TYPE Original Research PUBLISHED 18 May 2023 DOI 10.3389/fpubh.2023.1175482 Disseminated tuberculosis and OPEN ACCESS diagnosis delay during the COVID-19 era in a Western EDITED BY Monica Catarina Botelho, Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Portugal REVIEWED BY European country: a case series Silvia Shinpei Chiang, Rhode Island Hospital, United States Gobena Ameni, analysis United Arab Emirates University, United Arab Emirates Sílvia Roure 1,2,3*, Xavier Vallès 1,2,3,4, Nieves Sopena 3,5, *CORRESPONDENCE Rosa Maria Benítez 3,5, Esteban A. Reynaga 3,5, Carmen Bracke 3,5, Sílvia Roure sroura.mn.ics@gencat.cat Cora Loste 3,5, Lourdes Mateu 3,5, Adrián Antuori 6, Tania Baena 3, Cristina Vilaplana cvilaplanam.germanstrias@gencat.cat Germán Portela 6, Judith Llussà 6, Clara Flamarich 6, RECEIVED 27 February 2023 Laura Soldevila 1,2, Montserrat Tenesa 7,8, Ricard Pérez 7, ACCEPTED 28 April 2023 PUBLISHED 18 May 2023 Elsa Plasencia 9, Jordi Bechini 7,8, Maria Lluïsa Pedro-Botet 3,5,10,11, CITATION Bonaventura Clotet 3,5 and Cristina Vilaplana 2,4,10,11,12* Roure S, Vallès X, Sopena N, Benítez RM, 1 Unitat de Salut Internacional Metropolitana Nord, PROSICS Metropolitana Nord, Badalona, Spain, Reynaga EA, Bracke C, Loste C, Mateu L, 2 Direcció Clínica Territorial de Malalties Infeccioses i Salut Internacional de Gerència Territorial Antuori A, Baena T, Portela G, Llussà J, Metropolitana Nord, Barcelona, Spain, 3 Fundació Lluita Contra les Infeccions, Hospital Germans Trias Flamarich C, Soldevila L, Tenesa M, Pérez R, i Pujol, Badalona, Spain, 4 Germans Trias i Pujol Research Institute, Badalona, Spain, 5 Servicio de Plasencia E, Bechini J, Pedro-Botet ML, Enfermedades Infecciosas, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 6 Microbiology Clotet B and Vilaplana C (2023) Disseminated Department, Northern Metropolitan Clinical Laboratory, Hospital Germans Trias i Pujol, Badalona, Spain, tuberculosis and diagnosis delay during the 7 Servei de Radiodiagnòstic de l’Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 8 Direcció COVID-19 era in a Western European country: Clínica de Diagnòstic per la imatge de la Gerència Territorial Metropolitana Nord, Badalona, Spain, a case series analysis. 9 Departament de Salut, Subdirecció General de Vigilancia i Resposta a Emergències de Salut Pública, Front. Public Health 11:1175482. Barcelona, Catalonia, Spain, 10 Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain, 11 Centro doi: 10.3389/fpubh.2023.1175482 de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain, 12 Unitat de COPYRIGHT Tuberculosi Experimental, Microbiology Department, Germans Trias i Pujol, Badalona, Spain © 2023 Roure, Vallès, Sopena, Benítez, Reynaga, Bracke, Loste, Mateu, Antuori, Baena, Portela, Llussà, Flamarich, Soldevila, Tenesa, Pérez, Plasencia, Bechini, Pedro-Botet, Clotet and Vilaplana. This is an open-access article Background: Disseminated tuberculosis is frequently associated with delayed distributed under the terms of the Creative diagnosis and a poorer prognosis. Commons Attribution License (CC BY). The use, distribution or reproduction in other Objectives: To describe case series of disseminated TB and diagnosis delay in a forums is permitted, provided the original low TB burden country during the COVID-19 period. author(s) and the copyright owner(s) are credited and that the original publication in this Methodology: We consecutively included all patients with of disseminated TB journal is cited, in accordance with accepted reported from 2019 to 2021 in the reference hospital of the Northern Crown of the academic practice. No use, distribution or Metropolitan Area of Barcelona. We collected socio-demographic information, reproduction is permitted which does not comply with these terms. clinical, laboratory and radiological findings. Results: We included all 30 patients reported during the study period—5, 9, and 16 in 2019, 2020, and 2021 respectively—20 (66.7%) of whom were male and whose mean age was 41 years. Twenty-five (83.3%) were of non-EU origin. The most frequent system involvement was central nervous system (N=8; 26.7%) followed by visceral (N=7; 23.3%), gastro-intestinal (N=6, 20.0%), musculoskeletal (N=5; 16.7%), and pulmonary (N=4; 13.3%). Hypoalbuminemia and anemia were highly prevalent (72 and 77%). The median of diagnostic delay was 6.5months (IQR 1.8–30), which was higher among women (36.0 vs. 3.5months; p=0.002). Central nervous system involvement and pulmonary involvement were associated with diagnostic delay among women. We recorded 24 cured patients, two deaths, three patients with post-treatment sequelae, and one lost-to-follow up. We observed a clustering effect of patients in