Impact of immunization-preventable infectious diseases on population health using disability-adjusted life years (DALYs) in Spain

doi:10.21203/rs.3.rs-3621222/v1

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Research Article

Impact of immunization-preventable infectious diseases on population health using disability-adjusted life years (DALYs) in Spain

https://doi.org/10.21203/rs.3.rs-3621222/v1

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published 05 Aug, 2024

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Background

The objective of this study is to estimate the burden of immunization-preventable infectious diseases in Spain using the Burden of Communicable Diseases in Europe (BCoDE) methodology and focusing on the national immunization program and potential new inclusions.

Methods

The BCoDE methodology relies on an incidence and pathogen-based approach to calculate disease burden via disability-adjusted life year (DALY) estimates. It considers short and long-term sequelae associated to an infection via outcome trees. The BCoDE toolkit was used to populate those trees with Spanish-specific incidence estimates, and de novo outcome trees were developed for four infections (herpes zoster, rotavirus, respiratory syncytial virus [RSV], and varicella) not covered by the toolkit. Age/sex specific incidences were estimated based on data from the Spanish Network of Epidemiological Surveillance; hospitalization and mortality rates were collected from the Minimum Basic Data Set. A literature review was performed to design the de novo models and obtain the rest of the parameters. The methodology, assumptions, data inputs and results were validated by a group of experts in epidemiology and disease modelling, immunization and public health policy.

Results

The total burden of disease amounted to 163.56 annual DALYs/100,000 population. Respiratory infections represented around 90% of the total burden. Influenza exhibited the highest burden, with 110.01 DALYs/100,000 population, followed by invasive pneumococcal disease and RSV, with 25.20 and 10.57 DALYs/100,000 population, respectively. Herpes zoster, invasive meningococcal disease, invasive Haemophilus influenza infection and hepatitis B virus infection fell behind in the ranking with less than 10 DALYs/100,000 population each, while the rest of infections had a limited burden (< 1 DALY/100,000 population). A higher burden of disease was observed in the elderly (≥ 60 years) and children < 5 years, with influenza being the main cause. In infants < 1 year, RSV represented the greatest burden.

Conclusions

Aligned with the BCoDE study, the results of this analysis show a persisting high burden of immunization-preventable respiratory infections in Spain and highlight for the first time a high number of DALYs due to RSV. These estimates provide a basis to guide prevention strategies and make public health decisions to prioritize interventions and allocate healthcare resources in Spain.

burden

DALY

infectious diseases

immunization

vaccines

Infectious diseases are a challenge for healthcare systems worldwide. Nonetheless, the continuous emergence of effective immunization strategies, followed by the implementation of national immunization programs (NIP) and coupled to surveillance systems, have proven to be an efficient approach to control them (1–4). According to the World Health Organization (WHO), the global burden of infectious diseases decreased from 821.8M to 420.4M disability-adjusted life years (DALYs) (-49%) from 1990 to 2019 and from 20.7M to12.0M DALYs (-42%) in the European Union (EU) (calculated from (5)). In Europe, this evolution was mainly driven by the reduction of the burden of respiratory infections, which accounted for 72% of the total reduction (calculated from (5)).

Similar to the global and European trends, a reduction in the burden of infectious diseases was observed in Spain between 1990 and 2019, although it was lower (from 0.4M to 0.3M DALYs; -23%) (calculated from (5)). In 2019, respiratory infections represented 63% of the total infectious diseases burden (calculated from (5)) and despite the implementation of routine vaccination against respiratory viruses, such as influenza and invasive pneumococcal disease in 1980 and 2016, respectively (6, 7), the reduction of the burden of respiratory infectious diseases was only 6% since 1990 (calculated from (5)). As a matter of fact, according to a study that assessed the burden of infectious diseases in Europe, regardless of vaccination and/or surveillance systems in place, 90% of the burden of infectious diseases across Europe derives from immunization-preventable infections, with influenza ranking the highest (8).

Studies estimating the burden of disease using composite health measures are conducted to provide relevant information about its impact and support public health decisions (8–10). In 2006, the European Centre for Disease Prevention and Control (ECDC) initiated the Burden of Communicable Diseases in Europe (BCoDE) project to develop a methodology to assess the impact of infectious diseases on population health in EU/EEA countries, and ultimately provide a tool for the planning and prioritisation of infectious disease prevention, preparedness, and control measures (8, 11, 12). This methodology uses a composite health measure, the DALY (13), to express the disease burden of an infectious disease. DALYs reflect not only the impact of a clinical condition on life expectancy, but also on quality of life. The BCoDE work estimated a total of 275 DALYs per 100,000 population/year were lost due to infectious diseases in Europe before 2013 (8).

