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PLOS ONE logoLink to PLOS ONE
. 2023 Jan 25;18(1):e0280940. doi: 10.1371/journal.pone.0280940

Healthcare resource use and associated costs in a cohort of hospitalized COVID-19 patients in Spain: A retrospective analysis from the first to the third pandemic wave. EPICOV study

Georgina Drago 1,*, Francisco Javier Pérez-Sádaba 2, Susana Aceituno 2, Carla Gari 2, Juan Luis López-Belmonte 3
Editor: Martial L Ndeffo-Mbah4
PMCID: PMC9876243  PMID: 36696406

Abstract

Objectives

Describe healthcare resource use and costs per hospitalized coronavirus disease-2019 (COVID-19) patient during the three main outbreak waves.

Methods

A retrospective observational study. COVID-19 patient data were collected from a dataset from 17 hospitals in the HM Hospitals Group. Mean total costs per hospitalized patient and per day were estimated in each wave, as defined by the Spanish National Health System perspective. In addition, costs were estimated for both patients admitted and those not admitted to the intensive care unit (ICU) and were stratified by age groups.

Results

A total of 3756 COVID-19 patients were included: 2279 (60.7%) for the first, 740 (19.7%) for the second, and 737 (19.6%) for the and third wave. Most (around 90%) did not require ICU treatment. For those patients, mean ± SD cost per patient ranged from €10 196.1 ± €7237.2 (mean length of stay [LOS] ± SD: 9.7 ± 6.2 days) for the second wave to €9364.5 ± €6321.1 for the third wave (mean 9.0 ± 5.7 days). Mean costs were around €1000 per day for all the waves. For patients admitted to the ICU, cost per patient ranged from €81 332.5 ± €63 725.8 (mean 31.0 ± 26.3 days) for the second wave to €36 952.1 ± €24 809.2 (mean 15.7 ± 8.2 days) for the third wave. Mean costs per day were around €3000 for all the waves. When estimated by age, mean LOS and costs were greater in patients over 80 when not admitted to the ICU and for patients aged 60 to 79 when admitted to the ICU.

Conclusions

LOS was longer for patients admitted to the ICU (especially in the first two waves) and for older patients in our study cohort; these populations incurred the highest hospitalization costs.

Introduction

The coronavirus disease-2019 (COVID-19) pandemic caused by the respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has represented a great clinical burden. Approximately 10% of infected patients developed severe acute respiratory syndrome (SARS) and required hospitalization, with mortality rates reaching between 2% and 5% [1, 2]. Spain was one of the most seriously affected countries, especially during the first outbreak wave of the pandemic, starting in February 2020 and lasting until June 2020 (five months) and leading to a nationwide lockdown [3]. In this outbreak wave, the seroprevalence of SARS-CoV-2 was as high as 5.0% (95% CI 4.7–5.4) of the population and exceeded 10% in certain regions, such as Madrid [4]. In this scenario, it is hardly surprising that the pandemic exerted great pressure on the Spanish national healthcare system and on society [5, 6].

As the incidence of SARS-CoV-2 infection increased exponentially in March 2020 in Spain, the number of infected patients requiring hospitalization began to exceed hospital capacity in many public hospitals. This critical situation forced the Spanish authorities to take extraordinary measures to decongest public hospitals, such as relocating patients from the public to private healthcare facilities or creating temporary healthcare structures to absorb the surplus of patients [7, 8]. Subsequently, two more outbreak waves followed at the national level: the second occurred from summer (July 2020) until early December 2020 (five months) [9] and the third started after the Christmas season in 2020 and lasted until the vaccination campaigns in February 2021 (two months) [10]. From then on, there was a rebound of infections in the spring of 2021, but the pressure on hospitals was much lower than during the previous waves [11].

Over this period of approximately one year (from March 2020 to February 2021), healthcare providers were forced to confront an unknown disease that often required hospitalization and complex management. These included ventilation support and the use of multiple treatments, usually without sufficient evidence of their effectiveness or safety [12]. However, the hospital management of COVID-19 patients evolved rapidly over the first months with continuous learning from clinical experience and the constant emergence of new clinical evidence [13].

In order to understand the impact on healthcare systems during the first year of the pandemic, it is essential to know how hospital expenses were allocated and how they changed during the different outbreak waves. Average healthcare hospital costs of COVID-19 are available in different settings [1419]; however, so far, none of these cost analyses have taken into account the evolving nature of the COVID-19 pandemic from its onset until the systematic vaccination campaigns in 2021. In the present study, we aimed to use real-world data to describe the use of healthcare resources and the associated costs in a cohort of hospitalized patients due to SARS-CoV-2 during three different outbreak waves from the perspective of Spain’s national health system (NHS).

Material and methods

Design

A retrospective, descriptive, observational study was carried out based on a dataset of patients with SARS-CoV-2 in Spain: “COVID Data Saves Lives” [20]. This dataset includes extensive anonymized information from hospitalized COVID-19 patients admitted to 17 tertiary hospitals belonging to the HM Hospitals Group (Spanish consortium of private hospitals) and amounting to over 1400 beds, located across four Autonomous regions in Spain: Autonomous Community of Madrid, Castilla and Leon, Catalonia, and Galicia [21]. Due to the pandemic situation, these hospitals stopped their scheduled private care activity to attend to emergency cases referred from public centers that could no longer admit patients. Patients were included for the analysis if they were admitted with confirmed SARS-CoV-2 infection by real-time reverse transcription-polymerase chain reaction (PCR) and followed-up between 31st January 2020 and 13th February 2021 in any of the HM Hospitals participating in the study. In addition, the reasons for patient admission and discharge must be available. The study period was divided into the three main waves of SARS-CoV-2 incidence in Spain, also known as outbreak waves. The data were grouped according to the RENAVE epidemiological surveillance system into three periods corresponding to the different waves as follows: first wave, from 31st January 2020 to 21st June 2020 [22, 23]; second wave, from 22nd June 2020 to 6th December 2020 [9, 23]; and third wave, from 7th December 2020 to 13th February 2021 [10, 23], as far as data in our database were available.

During the study period (31st January 2020 to 13th February 2021), anonymized data from 4475 COVID-19 patients were recorded in the “COVID Data Saves Lives” dataset [20]. All patients were admitted through the emergency department (ED). Dataset was extracted from the Electronic Health Record (EHR) system of the HM Hospitals. The information was organized in tables or datasets including information about the COVID-19 treatment process, complete information on admission and diagnoses treatments, ICU admissions, diagnostic imaging tests, laboratory results, drug administration, and cause of discharge/death. All datasets are linked by a unique admission identifier as a de-anonymization key, created for this purpose, and dissociated from each admission identifier. Among this population, 3756 patients met the study inclusion criteria: n = 2279 were admitted during the first wave, n = 740 during the second, and n = 737 during the third outbreak wave of SARS-CoV-2 (Fig 1).

Fig 1. Flow chart of the study cohort.

Fig 1

Abbreviations: COVID-19 (coronavirus disease-2019); ICU (intensive care unit).

The study protocol was approved by the Ethics Committees of the HM Hospitals Group. The collection of patients’ written informed consent was not required as patient data were anonymized and gathered retrospectively.

The present study is reported according to the Reporting of Observational Studies in Epidemiology (STROBE) checklist (S1 Table) [24].

Variables

The following patients’ demographic and clinical variables were extracted from the HM Hospitals Group’s “COVID Data Saves Lives” dataset [20]: age, gender, vital signs recorded at the ED (temperature, heart rate, blood pressure, oxygen saturation, and requirement for mechanical ventilation), primary diagnosis at the ED and at hospital admission, secondary diagnosis at hospital admission, and deaths during stay in hospital wards and intensive care units (ICU).