low-income neighborhoods (p<0.001). Frontiers in Public Health 01 frontiersin.org Roure et al. 10.3389/fpubh.2023.1175482 Conclusion: There was a substantial delay in the diagnosis of disseminated TB in our study region, which might impacted the prognosis with women affected more negatively. Our results suggest that an increase in the occurrence of disseminated TB set in motion by diagnosis delay may have been a secondary effect of the COVID-19 pandemic. KEYWORDS disseminated tuberculosis, tuberculosis, delayed diagnosis, hard-to-reach populations, clinical presentation 1. Introduction 2. Materials and methods Disseminated tuberculosis (dTB) is defined as the 2.1. Study setting and design identification or isolation of Mycobacterium tuberculosis or compatible histopathology obtained from two non-contiguous This study consisted of a retrospective analysis of all new dTB organs in a single patient, from blood or bone marrow specimens cases diagnosed at the Hospital Universitari Germans Trias i Pujol and/or a chemotherapeutic response in clinical or image-based in Badalona, Spain, from January 2019 to December 2021. This is compatible cases with multiple foci (1). It is primarily due to the the referral hospital for the Northern Crown of the Metropolitan lymph-haematogenous dissemination of M. tuberculosis from a area of Barcelona, the northern urban crown of Barcelona, with pulmonary focus or, less frequently, from another primary TB 406,000 inhabitants. Immigrants constitute roughly 17% of the focus. Disseminated TB accounts for <2% of TB cases and up to population (20). For all new dTB patients reported, we collected 20% of extra pulmonary TB cases (2, 3) but the incidence is socio-demographic, clinical, and laboratory data including patient modulated by the population-level prevalence of recognized risk age, sex, Body Mass Index (BMI), country or region of origin, factors, especially HIV/AIDS (3–5). It is a severe TB presentation, current household location, and primary and secondary TB foci at with much higher mortality compared to classical pulmonary TB diagnosis and laboratory and image findings. Additionally, we noted [as high as 31.1% (4)] or non-disseminated extrapulmonary TB the date of the first contact with the health system at which (6), and similar to TB meningitis (7, 8) which is by large the most symptoms compatible with the initial TB focus diagnosed, and the severe TB form with unique focus. Like extrapulmonary TB number of visits between the first recorded symptoms and final forms, the diagnosis of dTB can be elusive due to the frequently TB diagnosis. non-specific (like fever of unknown origin) and pleomorphic clinical presentations, lack of clear focus in the early phases of the disease, and its sub-acute or chronic evolution (9, 10). In turn, 2.2. Data management and statistical diagnosis delay is associated to dissemination of TB, as it has been methods reported in HIV positive patients (11) and be by itself a prognostic factor (12). The diagnosis may be hampered by the difficult access Disseminated tuberculosis was defined as the involvement of TB to sampling sites and is frequently based on image findings (13). infection in two or more non-contiguous organs in a single patient. TB A limited availability of diagnostic tools and lack of clinical infection was determined by either (i) identification or isolation of awareness may lead to an underestimation of the disease, which M. tuberculosis or compatible histopathology in samples obtained from is frequently encountered as an autopsy finding (14). One factor lesions of any location or (ii) positive clinical response upon specific rarely examined is the delayed diagnosis of the primary focus treatment in clinical and/or image-based cases compatible with TB before dissemination occurs. In some instances, such a delay in infection once other alternative diagnostics had been excluded. diagnosis may be due to the quality of the health system (i.e., Conclusive diagnosis of TB was established by the direct culture of inadequate coverage, resources, or awareness), which could M. tuberculosis in conventional media, direct observation in tissue be aggravated by disruptions of health care services such as samples (Ziehl-Neelsen or auramine), and means of molecular biology occurred during the COVID-19 pandemic and observed among ® (GenXpert ). Or clinical-based when clinical, laboratory, image other health conditions (15–17). Socio-cultural barriers to access findings (RX, RMN, echography, or TC scan) were compatible with TB to care among migrant or low-resourced populations can also be a infection and therapeutic response was positive upon specific factor (18, 19). Here we present a detailed