%: 7044–7119). When gathering
data for diagnosis, EUR 5247 (CI 95%: 5195–5299) was the mean cost per PP hospitalization,
EUR 9169 (CI 95%: 8761–9577) was the mean cost for sepsis, and EUR 12,608 (CI 95%: 12,107–
13,109) was the mean cost for meningitis. The estimated cost of these hospitalizations
per year was more than EUR 359 million in total, with EUR 71, 5, and 4.4 million for
pneumococcal pneumonia, sepsis, and meningitis, respectively.

3. Discussion
In this study, we provide data on the burden of hospitalizations for pneumococcal
infection in Spain. Our results show that these diseases continue to pose a high burden of
both morbidity and mortality and health care costs, with an annual general hospitalization
rate of 10.84 hospitalizations per 10,000 population and reaching 65.75 per 10,000 population
in those aged >85, with an annual cost of more than EUR 359 million.
The hospitalization rates obtained in this study are in line with previously published
hospitalization rates (1.09/1000) reported for pneumococcal pneumonia in adults older
than 50 years old in Spain for the period 2003–2007 [9] and with the decreasing trend in
hospital incidence of pneumococcal pneumonia reported in the last decade [6].
When comparing our results with other European countries, Italy showed a general
hospitalization rate of 753/100,000 inhabitants after the introduction of the pneumococcal
conjugate vaccine in children [10], whereas Norway observed a decrease in the incidence
of pneumococcal pneumonia from 50.8 cases per 100,000 in 2008 to 35.6 cases per 100,000
in 2009 in those aged 65 years and older [11]. A study performed in Portugal showed an
average annual rate of hospital admissions for adults with community-acquired pneumonia
of 3.61 per 1000 total population, rising to 13.4 for those aged ≥65 years and increasing
between 2000 and 2009 [12]. This increase is believed to be related to the impact of age on
the increase in admissions for community-acquired pneumonia (CAP), as the average age
grew from 70.1 years in 2000 to 73.6 years in 2009. In general, a higher hospitalization rate
is seen in Spain. This phenomenon was previously observed in a recent systematic review,
which highlights Spain as having the highest prevalence of pneumococcal pneumonia
among Southern European countries. [13,14]. The multiple changes in vaccinations in
the last two decades and the consequent impact on the pneumococcal disease-related
hospitalization rate have made it difficult to compare between countries due to the different
time ranges of the studies.
The hospitalization rates for pneumococcal disease remained stable from 2016 to 2019
in our study, similar to what was found in northern France, where the incidence of hospital-
izations related to invasive pneumococcal disease remained stable from 2014 to 2018, with
no significant increase in pneumococcal serotypes not included in the vaccines [15,16]. The
decrease in the hospitalization rates shown in 2020 may have been due to the COVID-19
pandemic. This effect was also observed among seven US children’s hospitals, in which
the cumulative incidence of invasive pneumococcal disease decreased by 46% in 2020 vs.
2017–2019 [17]. Since SARS-CoV-2 is a respiratory virus, there are some concerns that
COVID-19 can increase susceptibility to pneumonia and invasive pneumococcal diseases.
However, early reports during the pandemic demonstrated reduced IPD rates [18], and
coinfections of these two pathogens were infrequent [19]. It is thought that the reduction in
pneumococcal disease in children observed during the COVID-19 pandemic was mainly
Antibiotics 2023, 12, 172 8 of 13