The objective of this study is to estimate the burden of immunization-preventable infectious diseases in Spain using the BCoDE methodology, focusing on the current NIP and future potential inclusions.

Selection of infectious diseases

The following diseases were included in the analysis: hepatitis A virus (HAV) infection, hepatitis B virus (HBV) infection, herpes zoster, influenza, invasive Haemophilus influenzae infection, invasive meningococcal disease, invasive pneumococcal disease, measles, mumps, rotavirus, respiratory syncytial virus (RSV) and varicella zoster. These 12 diseases were selected based on the current Spanish immunization calendars (2023–2024) (14, 15), excluding infections that are currently classified as eradicated and adding rotavirus as a potential immunization target (Supplementary Table 1). Human papillomavirus infection was not included since it was not feasible to adapt the survival model of this infection using the BCoDE toolkit due to the associated complex cancer outcomes. SARS-CoV-2 infection was also excluded due to uncertainties regarding its clinical course and future vaccination recommendations.

DALY estimates

The BCoDE methodology relies on an incidence and pathogen-based approach to calculate disease burden via DALY estimates (8, 11, 12). DALYs result from the sum of two variables: years of life lived with disability (YLD) following a disease and years of life lost due to premature mortality (YLL). This approach considers short- and long-term sequelae associated to an infection via outcome trees (11, 12). For the Spanish-adaptation we used the outcome trees available in the BCoDE toolkit, as well as the mortality probabilities and disability weights data, and populated the model with national age- and sex-specific incidence and socio-demographic data (16). Additionally, we, generated de novo outcome trees for four infections (herpes zoster, rotavirus, RSV and varicella) that were not included in the toolkit at the time of our analysis (17) (see De novo models methodology section).

Incidence and mortality

Age- and sex-specific incidence for each infection was approximated based on estimates from the Spanish Network of Epidemiological Surveillance (RENAVE) (18) (data on file; Table 1). The annual number of cases corresponds to primary and secondary diagnoses for 2018, the latest available data prior to the SARS-COV-2 pandemic to avoid bias in incidence derived from this healthcare situation. The age-specific incidence of influenza obtained from the annual RENAVE report (18) was adjusted for underestimation for age groups between 15 and 64 years according to a previous study from the UK (19) (Supplementary Table 2); however, no sex-specific estimates were found for influenza in Spain. For RSV, at the time of this analysis, while no pre-or post-pandemic data were available in the RENAVE reports, the SIVIRA (Sistema de Vigilancia de las Infecciones Respiratorias Agudas) weekly-reported incidence rates did not allow the estimation of the total annual cases in Spain due to low transparency in the estimation method (20). Hence, reported cases of RSV in primary care during 2019 were collected from the Catalonian surveillance system for infections (SIVIC) (21), which has a larger and consistent experience monitoring this infection and a higher degree of detail regarding age and sex (Supplementary Table 3). Since there was no available RSV data for all the age groups defined in the model, especially for groups older than 5 years, we used the age distribution among the hospitalized patients due to RSV as a proxy measure (21).

Table 1

Annual incidence of selected infectious diseases.
Infectious disease	Annual number of cases
Infectious disease	Female	Male
HAV infection	537	1,179
HBV infection	101	291
Herpes Zoster	37,562	26,834
Influenza^a	1,839,426	1,839,426
Invasive Haemophilus influenzae infection	161	192
Invasive meningococcal disease	197	154
Invasive pneumococcal disease	1,830	2,588
Measles	98	91
Mumps	3,822	5,116
RSV^b	73,543	77,105
Rotavirus	2,122	2,443
Varicella zoster	27,652	29,618
HAV: hepatitis A virus; HBV: hepatitis B virus; RSV: respiratory syncytial virus
^aUnder-estimation factors were considered at 17.85% for the age groups between 14 and 44 years and at 14.43% for age groups corresponding to 45–64 years based on the Flu Watch study (19).
^bAnnual number of cases correspond to primary care data for 2019 from the Catalonian surveillance system for infections (SIVIC).