analysis of a series of treatment. We classified patients with dTB according to the system dTB patients that occurred in the metropolitan area of Barcelona, involved as central nervous system (CNS), gastrointestinal (GI), Spain, from 2019 prior to the onset of the COVID-19 pandemic, musculoskeletal (MSK, including bone, muscle, or joints), pulmonary to the end of 2021. We aim to examine the link between diagnosis (including pleural), or visceral (involving liver, spleen, peritoneum, or delay and the presentation of dTB, to ascertain the underlying risk pericardium). Ganglionic involvement was considered separately. factors and to undertake a detailed analysis of clinical, image, and We considered the system involvement as initial clinical focus from a laboratory findings of this life-threatening form of TB in a clinical perspective, when the given organ or system produced the low-endemic country. main guiding symptoms for diagnosis, irrespective of the diagnostic Frontiers in Public Health 02 frontiersin.org Roure et al. 10.3389/fpubh.2023.1175482 TABLE 1 General description of the study sample. Variable Overall (N=30) 2019 (N=5) 2020 (N=9) 2021 (N=16) p1 Median age (IQR) 41 (29–49) 39 (28–45) 30 (25–45) 46 (34–61) 0.06 Males (N, %) 20 (66.7) 2 (40.0) 5 (55.6) 13 (81.3) 0.07 Females (N, %) 10 (33.3) 3 (60.0) 4 (44.4) 3 (18.8) Organ system involvement (N, %) Initial clinical focus at diagnosis (N, %) CNS 8 (26.7) 2 (40.0) 2 (22.2) 4 (25.0) 0.6 GI 6 (20.0) 1 (20.0) 1 (11.1) 4 (25.0) 0.4 MSK 5 (16.7) 1 (20.0) 3 (33.3) 1 (6.3) 0.1 Visceral 7 (23.3) — 2 (22.2) 5 (31.3) 0.3 Pleuropulmonary 4 (13.3) 1 (20.0) 1 (11.1) 2 (12.5) 0.6 Overall involvement CNS 10 (33.3) 2 (40.0) 4 (44.4) 4 (25.0) 0.4 GI 6 (20.0) 1 (20.0) 1 (11.1) 4 (25.0) 0.7 MSK 7 (23.3) 2 (40.0) 3 (33.3) 2 (12.5) 0.2 Visceral 13 (43.3) 0 (0.0) 2 (22.2) 11 (68.8) 0.004 Pleuropulmonary 18 (60.0) 5 (100) 2 (22.2) 11 (68.8) 0.5 Ganglionic 19 (63.3) 2 (40.0) 6 (66.7) 11 (68.8) 0.7 Region of origin (N, %) South Asia 17 (56.7) 3 (60.0) 4 (44.4) 10 (62.5) 0.5 North Africa 5 (16.7) 1 (20.0) 2 (22.2) 2 (12.5) 0.6 Sub-Saharan Africa 2 (6.7) 1 (20.0) 1 (11.1) — 0.2 South America 1 (3.3) — 1 (11.1) — 0.5 Spain 5 (16.7) — 1 (11.1) 4 (25.0) 0.3 Delay in diagnosis (median, IQR) By months 6.5 (1.8–30) 24 (12.5–66) 4 (1.5–78) 6 (1.3–11.5) 0.2 By number of visits 5 (1–8) 11 (5–13) 6 (1–9) 3 (1–7) 0.04 p value comparing 2021 to 2019–2020. 1 site (i.e., from which the diagnostic sample was obtained). In contrast, in Spain (21) and then we carried out a multi-distance spatial cluster we refer to primary focus as the first focus of the dTB disease from a analysis. We considered a value of p ≤ 0.05 significant. pathophysiology perspective, which is most frequently difficult to ascertain. Data were collected from the electronic records of patients. The clinical electronic records are a backbone of the health system in 2.3. Ethical issues Catalonia. It is a shared electronic clinical history accessible by all medical and health providers to the Public health system of the region, The present study forms part of the STAGE-TB project, which has with a standard interface. Data are fully accessible for research purposes been approved by the Ethics Board of the Hospital Universitari including previous visits before diagnostic, clinical background, Germans Trias i Pujol (study approval code: PI-17-064). symptoms, number of visits and underlying clinical conditions. Data were analyzed using Stata version 14.0 (StataCorp LLC, https://www. stata.com) and R version 4.1.2 (The R Project for Statistical Computing, 3. Results https://www.r-project.org) software. For descriptive analysis, we used medians and interquartile ranges (IQRs) for continuous variables and 3.1. General description proportions and CI: 95% Confidence Intervals (CI) for categorical variables. For univariate analysis, we used the χ2 test to compare Between January 2019 and December 2021, a total of 41 patients categorical variables and for trends, when appropriate, or with dTB were diagnosed with 9, 9, and 23 cases in 2019, 2020, and nonparametric Fisher or Wilcoxon tests, when necessary. 