Clinical phenotypes and short-term outcomes based on prehospital point-of-care testing and on-scene vital signs.

Emergency medical services (EMSs) face critical situations that require patient risk classification based on analytical and vital signs. We aimed to establish clustering-derived phenotypes based on prehospital analytical and vital signs that allow risk stratification. This was a prospective, multicenter, EMS-delivered, ambulance-based cohort study considering six advanced life support units, 38 basic life support units, and four tertiary hospitals in Spain. Adults with unselected acute diseases managed by the EMS and evacuated with discharge priority to emergency departments were considered between January 1, 2020, and June 30, 2023. Prehospital point-of-care testing and on-scene vital signs were used for the unsupervised machine learning method (clustering) to determine the phenotypes. Then phenotypes were compared with the primary outcome (cumulative mortality (all-cause) at 2, 7, and 30 days). A total of 7909 patients were included. The median (IQR) age was 64 (51-80) years, 41% were women, and 26% were living in rural areas. Three clusters were identified: alpha 16.2% (1281 patients), beta 28.8% (2279), and gamma 55% (4349). The mortality rates for alpha, beta and gamma at 2 days were 18.6%, 4.1%, and 0.8%, respectively; at 7 days, were 24.7%, 6.2%, and 1.7%; and at 30 days, were 33%, 10.2%, and 3.2%, respectively. Based on standard vital signs and blood test biomarkers in the prehospital scenario, three clusters were identified: alpha (high-risk), beta and gamma (medium- and low-risk, respectively). This permits the EMS system to quickly identify patients who are potentially compromised and to proactively implement the necessary interventions.

Apnea-Specific Pulse-Rate Response is Associated With Early Subclinical Atherosclerosis in Obstructive Sleep Apnea.

INTRODUCTION: In patients with obstructive sleep apnea (OSA), novel metrics such as hypoxic burden (HB) and sleep apnea-specific pulse-rate response (ΔHR) may better correlate with cardiovascular diseases (CVD) than the apnea-hypopnea index (AHI). This manuscript aims to assess the correlation between ΔHR and HB with subclinical atherosclerosis in patients with OSA, testing the hypothesis that elevated ΔHR and HB are associated with subclinical atherosclerosis development. METHODS: In a prospective study, individuals aged 20-65 years with suspected OSA without known comorbidities were consecutively recruited and defined as OSA (AHI≥5events/h) or healthy controls. Using bilateral carotid ultrasonography, common carotid intima-media thickness (CIMT) was assessed and the identification of at least one atheromatous plaque defined the presence of subclinical atherosclerosis. ΔHR, and HB were derived from pulse-oximetry. RESULTS: We studied 296 patients of age 45±10 years old, of whom 28% were women, and with a BMI of 30.3±5.3kg/m2. Overall, 245 had OSA and 51 were healthy controls. After controlling for confounding variables higher ΔHR but not HB, was associated with higher CIMT (p=0.006) and higher time spent with oxygen saturation below 90% (T90) was associated with an increase in carotid atheroma plaques (p=0.032). When stratifying OSA based on HB tertiles, we observed that within tertile 2 of HB, an increase in ΔHR was associated with larger CIMT (p=0.017). CONCLUSION: A higher ΔHR is associated with an increase in CIMT among adult patients with OSA. This study suggests that ΔHR could be a biomarker of risk for CVD in patients with OSA.

Incidence and Determinants of COVID-19 Among People Who Smoke (2018-2021): Findings From the ITC EUREST-PLUS Spain Surveys.

OBJECTIVE: To estimate the cumulative incidence of COVID-19 and its determinants among a nationally representative sample of adults from Spain who smoke. METHODS: This is a prospective cohort study that uses data from two waves (Wave 2 in 2018 and Wave 3 in 2021) of the ITC EUREST-PLUS Spain Survey. At baseline (Wave 1 in 2016), all respondents were adults (aged ≥18) who smoked. In total, 1008 respondents participated in Wave 2, and 570 out of 888 eligible participants were followed up in Wave 3 (64.2%). We estimated the cumulative incidence and the relative risk of COVID-19 (RR) and 95% confidence intervals (CI) during follow-up using self-reported information on sociodemographic, smoking-related and health-related characteristics and identified associated factors using multivariable Poisson models with robust variance adjusted for the independent variables. RESULTS: The overall cumulative incidence of self-reported COVID-19 was 5.9% (95% CI: 3.9-8.0%), with no significant differences between males (6.3%; 95% CI: 3.6-9.0%) and females (5.6%; 95% CI: 3.2-8.0%). After adjusting for age, sex, and educational level, COVID-19 incidence was positively associated with moderate nicotine dependence (RR: 2.37; 95% CI: 1.04-5.40) and negatively associated with having a partner who smoked (RR: 0.12; 95% CI: 0.03-0.42), and having friends but not a partner who smoked (RR: 0.28; 95% CI: 0.14-0.56). CONCLUSION: The correlates of having had COVID-19 among people who smoke should be considered when tailoring information and targeted non-pharmacological preventive measures.