Diagnoses were identified by the 10th revision of the International Statistical Classification of Diseases and Related Health Problems codes (ICD-10) [25]. Primary diagnoses at admission corresponded with the COVID-19-diagnosis codes. Because the COVID-19-related ICD-10 (U07.1) took effect as of the second wave, non-specific codes were assigned to COVID-19 (i.e., other viral pneumonia [J12.89], or unspecified pneumonia [J18.9]) during the first wave. In contrast, secondary diagnoses at admission corresponded with either the symptoms or consequences of COVID-19 or the patient’s comorbidities. The following healthcare resources were retrieved from the HM Hospitals dataset: procedures at ED, hospital length of stay (LOS), laboratory tests during hospitalization (both in hospital wards and ICU), procedures during hospitalization (both in hospital wards and ICU) and pharmacological treatments during hospitalization in hospital wards (not available for ICU stays). Procedures were identified by the ICD-10 diagnosis and procedure codes [25] whereas the treatments were classified by the Anatomical Therapeutic Chemical-4 (ATC4) Classification system [26]. Laboratory tests were identified in a Spanish healthcare cost lists database [27].

Analysis

Descriptive statistics were used to summarize patients’ sociodemographic and clinical characteristics at the ED and hospital admission, in addition to healthcare resources used and in-hospital mortality. Absolute and relative frequencies were estimated for qualitative variables (gender [male; female], primary and secondary diagnoses, temperature [> 38°C; ≤ 38°C], oxygen saturation [< 95%, ≥ 95%], the requirement for mechanical ventilation [yes; no], laboratory tests, ED and hospital procedures, pharmacological treatments, or in-hospital mortality). At the same time, measures of central tendency and dispersion (mean, standard deviation [SD]) were used for quantitative variables (age, heart rate, blood pressure, hospital, and ICU length of stay, added to laboratory tests and procedures required per patient). To estimate the mean number of procedures and laboratory tests per hospitalized COVID-19 patient (either per patient who was admitted to the ICU, or per patient who was not admitted to the ICU), we added up the number of the resources registered for each patient during the study period. The mean number of procedures or laboratory tests per patient was then obtained by dividing individual patient numbers by the number of patients in each wave. To estimate the number of laboratory tests, we considered them on a disaggregated level (e.g., “red blood cell counts” rather than “blood count”).

The primary outcome of the analysis was the use of healthcare resources and its associated costs per hospitalized COVID-19 patient in the different outbreak waves. As the pharmacological treatment was not available during the ICU stays, we conducted the cost analysis in two separate groups of patients: patients who received care exclusively in the hospital ward and, therefore, had completed treatment data records; and patients who were admitted to the ICU at some point during the hospital stay.

To estimate the mean costs per hospitalized COVID-19 patient (either per patient who was admitted or per patient who was not admitted to the ICU), we calculated total healthcare costs for each patient by estimating the sum of the costs of each resource considered during hospitalization. This estimation was done by multiplying the frequency of use of each resource by its unitary costs in the different outbreak waves. Mean costs per patient were then obtained by the sum of individual patient costs divided by the number of patients in each wave. The costs per patient and day were also estimated. First, individual costs per hospitalized COVID-19 patient were divided by the days spent in hospital. Average cost per patient and day was then obtained from all the individual costs per day. For the main cost results, in order to show how the costs are distributed in our population, we also estimate the median cost.

The cost analysis was conducted from the perspective of the Spanish National Health System (NHS); thus, unit costs for procedures, laboratory tests, hospital, ICU stay, and treatments were derived from official local sources, reported in euros (€) and update to 2021. Specifically, unitary costs for procedures were based on the Diagnosis Related Groups (DRGs) costs for Spanish General Hospitals or from Autonomous Region’s tariffs when DGRs were not available [27], whereas pharmacological costs corresponded to the official selling price or PVL (Precio de Venta Libre) published in the BotPlus database [28]. Laboratory tests and hospital stay tariffs varied among the Autonomous Regions [27]; therefore, mean costs among different regions were estimated for each resource to obtain representative costs at a national level. In addition, to estimate laboratory test costs, we considered costs for aggregate tests (e.g., the cost of a blood count instead of the cost of the different components separately) since the total cost of aggregated tests was not deemed to significantly vary, regardless of the number of individual assessments they included.

Both mean costs per patient and cost per patient and day were stratified by the vaccination age bands in Spain: < 12, 12–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and > 80 years [29]. Additionally, costs per patient were also stratified by the different cost types: hospital stay, treatment, laboratory tests, and procedures.

To identify cost drivers of the covariates in the study population a Generalized Linear Model (GLM) with gamma distribution and log link with stepwise algorithm was used. The stepwise regression consists of iteratively adding and removing predictors, in the predictive model, in order to find the subset of variables in the data set resulting in the best performing model, that is a model that lowers prediction error. Outliers in the residuals of the selected model were removed using the interquartile range. In this process, total cost was selected as the dependent variable, and gender, age, wave, and length of stay were independent variables. The estimated coefficients were converted into cost ratios that can be interpreted as a ratio of adjusted costs between the category of interest versus the reference category for binary predictors or as the percentage increase in average cost per unit increase in a continuous covariate. A p-value of less than 0.05 was considered statistically significant. Two modelling runs were performed, one for ICU patients and one for non-ICU patients.

A deterministic sensitivity analysis was conducted to estimate the impact of selecting particular costs rather than others in the cost analysis results. For this analysis, only laboratory tests and hospital stay were considered as the costs as these resources varied among the different Autonomous Regions. For the base case, we applied the mean costs among the different tariffs available. Meanwhile, for the sensitivity analysis, we evaluated two different scenarios: one including the minimum individual costs for laboratory tests and hospital stay resources and the other with the respective maximum costs reported among the Autonomous Regions.

The data analysis was performed using the STATA version 14 statistical software package.

Results

Cohort description

A total of 3756 patients with confirmed COVID-19 diagnosis were admitted and discharged during the study period (Fig 2), of which 60.7% were admitted during the first wave, 19.7% during the second and 19.6% during the third outbreak wave. Of the hospitalized patients included in the study, around 10% required ICU admission at some point of the hospital stay (Table 1).

Fig 2. Inpatient pathway of the study cohort.

Fig 2

*Patients who were only admitted to the hospital ward.

Table 1. Summary of patients’ demographic and clinical parameters at hospital admission (grouped by outbreak waves).