2021, respectively (Table 1; Figure 1), from which 5, 9, and 16, We performed a geo-location of index cases with cross-reference to respectively (N = 30) where referred to the study Hospital. Twenty estimated mean annual household income in Euros in 2020 obtained (66.7%) were males. The median age was 41 years (IQR 28.8–48.5, from the Spanish government’s National Statistics Institute of Statistics range 18–70), without significant differences between sexes (p = 0.6). Frontiers in Public Health 03 frontiersin.org Roure et al. 10.3389/fpubh.2023.1175482 prominent among patients of South Asian origin (see Figure 2). All patients initially diagnosed as visceral were males (7/20 vs. 0/10; p = 0.008) whereas all patients initially diagnosed as pleuropulmonary were females (0/20 vs. 4/10; p = 0.04). There was a significant increase in overall visceral involvement in 2021 compared to the 2019/2020 period [11 out of 13 (68.8%) vs. 5 out of 17 (31.3%); p = 0.004]. No differences in terms of age at diagnosis, sex, years spent living in the EU, BMI, and other laboratory findings. Diagnosis delay was more prominent among females compared to males [median 36.0 months (IQR 5.5–87) vs. 3.5 months (IQR 1–11.5); p = 0.02], but the number FIGURE 1 of prior visits was not (median 8 [IQR 1–12] vs. 4 [IQR 1–12], p = 0.18, Number of cases by year and initial focus at diagnosis including dTB cases not referred to the HUGTiP (PP, pleuropulmonary; MSK, see Figure 3). The number of prior visits decreased over time (2019– musculoskeletal; GI, gastrointestinal; and CNS, central nervous 2020 vs. 2021; p = 0.04, see Table 1). There were no significant system). System involvement refers to the initial TB focus at differences regarding diagnostic delay and initial clinical focus at diagnosis. diagnosis. However, the number of previous visits was significantly higher among patients with an initial MSK focus [MSK focus median 9 visits (IQR 8–14) vs. all other foci 3 visits (IQR 1–8); p = 0.006, see Four of the 10 females were in the puerperium period. The most Figure 4]. Otherwise, we found an association between diagnosis delay frequent region of origin was South Asia (India, Pakistan, or among females with CNS involvement as initial diagnosis focus Bangladesh, n = 17, 56.8%), followed by North-Africa (n = 5, 16.7%), (p = 0.03) or overall CNS involvement (p = 0.01). Females with overall and Spain (n = 5, 16.7%). The median period of time that migrant pleuropulmonary involvement were associated as well with diagnostic patients (N = 25) had lived in Spain was 10 years (IQR 5.3–16, range delay (p = 0.02). 1–22). The most frequent initial focus at diagnosis was CNS (N = 8; 26.7%) followed by Visceral (N = 7; 23.3%), GI (N = 6, 20.0%), MSK (N = 5; 16.7%), and pleuropulmonary (N = 4; 13.3%). Conclusive 4. Discussion diagnosis was established by laboratory means in 23 out of 30 patients (76.7%), two of them with a M. tuberculosis strain with multi-drug We observed a sharp increase in the number of dTB over the resistance. Two patients were associated with a new diagnosis of HIV 2019–2021 period, which is difficult to regard as random oscillation. with a CD4 count <100, four patients (13.3%) had diabetes mellitus This trend may reflect the impact of the COVID-19 pandemic, which type II, three patients (10%) were associated with alcohol in many parts of the world has resulted in a substantial reduction in consumption, and one case had renal insufficiency. The most frequent TB testing and access to TB health services (22). The impact of the organ involvement, including initial and secondary diagnosed foci pandemic on TB surveillance and diagnosis in Catalonia has been was pleuropulmonary (N = 18; 60.0%), all with abnormal chest X-ray well-documented (23). The fact that fewer visits prior to TB diagnosis (CXR) findings, including four with a miliary pattern (22.2%). The took place in 2021 compared to 2019–2020 may be precisely due to median diagnostic delay was 6.5 months (IQR 2–30, range 1–108), and the more difficult access to diagnostic and care services during the the median number of prior visits was 4–5 (IQR 1–8, range 1–15). At COVID-19 period. the moment of diagnostic 21 out of 29 (72.4%) had low levels of More striking is the clustering of dTB patients around a albumin (<3.5 g/dL), including three patients (10.3%) with clinically low-income area, which represents a small section of the study region. significant hypoalbuminemia (<2.5 g/dL). Twenty patients (76.9%) It could be argued that this merely reflects the tendency of migrant met the criteria for anemia (<12.1 g/dL among women and < 13.8 g/dL communities (coming from high TB-burden countries and therefore among men). The median BMI at diagnosis was 24.4 (IQR 20.6–27.6, with higher chances of developing the infection), to share the same range 15.8–36.2), and four patients met the criteria for undernutrition neighborhood. However, our data suggest a more complex interaction. (BMI < 18.5). Firstly, migrant communities tend to be low-resourced populations At the time of analysis, 24 (80%) patients had successfully with associated risk factors for TB transmission (i.e., overcrowding). completed treatment with clinical recovery, 2 (7.7%) had died, 2 According to a previous study, local reinfection is