Annual mortality rates were obtained from the BCoDE for the already modelled infections assuming mortality to be disease-specific. Regarding the four de novo models, the annual age- and sex-specific mortality data for primary and secondary diagnoses were collected from the Minimum Basic Data Set (MBDS) published by the Spanish Ministry of Health for the 2016–2019 period (22), employing the ICD-10-CM codes listed in Supplementary Table 4.

De novo models methodology

New outcome trees were generated for four infections: herpes zoster, rotavirus, RSV and varicella zoster (Fig. 1). For this purpose, an analysis of previously published literature was conducted to define the course of each disease, as well as its associated health conditions. The parameters for each model were characterized based on publicly available data and are listed in Table 2. The parameters assigned to the different infections already defined in the BCoDE model are described in Supplementary Table 5.

Table 2

Proportion, duration and disability weight of health conditions associated to the infectious diseases modelled *de novo*.
Infectious disease	Clinical state	Proportion	Disability weight (UI)	Duration
Herpes zoster	Symptomatic infection complicated	0.06–0.09¹	0.131²	8.7 days³
	Symptomatic infection uncomplicated	0.91–0.94¹	0.051^4a (0.039–0.06)	28 days⁵
	Symptomatic infection: postherpetic neuralgia	0.1²	0.068⁶	9 months⁷
	Symptomatic infection: fatal	0.06–0.07³	n/a	n/a
RSV	Symptomatic infection complicated	0.98-1⁸	0.133⁹ (0.008–0.19)	5.3 days³
	Symptomatic infection uncomplicated	0-0.02⁸	0.051⁹ (0.032–0.074)	5.11 days^4b
	Symptomatic infection: long-term complications	0.28⁹	0.015¹⁰	5 years⁵
	Symptomatic infection: fatal	0.012³	n/a	n/a
Rotavirus	Symptomatic infection complicated	0.063¹	0.239^4c (0.202–0.285)	3.38 days³
	Symptomatic infection uncomplicated	0.933¹	0.073^4d (0.061–0.092)	5.48 days^4d
	Symptomatic infection: fatal	0.0032³	n/a	n/a
Varicella zoster	Symptomatic infection complicated	0.078¹	0.131²	7 days³
	Symptomatic infection uncomplicated	0.922¹	0.051^4e (0.039–0.06)	14 days¹¹
	Symptomatic infection: fatal	0.0032³	n/a	n/a
KOLs: key opinion leaders; MBDS: Minimum Basic Data Set; n/a: not applicable; RENAVE: Spanish Network of Epidemiological Surveillance; RSV: respiratory syncytial virus; SIVIC: Catalonian surveillance system for infections; UI: uncertainty intervals.
¹MBDS/RENAVE
²Matthews et al. (31)
³MBDS
⁴BCoDE: ^aDisability weight from BCoDE for uncomplicated symptomatic measles applied. ^bDuration from BCoDE for uncomplicated influenza applied. ^cDisability weight from BCoDE for severe diarrhoea due to salmonellosis infection applied. ^dDisability weight and duration from BCoDE for mild diarrhoea due to salmonellosis infection applied. ^eFor individuals older than 15 years, disability weight from BCoDE for uncomplicated symptomatic measles applied. No burden of disease was considered for children under 15 years based on expert’s opinion.
⁵Expert opinion
⁶Kwong et al. (36)
⁷Lopez-Belmonte et al. (35)
⁸MBDS/SIVIC
⁹Villamil et al. (24)
¹⁰Emerson et al. (29)
¹¹Patil et al. (32)

The proportion of complicated and uncomplicated cases were estimated integrating incidence data from RENAVE (SIVIC for RSV) (18, 21) and hospitalization ratios for primary and secondary diagnoses from the MBDS (22) registered for the 2016–2019 period. In particular, the number of complicated cases was assumed as the number of hospitalizations, while the duration of complicated infections was approximated as the length of hospital stay.

RSV

RSV is one of the main causes of acute respiratory tract infections and can lead to long-term complications (23–25). At the time of this analysis, the monoclonal antibody nirsevimab had been approved for the prevention of RSV lower respiratory tract disease in neonates and infants during their first RSV season in Spain, although no population-wide immunization strategy was yet at play (26).