Sexual activity and respiratory disease: A systematic review.

CONTEXT: Sex and gender are related concepts, but they have distinct meanings and implications. Respiratory diseases are a major driver of morbi-mortality. It is frequent that respirologists, primary care doctors, or other specialists, when dealing with respiratory patients, and aiming for a holistic management of their patients, they all skip any question or matter associated with sexual activity or behavior. OBJECTIVES: To review how sexual activity is explored in respiratory patients. METHODS: To conduct this review, we endorse PRISMA guidance for reporting systematic reviews, and also the sex and gender equity in research (SAGER) guidelines. RESULTS: Compared to other conditions such as heart disease, mental disorders, Alzheimer's, or even COVID-19, to date there is no review focused on sexual activity and respiratory health and disease. Asthma, COPD and other respiratory patients can have their sexual activity and behaviors affected by their disease, but also limitations in sex might be the sentinel event of an incident respiratory disease. Asking on sexual desire and related sex issues should not be considered taboo in any respiratory consultation. Importantly, any marketed stereotypes on cigarettes after any sexual activity should be counteracted. Many clinical trials of respiratory drugs keep recruiting few or no women, so research on women's sexual desire and satisfaction lags behind that of men's. By using the available objective tools and validated questionnaires summarized in this review, these important domains of respiratory patients and their partners can be properly identified and managed. CONCLUSIONS: Sexual activity, depending on age and individual specific conditions, is a fundamental driver of overall health, and therefore of lung health.

Clinical characteristics and outcomes among hospitalised COVID-19 patients across epidemic waves in Spain: An unCoVer analysis.

BACKGROUND AND OBJECTIVES: The COVID-19 pandemic had a significant impact in population health worldwide, and particularly in people with pre-existing chronic diseases. Early risk identification and stratification is essential to reduce the impact of future outbreaks of pandemic potential. This study aimed to comprehensively examine factors associated with COVID-19 mortality across the pandemic waves in Spain. METHODS: A retrospective study analyzed the characteristics of 13,974 patients admitted to Spanish hospitals due to SARS-CoV-2 infection from 2020-01-28 to 2022-12-31. The demographic and clinical features of patients during hospitalization on each pandemic waves were analyzed. MAIN FINDINGS: The findings highlight the heterogeneity of patient characteristics, comorbidities and outcomes, across the waves. The high prevalence of cardiometabolic diseases (53.9%) among COVID-19 patients emphasizes the importance of controlling these risk factors to prevent severe COVID-19 outcomes. CONCLUSIONS: In summary, the study associate hospital mortality with factors such as advanced age and comorbidities. The decline in mortality after the 4th wave indicates potential influences like vaccination, viral adaptation, or improved treatments. Notably, dementia and cancer metastases emerge as critical factors linked to higher mortality, highlighting the importance of addressing these conditions in COVID-19 management and preparing for future challenges.

Psychometric Validation of the Patient-Reported Experience Measure (PREM) Questionnaire "HowRwe" in Patients With Respiratory Disease Receiving Home Respiratory Therapies.