due to the reduction in the incidence of these seasonal respiratory viruses rather than to
reductions in transmission of pneumococcus [16].
Similar to previous studies, the high direct costs of pneumococcal disease were con-
firmed, with more than EUR 359 million annually. In 2011, a study on the risk of hospi-
talization due to pneumococcal disease in Spain [20] reflected a direct economic burden
of PP of EUR 47 million, with EUR 57 million accounting for all invasive pneumococcal
disease. This is consistent with the data offered by another study in 2015 on the impact
of four vaccine-preventable diseases in older adults in Spain [5] and Italy, where, despite
reductions in pneumococcal disease-related expenditures following the introduction of
PCV13, there continues to be an important economic burden associated with pneumococcal
disease [21]. In Norway, a recent study indicated that the burden of noninvasive pneumo-
coccal pneumonia hospitalization had a substantial impact on the health and health care
use of the 50+ population in Norway, despite the childhood immunization program [22].
It has been hypothesized that adult pneumococcal pneumonia caused by the serotypes
included in the conjugate vaccine also declined following the introduction of pediatric
PCVs in national immunization programs, possibly due to the indirect effects of pediatric
PCVs. The introduction of PCVs into the US routine infant vaccination schedule led to
important reductions in the burden of IPD and noninvasive pneumonia among vaccinated
and unvaccinated populations [23], but despite the herd protection observed in US adults,
noninvasive pneumococcal CAP and vaccine-type pneumococcal CAP remain a burden in
older adults [24,25]. Data from Italy showed that, although the pneumococcal pediatric
vaccination resulted in a decrease in hospitalizations in children, the expected indirect effect
in the elderly was not reported, leading to the recommendation to extend the vaccination
to subjects >64 years of age [10,26]. Similarly, in Israel, pediatric pneumonia hospitaliza-
tion rates have continued to decline since the introduction of PCV without increasing the
frequency of complications, but pneumococcal serotype distribution shifted in parallel,
confirming the efficacy of PCV and supporting the evidence to include more serotypes
in the next generation of PCV [27]. The proportion of adult pneumococcal pneumonia
caused by PCV13 serotypes in Japan also declined after pediatric PCV introduction into
national immunization programs, possibly due to the indirect effects of pediatric PCVs [28].
PCV13 implementation in France led to a major reduction in the incidence of invasive
pneumococcal disease. However, a rebound in cases among children and adults since
2015, driven by several emerging non-PCV13 serotypes, jeopardizes the long-term PCV
benefits [10,29]. In the context of a robust pediatric PCV13 immunization program, the
PCV13 vaccination of adults aged 65 years or older was associated in the US with significant
reductions in hospitalizations for all-cause pneumonia and low respiratory tract infections.
Vaccinating older adults with PCVs may provide broader public health benefits against
pneumonia hospitalizations [30]. These findings indicate the importance of having conju-
gate vaccines with high serotype coverage and might guide policymakers in the selection
of future pneumococcal vaccines.
PCV13 has been widely used in the last decade and has been associated with an
important decrease in the rate of pneumococcal pneumonia in comparison to PPV23. A
study in older US veterans showed a 31% decrease in the rate of pneumococcal pneumonia
with the conjugate vaccine in comparison to PPV23, recommending routine vaccination
with pneumococcal conjugate vaccines in all older adults [31]. Sequential PCV13/PPV23
vaccination was more effective at preventing pneumococcal CAP among elderly individuals
aged 65–74 years than single-dose PCV13 or single-dose PPV23 [32]. More recently, the
immunogenicity of PCV20 in adults has been demonstrated in several clinical trials that
showed that PCV20 administered as a single dose induced robust immune responses and
was well tolerated [33].
The present study was not designed to evaluate the efficacy of preventive measures.
The early direct effect of PCV13 and PPV23, since their inclusion in the regional calendars
of immunocompetent adults, has been broadly discussed [34]. Long periods of time are
needed to see the indirect effects of PCV13 in childhood; approximately 3 years are needed
Antibiotics 2023, 12, 172 9 of 13