Variables 1st Wave 2nd Wave 3rd Wave
Age (years), mean ± SD 67.9 ± 16.2 65.6 ± 16.8 65.4 ± 16.6
Gender (male), n/N (%) 1360/2279 (59.7) 465/740 (62.8) 449/737 (60.9)
Vital signs at the ED, n/N (%)
Temperature > 38°C, n/N (%) 1598/1732 (92.3) 595/631 (94.3) 607/628 (96.7)
Oxygen saturation < 95%, n/N (%) 945/1779 (53.1) 287/618 (46.4) 333/644 (51.7)
Requirement for mechanical ventilation, n/N (%)
    Oxygen saturation < 95% 608/945 (64.3) 171/287 (59.6) 201/333 (60.4)
    Oxygen saturation ≥ 95% 402/834 (48.2) 165/331 (49.8) 139/311 (44.7)
Heart rate (bpm), mean ± SD 89.8 ± 16.9 88.3 ± 16.3 89.1 ± 17.3
Systolic blood pressure (mmHg), mean ± SD 131.3 ± 22.8 132.1 ± 20.6 134.1 ± 20.9
Diastolic blood pressure (mmHg), mean ± SD 74.7 ± 13.0 76.6 ± 12.3 77.7 ± 13.2
Diagnosis at the ED, n/N (%)
    Common cold 216/2200 (9.8) 5/691 (0.7) 5/707 (0.7)
    Cough 139/2200 (6.3) 14/691 (2.0) 12/707 (1.7)
    General discomfort 73/2200 (3.3) 20/691 (2.9) 11/707 (1.6)
    Fever 274/2200 (12.5) 64/691 (9.3) 26/707 (3.7)
    Shortness of breath 1268/2200 (57.6) 91/691 (13.2) 114/707 (16.1)
    Suspicion of COVID 19 0/2200 (0) 395/691 (57.2) 437/707 (61.8)
    Another diagnosis 230/2200 (10.5) 102/691 (13.0) 102/707 (14.4)
Primary diagnosis at the hospital admission, n/N (%)
    Other viral pneumonia (J12.89) 1466/2279 (64.3) 0/740 (0) 0/737 (0)
    Pneumonia, unspecified organism (J18.9) 225/2279 (9.9) 2/740 (0.3) 2/737 (0.3)
    COVID 19 (U07.1) * 0/2279 (0) 684/740 (92.4) 703/737 (95.4)
    Another diagnosis 588/2279 (25.8) 54/740 (7.3) 32/737 (4.3)
Secondary diagnosis at hospital admission, n/N (%)
    Essential (primary) hypertension (I10) 809/2279 (35.5%) 251/740 (33.9%) 260/737 (35.3%)
    Decompensated type 2 diabetes mellitus (E11.9) 249/2279 (10.9%) 72/740 (9.7%) 64/737 (8.7%)
Grouped secondary diagnosis at hospital admission, d/D (%)
    Diseases of the circulatory system (I00-I99) 2030/11912 (17.0) 605/3994 (15.1) 632/3730 (16.9)
    Certain infectious and parasitic diseases (A00-B99) 1866/11912 (15.7) 81/3994 (2.0) 40/3730 (1.1)
    Endocrine, nutritional, and metabolic diseases (E00-E89) 1761/11912 (14.8) 547/3994 (13.7) 562/3730 (15.1)
    Other coronaviruses as a cause of diseases classified under other headings (B97.29) 1736/11912 (14.6) 0/3994 (0) 0/3730 (0)
    Diseases of the respiratory system (J00-J99) 1459/11912 (12.2) 1133/3994 (28.4) 1142/3730 (30.6)
    Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified (R00-R99) 844/11912 (7.1) 232/3994 (5.8) 208/3730 (5.6)
    Diseases of the digestive system (K00-K94) 591/11912 (5.0) 241/3994 (6.0) 209/3730 (5.6)

Abbreviations: COVID-19 (coronavirus disease-2019); d/D where d is the number of secondary diagnoses identified with that code, and D is the number of total secondary diagnoses for our study population; ED (emergency department); SD (standard deviation); *the implementation of the new code for COVID-19 (U07.1) took place in July 2020.

The mean ± SD age of COVID-19 hospitalized patients was 67.9 ± 16.2 years in the first wave, 65.6 ± 16.8 years in the second, and 65.4 ± 16.6 in the third wave, with the population ≥60 accounting for more than two-thirds of the total, and that over 80 ranging from 20.9% in the third wave to 26.3% in the first wave (S1 Fig). Regarding the gender, the proportion of men was approximately 60% in all three waves. At the ED, most patients presented fever (temperature > 38°C), and around half had an oxygen saturation < 95% across the different outbreak waves. The requirement for mechanical ventilation was particularly higher in those patients with oxygen saturation < 95%. Patients were mainly identified at ED admission by shortness of breath (57.6%) during the first wave, whereas they were mostly classified by suspicion of COVID-19 during the second (57.2%) and the third (61.8%) waves. At hospital admission, patients in the first wave were mainly diagnosed with viral pneumonia (64.3%) since the specific code for COVID-19 was not yet available, whereas patients in the second (92.4%) and third (95.4%) waves were confirmed with COVID-19 diagnosis. Of the grouped secondary diagnosis identified at hospital admission, the most prevalent were circulatory system diseases, endocrine, nutritional and metabolic diseases, with essential hypertension and decompensated type 2 diabetes being particularly prevalent (Table 1). The number of secondary diagnoses increased with age (S2 Table).

Use of healthcare resources and costs

The mean ± SD LOS for the whole population was 11.2 ± 10.4 days for the first wave, 12.0 ± 12.3 days for the second, and 9.6 ± 6.3 days for the third, representing a decrease of approximately two days between the first two and the third wave.

Regarding the use of procedures, the percentage of COVID-19 patients who had undergone at least one ED procedure was higher during the first (75.8%; n/N = 1667/2198) and second (74.1%; n/N = 488/659) waves than during the third (27.0%; n/N = 180/667). However, each patient received a similar mean ± SD number of procedures throughout the different outbreak waves (1.4 ± 0.6 for the first, 1.2 ± 0.5 for the second, and 1.2 ± 0.4 for the third wave). Likewise, all patients received at least one procedure during hospitalizations, and the mean ± SD number per patient was similar among the different outbreak waves (7.7 ± 3.5 for the first, 9.1 ± 3.5 for the second, and 8.8 ± 3.2 for the third wave) (S3 and S4 Tables describe the procedures followed during the ED and the hospital stay).

Concerning laboratory tests, the proportion of patients receiving at least one amounted to around 70% throughout the different waves, although the mean ± SD number of tests per patient was considerably higher for the first wave (129 ± 384) compared with the second (3.6 ± 10.3) and the third (3.8 ± 10.7) waves.

The pharmacological treatment, which was only recorded during the hospital ward stay, also differed between the first wave, where aminoquinolines (87.9%; n/N = 1814/2066) and antivirals for the human immunodeficiency virus (51.8%; n/N = 1070/2066) were generally administered, and the second and the third waves, where glucocorticoids were the most frequently prescribed treatment, administered to 89.9% (n/N = 588/661) of patients in the second and 91.4% (n/N = 606/667) in the third wave. In addition, during the three outbreak waves, other treatments like heparin, cephalosporins, or anilids were broadly administered to hospitalized patients (details of treatments for the different waves are presented in S5 Table).

Cost analysis for patients not admitted to the ICU (only treated in the general ward)

The mean ± SD LOS for patients who were not admitted to the ICU was similar among outbreak waves: 9.6 ± 6.6 days for the first, 9.7 ± 6.2 days for the second, and 9.0 ± 5.7 days for the third wave. The mean ± SD costs per hospitalized patient amounted to €9895.3 ± €7672.1 for the first wave, €10 196.1 ± €7237.2 for the second, and were slightly lower €9364.5 ± €6321.1 for the third wave. However, when estimated per day, results obtained among waves were comparable: €1050.0 ± €438.5 for the first, €1068.0 ± €342.6 for the second and €1088.6 ± €472.2 for the third wave. Among total costs per patient, hospital LOS incurred the highest cost percentage across outbreak waves and represented approximately 75% of costs, followed by hospital procedures, accounting for 15%, and pharmacological costs, representing around 7% to 9% of total hospital costs (See details in Table 2 for patients who were not admitted to the ICU).