Introduction: The patient experience is defined as all the interactions that occur between patients and the healthcare system. The experience of patients with respiratory disease with home respiratory treatments (HRT) is not captured in currently available Patient-Reported Outcome Measures (PROM). We present the psychometric validation of the Patient-Reported Experience Measure (PREM) 'HowRwe' in Spanish and for respiratory patients with HRT. Methods: After translation following ISPOR guidelines (International Society for Pharmacoeconomics and Outcomes Research), the questionnaire was administered to adult respiratory patients who were receiving treatment at Hospital Universitario de La Princesa. The administration was done in two stages with 6 months of difference between the pre- and post-test. Results: We studied 228 respiratory patients, with a mean (SD) age of 64.1 (13.2) years, 52.2% were men, 68.0% were married or coupled, and 56.6% were retired. Reliability coefficients of the scale were adequate, with α = .921 and Ω = .929 for pre-test, and α = .940 and Ω = .958 for post. The confirmatory factor analysis tested for pre- and post-intervention, showed an excellent overall fit: χ2(2) = 49.380 (p < .001), CFI = .941 and SRMR = .072; and χ2(2) = 37.579 (p < .001), CFI = .982 and SRMR = .046, respectively. No statistically significant associations were observed for neither age, adherence nor quality of life, except between HowRwe post-test and quality of life pre-test (r = .14 [.01,.26]; p = .035). No significant differences were found in sociodemographic variables. No differences in pre-test or post-test were found in effect of HRT. 85.6% of patients found the content of HowRwe "Useful", and the preferred channel to respond it were paper, app and email. Conclusions: The Spanish version of the 'HowRwe' questionnaire to measure the experience in respiratory patients with home respiratory treatments (HRT), has adequate psychometric properties and conceptual and semantic equivalence with the original English version.

Introducción: La experiencia del paciente se define como todas las interacciones que ocurren entre los pacientes y el sistema de salud. La experiencia de los pacientes con enfermedades respiratorias con terapias respiratorias domiciliarios (TRD) no se refleja en las Medidas de resultados informados por el paciente (PROM) disponibles actualmente. Presentamos la validación psicométrica de la Medida de Experiencia Reportada por el Paciente (PREM por sus siglas en inglés) 'HowRwe' en español y para pacientes respiratorios con TRD. Métodos: Después de la traducción siguiendo las pautas de ISPOR (Sociedad Internacional de Farmacoeconomía e Investigación de Resultados), el cuestionario se administró a pacientes respiratorios adultos que estaban recibiendo tratamiento en el Hospital Universitario de La Princesa. La administración se realizó en dos etapas con 6 meses de diferencia entre el pre y post test. Resultados: Se estudiaron 228 pacientes respiratorios, con una edad media (DE) de 64,1 ± 13,2 años, el 52,2% eran hombres, el 68,0% estaban casados o en pareja y el 56,6% eran jubilados. Los coeficientes de confiabilidad de la escala fueron adecuados, con α = .921 y Ω = .929 para el pretest, y α = .940 y Ω = .958 para el post. El análisis factorial confirmatorio testado para pre y postintervención, mostró un ajuste global excelente: χ2(2) = 49.380 (p < .001), CFI = .941 y SRMR = .072; y χ2(2) = 37,579 (p < .001), CFI = .982 y SRMR = .046, respectivamente. No se observaron asociaciones estadísticamente significativas ni para la edad, la adherencia ni para la calidad de vida, excepto entre HowRwe postest y calidad de vida pretest (r = .14 [.01,.26];p = .035). No se encontraron diferencias significativas en las variables sociodemográficas. No se encontraron diferencias en el efecto de la TRH en el pretest o postest. El 85,6% de los pacientes encontró "útil" el contenido de HowRwe y el canal preferido para responder fue el papel, la aplicación y el correo electrónico. Conclusiones: La versión española del cuestionario 'HowRwe' para medir la experiencia en pacientes respiratorios con tratamientos respiratorios domiciliarios (TRH), tiene adecuadas propiedades psicométricas y equivalencia conceptual y semántica con la versión original en inglés.

Comparison of eight prehospital early warning scores in life-threatening acute respiratory distress: a prospective, observational, multicentre, ambulance-based, external validation study.