to see a reduction of 50% in the incidence of the cases caused by the serotypes included
in this vaccine and a decade to be nearly eradicated [35]. According to data from De
Miguel et al. [34], the three serotypes most frequently involved in IPD and causing high
mortality in 2019 in Spain were 8 (18.72%), 3 (13.2%), and 22F (5.3%). Compared with PCV13
serotypes, the additional 2 and 7 serotypes covered by PCV15 and PCV20 would cover
550,475 and 991,220 annual pneumococcal disease cases, as well as 1425 and 3226 annual
deaths, respectively, with savings ranging from USD 903 to USD 1928 million in the United
States [36]. It is estimated that the new PCV15 and PCV20 vaccines would achieve coverage
of 15% and 24% of all-cause pneumonia and 43% and 70% of pneumococcal pneumonia by
studying the most prevalent serotypes in the 2016–2018 period, respectively [14]. The use
of PCV20 among adults currently eligible for PPV23 in England would substantially reduce
the burden of pneumococcal disease, with a modest budgetary impact [37]. The Advisory
Committee on Immunization Practices (ACIP) recommends the use of a pneumococcal
conjugate vaccine (either PCV20 or PCV15) for adults 65 years of age or older, those risk
groups who have not previously received a pneumococcal conjugate vaccine, or those
whose previous vaccination history is unknown. If PCV15 is used, the recommendation
is that it should be followed by a dose of PPV23 [38]. Considering that a single dose of
PCV20 would cover the majority of pneumococcal disease in Spain and improve vaccine
compliance [39], the recommendation by the NeumoExperts group is using a single dose
of PCV20. Some Spanish regions have recently recommended the use of a single dose of
PCV20 [40,41].
Regarding the limitations of this study, it is important to note that, despite gathering
all cases of hospitalizations related to pneumococcal disease, we were unable to take into
account the cases that were managed in primary care and did not provide information on
microbiological confirmation; thus, our results may have underestimated the true impact
of pneumococcal pneumonia. Incidences were not given in this study, only hospitalization
rates. There is a potential undercoding of clinical variables due to the limited number of
codes for secondary diagnoses or to deficiencies in the preparation of hospital discharge
reports. The MBDS encodes hospital admissions; thus, there could potentially be data
redundancy for patients who had been hospitalized more than once during the period
analyzed. This potential redundancy could have affected the point estimates of the preva-
lence (overestimation) and lethality (underestimation) of the disease. However, due to
the large number of records in the database, it is unlikely that a certain percentage of
redundant data could have altered the general trends in hospitalization and death rates
in the long term. Despite this limitation, the MBDS is currently one of the most valuable
tools available for clinical and epidemiological research. The main strength of our study is
derived from the use of the MBDS database, which, due to its large sample size, provides
high statistical power and representativeness when analyzing clinical variables such as
case-fatality rate. Additionally, the MBDS is subject to a high-quality data audit at the state
level. This makes it a valuable tool for epidemiological analyses of respiratory diseases
such as pneumonia [42]. The transition from ICD-9-CM to ICD-10-CM coding, starting in
2016, probably had some impact on the epidemiological analysis, affecting the comparison
with hospitalization and mortality data previously published by this research group. It
may be necessary to wait for longer-term epidemiological data to assess the true dimension
of this transition [43]. However, a strength of this study is that the data were gathered
nationwide over 5 years. This will make it easier to calculate the real impact of future
vaccination on hospitalizations due to pneumococcal disease in the Spanish population. On
the other hand, the use of the national hospital discharge database means that the reliability
of hospital surveillance depends on the quality of the discharge reports and the precision
of ICD-10 to detect cases of pneumococcal infection through the corresponding codes [44].
Continuous epidemiological surveillance is needed to assess the long-term effects of
current preventive measures and the implementation in the coming years of new vaccines
with more serotypes, such as PCV15 and PCV20, which will increase the potential coverage
for children and adults.
Antibiotics 2023, 12, 172 10 of 13