Table 2. Mean and median costs per patient associated with COVID-19 hospitalization in the different outbreak waves stratified by thy type of healthcare costs.
Population Waves N (%) Type of healthcare costs
Hospital procedures Emergency procedures Laboratory test Pharmacological treatment Hospital LOS TOTAL COSTS PER PATIENT
Mean (median) costs (€) Percentage of total costs (%) Mean (median) costs (€) Percentage of total costs (%) Mean (median) costs (€) Percentage of total costs (%) Mean (median) costs (€) Percentage of total costs (%) Mean (median) costs (€) Percentage of total costs (%) Mean (median) costs (€)
Patients not admitted to the ICU 1st Wave 2066 (90.7%) 1441 (734) 14.6 63 (22) 0.6 241 (93) 2.4 602 (497) 6.1 7 547 (6 300) 76.3 9895 (7 715)
2nd Wave 661 (89.3%) 1472 (1014) 14.4 54 (22) 0.5 106 (93) 1.0 902 (224) 8.9 7 661 (6 300) 75.1 10 196 (8 529)
3rd Wave 667 (90.5%) 1477 (1046) 15.8 21 (0) 0.2 104 (93) 1.1 696 (1634) 7.4 7 066 (6 300) 75.5 9364 (7 920)
Patients admitted to the ICU 1st Wave 213 (9.3%) 28 400 (37 033) 36.5 53 (22) 0.1 1931 (302.6) 2.5 8 070 (4 370) 10.4 39 445 (27 366) 50.6 77 899 (67 343)
2nd Wave 79 (10.7%) 27 181 (22 848) 33.4 29 (22) 0.0 238 (186) 0.3 9 766 (4 834) 12.0 44 117 (31 277) 54.2 81 332 (63 170)
3rd Wave 70 (9.5%) 14 155 (5 215) 38.3 12 (0) 0.0 154 (139) 0.4 2 375 (1 803) 6.4 20 255 (18 085) 54.8 36 952 (27 930)

Abbreviations: ICU (intensive care unit); LOS (length of stay)

When total costs per patient were stratified by age groups, they showed a growing trend with older age: the highest costs were observed in patients over 80 (from €10 416.5 to €13 093.3 in the third and second waves, respectively), whereas the lowest corresponded to pediatric patients (from €2102.1 to €4350.0 in the second and third waves, respectively). In addition, mean LOS went from 2.3 to 4 days for pediatric patients (< 12 years) and 10.4 to 12.8 days in patients over 80 (Fig 3A. For patients who were not admitted to the ICU). As a result of the GLM model for non-ICU patients, it was found that age and length of stay significantly increased the total cost per patient by 0.06% (95% CI 0.007%-0.11%) and 11.57% (95% CI 11.32%-11.82%) per unit respectively.

Fig 3.

Fig 3

Mean costs and LOS per patient associated with COVID-19 hospitalization in the different outbreak waves stratified by the vaccination age bands for patients who were not (A) and who were (B) admitted to the ICU. Abbreviations: ICU (intensive care unit); LOS (length of stay). Costs are estimated as unadjusted means.

However, this trend was not maintained when estimating mean healthcare costs per patient and day, with a mean cost of approximately €1000 for all age groups and waves (Fig 4A. For patients who were not admitted to the ICU). S6 Table shows mean costs per patient and wave stratified by age and by type of healthcare costs for patients who were not admitted to the ICU.

Fig 4.

Fig 4

Mean costs per patient and day associated with COVID-19 hospitalization in the different outbreak waves stratified by the vaccination age bands for patients who were not (A) and who were (B) admitted to the ICU. Abbreviations: ICU (intensive care unit). Costs are estimated as unadjusted means.

Cost analysis for patients admitted to the ICU (treated in the ICU at some point of the inpatient hospital stay)

The mean ± SD LOS for patients who were admitted to the ICU was 26.7 ± 21.6 days for the first, 31.0 ± 26.3 days for the second, and 15.7 ± 8.2 days for the third wave. This represents a difference of approximately nine days between the first two waves and the third wave. Likewise, the mean ± SD cost per hospitalized patient amounted to €77 899,4 ± €63 004.8 and €81 332.5 ± €63 725.8 for the first and second waves, respectively, but decreased to €36 952.1 ± €24 809.2 for the third wave. However, the difference in cost between the first two waves and the third were not as remarkable when estimated per day, in which case they amounted to €3299.4 € ± €3263.6 and €3072.4 ± €2161.0 for the first and second waves, respectively, and €2972.4 ± €3117.9 for the third.

The hospital LOS incurred the largest percentage of costs across outbreak waves and represented around half of the total costs, followed by hospital procedures accounting for more than 30% of costs, and pharmacological costs accounting for 6% to 12% of total hospital costs (See details in Table 2 for patients who were admitted to the ICU). Likewise, mean healthcare costs per patient also increased with age. However, they reached their highest value in patients aged 60 to 79 (exceeding €100 000 per patient) but decreased by about two thirds for those over 80 (€35 928.9). Mean LOS followed the same pattern with a peak in the second wave for patients aged 60 to 79 (mean LOS over 35 days) and declined by 50% for patients over 80 years of age (mean of 16.1 days) (Fig 3B. For patients who were admitted to the ICU). GLM model showed that the third wave vs first wave, as well as sex (female vs male), had a significant impact on the total cost per patient decreasing it with respect to the baseline category by 19.58% (95% CI 5.74%-31.38%) and 12.97% (95% CI 0.47%-23.90%) respectively. On the other hand, in this group, the length of stay significantly increased the total cost per patient by 3.48% (95% CI 3.05%-3.90%) per unit.

When estimating the mean cost per patient and day, differences among age groups were reduced and varied across waves from €1691 to €4013 for patients over 40 (Fig 4B. For patients admitted to the ICU). S7 Table shows mean costs per patient and wave stratified by the age and by the type of healthcare costs for patients who were admitted to the ICU.

Sensitivity analysis with two alternative scenarios

Results from the sensitivity analysis were consistent across the populations evaluated, outbreak waves and age groups: the analysis with the scenario including the minimum individual costs from laboratory tests and hospital stay resulted in lower mean costs; whereas the scenario with the maximum costs generated higher mean costs across all the subgroups evaluated. (See the details of sensitivity results in S1 Text and S8 Table).

Discussion

We have described the use of healthcare resources and costs in a cohort of hospitalized COVID-19 patients in Spain and reported trends across the different outbreak waves during the first year of the pandemic. We retrieved the data from the HM Hospitals consortium’s centralized database: “COVID Data Saves Lives”. This database registered data on the COVID-19 patients who were attended in any of these private hospitals across different Spanish regions during the main peaks of infection in Spain: from February 2020 until the mass vaccination campaigns at the beginning of 2021 [20].

Most patients in our study received care exclusively in the hospital ward (about 90%); for this population, the resulting costs per patient were similar across outbreak waves (from a mean ± SD of €9364.5 ± €6321.1 in the third wave to €10 196.1 ± €7237.2 in the second). In addition, our mean values were within those obtained in other countries: €1877.5 to €14 232.8 per hospitalized patient [1418] but lower than that reported for a Spanish cohort by Carrera-Hueso et al. [19] including patients who were not admitted to the ICU (€50 132). In the aforementioned study, higher costs were attributed to a longer mean LOS than that observed in our study (mean of 44.1 days vs 9 days in our study). Additionally, unlike ours, their analysis included other direct medical costs such as medical visits and nursing hours, which may also have contributed to the higher per-patient costs.

In our study, patients who required intensive care at some point of their hospital stay represented around 10% of our study population. As expected, they incurred considerably higher costs than those who were not admitted to the ICU—costs per hospitalized patient were up to eight-fold higher in this population. Furthermore, the increase in costs was linked to a considerably longer LOS, up to three times longer than for patients not admitted to the ICU. In agreement with our findings, prior research found a considerable difference between the group of patients requiring ICU admission and those that did not require intensive care. In this respect, the average costs were between 4 [19, 30] and 6 times [16] higher in patients requiring ICU admission than in those who did not. Another noteworthy point regarding patients requiring intensive care was that their mean LOS, and consequently mean costs, decreased by approximately half in the third wave. This decline in LOS in the third wave might be due to various factors. On the one hand, the improvement in the management of critical patients during the first months of the pandemic led to faster patient recovery. And, on the other hand, the introduction of rapid antigen diagnostic tests in the third wave, which allowed early detection and treatment of critical COVID-19 patients [31] and, therefore, contributed to an earlier discharge from hospital.

We should also point out that mean costs per patient and per day in our study cohort did not differ substantially between the outbreak waves and were similar to those obtained in another analysis conducted at a private hospital in Spain, where mean costs per patient and per day were €875.6 for general ward stay, and €2486.2 for ICU stay [32].