In this analysis, two health conditions were defined for the outcome tree of RSV: hospitalization and uncomplicated infection (Fig. 1A). For the hospitalized patients, we extracted incidence, in-hospital mortality, and duration of hospitalization data from the MBDS (22). Moreover, hospitalized patients could develop long-term complications, out of which asthma would be the most serious (27, 28). Therefore, in our model, some patients (28%) progressed to a third health state, namely asthma (27, 28). According to expert opinion, a mean duration of 5 years was assumed for asthma. Uncomplicated RSV was associated with a reduction in quality of life only for the duration of the infection (assumed to be 5.11 days similar to uncomplicated influenza) (Table 2). Disability weights for both uncomplicated and complicated (hospitalizing) disease were obtained from a previous study in children under 2 years (24), while the disability weight for asthma was retrieved from the Tufts Medical Center database (29) (Table 2).

Varicella zoster

The classic symptom of varicella infection is a rash throughout the body, which can lead to more severe complications, such as meningitis, that require hospitalization and can be fatal (30). In Spain, vaccination against varicella in children was firstly introduced in 2006 (7).

The outcome tree for this infection comprised two health states: complicated and uncomplicated (Fig. 1B). To describe the outcomes of complicated infection we used hospitalization data from MBDS (22) and extracted the disability weight of varicella from the Matthews et al. analysis (31) (Table 2). Uncomplicated disease was assumed to last 14 days, following the study from Patil et al. (32), with a disability comparable to uncomplicated measles (Table 2). However, based on expert opinion, no burden of the uncomplicated disease was considered for children under 15 years, given the increasing rates of varicella vaccination in Spain and subsequent reduction in hospital burden according to MBDS data (22).

Herpes zoster

Herpes zoster appears upon reactivation of varicella zoster, which might remain in latency after a primary infection (33, 34).

Two health conditions were included in the outcome tree for herpes zoster: complicated and uncomplicated infection (Fig. 1C). Similar to RSV and varicella, complicated herpes zoster outcomes were extracted from the MBDS database (22). Post-herpetic neuralgia, characterized by intense pain, was considered the main long-term sequela of this disease (32, 33). A proportion of 10% of herpes zoster patients were assumed to progress to post-herpetic neuralgia (31), with a mean duration of 9 months (35) (Table 2). The disability weight for this health condition was obtained from a study from Kwong et al. (36) (Table 2). Based on the duration of symptoms and expert’s opinion, a 28-day duration of uncomplicated disease was assumed (37). The disability weight for the uncomplicated state was assumed as the value for uncomplicated measles from the BCoDE model, since skin rash is the main clinical manifestation in both cases (37).

Rotavirus

Gastroenteritis is the primary symptom associated to rotavirus infection, which can worsen and ultimately require hospitalization (38). Vaccination against this virus was first recommended for newborns in Spain in 2019 (39).

Based on previous literature, the outcome tree for rotavirus was divided in two categories: complicated and uncomplicated infection (Fig. 1D). Again, complicated disease was modelled through hospitalization data from MDBS (22). In the absence of specific values for rotavirus, we assumed a clinical behaviour similar to mild and severe diarrhoea due to salmonellosis, for which disability values and duration were available in the BCoDE model (Table 2).

Uncertainty

Uncertainty intervals were used for those parameters with elevated uncertainty levels in the BCoDE toolkit, as described in Cassini et al. (8) (Supplementary Table 5). The ones used in the de novo models are depicted in Table 2. All the other inputs from the Spanish adaptation used point estimates. Intervals were incorporated in the models as uniform distributions (containing two values) or as Project Evaluation and Review Techniques (PERT; containing three values). Similar to Cassini et al. (8), we used the BCoDE toolkit to run the models at 10,000 iterations of the Monte Carlo simulations, without time discounting and age-weighting. All model outputs report the median and the 95% uncertainty intervals (UIs).

The selected infectious diseases accounted for an incidence and mortality of 8,549.71 and 10.44 cases per 100,000 population/year in Spain, respectively (Table 3). The total burden of disease amounted to 163.56 annual DALYs per 100,000 population. Respiratory infections represented around 90% of the total burden within the Spanish population. Influenza exhibited the highest burden, with 110.01 DALYs per 100,000 population/year, followed by invasive pneumococcal disease and RSV, with 25.20 and 10.57 DALYs per 100,000 population/year, respectively (Table 3, Fig. 2). Interestingly, the burden of influenza at the individual level is relatively low (0.01 DALYs per case) compared to other infections, which highlights the high incidence of this disease. Herpes zoster, invasive meningococcal disease, invasive Haemophilus influenza infection and HBV infection fall behind in the ranking with a burden lower than 10 annual DALYs per 100,000 population each. Nonetheless, invasive meningococcal disease exhibits the highest individual burden by far (4.5 DALYs per case) due to the severity of this infection. The rest of infections had a limited burden, with less than 1 annual DALY per 100,000 population, being measles and mumps the least burdensome at population level.