4. Materials and Methods

In this retrospective study, the Spanish National Hospital Data Information System
(Minimum Basic Data Set; MBDS) of the Spanish Ministry of Health was used to collect
all retrospective cases with a diagnosis of pneumococcal disease from 1 January 2016 to 31
December 2020. The MBDS provides a complete registry of hospitalizations, as it covers
approximately 98% of public hospitals, offering health coverage to approximately 99.5%
of the Spanish population and is validated for data quality and overall methodology by
the Spanish Ministry of Health. It is considered a valuable system for the epidemiological
analysis [45] of disease, according to the 10th Clinical Revision of the International Classifi-
cation of Diseases (ICD-10-CM), in any diagnostic position were included. The ICD-10-CM
codes used were J13—Pneumonia due to Streptococcus pneumoniae, J86.9—Pyothorax
without fistula, J91.0—Malignant pleural effusion, J91.8—Pleural effusion in other condi-
tions classified elsewhere, I30.1—Infective pericarditis, J98.11—Atelectasis, A 40.3—Sepsis
due to Streptococcus pneumoniae, and G 00.1—Pneumococcal meningitis.

Statistics
The annual hospitalization rates were calculated. For the rates, we used data on the
population covered by hospitals included in the MBDS information system, adjusted for
population figures obtained from municipal registers as the denominators. It was assumed
that the distribution by age of the population covered by these public hospitals was equal
to the general population. The case fatality rate, which reflects the severity of the cases,
was calculated by dividing the number of deaths by the total number of hospitalizations
(%). The average length of stay (ALOS) was calculated (total length of stay/total number
of hospitalizations).
The chi-square test was used to assess significant differences in proportions. Poisson
regression models were used to assess the differences in the rates of hospitalization during
the study period by age group and sex. To assess the differences in the case fatality rates,
logistic regression was used.
The cost of these hospitalizations to the health care system is estimated by the Ministry
of Health. The cost was calculated by taking into account the diagnosis cost group, the
total cost, and the number of discharges. The diagnostic cost group was based on the
diagnosis-related groups (DRGs) for hospitalized patients based on the ICD classification,
age, sex, and resource consumption. Each group has a similar weight in hospital costs and
can be applied to each related patient. The DRG calculations were performed by 3 M with
the Core Grouping System software [46].
For all tests, the significance level used was p < 0.05. Statistical analyses were per-
formed with SPSS 27 and Stata 16.1 software.
The patient data were anonymized and deidentified prior to analysis. The local ethics
committee (Rey Juan Carlos University Research Ethics Committee) ruled that no formal
ethical approval was required for this study.

Author Contributions: Á.G.-d.-M., I.J., and R.G.-P. participated in the conception and design of the
study. Á.G.-d.-M. and R.G.-P. participated in the acquisition of data. N.A., V.H.-B., R.A.-S., and R.G.-P.
analyzed and interpreted the patient data. All authors contributed to writing the manuscript. I.J.,
Á.G.-d.-M. and R.G.-P. supervised the study. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The patient information was anonymized and deidentified
prior to the analysis. The local ethics committee (Comité de Ética de la Investigación de la Universidad
Rey Juan Carlos) ruled that no formal ethics approval was required for this study.
Informed Consent Statement: Not applicable.
Antibiotics 2023, 12, 172 11 of 13

Data Availability Statement: All of the data generated or analyzed during this study are included
in this published article and are available on reasonable request at https://pestadistico.inteligenc
iadegestion.mscbs.es/publicoSNS/S/rae-cmbd. (accessed on 10 October 2021).
Acknowledgments: The authors thank the Subdirección General del Instituto de Información Sani-
taria for providing the information on which this study is based.
Conflicts of Interest: R.G.-P. received travel and research grants and has participated in advisory
boards for Sanofi, Moderna, Janssen, Pfizer, and Merck. A.G.d.M. received travel and research grants
and has participated in advisory boards for Sanofi, Moderna, Janssen, Pfizer, and Merck. I.J. received
travel and research grants and has participated in advisory boards for Sanofi, Moderna, Janssen,
Pfizer, and Merck. N.A., R.A.S., and V.H.-B. have no conflicts of interest to report.

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