more common (6.7%) had neurological sequelae, and 1 (3.9%) had constrictive among long-term migrants like those from our sample, and is pericarditis (3.9%). The remaining patient was reported as lost to associated with social risk (24, 25). The long-term residence in the EU follow-up. Descriptive data for patients are shown in Table 1. supports this notion. Secondly, they are more prone to develop Supplementary Table S1 in Appendix 1 summarizes the main findings poverty-related underlying conditions for TB diseases, such as case by case, including initial and secondary diagnosed foci and undernutrition, alcohol abuse, and diabetes mellitus (25). Thirdly, they driving symptoms at diagnosis. commonly experience socio-cultural barriers to access to health services (18, 19, 25). All of these factors may increase the risk of TB disease. The development toward a disseminated TB form will 3.2. Association analysis of dTB patients, TB be facilitated by delayed diagnosis of the primary focus. Although this foci, and studied variables last hypothesis should be further explored (13), it is supported in our study sample by, first, the high prevalence of pulmonary involvement, Patient data for geographic location and socio-economic status which is a priori, an easier form of TB to diagnose and the most showed a clustering pattern (p < 0.001), which was especially frequent primary focus before dissemination. And second, the Frontiers in Public Health 04 frontiersin.org Roure et al. 10.3389/fpubh.2023.1175482 FIGURE 2 Map showing geo-location of TB disseminated cases in the northern crown of the greater Barcelona metropolitan area (N=23). Patient’s region of origin is indicated by the type of symbol. Symbols have been placed very approximately to protect patient anonymity. Household income map was obtained from (17). FIGURE 3 Plot of diagnostic delay (months) stratified by sex (A) and by number of visits prior to diagnosis (B). Horizontal bar indicates the median. Frontiers in Public Health 05 frontiersin.org Roure et al. 10.3389/fpubh.2023.1175482 FIGURE 4 Plot of diagnostic delay (months) stratified by TB initial focus at diagnosis (A) and by number of visits prior to diagnosis (B) (CNS, central nervous system; GI, gastrointestinal; MSK, musculoskeletal; V, visceral; and PP, pleuropulmonary). Horizontal bar indicates the median. increasing degree over time of visceral involvement with more atypical burden could be avoided with prompt treatment. In the event of TB TB locations, which might correspond to late stages of TB suspicion and considering the risk–benefit, the initiation of dissemination expedited by the delayed diagnosis. In this regard, our presumptive treatment should be imposed (2). study underscores the incidence of delayed diagnosis of TB in our Finally, the occurrence of dTB in a well-defined pocket of the study sample, which is much higher than what has been reported for migrant population should be considered an index event of other overall TB cases in Catalonia region during the 2019–2022 period health issues, which may deserve further attention like diagnosis of (52 days) (23). These delays were preceded by frequent visits to the other sub-acute and chronic conditions. primary and secondary health care services. The unspecific symptoms As a main limitation, our small series of dTB patients does not reported, language barriers, and the lack of TB awareness on the part allow us to draw conclusive generalizations and should be confirmed of clinicians might have been contributors. Overall, the stressors with a pooled analysis of dTB patients from other low TB burden experienced by our study sample were similar to those reported for a countries during the same period. Secondly, we cannot exclude some series of HIV-negative migrants with dTB (26). Women may bias since not all dTB patients notified in the study area were referred experience the factors described with higher intensity. The delay in to the reference hospital (11 out of 41). However, the trends and diagnosis tends to be more pronounced for women with pulmonary associations observed here might well be representative of other urban involvement, which is a more easily diagnosable TB form than it is for areas of Western Europe, and need consideration. men, according to a recent study in Portugal (27). Women’s access to In conclusion, we suggest that TB should be actively ruled out healthcare is limited and often dependent on their husbands, and they when confronting migrants with recurrent insidious headache, are likely to face greater language barriers (28). The high prevalence abdominal pain, or back pain, with or without nonspecific chronic of hypoalbuminemia may be a risk factor for