However, although the costs were similar among the waves in our study, the use of some hospital resources changed dramatically; for example, the percentage of patients who underwent an ED procedure decreased by approximately 64% in the third wave compared to the first and second waves (from 75.8% in the first, 74.1% in the second to 27.0% in the third wave). Also, the mean number of laboratory tests per patient declined greatly after the first wave (from a mean of 129 tests per patient in the first to 3.6 in the second and 3.8 in the third wave). This substantial decrease in certain procedures might also be attributed to the continuous learning process during the first months of the pandemic and the rapid adoption of clinical guidelines for COVID-19 patient management [3335]. The fact that the total costs per patient were not affected by this decrease might be because laboratory tests only represented a small percentage of the total healthcare costs in our study (i.e., 2.4% for patients not admitted to the ICU and 2.5% for those admitted to the ICU in the first wave), with hospital admission representing the largest share of the costs.

In addition, the treatments administered to patients differed drastically between the first wave and the other two. In this respect, during the first wave, most patients in our sample were treated with aminoquinolines and antivirals, whereas in the second and third waves, patients were treated mainly with corticosteroids. This shift in treatment type in favor of corticosteroids was also found in other studies in Spain [9, 10, 36, 37] and other settings [38] and might also reflect the rapid incorporation of clinical evidence generated during this short period [35].

Another interesting observation was that mean costs per COVID-19 patient and, especially, the LOS increased with age in our study cohort. Mean LOS increased approximately four-fold for the population over 80 compared to pediatric patients (< 12 years) (from a mean of 2.3 to 4.0 days per patient < 12 years to a mean of 10.4 to 12.8 days for patients >80). The relationship between age and hospital costs has been observed in previous studies, reporting older age as one of the major drivers of costs and hospital LOS [14, 30]. The results of the regression model confirm that length of stay is one of the main factors influencing cost in both ICU and non-ICU populations of our study sample. In the non-ICU population, age was also an important driver. The fact that older patients incurred higher costs and LOS than younger ones can be explained, as older patients are more likely to suffer certain comorbidities such as hypertension, diabetes, or cardiovascular diseases, which increase the risk of severe disease [39]. This relationship between older patients with comorbidities was also observed in our study, where the number of secondary diagnoses, such as circulatory systemic or endocrine diseases, increased with the patient’s age. Furthermore, older patients suffer from declining immunity, making them more vulnerable to developing severe or critical COVID-19 [40]. Both comorbidities and diminished immunity increase the need for admission to intensive care and longer LOS, thus considerably raising healthcare costs [14, 30].

Nonetheless, the fact that older patients might be more prone to developing severe or critical COVID-19 does not always involve higher hospital costs. In fact, among the patients admitted to the ICU in our study, patients over 80 incurred lower mean costs and LOS per patient than the 50- to 79-year-old age groups. A cost analysis by Tsai et al. [15] observed that, although patients aged 75 or older were more likely to be hospitalized, their hospitalizations involved lower costs than younger patients. The authors hypothesized that lower costs in older patients might be attributed to worse prognosis and higher mortality rates, resulting in shorter inpatient stays.

Limitations

Our cost analysis has some limitations that should be mentioned. First, the data were extracted from the HM Hospitals database, which agglutinated data from a consortium of private hospitals in Spain. Furthermore, this sample of hospitals represented 2.2% of Spanish hospitals [41]. In that respect, the study population might not accurately represent the population attended in the Spanish healthcare system. Nonetheless, we consider that our results could be reasonably representative of the Spanish healthcare system at the population and cost-analysis level. At the population level, unlike other studies that represented only one area or autonomous region [9, 10, 19, 42], our database included data from COVID-19 patients in 17 hospital catchment areas across four regions in Spain (Autonomous Community of Madrid, Castilla and Leon, Catalonia, and Galicia), covering an extensive and diverse demographic population. In addition to the extensive geographic area, HM Hospitals put their facilities at the public administration’s disposal and absorbed COVID-19 patients from public hospitals during the outbreaks, treating more than 40,000 COVID-19 patients during 2020 [43, 44]. We believe that the main differences between the public and private hospitals prior to the pandemic may be precisely in the length of stay, however, the average length of stay is highly dependent on the pathology [45], which management was equally unknown in both settings. It is important to note that previous studies carried out in Spain in public hospitals during the first wave showed the average length of stay figures similar to those described in our study [46, 47]. At a cost-analysis level, the unitary costs corresponding to procedures, laboratory tests or hospital stays were obtained from official sources at a national level or from the different regions. Therefore, we suggest that the costs obtained are an approximation of the actual costs of the Spanish public healthcare system.

Secondly, data on the pharmacological treatments used were not available for the ICU stays; consequently, costs for patients admitted to the ICU at some point of their stay might be underestimated. Additionally, as we recorded pharmaceutical prices from official sources (selling price), we might have ignored the actual subsidized prices applied in public hospitals. Thirdly, all the treatments and procedures during hospitalization were recorded regardless of whether they were aimed at treating COVID-19 or not. Similarly, secondary diagnoses were recorded regardless of whether they were comorbidities or symptoms and consequences of COVID-19 itself. As a result, costs could have been overestimated for older patients or patients with various comorbidities or more symptoms due to COVID-19. However, we believe our results reflect the real impact of this disease, which affects older patients with different comorbidities the most. For this reason, we deemed it appropriate to consider all costs together, as they better reflect patients’ health status and care needs. Finally, only healthcare costs related to hospital admission and the use of medical resources were considered in the cost analysis, whereas other costs such as those related to healthcare workers were not considered, thus we could have underestimated the total costs. We also acknowledge that the non-inclusion of other costs, such as those related to the loss of productivity might also underestimate the costs in working-age patients, especially those aged between 40 and 60, who account for about one-fourth of the population (from 23.6% to 28.2%).

Conclusions

This study describes the use of healthcare resources and costs in a cohort of hospitalized COVID-19 patients over the course of the first year of the pandemic. Accordingly, our main observation is that mean costs per hospitalization COVID-19 patient did not consistently differ across the three main outbreak waves in our sample, especially for those patients who were not admitted to the ICU. However, longer LOS in patients admitted to the ICU (especially in the first two waves) and in older patients were the most important drivers of hospitalization costs. Also, the use of resources changed across outbreak waves, with a decrease in hospital procedures and laboratory tests, and an increase in the use of corticosteroids, reflecting the rapid incorporation of clinical evidence into routines during this short period.

In summary, our cost analysis provides robust data that could be useful to inform decision-makers about how health systems were impacted across the different outbreak waves in the first year of the COVID-19 pandemic.

Supporting information

S1 Fig. Distribution of patients according to vaccination age bands in the different outbreak waves.

(TIF)

S1 Table. STROBE checklist.

(DOC)

S2 Table. Distribution of number of secondary diagnoses according to age vaccinations.

(DOC)

S3 Table. Distribution of procedures during ED stay in the different outbreak waves.

All patients.

(DOC)

S4 Table. Distribution of procedures during hospital stay in the different outbreak waves.

All patients.

(DOC)

S5 Table. Proportion of patients receiving different pharmacological treatments in the different outbreak waves.

Recorded only during the hospital ward stay.

(DOC)

S6 Table. Mean costs per patient associated with COVID-19 hospitalization in the different outbreak waves stratified by the vaccination age bands and by the type of healthcare costs.

Patients who were not admitted to the ICU.

(DOC)

S7 Table. Mean costs per patient associated with COVID-19 hospitalization in the different outbreak waves stratified by the vaccination age bands and by the type of healthcare costs.

Patients admitted to the ICU.

(DOC)

S8 Table. Results from the sensitivity analysis: Mean costs per patient associated with COVID-19 hospitalization in the base case and in the alternative scenarios (minimum costs and maximum costs) in the different outbreak waves.

(DOC)

S1 Text. Detailed results from the sensitivity analysis.

(DOC)

Acknowledgments

The authors want to thank Lucía Pérez-Carbonell at Outcomes’10 (Castellón, Spain) for their assistance with medical writing.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was funded by Sanofi. G.D. and J.L.L-B are Sanofi employees, and they played a role in the study design and manuscript preparation. Outcomes’10 was funded by Sanofi to support the study design, analysis, and manuscript preparation.