Table 3

Ranking of selected infectious diseases according to their burden measured as annual DALYs per 100,000 population.
Infectious disease	Incidence per 100,000	Mortality per 100,000	DALYs per case	YLD per 100,000 UI 95%	YLL per 100,000 UI 95%	DALYs per 100,000 UI 95%	% of total DALYs
Influenza	7,918.41	7.92	0.01	7.33 (6.43–8.27)	102.66 (102.66-102.66)	110.01 (109.09-110.94)	67.26
Invasive pneumococcal disease	9.51	1.03	2.65	2.15 (1.96–2.36)	23.04 (23.04–23.04)	25.20 (25.00-25.40)	15.41
RSV	324.32	0.58	0.03	1.2 (1.2–1.2)	9.37 (9.37–9.37)	10.57 (10.57–10.57)	6.46
Herpes zoster	138.64	0.66	0.06	1.23 (1.21–1.24)	7.75 (7.75–7.75)	8.97 (8.96–8.99)	5.48
Invasive meningococcal disease	0.76	0.08	4.50	0.35 (0.31–0.39)	3.06 (3.06–3.06)	3.40 (3.37–3.44)	2.08
Invasive Haemophilus influenzae infection	0.76	0.09	3.23	0.14 (0.12–0.15)	2.32 (2.32–2.32)	2.46 (2.45–2.47)	1.50
HBV infection	0.84	0.02	1.25	0.08 (0.12–0.15)	0.97 (0.69–1.28)	1.05 (0.02–0.02)	0.65
Rotavirus	9.83	0.02	0.09	0.02 (0.02–0.02)	0.90 (0.90–0.90)	0.92 (0.68–1.34)	0.56
Varicella zoster	123.30	0.03	0.00493	0.03 (0.03–0.03)	0.58 (0.58–0.58)	0.61 (0.61–0.61)	0.37
HAV infection	3.69	0.00739	0.07	0.06 (0.05–0.08)	0.21 (0.18–0.24)	0.27 (0.24–0.31)	0.17
Mumps	19.24	0.00289	0.00359	0.05 (0.05–0.05)	0.02 (0.02–0.02)	0.07 (0.06–0.07)	0.04
Measles	0.41	0.00313	0.06	0.006 (0.005–0.007)	0.02 (0.02–0.02)	0.02 (0.02–0.02)	0.01
Total	8,549.71	10.44	n/a	12.65	150.90	163.55	100
HAV: hepatitis A virus; HBV: hepatitis B virus; n/a: not applicable; RSV: respiratory syncytial virus; UI: uncertainty intervals.

The burden of the selected infectious diseases mainly derived from YLL (mortality), which reached 92% of the total (Fig. 3). Morbidity showed a major impact in mumps, with YLD representing 76% of the total DALYs, although its burden was discreet in the Spanish population (0.07 DALYs per 100,000 population/year).

Influenza had the greatest incidence and mortality among the infections analyzed, which was in line with the large burden of the infection (Fig. 4). Similarly, RSV and herpes zoster classified as high incidence/high mortality infections. Invasive pneumococcal disease, while second in terms of total burden of disease, fell into the high mortality, but low incidence group. Varicella zoster has considerable incidence, but low mortality, translating in a minor disease burden (0.61 DALYS per 100,000 population/year; Table 3), although still higher than the rest of the low mortality diseases. The remaining infections showed discreet incidence and mortality numbers and, thus, a minor disease burden. Altogether, respiratory infections, especially influenza and RSV, which combine both high mortality and high incidence, arise as relevant infectious diseases within the Spanish population.

Burden of disease by age groups

Stratification of DALY estimates by age brought to light that there is substantial increase in disease burden among individuals of 60 years or older (55% of DALYs over the total population), with the highest overall burden identified for population over 85 years (Fig. 5). Children under 5 years also accounted for a significant proportion of DALYs (11% of DALYs over the total population) compared to other age groups. In general, the burden of disease calculated for the different age groups was mainly driven by premature mortality (Supplementary Fig. 1). Similar disease burden was found between male and female groups.