developing TB by itself symptoms or unexplained weight loss and several prior visits. This is but likely also a late consequence of delayed diagnosis. Therefore, now especially relevant, since it is expected that the major impact of various factors may overlap with reverse causality effects to favor the COVID-19 on TB incidence and mortality would be much larger in development of dTB: social aspects, individual level factors, barriers 2022 and beyond (32). Supplementary Figure S1 in Appendix 2 to healthcare access, and the difficulty of diagnosing extrapulmonary includes a chart for clinicians describing the prototypical profiles of TB. COVID-19 pandemic may have exacerbated these underlying patients studied which might help them to screen extra-pulmonary of factors through a more difficult access to primary health care (lower dTB. We provide as well radiological images in the number of visits) and the exacerbation of poverty-related conditions. Supplementary material (Appendix 2). Otherwise, the occurrence and Overall, this could explain the increase of dTB cases over time once delayed diagnosis of disseminated TB could be tempered with other confounding factors have been excluded (i.e., the reference of interventions aimed at pockets of vulnerable populations, such as cases from other facilities overwhelmed by COVID-19), with a raising awareness among clinicians or lowering barriers to access to differential effect regarding sex. The high prevalence of health services with a gender perspective. Such strategies could hypoalbuminemia and anemia among our study sample indicates mitigate the contributing background conditions such as malnutrition significant physical deterioration in our patients at the time and overcrowding of underserved migrant communities and of diagnosis. strengthen the resilience of the health system in the face of socio- The association of TB with pregnancy puerperium has been economic crises. described in the literature, showing poor outcomes for both women and their infants, even in low-incidence countries (29–31). It might explain the high proportion of female patients in the post-partum Data availability statement period (four out of 10). Our case series showed a high incidence of morbidity and The data analyzed in this study is subject to the following licenses/ mortality, including two deaths, three patients which required restrictions: data were obtained from clinical records of patients and intensive care, two patients with serious neurological sequelae and one are subject to confidentiality. It could not be shared to personnel case with constrictive pericarditis. This morbidity and mortality outside the research institution (Hospital Universitari Germans Trias Frontiers in Public Health 06 frontiersin.org Roure et al. 10.3389/fpubh.2023.1175482 i Pujol). Requests to access these datasets should be directed to ceic. Acknowledgments germanstrias@gencat.cat. We acknowledge Molebogeng Rangaka for the critical reading of the text and her valuable inputs. Ethics statement The studies involving human participants were reviewed and Conflict of interest approved by Ethics Board of the Hospital Universitari Germans Trias I Pujol, study approval code: PI-17-064. Written informed consent for The authors declare that the research was conducted in the participation was not required for this study in accordance with the absence of any commercial or financial relationships that could national legislation and the institutional requirements. be construed as a potential conflict of interest. Author contributions Publisher’s note SR, XV, NS, RB, ER, CB, CL, LM, AA, TB, GP, JL, CF, LS, MT, RP, All claims expressed in this article are solely those of the EP, JB, MP-B, BC, and CV: study design, data curation, statistical authors and do not necessarily represent those of their affiliated analysis, supervision, and article writing. All authors contributed to organizations, or those of the publisher, the editors and the the article and approved the submitted version. reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Funding This work was supported by the Catalan Government (2021 SGR Supplementary material 00920), the Spanish Government-FEDER Funds (CPII18/00031 and PI20/01424), the CIBER Enfermedades Respiratorias (CB06/06/0031), The Supplementary material for this article can be found online and European Union’s Horizon 2020 research and innovation program at: https://www.frontiersin.org/articles/10.3389/fpubh.2023.1175482/ (847762). full#supplementary-material References 1. American Thoracic Society and the Centers for Disease Control and Prevention. 12. Storla DG, Yimer S, Bjune GA. 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