References

Decision Letter 0

Martial L Ndeffo-Mbah

18 Jul 2022

PONE-D-22-09612Healthcare resource use and associated costs of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.PLOS ONE

Dear Dr. Drago,

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Martial L Ndeffo Mbah, Ph.D

Academic Editor

PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Partly

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Reviewer #1: No

Reviewer #2: No

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Reviewer #1: No

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the opportunity to review this manuscript on healthcare utilization and cost of COVID-19. While the information on cost of COVID-19 care is important, I believe it is important that it includes adjusted measures of association, in order to answer the questions asked in the paper.

Page 5, line 97: Please give some insight into how representative these hospitals are of the whole Spain population. What % of total hospitals do they amount to? Are patient or hospital characteristics different? For example, are private hospitals characterized by better standards of care, compared to public ones? It is important in understanding who is represented in this study.

Page 5, line 107: Suggest making this sentence more concise and list the specific date ranges here right away, supported by citations. It does not seem that holiday information (eg Christmas) adds much important information to this.

Page 6, line 114: Please provide more information on how the anonymized data were collected. What was the response rate? Are all patients with COVID-19 in these hospitals included?

Page 7, line 134: Were patients exclusively admitted through the ED? If so please specify in the text.

Page 7: Was information available on underlying medical conditions?

Page 8: Were any statistical models used? It seems that GLM models with Gamma distribution accounting for specific patient and/or hospital characteristics are needed to compare the costs by these characteristics. All models should be adjusted for age, sex, race/ethnicity, underlying medical conditions (if available) With unadjusted measures of association, it is hard to say whether some of these subpopulations or waves are actually different or whether the difference is driven by other characteristics. For example, the statement in the Conclusions section states that age and ICU admission were the most important drivers of the cost; but it is not possible to assess that without adjusting for all these factors in one model.

Page 8: Means in this skewed distribution are very much affected by the tail length and outliers; suggest using median costs, in addition to mean costs.

Page 18: The “increase” of LOS and costs with age represents unadjusted means (is that correct?). Suggest using GLM models with age group as the covariate of interest (adjusted for other important controls) to estimate whether this difference was indeed meaningful and significant.

Methods: Suggest plotting the cost distribution for full sample and/or certain subsets – so that we can understand the skewness and min/max costs.

Methods: Please consider a supplemental analysis that would censor the costs above 99th percentile. It is possible that means may not be so different after removing those super-utilizers with extremely high costs.

Methods and Results: While mean costs are interesting, it would also be interesting to understand the specific contributions of all patient characteristics to cost in terms of percent. For example, as age increases, what is the increase in costs in percent? This gives us some understanding of the magnitude of this difference (2% or 50%), rather than just dollar terms.

Figures: Please add footnotes describing what is shown in each figure (whether these are adjusted or unadjusted cost means). Each figure must stand alone and be interpretable without looking at the Methods.

Reviewer #2: Major issues:

(1) There is already a paper which present costs related to cost of COVID cases. The authors cited it https://healtheconomicsreview.biomedcentral.com/articles/10.1186/s13561-021-00340-0

Then what is the added value of the current paper?

(2) In my view it is not ok to mix cost and mortality. Your paper deals mainly with cost and there are a lot of information that you can present about costs. I recommend to make a different paper in mortality/survival, etc.

(3) The paper has rather a descriptive manner, rather a case-study. If the sample is random, I suggest to make an inference of COVID cost’s

(4) Related to (1),(3) . Probably is more important to see what combination of factors/covariates drive to higher costs? This can be an added value of the paper. In this sense, I suggest to use for example regression modelling.

(5) You present some results about sensitivity, but in the methods the sensitivity analysis is described too vague. It is DeterministicSA or ProbabilitySA, I guess is DSA.

(6) You deal with samples in each wave, why you do not test if the difference is statistically significant? Between waves and or between groups of patients.

(7) We know that LOS and age are determinants for higher costs, but it is something else a characteristic of COVID hospitalized cases? If you want to add a value to your study, why not a comparison with severe classic Pneumonia cases? If the cost are not significantly higher, than….

(8) In the sense of (7) I suggest to search for a combination of factors such as , age-group+ group of comorbidities.

(9) Can we see a distribution of patients by cost? I believe is a long tail distribution, then the mean cost may be not relevant….Eg. you sum 3patients*2000 +1patients *10000 and you have a mean of 4000. The range of cost is not enough relevant.

(10) Maybe a synthetic 8 figure/diagram is useful to understand the patient path-way. Eg diagnosed at family medicine-� covid ward-� ICU, or Non-diagnosed----emergency---ICU.

(11) For the hospital costs we have a DRG cost? Then, the structure of patients per hospital is the same in each wave? I think we have a hospital or regional effect cost when DRG is computed. Please clarify!

Minor issues

(1) Reference [27] has a broken link

(2) If you decide to keep mortality in the analysis then , in the methodology some description, formula or something else should appear about mortality. Then if then, maybe you should take into account

(3) I don’t know if it so important to use so many age-groups . The difference are small. Using so many age-groups you reduce sub-sample size. Why not children? (<18), Then 18-29, 30-49, 50-69, 70+, or something similar.

(4) Secondary diagnosis at hospital admission, n/N (%) please use other notation, Usually n= the sample size and N is the population size.

(5) Secondary diagnosis at hospital admission, n/N (%). I don’t understand the shares. In my view we should see how many COVID patients have an I10 or E11 as secondary diagnostic. Now I think it is a share of how many I10 are in the secondary diagnostics divided by patients*nr_of secondary diagnostics ?!. Please clarify!

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PLoS One. 2023 Jan 25;18(1):e0280940. doi: 10.1371/journal.pone.0280940.r002

Author response to Decision Letter 0


21 Oct 2022

Because the response to the reviewers includes tables and graphs, we have included it in one of the documents attached to the manuscript. See Response to reviewers_V.01_SAN

Attachment

Submitted filename: Response to reviewers_V.01_SAN.docx

Decision Letter 1

Martial L Ndeffo-Mbah

21 Nov 2022

PONE-D-22-09612R1Healthcare resource use and associated costs of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.PLOS ONE

Dear Dr. Drago,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jan 05 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

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  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Martial L Ndeffo Mbah, Ph.D

Academic Editor

PLOS ONE

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Reviewer #1: (No Response)

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #2: No

**********

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Reviewer #1: No

Reviewer #2: No

**********

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Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I appreciate the authors’ responses to my comments. While most of my comments and questions have been resolved, I have two that have not been fully resolved. My focus is especially on the adjusted measures of association; although authors have provided them, I feel that the table/figure needs to be included in the manuscript and explained in more detail as well.

R1, Comment 1: I feel that my comment about the representativeness was only partially addressed. Could the authors add in the text the total number of hospitals in Spain that were open during the pandemic, as well as the % that the 17 hospitals included in the study represent? I appreciate the added limitation, but quantifying the representativeness would be helpful here.

R1, Comment 6: I appreciate that the authors addressed my comment by using adjusted GLM models and providing adjusted measures of association in the text. I have some more comments on the modeling, however.

. More comments below:

- Estimates need to include confidence intervals.

- Why aren’t all estimates shown in the table in the authors’ responses? I see only age and LOS as predictors of cost among non-ICU patients and wave (but only third wave vs first wave), sex, and LOS as a predict among ICU patients. I would suggest that all coefficients are presented.

- Even more important than coefficients, predicted costs from the GLM models can be used in the place of unadjusted mean costs in the figures. Their 95% Cis can show whether the costs in the three waves were truly different.