A deeper analysis of the individual burden in the elderly population (60 years or over) revealed that influenza remains as the infectious disease with the greatest burden, closely followed by invasive pneumococcal disease (Fig. 6A). In line with these results, respiratory infections had a large burden in children (Fig. 6B,C). In children under 5 years, influenza, RSV and invasive pneumococcal disease are the infections with the highest burden, whereas RSV takes first place for infants under 1 year, followed by influenza and invasive pneumococcal disease. In general, mumps and measles remain as low-burden infections across all these age groups. It is worth mentioning that herpes zoster appears in third place for older adults, exhibiting certain burden for this age group (6.82 DALYs per 100,000 population/year), whereas it has little impact in children, with an estimated burden under 0.01 annual DALYs per 100,000 population.

Previous studies have brought to attention the high burden of immunization-preventable diseases in Spain in terms of epidemiology and costs (40–45). Here, we provide an updated estimation of disease burden employing the BCoDE methodology, considering a holistic DALY approach.

Our analysis showed that, despite immunization efforts, the burden of disease for certain immunization-preventable infections remains high in Spain. Respiratory infections exhibit the highest burden, with 110.01, 25.20 and 10.57 annual DALYs per 100,000 population estimated for influenza, invasive pneumococcal disease and RSV, respectively. In general, disease burden derives from YLLs for most infections, in line with previously published results at a European level (8).

Influenza ranked highest across all the infections studied herein and had the greatest annual burden of disease in Europe, with 81.8 annual DALYs per 100,000 population, being primarily associated to mortality as well (76.3 YLLs vs 5.42 YLDs) (8). These data are further supported by BCoDE studies from individual European countries, such as Germany (46) and the Netherlands (47, 48), that identify influenza as a high-burden disease. Influenza stands as the infection with the highest burden in older adults (60 years or over), with 12.4 DALYs per 100,000/year for this sub-group population. This might be a consequence of a limited vaccination coverage rate (VCR), since the Spanish vaccination campaign only reached around 53.5% of adults over 64 years in 2019–2020, a percentage that has barely changed since 2010 (49, 50). Although high compared to other European countries, the Spanish coverage rates for influenza vaccination fall far from the EU goal of 75% (51, 52), which highlights the need to maximize immunization especially in adults over 60 years. While an increase in influenza VCR was observed post COVID-19 pandemic (22), Spanish experts propose several measures for continued improvement and steps are already being taken. Based on evidence on the improved efficacy in reducing the influenza viral load and severe complications, such as pneumonia and cardiorespiratory events, and consequent hospitalizations in the elderly (53–56), the Spanish Society of Geriatrics and Gerontology recommends universal vaccination to all adults ≥ 60 years of age with the high-dose (HD) influenza vaccine as first option, being the adjuvant alternative the second choice. It also advocates for progressively extending the benefits of vaccination to individuals over 50 years (57). And while the Spanish Ministry of Health recommends vaccination for individuals ≥ 65 years, some regions are already lowering the threshold to 60 years. DALY estimates for invasive pneumococcal disease and RSV follow that of influenza, uncovering these respiratory infections as a major healthcare problem in Spain. The burden of invasive pneumococcal disease increases with age, being significantly higher in older adults (60 years or over), in coherence with general observations in Europe (8). However, Spanish estimates for age groups between 60 and 85 years are inferior to those reported in the Netherlands (48), where invasive pneumococcal disease burden exceeds that of influenza for the overall population (47).

RSV is associated with a significant burden in children under 5 years, with 2.92 DALYs per 100,000 population/year, driven by high infectivity and incidence coupled to high mortality (58, 59), as indicated by a vast number of studies that highlight the burden of hospitalizations due to bronchiolitis and RSV in children in Spain (42, 44, 60–63). Moreover, findings from a recently published longitudinal study that followed 51,292 Spanish children < 5 years suggest that hospitalization data alone underestimate the RSV infections requiring medical care and describe a larger clinical and economic burden in both primary care and hospital setting (64, 65). Given the significant burden of RSV, especially in children under 1 year, the Spanish Association of Pediatrics recommends immunization of neonates and infants under 6 months at the beginning of their first RSV season (66). At the time of this study, the only efficient preventive strategy in Spain was the single-dose monoclonal antibody nirsevimab, approved to prevent RSV in neonates and infants during their first RSV season (26). The Spanish Ministry of Health has recently published the first national RSV immunization recommendations, with nirsevimab addressing high-risk children under 24 months as well as infants under 6 months (15). Immunization with this long-acting antibody reduces the risk of medically attended infections and hospitalizations in term and preterm neonates (67), highlighting the potential of this approach to reduce the burden of RSV in infants.