BACKGROUND: A myriad of early warning scores (EWSs) exist, yet there is a need to identify the most clinically valid score to be used in prehospital respiratory assessments to estimate short-term and midterm mortality, intensive-care unit admission, and airway management in life-threatening acute respiratory distress. METHODS: This is a prospective, observational, multicentre, ambulance-based, external validation study performed in 44 ambulance services and four hospitals across three Spanish provinces (ie, Salamanca, Segovia, and Valladolid). We identified adults (ie, those aged 18 years and older) discharged to the emergency department with suspected acute respiratory distress. The primary outcome was 2-day all-cause in-hospital mortality, for all the patients or according to prehospital respiratory conditions, including dyspnoea, chronic obstructive pulmonary disease (COPD), COVID-19, other infections, and other conditions (asthma exacerbation, haemoptysis, and bronchoaspirations). 30-day mortality, intensive-care unit admission, and invasive and non-invasive mechanical ventilation were secondary outcomes. Eight EWSs, namely, the National Early Warning Score 2, the Modified Rapid Emergency Medicine Score, the Rapid Acute Physiology Score, the Quick Sequential Organ Failure Assessment Score, the CURB-65 Severity Score for Community-Acquired Pneumonia, the BAP-65 Score for Acute Exacerbation of COPD, the Quick COVID-19 Severity Index, and the Modified Sequential Organ Failure Assessment (mSOFA), were explored to determine their predictive validity through calibration, clinical net benefit as determined through decision curve analysis, and discrimination analysis (area under the curve of the receiver operating characteristic [AUROC], compared with Delong's test). FINDINGS: Between Jan 1, 2020, and Nov 31, 2022, 902 patients were enrolled. The global 2-day mortality rate was 87 (10%); in proportion to various respiratory conditions, the rates were 35 (40%) for dyspnoea, nine (10%) for COPD, 13 (15%) for COVID-19, 28 (32%) for other infections, and two (2%) for others conditions. mSOFA showed the best calibration, a higher net benefit, and the best discrimination (AUROC 0·911, 95% CI 0·86-0·95) for predicting 2-day mortality, and its discrimination was statistically significantly more accurate (p<0·0001) compared with the other scores. The performance of mSOFA for predicting 2-day mortality was higher than the other scores when considering the prehospital respiratory conditions, and was also higher for the secondary outcomes, except for non-invasive mechanical ventilation. INTERPRETATION: Our results showed that mSOFA outperformed other EWSs. The inclusion of mSOFA in prehospital decision making will entail a quick identification of patients in acute respiratory distress at high risk of deterioration, allowing prioritisation of resources and patient care. FUNDING: Gerencia Regional de Salud, Public Health System of Castilla y León (GRS Spain). TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Alpha-1 Antitrypsin Gene Variants in Patients without Severe Deficiency Diagnosed with Pulmonary Emphysema on Chest CT.

Introduction: Although pulmonary involvement due to alpha-1 antitrypsin (AAT) deficiency has been widely described, most studies focus on the genotypes causing severe deficiency (<60 mg/dL). Objective: The aim of this study was to analyze the prevalence of the different AAT gene variants that do not cause severe deficiency in patients with pulmonary emphysema diagnosed by thoracic computed tomography (CT). Furthermore, we assessed the risk associated with a non-severe decrease in AAT values in the pathogenesis of emphysema. Methods: Case-control study design that included patients who had a CT scan available of the entire thorax. In total, 176 patients with emphysema (cases) and 100 control subjects without emphysema were analyzed. Results: The prevalence of variants was higher among cases (25.6%; 45/176) than controls (22%; 22/100), although the difference was not statistically significant (P=0.504) when analyzed globally. In the control group, all the variants detected were MS. Excluding this variant, statistically significant differences were observed in the remaining variants (MZ, SS and SZ). Only 18% of the controls (all MS) presented values below our limit of normality, and all had values very close to the reference value (90 mg/dL). In contrast, 76% of patients with the other variants presented pathological levels. In a logistic regression model, both smoking and a non-severe reduction in AAT (60 to 90 mg/dL) increased the probability of emphysema. Conclusion: Our study confirms an association between certain variants in the alpha-1 antitrypsin gene that do not cause severe deficiency and the presence of pulmonary emphysema. This association with variants that are associated with reductions in serum AAT values is statistically significant and independent of smoking habit.

Association between occupational exposure and chronic obstructive pulmonary disease and respiratory symptoms in the Spanish population.

INTRODUCTION: The aim of this study was to analyze the impact of occupational exposure on chronic obstructive pulmonary disease (COPD) and respiratory symptoms in the general Spanish population. METHODS: This was a study nested in the Spanish EPISCAN II cross-sectional epidemiological study that included participants who had completed a structured questionnaire on their occupational history, a questionnaire on respiratory symptoms, and forced spirometry. The data were analyzed using Chi-square and Student's t tests and adjusted models of multiple linear regression and logistic regression. RESULTS: We studied 7502 subjects, 51.1% women, with a mean age of 60±11 years. Overall, 53.2% reported some respiratory symptoms, 7.9% had respiratory symptoms during their work activity, 54.2% were or had been smokers, and 11.3% (851 subjects) met COPD criteria on spirometry. A total of 3056 subjects (40.7%) reported exposure to vapors, gases, dust or fumes (VGDF); occupational exposure to VGDF was independently associated with the presence of COPD (OR 1.22, 95% CI: 1.03-1.44), respiratory symptoms (OR 1.45, 95%: CI 1.30-1.61), and respiratory symptoms at work (OR 4.69, 95% CI: 3.82-5.77), with a population attributable fraction for COPD of 8.2%. CONCLUSIONS: Occupational exposure is associated with a higher risk of COPD and respiratory symptoms in the Spanish population. These results highlight the need to follow strict prevention measures to protect the respiratory health of workers.