- Are these estimates currently included in the main figures? If estimates are not included in the main results, I would suggest replacing one of the figures with the adjusted predicted costs (and 95% CI) in each wave. That can be easily done by using the “margins” Stata post-estimation command to get predicted costs. This would help us see if the costs were truly different by wave after controlling for other covariates.

- To estimate differences by wave for each characteristic (Figure 3A), authors may want to include both wave categorical variable and its interaction with those characteristics (eg wave (1,2,3), age (<12, 12-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80), and wave*age). They can then use the Stata “margins” post-estimation command to predict the cost in each wave and at each level of covariate included in the interaction.

Reviewer #2: I appreciate the work of authors but there are some issue which in my view do not match.

The major thing is that the title, the abstract and the conclusions suggest that achieved results characterize the cost/patient for entire population of COVID-19 patient in Spain. The sample selection and thus the methods and the results do not support this hypothesis. In my view there two options (1) if the authors try to extend the costs results for a typical ICU/non-ICU patient from Spain, then they need a representative sample; (2) if the authors cannot achieve a representative sample, I recommand to underline the fact, that this is work is just a case-study, and everywhere in the paper should be clearly specified that "in our/current sample"/ "in our/current case", the results are. The phrases which induce the extension of results should be avoided in my view. Indeed in the limitations paragraph the authors try to explain differences between the current sample and the population, but the arguments are not solid. My worries are related to the thing that costs may be overestimated in particular hospitals compared with anothers. There is no proof that error are compensating each-other.

**********

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Reviewer #2: No

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PLoS One. 2023 Jan 25;18(1):e0280940. doi: 10.1371/journal.pone.0280940.r004

Author response to Decision Letter 1


16 Dec 2022

Reviewer #1:

I appreciate the authors’ responses to my comments. While most of my comments and questions have been resolved, I have two that have not been fully resolved. My focus is especially on the adjusted measures of association; although authors have provided them, I feel that the table/figure needs to be included in the manuscript and explained in more detail as well.

Response to reviewer #1:

We appreciate very much the comments received towards our work. Find below the detailed responses to each of the proposed questions.

R1, Comment 1: I feel that my comment about the representativeness was only partially addressed. Could the authors add in the text the total number of hospitals in Spain that were open during the pandemic, as well as the % that the 17 hospitals included in the study represent? I appreciate the added limitation, but quantifying the representativeness would be helpful here.

We welcome suggestions in this regard. Even though the hospitals included are only a small sample of hospitals in the Spanish health system (2.2% of all Spanish hospitals, public and private), we suggest that the patients included in this study could represent the reality of the health system during the first waves of the pandemic. However, the reader could interpret this as inferential statistics, which is not our objective, but rather describe what happens in our study population. For this reason, we wanted to clarify and highlight at some points in the manuscript that our findings refer to the studied sample.

In this regard, we have introduced the following changes in different sections of the manuscript:

- Title of the manuscript to: “Healthcare resource use and associated costs in a cohort of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.”

- Conclusions section from the Abstract (line 39): “LOS was longer for patients admitted to the ICU (especially in the first two waves) and for older patients in our study cohort; these populations incurred the highest hospitalization costs.”

- Introduction section (lines 81-82): “In the present study, we aimed to use real-world data to describe the use of healthcare resources and the associated costs in a cohort of hospitalized patients due to SARS-CoV-2 during three different outbreak waves from the perspective of Spain's national health system (NHS).”

- Discussion section:

Lines 396-396: “We have described the use of healthcare resources and costs in a cohort of hospitalized COVID-19 patients in Spain”

Line 432: “We should also point out that mean costs per patient and per day in our study cohort did not differ substantially between the outbreak waves”

Lines 449-450: “In addition, the treatments administered to patients differed drastically between the first wave and the other two. In this respect, during the first wave, most patients in our sample were treated with aminoquinolines and antivirals”

Lines 458-459: “Another interesting observation was that mean costs per COVID-19 patient and, especially, the LOS increased with age in our study cohort.”

Line 464: “The results of the regression model confirm that length of stay is one of the main factors influencing cost in both ICU and non-ICU populations of our study sample.”

Lines 486-492: “Our cost analysis has some limitations that should be mentioned. First, the data were extracted from the HM Hospitals database, which agglutinated data from a consortium of private hospitals in Spain. Furthermore, this sample of hospitals represented 2.2% of Spanish hospitals (41). In that respect, the study population might not accurately represent the population attended in the Spanish healthcare system. Nonetheless, we consider that our results could be reasonably representative of the Spanish healthcare system at the population and cost-analysis level.”

A reference has been included to support the included text: Hospital statistics - National tables (2020). [Cited 7 December 2022]. In: Spanish Ministry of Health [Internet]. Available from: https://www.sanidad.gob.es/estadEstudios/estadisticas/docs/TablasSIAE2020/Tablas_Nacionales_2020.pdf

Regarding this point, we would like to point out that a sensitivity analysis was carried out taking into account a possible under- or overestimation of the cost.

Lines 506-508: “Therefore, we suggest that the costs obtained are an approximation of the actual costs of the Spanish public healthcare system.”

- Conclusions section:

Lines 530-534: “This study describes the use of healthcare resources and costs in a cohort of hospitalized COVID-19 patients over the course of the first year of the pandemic. Accordingly, our main observation is that mean costs per hospitalization COVID-19 patient did not consistently differ across the three main outbreak waves in our sample, especially for those patients who were not admitted to the ICU”

Lines 540-541: “In summary, our cost analysis provides robust data that could be useful to inform decision-makers about how health systems were impacted across the different outbreak waves in the first year of the COVID-19 pandemic.”

R1, Comment 6: I appreciate that the authors addressed my comment by using adjusted GLM models and providing adjusted measures of association in the text. I have some more comments on the modeling, however.

More comments below:

- Estimates need to include confidence intervals.

Thank the reviewer for this comment. We have added the confidence intervals in the manuscript in section Results, lines 333-334 and lines 378-380.

To facilitate the interpretation of the results obtained, they have been included in the form of percentages, so that the explanation of the coefficients obtained is more intuitive for the reader.

Variable Coef. (exponentiated form) Std. Error p-value IC 95%

Non ICU-patients

Age 1.000593 0.000265 0.025 1.000074 1.001113

Length of stay 1.115735 0.0012762 0.000 1.113236 1.118239

ICU patients

Third wave vs fisrt wave 0.8042193 0.0651603 0.007 0.6861319 0.9426303

Second wave vs fisrt wave 1.00022 0.0769607 0.998 0.8602026 1.163028

Sex (Female vs male) 0.8703277 0.0595943 0.043 0.7610236 0.995331

Length of stay 1.034786 0.0021719 0.000 1.030538 1.039051

- Why aren’t all estimates shown in the table in the authors’ responses? I see only age and LOS as predictors of cost among non-ICU patients and wave (but only third wave vs first wave), sex, and LOS as a predict among ICU patients. I would suggest that all coefficients are presented.

A stepwise GLM model was used to carry out the estimation; this type of modelling eliminates those factors that are not significant from the estimation. For predictors whose p-value is greater than 0.05, no coefficient is obtained.

In the case of ICU patients, only the third wave vs. the first wave was significant. However as a categorical variable, the coefficient for the second wave vs. the first wave was estimated too, as it should be included in the modelling.

We have added an additional more detailed explanation of Stepwise in the manuscript in section Analysis, lines 215-219:

“To identify cost drivers of the covariates in the study population a Generalized Linear Model (GLM) with gamma distribution and log link with stepwise algorithm was used. The stepwise regression consists of iteratively adding and removing predictors, in the predictive model, in order to find the subset of variables in the data set resulting in the best performing model, that is a model that lowers prediction error.”

- Even more important than coefficients, predicted costs from the GLM models can be used in the place of unadjusted mean costs in the figures. Their 95% Cis can show whether the costs in the three waves were truly different.