Our study revealed a great variability in the burden across the different infections evaluated, in agreement with a previous study in the EU/EEA countries (8), but also across distinct geographies. This may be linked to many factors, such as different moments of analysis or data availability, but also to the immunization strategies in place and their effectiveness, since Spain reports higher VCRs when compared to other countries in the EU. For instance, the burden of HBV infection is calculated at 1.06 DALYs per 100,000/year in Spain, compared to 10.57 as reported in a German study (46), or the European average of 7.86 (8). Also, measles incidence is estimated at 0.41 cases per 100,000, as opposed to the median of 7.46 calculated for Europe (8).

The major strength of this study is that it uses the BCoDE toolkit, which employs a thoroughly validated methodology already used in previous European studies (8, 46–48), allowing for consistent comparisons between infectious diseases and geographies. Another strength of this analysis is that it relies on the Spanish epidemiological surveillance system, considered of high quality since it integrates reports for respiratory infections from all regions in Spain, unlike other European countries (20, 68). In this work, annual case numbers were collected from reliable nationwide sentinel systems, bringing forward influenza, RSV, herpes zoster and varicella as the infectious diseases with the greatest incidence among the Spanish population. However, one of the limitations of surveillance data is that not all reported cases are tested for the virus in sentinel programs (8, 49). Furthermore, as unveiled by a study in the UK, routine surveillance systems fail to capture a large proportion of subclinical and clinical cases of influenza, since not all cases seek medical consultation (19). In this model we assumed that due to the severity of disease in the elderly and school attendance requirements, all children < 15 years and adults over 65 years would seek medical care. For the rest of age groups, we applied an underestimation factor that reflects the proportion of people with influenza-like symptoms (with and without fever) that attended a GP consultation in the Flu Watch cohort among the ones who tested positive in a PCR test (19). However, even when not considering underestimation, influenza would remain the most burdensome infectious disease in our model with a total of 31.45 annual DALYs/100,000 population.

In addition, our study covers most of the diseases encompassed in the Spanish vaccination calendar that are not labelled as eradicated, representing a reasonably accurate approach to infectious disease burden estimation in Spain (14). Compared to previously published BCoDE analysis, it also incorporates four infections (herpes zoster, rotavirus, RSV and varicella zoster) as de novo models.

Four de novo models were built for this study and the epidemiological profile defined for each new infection arises from the interpretation and integration of a series of data sources. While a thorough literature review and step by step validation process was performed for each of them, these publicly available data have their strengths and limitations. On the one hand, mortality rates were collected from the MBDS (22), which provided reliable and robust data in comparison to published literature. On the other hand, it is worth mentioning that these estimates correspond to in-hospital fatality across the reported cases for a particular infection, whether the infectious agent was the ultimate cause of death or not. Thus, mortality probabilities might be over or underestimated. This was minimized by including mean mortality rates associated to main and secondary diagnosis hospitalizations, an approach used in previously published studies assessing mortality estimates in Spain (42, 44, 62, 69). Besides, probabilities of developing complications and disability weights for the de novo models come from the limited information accessible in the literature, except for some cases where it was collected from healthcare databases (e.g., MBDS). Age-specific risk of developing certain sequelae is not usually available, so the impact of complications that worsen in older population could not be considered. As a conservative approach, long-term clinical conditions were simplified, and outcome trees were built considering only severe complications (asthma for RSV (27, 28) and postherpetic neuralgia for herpes zoster (31)), given that other sequelae account for a low burden in these infections.

In the absence of publicly available data to estimate the percentage of individuals that develop asthma as a consequence of RSV, we utilized the probability of recurrent wheeze employed in a previous pharmacoeconomic analysis, for which we conservatively used the disutility value associated to controlled asthma for 5 years (64, 65). Disability associated with partially controlled and uncontrolled asthma is higher, and if considered in the model, it would have increased the number of annual DALYs associated with RSV to 11.84/100,000 and 17.71/100,000, respectively.

Lastly, no national surveillance data was reported by RENAVE for RSV in a pre- or post-pandemic setting, at the time of our analysis. Therefore, primary care estimates were collected from the Catalonian surveillance system and further extrapolated to the entire country. To minimize incidence variations, a conservative strategy was followed, so that (1) uncomplicated cases were calculated assuming that all hospitalizations were previously reported in primary care, on the basis of the BARI study (64, 65); and (2) just those cases corresponding to RSV-specific ICD-10-CM codes were included, following a study by Heppe-Montero et al. (42).