Risk of Pneumonia in Patients with COPD Initiating Fixed Dose Inhaled Corticosteroid (ICS) / Long-Acting Bronchodilator (LABD) Formulations Containing Extrafine Beclometasone Dipropionate versus Patients Initiating LABD Without ICS.

Background: Combined ICS and long-acting bronchodilators (LABD) more effectively reduce COPD exacerbations than LABD therapy alone. Corticosteroid-related adverse effects, including pneumonia, limit ICS use. Previous data suggest this risk is lower for extrafine beclometasone (ef-BDP). We compared pneumonia risk among new users of fixed dose ICS/LABD formulations containing ef-BDP, versus patients initiating LABD without any ICS. Methods: A propensity-matched historical cohort study design used data from OPCRD. COPD patients with ≥1 year of continuous data who initiated LABD or ICS/LABD formulations containing ef-BDP were matched. Primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions, with non-inferiority boundary of 15%. Results: 23,898 COPD patients were matched, who were 68±11 years, 54.3% male and 56% current-smokers, while 43% were former-smokers. Initiation of ef-BDP/LABD was not associated with an increased risk of pneumonia versus LABD, for either a sensitive 0.89 (0.78-1.02), P = 0.08 or a specific 0.91 (0.78-1.05), P = 0.18 definition of pneumonia. The probability of remaining pneumonia free 1-year after ef-BDP/LABD was 98.4%, which was comparable to LABD at 97.7%, and was sustained up to 6 years of observation; non-inferiority criterion was met for both definitions. Initiation of ef-BDP/LABD was also associated with a reduced risk of developing LRTIs in the propensity matched cohort. Conclusion: Risk of pneumonia when using ICS for the management of COPD reported in several randomised controlled trials may not be relevant with ef-BDP in a diverse real-world clinical population.

Consensus on post COVID in the Spanish national health system: Results of the CIBERPOSTCOVID eDelphi study.

BACKGROUND: In 2021, the Spanish Ministry of Health launched the CIBERPOSTCOVID project to establish what post COVID was. The present study reports the level of agreement among stakeholders on post COVID and its clinical and diagnostic characteristics in the Spanish health system. METHODS: The agreement on post COVID among clinicians, public health managers, researchers and patients' representatives was explored in a real-time, asynchronous online Delphi. In a two-wave consensus, respondents rated from 1 (total disagreement) to 6 (total agreement) 67 statements related to terminology, duration, etiology, symptoms, impact on quality of life, severity, elements to facilitate diagnosis, applicability in the pediatric population, and risk factors. Consensus was reached when 70 % of ratings for a statement were 5 or 6, with an interquartile range equal or less than 1. FINDINGS: A total of 333 professionals and patients participated in this eDelphi study. There was agreement that post COVID was "a set of multi-organic symptoms that persist or fluctuate after acute COVID-19 infection and are not attributable to other causes" with a minimum duration of 3 months. The highest levels of agreement were found in the most frequent symptoms and its impacts on everyday activities. Aspects related to the diagnostic process and the measurement of its severity reached a lower level of consensus. There was agreement on the need to rule out previous health problems and assess severity using validated functional scales. However, no agreement was reached on the risk factors or specific features in the pediatric population. INTERPRETATION: This policy-based consensus study has allowed the characterization of post COVID generating collective intelligence and has contributed to an operational definition applicable in clinical practice, health services management and useful for research purposes in Spain and abroad. Agreements are consistent with existing evidence and reference institutions at European and international level.

The global fatty liver disease Sustainable Development Goal country score for 195 countries and territories.