We are very grateful to the reviewer for this and the following two comments, we consider that including the GLM model in the publication has helped us to compare costs according to different population characteristics and has reinforced the conclusions that a priori were drawn from a purely descriptive analysis. However, modifying the mean costs obtained by post-estimation of these through the coefficients, we believe that it modifies the descriptive objective of the project and would imply completely restructuring the publication. The aim of this analysis is not to model the results and thus smooth out heterogeneity, but to evaluate and describe the results obtained directly by the patient, so we consider that presenting the median helped to present greater detail in this respect. Even though this estimation would be of real interest, it may require a refocusing of the project. This would not only include additional analyses but replace the analysis that we have carried out as the aim of the study. Moreover, including all this analysis would overextend and complicate the interpretation of the results.

- Are these estimates currently included in the main figures? If estimates are not included in the main results, I would suggest replacing one of the figures with the adjusted predicted costs (and 95% CI) in each wave. That can be easily done by using the “margins” Stata post-estimation command to get predicted costs. This would help us see if the costs were truly different by wave after controlling for other covariates.

- To estimate differences by wave for each characteristic (Figure 3A), authors may want to include both wave categorical variable and its interaction with those characteristics (eg wave (1,2,3), age (<12, 12-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80), and wave*age). They can then use the Stata “margins” post-estimation command to predict the cost in each wave and at each level of covariate included in the interaction.

Reviewer #2:

I appreciate the work of authors but there are some issue which in my view do not match.

The major thing is that the title, the abstract and the conclusions suggest that achieved results characterize the cost/patient for entire population of COVID-19 patient in Spain. The sample selection and thus the methods and the results do not support this hypothesis. In my view there two options (1) if the authors try to extend the costs results for a typical ICU/non-ICU patient from Spain, then they need a representative sample; (2) if the authors cannot achieve a representative sample, I recommand to underline the fact, that this is work is just a case-study, and everywhere in the paper should be clearly specified that "in our/current sample"/ "in our/current case", the results are. The phrases which induce the extension of results should be avoided in my view. Indeed in the limitations paragraph the authors try to explain differences between the current sample and the population, but the arguments are not solid. My worries are related to the thing that costs may be overestimated in particular hospitals compared with anothers. There is no proof that error are compensating each-other.

Response to reviewer #2:

Many thanks to the reviewer for his comments as we consider that they have improved the manuscript. The changes implemented in response to the concerns raised by the reviewer are included below.

We have introduced the following changes in different sections of the manuscript:

- Title of the manuscript to: “Healthcare resource use and associated costs in a cohort of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.”

- Conclusions section from the Abstract (line 39): “LOS was longer for patients admitted to the ICU (especially in the first two waves) and for older patients in our study cohort; these populations incurred the highest hospitalization costs.”

- Introduction section (lines 81-82): “In the present study, we aimed to use real-world data to describe the use of healthcare resources and the associated costs in a cohort of hospitalized patients due to SARS-CoV-2 during three different outbreak waves from the perspective of Spain's national health system (NHS).”

- Discussion section:

Lines 396-396: “We have described the use of healthcare resources and costs in a cohort of hospitalized COVID-19 patients in Spain”

Line 432: “We should also point out that mean costs per patient and per day in our study cohort did not differ substantially between the outbreak waves”

Lines 449-450: “In addition, the treatments administered to patients differed drastically between the first wave and the other two. In this respect, during the first wave, most patients in our sample were treated with aminoquinolines and antivirals”

Lines 458-459: “Another interesting observation was that mean costs per COVID-19 patient and, especially, the LOS increased with age in our study cohort.”

Lines 464: “The results of the regression model confirm that length of stay is one of the main factors influencing cost in both ICU and non-ICU populations of our study sample.”

Lines 486-492: “Our cost analysis has some limitations that should be mentioned. First, the data were extracted from the HM Hospitals database, which agglutinated data from a consortium of private hospitals in Spain. Furthermore, this sample of hospitals represented 2.2% of Spanish hospitals. In that respect, the study population might not accurately represent the population attended in the Spanish healthcare system. Nonetheless, we consider that our results could be reasonably representative of the Spanish healthcare system at the population and cost-analysis level…”

A reference has been included to support the included text: Hospital statistics - National tables (2020). [Cited 7 December 2022]. In: Spanish Ministry of Health [Internet]. Available from: https://www.sanidad.gob.es/estadEstudios/estadisticas/docs/TablasSIAE2020/Tablas_Nacionales_2020.pdf

Regarding this point, we would like to point out that a sensitivity analysis was carried out taking into account a possible under- or overestimation of the cost.

Lines 506-508: “Therefore, we suggest that the costs obtained are an approximation of the actual costs of the Spanish public healthcare system.”

- Conclusions section:

Lines 530-534: “This study describes the use of healthcare resources and costs in a cohort of hospitalized COVID-19 patients over the course of the first year of the pandemic. Accordingly, our main observation is that mean costs per hospitalization COVID-19 patient did not consistently differ across the three main outbreak waves in our sample, especially for those patients who were not admitted to the ICU”

Lines 540-541: “In summary, our cost analysis provides robust data that could be useful to inform decision-makers about how health systems were impacted across the different outbreak waves in the first year of the COVID-19 pandemic.”

Attachment

Submitted filename: Response to reviewers_2_V.02.docx

Decision Letter 2

Martial L Ndeffo-Mbah

12 Jan 2023

Healthcare resource use and associated costs in a cohort of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.

PONE-D-22-09612R2

Dear Dr. Drago,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Martial L Ndeffo Mbah, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: No

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: (No Response)

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Furthermore, this sample of hospitals represented 2.2% of

489 Spanish hospitals [41]. In that respect, the study population might not accurately represent

490 the population attended in the Spanish healthcare system. Nonetheless

Therefore, we suggest that

507 the costs obtained are an approximation of the actual costscosts were considered

508 representative of the Spanish public healthcare system.

If you assume that your patients sample might not accurately represent the entire population of patients, then in my view there are not enough suport information to conclude that estimated cost are a bad or a good representation of the real costs. I really appreciate your efforts but I cannot accept the conclusion without a strong evidence report.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

**********

Acceptance letter

Martial L Ndeffo-Mbah

16 Jan 2023

PONE-D-22-09612R2

Healthcare resource use and associated costs in a cohort of hospitalized COVID-19 patients in Spain: a retrospective analysis from the first to the third pandemic wave. EPICOV study.

Dear Dr. Drago:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Martial L Ndeffo-Mbah

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Distribution of patients according to vaccination age bands in the different outbreak waves.

    (TIF)

    S1 Table. STROBE checklist.

    (DOC)

    S2 Table. Distribution of number of secondary diagnoses according to age vaccinations.

    (DOC)

    S3 Table. Distribution of procedures during ED stay in the different outbreak waves.

    All patients.

    (DOC)

    S4 Table. Distribution of procedures during hospital stay in the different outbreak waves.

    All patients.

    (DOC)

    S5 Table. Proportion of patients receiving different pharmacological treatments in the different outbreak waves.

    Recorded only during the hospital ward stay.

    (DOC)

    S6 Table. Mean costs per patient associated with COVID-19 hospitalization in the different outbreak waves stratified by the vaccination age bands and by the type of healthcare costs.

    Patients who were not admitted to the ICU.

    (DOC)

    S7 Table. Mean costs per patient associated with COVID-19 hospitalization in the different outbreak waves stratified by the vaccination age bands and by the type of healthcare costs.

    Patients admitted to the ICU.

    (DOC)

    S8 Table. Results from the sensitivity analysis: Mean costs per patient associated with COVID-19 hospitalization in the base case and in the alternative scenarios (minimum costs and maximum costs) in the different outbreak waves.

    (DOC)

    S1 Text. Detailed results from the sensitivity analysis.

    (DOC)

    Attachment

    Submitted filename: Response to reviewers_V.01_SAN.docx

    Attachment

    Submitted filename: Response to reviewers_2_V.02.docx

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.


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