Considering these data source limitations, together with the ones inherent to the modelling of disease process, the methodology, assumptions, data inputs and results of this analysis were validated by a group of experts in epidemiology and disease modelling, immunization, health economics and public health policy. Taken all into account, we consider that the estimated burden of infectious diseases presented herein is based on a robust and reproducible methodology and it is a fair reflection of the Spanish context, which can contribute to the evaluation of the impact of current vaccination strategies and future programs.

These estimates provide a basis to guide prevention strategies, prioritize interventions and make public health decision in the field of infectious diseases in Spain. It is noteworthy that in 2019, the Spanish public spending in vaccines for influenza prevention was lower than the one for invasive pneumococcal disease, HBV and meningococcal disease prevention vaccines (70), despite having the highest disease burden. Since then, the emergence of the COVID-19 pandemic, and the subsequent in-hospital burden generated, potentially influenced priority setting. By 2022, the public spending investment in prevention increased by 36.5% and preventing influenza became top priority together with invasive pneumococcal disease (70), highlighting the importance of prioritizing and increasing investment in public health measures aimed to reduce the burden of those diseases with a major impact on population health and healthcare resources.

The results of this analysis highlight a persisting high burden of disease due to respiratory infections, despite the availability of some effective vaccines and immunization recommendations in the NIP (e.g., influenza, invasive pneumococcal disease), and point towards the necessity of increasing VCRs.

In addition to boost vaccination and tightly monitor infection in high incidence diseases, inclusion of novel and more effective immunization strategies, such as HD influenza vaccines for routine vaccination in the elderly or the recently approved long-acting antibody for RSV prevention in children, could further reduce this burden (54, 67, 71). At the same time, it is crucial to maintain VCR of low burden diseases over time to avoid outbreaks and keep these diseases under control.

BCoDE: Burden of Communicable Diseases in Europe

DALY: Disability-adjusted life year

EU: European Union

HAV: Hepatitis A virus

HBV: Hepatitis B virus

HD: High-dose

MDBS: Minimum Basic Data Set

NIP: National immunization program

RENAVE: Spanish Network of Epidemiological Surveillance

RSV: Respiratory syncytial virus

SIVIC: Catalonian Surveillance Systema for Infections

VCR: Vaccination coverage rates

WHO: World Health Organization

YLL: Years of life lost due to premature mortality

YLD: Years of life lived with disability

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Availability of data and materials: The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: AD and JLLB are employees of Sanofi and may hold shares and/or stock options in the company. SLH and CC are consultants of Axentiva Solutions, which received consultancy fees from Sanofi, Spain and, during the conduct of this study, from other pharmaceutical companies in unrelated projects. JMF reports having received a consulting fee from Axentiva Solutions for collaboration in this study and, during the conduct of this study, from other Sanofi funded projects related to RSV. AP reports having received funding from Sanofi for collaboration in this study and, during the conduct of this study, from other pharmaceutical companies in unrelated projects.

Funding: This work was funded by Sanofi, Spain

Authors’ contributions: AP and JMF participated in the review and interpretation of the model methodology, inputs and results, as well as in the manuscript review process. JLLB participated in the project conceptualization. AD participated in the project administration, supervision and manuscript drafting. CC participated in the conceptualization of the study, methodology, analysis and manuscript drafting. SLH participated in the analysis and manuscript drafting. All authors reviewed the manuscript. All authors agree to be accountable for all aspects of the work and give their consent to publish this study.

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Competing interest reported. AD and JLLB are employees of Sanofi and may hold shares and/or stock options in the company. SLH and CC are consultants of Axentiva Solutions, which received consultancy fees from Sanofi, Spain and, during the conduct of this study, from other pharmaceutical companies in unrelated projects. JMF reports having received a consulting fee from Axentiva Solutions for collaboration in this study and, during the conduct of this study, from other Sanofi funded projects related to RSV. AP reports having received funding from Sanofi for collaboration in this study and, during the conduct of this study, from other pharmaceutical companies in unrelated projects.

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16 Nov, 2023

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Impact of immunization-preventable infectious diseases on population health using disability-adjusted life years (DALYs) in Spain

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

BACKGROUND

METHODS

Selection of infectious diseases

DALY estimates

Incidence and mortality

De novo models methodology

RSV

Uncertainty

RESULTS

Burden of disease by age groups

DISCUSSION

CONCLUSIONS

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1