BACKGROUND AND AIMS: Fatty liver disease is highly prevalent, resulting in overarching wellbeing and economic costs. Addressing it requires comprehensive and coordinated multisectoral action. We developed a fatty liver disease Sustainable Development Goal (SDG) country score to provide insights into country-level preparedness to address fatty liver disease through a whole-of-society lens. APPROACH AND RESULTS: We developed 2 fatty liver disease-SDG score sets. The first included 6 indicators (child wasting, child overweight, noncommunicable disease mortality, a universal health coverage service coverage index, health worker density, and education attainment), covering 195 countries and territories between 1990 and 2017. The second included the aforementioned indicators plus an urban green space indicator, covering 60 countries and territories for which 2017 data were available. To develop the fatty liver disease-SDG score, indicators were categorized as "positive" or "negative" and scaled from 0 to 100. Higher scores indicate better preparedness levels. Fatty liver disease-SDG scores varied between countries and territories (n = 195), from 14.6 (95% uncertainty interval: 8.9 to 19.4) in Niger to 93.5 (91.6 to 95.3) in Japan; 18 countries and territories scored > 85. Regionally, the high-income super-region had the highest score at 88.8 (87.3 to 90.1) in 2017, whereas south Asia had the lowest score at 44.1 (42.4 to 45.8). Between 1990 and 2017, the fatty liver disease-SDG score increased in all super-regions, with the greatest increase in south Asia, but decreased in 8 countries and territories. CONCLUSIONS: The fatty liver disease-SDG score provides a strategic advocacy tool at the national and global levels for the liver health field and noncommunicable disease advocates, highlighting the multisectoral collaborations needed to address fatty liver disease, and noncommunicable diseases overall.

ChatGPT: unlocking the potential of Artifical Intelligence in COVID-19 monitoring and prediction.

BACKGROUND: The COVID-19 pandemic has had an unprecedent impact of everyday life with deleterious consequences on global health, economics, and society. Thus, accurate and timely information is critical for monitoring its spread and mitigating its impact. ChatGPT is a large language model chatbot with artificial intelligence, developed by OpenAI, that can provide both textual content and R code for predictive models. It may prove to be useful in analyzing and interpreting COVID-19-related data. METHODS: This paper explores the application of ChatGPT to the monitoring of the COVID-19 pandemic, presenting R code for predictive models and demonstrating the model's capabilities in sentiment analysis, information extraction, and predictive modelling. We used the prediction models suggested by ChatGPT to predict the daily number of COVID-19 deaths in Italy. The prediction accuracy of the models was compared using the following metrics: mean squared error (MSE), mean absolute deviation (MAD) and root mean squared error (RMSE). RESULTS: ChatGPT suggested three different predictive models, including ARIMA, Random Forest and Prophet. The ARIMA model outperformed the other two models in predicting the daily number of COVID-19 deaths in Italy, with lower MSE, MAD, and RMSE values as compared to the Random Forest and Prophet. CONCLUSIONS: This paper demonstrates the potential of ChatGPT as a valuable tool in the monitoring of the pandemic. By processing large amounts of data and providing relevant information, ChatGPT has the potential to provide accurate and timely insights, and support decision-making processes to mitigate the spread and impact of pandemics. The paper highlights the importance of exploring the capabilities of artificial intelligence in the management of public emergencies and provides a starting point for future research in this area.

Impact of the COVID-19 pandemic in mortality due to respiratory diseases: A comparative analysis of 2021 and 2020 vs 2019 in Spain.

INTRODUCTION: We previously reported an increase in respiratory mortality in 2020 in Spain after COVID-19. It is unclear if this rise is sustained in the longer-term. We aimed to determine whether respiratory mortality in 2021 in Spain returned to pre-pandemic levels. MATERIAL AND METHODS: In an observational, large study using official National Institute of Statistics data, we explored deaths due to respiratory diseases, that is, all causes of death by the standard WHO list of diseases of the respiratory system plus COVID-19, tuberculosis and lung cancer. Using the latest available official data of Spain, we analyzed changes in the mortality pattern in Spain from January 2019 to December 2021. We endorsed STROBE guidance for observational research. RESULTS: There were 98,714 deaths due to respiratory diseases in 2021 in Spain, corresponding to 21.9% of all deaths, becoming second in the ranking of causes of death. Respiratory diseases mortality in Spain has not returned to pre-pandemic levels in 2021, still with an increase of 30.3% (95% CI 30.2-30.4) compared to rates in 2019. All respiratory-specific causes of death decreased in 2021, except for lung cancer, that increased in women and decreased in men compared to 2019 (both p<0.05). In a multivariate analysis some established risk factors for respiratory diseases mortality were confirmed, such as male gender and older age; further, an association with reduced mortality in rural Spain was observed, still with a large geographical variability. CONCLUSIONS: The COVID-19 pandemic has had a lasting impact on deaths due to respiratory diseases and certain specific causes of death in 2021, and it has disproportionately affected certain regions.